Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9].[H-].[Na+].[S:12]1[C:16]([C:17]2[C:22]([Br:23])=[CH:21][N:20]=[C:19](Cl)[N:18]=2)=[CH:15][C:14]2[CH:25]=[CH:26][CH:27]=[CH:28][C:13]1=2>C1COCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[S:12]1[C:16]([C:17]2[C:22]([Br:23])=[CH:21][N:20]=[C:19]([O:1][CH2:2][CH2:3][N:4]3[CH2:8][CH2:7][NH:6][C:5]3=[O:9])[N:18]=2)=[CH:15][C:14]2[CH:25]=[CH:26][CH:27]=[CH:28][C:13]1=2
Reactant: Clc1ncc(Br)c(-c2cc3ccccc3s2)n1
Reactant: O=C1NCCN1CCO
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1NCCN1CCOc1ncc(Br)c(-c2cc3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2-Hydroxyethyl)imidazolidin-2-one (0.6 g, 4.6 mmol) was taken up in anhydrous THF (5 mL) and added dropwise to a reaction flask containing a suspension of sodium hydride (0.147 g (60% in oil), 3.68 mmol) in anhydrous THF (10 mL) at 0° C. The ice bath was removed and the reaction allowed to warm up to room temperature over a 2 h period. 4-(benzo[b]thiophen-2-yl)-5-bromo-2-chloropyrimidine (0.3 g, 9.2 mmol), dissolved in THF was added dropwise. The reaction was stirred overnight. The reaction was then diluted with ethyl acetate and saturated sodium bicarbonate. The organic layer was then washed with water and brine. The organic portion was dried with sodium sulfate and then purified by flash chromatography on silica gel using a gradient of 0 to 10% methanol in dichloromethane to give a white solid. Yield=0.085 g. MS (M+H)+ 420.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[C:12]([NH:14][C@H:15]([C:19]([NH:21][CH:22]([C:31](=[O:34])[CH2:32][F:33])[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1.C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[C:12]([NH:14][C@H:15]([C:19]([NH:21][CH:22]([C:31](=[O:34])[CH2:32][F:33])[CH2:23][C:24]([OH:26])=[O:25])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13]
Reactant: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF)C(C)C)n(C)c2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)O)C(=O)CF)C(C)C)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A solution of N-[(1,3-dimethylindole-2-carbonyl)valinyl]-3-amino-4-oxo-5-fluoropentanoic acid, t-butyl ester (40 mg) in anisole (0.2 mL) and methylene chloride (2 mL) was treated with trifluoroacetic acid (1 mL), and the resultant reaction mixture was stirred for 30 minutes under a nitrogen atmosphere at room temperature. The reaction mixture was concentrated and chased with methylene chloride to give a solid. The solid was triturated with ether to yield the title product as a brown powder (17 mg). TLC: (methylene chloride/methanol/acetic acid, 20:1:1): Rf=0.40. MS (El) for C12H26FN3O5: MH+=420; MH=418.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][O:8][CH2:7][C:6]2([CH3:14])[CH3:13].BrB(Br)Br.O>C(Cl)Cl>[CH3:13][C:6]1([CH3:14])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([OH:2])[CH:4]=2)[CH2:9][O:8][CH2:7]1
Reactant: COc1ccc2c(c1)C(C)(C)COC2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC1(C)COCc2ccc(O)cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 12.9 %

Procedure:
6-methoxy-4,4-dimethyl-3,4-dihydro-1H-isochromene (Intermediate 41, 350 mg, 1.8205 mmol) was dissolved in DCM (10 mL) and the solution was cooled to 0° C. Tribromoborane (228.04 mg, 0.9102 mmol) was added and the resulting mixture was stirred at 0° C. for 2 hours. Water (10 mL) was added and the two phases were separated. Organics were dried over Na2SO4, filtered and dried in vacuo. The crude was purified by flash chromatography (Biotage system) on silica gel using a SNAP 25 g as column and cyclohexane/ethyl acetate from 100:0 to 70:30 as eluent affording the title compound (42 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@:8]([CH:28]=[CH2:29])([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.C1COCC1>[Pd].CO>[CH2:28]([C@@:8]12[CH2:7][CH2:6][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][C:18]=3[C@H:17]1[CH2:16][CH2:15][C@@:13]1([CH3:14])[C@H:9]2[CH2:10][CH2:11][C@@H:12]1[O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH3:29]
