Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=2)[N:10]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]1=[O:31])(C)(C)C.C(N1C2C(=CC(Br)=CC=2)CC(N[S:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)(=[O:54])=[O:53])C1=O)C1C=CC=CC=1>>[CH2:24]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH2:17][CH:8]([NH:7][S:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)(=[O:54])=[O:53])[C:9]1=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1C(NS(=O)(=O)c2ccccc2)Cc2cc(Br)ccc2N1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1Cc2cc(-c3ccccc3)ccc2N(Cc2ccccc2)C1=O
Product: O=C1C(NS(=O)(=O)c2ccccc2)Cc2cc(-c3ccccc3)ccc2N1Cc1ccccc1

Procedure:
The title compound (15 mg) was prepared from 4B (22 mg) according to the procedures described in 3D and 3E. HPLC/MS retention time=4.0 min (Phenomenex Luna 5 micron C18 4.6 mm×50 mm column eluted with a 0% to 100% B solvent gradient over 4 min; solvent A=90% H2O, 10% MeOH, 0.1% TFA and solvent B=10% H2O, 90% MeOH, 0.1% TFA; flow rate=4.0 mL/min; UV detection at 220 nm); m/z=469 [M+H]+, 491 [M+Na]+.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Br[CH2:22][C:23]1[O:24][CH:25]=[CH:26][C:27]=1[C:28]([O:30][CH3:31])=[O:29]>>[CH3:31][O:30][C:28]([C:27]1[CH:26]=[CH:25][O:24][C:23]=1[CH2:22][N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19])=[O:29]
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: COC(=O)c1ccoc1CBr
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2occc2C(=O)OC)c(=O)[nH]c1=O
Yield: 38 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2-bromomethyl-3-methoxycarbonylfurane were reacted by the same way with the example 1 to obtain the titled compound (150 mg, yield: 38.0%).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]([C:19]([NH:22][C:23](=[O:28])[C:24]([O:26]C)=O)([CH3:21])[CH3:20])[N:13]([CH3:18])[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1.[CH3:31][NH:32][CH3:33]>C1COCC1>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]([C:19]([NH:22][C:23](=[O:28])[C:24]([N:32]([CH3:33])[CH3:31])=[O:26])([CH3:20])[CH3:21])[N:13]([CH3:18])[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)C(=O)NC(C)(C)c1nc(C(=O)NCc2ccc(F)cc2)c(O)c(=O)n1C
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)C(=O)NC(C)(C)c1nc(C(=O)NCc2ccc(F)cc2)c(O)c(=O)n1C
Temperature: 25 °C

Procedure:
Methyl {[1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-methylethyl]amino}(oxo)acetate was refluxed in an excess of 2 M solution of dimethylamine in THF for 2 h. Reaction mixture was cooled to room temperature, evaporated and residue was purified by RP HPLC (C18, water/acetonitrile containing 0.1% of trifluoroacetic acid as eluant). Collection and lyophilization of appropriate fractions afforded the title product.
Reaction SMILES: [CH:1](=[O:3])[CH3:2].[CH:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(C=O)CCCC1>>[CH:6]1(/[CH:5]=[CH:2]/[CH:1]=[O:3])[CH2:7][CH2:8][CH2:9][CH2:4]1
Reactant: CC=O
Reactant: c1ccccc1
Agent: O=CC1CCCC1
Product: O=C/C=C/C1CCCC1
Temperature: 80 °C
Yield: 58 %

