Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:30][C:21]3=[N:22][CH:23]=[C:24]([CH:26]([OH:29])CO)[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:30][C:21]3=[N:22][CH:23]=[C:24]([CH:26]=[O:29])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(C(O)CO)cnc3[nH]2)cc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(C=O)cnc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a stirred solution of a diastereomeric mixture of 1-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-ethane-1,2-diol (366 mg, 0.86 mmol) in 50% aqueous tetrahydrofuran (10 mL) was added sodium metaperiodate (366 mg, 1.71 mmol) at 0° C. The resulting mixture was stirred at room temperature for 2 h and extracted with ethyl acetate and washed with brine, dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to give 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carbaldehyde (340 mg, quant.) as a light yellow solid: LC/MS m/e calcd for C22H24N2OS [M+H]+ 397.51, observed 397.0.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[N:5]([CH3:16])[C:4](=[O:17])[C:3]=1[C:18](O)=[O:19].Cl.[CH2:22]([O:29][C:30](=[O:33])[CH2:31][NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.CCOC(C)=O>CN(C=O)C.O.C(Cl)Cl>[CH2:22]([O:29][C:30](=[O:33])[CH2:31][NH:32][C:18]([C:3]1[C:4](=[O:17])[N:5]([CH3:16])[C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=2)=[O:19])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc2c(O)c(C(=O)O)c(=O)n(C)c2c1
Reactant: NCC(=O)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(O)c(C(=O)NCC(=O)OCc3ccccc3)c(=O)n(C)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.5 %

Procedure:
4-hydroxy-7-(methoxycarbonyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (107 mg, 386 μmol), glycine benzyl ester hydrochloride (117 mg, 579 μmol), pybop (603 mg, 1158 μmol), and diisopropylethylamine (403 μl, 2316 μmol) were dissolved in DMF and stirred at room temperature for 24 hours. The reaction mixture was diluted with H2O and DCM, the layers were separated and the aqueous layer was extracted with DCM (3×), the organics were washed with H2O (2×) and dried over MgSO4, filtered and concentrated to yield a yellow solid. Flash column chromatography was performed using 2:1 Hex/EtOAc to give 45 mg of desired product.
Reaction SMILES: [C:1]([C:3]([CH3:16])([CH3:15])[CH:4]([NH:8]S(C(C)(C)C)=O)[CH:5]1[CH2:7][CH2:6]1)#[N:2].[ClH:17].O1CCOCC1>CO>[ClH:17].[NH2:8][CH:4]([CH:5]1[CH2:7][CH2:6]1)[C:3]([CH3:16])([CH3:15])[C:1]#[N:2]
Reactant: CC(C)(C#N)C(NS(=O)C(C)(C)C)C1CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C#N)C(N)C1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
To a solution of 2-methylpropane-2-sulfinic acid (2-cyano-1-cyclopropyl-2,2-dimethyl-ethyl)-amide (0.70 g, 2.90 mmol) in MeOH (5 mL) at room temperature was added 4.0 M HCl in dioxane (1.5 mL, 6.0 mmol). The reaction mixture was stirred at room temperature for 15 min then concentrated to afford 0.45 g (89%, 2 steps) of 3-amino-3-cyclopropyl-2,2-dimethyl-propionitrile hydrochloride as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)=[N:4][N:3]=1.[CH3:16][C@:17]1([NH:23][C:24]2[CH:29]=[N:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)[CH2:21][CH2:20][CH2:19][C@@H:18]1[NH2:22].N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([NH:22][C@H:18]2[CH2:19][CH2:20][CH2:21][C@:17]2([CH3:16])[NH:23][C:24]2[CH:29]=[N:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)=[O:11])=[N:4][N:3]=1
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Reactant: Cc1nnc(-c2ccccc2C(=O)O)o1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nnc(-c2ccccc2C(=O)N[C@H]2CCC[C@]2(C)Nc2cnc(C(F)(F)F)cn2)o1