Reactant: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1CC[C@]1(C)[C@@H](OC3CCCCO3)CC[C@H]12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@@]12CCc3cc(OC)ccc3[C@H]1CC[C@]1(C)[C@@H](OC3CCCCO3)CC[C@H]12

Procedure:
0.50 g of 13a was dissolved in 25 ml of solvent mixture that consists of THF and methanol (v/v=7/3) and stirred with 0.30 g of palladium (10% on magnesium carbonate) for 3.75 hours at room temperature under hydrogen atmosphere. Then, the reaction solution was filtered on Celite, the filtrate was evaporated to the dry state in a rotary evaporator and the bright foam that was obtained was used without additional purification in the next stage.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:13]=1[C:14](Cl)=[O:15].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:14](=[O:15])[C:13]2[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:12]=2[Cl:11])=[CH:5][CH:4]=1
Reactant: Cc1cccc(Cl)c1C(=O)Cl
Reactant: COc1ccc(CN)cc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2c(C)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (4-methoxyphenyl)methanamine (264 g, 2.4 mol, 1.eq) in DCM (1800 mL), a solution of 2-chloro-6-methylbenzoyl chloride (340) in DCM (150 mL) was added dropwise while keeping the reaction temperature between 25° C. to 40° C. The resulting mixture was stirred at RT for 2 h, and then water (600 mL) was added. The organic layer was separated, washed with water (2×300 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was slurried in petroleum ether (300 mL) and stirred at RT for 30 min. The solid was collected by filtration and further dried in vacuo to afford N-(4-methoxybenzyl)-2-chloro-6-methylbenzamide (341).
Reaction SMILES: BrCCBr.[O:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11].Br[C:13]([F:20])([F:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1COCC1.CCOCC.[Zn].[Cl-].[Cl-].[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Ti+2]>[F:19][C:13]([F:20])([C:6]1([OH:11])[CH2:7][CH2:8][CH2:9][CH2:10][O:5]1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=C1CCCCO1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Ti+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: BrCCBr
Solvent: CCOCC
Product: CCOC(=O)C(F)(F)C1(O)CCCCO1
Temperature: 25 °C
Reaction time: 0.21 h
Yield: 32.6 %

Procedure:
Neat 1,2-dibromoethane (0.094 g, 0.500 mmol) was added to a suspension of zinc (1.308 g, 20.00 mmol) in THF (7 mL). The reaction mixture was sonicated for 3 h and cooled to rt and was added with titanocene dichloride (0.062 g, 0.250 mmol) and stirred for 10-15 min. A solution of tetrahydro-2H-pyran-2-one (0.501 g, 5 mmol) in THF (3 ml) was added, then followed by addition of a solution of ethyl 2-bromo-2,2-difluoroacetate (1.218 g, 6.0 mmol) in THF (3 mL) and the mixture was stirred at rt overnight. The reaction was cooled (0° C.) and diluted with ether and washed with 1 N HCl, water, brine and dried (MgSO4). Evaporation of solvents afforded an oil which was purified by silica gel FCC (5-10% EtOAc in DCM) to afford ethyl 2,2-difluoro-2-(2-hydroxytetrahydro-2H-pyran-2-yl)acetate as a clear oil (365 mg, 32.5%). A neat mixture of ethyl 2,2-difluoro-2-(2-hydroxytetrahydro-2H-pyran-2-yl)acetate (˜200 mg), triethylsilane (0.799 mL, 5.00 mmol) and TFA (0.385 mL, 5.00 mmol) was heated at 60° C. for 3 h and evaporated to dryness to afford an oil which was purified by silica gel FCC (DCM0 to yield ethyl 2,2-difluoro-2-(tetrahydro-2H-pyran-2-yl)acetate as a clear oil (145 mg, 78%) which was saponified (1 N NaOH, THF-MeOH, rt) to provide Cap P-35 as a white solid (75 mg, 83%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.35-7.13 (m, 1H), 4.14-4.05 (m, J=11.2, 4.3 Hz, 1H), 3.95-3.82 (m, 1H), 3.57-3.47 (m, J=11.7, 11.7, 2.3 Hz, 1H), 2.05-1.94 (m, 1H), 1.86-1.76 (m, 1H), 1.73-1.50 (m, 4H).