Procedure:
To a stirred suspension of triphenylphosphoranylidene)acetaldehyde (27, 62.75 g, 200.0 mmol, 1.0 equiv) in anhydrous benzene (400 mL, 4476 mmol) was added cyclopentanecarbaldehyde (26, 21.36 mL, 200.0 mmol) at room temperature. The resulting reaction mixture was then heated at 80° C. for 16 h. When TLC and HPLC showed that the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure. The residue was then directly purified by Combiflash (SiO2) with 0-10% EtOAc/hexane gradient elution to afford (2E)-3-cyclopentylacrylaldehyde (28, 14.4 g, 24.84 g theoretical, 58% yield) as a yellow oil. For 28: 1H NMR (DMSO-d6, 400 MHz) δ ppm 1H NMR (CDCl3, 400 MHz) δ 9.49 (d, 1H, J=7.8 Hz), 6.82 (dd, 1H, J=15.6, 7.8 Hz), 6.08 (dd, 1H, J=15.6, 8.0 Hz), 2.72 (m, 1H), 1.89 (m, 2H), 1.67 (m, 4H), 1.44 (m, 2H); C8H12O (MW, 124.18) LCMS (EI) m/e 125 (M++H).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][C:15]1[O:16][C:17]2[C:26]3[C:25](=O)[CH2:24][CH2:23][C:22]=3[CH:21]=[CH:20][C:18]=2[N:19]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:14][C:15]1[O:16][C:17]2[C:26]3[C:25](=[CH:5][C:3]#[N:4])[CH2:24][CH2:23][C:22]=3[CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: Cc1nc2ccc3c(c2o1)C(=O)CC3
Reactant: CCOP(=O)(CC#N)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nc2ccc3c(c2o1)C(=CC#N)CC3
Reaction time: 0.25 h
Yield: 76.3 %

Procedure:
To a suspension of 60% sodium hydride (90.0 mg, 2.24 mmol) in tetrahydrofuran (9 mL) was added diethyl cyanomethylphosphonate (393 μL, 2.43 mmol) under ice-cooling, and the mixture was stirred for 15 min. Thereto was added a solution of 2-methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-one (350 mg, 1.87 mmol) in tetrahydrofuran (9 mL), and the mixture was further stirred for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (300 mg, yield 76%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:16][CH2:17][NH:18][C:19]([NH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[C:24]([CH3:32])[CH:23]=1)=[O:20].C([O-])(O)=O.[Na+].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:16][CH2:17][NH:18][C:19]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[C:24]([CH3:32])[CH:23]=2)=[O:20])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1cc(NC(=O)NCCCl)c2ccccc2n1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)NCCN2CCC(NC(=O)OC(C)(C)C)CC2)c2ccccc2n1
Temperature: 70 °C
Reaction time: 144 h

Procedure:
A mixture of piperidin-4-yl-carbamic acid tert-butyl ester (10 mmol), 1-(2-chloro-ethyl)-3-(2-methyl-quinolin-4-yl)-urea (10 mmol), NaHCO3 (20 mmol), Nal (0.5 mmol), and THF (70 mL) is stirred in a sealed vessel at 70° C. for 6 d. The reaction mixture is filtered, evaporated to dryness, and the residue is purified by preparative HPLC to provide the title compound.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3]1.Cl.[NH2:13][OH:14].[OH-].[Na+]>CO.O>[CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:13][OH:14])[CH2:3]1
Reactant: NO
Reactant: CC1CC(=O)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1CC(=NO)c2ccccc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 3-methylindan-1-one (221 mg, 1.51 mmol) and hydroxylamine hydrochloride (295 mg, 4.25 mmol) in MeOH (4.00 mL) was added a solution of NaOH (200 mg, 5.00 mmol) in H2O (2.00 mL) and the mixture was stirred at 80° C. for 2 h. The cooled reaction was concentrated in vacuo to remove most of the MeOH, and the residue was partitioned between DCM and H2O. The organic layer was concentrated in vacuo to afford the title compound as a waxy solid (232 mg, 95%). LC/MS: Rt=1.51 min, ES+ 162 (AA standard).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:19]3[CH2:25][CH:24]4[N:26]([CH3:27])[CH:21]([CH2:22][CH2:23]4)[CH2:20]3)[C:10]3[C:15]([O:16][C:17]=2[CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:4].[OH-].[Na+]>C1COCC1>[CH3:27][N:26]1[CH:24]2[CH2:23][CH2:22][CH:21]1[CH2:20][CH:19]([N:9]1[C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:18][C:17]=3[O:16][C:15]3[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:25]2
Reactant: COC(=O)c1ccc2c(c1)Oc1ccccc1N2C1CC2CCC(C1)N2C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1C2CCC1CC(N1c3ccccc3Oc3cc(C(=O)O)ccc31)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of 10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid methyl ester, 2a (440 mg, 0.646 mmol) in THF (5 mL) was added 1N NaOH (5 mL), and the mixture was stirred for 3 hr at rt. The solvent was removed, the residue was dissolved in DMF and acidified with a 2N TFA solution, and purified via reverse phase HPLC to yield 295 mg (63%) of 10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid, 3a, as a TFA salt. MS m/z (MH+) 351.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:12])[C:10]#[N:11].[CH2:13](N)[CH2:14][NH2:15]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([C:10]1[NH:15][CH2:14][CH2:13][N:11]=1)[CH3:12]
Reactant: COc1ccccc1C(C)C#N
Reactant: NCCN
Product: COc1ccccc1C(C)C1=NCCN1