Procedure:
A solution of 2-(5-methyl-1,3,4-oxadiazol-2-yl)benzoic acid (CAS number 898289-64-0; 82 mg, 0.40 mmol), (1S,2S)-1-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 25; 80 mg, 0.31 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (54 mg, 0.40 mmol), EDC (77 mg, 0.40 mmol) and triethylamine (0.13 ml, 0.92 mmol) in DCM (3 ml) was stirred at room temperature for 72 hours. The reaction was diluted with DCM and washed with a saturated solution of sodium bicarbonate, passing through a hydrophobic frit and concentrated in vacuo. The crude product was purified by reverse phase chromatography (C18 silica, 5-100% acetonitrile/water with 0.05% ammonia) to afford the title compound.
Reaction SMILES: [Na].C(O[C:5]([NH:7][N:8]([CH2:11][CH3:12])[C:9]#[N:10])=[O:6])C.[CH2:13]([OH:15])[CH3:14]>>[CH2:11]([N:8]1[C:9]([O:15][CH2:13][CH3:14])=[N:10][C:5]([OH:6])=[N:7]1)[CH3:12]
Reactant: CCOC(=O)NN(C#N)CC
Reactant: CCO
Agent: [Na]
Product: CCOc1nc(O)nn1CC
Yield: 60 %

Procedure:
To a solution of 4.6 g of sodium in 150 ml of absolute ethanol there is added dropwise at 60° C 31.4 g of 2-ethyl-2-cyanohydrazinecarboxylic acid ethyl ester. The solution is subsequently refluxed for 4 hours. From the cooled solution there precipitates, after the addition of 12 g of glacial acetic acid, sodium acetate, which is separated by filtration. The filtrate is concentrated in vacuo to dryness, and the residue is extracted with 200 ml of chloroform. The extract is again concentrated to dryness and the residue is recrystallised from cyclohexane. There is obtained 18.8 g (60% of theory) of 1-ethyl-5-ethoxy-3-hydroxy-1,2,4-triazole, m.p. 64° to 67° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.[OH-].[Na+].CN(C)[CH:23]=[O:24]>O>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:23]=[O:24])[C:10]([CH3:13])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccn(Cc2ccccc2)n1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nn(Cc2ccccc2)cc1C=O
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 1-benzyl-3-methyl-1H-pyrazole (compound 314.1, 1.00 g, 5.81 mmol) in N,N-dimethylformamide (3 mL) was added POCl3 (493 μL, 5.28 mmol) dropwise. The reaction mixture was stirred for 3 h at 90° C. under nitrogen. The reaction mixture was diluted with 50 mL of H2O. The pH of the solution was adjusted to 7 with sodium hydroxide (2 M). The aqueous phase was extracted with 3×20 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 1.42 g (crude) of the title compound as a brown oil.
Reaction SMILES: Br[C:2]1[C:3]2[CH:14]=[C:13]([C:15]([O:17]CC)=[O:16])[S:12][C:4]=2[N:5]([CH:7]([O:9][CH2:10][CH3:11])[CH3:8])[N:6]=1.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>[Cu]I.O1CCOCC1>[CH2:10]([O:9][CH:7]([N:5]1[C:4]2[S:12][C:13]([C:15]([OH:17])=[O:16])=[CH:14][C:3]=2[C:2]([NH:28][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:30][CH:29]=2)=[N:6]1)[CH3:8])[CH3:11]
Reactant: CCOC(=O)c1cc2c(Br)nn(C(C)OCC)c2s1
Reactant: COc1ccc(C(N)=O)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(C)n1nc(NC(=O)c2ccc(OC)cc2)c2cc(C(=O)O)sc21
Temperature: 110 °C

