Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH:18][CH:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]1)([O:3][CH2:4][CH3:5])=[O:2].[IH:32].C(OCC)C>C(O)C>[IH:32].[C:1]([CH2:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CCCn1c(NC2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Agent: I
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)CCCn1c(NC2CCNCC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine (1-(3-carboethoxypropyl)-1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine (0.59 g, 1.37 mmol) and aqueous hydriodic acid (2 mL, 57%) in ethanol (25 mL). Heat to reflux. After 2 hours, cool to ambient temperature, pour the reaction mixture into diethyl ether (450 mL), and cool to about −30° C. to give a solid. Collect the solid by filtration and dry to give the title compound.
Reaction SMILES: C([O:3][C:4](=[O:43])[CH:5]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([N:32]([C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:33][CH:34]([CH3:36])[CH3:35])[CH:25]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)C.[OH-].[Na+]>CO.O1CCCC1>[Cl:22][C:21]1[CH:20]=[N:19][CH:18]=[C:17]([Cl:23])[C:16]=1[C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([N:32]([C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:33][CH:34]([CH3:36])[CH3:35])[CH:25]=2)[C:4]([OH:43])=[O:3])=[CH:8][CH:9]=1)=[O:15]
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1)c1ccc(OC)c(N(CC(C)C)C(=O)C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(Cc2ccc(NC(=O)c3c(Cl)cncc3Cl)cc2)C(=O)O)cc1N(CC(C)C)C(=O)C(C)(C)C

Procedure:
Thus obtained 3-[4-(3,5-dichloropyridine-4-carbonylamino)phenyl]-2-{3-[(2,2-dimethylpropionyl) isobutylamino]-4-methoxyphenyl}propionic acid ethyl ester (400 mg, 0.64 mmol) was dissolved in a mixed solvent of methanol (5 mL) and tetrahydrofuran (5 mL), and added with a 2 mol/L aqueous sodium hydroxide solution (5 mL, 10 mmol). The solvent was evaporated under reduced pressure, the resultant residue was added with water to be dissolved, and the solution was washed with diethyl ether. The separated aqueous phase was added with a 1 mol/L hydrochloric acid so as to adjust pH of the solution to 5 to 7. The solution was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure so as to remove the solvent to thereby obtain 3-[4-(3,5-dichloro pyridine-4-carbonylamino)phenyl]-2-{3-[(2,2-dimethyl propionyl)isobutylamino]-4-methoxyphenyl}propionic acid (yield: 353 mg, yield ratio: 92%) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[CH:12][CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=O.[N+:19]([CH2:22][CH3:23])([O-:21])=[O:20].C(N)C1C=CC=CC=1>C1(C)C=CC=CC=1>[N+:19]([C:22]([CH3:23])=[CH:1][C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[CH:12][CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-:21])=[O:20]
Reactant: CC[N+](=O)[O-]
Reactant: CCOC(=O)c1ccc(C=O)cc1C(=O)OCC
Solvent: NCc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(C=C(C)[N+](=O)[O-])cc1C(=O)OCC

Procedure:
A mixture of one equivalent of diethyl 4-methylphthalate, two equivalents of N-bromosuccinimide and carbon tetrachloride is irradiated with a 500 W tungsten lamp for three hours. The mixture is filtered and the solution is shaken with excess sodium carbonate solution. Evaporation of the organic phase gives diethyl 4-formylphthalate. This aldehyde is combined with excess nitroethane, toluene and a catalytic amount of benzyl amine. The mixture is heated on a steam bath for 48 hours and evaporated in vacuo to give diethy 4-(2-nitropropen-1-yl)phthalate.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:36]=O>[Pd].C(O)CCC>[C:27]([C:25]1[CH:26]=[C:21]([CH2:20][CH2:19][N:18]([CH3:36])[CH2:17][CH2:16][C:7]2[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[CH:8]=2)[CH:22]=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]=1[OH:31])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1cc(CCNCCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Reactant: C=O
Agent: [Pd]
Solvent: CCCCO
Product: CN(CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 100.9 %

