Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]Cl.Cl.N[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([I:12])=[CH:7][N:6]=1.N([O-])=O.[Na+]>O>[Cl:1][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([I:12])=[CH:7][N:6]=1
Reactant: Cc1cc(I)cnc1N
Reactant: ClCl
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(I)cnc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 14.2 %

Procedure:
At −10° C., 21.3 g of chlorine gas were introduced into a suspension of 146 g of 10% strength by weight hydrochloric acid and 23.4 g of 2-amino-3-methyl-5-iodopyridine [J. Org. Chem. (1995), p. 5356]. At about −50° C., a solution of 48.3 g of sodium nitrite in 120 ml of water was subsequently added dropwise. After about 2 hours of stirring at 0° C., the mixture was diluted with 1 l of water and extracted with methyl tert-butyl ether (MtBE). The organic phases were washed with NaHCO3 solution and water and then dried. Distillative removal of the solvent under reduced pressure and silica gel chromatography (cyclohexane/MtBE=1:10) gave 3.6 g of the product in the form of dark crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:20])[C@H:15]([CH:17]([CH3:19])[CH3:18])[NH2:16])[CH3:12].CCN(CC)CC.CN1CCCC1=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:16][CH:15]([CH:17]([CH3:19])[CH3:18])[C:14]([O:13][CH2:11][CH3:12])=[O:20])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CCOC(=O)[C@@H](N)C(C)C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Nc1ccc([N+](=O)[O-])cc1)C(C)C
Temperature: 70 °C
Yield: 32.7 %

Procedure:
162 mg of 4-fluoronitrobenzene, 200 mg of L-valine ethyl ester and 0.4 ml of Et3N were added to a solution of 10 ml of N-methylpyrrolidinone (NMP). The reaction medium was heated at 70° C. for 8 hours and, after cooling to room temperature, then poured into a water and ice mixture. The yellow precipitate formed was filtered off, re-slurried in water and then dried over P2O5. 100 mg of ethyl 2-(4-nitrophenylamino)-3-methylbutyrate (8) were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[N:4]([N:12]([CH2:19][CH2:20][CH3:21])[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:28]([N:32]=[C:33]=[O:34])[CH2:29][CH2:30][CH3:31]>O1CCCC1>[CH2:28]([NH:32][C:33](=[O:34])[O:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([N:12]([CH2:19][CH2:20][CH3:21])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH:3]=[C:2]2[CH3:1])[CH2:29][CH2:30][CH3:31]
Reactant: CCCN(c1ccncc1)n1cc(C)c2cc(O)ccc21
Reactant: CCCCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCNC(=O)Oc1ccc2c(c1)c(C)cn2N(CCC)c1ccncc1
Reaction time: 2 h

Procedure:
To a stirred solution consisting of 3-methyl-1-(propyl-4-pyridinylamino)-1H-indol-5-ol (2.11 g) and tetrahydrofuran (50 ml) was added milled K2CO3 (1.09 g), followed by dropwise addition of butyl isocyanate (0.93 ml) at room temperature under nitrogen. Stirring was continued for 2.0 hours at which time the reaction mixture was filtered through a pad of celite and the solids washed with EtOAc. Concentration afforded the crude product. Purification via flash column chromatography (silica gel, 2% Et3N/EtOAc) afforded 2.65 g of the desired carbamate as an oil. This oil was dissolved in a small amount of EtOAc and diluted with ether, whereupon the product crystallized as a white powder, m.p. 120°-122° C.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C@@H:5]1([N:14]2[C:18]3[CH:19]=[C:20]([Cl:24])[C:21]([Cl:23])=[CH:22][C:17]=3[N:16]=[C:15]2Cl)[O:11][C@@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]1[OH:7]>>[CH:1]1([NH:4][C:15]2[N:14]([C@@H:5]3[O:11][C@@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]3[OH:7])[C:18]3[CH:19]=[C:20]([Cl:24])[C:21]([Cl:23])=[CH:22][C:17]=3[N:16]=2)[CH2:3][CH2:2]1
Reactant: OC[C@@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Reactant: NC1CC1
Product: OC[C@@H]1O[C@@H](n2c(NC3CC3)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O

