Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([OH:28])[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([O:28][CH2:36][C:35]5[CH:38]=[CH:39][C:32]([F:31])=[CH:33][CH:34]=5)[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C(NC1CCCCC(O)C1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(NC1CCCCC(OCc2ccc(F)cc2)C1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
As described for example 138, 4-(7-chloro-4-quinolinyl)-N-(3-hydroxycycloheptyl)-1-piperazinecarboxamide (50 mg, 0.124 mmol), NaH (8.9 mg, 0.37 mmol), and 4-fluorobenzyl bromide (28.2 mg, 0.15 mmol) are reacted to give the title product after flash chromatography with CH2Cl2-MeOH. LC-MS: 511 (M++1). 1H NMR (CDCl3) δ 8.75 (d, 1H), 8.05 (s, 1H), 7.95 (d, 1H), 7.45 (d, 1H), 7.35 (m, 2H), 7.00 (m, 2H), 6.85 (d, 1H), 4.50 (m, 2H), 4.40 (m, 1H), 4.10 (m, 1H), 3.65 (m, 4H), 3.20 (m, 4H), 2.20 (m, 1H), 2.10 (m, 1H), 1.50–1.90 (m, 6H), 1.40 (m, 2H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9](F)[C:10]([F:22])=[C:11]([N:15]4[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:3][CH2:2]1.[NH3:28]>>[NH2:28][C:9]1[C:10]([F:22])=[C:11]([N:15]2[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[CH2:16]2)[C:12]([F:14])=[C:13]2[C:8]=1[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5][N:4]2[CH:1]1[CH2:3][CH2:2]1
Reactant: N
Reactant: CC1CN(c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCN1
Product: CC1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCN1
Temperature: 100 °C

Procedure:
A mixture of 1-cyclopropyl-5,6,8-trifluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (150 mg) and 28% aqueous ammonia (15 ml) was heated at 100° C. for 48 hours in a sealed tube. The reaction mixture was evaporated to dryness under reduced pressure and water was added to the residue. The mixture was extracted with chloroform. After drying, the extract was evaporated and the residue was recrystallized from chloroform-ethanol to give 5-amino-1-cyclopropyl-6,8-difluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (93 mg), m.p. 251°-253° C.
Reaction SMILES: C([NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Br:14])=[CH:7][C:6]=1[C:15]([F:18])([F:17])[F:16])(=O)C>Cl>[NH2:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Br:14])=[CH:7][C:6]=1[C:15]([F:18])([F:16])[F:17]
Reactant: CC(=O)Nc1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Agent: Cl
Product: Nc1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Yield: 72.8 %

Procedure:
A mixture of 2-acetamido-5-bromo-3-nitrobenzotrifluoride (400 mg, 1.258 mmol) in concentrated HCl (3.5 mL) was refluxed overnight, then it was extracted by ethyl acetate (2×3 mL). The extract was dried over Mg2SO4 and evaporated to give 261 mg (75.6%) of 2-amino-5-bromo-3-nitrobenzotrifluoride. 1H NMR (CDCl3): δ6.663 (S, 2H); 7.825 (d, 1H, J=1.2 Hz); 8.487 (d, 1H, J=1.2 Hz).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH:20]1[C:25]([C@@H:26]([NH2:29])[CH2:27][OH:28])=[CH:24][CH:23]=[C:22]([F:30])[CH:21]=1.CCN(C(C)C)C(C)C>>[F:30][C:22]1[CH:21]=[CH:20][C:25]([C@@H:26]([NH:29][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[CH2:27][OH:28])=[CH:24][CH:23]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: N[C@@H](CO)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@@H](CO)c2ccc(F)cc2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Then the similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (R)-4-fluoro-phenylglycinol and DIEA to give 2-[(R)-1-(4-fluoro-phenyl)-2-hydroxy-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 394 (MH+).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si]([N:13]=[N+:14]=[N-:15])(C)(C)C.CCCCCC>CCOCC>[C:1]1([C:7]2[N:13]=[N:14][NH:15][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Product: c1ccc(-c2c[nH]nn2)cc1
Temperature: 150 °C
Yield: 76.3 %