Reaction SMILES: [O-:1][C:2]([CH:4]([C:6]1[CH:15]=[CH:14][C:9]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=1)[CH3:5])=[O:3].[Na+].S(=O)(=O)(O)O.[Cl-].[Na+]>>[OH:3][C:2]([CH:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:14][CH:15]=1)[CH3:5])=[O:1]
Reactant: CC(C)Cc1ccc(C(C)C(=O)[O-])cc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Yield: 93.2 %

Procedure:
The aqueous basic fraction containing sodium ibuprofen salt was acidified with 6N sulfuric acid, sodium chloride was added, and then extracted twice with Skellysolve B to take up the ibuprofen acid product therein. The Skellysolve B phase was dried over sodium sulfate and evaporated to leave as residue 867.7 mg. (93.2 percent yield) of ibuprofen which was 99.9 percent pure by gas liquid chromatographic (GLC) analysis.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[CH3:26][N:27]1[C:31](=[O:32])[CH2:30][NH:29][C:28]1=[O:33]>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:29]4[CH2:30][C:31](=[O:32])[N:27]([CH3:26])[C:28]4=[O:33])=[CH:3][C:4]=3[F:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: CN1C(=O)CNC1=O
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CC(=O)N(C)C4=O)cc3F)CC2)c(C)c1
Yield: 65.2 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (163 mg) described in Preparation Example 211 and 3-methylimidazolidine-2,4-dione (68 mg) described in Preparation Example 214 and by the reaction and treatment in the same manner as in Example 536, the title compound (115 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[S:13][C:14]([C:21]3([CH3:24])[CH2:23][CH2:22]3)=[C:15]([CH2:17][N:18]([CH3:20])[CH3:19])[N:16]=2)=[O:10])=[C:4]([F:25])[CH:3]=1.[N:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N:35]3[CH:38]=[CH:39][N:40]=[C:34]3[CH:33]=2)=[CH:28][CH:27]=1.C([O-])(=O)C.[K+].C(C1C=C(C(C)(C)C)C=CC=1OP(OC1C=CC(C(C)(C)C)=CC=1C(C)(C)C)OC1C=CC(C(C)(C)C)=CC=1C(C)(C)C)(C)(C)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN1C(=O)CCC1>[CH3:19][N:18]([CH2:17][C:15]1[N:16]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:38]3[N:35]4[CH:36]=[CH:37][C:32]([C:29]5[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=5)=[CH:33][C:34]4=[N:40][CH:39]=3)=[CH:3][C:4]=2[F:25])[S:13][C:14]=1[C:21]1([CH3:24])[CH2:23][CH2:22]1)[CH3:20]
Reactant: c1cc(-c2ccn3ccnc3c2)ccn1
Reactant: CN(C)Cc1nc(NC(=O)Cc2ccc(Br)cc2F)sc1C1(C)CC1
Agent: CC(=O)[O-]
Agent: CC(C)(C)c1ccc(OP(Oc2ccc(C(C)(C)C)cc2C(C)(C)C)Oc2ccc(C(C)(C)C)cc2C(C)(C)C)c(C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN1CCCC1=O
Product: CN(C)Cc1nc(NC(=O)Cc2ccc(-c3cnc4cc(-c5ccncc5)ccn34)cc2F)sc1C1(C)CC1
Temperature: 120 °C
Yield: 20.7 %

Procedure:
Combine 2-(4-bromo-2-fluoro-phenyl)-N-[4-dimethylaminomethyl-5-(1-methyl-cyclopropyl)-thiazol-2-yl]-acetamide (0.45 g, 1.06 mmol), 7-pyridin-4-yl-imidazo[1,2-a]pyridine (0.206 g, 1 equiv.), potassium acetate (0.52 g, 5 equiv.), tetrabutylammonium bromide (0.34 g, 1 equiv.), tris(2,4-di-t-butylphenyl)phosphite (0.034 g, 5 mol %) and NMP (10 mL). De-gas with nitrogen then add palladium (II) acetate (0.012 g, 5 mol %) and place under nitrogen. Heat at 120° C. for 24 hours then let stir at room temperature for an additional day. Dilute with ethyl acetate then wash with water, 1 N NaOH (aq), and aqueous saturated sodium chloride. Dry organics over MgSO4, then filter and concentrate. Purify by reverse phase C18 column HPLC employing a gradient of 5 to 65% to 100% acetonitrile versus 0.03% aqueous HCl then freebase by extraction with ethyl acetate versus 1 N NaOH (aq). Dry the organics over MgSO4, then filter, and concentrate to give product (118 mg tan solid, 21%). MS (ES), m/z 541 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12]O)=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2].ClC(Cl)(Cl)C1N(C(=O)C(Cl)Cl)CCS1>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(OO)c1ccc([N+](=O)[O-])cc1
Agent: O=C(C(Cl)Cl)N1CCSC1C(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
A solution of 22 g (0.12 mole) of 90% p-nitroperbenzoic acid in 500 ml of methylene chloride is slowly added, while maintaining the temperature between -5° C. and -10° C., to a solution of 31.7 g (0.1 mole) of 2-trichloromethyl-3-dichloroacetyl-1,3 thiazolidine in 200 ml of methylene chloride. The addition is carried out with stirring. Then the reaction mixture is stirred for 4 further hours, the temperature being ambient. Then the reaction mixture is cooled to 0° C. and the p-nitrobenzoic acid which has formed is separated by filtration. The filtrate is washed with a dilute aqueous solution of sodium carbonate, then with water. After separation the organic phase is dried on sodium sulfate. The methylene chloride is removed by distillation under vacuum. 31.5 g (yield 94%) of 1-oxo-2-trichloromethyl-3-dichloroacetyl-1,3-thiazolidine, which is white solid melting at 140° C., is thus obtained. The structure of the product is confirmed by the infra-red and elemental analysis:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][CH:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH:10]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O.Br[C:28]1[N:33]=[CH:32][C:31]([NH:34][C:35]([C:37]2[CH:38]=[N:39][N:40]([C:43]3[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][N:44]=3)[C:41]=2[CH3:42])=[O:36])=[CH:30][C:29]=1[CH3:53]>O1CCOCC1.C(OCC)(=O)C>[CH3:42][C:41]1[N:40]([C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:50])([F:52])[F:51])=[CH:45][N:44]=2)[N:39]=[CH:38][C:37]=1[C:35]([NH:34][C:31]1[CH:32]=[N:33][C:28]([C:9]2[CH2:14][CH2:13][CH:12]([C:15]([F:16])([F:17])[F:18])[CH2:11][CH:10]=2)=[C:29]([CH3:53])[CH:30]=1)=[O:36]
Reactant: CC1(C)OB(C2=CCC(C(F)(F)F)CC2)OC1(C)C
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCC(C(F)(F)F)CC1
Temperature: 100 °C
Yield: 63.1 %

Procedure:
4,4,5,5-Tetramethyl-2-[4-(trifluoromethyl)cyclohex-1-en-1-yl]-[1,3,2] dioxaborolane (163 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex (37 mg), sodium carbonate (144 mg) and water (1.0 ml) were added at room temperature to a solution of N-(6-bromo-5-methylpyridin-3-yl)-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (200 mg) described in Reference Example 189 in 1,4-dioxane (3.0 ml), and stirred at 100° C. under radiation of microwave for an hour. After completion of the reaction, water and ethyl acetate were added, filtered through Celite and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (chloroform/methanol) to give the titled compound (146 mg) as a white solid.
