Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1.O>CN1C(=O)CCC1>[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:2]2[C:3]([CH:8]3[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:33][CH:32]=1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: O=C1CCCC(c2nccnc2F)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1CCCC(c2nccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)C1
Temperature: 125 °C

Procedure:
Argon was bubbled through a mixture of (rac)3-(3-fluoropyrazin-2-yl)cyclohexanone (250 mg, 1.287 mmol), cesium carbonate (1258 mg, 3.86 mmol) and 4-(benzo[d]thiazol-2-ylamino)phenol (468 mg, 1.931 mmol) in NMP (3 ml) for 5 min. The mixture was heated to 125° C. for 3 hrs and was then cooled to RT. Distilled water (100 ml) was added and the resulting mixture was extracted with EtOAc (3×50 ml). The organic layer was washed with water and brine and dried over sodium sulfate. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (20% to 50% EtOAc in hexanes) afforded (rac)-3-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)cyclohexanone as a white solid. MS (ESI, pos. ion) m/z: 417.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH:6]([N:14]([CH2:21][C:22]1[N:23]=[C:24]2[C:29](=[N:30][CH:31]=1)[N:28]=[C:27]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[NH:26][C:25]2=[O:38])[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[C:7]([O:9]C(C)(C)C)=[O:8]>C(O)(C(F)(F)F)=O.ClCCl>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH:6]([N:14]([CH2:21][C:22]1[N:23]=[C:24]2[C:29](=[N:30][CH:31]=1)[N:28]=[C:27]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[NH:26][C:25]2=[O:38])[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[C:7]([OH:9])=[O:8]
Reactant: COC(=O)CCC(C(=O)OC(C)(C)C)N(Cc1cnc2nc(NC(=O)C(C)C)[nH]c(=O)c2n1)C(=O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCC(C(=O)O)N(Cc1cnc2nc(NC(=O)C(C)C)[nH]c(=O)c2n1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 120.8 %

Procedure:
The ester 143 (2 g, 2.9 mmol) was dissolved in 20 mL of 50% TFA in dichloromethane and the solution was stirred at room temperature for 30 min. after which the TLC showed the complete disappearance of the starting ester. The reaction mixture was concentrated and the residue was crystallized from CH2Cl2:Hexanes (2:3) and crystallized product was filtered off and dried to obtain the pure product 144 (1.76 g, 96%) as off white powder. 1H NMR (DMSO-d6, 400 MHz) δ=12.32 (bs, 1H), 11.94 (s, 1H), 8.88 (s, 1H), 8.84 (d, J=7.4 Hz, 1H), 7.90 (d, J=8.3 Hz, 2H), 7.69 (d, J=8.3 Hz, 2H), 5.22 (s, 2H), 4.45-4.41 (m, 1H), 3.62 (s, 3H), 2.78-2.75 (m, 1H), 2.35 (t, J=7.4 Hz, 2H) 2.07-1.92 (m, 2H), 1.12 (d, J=6.8 Hz, 6H). 13C NMR DMSO-d6) δ=180.77, 173.70, 172.19, 165.70, 159.21, 155.54, 149.93, 149.84, 147.75, 141.78, 134.18, 130.53, 128.71, 128.49, 117.51, 114.64, 53.98, 52.06, 51.93, 34.97, 30.11, 25.68, 18.73. MS. Molecular weight calculated for C26H26F3N7O8, Cal. 621.18, Found 620.18 (M−H−).
Reaction SMILES: C(OC(O[CH2:8][CH3:9])CBr)C.COCCOC.C(=O)([O-])O.[Na+].[NH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:25]=[CH:24][N:23]=1>Br.O>[F:31][C:28]([F:29])([F:30])[C:26]1[N:25]=[CH:24][N:23]2[CH:8]=[CH:9][N:21]=[C:22]2[CH:27]=1
Reactant: CCOC(CBr)OCC
Reactant: Nc1cc(C(F)(F)F)ncn1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: FC(F)(F)c1cc2nccn2cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 105.4 %