Procedure:
Ethyl 3-bromo-1-(1-ethoxyethyl)-1H-thieno[2,3-c]pyrazole-5-carboxylate (10 g, 28 mmol), 4-methoxybenzamide (7.39 g, 48 mmol, 1.7 eq.), copper(I)iodide (0.548 g, 2.88 mmol, 0.1 eq.), preground tripotassium phosphate (18.34 g, 86 mmol, 3 eq.) and 180 mL of anhydrous dioxane degassed beforehand with argon are introduced into a 500 mL round-bottomed flask under argon. 0.306 mL (2.88 mmol, 0.1 eq.) of N,N′-dimethylethylenediamine is added to this suspension by syringe. The reaction mixture is then heated to a temperature in the region of 110° C. for a period of 24 hours. The dioxane is then evaporated off under vacuum and the residue is diluted with ethyl acetate (300 mL) and 150 mL of water. The organic phase is washed once with 100 mL of water and is then dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue is purified by chromatography on silica gel, eluting with an ethyl acetate/heptane mixture (1:1). The pale yellow oil obtained after purification corresponds to ethyl 1-(1-ethoxyethyl)-3-(4-methoxybenzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylate (7.41 g, 64%). The combined aqueous phases are acidified with 5 N hydrochloric acid to pH 5-6. A thick precipitate appears, which is extracted with (2×100 mL) of ethyl acetate. The organic phase is in turn dried over magnesium sulfate and concentrated to dryness under reduced pressure. The white solid obtained after evaporation is triturated in a heptane/dimethyl ether mixture (1:1). After filtration, 1-(1-ethoxyethyl)-3-(4-methoxybenzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid is obtained in the form of a white solid (1.27 g, 11%). The ethyl 1-(1-ethoxyethyl)-3-(4-methoxybenzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylate is subjected to saponification using 50 mL of tetrahydrofuran and 20 mL of 5 N sodium hydroxide at a temperature in the region of 50° C. for 5 hours. The tetrahydrofuran is then evaporated off, the aqueous phase is diluted with 150 mL of water and the pH is adjusted to 3-4 with 5 N hydrochloric acid. The white precipitate obtained is filtered off and washed with water, and then dried under vacuum at a temperature in the region of 60° C. 7.04 g of 1-(1-ethoxyethyl)-3-(4-methoxybenzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid are thus obtained, i.e. 98%, which product is used directly in the following step.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:24]([CH3:25])=[CH:23][S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[C:24]([CH3:25])=[CH:23][S:22][C:12]=3[N:13]=2)[CH:17]=1
Reactant: Cc1csc2nc(-c3cccnc3)nc(Cl)c12
Reactant: NCc1ccccc1
Product: Cc1csc2nc(-c3cccnc3)nc(NCc3ccccc3)c12

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-3-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-benzylamino-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[N:3]([CH2:12][C:13]#[C:14][CH3:15])[C:4]2[C:9](=[O:10])[NH:8][N:7]=[CH:6][C:5]=2[N:11]=1.C(=O)([O-])[O-].[K+].[K+].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].O>CN(C)C=O>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:2]2[N:3]([CH2:12][C:13]#[C:14][CH3:15])[C:4]3[C:9](=[O:10])[NH:8][N:7]=[CH:6][C:5]=3[N:11]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC#CCn1c(Br)nc2cn[nH]c(=O)c21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cn[nH]c(=O)c21
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of 2.11 g of 2-bromo-3-(2-butyn-1-yl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one, 1.64 g potassium carbonate and 1.91 g 1-tert.-butyloxycarbonyl-piperazine in 20 ml N,N-dimethylformamide is stirred for six hours at 80° C. After cooling to ambient temperature the reaction mixture is combined with water and the precipitate formed is suction filtered. The crude product is purified by chromatography over a silica gel column with methylene chloride/methanol (95:5 to 90:10).
Reaction SMILES: [CH:1]([C:3]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:6]=2[O:5][CH:4]=1)=[O:2].B.[Na]>>[OH:2][CH2:1][C:3]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]([NH:14][S:15]([CH3:18])(=[O:16])=[O:17])=[CH:13][C:6]=2[O:5][CH:4]=1
Reactant: CS(=O)(=O)Nc1cc2occ(C=O)c(=O)c2cc1Oc1ccccc1
Agent: B
Agent: [Na]
Product: CS(=O)(=O)Nc1cc2occ(CO)c(=O)c2cc1Oc1ccccc1