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([CH:34]=[C:35]([Cl:37])[N:36]=2)[C:31]([OH:33])=[O:32])[CH2:24][CH:23]1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.Cl.C(OCC)(=O)C>O1CCOCC1>[ClH:37].[Cl:37][C:35]1[CH:34]=[C:30]([CH:29]=[C:28]([N:25]2[CH2:26][CH2:27][CH:22]([CH2:21][NH:8][C@@H:9]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH:23]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:24]2)[N:36]=1)[C:31]([OH:33])=[O:32]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2cc(C(=O)O)cc(Cl)n2)CC1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H](NCC1CCN(c2cc(C(=O)O)cc(Cl)n2)CC1c1ccccc1)c1cccc2ccccc12
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a solution of 68 mg of 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-6-chloroisonicotinic acid in 1.0 mL of 1,4-dioxane was added 1.00 mL of a 4 M hydrogen chloride/ethyl acetate solution at room temperature, followed by stirring for 2 hours. The solvent was removed by distillation under reduced pressure. The residue was washed with diisopropylether, and dried under reduced pressure to obtain 29 mg of 2-chloro-6-[4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]isonicotinic acid hydrochloride as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([CH2:19][OH:20])=[C:16]([CH3:21])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1>ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:23])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([CH:19]=[O:20])=[C:16]([CH3:21])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C=O
Reaction time: 2 h
Yield: 92.2 %

Procedure:
Manganese dioxide (12.0 g) is added portion wise to a solution of {5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-yl}-methanol (4.63 g) in dichloromethane (80 ml). After 2 hours at room temperature, the reaction mixture is filtered through a plug of Celite and the filtration cake is washed with dichloromethane. The filtrate is concentrated in vacuo to yield 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carbaldehyde (4.25 g) as a yellowish solid. The crude product obtained is used without further purification. MS (HPLC/MS): 408 (MH+). Retention time: 2.16 min.
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[N:9]=[CH:10][S:11][C:12]=1[S:13][CH2:14][CH3:15])=[O:7])C.[ClH:16]>CO>[ClH:16].[CH2:14]([S:13][C:12]1[S:11][CH:10]=[N:9][C:8]=1[C:6]([OH:7])=[O:5])[CH3:15]
Reactant: CCOC(=O)c1ncsc1SCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCSc1scnc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.37 g of potassium hydroxide dissolved in 1 ml of an aqueous solution was added to a mixture of 0.71 g of 5-ethylthiothiazole-4-carboxylic acid ethyl ester and 5 ml of methanol, under ice cooling, then the mixture was stirred at room temperature for 2 hours. 1 N hydrochloric acid was poured into the reaction mixture under ice cooling, and the precipitated solid was filtered. The resulting solid was washed with 0.1 N hydrochloric acid and n-hexane, then dried to obtain 0.59 g of 5-ethylthiothiazole-4-carboxylic acid hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:11])[C:6]([NH:9][CH3:10])=[CH:7][CH:8]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=O)[CH:16]=[N:17][CH:18]=1.OOS([O-])=O.[K+].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:12][C:13]1[CH:14]=[C:15]([C:19]2[N:9]([CH3:10])[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:11]=2)[CH:16]=[N:17][CH:18]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: CNc1ccc(OC)cc1N