Procedure:
Charge a suitable reaction vessel with 3.0 g (6.2 mmols) of N,N-bis[β-(3,5-di-t-butyl-4-hydroxyphenyl)ethyl]amine, 2.2 g of 37% formaldehyde (27.1 mmols), 0.6 g of 10% Pd/C, and 15 mL of n-butanol. Purge with hydrogen and shake the vessel on a Parr Series 3900 Hydrogenation Apparatus at 60 psi (0.4 MPa) hydrogen pressure and room temperature for 5 hours. Dilute the resulting slurry with 30 mL of methylene chloride, filter, and concentrate the filtrate in vacuo to give 3.1 g of N,N-bis[β-(3,5-di-t-butyl-4-hydroxyphenyl)ethyl]methylamine as a yellow oil which slowly crystallizes on standing. GC area % analysis shows the product to be 98.8% pure.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][C@H:16](OS(C)(=O)=O)[CH2:15][CH2:14][C@@H:13]1[C:23]([O:25][CH3:26])=[O:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:27]=[N+:28]=[N-:29].[Na+].C([O-])(O)=O.[Na+].O>CN(C)C=O>[N:27]([C@H:16]1[CH2:15][CH2:14][C@H:13]([C:23]([O:25][CH3:26])=[O:24])[C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:17]1)=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)C[C@H]1NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](N=[N+]=[N-])C[C@H]1NC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 72.1 %

Procedure:
To a solution of methyl (1S,2R,4R)-2-{[(benzyloxy)carbonyl]amino}-4-[(methylsulfonyl)oxy]cyclohexanecarboxylate (0.30 g, 0.78 mmol) in N,N-dimethylformamide (2.6 mL) was added sodium azide (0.20 g, 3.1 mmol). The reaction was heated to 80° C. and stirred for 2.5 h. After cooling, the reaction mixture was poured into sat. NaHCO3/water and extracted with EtOAc (3 x). The combined extracts were washed with brine, dried (Na2SO4), and concentrated. The crude was purified on silica gel, eluting with 0-40% EtOAc in hexanes to give 187 mg (72%) of the desired product as a clear gum. LCMS calculated for C16H21N2O4 (M+H-28)+: m/z=305.2. Found: 305.1.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][NH2:47])=[CH:41][C:40]=1[O:48][CH3:49])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>O1CCCC1>[CH2:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][NH:47][C:13](=[O:15])[C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH:10]([CH3:11])[CH3:12])=[CH:41][C:40]=1[O:48][CH3:49])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1cc(CCN)ccc1OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cc(CCNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)ccc1OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
32.9 g of BOC-L-valine and 16.7 ml of N-methylmorpholine are dissolved in 350 ml of tetrahydrofuran and cooled to −20° C. 19.8 ml of isobutyl chloroformate are added dropwise to that solution over a period of 15 minutes. The mixture is stirred for 30 minutes, during which time the temperature rises to −7° C. The mixture is then cooled to −20° C., and 35.4 g of 2-(4-benzyloxy-3-methoxy-phenyl)-ethylamine in 50 ml of tetrahydrofuran are added dropwise over a period of 10 minutes. The reaction mixture is stirred for 30 minutes at −20° C. and then for 4 hours at room temperature. It is introduced into 300 ml of 1N hydrochloric acid. Extraction is carried out twice using 400 ml of ethyl acetate each time. The organic phases are washed once with 300 ml of 1N hydrochloric acid and once with 300 ml of saturated sodium chloride solution, dried over magnesium chloride and concentrated, yielding (S)-2-(tert-butoxycarbonyl-amino)-3-methyl-butyric acid N-[2-(4-benzyloxy-3-methoxy-phenyl)-ethyl]-amide, which is recrystallised from ethyl acetate/n-hexane, m.p. 115-118° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@H:10]([NH:12][C:13]2[C:22]3[C:17](=[C:18]([C:23]([NH2:25])=[O:24])[CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C@H:10]([NH:12][C:13]2[C:22]3[C:17](=[C:18]([C:23]([NH2:25])=[O:24])[CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: C[C@@H](Nc1ncnc2c(C(N)=O)cccc12)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: C[C@@H](Nc1ncnc2c(C(N)=O)cccc12)c1cccc(N)c1
Yield: 93 %