Procedure:
3-Formyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was reduced by sodium boron hydride to obtain 3-hydroxymethyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH3:21])(=O)C>FC(F)(F)C(O)=O>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH3:21])[N:7]([CH2:6][CH2:5][OH:4])[C:19]=2[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[N:12]=1
Reactant: CC(=O)OCCn1c(C)nc2c(N)nc3ccccc3c21
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c(N)nc3c(c2n1CCO)CCCC3
Reaction time: 312 h
Yield: 31.5 %

Procedure:
A Parr flask was charged with 2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl acetate (3.61 g, 12.64 mmol), trifluoroacetic acid (50 mL) and purged with nitrogen. To this solution was added platinum(IV) oxide (0.5 g). The reaction was judged to be complete after 13 days of hydrogenation at ambient temperature. The solution was filtered and the volatiles removed under reduced pressure. The resulting brown oil was partitioned between dichloromethane and saturated aqueous sodium bicarbonate to a pH of ˜8. The layers were separated. The aqueous layer was extracted with dichloromethane (4×). The organic fractions were combined, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting white solid was purified by recrystallization from ethyl acetate/methanol (9/1) and dried to provide 0.98 g of 2-(4-amino-2-methyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)ethanol as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([I:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][NH:19][CH3:20].O>CS(C)=O>[I:11][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=1)[N:19]([CH3:20])[CH3:18]
Reactant: O=[N+]([O-])c1cc(F)cc(I)c1
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)c1cc(I)cc([N+](=O)[O-])c1
Temperature: 125 °C
Reaction time: 0.25 h
Yield: 58.6 %

Procedure:
1-Fluoro-3-iodo-5-nitrobenzene (500 mg, 1.87 mmol), and potassium carbonate (260 mg, 1.88 mmol) were suspended in DMSO (7 ml) and dimethylamine (2M in THF, 3 ml, 6 mmol) was added. The vial was sealed under argon and stirred for 15 min at 125° C. under microwave conditions. The reaction mixture was poured into 50 ml of water and extracted with ethyl acetate (3×40 ml). The organic phase was washed with brine (1×100 ml), dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified using SP1® Purification System (0% to 30%, hexane-ethyl acetate) to obtain 320 mg (59% yield) of the title compound as a brown solid. Purity 100%.
Reaction SMILES: [C:1]([N@@:4]1[CH2:6][CH:5]1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[CH2:11]([OH:14])[C:12]#[CH:13].B(F)(F)F.CCOCC>C(Cl)Cl>[C:1]([NH:4][C@H:5]([CH2:6][O:14][CH2:11][C:12]#[CH:13])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: C#CCO
Reactant: COC(=O)C1CN1C(C)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: C#CCOC[C@@H](NC(C)=O)C(=O)OC
Temperature: -20 °C
Reaction time: 2.5 h
Yield: 68.4 %