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)nc(-c1cncc(Br)c1)n2C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-methoxy-N1-methyl-benzene-1,2-diamine (34; 0.5 g, 0.00328 mol) and 5-bromo-pyridine-3-carbaldehyde (0.61 g, 0.00328 mol) in DMF (10 ml) and H2O (4 ml) was added OXONE® monopersulphate (2.42 g, 0.00394 mol). Reaction mass was stirred at room temperature for 3 h. The reaction mixture was basified with 10% K2CO3 solution to pH˜8-10 and extracted with EtOAc (3×20 ml). The combined organic layers were washed with brine dried over Na2SO4 and concentrated under vacuum to afford the crude compound which was purified by column chromatography to obtain title compound 2-(5-bromo-pyridin-3-yl)-5-methoxy-1-methyl-1H-benzoimidazole (35).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][CH:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]2=[O:26])=[C:11]([N+:27]([O-])=O)[CH:10]=1)C1C=CC=CC=1.C1COCC1.[H][H]>CCO.[Pd]>[NH2:27][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[N:15]1[CH2:19][CH2:18][CH:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]1=[O:26]
Reactant: [H][H]
Reactant: CCOC(=O)CC1CCN(c2ccc(OCc3ccccc3)cc2[N+](=O)[O-])C1=O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCN(c2ccc(O)cc2N)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Ethyl 2-(1-(4-(benzyloxy)-2-nitrophenyl)-2-oxopyrrolidin-3-yl)acetate (1.09 g, 2.73 mmol) was taken up in EtOH and THF (1:1 mixture, 40 mL) and Pd/C (500 mg) was added. The reaction was pressurized with hydrogen (500 psi) in a bomb reactor and stirred at room temperature for 1 h. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated under reduced pressure to provide the title compound (752 mg). LCMS m/z=279.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.27 (t, J=7.1 Hz, 3H), 1.96-2.08 (m, 1H), 2.38-2.48 (m, 1H), 2.70 (dd, J=16.9, 7.7 Hz, 1H), 2.86 (dd, J=17.0, 4.0 Hz, 1H), 2.95-3.05 (m, 1H), 3.63-3.79 (m, 2H), 4.18 (q, J=7.2 Hz, 2H), 6.53 (d, J=2.7 Hz, 1H), 6.59 (dd, J=8.6, 2.6 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H).
Reaction SMILES: [BH4-].[Na+].[S:3]1[C:7]([C:8]2[N:9]3[CH2:17][CH2:16][N:15]=[C:10]3[S:11][C:12]=2[CH:13]=[O:14])=[CH:6][C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]1=2.O>CO>[S:3]1[C:7]([C:8]2[N:9]3[CH2:17][CH2:16][N:15]=[C:10]3[S:11][C:12]=2[CH2:13][OH:14])=[CH:6][C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]1=2
Reactant: O=CC1=C(c2cc3ccccc3s2)N2CCN=C2S1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCC1=C(c2cc3ccccc3s2)N2CCN=C2S1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.4 %

Procedure:
Sodium borohydride (0.144 g) was added in portions over 10 minutes to a stirred suspension of 3-(benzo[b]thiophen-2-yl)-5,6-dihydroimidazo[2,1-b]-thiazole-2-carboxaldehyde (0.73 g) in methanol (20 ml), then the mixture was stirred at ambient temperature for 2 hours and allowed to stand at ambient temperature for 18 hours. Water (35 ml) was added and the mixture was stirred at ambient temperature for 10 minutes. The resulting solid was collected by filtration and dissolved in a 9:1 mixture of dichloromethane and ethanol (50 ml). The solution was dried (Na2SO4) and the solvents were removed in vacuo to give [3-(benzo[b]thiophen-2-yl)-5,6-dihydroimidazo[2,1-b]thiazol-2-yl]methanol (0.275 g) as a brown solid, m.p. 138-140° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)C=CC=CC=1.Br[CH2:30][C:31]#[CH:32]>>[CH2:32]([O:16][CH2:15][CH2:14][CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1)[C:31]#[CH:30]
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: C#CCBr
Product: C#CCOCCCc1c[nH]cn1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 5 mmol of 3-bromo-1-propyne are treated as described in Example 5. The title compound is crystallized in the form of the hydrogen oxalate from ethanol and diethyl ether.