Procedure:
The procedure is the same as that described for compound 7a, except that cyclopropylamine was used instead of isopropylamine, and compound 4a (300 mg, 0.80 mmoles) was used. Yield 299 mg (65%) as a white solid. Mp: 184-186° C. 1H NMR (DMSO-d6): δ7.47 (s, 1H), 7.36 (s, 1H), 7.05 (bs, 1H, D2O exchangeable), 5.72 (m, 1H), 5.24 (m, 1H, D2O exchangeable), 5.17 (m, 1H, D2O exchangeable), 4.65 (bs, 2H, D2O exchangeable), 4.53 (m, 1H), 4.42 (m, 1H), 4.15 (m, 1H), 3.66 and 3.57 (m, 2H), 0.86 (m, 2H), 0.57 (m, 1H), 0.50 (m, 1H). Anal. (C15H17O4N3Cl2) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])[N:5]2[CH:31]=1.[Cl:32][C:33]([Cl:38])([Cl:37])[C:34](Cl)=[O:35].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][S:17]([C:20]([F:21])([F:23])[F:22])(=[O:19])=[O:18])[N:5]2[C:31]=1[C:34](=[O:35])[C:33]([Cl:38])([Cl:37])[Cl:32]
Reactant: Cc1cn2c(CN(CCCCNS(=O)(=O)C(F)(F)F)C(=O)OC(C)(C)C)cccc2n1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nc2cccc(CN(CCCCNS(=O)(=O)C(F)(F)F)C(=O)OC(C)(C)C)n2c1C(=O)C(Cl)(Cl)Cl
Temperature: 0 °C
Yield: 64.9 %

Procedure:
To a solution of 2.90 g (6.24 mmol) of 2-methyl-5-[N-tert-butoxycarbonyl-N-[4-(trifluoromethanesulfonamido)butan-1-yl]aminomethyl]imidazo[1,2-a]pyridine and 2.29 g (18.73 mmol) of 4-dimethylaminopyridine in 25 ml of chloroform was added dropwise, for 3 minutes, 2.1 ml (18.73 mmol) of trichloroacetyl chloride. The reaction mixture was heated for 20 hours under reflux. The reaction mixture was then poured into ice-water, which was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with 100 ml of chloroform. The organic layer was washed with 200 ml of a saturated aqueous saline solution and dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=100:1) to give 2.47 g of the desired compound (65.2%, pale yellow liquid).
Reaction SMILES: [CH2:1]([S:3][C:4]([S:6][CH2:7][CH2:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])=[S:5])[CH3:2].[N+](=[CH2:21])=[N-]>C(OCC)(=O)C.C(O)(=O)C>[CH3:21][O:14][C:13](=[O:15])[C@@H:12]1[CH2:16][CH2:17][CH2:18][N:11]1[C:9](=[O:10])[CH2:8][CH2:7][S:6][C:4]([S:3][CH2:1][CH3:2])=[S:5]
Reactant: CCSC(=S)SCCC(=O)N1CCC[C@H]1C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCSC(=S)SCCC(=O)N1CCC[C@H]1C(=O)OC

Procedure:
A solution of 1-[3-[[(ethylthio)thiocarbonyl]thio]propanoyl]-L-proline in ethyl acetate is treated with an ethereal solution of diazomethane until persistent yellow color. After discharging the yellow color with a few drops of acetic acid, the solvents are removed in vacuo to yield 1-[3-[[(ethylthio)thiocarbonyl]thio]propanoyl]-L-proline methyl ester.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:23])[C@@H:9]([NH2:22])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[F:24][C:25]([F:39])([F:38])[CH2:26][CH2:27][O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1>>[C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:23])[C@@H:9]([NH:22][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][C:29]([O:28][CH2:27][CH2:26][C:25]([F:39])([F:38])[F:24])=[CH:30][CH:31]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCNC(=O)[C@@H](N)Cc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1ccc(OCCC(F)(F)F)cc1
Product: CC(=O)OCCNC(=O)[C@H](Cc1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(OCCC(F)(F)F)cc1