Procedure:
(R)-Methyl 1-acetylaziridine-2-carboxylate (1.50 g, 10.49 mmol) was dissolved in CH2Cl2 (40 mL) and cooled to −20° C. under Ar, and then propargyl alcohol (0.92 mL, 15.74 mmol) was added. After the solution was stirred (2 min), BF3.Et2O (1.39 mL, 11.01 mmol) was added dropwise. The reaction mixture was allowed to stir at room temperature (2-3 h) and then washed with saturated aqueous NaHCO3 (30 mL) and saturated aqueous brine (30 mL). The organic layer was dried (Na2SO4) and evaporated in vacuo, and then the crude product was purified by column chromatography (SiO2; 3/1 EtOAc/hexanes) and crystallized (cold hexanes) to yield 1.43 g (68%) of desired product as a white solid: mp 58.5-59.5° C.; [α]25D −64.6° (c 1, CHCl3); Rf=0.35 (3/1 EtOAc/hexanes); IR (nujol mull) 3301, 2919, 2114, 1750, 1639, 1542, 1457 cm−1; 1H NMR (CDCl3) δ 2.06 (s, CH3C(O)), 2.46 (t, J=2.3 Hz, CH2CCH), 3.78 (s, OCH3), 3.79 (dd, J=3.3, 9.6 Hz, CHH′OCH2), 3.98 (dd, J=2.9, 9.6 Hz, CHH′OCH2), 4.09-4.21 (m, OCH2C), 4.77-4.82 (m, CH), 6.33-6.35 (br d, J=7.2 Hz, NHCH); 13C NMR (CDCl3) δ 23.3 (CH3C(O)), 52.6 (CH), 52.8 (OCH3), 58.7 (CH2CCH), 69.6 (CH2OCH2), 75.3 (CH2CCH), 79.0 (CH2CCH), 170.1, 170.8 (2 C(O)); HRMS (ESI) 200.0916 [M+H+] (calcd. for C9H14NO4 200.0923); Anal. (C9H13NO4) Calcd.: C, 54.26%; H, 6.58%; N, 7.03%. Found: C, 54.30%; H, 6.66%; N, 6.89%.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@H:17]([C:26]([OH:28])=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>>[C:26]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([OH:28])=[O:27]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(O)cc1)C(=O)O
Yield: 71 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with L-tyrosine (2 eq.) to provide the title compound in 71% yield as yellow needles (recrystallization from acetone/water).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:5]([C:17]#[N:18])=[C:4]([S:19][CH2:20][CH2:21][NH2:22])[N:3]=1.[CH2:23]([N:25]=[C:26]=[O:27])C>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:19][CH2:20][CH2:21][NH:22][C:26]([NH:25][CH3:23])=[O:27])[C:5]([C:17]#[N:18])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[C:7]=1[C:8]#[N:9]
Reactant: CCN=C=O
Reactant: N#Cc1c(N)nc(SCCN)c(C#N)c1-c1ccc(O)cc1
Solvent: CN(C)C=O
Product: CNC(=O)NCCSc1nc(N)c(C#N)c(-c2ccc(O)cc2)c1C#N
Reaction time: 8 h

Procedure:
62.2 mg (0.2 mmol) of 2-amino-6-[(2-aminoethyl)sulfanyl]-4-(4-hydroxyphenyl)-3,5-pyridinedicarbonitrile are suspended in 0.4 ml of DMF, and 14.2 mg (0.2 mmol) of ethyl isocyanate are added at room temperature. The mixture is stirred overnight, filtered and purified by preparative HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:25][CH3:26])[C:8]=1[CH:9]([NH:18]S(C(C)(C)C)=O)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].Cl.O1CCOCC1>CO>[NH2:18][CH:9]([C:8]1[C:3]([O:2][CH3:1])=[CH:4][N:5]=[CH:6][C:7]=1[O:25][CH3:26])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CCCCC(NS(=O)C(C)(C)C)c1c(OC)cncc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CCCCC(N)c1c(OC)cncc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) yellow solution of methyl 6-(3,5-dimethoxypyridin-4-yl)-6-(1,1-dimethylethylsulfinamido)hexanoate (506 mg; 1.30 mmol) in MeOH (9 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (0.65 ml; 2.60 mmol). The resulting yellow mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 1 h. The reaction mixture was then concentrated to dryness under reduced pressure and the yellow oily residue was further dried under HV to give the chlorhydrate salt of methyl 6-amino-6-(3,5-dimethoxypyridin-4-yl)hexanoate as a brown solid. LC-MS (conditions A): tR=0.36 min.; [M+H]+: 284.25 g/mol.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[CH:22]=[C:21]([C:33]([F:36])([F:35])[F:34])[N:20]=3)[CH:18]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:32][C:27]1[CH:26]=[C:25]([C:23]2[CH:22]=[C:21]([C:33]([F:35])([F:34])[F:36])[N:20]=[C:19]([N:17]3[CH:18]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[N:15]=[CH:16]3)[N:24]=2)[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)cn2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.9 %

