Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[S:12][CH2:13]C.[Na].C(SC(C(=O)C)CO)C>>[CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[S:12][CH3:13]
Reactant: CCSc1cc([N+](=O)[O-])c(=O)[nH]c1C
Agent: CCSC(CO)C(C)=O
Agent: [Na]
Product: CSc1cc([N+](=O)[O-])c(=O)[nH]c1C

Procedure:
The corresponding 6-methyl-5-ethylthio-3-nitropyridin-2(1H)-one, prepared in a similar way, but starting with the sodium salt of 2-ethylthio-3-oxo-1-butanol had m.p. 190°-191° C. (Yield 43.6%).
Reaction SMILES: O[N:2]=[C:3]([C:11](=O)[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]2[NH:25][C:11]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[N:2]=2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1ccncc1
Reactant: NCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1nc(-c2ccc(Cl)cc2)[nH]c1-c1ccncc1
Yield: 34.3 %

Procedure:
tert-Butyl 2-hydroxyimino-3-oxo-3-(4-pyridyl)propionate (3.9 g) and 4-chlorobenzylamine (3.0 g) were dissolved in toluene (80 ml), and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 10 to give tert-butyl 2-(4-chlorophenyl)-5-(4-pyridyl)imidazole-4-carboxylate (1.9 g), melting point 206-207° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=O)[CH2:6][C:5]2([CH3:14])[CH3:13].[C:15]1(C)C=CC=CC=1>[CH3-].C[Al+]C.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Cl-].[Ti+3].[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[CH2:15])[CH2:6][C:5]2([CH3:14])[CH3:13]
Reactant: Cc1ccccc1
Reactant: CC1(C)CC(=O)Oc2ccc(Br)cc21
Agent: [Ti+3]
Agent: C[Al+]C
Agent: [CH3-]
Product: C=C1CC(C)(C)c2cc(Br)ccc2O1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
A stirred, cooled (ice bath) solution of 6-bromo-4,4-dimethyl-chroman-2-one available in accordance with U.S. Pat. No. 5,399,561 incorporated herein by reference (1 g, 3.92 mmol) in 8 mL of anhydrous tetrahydrofuiran was treated with a 0.5 M solution of μ-chloro-μ-methylene-[ bis(cyclopentadienyl)titanium]dimethylaluminum (Tebbe reagent) in toluene (8.23 mL, 4.12 mmol). After 10 minutes, the reaction mixture was poured into ice-water mixture containing 50 mL of 1M sodium hydroxide and extracted with hexane. The hexane extract was washed with brine (×1), filtered over a bed of celite and evaporated in vacuo to an oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using hexane as the eluent to afford the title compound (0.74 g, 74%) as a clear oil. 1H NMR (300 MHz, CDCl3): δ 7.34 (d, 1H, J=2.3 Hz), 7.23 (dd, 1H, J=2.3, 8.5 Hz), 6.77 (d, 1H, J=8.0 Hz), 4.61 (d, 1H, J=0.73 Hz), 4.17 (d, 1H, J=0.73 Hz), 2.33 (s, 2H), 1.27 (s, 6H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O.[CH3:12][C:13]([CH3:15])=[O:14]>>[Cl:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[CH:12][C:13](=[O:14])[CH3:15]
Reactant: CC(C)=O
Reactant: O=Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)C=Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixed solution of acetone (294 ml) and an aqueous solution (1.4 l) of sodium hydroxide (22.0 g) was added 2-chlorobenzaldehyde (70.3 g), and the mixture was stirred at room temperature for 5 hours. Excess acetone was evaporated under reduced pressure, and to the residue was added ethyl acetate (1.4 l). The mixture was subjected to extraction, and the ethyl acetate layer was washed with brine and dried (anhydrous magnesium sulfate). Under reduced pressure, ethyl acetate was evaporated to give crude 2-chlorobenzalacetone (94.6 g) as yellow oil, which was used for the following reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](O)=[CH:10][C:11](=O)[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8].[Li].Cl.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[NH:29][NH2:30]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:29]([C:23]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=3[Cl:21])[N:30]=[C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CCC(=O)C=C(O)c1ccc(Cl)c(Cl)c1
Reactant: NNc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Li]
Solvent: CCO
Product: O=C(O)CCc1cc(-c2ccc(Cl)c(Cl)c2)n(-c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 33 %