Procedure:
A reaction similar to that described in Example 50 was conducted using 2-({(2S)-2-amino-3-[4-(trifluoromethoxy)phenyl]propanoyl}amino)ethyl acetate and 4-(3,3,3-trifluoropropoxy)benzoic acid obtained in the preparation process of Example 33 (33a) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([CH3:17])[C:8]([C:12](=O)[CH2:13][C:14]#[N:15])=[N:9]2)=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>C(O)C.C(O)(=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([CH3:17])[C:8]([C:12]3[CH:13]=[C:14]([NH2:15])[NH:20][N:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nc2ccc(F)cc2nc1C(=O)CC#N
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Cc1nc2ccc(F)cc2nc1-c1cc(N)[nH]n1

Procedure:
To a suspension of 3-(7-fluoro-3-methylquinoxalin-2-yl)-3-oxopropanenitrile (48.6 g, 212 mmol) in ethanol (530 mL) and acetic acid (53 mL) was added hydrazine hydrate (79%, 19.6 mL, 318 mmol). The reaction mixture was reflux for 5 h, and then concentrated in vacuo. The residue was triturated with water and diisopropyl ether subsequently to give 3-(7-fluoro-3-methylquinoxalin-2-yl)-1H-pyrazol-5-amine. MS (APCI): m/z 244 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5]2.[CH:17]1([CH2:20][O:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=2)[CH2:19][CH2:18]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.O.C(OCC)(=O)C>[CH:17]1([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([CH3:11])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5]4)=[O:27])=[CH:29][CH:30]=2)[CH2:18][CH2:19]1
Reactant: O=C(O)c1ccc(OCC2CC2)cc1
Reactant: CCOC(=O)c1cc2cc(N)ccc2n1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(NC(=O)c3ccc(OCC4CC4)cc3)ccc2n1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 63.7 %

Procedure:
To a solution of ethyl 5-amino-1-methyl-1H-indole-2-carboxylate (2.293 g) and 4-(cyclopropylmethoxy)benzoic acid (1.897 g) in DMF (23 mL) were added 1-hydroxybenzotriazole monohydrate (1.965 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.460 g) and N,N-dimethylaminopyridine (1.326 g), and the mixture was stirred at room temperature for 17 hr. After dilution with ethyl acetate, water was added, and the organic layer was washed successively with 1N hydrochloric acid, 1N aqueous, sodium hydroxide solution and saturated brine, and concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the precipitate was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the title compound (2.466 g, yield 64%) as a beige solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CS(O)(=O)=O.[C:16]([C:20]1([CH2:28]O)[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22][CH2:21]1)([CH3:19])([CH3:18])[CH3:17].O>CN(C)C=O>[CH2:3]([S:10][CH2:28][C:20]1([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:21][O:22][C:23]([CH3:27])([CH3:26])[O:24][CH2:25]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: SCc1ccccc1
Reactant: CC1(C)OCC(CO)(C(C)(C)C)CO1
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCC(CSCc2ccccc2)(C(C)(C)C)CO1

