Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([S:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[S:7]2)[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31]Br)=[CH:26][CH:25]=1)([O-:23])=[O:22]>CO>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][SH:7]2[C:4]3([CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[S:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]2=3)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: c1ccc2c(c1)CSC1(CCNCC1)S2
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(CC[SH]2c3ccccc3CSC23CCNCC3)cc1

Procedure:
To 111 mgs (0.47 mmol) of dithioketal from Step A in 1 mL of methanol was added 157 mgs of sodium bicarbonate and 118 mg (0.54 mmol) of 2-(4-nitrophenyl)ethyl bromide. The reaction was refluxed for 6 hrs and then concentrated at reduced pressure. The residue was chromotographed (silica gel, 2.5% CH3OH/CH2Cl2) to give after concentration and crystallization from ethyl acetate/Hexanes, 120 mgs of product as the free base.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][C@@H:6]([O:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH2:5][N:4]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:14])#[N:2].N[CH2:27][CH2:28][SH:29]>O1CCCC1>[CH3:12][S:9]([O:8][C@H:6]1[CH2:5][N:4]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[O:14])[C@H:3]([C:1]2[S:29][CH2:28][CH2:27][N:2]=2)[CH2:7]1)(=[O:11])=[O:10]
Reactant: NCCS
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C#N)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C2=NCCS2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 24 h
Yield: 41.3 %

Procedure:
To a solution of (2S, 4R)-2-cyano-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl) pyrrolidine (2 g) in tetrahydrofuran (40 ml) was added 2-aminoethanethiol (630 mg) at ambient temperature. After stirring for 24 hours at the same temperature, the mixture was evaporated. The residue was extracted with dichloromethane, washed with water and brine successively, and dried over magnesium sulfate. The organic layer was evaporated, and then the obtained oil was subjected to a column chromatography on silica gel and eluted with a mixture of dichloromethane and acetone (4:1V/V) to give (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-(2-thiazolin-2-yl) pyrrolidine (0.96 g).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:25][CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]2)[CH2:24][CH2:23][CH2:22][CH2:21]1.C(#N)C.N>ClCCl.C1CCCCC1.CO>[N:20]1([CH2:25][CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][N:30]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:7](=[O:15])[C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:29]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CNCC(CCCN2CCCC2)C1
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ncccc21
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: C1CCCCC1
Product: O=C1Nc2ccccc2N(C(=O)N2CCCC(CCCN3CCCC3)C2)c2ncccc21
Yield: 56 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 3-[3-(1-pyrrolidinyl)propyl]piperidine in a yield of 56% of theory. Colourless crystals, m.p. 174°-176° C. (acetonitrile), Rf 0.65 (Macherey-Nagel, Polygram® SIL G/UV254, pre-coated plastic sheets for TLC; eluant: dichloromethane/cyclohexane/methanol/conc. ammonia 68/15/15/2, v/v/v/v)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH:12](=O)[CH2:13][CH3:14].N1CCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:12]([CH2:13][CH3:14])[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: CCC=O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Solvent: CC(=O)O
Product: CCC1CC(=O)c2cc(Br)ccc2O1
Temperature: 60 °C
Yield: 33 %

Procedure:
The mixture of 1-(5-bromo-2-hydroxyphenyl)ethanone (10 g, 46.50 mmol), propionaldehyde (6.7 mL, 93 mmol), pyrrolidine (3.9 mL, 47 mmol), and acetic acid (3.2 mL, 56 mmol) in toluene (20 mL) was heated to 60° C. for 18 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The mixture was diluted with diethyl ether and 1M aqueous HCl. The phases were separated. The organic phase was washed with 1M aqueous NaOH, then brine. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. Purification with silicagel column chromatography (EtOAc-hexane, a linear gradient of EtOAc from 1 to 10%) afforded 6-bromo-2-ethyl-2,3-dihydro-4H-chromen-4-one (3.92 g).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:6]=1[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])#[N:4].S(OCC)(O[CH2:29][CH3:30])(=O)=O.O>CN(C=O)C>[C:3]([C:5]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:6]=1[N:7]([CH2:29][CH3:30])[S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])#[N:4]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc([N+](=O)[O-])cc2C#N)cc1
Reactant: CCOS(=O)(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(c1ccc([N+](=O)[O-])cc1C#N)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.4 %