Procedure:
rac-2-[1-(2-Methoxy-phenyl)-ethyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(2-methoxyphenyl)-propionitrile and ethylene diamine in analogy to Example 19 b): light yellow solid; MS (ISP): 205.1 ((M+H)+.).
Reaction SMILES: [Cl:1]C1C=C(C(C)C(O)=O)C=CC=1.Cl[C:14]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:30]=[CH:29][C:15]=1[CH2:16][NH:17][C:18](=[O:28])[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[CH3:20]>>[Cl:1][C:32]1([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:30][CH:29]=[C:15]([CH2:16][NH:17][C:18](=[O:28])[CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[CH3:20])[CH2:14]1
Reactant: CC(C(=O)O)c1cccc(Cl)c1
Reactant: CC(C(=O)NCc1cccc(C(F)(F)F)c1Cl)c1ccccc1Cl
Product: CC(C(=O)NCC1=CC=CC(Cl)(C(F)(F)F)C1)c1ccccc1Cl
Yield: 22 %

Procedure:
The titled compound was prepared from 2-(3-Chlorophenyl)propionic acid in 22% yield in the same manner as the preparation of N-(2-Chloro-3-trifluoromethylbenzyl)-2-(2-chlorophenyl)propionamide in Example 184b. MS (ESI) 376 (MH+).
Reaction SMILES: [CH2:1]([S:3]([CH2:5][C:6]([NH:8][C:9]1[CH:31]=[CH:30][C:12]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH2:17][CH2:16]2)=[O:14])=[CH:11][CH:10]=1)=[O:7])=[O:4])[CH3:2].ClC1C=CC=C(C(OO)=[O:40])C=1>CN(C)C=O.O1CCCC1>[CH2:1]([S:3]([CH2:5][C:6]([NH:8][C:9]1[CH:31]=[CH:30][C:12]([C:13]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[CH2:19][CH2:20]2)=[O:14])=[CH:11][CH:10]=1)=[O:7])(=[O:40])=[O:4])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCS(=O)CC(=O)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCS(=O)(=O)CC(=O)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.4 g of 1-[4-(N-ethylsulfinylacetylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]piperazine (Example 46) are dissolved in 50 ml of dimethylformamide, and a solution of 3-chloroperbenzoic acid (85%) in 30 ml of tetrahydrofuran is added dropwise at RT. The clear solution is stirred overnight at RT. The mixture is concentrated by evaporation, the residue is dissolved in water and the solution is rendered neutral, extracted with dichloromethane, chromatographed over silica gel and crystallised from ether/petroleum ether/alcohol, yielding 1-[4-(N-ethylsulfonylacetylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]piperazine having a melting point of 135°-136°.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[CH2:13][NH:14]C(=O)OC(C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>Cl.O1CCOCC1>[C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[CH2:13][NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NC/C=C/C=C/CCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: NC/C=C/C=C/CCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (2E,4E)-7-phenylhepta-2,4-dienylcarbamate (800 mg) was dissolved in hydrochloric acid in dioxane (4.0M, 8.35 ml). The mixture was stirred at room temperature for 1 h. The solvent was evaporated and co-evaporated twice with Et2O, Et2O was added, the solids were filtered off under a stream of nitrogen to yield the product as an off white solid.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1CCCCC1>C(O)C>[CH:8](=[C:7]1[S:1][C:2](=[S:3])[NH:4][C:5]1=[O:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CSC(=S)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=S)SC1=Cc1ccccc1
Yield: 66.6 %