Procedure:
##STR9## Phenylethyne (12.0 g) and Me3SiN3 (7.8 g) were sealed into a heavy-walled glass reactor at -70° C. and 0.6 mm Hg. The mixture was heated at 150° C. for 10 hrs., cooled, and dissolved in Et2O. The Et2O was treated exactly as in Example 2, reduced to 100 ml total volume, a little hexane added and chilled in a refrigerator overnight. Filtration gave 7.5 g (76%) white crystals mp 146.9-149.0.
Reaction SMILES: [CH3:1][C:2]1[NH:8][C:7](=[O:9])[C:6]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:5]=2[O:4][CH:3]=1.[H-].[Na+].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>CN(C)C=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:8]1[C:7](=[O:9])[C:6]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:5]=2[O:4][CH:3]=[C:2]1[CH3:1]
Reactant: BrCCCCCBr
Reactant: CC1=COc2ccc(C)cc2C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=COc2ccc(C)cc2C(=O)N1CCCCCBr
Reaction time: 0.5 h

Procedure:
346 mg of 4,5-dihydro-3,7-dimethyl-1,4-benzoxazepin-5-one was dissolved in 20 ml of dimethylformamide, then 88 mg (1.2 equivalents) of 60% sodium hydride was added. This was agitated for 30 minutes, then 1.68 g (4 equivalents) of 1,5-dibromopentane was added and the resultant mixture was agitated at room temperature for 4 hours.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[C:13]([NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>C(Cl)(Cl)Cl>[C:5]([CH2:4][CH2:3][CH2:2][N:25]1[CH2:26][CH2:27][CH:22]([NH:21][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:23][CH2:24]1)(=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CCCCl)c1ccccc1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(CCCN1CCC(NC(=O)c2ccccc2)CC1)c1ccccc1
Yield: 9.1 %

Procedure:
A mixture of 4-chlorobutyrophenone (447 mg, 2.45 mmol), 4-benzamidopiperidine (500 mg, 2.45 mmol) and K2CO3 (338 mg, 2.45 mmol) was heated up in boiling water bath for 1 hour. The reaction mixture was portioned between water and CHCl3. The organic layer was separated and dried over Na2SO4. After filtration and removal of solvent, the residue was purified by chromatography (SiO2, MeOH:CHCl3, 5:95). Recrystallization from AcOEt/hexane gave a white powder (78 mg, 8.2%). mp 143-144° C.; 1H NMR (CD3OD, 400 MHz) δ 1.65 (dq, J1 =3.16 Hz, J2 =11.9 Hz, 2H), 1.90-2.00 (m, 4H), 2.18 (t, J=11.9 Hz, 2H), 2.48 (m, 2H), 3.00-3.10 (m, 4H), 3.88 (m, 1H), 7.40-8.00 (m, 10H); Mass spectrum (M+1)+ at m/z 351.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:13](=[O:30])[NH:14][CH:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:16]([F:19])([F:18])[F:17])[N:8]2[CH2:11][CH3:12])=[CH:4][C:3]=1[C:31]([O:33]CC)=[O:32].B(Br)(Br)Br.O>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:13](=[O:30])[NH:14][CH:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:16]([F:17])([F:18])[F:19])[N:8]2[CH2:11][CH3:12])=[CH:4][C:3]=1[C:31]([OH:33])=[O:32]
Reactant: CCOC(=O)c1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)n(CC)c2cc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(C(=O)O)c(Cl)cc21
Temperature: -10 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
Ethyl 6-chloro-1-ethyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylate (0.10 g, 0.19 mmol) was dissolved in 5 ml of dichloromethane and a solution of boron tribromide in dichloromethane (0.96 ml, 0.96 mmol) was added dropwise at −10° C. The reaction mixture was stirred at −10° C. for 1 h and then at room temperature for 2 h. Water was added and the precipitated solid was filtered off with suction and dried. 0.077 g (71% of theory) of 6-chloro-1-ethyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylic acid was obtained.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11].N1C=CC=CC=1.[O:30](S(C(F)(F)F)(=O)=O)[S:31]([C:34]([F:37])([F:36])[F:35])(=O)=[O:32]>C(Cl)Cl>[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:14]=[CH:15]/[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[O:11][S:31]([C:34]([F:37])([F:36])[F:35])(=[O:32])=[O:30]
Reactant: COc1ccc(/C=C/c2cc(OC)c(O)c(OC)c2)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: N#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(/C=C/c2cc(OC)c(OS(=O)(=O)C(F)(F)F)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round-bottomed flask (50 mL) equipped with magnetic stir bar and N2 bubbler was charged 6 (600 mg, 2 mmol), pyridine (332 mg, 4 mmol, 2 equiv) and CH2Cl2 (20 mL) The mixture was cooled in an ice bath before Tf2O (888 mg, 3 mmol, 1.5 equiv) was added dropwise over 20 min, during which the color changed from deep red to pale orange. Afterwards, the ice bath was removed and the reaction mixture was stirred at rt overnight. A work-up similar to that used in the preparation of 1a and 2a gave an oil that slowly crystallized in vacuo (790 mg, 90%). Recrystallization from heptanes/EtOAc gave compound 7 as clear, tan needles, mp. 104-106° C. (dec.). 1H NMR (CDCl3): δ 7.46 (d, J=8.7 Hz, 2H), 7.03 (d, Jab=16.1 Hz, 1H), 6.91 (d, J=8.7 Hz, 2H), 6.89 (d, Jab=16.3 Hz, 1H), 6.72 (s, 2H), 3.93 (s, 6H), 3.84 (s, 3H); 13C NMR (CDCl3): δ 160.00, 152.69, 138.64, 130.35, 129.59, 128.21, 125.75, 118.92 (q, 1JCF=321.3 Hz), 114.49, 102.94, 56.49, 55.58; 19F {13C} NMR (CDCl3): δ −74.11. Anal. Calcd for C18H17F3O6S: C, 51.67; H, 4.10. Found: C, 51.84; H, 3.97.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([N:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6](=[O:12])[N:7]([CH3:11])[C:8](Cl)=[O:9])[CH3:4]>C(OCC)C.ClC(Cl)C>[CH2:3]([N:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([N:7]([CH3:11])[C:8]([NH:2][CH3:1])=[O:9])=[O:12])[CH3:4]
Reactant: CN
Reactant: CCN(C(=O)N(C)C(=O)Cl)c1ccccc1
Solvent: CC(Cl)Cl
Solvent: CCOCC
Product: CCN(C(=O)N(C)C(=O)NC)c1ccccc1
Reaction time: 1 h
Yield: 74.8 %