Procedure:
A suspension of 4-{[(1R)-1-(3-nitrophenyl)ethyl]amino}quinazoline-8-carboxamide (1.50 g, 4.45 mmol) in methanol (125 mL) was shaken for 3 h in a Parr vessel under 35 psi hydrogen pressure in the presence of 30 wt % palladium on carbon (600 mg). The material was filtered through Celite, concentrated to get the title compound in 93% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.O>CCCCCC>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:10](=[O:12])[CH:9]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH2:8]2
Reactant: O=C(O)C(Cc1cccc(F)c1)c1ccc(F)cc1
Solvent: CCCCCC
Solvent: O
Product: O=C1c2ccc(F)cc2CC1c1ccc(F)cc1
Temperature: 110 °C

Procedure:
A solution of 500 g of polyphosphoric acid was heated to 60° C. and 43.0 g of the acid from step A was added. The mixture was then heated to 110° C. for 1 hour. After this time, the reaction was cooled to about 60° C. and 400 mL of water was added rapidly with externalcooling. The mixture was then partitioned between toluene and water, washed twice with toluene and the combined toluene extracts were then washed with 5% aqueous NaHCO3. The toluene extracts were then dried over MgSO4, filtered, concentrated and chromatographed on silica gel with 10% ethyl acetate in hexane as the eluent to afford, after trituration with hexane, 26.98 g of a yellow solid; mp 72°-74° C. 1H NMR (CDCl3) δ: 3.22 (dd, 1H), 3.70 (dd, 1H), 3.94 (dd, 1H), 7.0-7.3 (m, 5H), 7.82 (dd, 1H).
Reaction SMILES: [C:1]([O:6]CC)(=O)[C:2]([NH2:4])=[O:3].[NH2:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1>>[CH3:18][C:12]1([CH3:19])[CH2:11][CH:10]([NH:9][C:1]([C:2]([NH2:4])=[O:3])=[O:6])[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13]1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: CCOC(=O)C(N)=O
Product: CC1(C)CC(NC(=O)C(N)=O)CC(C)(C)N1
Reaction time: 3 h

Procedure:
The filtrate was transferred back to the 250 ml 3-neck flask and another 30.5 g of ethyl oxamate was added. An additional 39 g of 4-amino-2,2,6,6-tetramethylpiperidine were added over 7 minutes as the temperature slowly rose to 28° C. The reaction was stirred 3 hours and filtered. After air drying overnight, the filter cake weighed 50.0 g and had a melting point of 198°-200° C.
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[N:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:5]=1)[CH:2]=[CH2:3].C12BC(CCC1)CCC2.[OH-:35].[Na+].OO>O1CCCC1.O>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]2[N:8]=[N:9][C:4]([CH2:1][CH2:2][CH2:3][OH:35])=[CH:5][C:6]=2[C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[CH:15][CH:14]=1
Reactant: [OH-]
Reactant: C=CCc1cc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)nn1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(CCCO)nnc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.3 %

Procedure:
To a solution of 6-allyl-3,4-bis(4-methoxyphenyl)pyridazine (0.58 g, 1.7 mmol) in tetrahydrofuran (3 ml), a 0.5 M solution (8.7 ml) of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran was added dropwise under an argon gas atmosphere while cooling the reaction system with ice-water. The resulting mixture was then stirred at room temperature for 15 hours. To the reaction mixture, water (1 ml) and then, 3 N caustic soda (3 ml) and 31% hydrogen peroxide (3 ml) were added under ice cooling, followed by stirring at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate, the organic layer was washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and was then dried over anhydrous sodium sulfate. The extract was concentrated under reduced pressure and the resulting mixture was left over at room temperature for 3 days. The residue was separated and purified by chromatography on a silica gel column (ethyl acetate), whereby the title compound was obtained as a pale brown oil (0.54 g, 88.3%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[C:20]([C:21](=[O:29])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][N:18]=[C:17](S(C)(=O)=O)[N:16]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=1)[NH2:40]>CC(N(C)C)=O>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[C:20]([C:21](=[O:29])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][N:18]=[C:17]([NH:40][C:39]3[CH:41]=[CH:42][CH:43]=[C:37]([O:36][CH3:35])[CH:38]=3)[N:16]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2nc(S(C)(=O)=O)ncc2C(=O)Nc2ccccc2)c1
Reactant: COc1cccc(N)c1
Solvent: CC(=O)N(C)C
Product: COc1cccc(Nc2ncc(C(=O)Nc3ccccc3)c(Oc3cccc(NC(=O)OC(C)(C)C)c3)n2)c1
Temperature: 90 °C
Yield: 27.4 %

