Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-])=O)[CH:4]=1>CO.C(OCC)(=O)C.[C].[Pd]>[NH2:10][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[OH:9]
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(O)c(N)c1
Yield: 94.4 %

Procedure:
10 g of 4-methoxy-2-nitrophenol was dissolved in 120 ml of methanol and 80 ml of ethyl acetate. Thereafter, 800 mg of 10% palladium carbon was added to the reaction solution, followed by reduction under hydrogen atmosphere. After completion of the reaction, the catalyst was removed by filtration, and the residue was then concentration under a reduced pressure. The generated solid was suspended in hexane-t-butylmethyl ether, and the suspension was then filtered, so as to obtain 7.77 g of the subject compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]([NH:15][C:16]1[N:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH2:20])=[O:19])=O.CCN(C(C)C)C(C)C>CN(C=O)C>[O:19]=[C:18]1[NH:20][C:13]([CH2:12][N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])=[N:15][C:16]2[N:24]=[CH:23][CH:22]=[CH:21][C:17]1=2
Reactant: NC(=O)c1cccnc1NC(=O)CN1C(=O)c2ccccc2C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1nc2ncccc2c(=O)[nH]1
Yield: 88.3 %

Procedure:
A solution of 2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetylamino]-nicotinamide (7.24 g, 22.3 mmol) and DIPEA (14.4 ml, 111.6 mmol) in DMF (250 ml) was stirred overnight at 100° C. The reaction mixture was evaporated, redissolved in toluene and brought to dryness under reduced pressure. The residue was triturated with 100 ml EtOAc/MeOH (19/1) and filtrated to yield 2-(4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-isoindole-1,3-dione (6.03 g, 19.7 mmol; 88%) as light brown solid. MS (m/e): 307.2 [M+H+].
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][C:11]=1[O:12][C:13]([F:16])([F:15])[F:14])[NH2:8])(=[O:4])=[O:3].Cl.C1(C)C=CC=CC=1.[O:25]=[C:26](Cl)OC(Cl)(Cl)Cl>C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N:8]=[C:26]=[O:25])[CH:9]=[CH:10][C:11]=1[O:12][C:13]([F:14])([F:15])[F:16])(=[O:4])=[O:3]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1cc(N)ccc1OC(F)(F)F
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cc(N=C=O)ccc1OC(F)(F)F
Reaction time: 8 h

Procedure:
To 3-methylsulfonyl-4-trifluoromethoxyaniline (2.0 mmol, 500 mg) dissolved in ethyl acetate (6 mL) was added 3 N hydrochloric acid in ethyl acetate (5 mL) followed by concentration in vacuo. The residue was treated with toluene (3×5 mL) and each time concentrated in vacuo. To the residue was added toluene (10 mL) and diphosgene (6 mmol, 0.73 mL) under a nitrogen atmosphere and the suspension was gently refluxed for 2 hours. Additional diphosgene (6 mmol, 0.73 mL) was added and refluxing was continued overnight. The reaction mixture was concentrated in vacuo to afford 3-methylsulfonyl-4-trifluoromethoxyphenyl isocyanate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:20])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:21]#[N:22])[CH:5]=[CH:6][CH:7]=1.Br[CH2:24]Cl.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[CH:17]=[C:16]4[O:19][CH2:24][O:20][C:15]4=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[C:21]#[N:22])[CH:5]=[CH:6][CH:7]=1
Reactant: ClCBr
Reactant: N#Cc1cnc2cc(O)c(O)cc2c1Nc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cnc2cc3c(cc2c1Nc1cccc(Br)c1)OCO3
Temperature: 111 °C
Reaction time: 2 h
Yield: 42.4 %