Procedure:
In 30 ml of anhydrous ethyl ether, 6.2 g (0.2 mole) of methyl amine was dissolved and cooled below 0° C. Then a solution prepared by dissolving 24.1 g (0.1 mole) of 4-ethyl-2-methyl-4-phenylallophanoyl chloride in 80 ml of anhydrous dichloroethane was added dropwise under stirring. The reaction was continued at a room temperature for 1 hour, the reaction mixture was washed with water and dried with anhydrous sodium sulfate. The solvent was removed by distillation to obtain a residue, and the residue was recrystallized from ether-petroleum ether to obtain 17.6 g (yield 75%) of 1-ethyl-3,5-dimethyl-1-phenylbiuret having a melting point of 57°-58° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:35]2[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:34])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([O:27][CH:28]([CH3:33])[CH:29]([OH:32])[CH2:30][F:31])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[CH3:43]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:35]2[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:34])[N:11]([C@H:21]2[CH2:22][CH2:23][C@H:24]([O:27][CH:28]([C:29]3([CH2:30][F:31])[CH2:43][O:32]3)[CH3:33])[CH2:25][CH2:26]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)C(O)CF)CC2)c2ncnn12
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)C3(CF)CO3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 3′-fluoro-4′-({4-[trans-4-(3-fluoro-2-hydroxy-1-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.15 g), Dess-Martin periodinane (0.22 g) and acetonitrile (2 mL) was stirred at room temperature for 12 hr. Saturated aqueous sodium hydrogen carbonate solution and aqueous sodium thiosulfate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was added to a mixture of trimethylsulfoxonium iodide (0.057 g), sodium hydride (0.010 g) and dimethyl sulfoxide (4 mL) stirred at room temperature for 1 hr in advance, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.079 g, 52%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:29])[C@H:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:28])=[CH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:15][CH:14]=1)[CH3:11].[H-].[Na+].[CH3:32]I>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:32])[C:9](=[O:29])[C@H:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:28])=[CH:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:15][CH:14]=1)[CH3:11]
Reactant: C[C@@H](Oc1ccc(OC(F)=Cc2ccccc2)cc1)C(=O)Nc1ccccc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](Oc1ccc(OC(F)=Cc2ccccc2)cc1)C(=O)N(C)c1ccccc1F
Temperature: 0 °C
Reaction time: 5 h
Yield: 73.3 %