Procedure:
A stirred mixture of bromoacetaldehyde diethyl acetal (2.09 ml, 13.5 mmol) in concentrated hydrobromic acid (0.68 ml) and water (0.68 ml) was heated at reflux under nitrogen for 20 min. The solution was allowed to cool to room temperature, ethylene glycol dimethyl ether (5 ml) was added and the solution was neutralised to pH 7 with solid sodium hydrogen carbonate. The mixture was filtered and the solid was washed with more ethylene glycol dimethyl ether (7 ml). To the combined filtrates was added 4-amino-6-trifluoromethylpyrimidine (2.00 g, 12.3 mmol) and the mixture was stirred at 65° C. for 18 h. After allowing to cool, the solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 5% MeOH/CH2Cl2) to give 2.426 g of 7-trifluoromethylimidazo[1,2-c]pyrimidine: 1H NMR (360 MHz, CDCl3) δ 7.81 (1H, s), 7.86 (1H, s), 7.96 (1H, s), 9.13 (1H, s).
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[NH2:29][C@@H:30]([CH2:33][CH3:34])[CH2:31][OH:32]>>[CH2:33]([C@H:30]([NH:29][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:26])[CH3:27])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:6][CH:5]=1)=[O:28])[CH2:31][OH:32])[CH3:34]
Reactant: CC[C@H](N)CO
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Product: CC[C@@H](CO)NC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Yield: 79 %

Procedure:
By the same procedure as described in the example 31, synthesis was carried out starting with 4-[1-[3-(isopropylamino)-2-pyridyl]piperazin4-yl-carbonyl]benzoic acid methyl ester and using (S)-(+)-2-amino-1-butanol. Then, the product was recrystallized using acetonitrile and isopropyl ether to give the desired compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:5](=[N:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[S:6][CH:7]=1.[H-].[Na+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH2:33]([O:1][CH2:2][C:3]1[N:4]([CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:5](=[N:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:17])[F:18])=[CH:11][CH:10]=2)[S:6][CH:7]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCn1c(CO)csc1=Nc1ccc(OC(F)(F)F)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCn1c(COCc2ccccc2)csc1=Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (313 mg) obtained in the above (2) was dissolved in N,N-dimethylformamide (3 ml), and thereto was added sodium hydride (56 mg, 60% dispersion in oil) in an ice bath under nitrogen atmosphere, and the mixture was stirred for 30 minutes. To the reaction mixture was added benzyl bromide (179 mg), and the mixture was warmed to room temperature, and then stirred for one hour. The reaction mixture was poured into a 10% aqueous citric acid solution under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane:ethyl acetate (5:1)] to give the title compound (137 mg) as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[O:7])=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[O:7])=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: CC(C(=O)O)C(=O)c1ccc(Cl)cc1
Product: CC(C(=O)O)C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To fuming nitric acid (150 ml) was added p-chlorobenzoylpropionic acid (20.0 g), slowly portionwise at 0° C. After the addition was completed the resulting mixture was stirred at 0° C. for 30 minutes and the resulting white solid was suction filtered and washed with water until the pH of the washing liquids was neutral, then dried to yield 3-(4-chloro-3-nitrobenzoyl)propionic add as a white solid (13.0 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=1)#[N:2].[C:19](OC)(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[SH:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:13]1([CH2:12][CH2:11][CH2:10][S:9][C:5]2[N:4]=[C:3]([C:1]3[S:22][C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[C:19](=[O:27])[N:2]=3)[CH:8]=[CH:7][CH:6]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(SCCCc2ccccc2)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccc(SCCCc3ccccc3)n2)sc2ccccc12
Yield: 37.6 %

Procedure:
2-Cyano-6-(3-phenylpropylthio)pyridine (1.84 g, 7.22 mmol) and methyl thiosalicylate (1.21 g, 7.22 mmol) were dissolved in toluene (30 ml), and triethylamine (1.52 ml, 10.8 mmol) was added thereto. The reaction mixture was refluxed for 48 hrs. The solvent was evaporated and the residue was recrystallized from ethanol to give the titled compound (1.06 g, 38%) as pale yellow crystals.
Reaction SMILES: [CH2:1]1[O:5][CH2:4][O:3][CH:2]1[CH2:6][OH:7].N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][Cl:19])=[O:16]>CCOCC>[C:15](=[O:16])([O:7][CH:6]1[CH2:2][O:3][CH2:4][O:5][CH2:1]1)[O:17][CH2:18][Cl:19]
Reactant: O=C(Cl)OCCl
Reactant: OCC1COCO1
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(OCCl)OC1COCOC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 6.4 %