Procedure:
The 2-methylsulfone of 7 (1.0 g, 1.9 mmol) was mixed with 3-methoxyaniline (420 mg, 3.4 mmol) in DMA and the mixture was heated at 90° C. for 24 hours. Workup was done in a manner similar to that for Step-5 in Example 57 to give 9 (300 mg, 0.52 mmol).
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.[C:32]([O:35][CH2:36][C:37](Cl)=[O:38])(=[O:34])[CH3:33]>>[C:32]([O:35][CH2:36][C:37]([N:29]1[CH2:30][CH2:31][CH:26]([N:24]2[CH:25]=[C:21]([C:7]3[C:6]4[C:10](=[CH:11][C:3]([F:2])=[CH:4][CH:5]=4)[N:9]([S:12]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)(=[O:13])=[O:14])[CH:8]=3)[CH:22]=[N:23]2)[CH2:27][CH2:28]1)=[O:38])(=[O:34])[CH3:33]
Reactant: CC(=O)OCC(=O)Cl
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CCNCC3)c2)c2ccc(F)cc21
Agent: Cl
Product: CC(=O)OCC(=O)N1CCC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Yield: 100.3 %

Procedure:
Following the general method as outlined in Example 89, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole hydrochloride (Intermediate 17; 368 mg; 0.80 mmol) and 2-chloro-2-oxoethyl acetate (165 mg; 1.21 mmol), 421 mg (100%) of the title compound was obtained as a yellow solid, which was used directly without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:21]([C:17]1[S:16][C:15]([CH2:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:24])=[N:19][C:18]=1[CH3:20])=[O:23])([CH3:27])[CH3:26]
Reactant: CC(C)N
Reactant: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Product: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)NC(C)C
Yield: 91 %

Procedure:
As described for example 31b, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.20 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (71 mg, 91%) which was obtained as an off white solid. MS: m/e=389.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)[CH:27]=[C:28]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[Cl:39])[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[Cl:39])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)C=C(CBr)Oc1cccc(Cl)c1Cl
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.2 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.15 g, 0.062 mol) in N,N-dimethylformamide (5 mL) was added N,N-diisopropylethylamine (3.63 g, 0.282 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with 4-bromo-3-(2,3-dichloro-phenoxy)-but-2-enoic acid ethyl ester (2.0 g, 0.006 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification using flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (0.40 g, 17%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([CH3:34])[C:21](=[O:33])[CH2:22][NH:23][C:24](=[O:32])[CH2:25][N:26]4[CH2:31][CH2:30][S:29][CH2:28][CH2:27]4)[C:14]=3[Cl:35])[C:5]2=[N:4][C:3]=1[CH3:36].ClC1C=CC=C(C(OO)=[O:45])C=1>C(Cl)Cl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([CH3:34])[C:21](=[O:33])[CH2:22][NH:23][C:24](=[O:32])[CH2:25][N:26]4[CH2:27][CH2:28][S:29](=[O:45])[CH2:30][CH2:31]4)[C:14]=3[Cl:35])[C:5]2=[N:4][C:3]=1[CH3:36]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CN4CCSCC4)c3Cl)cccn2c1Br
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CN4CCS(=O)CC4)c3Cl)cccn2c1Br
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a solution of 3-bromo-8-[2,6-dichloro-3-[N-methyl-N-[(thiomorpholinoacetyl)glycyl]amino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (200 mg) in methylene chloride (2 ml) was added m-chloroperbenzoic acid (80% purity, 76 mg) under ice-bath cooling, and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was washed with water twice and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=5:1, V/V) to give 3-bromo-8-[2,6-dichloro-3-[N-methyl-N-[[(1-oxothiomorpholino)acetyl]glycyl]amino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (96 mg ) as an amorphous.
Reaction SMILES: [BH4-].[Na+].Cl[CH:4]([CH3:27])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:26])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)=[CH:9][CH:8]=1)=[O:6].[OH-].[Na+]>CO>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([CH2:15][C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([CH:5]3[CH:4]([CH3:27])[O:6]3)=[CH:8][CH:9]=2)=[O:26])[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)C(C)Cl)cc2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CC(=O)Nc2ccc(C3OC3C)cc2)cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
Sodium tetrahydroborate (0.0502 mol) was added portionwise at 0° C. to a mixture of (±)-N-[4-(2-chloro-l-oxopropyl)phenyl]-3,4-dimethoxybenzeneacetamide (0.0502 mol) in methanol (280 ml). The mixture was stirred at 0° C. for 1 hour, then poured out into a mixture of NaOH (280 ml) and ice, stirred for 1 hour and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 15.48 g (94%) of (±)-3,4-dimethoxy-N-[4-(3-methyl-2-oxiranyl)phenyl]benzeneacetamide (interm. 11).
Reaction SMILES: Br.[S:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][CH2:5][CH2:4][CH2:3]1.[Li][CH2:14]CCC.CI>C1COCC1>[CH3:14][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[S:2][CH2:3][CH2:4][CH2:5]1
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)NCCCS2
Agent: Br
Solvent: CI
Solvent: C1CCOC1
Product: CN1CCCSc2ccccc21
Reaction time: 1 h