Procedure:
0.4 g (1 mmol) of the compound obtained in Example 38 was dissolved in anhydrous tetrahydrofuran, and the mixture was cooled to 0° C. 40 mg (1 mmol) of 60% NaH and 0.14 g (1 mmol) of methyliodide were sequentially added to the reaction mixture, and the mixture was stirred at room temperature for 5 hours. Ice was added to the reaction mixture and resulting mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure. The resulting residue was subjected to column chromatography (ethyl acetate:n-hexane=1:2) to obtain the title compound (300 mg, 73.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][C:46]([N:49]4[CH2:54][CH2:53][NH:52][C:51](=[O:55])[CH2:50]4)=[CH:45][CH:44]=3)=[CH:39][CH:38]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C:23](=[O:25])[N:22](COCC[Si](C)(C)C)[S:21]3(=[O:35])=[O:34])=[CH:16][CH:15]=2)[CH:13]=1.I[CH3:57]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:44]=[CH:45][C:46]([N:49]4[CH2:54][CH2:53][N:52]([CH3:57])[C:51](=[O:55])[CH2:50]4)=[CH:47][CH:48]=3)=[CH:39][CH:38]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C:23](=[O:25])[NH:22][S:21]3(=[O:34])=[O:35])=[CH:16][CH:15]=2)[CH:13]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N5CCNC(=O)C5)cc4)cc3)cc2)S1(=O)=O
Reactant: CI
Product: CN1CCN(c2ccc(-c3ccc(Cc4nc(-c5ccc(Cl)cc5Cl)cn4-c4ccc(N5CC(=O)NS5(=O)=O)cc4)cc3)cc2)CC1=O

Procedure:
4-[4′-(4-(2,4-Dichloro-phenyl)-1-{4-[1,1,4-trioxo-5-(2-trimethylsilanyl-ethoxy methyl)-[1,2,5]thiadiazolidin-2-yl]-phenyl}-1H-imidazol-2-ylmethyl)-biphenyl-4-yl]-piperazin-2-one (17 mg, 0.02 mmol) was treated as described in general procedure L (using iodomethane) and general procedure W stepwise to give the desired compound 4-(4′-{4-(2,4-dichloro-phenyl)-1-[4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-imidazol-2-ylmethyl}-biphenyl-4-yl)-1-methyl-piperazin-2-one.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:30])[C:13]3[C:14](=[C:16]([CH2:28][CH3:29])[N:17]([C:19]4[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=4)[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:31]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH3:41])[CH2:36][CH2:35]2)(=[O:33])=[O:32])=[CH:6][N:5]=1)[CH3:2].[Cl-].[NH4+]>CO.O.[Fe]>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([N:17]2[C:16]([CH2:28][CH3:29])=[C:14]3[N:15]=[C:10]([C:9]4[C:4]([O:3][CH2:1][CH3:2])=[N:5][CH:6]=[C:7]([S:31]([N:34]5[CH2:35][CH2:36][N:37]([CH2:40][CH3:41])[CH2:38][CH2:39]5)(=[O:32])=[O:33])[CH:8]=4)[NH:11][C:12](=[O:30])[C:13]3=[N:18]2)=[CH:24][CH:23]=1
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(-c3ccc([N+](=O)[O-])cc3)nc2c(=O)[nH]1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(-c3ccc(N)cc3)nc2c(=O)[nH]1
Temperature: 60 °C

Procedure:
A solution of the title compound from example 63 (100 mg, 0.17 mmol) in methanol (2 ml) was added to a suspension of iron powder (29 mg, 0.52 mmol) in ammonium chloride (45 mg, 0.85 mmol) in water (2 ml), and the reaction heated at 60° C. for 1 hour. The cooled mixture was filtered, and the filtrate evaporated under reduced pressure to give the title compound as a pale brown solid, 93 mg.
Reaction SMILES: [CH2:1]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH:24]=[O:25])=[CH:20]N(C)C)=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[OH-:26].[Na+]>C(O)C>[CH2:1]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH:24]=[O:25])=[CH:20][OH:26])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCCCCCCCCOc1ccc(C(C=O)=CN(C)C)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: C=CCCCCCCCCCOc1ccc(C(C=O)=CO)cc1
Temperature: 25 °C