Procedure:
To a round-bottom flask was added 6-(3,4-dichloro-phenyl)-6-hydroxy-4-oxo-hex-5-enoic acid bis-lithium salt (9.48 g, 31.3 mmol, 1.0 equiv), 2,4-dichloro-phenyl hydrazine hydrochloride (6.66 g, 31.3 mmol, 1.0 equiv) and EtOH (250 mL) under nitrogen. The mixture was stirred at room temperature for 24 h. The solvent was removed, and the crude residue was partitioned between 5% HCl and diethyl ether (200 mL each). The layers were separated, and the aqueous layer was extracted with diethyl ether (2×100 mL). The combined organic layers were washed with water (100 mL) then brine (100 mL), dried (Na2SO4), and concentrated under reduced pressure. Purification by flash chromatography (25% ethyl acetate/dichloromethane) afforded the title intermediate (4.5 g, 33%). HPLC: Rt=3.04 (Method A). MS (ESI): mass calculated for C18H12Cl4N2O2, 427.97; m/z found, 429/431 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 12.20 (br s, 1H), 7.82 (d, J=2.2 Hz, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.61-7.59 (m, 2H), 7.50 (d, J=2.2 Hz, 1H), 7.05 (dd, J=8.2, 1.9 Hz, 1H), 6.73 (s, 3H), 2.88 (t, J=7.4 Hz, 2H), 2.64 (t, J=7.4 Hz, 2H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[NH:25]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([NH2:34])[C:28]=2[CH:27]=[N:26]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:34][C:29]3[CH:30]=[CH:31][CH:32]=[C:33]4[C:28]=3[CH:27]=[N:26][NH:25]4)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Reactant: Nc1cccc2[nH]ncc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2cccc3[nH]ncc23)ncn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 230 mg; 0.98 mmol) in DCM (5 ml) was treated with polymer-supported Mukaiyama reagent (400 mg) and triethylamine (0.41 ml; 2.9 mmol) followed by 1H-indazol-4-amine (Key Organics, 150 mg; 1.12 mmol). After stirring at RT for 72 hours the mixture was filtered and washed with saturated sodium bicarbonate solution. The organic phase was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid.
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[Cl:7][CH2:8][C:9](Cl)=[O:10]>C(OCC)(=O)C>[Cl:7][CH2:8][C:9]([N:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2])=[O:10]
Reactant: O=C(Cl)CCl
Reactant: CNCC(=O)O
Solvent: CCOC(C)=O
Product: CN(CC(=O)O)C(=O)CCl

Procedure:
8.8 Grams (0.1 mole) of sarcosine was suspended in 100 ml of ethyl acetate and refluxed under anhydrous conditions with 22.6 grams (0.2 mole) of chloroacetyl chloride for 12 hours. The unreacted sarcosine was then filtered and the excess solvent and chloroacetyl chloride removed from the filtrate by vacuum distillation. The resulting oil was crystallized with the aid of a small quantity of diethyl ether. There was obtained 12.5g (76%) of N-(Chloroacetyl)sarosine whose structure was consistent with infrared analysis and element analysis for C, H, N, and Cl.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.CN(C)CCN(C)C.C([Li])CCC.CCCCCC.[C:31](=[O:33])=[O:32]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:7]=1[C:31]([OH:33])=[O:32]
Reactant: FC(F)(F)c1ccc(Cl)cc1
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
The title compound was prepared according to the method described in Tetrahedron Lett., vol. 37, p. 2767 (1996). To a solution of 1-chloro-4-(trifluoromethyl)benzene (25.8 g, 143 mmol) and tetramethylethylene diamine (16.6 g, 143 mmol) in tetrahydrofuran (250 mL) cooled to −78° C., was added a solution of 1.6M butyllithium in hexane (89.4 mL, 143 mmol) was added dropwise under an argon atmosphere, and the mixture was stirred at the same temperature for 30 minutes. The solution was carefully poured onto crushed dry ice, and the resulting mixture was allowed to warm to room temperature. The solution was concentrated under reduced pressure, and the residue was poured into water. The solution was washed with diethylether, and subsequently made acidic by the addition of conc. hydrochloric acid, and organic matter was extracted with dichloromethane. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was crystallized from hexane to give the title compound (20.6 g, 64% yield). NMR (CDCl3) δ: 7.65. (1H, d, J=8.4 Hz), 7.75 (1H, dd, J=2.2 Hz. 8.4 Hz), 8.31 (1H, d, J=2.2 Hz), hidden (1H)
Reaction SMILES: CO[C:3]1[CH:8]=[C:7]([N+:9]([O-])=[O:10])[C:6]([Br:12])=[CH:5][C:4]=1[F:13].[C:14](O)(=O)C.C(O)C.C(=O)([O-])[O-].[K+].[K+]>O.[Fe]>[Br:12][C:6]1[CH:5]=[C:4]([F:13])[CH:3]=[CH:8][C:7]=1[NH:9][O:10][CH3:14]
Reactant: CC(=O)O
Reactant: COc1cc([N+](=O)[O-])c(Br)cc1F
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CONc1ccc(F)cc1Br
Temperature: 25 °C
Yield: 67 %