Procedure:
To a solution of 10 g (75.1 mmol) of rhodanine and 7.63 ml (75.1 mmol) of benzaldehyde in 150 ml of ethanol, 0.74 ml (7.5 mmol) of piperidine was added, and the mixture was heated under reflux for 5 hours. After cooling, the precipitated crystals were filtered and washed with cooled ethanol to give 11.07 g of the desired compound (66.6% yield, pale yellow crystals).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([OH:9])[CH:3]=1.[CH3:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=O)=[CH:13][CH:12]=1>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]2[N:6]=[C:10]([C:11]3[CH:19]=[CH:18][C:14]([CH3:15])=[CH:13][CH:12]=3)[O:9][C:4]=2[CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(Br)cc1O
Product: Cc1ccc(-c2nc3ccc(Br)cc3o2)cc1

Procedure:
Preparation is carried out analogously to 4.1.a from 4-bromo-2-hydroxy-aniline and 4-methyl-benzoic acid.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([CH2:9][CH3:10])[CH2:6][CH2:7][OH:8])[CH3:4].Br[CH2:12][C:13]1[N:18]=[C:17]([CH2:19][O:20][C:21]2[CH:42]=[CH:41][C:24]([C:25]([NH:27][C:28]3[CH:29]=[C:30]([CH:37]=[CH:38][C:39]=3[CH3:40])[C:31]([NH:33][CH:34]3[CH2:36][CH2:35]3)=[O:32])=[O:26])=[CH:23][CH:22]=2)[CH:16]=[CH:15][CH:14]=1>CC(N(C)C)=O>[CH:34]1([NH:33][C:31](=[O:32])[C:30]2[CH:37]=[CH:38][C:39]([CH3:40])=[C:28]([NH:27][C:25](=[O:26])[C:24]3[CH:41]=[CH:42][C:21]([O:20][CH2:19][C:17]4[CH:16]=[CH:15][CH:14]=[C:13]([CH2:12][O:8][CH2:7][CH2:6][N:5]([CH2:9][CH3:10])[CH2:3][CH3:4])[N:18]=4)=[CH:22][CH:23]=3)[CH:29]=2)[CH2:35][CH2:36]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2cccc(CBr)n2)cc1
Reactant: CCN(CC)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCN(CC)CCOCc1cccc(COc2ccc(C(=O)Nc3cc(C(=O)NC4CC4)ccc3C)cc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 35.3 %

Procedure:
To a 60% dispersion of NaH in mineral oil (25 mg, 0.625 mmol) in DMA (4 mL) was added N,N-diethylethanolamine (24 mg, 0.205 mmol). The reaction was stirred at room temperature for 20 minutes. A solution of 3-[(4-{[6-(bromomethyl)pyridin-2-yl]methoxy}benzoyl)amino]-N-cyclopropyl-4-methylbenzamide (77 mg, 0.155 mmol) in DMA (2 mL) was added dropwise to the reaction which was then stirred for 1 h at room temperature. The reaction was quenched by the addition of water (1 mL) and was purified by preparative HPLC to give the title compound as a white solid (29 mg, 35%); NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.69 (m, 2H), 0.96 (t, 6H), 2.26 (s, 3H), 2.50 (m, 4H), 2.64 (t, 2H), 2.86 (m, 1H), 3.59 (t, 2H), 4.59 (s, 2H), 5.75 (s, 2H), 7.18 (d, 2H), 7.33 (d, 1H), 7.42 (m, 2H), 7.64 (dd, 1H), 7.80 (s, 1H), 7.87 (t, 1H), 7.96 (d, 2H), 8.36 (d, 1H), 9.83 (s, 1H); Mass Spectrum: M+H+ 531.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10](Cl)(=[O:12])=[O:11]>C(OCC)C>[CH3:1][N:2]([CH3:3])[S:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][Cl:4])(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)CCCCCCl
Reactant: CNC
Solvent: CCOCC
Product: CN(C)S(=O)(=O)CCCCCCl
Yield: 95.1 %