Procedure:
A mixture of 2.17 g (6.09 mmole) of 4-[(3-bromophenyl)amino]-6,7-dihydroxy-3-quinolinecarbonitrile, 0.59 ml (1.18 g; 9.14 mmole) of bromochloromethane and 2.98 g (9.14 mmole) of cesium carbonate in 20 ml of N,N-dimethylformamide was heated and stirred for 2 hours in an oil bath at 111° C. The reaction was poured into 75 ml of water and extracted with four 50 ml portions of methylene chloride. The combined methylene chloride extracts were washed with several portions of water. This solution was taken to an oil in vacuo and this was dissolved in ethyl acetate. This solution was washed repeatedly with water, then with brine. The solution was dried over anhydrous magnesium sulfate, and taken to a solid in vacuo to give 0.95 g of 8-[(3-bromophenyl)amino]-[1,3]-dioxolo[4,5-g]quinoline-7-carbonitrile, m.p. 201-205° C.: mass spectrum (electrospray, m/e): M+H 368.1, 370.1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=O)[C:5](=O)[NH:6]2.[C:13]1([NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19]>C(O)(=O)C>[Br:1][C:2]1[C:3]2[C:4]3[C:5]([NH:19][C:14]4[C:13]([N:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[N:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1ccccc1N
Reactant: O=C1Nc2cccc(Br)c2C1=O
Solvent: CC(=O)O
Product: Brc1cccc2nc3[nH]c4ccccc4nc-3c12
Reaction time: 16 h

Procedure:
A solution of 3.40 g (15.0 mmol) of 4-bromoisatin and 1.63 g (1 eq.) of 1,2-phenylenediamine in 50 ml of acetic acid was refluxed for 2 hours. The reaction solution was allowed to stand at room temperature for 16 hours, and the resulting precipitate was collected by filtration to give 10-bromoindolo[2,3-b]quinoxaline.
Reaction SMILES: [F:1][C:2]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22]C(=O)C(F)(F)F)=[CH:18][C:17]=2[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])(=[O:15])=[O:14])=[CH:10][C:5]2[B:6]([OH:9])[O:7][CH2:8][C:4]=2[CH:3]=1.N>>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([S:13](=[O:14])(=[O:15])[NH:12][C:11]2[C:2]([F:1])=[CH:3][C:4]3[CH2:8][O:7][B:6]([OH:9])[C:5]=3[CH:10]=2)=[C:17]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:18]=1
Reactant: CCOC(=O)Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1cc2c(cc1F)COB2O
Agent: N
Product: CCOC(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1cc2c(cc1F)COB2O
Yield: 39.2 %

Procedure:
Ethyl 2-(2-(N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(2,2,2-trifluoroacetamido)phenyl)acetate (0.25 g, 0.50 mmol) and NH3 (7M in MeOH, 5 mL) was heated to 80° C. for 2 hrs. The reaction was monitored by LC/MS. Purification: The solvent was removed in vacuo and the product was recrystallized from EtOAc/MeOH to give 80 mg of the title compound as a white solid (yield: 40%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.62 (s, 1H), 9.27 (bs, 1H), 7.64 (d, J=8.2 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 7.16 (d, J=10 Hz, 1H), 6.41 (d, J=2.4 Hz, 1H), 6.36 (dd, J=8.8, 2 Hz, 1H), 5.94 (s, 2H), 4.88 (s, 2H), 4.05 (q, J=7.6 Hz, 2H), 3.87 (s, 2H), 1.17 (t, J=7.2 Hz, 3H); MS (ESI) m/z=407.1 (M−H, negative).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:15][CH:14]3[C:16]([O:18]C)=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:21][NH2:22]>C(O)C>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:15][CH:14]3[C:16]([NH:21][NH2:22])=[O:18])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: COC(=O)C1CC1c1ccc(C2CCCCC2)cc1
Solvent: O
Solvent: CCO
Product: NNC(=O)C1CC1c1ccc(C2CCCCC2)cc1
Temperature: 80 °C
Yield: 133.5 %