Procedure:
To a suspension of sodium hydride (60%, 0.12 g (3.00 mmol)) in 3.0 ml of DMF, 2′-cyano-4′-nitro-p-toluenesulfonanilide (0.80 g (2.52 mmol)) was added with′stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, diethyl sulfate (0.40 ml (3.05 mmol)) was added dropwise and the mixture was heated at 80° C. for 2 hours and at 100° C. for 2 hours with stirring. The reaction mixture was then cooled to room temperature, poured into water and extracted with diethyl ether. The extract was washed three times with 1% aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:2) as eluent, to give 0.23 g (26%) of the title compound as white crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17](CC#N)=[CH:16][CH:15]=2)=[C:4]([CH3:23])[N:3]=1.[C:24]([OH:27])(=[O:26])[CH3:25]>CO.[OH-].[K+].O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:25][C:24]([OH:27])=[O:26])=[CH:18][CH:19]=2)=[C:4]([CH3:23])[N:3]=1
Reactant: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1
Reactant: CC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1

Procedure:
The product from step (v) in MeOH (10 ml) and 5M KOH in water (3 ml) was heated under reflux for 18 h. The mixture was neutralised with acetic acid then purified by RPHPLC to afford the subtitle compound, 0.168 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[Cl:1])=[O:16])=[CH:13][CH:12]=1
Reactant: Cc1cc(C)cc(Cl)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 33.9 %

Procedure:
A stirred, 0° C. solution of 1-chloro-3,5-dimethylbenzene (10.9 g, 77.2 mmol) and 4-chlorobenzoyl chloride (13.6 g, 77.2 mmol) in carbon disulfide (165 ml) was treated with aluminum chloride (11.4 g, 85.0 mmol) in portions over 15 minutes. The mixture was stirred 15 minutes at 0° C., 60 minutes at ambient temperature, 20 hours at reflux and 3 days at ambient temperature. The mixture was cooled to 0° C. and quenched by addition of ice (250 g) followed by concentrated hydrochloric acid (60 ml). The mixture was extracted twice with diethyl ether and the combined extracts were washed with water (3X), saturated aqueous sodium carbonate, and brine, dried over anhydrous magnesium sulfate, and evaporated to dryness of 30° C. under vacuum. The residue was chromatographed in three approximately equal batches on silica gel (500 g) eluted with 97:3 (v/v) hexane-ethyl acetate using a preparative high performance liquid chromatograph to provide 7.3 g (34%) 1-(4-chlorobenzoyl)-2-chloro-4,6-dimethylbenzene, m.p. 84°-87° C. [IR (neat): 2100, 1660 cm-1 ; 60 MHz 'H NMR (CDCl3): 2.11 s (3H), 2.34 s (3H), 6.94 bs (1H), 7.04 bs (1H), 7.34 dm (J= 9 Hz, 2H), 7.70 dm (J=9 Hz, 2H)] and 3.4 g (16%) 1-(4-chlorobenzoyl)-4-chloro-2,6-dimethylbenzene, m.p. 41°-52° C. [IR (neat): 2100, 1660 cm-1 ; 60 MHz 'H NMR (CDCl3) 2.08 s (6H), 7.07 s (2H), 7.38 dm (J=9 Hz, 2H), 7.69 dm (J=9 Hz,2H)].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[NH2:15].C(O)(=O)C(C)(C)C>O1CCOCC1>[Br:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[N:7]=[C:6]([CH:8]3[CH2:10][CH2:9]3)[CH:5]=[CH:4][N:3]=2)[CH:16]=[C:17]([CH3:19])[CH:18]=1
Reactant: Cc1cc(N)cc(Br)c1
Reactant: Clc1nccc(C2CC2)n1
Agent: CC(C)(C)C(=O)O
Solvent: C1COCCO1
Product: Cc1cc(Br)cc(Nc2nccc(C3CC3)n2)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 2-chloro-4-cyclopropyl-pyrimidine (12.5 g, 81 mmol) and 3-bromo-5-methylaniline (18.1 g, 97 mmol) in 1,4-dioxane (100 mL) was added pivalic acid (9.3 mL, 81 mmol). The resulting mixture was heated to reflux and left stirring for 10 hours. The mixture was allowed to cool to room temperature and hexanes were added (80 mL). The slurry was filtered and the filtrate was washed with MeOH to afford a portion of N-(3-bromo-5-methylphenyl)-4-cyclopropylpyrimidin-2-amine. The mother liquors were concentrated, absorbed on silica gel and purified by silica gel column chromatography (EtOAc/Hex) to afford additional N-(3-bromo-5-methylphenyl)-4-cyclopropylpyrimidin-2-amine as a white solid. MS ESI calcd. for C14H15BrN3 [M+H]+ 304 and 306. found 304 and 306.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.C(O)(=O)C>O.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[Cl:11]
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cnc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of 3-bromo-2-chloro-5-nitropyridine (10.00 g, 42.1 mmol) and acetic acid (12.16 mL, 211 mmol) in water (100 mL) at 0° C. was added iron (11.76 g, 211 mmol, powder −325 mesh). The mixture was warmed to room temperature and stirred for 4 h. The reaction mixture was filtered and washed with water. The filtrate was then extracted with EtOAc. The filter cake was then washed with EtOAc, and the resulting filtrate was combined with the previous organic layer from the aqueous extraction. The two organic mixtures were then washed with water (2×), washed with sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated to give 5-bromo-6-chloropyridin-3-amine. MS (ESI, pos. ion) m/z: 207.9 and 209.9 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.N[C@@H]1CCCC[C@H]1N.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:27][C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=1.N#N>O1CCOCC1.[Cu]I>[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH2:1])=[CH:10][CH:9]=3)[CH:5]=[N:6]2)=[CH:30][CH:29]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: Fc1ccc(I)cc1
Agent: [Cu]I
Agent: N#N
Agent: N[C@@H]1CCCC[C@H]1N
Solvent: C1COCCO1
Product: Nc1ccc2c(cnn2-c2ccc(F)cc2)c1
Yield: 1090.4 %