Procedure:
Sodium hydride (1.25 g., 50% dispersion in oil) was added to a stirred solution of benzyl mercaptan (3.2 ml.) in dry dimethylformamide (75 ml) at 0°, under a current of nitrogen. Stirring was maintained for 30 minutes. 5-t-Butyl-2,2-dimethyl-5-hydroxymethyl-1,3-dioxane methanesulphonate (7.5 g.) was added and the mixture was maintained at 130°, with stirring for 7 hours. The reaction mixture was cooled and poured into water. The aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water, dried over anhydrous magnesium sulphate and then evaporated in vacuo. 5-Benzylthiomethyl-5-t-butyl-2,2-dimethyl-1,3-dioxane (7.0 g.) was obtained as a mobile oil and was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:15]2[C:10]3=[C:11]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[N:9]3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=3)[CH:12]=[C:13](B(O)O)[CH:14]=2.Br[C:27]1[C:28](Br)=[C:29]([CH:35]=[CH:36][C:37]=1[C:38]([O:40][CH2:41]C)=[O:39])[C:30]([O:32][CH2:33]C)=[O:31].C(=O)([O-])[O-].[K+].[K+].N#N>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[CH3:1][C:2]1([CH3:25])[C:15]2[C:10]3=[C:11]([C:19]4[CH:20]=[CH:21][C:22]([C:35]5[CH:36]=[C:37]([C:38]([O:40][CH3:41])=[O:39])[C:27]([C:21]6[CH:22]=[CH:23][C:24]7[N:9]8[C:8]9[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=9[C:2]([CH3:25])([CH3:1])[C:15]9[C:10]8=[C:11]([CH:12]=[CH:13][CH:14]=9)[C:19]=7[CH:20]=6)=[CH:28][C:29]=5[C:30]([O:32][CH3:33])=[O:31])=[CH:23][C:24]=4[N:9]3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=3)[CH:12]=[CH:13][CH:14]=2
Reactant: CC1(C)c2ccccc2-n2c3ccccc3c3cc(B(O)O)cc1c32
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c(Br)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(-c2ccc3c4cccc5c4n(c3c2)-c2ccccc2C5(C)C)c(C(=O)OC)cc1-c1ccc2c(c1)c1cccc3c1n2-c1ccccc1C3(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
268 g (820 mol) of 8,8-dimethyl-8H-indolo[3,2,1-de]acridine-6-boronic acid, 180.4 g (474 mmol) of diethyl dibromoterephthalate and 315.9 g (2.29 mol) of potassium carbonate are initially introduced in a mixture of 850 ml of toluene and 850 ml of water and saturated with N2 for 30 min. After addition of 1.36 g (1.18 mmol) of Pd(PPh3)4, the mixture is heated at the boil for 4 h. After cooling to RT and addition of 400 ml of EtOH, the mixture is cooled to room temperature and stirred for 1 h, and the precipitate is filtered off with suction, washed with water, EtOH and heptane and dried at 80° C. in vacuo. The yield is 295 g (390 mmol), corresponding to 71% of theory.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[N:17][C:18](Br)=[CH:19][CH:20]=3)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:24]([C:26]1[CH:41]=[CH:40][C:29]([CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([C:37]([NH2:39])=[O:38])[CH2:33][CH2:32]2)=[CH:28][CH:27]=1)#[N:25].CNCCNC.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.C1(C)C=CC=CC=1>[C:24]([C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:31]2[CH2:32][CH2:33][CH:34]([C:37]([NH:39][C:18]3[N:17]=[CH:16][C:15]([C:13]([N:10]4[CH2:11][CH2:12][N:7]([CH2:6][C:5]5[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=5)[CH2:8][CH2:9]4)=[O:14])=[CH:20][CH:19]=3)=[O:38])[CH2:35][CH2:36]2)=[CH:40][CH:41]=1)#[N:25]
Reactant: O=C(c1ccc(Br)nc1)N1CCN(Cc2ccc(F)cc2)CC1
Reactant: N#Cc1ccc(CN2CCC(C(N)=O)CC2)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(CN2CCC(C(=O)Nc3ccc(C(=O)N4CCN(Cc5ccc(F)cc5)CC4)cn3)CC2)cc1
Temperature: 100 °C
Yield: 117.7 %

Procedure:
To a mixture of (4-(4-fluorobenzyl)piperazin-1-yl)(6-bromopyridin-3-yl)methanone (0.040 g, 0.11 mmol, 1.0 eq), 1-(4-cyanobenzyl)piperidine-4-carboxamide (0.028 g, 0.12, 1.1 eq), and N,N′-dimethylethylenediamine (0.012 mL, 0.11 mmol, 1.0 eq) was added anhydrous toluene (1.0 mL). This mixture was purged with argon for 5 minutes and copper(I)iodide (0.011 g, 0.058 mmol, 0.5 eq) and potassium carbonate (0.044 g, 0.23 mmol, 2.1 eq) were added. The reaction mixture was heated at 100° C. for 4.5 hours and then absorbed on silica gel. Purification by column chromatography (silica, 0→5% MeOH—CH2Cl2) yielded a green solid (0.070 g). Further purification using preparative TLC (silica, 4% MeOH—CH2Cl2) provided Compound 46 as a white solid (0.040 g, 67%). 1H nmr (D6-DMSO) δ 10.64 (1H, s), 8.32 (1H, s), 8.10 (1H, d, J 8.5 Hz), 7.81-7.74 (3H, m), 7.53-7.46 (2H, m), 7.31 (2H, t, J 8.0 Hz), 7.12 (2H, t, J 9.0 Hz), 3.64-3.36 (9H, m), 2.79 (2H, m), 2.35 (m, 4H), 1.99-1.87 (2H, m), 1.79-1.54 (4H, m); m/z: 542 [M+H]+. More information about this type of coupling is provided in Wrona, Iwona E.; Gozman, Alexander; Taldone, Tony; Chiosis, Gabriela; Panek, James S. Journal of Organic Chemistry (2010), 75(9), 2820-2835.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[CH3:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=O>>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][CH:17]1[C:12]2([CH3:11])[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: NNc1ccc(Br)cc1
Reactant: CC1CCCCC1=O
Agent: Cl
Product: CC12CCCCC1Nc1ccc(Br)cc12
Yield: 63 %