Procedure:
To a room temperature solution of methyl 2-(4-cyclohexylphenyl)cyclopropanecarboxylate (150 mg, 0.58 mmol) in ethanol (40 mL) was added hydrazine hydrate (293 mg, 5.85 mmol). The reaction mixture was then heated at 80° C. for 16 h, concentrated in vacuo and the residue dissolved in DCM (50 mL). The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo to afford 2-(4-cyclohexylphenyl)cyclopropanecarbohydrazide (200 mg) which was taken on to the next step without further purification.
Reaction SMILES: F[C:2]1[C:21](F)=[CH:20][C:19]([I:23])=[CH:18][C:3]=1[C:4]([C:6](=[CH:12][NH:13][N:14]([CH:16]=[O:17])[CH3:15])[C:7]([O:9]CC)=[O:8])=[O:5].[OH-].[K+].C>O>[I:23][C:19]1[CH:18]=[C:3]2[C:2]3=[C:21]([O:17][CH2:16][N:14]([CH3:15])[N:13]3[CH:12]=[C:6]([C:7]([OH:9])=[O:8])[C:4]2=[O:5])[CH:20]=1
Reactant: CCOC(=O)C(=CNN(C)C=O)C(=O)c1cc(I)cc(F)c1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CN1COc2cc(I)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 105 °C
Reaction time: 96 h
Yield: 29.1 %

Procedure:
Ethyl 2-(2,3-difluoro-5-iodobenzoyl)-3-(2-formyl-2-methylhydrazino)prop-2-enoate (Preparation 30, 1.02 g) in 8 mL of water is treated with KOH pellets (0.410 g) and the reaction mixture is heated in an oil bath, under a nitrogen atmosphere, at 105° C. for 1.75 h while volatiles were condensed into a Dean-Stark trap. At this time, the Dean-Stark trap was removed, 1 mL of an aqueous solution of KOH (0.956 g) is added to the mixture, and heating is continued at 105° C. for 4 days. The mixture is cooled to room temperature, treated with formic acid (1.68 g), and is warmed to 45-50° C. A 37% aqueous formaldehyde (0.396 g) is added and the mixture is heated at 70° C. for 30 minutes. The resulting slurry is cooled in an ice bath at 0-5° C., reacted with 29% aqueous ammonium hydroxide (1.46 mL), and allowed to warm to room temperature where it is stirred for 35-40 minutes. Charcoal (44 mg) is added to the mixture which is stirred for 30 minutes and filtered through a pad of solka-floc rinsing with water. The filtrate is diluted with saturated brine and a mixture of chloroform/methanol (95/5) and filtered through a pad of solka-floc. The organic layer is separated, dried with anhydrous sodium sulfate, and concentrated at reduced pressure to obtain 252 mg (28%) of the title compound. Physical characteristics: MS (ESI+) m/z 373 (M+H)+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:10]#[N:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>O1CCCC1>[CH3:22][S:19]([O:1][N:2]=[C:3]([C:10]#[N:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC(=NO)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)ON=C(C#N)c1ccccc1
Temperature: -5 °C
Reaction time: 3 h

Procedure:
α-(Methylsulfonyloxyimino)benzyl cyanide was prepared in the following manner. Thus, 52.5 g (0.36 mole) of α-hydroxyiminobenzyl cyanide and a solution prepared by dissolving 44.0 g (0.43 mole) of triethylamine in 400 ml of tetrahydrofuran were introduced into a reaction vessel to form a uniform solution which was chilled to and kept at -5° C. Into the solution in the reaction vessel were added dropwise 49.0 g (0.43 mole) of mesyl chloride over a period of 2 hours under agitation. The reaction mixture in the vessel was agitated at -5° C. for 3 hours and then at about 10° C. for additional 2 hours. The reaction mixture was freed from tetrahydrofuran as the solvent by distillation under reduced pressure at 30° C. to give 75.0 g of a solid residue which was purified by repeating recrystallization from acetonitrile to give 64.5 g of a white crystalline product having a melting point of 120° C., which could be identified to be the target compound from the results of the analysis described below and coincidence of the melting point with the known value reported in literatures. The above mentioned yield of the product corresponds to 80.0% of the theoretical value.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][S:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>>[CH3:12][S:13][C:14]1[CH:15]=[C:16]([NH:17][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=2[F:11])[CH:18]=[CH:19][CH:20]=1
Reactant: CSc1cccc(N)c1
Reactant: O=C(O)c1ccc(Br)cc1F
Product: CSc1cccc(NC(=O)c2ccc(Br)cc2F)c1

