Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][N:26]=2)[CH:20]=1)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][N:26]=4)[CH:20]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncn2)c1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: Cc1ccccc1C
Product: O=C1CC(c2cccc(-c3ccncn3)c2)=Nc2cc(Cl)c(Cl)cc2N1

Procedure:
The title compound was prepared from 4,5-dichlorophenylenediamine (89 mg, 0.5 mmol) and 3-oxo-3-(3-pyrimidin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K43) (164 mg, 0.55 mmol) by refluxing in xylene according to the general procedure M. Obtained as a light yellow solid (63 mg).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:19]([OH:21])=O)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl.C(N(CC)CC)C>[CH2:22]([NH:29][C:19](=[O:21])[C@@H:9]([CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41 %

Procedure:
To a cooled (−20° C.) solution of N-Boc-O-benzyl-D-serine (1 g) in dichloro methane (12 mL), triethylamine (0.44 mL) was added and stirred for 5 minutes and subsequently isobutylchloformate (0.51 mL) was added to the reaction mixture in 5 minutes at −20° C. The solution was stirred for 5 minutes at −20° C. and benzyl amine (0.44 mL) was added to in it in 5 minutes at −20° C. The solution was stirred for 1 hr at −20° C. The solution was allowed to warm to room temperature and stirred for 1 hour. The hydrochloride salt of N-methylmorpholine was filtered. Organic layer was concentrated under vacuum to obtain solid, 0.53 g N-benzyl-O-benzyl-N2-Boc-D-serinamide after crystallization by diisopropylether.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[NH:12]1[C:16]2[CH:17]=[CH:18][C:19]([CH:21]=O)=[CH:20][C:15]=2[N:14]=[N:13]1>>[NH:12]1[C:16]2[CH:17]=[CH:18][C:19](/[CH:21]=[C:6]3/[C:7](=[O:11])[NH:8][C:9]4[C:5]/3=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=4)=[CH:20][C:15]=2[N:14]=[N:13]1
Reactant: O=Cc1ccc2[nH]nnc2c1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Product: O=C1Nc2cc(Cl)ccc2/C1=C\c1ccc2[nH]nnc2c1

Procedure:
The title compound was synthesized according to the method described for Example A1 except reacting 6-chlorooxindole (36 mg, 0.216 mmol) with 1H-benzo[d][1,2,3]triazole-5-carbaldehyde (35 mg, 0.238 mmol) to obtain 32 mg, 51%. 1H NMR (400 MHz, d6-DMSO) δ 15.95 (s, 1H), 10.81 (s, 1H), 8.27 (bs, 1H), 8.04 (bs, 1H), 7.85 (s, 1H), 7.76 (bs, 1H), 7.49 (d, J=8.8 Hz, 1H), 6.91 (bs, 2H); MS ESI 297.0 [M+H]+, calcd for [C15H9ClN4O+H]+ 297.05.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[NH:14]1[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15]1>C1(C)C=CC=CC=1>[OH:19][CH:16]1[CH2:17][CH2:18][N:14]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:15]1
Reactant: OC1CCNC1
Reactant: N#Cc1ccc(F)c2ccccc12
Solvent: Cc1ccccc1
Product: N#Cc1ccc(N2CCC(O)C2)c2ccccc12

Procedure:
1-Cyano-4-fluoronaphthalene (86 mg, 0.5 mmol) was transferred to a Pyrex tube and 3-pyrrolidinol (162 μL, 2.0 mmol) was added followed by toluene (0.5 mL). The tube was capped and the reaction tube was exposed to microwave irradiation (180° C., 5 min). The reaction mixture was concentrated and purified by re-crystallization with EtOH. Yield: 51 mg (43%).
Reaction SMILES: [C:1]1([C:7]([NH:9][C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)=[S:8])[CH:6]=[CH:5]C=C[CH:2]=1.C(Cl)(Cl)Cl.S(Cl)(Cl)(=O)=[O:20]>CO>[O:20]1[CH:5]=[CH:6][C:1]([C:7]2[S:8][N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[N:9]=2)=[CH:2]1
Reactant: S=C(Nc1ncc[nH]1)c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: c1cn2sc(-c3ccoc3)nc2n1