Procedure:
Glycerol formal (14 g) was dissolved in anhydrous ether (400 ml) and, after adding pyridine (15 g) at −10° C., a solution of chloromethyl chloroformate (25 g) in anhydrous ether (50 ml) was added dropwise over the period of 10 minutes. After the reaction solution was stirred at room temperature for 20 hours, the deposited pyridine hydrochloride was removed by filtration. The filtrate was washed with a saturated sodium chloride aqueous solution (400 ml×2), and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by subjecting it to silica gel chromatography (eluent: ethyl acetate/hexane=1/5→ethyl acetate/hexane=1/3) to obtain chloromethyl (1,3-dioxan-5-yl) carbonate (1.7 g) as a colorless oily product.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[C@H:3]1[CH2:17][CH2:18][C:19](O)=[O:20].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C1COCC1.C(Cl)Cl>[O:1]=[C:2]1[O:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[C@H:3]1[CH2:17][CH2:18][CH:19]=[O:20]
Reactant: O=C(O)CC[C@H]1C(=O)OCN1C(=O)OCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=CCC[C@H]1C(=O)OCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.4 %

Procedure:
A solution of 27 g (92.7 mmol) of the crude acid (43c) in 200 mL of THF is cooled to 0° C. and 13 mL (10.7 g, 141 mmol) of borane-methyl sulfide complex is added dropwise via an addition funnel. The reaction is allowed to warm gradually to room temperature and stirred for 12 h. The resulting mixture is concentrated in vacuo to give a white glassy material which is taken up in 500 mL of methylene chloride and treated with of pyridinium chlorochromate (61 g, 281 mmol) at 0° C. in the presence of 3 -- molecular sieve. The mixture is allowed to warm to room temperature and stirred for 3 h. The mixture is filtered through diatomaceous earth with ether (200 mL) then concentrated. The residue is taken up in ether and filtered again through diatomaceous earth with ether then concentrated to give 13.22 g of the crude aldehyde as a light green oil: NMR δ9.80 (br s, 1H), 7.40 (m, 5H), 5.55 (br s, 1H), 5.20 (m, 3H), 4.38 (t, J=6.0 Hz, 1H), 2.6-2.1 (m, 4H).
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7](I)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:22]([O:26][C:27]([N:29]1[CH2:30][CH:31]=[C:32]([C:7]2[N:6]=[C:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=23)[CH2:33][CH2:34]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Nc1nccn2c(C3CCC3)nc(I)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2nc(C3CCC3)n3ccnc(N)c23)CC1
Temperature: 100 °C

Procedure:
To a stirred mixture of 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-amine (100.00 mg, 0.318 mmol), potassium carbonate (154.0 mg, 1.11 mmol) in DME (3.0 mL) and H2O (0.70 mL) was added 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (118.1 mg, 0.38 mmol). The solution was bubbled with nitrogen for 5 min. Then Pd(PPh3)4 (18 mg, 0.016 mmol) was added and the resulting mixture was refluxed at 100° C. for 30 min. The solvent was then removed under reduced pressure and the resulting residue was purified by a flash chromatography (2% MeOH in DCM). 1H NMR (400 MHz, MeOD) δ 1.53 (s, 9H), 1.95-2.07 (m, 1H), 2.14-2.28 (m, 1H), 2.44-2.54 (m, 4H), 2.62-2.71 (m, 2H), 3.73 (t, J=5.68 Hz, 2H), 3.87-3.98 (m, 1H), 4.12-421 (m, 2H), 5.94-6.00 (m, 1H), 6.96 (d, J=5.20 Hz, 1H), 7.33 (d, J=5.20 Hz, 1H). MS (ES+): m/z: 369.94, [MH+], HPLC: tR=2.33 min (OpenLynx, polar—5 min).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]1[S:18][C:17]([N:19]2[C:23]([C:24](O)=[O:25])=[CH:22][C:21]([C:27]([F:30])([F:29])[F:28])=[N:20]2)=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][O:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH2:37].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:32][O:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH:37][C:24]([C:23]1[N:19]([C:17]2[S:18][C:14]([CH2:13][NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH3:31])=[CH:15][CH:16]=2)[N:20]=[C:21]([C:27]([F:29])([F:30])[F:28])[CH:22]=1)=[O:25]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccc(-n2nc(C(F)(F)F)cc2C(=O)O)s1
Reactant: COc1ccccc1CN
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1ccc(CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24.2 %