Procedure:
A 50% aqueous solution of dimethylamine (5.95 g, 66 mmol) was added dropwise to a solution of diethyl ether (60 ml) and 5-chloropentanesulfonyl chloride (6.15 g, 30 mmol) with stirring under ice-cooling. Thereafter, the mixture was stirred at the same temperature for 20 minutes. The reaction solution was washed twice with water (10 ml) and then with brine (10 ml), and thereafter dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The crude product was purified by column chromatography on silica gel with ethyl acetate-n-hexane (1:4), to give N,N-dimethyl-5-chloropentanesulfonamide (6.10 g) as a pale yellow oil.
Reaction SMILES: [N:1]1C=CC=C[CH:2]=1.Cl[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=1.CN.Cl>O>[CH3:2][NH:1][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: c1ccncc1
Agent: CN
Agent: Cl
Solvent: O
Product: CNc1ccc(C(=O)O)cn1
Temperature: 25 °C

Procedure:
A 20 ml pyridine solution of 10 g of 6-chloronicotinic acid and 27 ml of 40% methylamine aqueous solution was heated at 150° C. for 24 hours in a sealed tube. After spontaneous cooling to room temperature, this was mixed with water and adjusted to pH 3 with 1 N aqueous hydrochloric acid. The precipitated crystals were collected by filtration to obtain 5.82 g of the title compound as grayish white crystals.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C@H:6]([N:13]1[C:17]([CH2:18]O)=[CH:16][NH:15][C:14]1=[S:20])[CH2:7]2.CN(C=O)C.S(Cl)(Cl)=O.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C@H:6]([N:13]1[C:17]([CH2:18][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:16][NH:15][C:14]1=[S:20])[CH2:7]2
Reactant: C1CCNC1
Reactant: OCc1c[nH]c(=S)n1[C@H]1CCc2c(F)cc(F)cc2C1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Fc1cc(F)c2c(c1)C[C@@H](n1c(CN3CCCC3)c[nH]c1=S)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
A solution of (S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5-hydroxymethyl-1,3-dihydroimidazole-2-thione (140 mg, 0.47 mmol), prepared as in Example 18, in 20 mL of THF and I drop of DMF was cooled to between 0° and 5° C. and thionyl chloride (13.7 M, 109 μL, 1.49 mmol) was added drop-wise under a nitrogen atmosphere. The mixture was stirred at room temperature for 0.5 hours, under reflux for 0.5 hours and again at room temperature for 0.5 hours. The mixture then was cooled to between 0° and 5° C. and pyrrolidine (12.0 M, 818 μL, 9.8 mmol) was added drop-wise. The mixture was stirred under reflux for 1.5 hours. The solvents were removed by evaporation and the residue was diluted with water. Ethyl acetate was added to the dilution and the mixture was adjusted to pH 7. The ethyl acetate layer was dried and concentrated by evaporation. Purification of the residue by column chromatography gave (S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydro-5-(pyrrolidin-1-ylmethyl)-imidazole-2-thione (100 mg, 0.29 mmol). [α]D =-10.96° (C=1.3, DMSO).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:25]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])[C:5]([OH:24])=[C:6]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][N:8]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:7]=12.C[C:33]([N:35](C)C)=O>CS(C)=O.[C-]#N.[C-]#N.[Zn+2].[Zn].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].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[C:33]([C:2]1[N:3]=[C:4]([C:25]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])[C:5]([OH:24])=[C:6]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][N:8]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:7]=12)#[N:35]
Reactant: CC(=O)N(C)C
Reactant: O=C(O)CNC(=O)c1nc(Cl)c2c(c(-c3ccccc3)cn2-c2ccc(F)cc2)c1O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CS(C)=O
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(-c3ccccc3)cn(-c3ccc(F)cc3)c12
Temperature: 120 °C

Procedure:
A mixture of {[7-chloro-1-(4-fluoro-phenyl)-4-hydroxy-3-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (30 mg), Zn(CN)2 (4.0 mg), Zn dust (0.5 mg), Pd2(dba)3 (3.2 mg), dppf (3.8 mg) in DMA (1 mL) was heated to 120° C. for 90 min; then the mixture was cooled, diluted with DMSO and purified by C18 reverse phase chromatography to give the desired title compound (11 mg). The title compound, ESI MS (m/z): 431 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][NH:17][CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][N:17]([C:24]([C:20]5[O:19][CH:23]=[CH:22][CH:21]=5)=[O:25])[CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(c1)ncc1c3c([nH]c12)CCNC3
Reactant: O=C(Cl)c1ccco1
Product: O=C(c1ccco1)N1CCc2[nH]c3c(cnc4cc(Cl)ccc43)c2C1
Yield: 17.6 %