Procedure:
Commercially available 5-aminoindazole (15 g, 113 mmol) was dissolved in 100 mL dry dioxane in a stainless steel pressure bottle followed by the addition of trans-1,2-diaminocyclohexane (6.4 g, 56 mmol), CuI (2.1 g, 11.3 mmol), K3PO4 (43 g, 203 mmol), and 1-fluoro-4-iodobenzene (27.5 g, 11.3 mmol). The reactor was sealed and heated at 120 C for 72 h under a blanket of N2. The reaction was filtered through a large SiO2 plug on a fitted funnel using EtOAc until the eluent ran clear (˜1 L). The solution was concentrated in vacuo and the dark brown solid was taken up in hot EtOAc (˜150 mL) and hexane was added to induce precipitation. The dark black solid was filtered and dried under vacuum to give 28 g (73%) of pure N1-(4-fluorophenyl)-5-aminoindazole. MS found: (M+H)+=228.
Reaction SMILES: I[C:2]1[N:6]([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[O:9][C:8]2([CH3:19])[CH3:18])[CH:5]=[N:4][CH:3]=1.O1C=CC=C1P(C1O[CH:33]=[CH:34][CH:35]=1)C1OC=CC=1.C([Sn](CCCC)(CCCC)C1CC1)CCC>CN1CCCC1=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:34]1([C:2]2[N:6]([CH:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10](=[O:17])[O:9][C:8]3([CH3:19])[CH3:18])[CH:5]=[N:4][CH:3]=2)[CH2:35][CH2:33]1
Reactant: c1coc(P(c2ccco2)c2ccco2)c1
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1I
Agent: [Pd]
Agent: CCCC[Sn](CCCC)(CCCC)C1CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN1CCCC1=O
Product: CC1(C)OC(=O)c2ccccc2C1n1cncc1C1CC1
Temperature: 95 °C