Procedure:
To a stirred solution of 25 (0.059 g, 0.128 mmol) in pyridine (0.851 mL) at 0° C. was added 2-methoxybenzylamine (0.020 mL, 0.153 mmol) and followed by dropwise addition of POCl3 (0.013 mL, 0.140 mmol). The mixture was stirred for 30 min at 0° C., then for 1 h from 0° C. to 21° C., then for 16 h at room temperature. The mixture was quenched with water and extracted with ethyl acetate, washed with brine, dried (MgSO4) filtered and concentrated. The residue was purified by silica gel column chromatography with gradient of EtOAc (20-60%) in hexanes to afford 26e (18 mg, 24%) as a white solid. LRMS (ESI): calc. 581.2; found 604.3 (MNa)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[C:4]([F:24])[CH:3]=1.IC.[C:27](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:27])[CH:17]=2)=[O:11])=[C:4]([F:24])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(CC(c1ccc(Br)cc1F)C1CCCC1)c1ccc(=O)[nH]c1
Agent: [K+]
Solvent: CI
Product: Cn1cc(C(=O)CC(c2ccc(Br)cc2F)C2CCCC2)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-2-fluoro-phenyl)-3-cyclopentyl-propionyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless oil, MS (ESI+): m/z=406.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35].C([O-])(O)=O.[Na+]>ClCCl>[O:23]=[C:15]1[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:2]3([CH3:1])[CH2:7][CH2:6][N:5]([C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:4][CH2:3]3)[CH2:9][CH2:10]2)[C@@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]2[NH:16]1
Reactant: CC(C)OC(=O)Cl
Reactant: CC1(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
A solution of (3aR,7aR)-1-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (HCl salt, 99 mg, 0.25 mmol) and diisopropylethylamine (129.3 mg, 1.0 mmol) in dry dichloromethane (5 mL) at 0° C. was added dropwise with a solution of 1.0 N isopropyl chloroformate in dichloromethane (0.3 mL, 0.3 mmol) and was stirred at room temperature for 3 h. Saturated NaHCO3 (5 mL) was added followed by dichloromethane (20 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2×10 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified with preparative LC/MS (high pH) to give the title compound (52 mg, 51%). 1H NMR (400 MHz, METHANOL-D4) δ ppm 0.98 (s, 3H), 1.21 (d, J=6.25 Hz, 6H), 1.30-1.51 (m, 6H), 1.61 (d, J=11.33 Hz, 1H), 1.67-1.89 (m, 7H), 1.95 (d, J=7.42 Hz, 1H), 2.13-2.34 (m, 3H), 2.85-3.16 (m, 4H), 3.28-3.41 (m, 2H), 3.47-3.68 (m, 3H), 4.77-4.85 (m, 1H). MS (M+1): 407.3.
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][S:2]1(=[O:11])=[O:10].[Br:12]Br>C(Cl)(Cl)(Cl)Cl.[Fe]>[Br:12][C:9]1[C:4]2[CH2:3][S:2](=[O:10])(=[O:11])[CH2:1][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: BrBr
Reactant: O=S1(=O)Cc2ccccc2C1
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: O=S1(=O)Cc2cccc(Br)c2C1

Procedure:
1,3-Dihydrobenzo[c]thiophene 2,2-dioxide, previously described, is brominated with 1 equivalent of bromine in carbon tetrachloride solution in the presence of iron [CA 84, 89930 (1976)] at reflux until the bromine color disappears to give 4-bromo-1,3-dihydrobenzo[c]thiophene 2,2-dioxide.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:20][S:17]([C:14]2[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=2)(=[O:19])=[O:18])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: O=S(=O)(N=Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A stirred solution consisting of 7.03 g (5.0 mmol) of 4-chlorobenzaldehyde, 9.58 g (5.0 mmol) of 4-chlorobenzenesulfonamide, 8 g of 4A molecular sieves and 0.1 g of Amberlite IR-120 in 90 mL of toluene was heated to reflux. The reaction vessel was fitted with a Dean Stark trap which was filled with 4A molecular sieves. The mixture was heated for 4 hours, at which point TLC analysis showed conversion to sulfonimine. The mixture was allowed to cool to room temperature and was filtered. Concentration of the filtrate and subsequent recrystallization of the crude product from CHCl3 -hexane gave 7.84 g (50%) of sulfonimine as a white crystalline material: IR 3090, 1598, 1582, 1553, 1321, 1084 cm1 ; 1H NMR (CDCl3, TMS, 60 MHz) & 9.02 (s, 1), 7.73 (A2B2, 4, Δ√=24 Hz, JAB =8 Hz), 7.67 (A2B2, 4, Δ√=23 Hz, JAB =9 Hz); m.p. 128.0 ° C.
Reaction SMILES: [C:1]1([PH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(P(CCC)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(O[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=1[Br:68])(=O)=O.C(N(C(C)C)CC)(C)C.Cl>C1(C)C=CC=CC=1>[Br:68][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][C:62]=1[P:11]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(Pc3cccc4ccccc34)cccc2c1
Reactant: O=S(=O)(Oc1ccccc1Br)C(F)(F)F
Agent: CCCP(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Brc1ccccc1P(c1cccc2ccccc12)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.2 %