Procedure:
A mixture of 4-bromo-2-fluoro-5-nitrophenyl methyl ether (25.5 g, 102 mmol), acetic acid (250 mL), ethanol (250 mL) and iron powder (22.7 g, 408 mmol) was heated to 100 C for 4 hours. The reaction mixture was cooled to room temperature, diluted with water, neutralised by addition of potassium carbonate and filtered through Celite. The aqueous layer was extracted thrice with DCM. The combined organic layers were dried over magnesium sulfate and evaporated under vacuum to afford the title compound (15 g, 67%) as a white solid. LC-MS (ES) (M+H)+ m/z=220.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([NH:11][C:12](=O)[CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([NH:11][C:12](=[S:33])[CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)c1ccc(Cl)c(NC(=O)COCc2ccccc2)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cl)c(NC(=S)COCc2ccccc2)c1
Temperature: 120 °C
Yield: 137.2 %

Procedure:
To the solution of 3-(2-Benzyloxy-acetylamino)-4-chloro-benzoic acid methyl ester (1.70 g, 5.10 mmol) in 20 ml of toluene was added Lawesson's reagent (1.03 g, 2.50 mmol) and the reaction mixture was heated at 120° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (5:95) as the eluent to provide the title compound (1.20 g, 67%).
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)(=O)C.[C:13](OC)(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[C:13](=[O:21])[N:10]=2)=[CH:11][CH:12]=1
Reactant: CC(=O)Oc1ccc(C#N)cc1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2ccc(O)cc2)sc2ccccc12
Yield: 15.9 %

Procedure:
A mixture of 4-acetoxybenzonitrile (1.35 g, 8.4 mmol), methyl thiosalicylate (2.12 g, 13 mmol), triethylamine (1.50 g, 15 mmol) and toluene (10 ml) was heated and refluxed under a nitrogen flow for 26 hours. The precipitated crystals were taken by filtration and recrystallized from tetrahydrofuran-ethyl acetate to give the title compound (0.34 g, 16%) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][N:8]=[C:7]([S:15]([CH3:17])=[O:16])[C:6]2=[O:18].[OH-].[Na+].[CH3:21]OS(OC)(=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([CH3:21])[N:8]=[C:7]([S:15]([CH3:17])=[O:16])[C:6]2=[O:18]
Reactant: COc1cc2[nH]nc(S(C)=O)c(=O)c2cc1OC
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(=O)c(S(C)=O)nn(C)c2cc1OC

Procedure:
A solution of 10 g of 6,7-dimethoxy-3-(methylsulfinyl)-4(1H)-cinnolinone in 148 ml of 1 normal NaOH was treated with 14 g of (CH3)2SO4 with stirring. As the (CH3)2SO4 dissolved, the temperature rose to ca. 35° and a pasty precipitate formed. The mixture was stirred for 45 minutes and the precipitate was filtered off, washed with cold H2O and recrystallized from CH3CN, mp. 262°-64°; yield 6 g (57%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]([NH:17][S:18]([CH2:21][C:22](O)=[O:23])(=[O:20])=[O:19])=[CH:15][CH:14]=1>C(O)(=O)C>[Br:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:10][C:22](=[O:23])[C:21]([S:18]([NH:17][C:16]1[CH:25]=[CH:26][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)(=[O:20])=[O:19])=[CH:7]2
Reactant: O=Cc1cc(Br)ccc1O
Reactant: COc1ccc(NS(=O)(=O)CC(=O)O)cc1
Solvent: CC(=O)O
Product: COc1ccc(NS(=O)(=O)c2cc3cc(Br)ccc3oc2=O)cc1