Procedure:
To a flask charged with 4-(5-iodo-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one (350 mg, 0.95 mmol) (Example 2b), tris(dibenzylideneacetone)dipalladium(0) (98 mg, 0.095 mmol) and trifuran-2-yl-phosphane (33 mg, 0.142 mmol) and flushed with N2 is added tributylcyclopropyltin (1.89 g, 5.7 mmol) in degassed N-methylpyrrolidinone (3 mL). The mixture is degassed for 15 min and heated to 95° C. for 25 h. The reaction mixture is quenched with water and extracted with ethyl acetate three times. The organic phase is combined, dried over sodium sulfate, concentrated and the residue is purified by semi-preparative reverse phase HPLC to give 4-(5-cyclopropyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one as white solid; (ESI) m/z 283.2 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 0.69 (s, 1 H), 0.81 (br. s, 1 H), 1.09 (br. s, 2 H), 1.29 (s, 3 H), 1.56 (s, 3 H), 1.94 (br. s, 1 H), 5.78 (s, 1 H), 6.68 (s, 1 H), 7.14 (br. s, 1 H), 7.42 (d, J=7.1 Hz, 1 H), 7.63 (td, J=7.6, 1.3 Hz, 1 H), 7.75 (td, J=7.6, 1.3 Hz, 1 H), 8.21 (dd, J=7.8, 1.3 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=2[OH:24])[N:7]=1)=[O:5])[CH3:2].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O.C(OCC)C>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=2[O:24][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)c1cccc(C2=C(c3cc(C)ccc3O)CCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOCC
Product: CCOC(=O)c1cccc(C2=C(c3cc(C)ccc3OCc3ccc(F)cc3)CCC2)n1
Yield: 85.7 %

Procedure:
A mixture of 6-[2-(5-methyl-2-hydroxyphenyl)cyclopent-1-enyl]pyridine-2-carboxylic acid ethyl ester (129 mg, 0.4 mmol), 4-fluorobenzyl bromide (83 mg, 0.44 mmol) and potassium carbonate (138 mg, 1 mmol) in acetone (4 ml) was stirred and refluxed for 20 hours. After cooling the mixture was diluted with water/diethyl ether and the organic phase dried (magnesium sulphate) evaporated and purified by chromatography on silica (8% ethyl acetate in iso-hexane) to give the title compound as a colourless gum (148 mg, 86%). 1H NMR (CDCl3)δ:1.41 (3H, t, J=7 Hz), 2.04–2.09 (2H, m), 2.18 (3H, s), 2.88–2.91 (2H, m), 3.11–3.15 (2H,m), 4.41 (2H, q, J=7 Hz), 4.91 (2H, s), 6.80 (1H, d, J=8 Hz), 6.87 (1H, d, J=2 Hz), 6.95–7.04 (4H, m), 7.17–7.21 (2H, m), 7.40 (1H, t, J=8 Hz), 7.79 (1H, d, J=8 Hz).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[H-].[Na+].Br[CH2:18][C:19]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][C:24]([Cl:30])=[CH:25][CH:26]=2)[N:21]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:20]=1[C:37]([O:39][CH3:40])=[O:38]>CN1C(=O)CCC1>[CH3:40][O:39][C:37]([C:20]1[N:21]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:22]2[C:27]([C:28](=[O:29])[C:19]=1[CH2:18][N:2]([C:3](=[O:14])[C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:8][CH:9]=1)[CH3:1])=[CH:26][CH:25]=[C:24]([Cl:30])[CH:23]=2)=[O:38]
Reactant: COC(=O)c1c(CBr)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: CNC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1c(CN(C)C(=O)c2ccc(S(C)(=O)=O)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reaction time: 0.08 h
Yield: 20.8 %

Procedure:
To a stirred solution of N-methyl-4-(methylsulfonyl)benzamide (25.2 mg, 0.118 mmol) in NMP was added sodium hydride (60% suspension) (3.54 mg, 0.148 mmol). After 5 min., methyl 3-(bromomethyl)-7-chloro-4-oxo-1-phenyl-1,4-dihydroquinoline-2-carboxylate (40 mg, 0.098 mmol) was added and the mixture was allowed to stir for 3 hr. at room temp. The mixture was then quenched with water and acidified with 1N aqueous HCl. The mixture was then extracted with CH2Cl2. The extracts were dried (Na2SO4), filtered and concentrated in vacuo. Preparative reverse-phase HPLC afforded 7-chloro-3-{[(4-methanesulfonyl-benzoyl)-methyl-amino]-methyl}-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (11 mg, 20%) as an off-white foam. MS calcd. for C27H23ClN2O6S [(M+H)+] 539, obsd. 539.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]2[NH:12][C:11](=[O:13])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.CI.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:12]1[C:6]2[CH:5]=[C:4]([O:21][CH3:22])[C:3]([O:2][CH3:1])=[CH:20][C:7]=2[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:9][CH2:10][C:11]1=[O:13])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)=NCC(=O)N2
Solvent: CI
Product: COc1cc2c(cc1OC)N(Cc1ccccc1)C(=O)CN=C2c1ccccc1
Yield: 64 %