Procedure:
To a cooled and stirred solution of 5-{1-[4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.34 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by column chromatography on silica gel (dichloromethane/MeOH/NH4OH 80:10:1) and crystallization (MeOH/diethyl ether) to yield the title compound as a light yellow solid (0.23 g, 62%). MS (ISN) 520.3 [(M−H)−]; mp 282° C. (dec.).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][C:7]([C:22]([NH2:24])=[O:23])=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1>[Pd].CO>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH:8]=[C:7]([C:22]([NH2:24])=[O:23])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)C1=Cc2ccccc2-c2cc3ccc(C(N)=O)cc3n2C1
Agent: [Pd]
Solvent: CO
Product: NC(=O)C1=Cn2c(cc3ccc(C(N)=O)cc32)-c2ccccc2C1
Reaction time: 8 h

Procedure:
10% Palladium on carbon (50 mg, 0.05 mmol) was added to a solution of 7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxamide, 13-cyclohexyl-N6-[2-(diethylamino)-2-oxoethyl]-N10-[(dimethylamino)sulfonyl]-3-methoxy-N6-methyl- (51 mg, 0.08 mmol) in MeOH (2 mL) and the reaction mixture was vacuum flushed with nitrogen (3×) and then with hydrogen (3×). The reaction mixture was stirred under a balloon of hydrogen overnight, filtered through a pad of celite and concentrated to yield 5H-indolo[2,1-a][2]benzazepine-6,10-dicarboxamide, 13-cyclohexyl-N6-[2-(diethylamino)-2-oxoethyl]-N10-[(dimethylamino)sulfonyl]-6,7-dihydro-3-methoxy-N6-methyl- (44 mg, 0.07 mmol, 86%) as an off-white solid. Partial 1HNMR (300 MHz, CDCl3) δ 11.3 (s, 1H), 8.04 (s, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 6.94-6.86 (m, 2H), 4.80-4.71 (m, 1H), 4.60-4.52 (m, 1), 3.86 (s, 3H), 3.33 (s, 3H), 3.01 (s, 6H). LCMS: m/e 664 (M−H)−, ret time 3.12 min, column A, 4 minute gradient.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9]O.Cl.[OH-].[Na+]>[Zn].O>[OH:8][C:5]1[C:6](=[O:7])[CH:1]=[C:2]([CH3:9])[O:3][CH:4]=1
Reactant: O=c1cc(CO)occ1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(=O)c(O)co1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Kojic acid, 30 g, as added to 150 ml of water and dissolved at 70° C. To the solution was added 30 g of zinc powders and, 90 ml of conc. hydrochloric acid (12 N) was dropwise added to the mixture over 2 hours. The mixture was stirred at the same temperature for 30 minutes. Insoluble matters (zinc powders) were removed and the reaction liquid was cooled to 5° C. After adjusting its pH to 2 with 50% aqueous sodium hydroxide solution, the mixture was concentrated under reduced pressure and the residue was dissolved in 100 ml of dichloromethane. The solution was washed with water (100 ml, 3 times). After drying over anhydrous magnesium sulfate, the system was separated and purified by flash column chromatography (eluting solution; chloroform: methanol=20:1) using Wako Gel C-300 (200 g) to give 2.4 g of the title compound as crystals. Physical data of this compound were identical with those of the compound obtained in Reference Example 11.