Procedure:
8.30 g of 3,4-dihydro-2H-1,5-benzothiazepine hydrobromide were placed in 150 ml of THF and deprotonized with 48 ml of 1.55M nBuLi (hexane) under an Argon atmosphere at -10° C. After 1/4 hour, 4.64 ml of Methyl iodide (MeI) were added dropwise to the yellow solution of the Li amide and the mixture was stirred for 1 hour. It was then poured on to ice, extracted with ether, washed with water, dried and evaporated. Column chromatography on silica gel (petroleum ether/ethyl acetate 96/4) yielded 5.70 g of 3,4-dihydro-5-methyl-2H-1,5-benzothiazepine as a colorless oil which was formylated as follows:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:13][CH2:12][C@:11]2([CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)[C:10]1=[O:19].Cl[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([N:15]2[CH2:16][CH2:17][CH2:18][C@@:11]3([C:10](=[O:19])[N:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[Cl:2])[CH2:13][CH2:12]3)[CH2:14]2)=[N:22][CH:23]=1
Reactant: O=C1N(c2ccccc2Cl)CC[C@]12CCCNC2
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(N2CCC[C@]3(CCN(c4ccccc4Cl)C3=O)C2)nc1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
A mixture of (5S)-2-(2-chlorophenyl)-2,7-diazaspiro[4.5]decan-1-one hydrochloride (40.0 mg, 0.000133 mol, prepared by using a procedure analogous to that used for the synthesis of example 92, steps 1-3), 2-chloro-5-nitropyridine (23 mg, 0.00015 mol), and potassium carbonate (55 mg, 0.00040 mol) in N,N-dimethylformamide (1.0 mL, 0.013 mol) was stirred at 120° C. for 1.5 hours. After cooling the reaction mixture to ambient temperature the solid was filtered off and the filtrate was concentrated in-vacuo to afford the desired product. LC-MS: 387.1 (M+H)+. The resulting residue was dissolved in methanol and to this solution was added platinum [5 wt. % (dry basis) on activated carbon, wet, Degussa type F101, RAW (Aldrich #330159), 15 mg] under an atmosphere of H2 (g) at rt for 2 h. The catalyst was filtered off from the mixture and the filtrate was concentrated in-vacuo to afford the product in quantitative yield. LC-MS: 357.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[S:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30]>>[CH3:1][N:2]([CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[C:28]2[S:24][C:25](=[O:30])[NH:26][C:27]2=[O:29])=[CH:18][CH:17]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: O=C1CSC(=O)N1
Reactant: CN(CCCOc1ccc(C=O)cc1)c1nc2ccccc2o1
Product: CN(CCCOc1ccc(C=C2SC(=O)NC2=O)cc1)c1nc2ccccc2o1

Procedure:
The title compound (m.p. 202°-204° C.) was prepared from 4-[3-(N-methyl-N-(2-benzoxazolyl)amino)propoxy]benzaldehyde (5.3 g) and 2,4-thiazolidinedione (2.2 g) by a similar procedure to that described in Example 4.