Procedure:
460 mg of N1-[3-(methylsulfanyl)phenyl]-4-bromo-2-fluorobenzamide obtained in the same manner as in Production Example 32 from 4-bromo-2-fluorobenzoic acid and 3-(methylthio)aniline was stirred for 1.5 hours together with 1.23 g oxone in 15 mL tetrahydrofuran, 10 mL methanol and 10 mL water. The reaction solution was extracted with ethylacetate and purified by NH silica gel column to give 500 mg of the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[N:8]=[C:9]([CH3:11])[CH:10]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:3][CH2:4][C:6]1[N:7]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[N:8]=[C:9]([CH3:11])[CH:10]=1
Reactant: CCOC(=O)c1cc(C)nn1-c1ccc(O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(CO)n(-c2ccc(O)cc2)n1
Reaction time: 8 h

Procedure:
2-(4-Hydroxyphenyl)-5-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (233 mg, 0.946 mmol) was dissolved in tetrahydrofuran (20 mL). Lithium aluminum hydride (1.42 mL, 1 M in THF, 1.42 mmol) was added, and the reaction was stirred overnight. The reaction was quenched with water and extracted with ethyl acetate. The ethyl acetate solution was dried (MgSO4) and concentrated to give the crude product in quantitative yield. LC-MS (C11H12N2O2 calculated 204) m/z 205 (M+H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[CH:11][C:12]([N+:23]([O-:25])=[O:24])=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=2)[CH2:5][CH2:4]1.CC1(C)C(C)(C)OB([C:34]2[CH2:39][C:38]([CH3:41])([CH3:40])[CH2:37][C:36]([CH3:43])([CH3:42])[CH:35]=2)O1>COCCOC.O>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[CH:11][C:12]([N+:23]([O-:25])=[O:24])=[C:13]([C:34]3[CH2:39][C:38]([CH3:41])([CH3:40])[CH2:37][C:36]([CH3:43])([CH3:42])[CH:35]=3)[CH:14]=2)[CH2:5][CH2:4]1
Reactant: COC1CCN(c2ccc([N+](=O)[O-])c(OS(=O)(=O)C(F)(F)F)c2)CC1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)C1
Solvent: O
Solvent: COCCOC
Product: COC1CCN(c2ccc([N+](=O)[O-])c(C3=CC(C)(C)CC(C)(C)C3)c2)CC1

Procedure:
Trifluoromethanesulfonic acid 5-(4-methoxypiperidin-1-yl)-2-nitrophenyl ester (3 g, 7.81 mmol) prepared in Example (7c) was used as the starting material. 4,4,5,5-Tetramethyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)-[1,3,2]dioxaborolane prepared in Example (4b) was used instead of 4-t-butylcyclohex-1-enyl-(4,4,5,5-tetramethyl)-[1,3,2]dioxaborolane, and a mixed solvent of 1,2-dimethoxyethane-water was used as the solvent, for reaction in a manner similar to Example (7e) and treated in a similar manner, to give 2.89 g of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)=[C:6]([O:30][CH3:31])[CH:5]=1)=[S:3].[CH2:32](OC(OCC)CBr)[CH3:33]>CCO.O>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C@H:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]3[CH:28]=[CH:29][C:4]([C:2]4[S:3][CH:32]=[CH:33][N:1]=4)=[CH:5][C:6]=3[O:30][CH3:31])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)[CH3:27]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C(N)=S)cc3OC)ccc21
Reactant: CCOC(CBr)OCC
Solvent: CCO
Solvent: O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4nccs4)cc3OC)ccc21
Temperature: 70 °C
Yield: 56.7 %