Procedure:
By replacing 5-(4-bromophenyl)-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaf) in example IIba by 7,8-dimethoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaa), and MeI by benzyl bromide, and proceeding in the same manner, the abovenamed product is obtained. Yield: 64%. M: 148–149° C. 1H-NMR (CDCl3, 200 MHz): d 3.67 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 4.38 (AB system, ? d=0.96, JAB=10.0 2H, CH2), 5.15 (AB system, ? d=0.70, JAB=15.4, 2H, —NCH2), 6.56 (s, 1H Ar), 6.81 (s, 1H Ar), 7.07–7.46 (m, 10H Ar).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18](=[O:28])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1)[CH3:16]>CCOC(C)=O>[CH2:15]([O:17][C:18](=[O:28])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:12]([C:10]2[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[O:14])[CH:22]=1)[CH3:16]
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Reactant: CCOC(=O)COc1cccc(N)c1
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cccc(NC(=O)c2ccc(-c3ccccc3)o2)c1

Procedure:
Carboxylic acid (56) (50 mg, 0.27 mmol) was coupled to aniline (64) (52 mg, 0.27 mmol) using Method C. During this reaction, partial hydrolysis occurred. The residue was re-dissolved in EtOAc (2 ml) and the organic layer was washed with 1M HCl (2×1 ml), dried (Na2SO4), filtered and the solvent removed in vacuo to give a mixture of acid and ester, which was used without further purification.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:11]=[N:12][C:13](/[CH:16]=[CH:17]\[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:15]=1)=O)(C)(C)C.Cl>CO>[NH2:8][CH2:9][C:10]1[CH:11]=[N:12][C:13](/[CH:16]=[CH:17]\[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(/C=C\C2CCCCC2)nc1
Agent: Cl
Solvent: CO
Product: NCc1ccc(/C=C\C2CCCCC2)nc1
Temperature: 0 °C
Yield: 309.3 %

Procedure:
Add (Z)-3-(tert-butoxycarbonylamino-methyl)-6-(2-cyclohexylvinyl)-pyridine (0.42 g, 1.33 mmol) to methanol (20 mL) and cool to 0° C. Bubble hydrogen chloride into the solution until saturated, and allow the mixture to warm to room temperature. Concentrate the mixture in vacuo and partition the residue between 3N aqueous NaOH (30 mL) and DCM (30 mL). Separate the layers and extract the aqueous phase with DCM (3×30 mL). Wash the combined organic extracts with brine (30 mL), dry over Na2SO4, filter, and concentrate in vacuo to obtain the title compound as a colorless oil (0.89 g, 80%). MS (APCI+) m/z: 217 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:29]([OH:32])[C:30]#[CH:31].C(N(C(C)C)CC)(C)C>[Cl-].[Na+].O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCCC1>[CH3:9][C:4]1[CH:3]=[C:2]([C:31]#[C:30][CH2:29][OH:32])[CH:7]=[CH:6][C:5]=1[CH3:8]
Reactant: C#CCO
Reactant: Cc1ccc(I)cc1C
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C#CCO)cc1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 1-iodo-3,4-dimethylbenzene (5.00 g), copper(I) iodide (82.1 mg), triphenylphosphine (283 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (446 mg), propargyl alcohol (1.40 ml), diisopropylethylamine (15.0 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 5 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-80:20) to give the object product (2.12 g) as a brown oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[OH:9].[C:10]1([C:16](Cl)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.O>C(Cl)Cl>[C:10]1([C:16]([NH:2][C@H:3]2[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]2[OH:9])([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N[C@H]1CCCC[C@H]1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O[C@@H]1CCCC[C@@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of cis-2-aminocyclohexanol hydrochloride (4.88 g; 32 mmol) (William S. Johnson and Elliot N. Schubert, J.A.C.S., Vol. 72, pp. 2187-2190 (1950), triphenylmethylchloride (10.7 g; 38.4 mmol) and triethylamine (16 ml; 115 mmol) in 250 ml methylene chloride are refluxed for 3 hrs. then stirred at room temperature overnight. The mixture is poured into H2O and extracted with CH2Cl2 (200 ml), dried (Na2SO4) concentrated in vacuo and flash chromatographed using 9:1 7:1; hexane:EtOAc to obtain cis-2-triphenylmethylaminocyclohexanol which is used directly in the next step.