Procedure:
A solution of 5-bromosalicylaldehyde (1 mmol) and 4-methoxyanilinosulfonyl acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 1, Method A to yield the title compound; m.p. 182-184° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH2:11][CH2:12][OH:13].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:13][CH2:12][CH2:11][C:5]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=1[CH3:3]
Reactant: Cc1cccc(C)c1CCO
Reactant: BrCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc(C)c1CCOCCCCCCBr
Yield: 52.7 %

Procedure:
NaH (46% dispersion in oil; 4.2 g) was added portionwise to a solution of 2,6-dimethylbenzeneethanol (6.0 g) and 1,6-dibromohexane (19.52 g) in THP (50 ml) under nitrogen. The mixture was refluxed for 18 h and treated cautiously with H2O (20 ml). The resulting emulsion was extracted with ER (3×100 ml) and the dried extract was evaporated to leave a yellow oil. Excess 1,6-dibromohexane was removed under reduced pressure and the residue was purified on a column of silica (300 ml) [B] to give the title compound as a colorless oil (6.6 g) b.p. 110°-115°/0.4 mmHg.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:25].[K+]>O>[I:25][C:2]1[CH:11]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)cc1N
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: COC(=O)c1ccc(S(C)(=O)=O)cc1I
Temperature: 0 °C
Reaction time: 2 h

Procedure:
600 mg of methyl 2-amino-4-(methylsulfonyl)benzoate was added to a solution of 4 mL of H2O and 1 ml, of concentrated sulfuric acid. The solution was cooled to 0° C. and a solution of 206 mg of sodium nitrite in 1 mL of H2O was added slowly. The reaction mixture was stirred for 2 h and then a solution of 782 mg of potassium iodide in 2 mL of H2O was added dropwise at 0° C. The reaction was allowed to warm to room temperature and stirred for 5 h. The mixture was extracted with ethyl acetate. The combined organic extracts were washed with saturated Na2S2O3, dried (MgSO4) and evaporated. Purified by silica gel chromatography (5-50% ethyl acetate/hexane) to afford methyl 2-iodo-4-(methylsulfonyl)benzoate. 160 mg of methyl 2-iodo-4-(methylsulfonyl)benzoate was hydrolyzed via Procedure M to give 2-iodo-4-(methylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-iodo-4-(methylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-iodo-4-(methylsulfonyl)benzamide. MS (Q1) 513.0 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:13][CH2:12][C@@H:11]([CH3:14])[CH2:10][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: C[C@H](CCl)CBr
Reactant: Oc1cccc(Br)c1
Product: C[C@H](CCl)COc1cccc(Br)c1

Procedure:
Prepared by Procedure U and Scheme AK using 3-bromophenol and (2R)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:22]=[CH:21][C:6]2[N:7]=[C:8]([NH:11][C@H:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][CH2:13]3)[O:9][CH2:10][C:5]=2[CH:4]=1.C(N(CC)CC)C.[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1.O>O1CCCC1>[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:1][CH2:2][C:3]2[CH:22]=[CH:21][C:6]3[N:7]=[C:8]([NH:11][C@H:12]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[CH2:14][CH2:13]4)[O:9][CH2:10][C:5]=3[CH:4]=2)=[O:36])=[CH:33][CH:32]=1
Reactant: NCc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 67.6 %

Procedure:
To a cooled (ice bath) and stirred solution of (6-aminomethyl-4H-benzo[d][1,3]oxazin-2-yl)-(R)-indan-1-yl-amine (example 129) (200 mg, 0.68 mmol) and triethylamine (76 mg, 0.75 mmol) in tetrahydrofuran (4 ml) was added 4-fluorobenzoyl chloride (119 mg, 0.75 mmol) and the mixture was allowed to stir at 0° C. for 1 h and afterwards at room temperature for 16 h. The reaction mixture was poured into water (15 ml) and extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with brine (20 ml), dried (magnesium sulfate) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel to yield the title compound as white foam (191 mg, 67%). MS (ISP): m/e=416.3 (M+H+).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:27]=[CH:26][C:15]2[C:16](=[O:25])[CH:17]=[C:18]([C:20]#[C:21][C:22]([OH:24])=[O:23])[O:19][C:14]=2[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1>C(O)C.[Pd]>[O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:27]=[CH:26][C:15]2[C:16](=[O:25])[CH:17]=[C:18]([CH:20]=[CH:21][C:22]([OH:24])=[O:23])[O:19][C:14]=2[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C#Cc1cc(=O)c2ccc(OCCCOc3ccccc3)cc2o1
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: CCO
Product: O=C(O)C=Cc1cc(=O)c2ccc(OCCCOc3ccccc3)cc2o1