Procedure:
The same reaction procedure and workup is followed as for the compound of Example 8 using 0.50 g (1.94 mmol) of 3-chloro-8,9,10,11-tetrahydro-7H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline and 0.253 g (1.94 mmol) of 2-furoylchloride to yield 0.12 g (17%) of the title compound as a white solid: m.p >250° C.; m/e 351.
Reaction SMILES: C(O[CH:5]([C:28]1[N:41]=[C:31]2[N:32]=[C:33]([CH3:40])[C:34]3[CH2:35][CH2:36][CH2:37][CH2:38][C:39]=3[N:30]2[N:29]=1)[C:6]1(Br)[C:12](=[O:13])[N:11]2[C@@H:7]1[S:8][CH:9]=[C:10]2[C:14]([O:16]CC1C=CC([N+]([O-])=O)=CC=1)=[O:15])(=O)C.C(#N)C.P([O-])([O-])([O-])=O>C1COCC1.[Pd]>[CH3:40][C:33]1[C:34]2[CH2:35][CH2:36][CH2:37][CH2:38][C:39]=2[N:30]2[N:29]=[C:28](/[CH:5]=[C:6]3\[C@@H:7]4[N:11]([C:12]\3=[O:13])[C:10]([C:14]([OH:16])=[O:15])=[CH:9][S:8]4)[N:41]=[C:31]2[N:32]=1
Reactant: CC(=O)OC(c1nc2nc(C)c3c(n2n1)CCCC3)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1nc2nc(/C=C3/C(=O)N4C(C(=O)O)=CS[C@H]34)nn2c2c1CCCC2
Temperature: 3 °C

Procedure:
4-nitrobenzyl (5R)-6-[(acetyloxy)(5-methyl-6,7,8,9-tetrahydro[1,2,4]triazolo[1,5-a]quinazolin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (600 mg, 0.93 mmol) was dissolved in THF (20 mL) and acetonitrile (20 mL) and phosphate buffer (6.5 pH) (20 ml) and hydrogenated over Pd/C (10%) (200 mg) under 40 psi pressure. At the end, reaction mixture was filtered, cooled to 3° C., and 0.1 N NaOH was added to adjust the pH to 8.5. The filtrate was washed with ethyl acetate and the aqueous layer was separated. The aqueous layer was concentrated under high vacuum at 35° C. to give a yellow precipitate. The product was purified by HP21 resin reverse phase column chromatography. Initially the column was eluted with deionized water (2 L) and latter with 10% acetonitrile:water. The fractions containing the product were collected and concentrated under reduced pressure at room temperature. The yellow solid was washed with acetone, filtered and dried. Yield: 37 mg, 11%; as yellow crystals; mp 250° C. (Dec); (M+H+Na) 392. 1H NMR (DMSO-d6) δ 6.90 (s, 1H), 6.85 (s, 1H), 6.28 (s, 1H), 2.98 (m, 2H), 2.77 (m, 2H), 2.55 (m, 3H), 1.78 (m, 4H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N:5]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.[Cl:20][CH2:21][CH2:22][C:23](Cl)=[O:24].O>ClCCl>[Cl:20][CH2:21][CH2:22][C:23]([C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:6][CH2:7][CH2:8]2)=[O:24]
Reactant: CCOC(=O)N1CCCc2ccccc21
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1CCCc2cc(C(=O)CCCl)ccc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Aluminum chloride (23.5 g, 176 mmol) was added to a solution of ethyl 3,4-dihydro-1(2H)-quinoline carboxylate (14.5 g, 70.4 mmol) and 3-chloropropionyl chloride (7.39 ml, 77.4 mmol) in dichloromethane under cooling with water-bath, and the mixture was stirred at room temperature for 14 hours. The reaction solution was poured into iced water and extracted with dichloromethane. The extract was washed with a saturated saline solution and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The resulting residues were purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=3:1) and crystallized from hexane, whereby the title compound (15.6 g) was obtained as colorless powder with a mp. of 78 to 79° C.