Procedure:
This compound was prepared by the procedure of Example 1 using 4-bromo-phenyl hydrazine hydrochloride (2.0 g, 8.95 mmol) and 2-methylcyclohexanone (1.0 g, 8.95 mmol). The subtitled compound (1.5 g, 65%) was obtained as a yellow oil: 1H NMR (CDCl3) δ1.26 (s, 3H), 1.38-1.46 (m, 4H), 1.56-1.68 (m, 4H), 3.4 (t, J=4.4 Hz, 1H), 3.6 (br s, 1H), 6.53 (d, J=8 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 7.09 (dd, J=8.0, 2.0 Hz, 1H); 13C-NMR (CDCl3) δ21.45, 21.87 (t), 23.96 (q), 27.92, 35.32 (t), 43.56 (s), 66.65 (d), 110.73 (s), 111.88, 125.25, 129.99 (d), 142.17, 149.03 (s); MS (EI) m/z 268, 270 (M+H)+.
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:56])[C@@H:6]([NH:23][C:24]([C@@H:26]1[CH2:35][C:34]2[CH:33]=[C:32]3[O:36][CH2:37][C@H:38]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]5[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([Cl:55])[CH:49]=5)=[CH:42][CH:41]=4)[O:39][C:31]3=[CH:30][C:29]=2[CH2:28][NH:27]1)=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])=[CH:10][CH:9]=1.[CH3:57][N:58]([CH3:63])[S:59](Cl)(=[O:61])=[O:60]>>[Cl:55][C:50]1[CH:49]=[C:48]([CH:53]=[CH:52][C:51]=1[Cl:54])[CH2:47][O:46][C:43]1[CH:44]=[CH:45][C:40]([C@H:38]2[CH2:37][O:36][C:32]3=[CH:33][C:34]4[CH2:35][C@@H:26]([C:24]([NH:23][C@@H:6]([CH2:7][C:8]5[CH:9]=[CH:10][C:11]([O:14][C:15]6[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[C:16]=6[CH3:22])=[CH:12][CH:13]=5)[C:5]([OH:4])=[O:56])=[O:25])[N:27]([S:59](=[O:61])(=[O:60])[N:58]([CH3:63])[CH3:57])[CH2:28][C:29]=4[CH:30]=[C:31]3[O:39]2)=[CH:41][CH:42]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: Cl
Product: Cc1nccc(Oc2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3S(=O)(=O)N(C)C)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester bis hydrochloride was coupled with N,N-dimethylsulfamoyl chloride according to General Procedure E. The resulting compound was hydrolyzed according to General Procedure B to give the title compound (9 mg). LCMS (m/z) 862.
Reaction SMILES: [CH2:1]([C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:23]=[C:24]([CH:29]=[C:30]([N:32]([S:36]([CH3:39])(=[O:38])=[O:37])[CH2:33][CH2:34][CH3:35])[CH:31]=1)[C:25]([O:27][CH3:28])=[O:26].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>ClCCl.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[C:15]([O:14][C:13]([NH:12][C:8]([CH3:11])([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][O:10][CH2:21][C:22]1[CH:23]=[C:24]([CH:29]=[C:30]([N:32]([S:36]([CH3:39])(=[O:37])=[O:38])[CH2:33][CH2:34][CH3:35])[CH:31]=1)[C:25]([O:27][CH3:28])=[O:26])=[O:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(CO)(Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CCCN(c1cc(CBr)cc(C(=O)OC)c1)S(C)(=O)=O
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C(=O)OC)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl (1-benzyl-2-hydroxy-1-methylethyl)carbamate (728 mg, 2.75 mmol) and methyl 3-(bromomethyl)-5-[(methylsulfonyl)(propyl)amino]benzoate (500 mg, 1.37 mmol) in dichloromethane (30 mL) were added silver triflate (423 mg, 1.65 mmol) and 2,6-ditertbutylpyridine polymer bound (1.53 g, 2.75 mmol, loading=1.8 mmol N/g resin, Aldrich 37, 782-1). The reaction mixture was stirred at rt in a sealed flask for 16 h. The reaction mixture was filtered on celite, rinsed with dichloromethane and MeOH, concentrated in vacuo and purified by flash chromatography (silica, 0-45% EtOAc/hexanes) to provide methyl 3-({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-5-[(methylsulfonyl)(propyl)amino]benzoate as a white foam (intermediate xx). 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.92 (s, 1H), 7.57 (s, 1H), 7.30-7.20 (m, 3H), 7.18-7.7.14 (m, 2H) 4.60 (s, 2H), 4.56 (s, 1H), 3.95 (s, 3H), 3.68 (t, J=6.7 Hz, 2H), 3.57 (A of AB, d, J=8.9 Hz, 1H), 3.47 (B of AB, d, J=8.9 Hz, 1H), 3.15 (A of AB, d, J=13.2 Hz, 1H), 2.94 (B of AB, d, J=13.2 Hz, 1H), 2.90 (s, 3H), 1.55-1.45 (m, 2H), 1.47 (s, 9H), 1.27 (s, 3H), 0.92 (t, J=7.3 Hz, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:10]([O:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)[CH2:28][CH2:27]1)[C:9]2=[O:43])=[O:5])C.C(=O)([O-])O.[Na+].C(O)(=O)C>C(O)C>[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[C:10]([O:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:27][CH2:28][N:29]([CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)[CH2:30][CH2:31]1)[C:9]2=[O:43])([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc2oc(-c3ccccc3)c(OCCCN3CCN(Cc4ccc5ccccc5n4)CC3)c(=O)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)c1ccc2oc(-c3ccccc3)c(OCCCN3CCN(Cc4ccc5ccccc5n4)CC3)c(=O)c2c1
Yield: 74 %