Procedure:
3-[7-(3-Phenoxypropyloxy)-4-oxo-4H-1-benzopyran-2-yl]propiolic acid (1 g) in ethanol was hydrogenated at atmospheric pressure in the presence of palladium on barium sulphate poisoned with quinoline. Isolation procedures yielded the title acrylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:21]2[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:22]=2[O:30][CH3:31])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:21]2[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:22]=2[O:30][CH3:31])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COc1ccc(C(NC(C)c2cc(F)cc(F)c2)c2cc([N+](=O)[O-])ccc2OC)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(NC(C)c2cc(F)cc(F)c2)c2cc(N)ccc2OC)cc1

Procedure:
Following a reaction and purification procedure similar to those described in Example (59b), 1.75 g of N-[1-(3,5-difluorophenyl)ethyl]-N-[(2-methoxy-5-nitrophenyl)-(4-methoxyphenyl)methyl]amine [prepared as described in step (a) above], 2.24 g of nickel chloride hexahydrate and 651 mg of sodium borohydride were reacted, to obtain 471 mg of isomer A and 650 mg of isomer B of the title compound were obtained as a yellow oil and an orange solid, respectively.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH:11]([CH2:13][CH3:14])[CH3:12]>>[CH:11]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)([CH2:13][CH3:14])[CH3:12]
Reactant: CCC(C)Br
Reactant: c1ccc2[nH]ccc2c1
Product: CCC(C)n1ccc2ccccc21

Procedure:
The title compound was prepared according to general procedure A described in Scheme 1 from indole and 2-bromobutane. The crude material was used directly without further purification.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][CH2:10][OH:11]>>[NH:7]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]=[CH:9][C:10]1=[O:11]
Reactant: CCO
Reactant: Nc1ccccc1N
Product: O=c1cnc2ccccc2[nH]1

Procedure:
A mixture of the 1,2-phenylene-diamine derivative (1 g) and the 2-oxo-carboxylic acid derivative (1 eq) in dry EtOH (35 mL) was stirred at reflux for 2 h under nitrogen. After cooling, the EtOH was evaporated to give a crude brown solid. Recrystallisation from EtOH gave the desired quinoxalin-2-one derivative.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].O=[C:8]1[NH:17][CH:16]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=2[S:26]([CH3:29])(=[O:28])=[O:27])[C:15]2[C:14](=[O:30])[CH2:13][CH2:12][CH2:11][C:10]=2[N:9]1[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1.C(OCC)(=O)C>CN(C)C=O>[CH3:8][N:17]1[CH:16]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=2[S:26]([CH3:29])(=[O:27])=[O:28])[C:15]2[C:14](=[O:30])[CH2:13][CH2:12][CH2:11][C:10]=2[N:9]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=2)[C:1]1=[O:4]
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2ccnc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)N(c2ccnc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cesium carbonate (265 mg, 0.82 mmol) and methyl idodide (51 μL, 0.82 mmol) are added to a solution of 4-(2,5-dioxo-1-(2-(trifluoromethyl)pyridin-4-yl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-3-(methylsulfonyl)benzonitrile (example 57, 200 mg, 0.41 mmol) in N,N-dimethylformamide (3 mL), and the mixture is stirred at room temperature for 2 h. Ethyl acetate is added, and the mixture is extracted three times with water. The organic phase is dried over Mg2SO4 and concentrated under reduced pressure. The residue is it) purified by flash chromatography on silica (gradient dichloromethane/methanol 99:1 to 97:3). Yield: 134 mg; ESI mass spectrum [M+H]+=505; Retention time HPLC: 0.60 min (X012_S02).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:23])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[CH:20]1[CH2:22][CH2:21]1.[C:24]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:1][C@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:12][C:11]=2[CH:20]2[CH2:22][CH2:21]2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1CCCC1
Reactant: N[C@H]1CCCC[C@H]1NC(=O)c1ccc(C(F)(F)F)cc1C1CC1
Product: O=C(N[C@@H]1CCCC[C@@H]1NC1CCCC1)c1ccc(C(F)(F)F)cc1C1CC1

Procedure:
The title compound, yellow solid, MS: m/e=395.3 [(M+H)+], was prepared in accordance with the general method of example 11 from cis-N-(2-amino-cyclohexyl)-2-cyclopropyl-4-trifluoromethyl-benzamide (intermediate L) and cyclopentanone.