Procedure:
To 0.2 g. of 2-(3-furylthiocarbonylamino)-imidazole [(IV), R = 3-furyl] in 10 ml. of chloroform, at 20°-25°C, there is added dropwise 0.1 ml. of sulfuryl chloride in 2 ml. of chloroform. After 10 minutes the reaction mixture is concentrated at 10°-20°C. under vacuum to give a residue which is treated with methanol and filtered. The residue obtained following filtration is treated with dilute aqueous ammonia to give a precipitate which is filtered and dried to yield 2-(3-furyl)-1,2,4-thiadiazolo-[2,3-a]-imidazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[O:14]1[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15]1.B(F)(F)F.CCOCC.Cl>C1COCC1>[F:1][C:2]1[C:3]([F:8])=[CH:4][CH:5]=[CH:6][C:7]=1[CH2:15][CH:16]([OH:14])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCC1CO1
Reactant: Fc1ccccc1F
Agent: Cl
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCC(O)Cc1cccc(F)c1F
Temperature: -70 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a stirred solution of 1,2-difluorobenzene 1 (20.0 g, 0.175 mol) in dry THF (300 ml) was added dropwise a solution of 2.5 M n-butyllithium (68 ml, 0.17 mol) at −70° C. under dry nitrogen. The addition rate was such that the temperature did not rise above −60° C. After the addition was completed the reaction was stirred at −70° C. for 2 h. 1,2-Epoxyoctane (21.6 g, 0.169 mol) was added slowly followed by the dropwise addition of boron trifluoride etherate (21 ml, 0.17 mol). The mixture was allowed to warm to room temperature overnight, acidified with 10% hydrochloric acid and extracted into ether. The combined extracts were washed with sat. aqueous sodium chloride and evaporated to give a viscous liquid. Kugelrohr distillation (130° C., 0.15 mm Hg) yielded 1-(2,3-difluorophenyl)-octan-2-ol (30.8 g, 74%) which crystallised on standing; Vmax 3370 br (OH), 2950, 2920, 2850, 1620, 1590, 1480 s, 1280, 1205, 1070 br, 825, 775, and 730 cm−1, δH 0.88 (3 H, t, Me), 1.23-1.40 (10H, m, CH2), 1.40-1.58 (4 H, m overlapping br s, CH2CHOH and OH), 2.72 (1 H, ddd, J16, 8 and 2 Hz, ArCH2), 2.91 (1 H, ddd, J16, 6, and 2 Hz, ArCH2), 3.86 (1 H, m, CHOH), and 6.94-7.09 (3 H, m, ArH); m/z 242 (M+), 225, 198, 157, 139, 128, and 97.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=1.[OH-].[Na+].O1CCCC1.Cl>CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
A mixture of methyl 4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoate (2.00 g), 1N aqueous sodium hydroxide solution (18.6 mL), tetrahydrofuran (30 mL) and methanol (20 mL) was stirred at room temperature for 2 hrs, and at 50-60° C. for 1 hr. The reaction mixture was acidified by adding 1N hydrochloric acid and concentrated. The residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was filtered with diisopropyl ether to give 4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoic acid as a white solid (1.73 g, yield 85%). Recrystallization from ethyl acetate-diisopropyl ether gave needle crystals. melting point: 190-191° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH3:9][O:10][C:11]1[C:16](B(O)O)=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH3:9][O:10][C:11]1[C:16]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COc1ncccc1B(O)O
Reactant: Nc1cc(Br)ccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncccc1-c1ccnc(N)c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
To 4-bromopyridin-2-amine (0.5 g, 2.8 mmol), 2-methoxypyridin-3-ylboronic acid (0.52 g, 3.4 mmol) in DMF (25 mL) was added 1N sodium carbonate (10 mL, 2.3 mmol), followed by 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.21 g, 0.26 mmol). The reaction mixture was stirred for 3 hours at 85° C. and then cooled to room temperature. The product was extracted with ethyl acetate (2×50 mL), dried with MgSO4, filtered, and concentrated in vacuo. The crude product was purified by chromotography (Biotage: 100 to 90/10% ethyl acetate-ethyl acetate/methanol) to yield 2-methoxy-3,4′-bipyridin-2′-amine (0.53 g, 2.63 mmol, 93% yield) as a brown powder. The product was taken directly to the next step.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[C:32](=[O:40])[C:33](=[O:39])[C:34]=2[O:35][CH:36]([CH3:38])[CH3:37])=[CH:21][CH:20]=1>CN(C)C=O>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[C:32](=[O:40])[C:33](=[O:39])[C:34]=3[O:35][CH:36]([CH3:38])[CH3:37])=[CH:23][CH:24]=2)[C:7]([C:11]([O:13][CH3:14])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(=O)OC)[nH]1
Reactant: CC(C)Oc1c(-c2ccccc2-c2ccc(CBr)cc2)c(=O)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2c(OC(C)C)c(=O)c2=O)cc1
Reaction time: 0.5 h