Procedure:
Into a four-neck flask were weighed 16.89 g (59.0 mmol) of di(1-naphthyl)phosphine, 1.27 g (2.5 mmol) of Pd2(dba)3CHCl3 (dba represents dibenzylideneacetone), and 1.01 g (2.5 mmol) of diphenylphosphinopropane. The atmosphere of the reaction vessel fitted with a thermometer, a condenser tube, and a dropping funnel with a pressure-equalizing tube was completely replaced with nitrogen. Thereto were added 150 mL of toluene, 15.00 g (49.2 mmol) of 2-(trifluoromethanesulfonyl)oxy-bromobenzene (5), and 9.53 g (73.8 mmol) of diisopropylethylamine, followed by 16 hours of heating at reflux. After the completion of the reaction, the reaction mixture was cooled to room temperature and poured into 150 mL of 5% hydrochloric acid aqueous solution. After 30 minutes of stirring, the layers were separated from each other. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. Toluene was removed by evaporation and the residue was purified by silica gel column chromatography to obtain the title compound (10.68 g, a pale yellow solid). Yield 49.2%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[S:9][CH:10]=[CH:11][N:12]=1>COC(O)C>[N:1]1([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Brc1nccs1
Reactant: C1CNCCN1
Agent: COC(C)O
Product: c1csc(N2CCNCC2)n1
Yield: 72.3 %

Procedure:
A mixture of piperazine (6.88 g) and 2-bromothiazole (2.28 g) in methoxyethanol (30 ml) was refluxed for 2.5 hr and evaporated. Water was added and the mixture was extracted with dichhloromethane. The extract was washed with water, dried over sodium sulfate and evaporated to give an oil (1.7 g) of 2-(1-piperazinyl)-thiazole.
Reaction SMILES: C(NC(=S)NC1C=CC=CC=1)CCC.[Br:15]CC(C1C=CC(Cl)=C(S(=O)(=O)N(C)C)C=1)=O.Br.[CH2:33]([N:37]1[C:41]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([S:50](=[O:55])(=[O:54])[N:51]([CH3:53])[CH3:52])[CH:44]=2)(O)[CH2:40][S:39][C:38]1=[N:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[CH3:63])[CH2:34][CH2:35][CH3:36]>>[BrH:15].[CH2:33]([N:37]1[C:41]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([S:50](=[O:54])(=[O:55])[N:51]([CH3:53])[CH3:52])[CH:44]=2)=[CH:40][S:39][C:38]1=[N:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[CH3:63])[CH2:34][CH2:35][CH3:36]
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Reactant: CCCCN1C(=Nc2ccccc2C)SCC1(O)c1ccc(Cl)c(S(=O)(=O)N(C)C)c1
Agent: Br
Agent: CCCCNC(=S)Nc1ccccc1
Product: CCCCn1c(-c2ccc(Cl)c(S(=O)(=O)N(C)C)c2)csc1=Nc1ccccc1C

Procedure:
Obtained (a) by a procedure analogous to that indicated in Example 1(a), from 3-n-butyl-1-phenylthiourea and 2-bromo-4'-chloro-3'-dimethylsulfamoylacetophenone, or (b) from 3-n-butyl-4-(4-chloro-3-dimethylsulfamoylphenyl)-2-(2-methylphenyl-imino)-thiazolidin-4-ol hydrobromide. Colorless crystals; melting point 238° C.