Procedure:
A solution of 21 in ethanol (75 ml) was hydrolysed with aqueous sodium hydroxide solution (60 ml, 25%). The reaction mixture was stirred and heated under reflux (3 h), cooled to room temperature and the ethanol removed in vacuo to yield an off-white solid which was filtered and washed thoroughly with water. The solid was suspended in a 50% ethanol/water mixture (150 ml) and acidified with concentrated hydrochloric acid. The suspended solid whitened in colour and was collected by filtration, then recrystallised from petroleum ether (bp 60-80° C.). Yield=3.97 g (38%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18](C4C=NC(Cl)=CC=4)([C:20]4[N:21]([CH3:25])[CH:22]=[N:23][CH:24]=4)[OH:19])[CH:16]=3)[N:11]=[C:10]([O:33]C)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[ClH:35]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:10]4[CH:9]=[CH:8][C:17]([Cl:35])=[CH:12][N:11]=4)([OH:19])[C:20]4[N:21]([CH3:25])[CH:22]=[N:23][CH:24]=4)[CH:16]=3)[NH:11][C:10](=[O:33])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cl
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)nc3)c3cncn3C)ccc2n1
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1)c1ccc(Cl)cn1
Yield: 26 %

Procedure:
Following the same procedure as described in example 1 F, the obtained [4-(3-chloro-phenyl)-2-methoxy-quinolin-6-yl]-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methanol was treated with HCl in aqueous THF to yield the title compound, 1.02 g, (2.14 mmol, 26% yield).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH:18]([C:19](O)=[O:20])[CH2:17][CH:16]3[CH2:22][CH2:23][CH2:24][CH:15]23)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].ClC(OCC)=O.C(N1CCOCC1)C.C[Si]([NH:43][OH:44])(C)C>CN(C=O)C>[OH:44][NH:43][C:19]([CH:18]1[N:14]([S:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)(=[O:13])=[O:12])[CH:15]2[CH2:24][CH2:23][CH2:22][CH:16]2[CH2:17]1)=[O:20]
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)N2C(C(=O)O)CC3CCCC32)cc1
Reactant: C[Si](C)(C)NO
Agent: CCN1CCOCC1
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(S(=O)(=O)N2C(C(=O)NO)CC3CCCC32)cc1
Temperature: 80 °C

Procedure:
200 mg (0.55 mmol) of 1-(4-methanesulfonylbenzenesulfonyl)octahydrocyclopenta-[b]pyrrole-2-carboxylic acid were dissolved in 10 ml of DMF, after which 0.60 mmol of ethyl chloroformate, 1.22 mmol of N-ethylmorpholine and 1.67 mmol of trimethylsilylhydroxylamine were added. After the mixture had been heated at 80° C. for 4 h, the solvent was removed under reduced pressure and the crude product was purified using chromatographic methods.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([OH:20])=[O:19].[I:21]N1C(=O)CCC1=O>C1COCC1>[I:21][C:17]1[S:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=1
Reactant: O=C(O)c1cccs1
Reactant: O=C1CCC(=O)N1I
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1ccc(I)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 10.9 mL (78.0 mmol) of freshly distilled diisopropylamine in 150 mL of THF under argon at -78° C. was added 48.7 mL (78.0 mmol) of 1.6 M n-BuLi in hexanes to give a pale yellow solution which was allowed to stir at -78° C. for 10 min when 5.0 g (39.0 mmol) of 2-thiophenecarboxylic acid in 31 mL of THF was added dropwise over 10 min to give a grey-white suspension. The metallation was allowed to proceed for 30 min when 8.77 g (39.0 mmol) of N-iodosuccinimide in 25 mL of THF was added very rapidly to give an orange-yellow solution which was allowed to gradually warm to 0° C. After 0.5 h at 0° C., the brown-yellow mixture was quenched with water, diluted with ether and made acidic by the addition of solid citric acid to give a very dark brown-orange solution. The organic layer was separated and washed with water, saturated NaHSO3, brine, dried over MgSO4 and evaporated to provide 9.5 g (96%) of title acid as a brown-yellow solid which was used directly in the following reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: COc1cccc(/C=C\C(=O)O)c1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cccc(CCC(=O)O)c1OC
Yield: 95.9 %

Procedure:
Nitrogen was passed through a stirred suspension of (Z)-3-(2,3-dimethoxyphenyl)-2-propenoic acid (14,67 g) in 400 ml of methanol during 15 minutes. Then 1.4 g of 10% palladium on activated carbon were added and a stream of hydrogen was passed through the reaction mixture for 16 hours. After removing the palladium catalyst by filtration, the filtrate was evaporated to yield 14.2 g of 3-(2,3-dimethoxyphenyl)-propanoic acid, M.S. (C.I.) (MZ): 211 [M+H]+.