Procedure:
Methyl 2-butyl-4-chloro-1H-imidazole-5-carboxylate (0.19 g) was added to a stirring suspension of sodium hydride (60% dispersion in mineral oil; 35 mg) in dry dimethylformamide (2 ml) at ambient temperature under a nitrogen atmosphere and stirring was continued for 30 minutes. A solution of 3-(4'-bromomethylbiphenyl-2-yl)-4-isopropoxycyclobut-3-ene-1,2-dione (0.64 g; preparable as in Example 1(c)) in dry dimethyl formamide (3 ml) was added and stirring was continued for 24 hours. The reaction mixture was partitioned between water (20 ml) and diethyl ether (20 ml), and the aqueous layer was separated and extracted with diethyl ether (20 ml). The combined ether solutions were dried over magnesium sulphate and the solvent was evaporated in vacuo. The residue obtained was purified by flash chromatography on silica gel (eluting with 20% ethyl acetate in petroleum ether (b.p. 40°-60° C.)) to give methyl 2-butyl-4-chloro-1-[2'-(2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-1H-imidazole-5-carboxylate, an active compound of the present invention, as a yellow oil (0.17 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.[CH2:12](Br)/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:12]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)=CCC/C(C)=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reaction time: 6 h
Yield: 71.5 %

Procedure:
Methyl 4-hydroxybenzoate (7.6 g), geranyl bromide (10.9 g), and potassium carbonate (13.8 g) were refluxed in acetone (80 ml) with stirring for 6 hours. The reaction mixture, with water added thereto, was extracted with chloroform. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was dissolved in methanol (50 ml) and the resulting mixture, with potassium hydroxide (3.9 g) and water (10 ml) added thereto, was stirred overnight at room temperature. The reaction mixture was neutralized with hydrochloric acid and then extracted with chloroform. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The resulting solid was recrystallized from n-hexane/ethanol to yield 9.8 g of the aimed compound.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][N:14]=3)[O:8][C:4]=2[CH:3]=1.CN(C=O)C.C1C(=O)N([Br:30])C(=O)C1>C(OCC)(=O)C>[Br:30][C:13]1[N:14]=[C:9]([C:7]2[O:8][C:4]3[CH:3]=[C:2]([F:1])[CH:17]=[CH:16][C:5]=3[N:6]=2)[C:10]([NH2:15])=[N:11][CH:12]=1
Reactant: Nc1nccnc1-c1nc2ccc(F)cc2o1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ncc(Br)nc1-c1nc2ccc(F)cc2o1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
3-(6-Fluoro-1,3-benzoxazol-2-yl)pyrazin-2-amine (300 mg) was dissolved into DMF (15 ml) at 50° C. N-bromosuccimide (325 mg) was added. The mixture was stirred at 40° C. for 2 hours. The resulting mixture was diluted with ethyl acetate (15 ml), and washed with brine (10 ml×3). The organic layer was dried and concentrated to give 5-bromo-3-(6-fluoro-1,3-benzoxazol-2-yl)pyrazin-2-amine, which was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([NH:8][C:9]([C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][CH:12]=2)=[O:10])[CH:7]=1.CC([O-])=O.[K+].Br[C:27]#[N:28]>CO>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([NH:8][C:9]([C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][CH:12]=2)=[O:10])[CH:7]=1)[C:27]#[N:28]
Reactant: Cc1ccc(N)cc1NC(=O)c1cnc2ccccn12
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ccc(NC#N)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To N-(5-amino-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (67) (4.53 g, 15 mmol) in MeOH (100 mL) was added KOAc (4.41 g, 45 mmol) and the mixture was stirred at room temperature for 5 minutes then cooled to 0° C. before a solution of BrCN (1.62 g, 15 mmol) in MeOH (30 mL) was added dropwise. The resulting mixture was slowly warmed to room temperature and stirred overnight. The solvent was evaporated and to the residue was added water (150 mL). The mixture was stirred at room temperature for 1 hour, filtered and washed with water (2×20 mL), then air dried to give N-(5-cyanamido-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (68) as a white solid.
Reaction SMILES: C([O:8][C:9](=[O:46])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:45])[C@H:16]([CH2:30][CH2:31][CH2:32][CH2:33][NH:34]C(OCC1C=CC=CC=1)=O)[NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-])=O)(=[O:20])=[O:19])C1C=CC=CC=1.[H][H]>CO.[C].[Pd].O>[NH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C@H:16]([C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:46])=[O:8])=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])(=[O:20])=[O:19]
Reactant: O=C(NCCCC[C@H](NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: NCCCC[C@H](NS(=O)(=O)c1ccccc1N)C(=O)N1CCC[C@H]1C(=O)O
Yield: 91.1 %