Procedure:
6-Ethoxycarbonyl-3-[3-{4-(2-quinolinylmethyl)piperazin-1-yl}propoxy]flavone (0.8 mmol) was dissolved in 20 ml of ethanol, followed by the addition of 2 ml of a saturated aqueous solution of sodium hydrogencarbonate. The reaction mixture was refluxed for 2 hours and was then allowed to cool down. The solvent was driven off under reduced pressure. Acetic acid was added to the residue to neutralize the same, followed by extraction with chloroform. After the organic layer was concentrated under reduced pressure, the residue was recrystallized from EtOH-ether, whereby the title compound represented by the following formula was obtained (yield: 74%). ##STR67##
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[C:10]=1[CH3:17].[C:18](Cl)(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(#N)C.C(Cl)Cl>[C:18]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[C:10]=1[CH3:17])(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Cc1c(O)c(=O)ccn1C
Reactant: CCCCCCCC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC(=O)Oc1c(C)n(C)ccc1=O
Reaction time: 0.05 h

Procedure:
With stirring, 0.56 ml of triethylamine is added at room temperature to a suspension of 0.556 g of 3-hydroxy-1,2-dimethyl-4(1H)-pyridinone in 40 ml of acetonitrile and 40 ml of methylene chloride, followed by the addition of 1.02 ml of caprylyl chloride. A solution forms within 3 minutes and after 30 minutes the reaction is complete, and the volatile constituents are removed by evaporation under reduced pressure. The residue is dried under a high vacuum and crystallised from a mixture of methylene chloride and ethyl acetate. The 3-(n-octanoyloxy)-1,2-dimethyl-4-(1H)-pyridinone so obtained begins to sinter at 140° C. and decomposes at 180° C.