Procedure:
Ethyl ((1S)-5-{3-[4-(aminocarbonothioyl)-2-methoxyphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (1.00 g, 2.3 mmol) (Example 146) and bromoacetaldehyde diethyl acetal (1.78 g, 9.2 mmol) were dissolved in EtOH (30 mL) and water (2 drops) was added. The mixture was heated at 70° C. for 18 h, and then the reaction mixture was cooled to rt, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc:hexane (v/v)=1:1) gave 610 mg (58%) of the title compound as a clear oil. LC-MS: RT=3.81 min; (M+H)+ 468.1.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH2:6]([O:8][C:9]([CH2:11][S:12](Cl)(=[O:14])=[O:13])=[O:10])[CH3:7]>C1COCC1>[CH2:6]([O:8][C:9](=[O:10])[CH2:11][S:12](=[O:14])(=[O:13])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:7]
Reactant: CCOC(=O)CS(=O)(=O)Cl
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Product: CCOC(=O)CS(=O)(=O)NC(C)(C)C
Temperature: -20 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
tert-Butylamine (7.9 mL, 75 mmol.) was dissolved in 50 mL of THF. The solution was cooled to −20° C. and (ethoxycarbonyl)methanesulfonyl chloride dissolved in 10 mL of THF was added slowly. The reaction mixture was allowed to warm to room temperature and stirred for 24 h. The mixture was filtered, and the filtrate concentrated in vacuo. The residue was purified by column chromatography (PE/EtOAc; 2:1) to afford ethyl-2-(N-tert-butylsulfamoyl)acetate (4.1 g, 43%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16](=O)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:28]([NH2:31])[CH2:29][CH3:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([NH:31][CH2:28][CH2:29][CH3:30])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)[nH]c3cc(Cl)ccc23)CC1
Reactant: CCCN
Agent: [H-]
Agent: [Na+]
Product: CCCNc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1

Procedure:
4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-7-chloroquinol-2-one (150 mg, 0.41 mmol), sodium hydride (15 mg, 0.6 mmol), N-phenyl(trifluoromethylsulfon)imide (208 mg, 0.58 mmol), and propylamine (0.14 mL, 1.65 mmol) are treated according to method E yielding the title product.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[I:10]N1C(=O)CCC1=O.C1C(=O)N(I)C(=O)C1.CN(C=O)C>CN(C)C=O>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1I
Reactant: N#Cc1ccccc1N
Solvent: CN(C)C=O
Product: N#Cc1cc(I)ccc1N
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-Aminobenzonitrile (2.0 g, 16.9 mmol, 1 equiv.) was dissolved in dry N,N-dimethylformamide (30 mL), and the solution was cooled to 0° C. A solution of N-iodosuccinimide, NIS (3.81 g, 16.9 mmol, 1 equiv.) in 30 mL of DMF was added dropwise with an addition funnel. After the NIS/DMF solution was, added, the ice bath was removed, and the reaction was stirred at room temperature overnight. The reaction was quenched by pouring into 3N NaOH (300 mL) and diluted with an additional 200 mL of water. 2-Amino-5-iodobenzonitrile formed as a precipitate, which was collected by filtration.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:17]=[C:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH:34][C:35](=O)[O:36]C1C=CC([N+]([O-])=O)=CC=1>C(#N)C>[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH:34][C:35]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]3[N:17]=[C:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:15]=[CH:14][CH:13]=3)[CH:7]=2)[N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:36]
Reactant: CN1CCNc2cc(-c3cccc(C(=O)OC(C)(C)C)n3)ccc21
Reactant: O=C(Nc1nc2ccccc2s1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: CN1CCN(C(=O)Nc2nc3ccccc3s2)c2cc(-c3cccc(C(=O)OC(C)(C)C)n3)ccc21
Temperature: 25 °C
Yield: 85.2 %