Procedure:
Nα -o-nitrobenzenesulfonyl-Nε -benzyloxycarbonyl-L-lysyl-L-proline benzylester (5.82 g, 8.9 mmole) was dissolved in methanol (40 ml), and hydrogen gas was Passed through the solution in the presence of 5% palladium-carbon as a catalyst for 6 hours. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. The residue thus obtained was dissolved in water (25 ml). The solution was washed with three 25 ml portions of diethyl ether and the water layer as separated was freeze-dried to obtain Nα -o-aminobenzenesulfonyl-L-lysyl-L-proline (yield: 3.23 g, 90.9%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:15]([O-])=O)=[C:12]([CH:14]=2)[NH2:13])[CH2:4][CH2:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:14]=[C:12]([NH2:13])[C:11]([NH2:15])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CC1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1CCN(c2ccc(N)c(N)c2)CC1
Yield: 86 %

Procedure:
5-(4-Methylpiperidin-1-yl)-2-nitroaniline (200 mg, 0.850 mmol) was added to 10% Pd/C (10 mg) in ethanol (25 mL) and then hydrogen gas (60 psi) was applied for 24 h at room temperature. Upon TLC-based completion of the reaction, the reaction mixture was filtered through Celite, and the solvent was removed in vacuo. Purification by flash chromatography (5% CH3OH/CH2Cl2) afforded the title compound (150 mg) as a brown solid. 1H NMR: (400 MHz, DMSO-d6): δ 6.35 (d, 1H, J=8.4 Hz), 6.19 (d, 1H, J=2.4 Hz), 5.99 (m, 1H), 4.29 (bs, 2H), 3.92 (bs, 2H), 3.26 (m, 2H), 2.39 (m, 2H), 1.61 (m, 2H), 1.36 (m, 1H), 1.20 (m, 2H), 0.89 (d, 3H, J=6.8 Hz); ESI-MS [M+H]+: 206.1.
Reaction SMILES: [CH3:1][N:2]1[CH:11]2[C:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[N:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CCC2(C)c3ccc(S)cc3CCC12
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ncccn4)cc3CC[C@@H]12
Yield: 23.3 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloropyrimidine (53 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 30 mg (23%) of the title compound as an oil. FDMS: m/e=339.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH2:20][CH:21]=[CH2:22])([S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH2:6][CH:7]=[CH2:8])C>CO.[OH-].[Na+]>[CH2:6]([C:5]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH2:20][CH:21]=[CH2:22])[C:4]([OH:23])=[O:3])[CH:7]=[CH2:8]
Reactant: C=CCC(CC=C)(C(=O)OCC)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCC(CC=C)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1

Procedure:
2-Allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic acid was prepared starting from 2-allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic acid ethyl ester (2.2 g, 6.5 =mol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield 1.76 g, 87%; yellowish oil; MS: 311 (M+H)+.
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[S:9][C:8]([S:10]([NH:13][C@H:14]([CH:20]=[O:21])[CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])(=[O:12])=[O:11])=[CH:7][CH:6]=1>C1(C)C=CC=CC=1.C1COCC1.C1COCC1>[Cl:4][C:5]1[S:9][C:8]([S:10]([NH:13][C@H:14]([CH:20]([OH:21])[CH3:1])[CH:15]([CH2:16][CH3:17])[CH2:18][CH3:19])(=[O:12])=[O:11])=[CH:7][CH:6]=1
Reactant: CCC(CC)[C@@H](C=O)NS(=O)(=O)c1ccc(Cl)s1
Reactant: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCC(CC)[C@H](NS(=O)(=O)c1ccc(Cl)s1)C(C)O
Temperature: 25 °C
Yield: 84 %