Procedure:
A mixture of tert-butyl 6-(1-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)picolinate (25G) (36 mg, 0.11 mmol) and 4-nitrophenyl benzo[d]thiazol-2-ylcarbamate (19) (42 mg, 0.13 mmol) in anhydrous acetonitrile (1.0 mL) was heated to reflux for 3 hours, cooled to rt, concentrated under reduced pressure, and the crude material was purified by flash column chromatography on silica gel eluting with a gradient of PE:EtOAc 100:0-70:30, to provide 47 mg (85%) of the desired product tert-butyl 6-(4-(benzo[d]thiazol-2-ylcarbamoyl)-1-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)picolinate (25H): 1H NMR (300 MHz, CDCl3) δ 8.14 (1H, s), 7.88-7.77 (2H, m), 7.74 (2H, d), 7.54 (1H, d), 7.34 (1H, t), 7.22 (1H, t), 6.71 (1H, d), 3.97 (2H, t), 3.49 (2H, t), 3.02 (3H, s), 1.56 (9H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[C:6]([CH:10]=1)[C:7]([O:9][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27])=[O:8]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccc(F)cc1F)c1cc(Br)ccc1OCc1ccc(F)cc1F
Yield: 99.7 %

Procedure:
To a solution of 5-bromo-2-hydroxybenzoic acid (2.5 g, 11.52 mmol) in acetone (100 ml) was added potassium carbonate (3.98 g, 28.8 mmol) and 1-(bromomethyl)-2,4-difluorobenzene (3.25 ml, 25.3 mmol). The mixture was heated to reflux for 4 hours. On cooling the mixture was filtered to remove the carbonate, the solid was washed with acetone (50 ml). The organics were evaporated under reduced pressure to give a white solid 5.39 g. No attempt was made to purify this compound it was taken on as is.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=1)(O)[CH:12]([CH3:14])[CH3:13].C(=O)([O-])O.[Na+]>Br>[CH:22]([C:19]1[CH:18]=[CH:17][C:16]([CH:11]2[C:4]3[CH:5]=[CH:6][C:7]([OH:9])=[CH:8][C:3]=3[O:2][C:12]2([CH3:14])[CH3:13])=[CH:21][CH:20]=1)([CH3:24])[CH3:23]
Reactant: COc1ccc(C(O)(c2ccc(C(C)C)cc2)C(C)C)c(OC)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)c1ccc(C2c3ccc(O)cc3OC2(C)C)cc1
Yield: 50.6 %

Procedure:
A mixture of 1-(2,4-dimethoxyphenyl)-1-(4-isopropylphenyl)-2-methylpropan-1-ol (5.58 g, 17.0 mmol) and 48% hydrobromic acid (30 mL) was heated under reflux for 24 hours in an argon atmosphere. After the reaction mixture was cooled, an aqueous saturated sodium hydrogencarbonate was added to the mixture, which was then extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=20/1 to 10/1) to obtain the title compound (2.43 g, yield 51%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[N:3]=1.[O-:19][CH2:20][CH3:21].[Na+]>C(O)C>[CH2:20]([O:19][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[NH:5][C:6](=[O:8])[CH:7]=1)[CH3:21]
Reactant: CCCOc1ccccc1-c1nc(O)cc(Cl)n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCOc1ccccc1-c1nc(OCC)cc(=O)[nH]1

Procedure:
A stirred solution of 4-chloro-6-hydroxy-2-(2-propoxyphenyl)pyrimidine (0.5 g) and sodium ethoxide (from 0.18 g sodium) in ethanol (25 ml) was heated in a pressure vessel at 125° C. for 24 hours. The residue left after evaporation was dissolved in water (20 ml), acetic acid was added to precipitate a gum, and the mixture was extracted with chloroform. Evaporation of the extract gave a solid which was recrystallized from ether to yield the title compound, 0.07 g, m.p. 95.5°-97° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
4-Hydroxybenzaldehyde of the formula (7) (100 g), potassium carbonate (226 g) and dimethylformamide (500 ml) were taken in a reaction flask and stirred for 15 minutes. Benzylchloride (114 g) was then added at room temperature and the reaction mass was stirred at the same temperature for a period of 8–10 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was dumped into ice water and extracted with toluene. The combined organic extracts were washed with 10% aq. sodium hydroxide solution followed by water The solvent was removed under reduced pressure and the resulting residue was triturated with pet. ether to afford the title compound of the formula (8) (160–165 g, 93–95%).