Procedure:
A solution of methylmagnesium bromide (1.4 M, 7.0 mL, 9.7 mmol) in toluene/THF (75:25) was added to a 0° C. solution of 5-chloro-N-[(S)-2-ethyl-1-formylbutyl]thiophene-2-sulfonamide (Example 221, 1.0 g, 3.2 mmol) in THF (30 mL). The mixture was warmed to 25° C. and after 2 h was quenched carefully with saturated aqueous ammonium chloride (25 mL). The mixture was extracted with EtOAc (3×25 mL). The organic extract was dried over Na2SO4, filtered and concentrated to give a colorless oil. The product was purified by column chromatography (Biotage), eluant: 1:4 EtOAc-hexane, to afford 5-chloro-N-[(S)-2-ethyl-1-(1-hydroxyethyl)butyl]thiophene-2-sulfonamide as a white solid (876 mg, 83%). The product is a diastereomeric mixture with a ratio of 3:7. mp 95-98° C. Anal. Calc'd for C12H20ClNO3S2: C, 44.23; H, 6.19; N, 4.30. Found: C, 44.25; H, 6.35; N, 4.29. Mass Spectrum (−ESI): 324 (M−H)−.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([I:18])=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([C:20](O)=[O:21])=[CH:9]1)[CH2:5][O:6][CH3:7].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.OC1C2N=NNC=2C=CC=1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH3:7][O:6][CH2:5][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([I:18])=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([C:20]([N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)=[O:21])=[CH:9]1)[CH2:3][O:2][CH3:1]
Reactant: CN1CCNCC1
Reactant: COCC(COC)n1cc(C(=O)O)c(=O)c2cc(I)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COCC(COC)n1cc(C(=O)N2CCN(C)CC2)c(=O)c2cc(I)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To a solution of 1-(1,3-dimethoxypropan-2-yl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Intermediate 78, 300 mg, 0.72 mmol) and 1-methylpiperazine (100 mg, 1.00 mmol) in dichloromethane (50 mL) was added hydroxybenzotriazole (HOBT) (110 mg, 0.72 mmol) and N-methylmorpholine (290 mg, 2.87 mmol). The reaction mixture was stirred for 1 h at room temperature and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HCl) (234 mg, 1.29 mmol) was added. The resulting reaction mixture was stirred at room temperature over night. The reaction mixture was quenched with 2N hydrochloric acid (30 mL) and the layers were separated. The organic layer was washed with saturated sodium bicarbonate solution (40 mL), water (60 mL) and finally with brine successively and dried over anhydrous sodium sulphate, filtered and concentrated under vacuum to afford 1-(1,3-dimethoxypropan-2-yl)-6-iodo-3-[(4-methylpiperazin-1-yl)carbonyl]quinolin-4(1H)-one 300 mg (80%) as thick oil.
Reaction SMILES: C([O:8][C:9]1[CH:25]=[CH:24][C:12]([CH2:13][NH:14][C:15]2[C:20](Cl)=[C:19]([CH3:22])[N:18]=[C:17]([CH3:23])[N:16]=2)=[CH:11][C:10]=1[O:26][CH2:27][CH:28]1[CH2:30][CH2:29]1)C1C=CC=CC=1.[H][H]>CO.C(O)(=O)C>[CH:28]1([CH2:27][O:26][C:10]2[CH:11]=[C:12]([CH2:13][NH:14][C:15]3[CH:20]=[C:19]([CH3:22])[N:18]=[C:17]([CH3:23])[N:16]=3)[CH:24]=[CH:25][C:9]=2[OH:8])[CH2:30][CH2:29]1
Reactant: [H][H]
Reactant: Cc1nc(C)c(Cl)c(NCc2ccc(OCc3ccccc3)c(OCC3CC3)c2)n1
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(NCc2ccc(O)c(OCC3CC3)c2)nc(C)n1

Procedure:
A solution of 2.0 g (4.7 mmol) of (4-benzyloxy-3-cyclopropylmethoxybenzyl)(5-chloro-2,6-dimethyl-pyrimidin-4-yl)amine (from example A5) in 50 ml of methanol and 20 ml of glacial acetic acid is admixed with 250 mg of Pd-on-carbon catalyst (type 38H, Johnson Matthey) and hydrogenated by circulation with hydrogen until about 2 equivalents of hydrogen (about 350 ml) have been taken up. After filtration to remove the catalyst, the solution is concentrated and the residue is chromatographed on silica gel (mobile phase: toluene/dioxane/ammonia=2:1:0.05). The fractions with Rf=0.15 are collected and concentrated. The residue (1.5 g), which is of poor solubility, is reacted further without additional purification (see example 7).