Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[C:31]([CH3:38])[CH:30]=1>CN(C)C=O.C(#N)C>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[C:31]([CH3:38])[CH:30]=4)[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: CC(=O)c1ccc(OCCCBr)cc1C
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(=O)c1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)cc1C
Temperature: 120 °C
Yield: 39.8 %

Procedure:
A stirred mixture of 6-fluoro-3(4-piperidinyl)-1,2 benzisoxazole hydrochloride (5.5 g, 21.6 mmol), K2CO3 (3.5 g), 1-[4-(3bromopropoxy)-2-methylphenyl]-ethanone (4.83 g, 17.8 mmol) in dimethylformamide (25 ml) and acetonitrile (75 ml) was heated at 120° C. for 5 hours. At the end of the reaction, the solvent was removed and the residue was extracted into dichloromethane (300 ml) and the solution was washed with water and brine. The organic solution was dried and evaporated to a crude oil. The purification was done by flash chromatography over a silica gel column (80 g, eluted with dichloromethane, 1 1; 1% methanol: dichloromethane, 1.2 1; 2% methanol:dichloromethane, 1.2 1). The purest fractions were combined and afforded 2.91 g of solid. Recrystallization from dichloromethane and ethanol gave 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxyl-2-methylphenyl]ethanone as off-white crystals: 2.42 g, m.p.=113°-114° C.
Reaction SMILES: CO[C:3]1(OC)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]2[CH2:14][CH:6]2[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.Cl.[NH2:22][OH:23]>N1C=CC=CC=1>[CH2:14]1[CH:7]2[CH:6]1[C:5]1[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=1[C:3](=[N:22][OH:23])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=12
Reactant: NO
Reactant: COC1(OC)c2ccccc2C2CC2c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1c2ccccc2C2CC2c2ccccc21

Procedure:
A solution of 1.5 g (5.6 moles) of 1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one dimethylketal, 2.5 g of hydroxylamine hydrochloride in 20 ml of pyridine was held at reflux for 18 hr. The solvent was removed under reduced pressure and the residue was dissolved with a mixture of water and methylene chloride. The layers were separated and the organic layer was in turn washed with 10% hydrochloric acid, saturated sodium bicarbonate solution and saturated brine, dried and solvent removed to give 1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one oxime. All of the physical properties were identical to those obtained by Example 1A. Note: The oxime forms a solvate with methanol.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)(Cl)Cl>[C:29]1([NH:28][C:12]([C:9]2[C:8](=[O:15])[N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]3=[N:11][CH:10]=2)=[O:14])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1ccccc1
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc2ncc(C(=O)Nc3ccccc3)c(=O)n12
Reaction time: 0.08 h
Yield: 78.8 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at a temperature between -10° C. and -13° C. during 20 minutes. After stirring for 5 minutes, 9.19 g (0.088 mol) of aniline dissolved in 80 ml of chloroform are dropped to the above solution at a temperature between -10° C. and -13° C. during 30 minutes. The reaction mixture is stirred below -10° C. for 1 hour and then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 17.6 g (78.8%) of the named compound as yellow crystals after recrystallization from ethanol, m.p.: 186°-188° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH:17]([CH2:22][CH2:23][CH2:24][Br:25])[C:18]([O:20][CH3:21])=[O:19]>>[Br:25][CH2:24][CH2:23][CH2:22][CH:17]([O:1][C:2]1[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C(Br)CCCBr
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(O)c1
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(OC(CCCBr)C(=O)OC)c1

Procedure:
By a process similar to that of Reference Example 5, ethyl 3-hydroxy-4-nitrobenzoate was allowed to react with methyl 2,5-dibromovalerate to give methyl 5-bromo-2-(5-ethoxycarbonyl-2-nitrophenoxy)valerate as an oily product (yield: 80.2%). This product was subjected to catalytic reduction to obtain ethyl 2-(3-bromopropyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-7-carboxylate, m.p. 118°-119° C. The yield was 90.7%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][S:35]([CH3:34])(=[O:37])=[O:36])[CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3ccc(O)cc23)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3ccc(OS(C)(=O)=O)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Step E (426 mg, 1.19 mmol) in 5 mL of DMF at 0° C. was added triethylamine (0.532 mL, 3.82 mmol), followed by methanesulfonyl chloride (0.212 mL, 2.73 mmol). The reaction was stirred at room temperature overnight, then partitioned between EtOAc and 50% NaHCO3 solution. The organic layer was washed with water and brine, dried (MgSO4), filtered, and concentrated in vacuo. The product was isolated as a yellow gum which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][CH2:23][CH2:24][CH3:25])=[O:21])=[C:15]([O:26][CH3:27])[CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:28][CH3:29].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1.O>CN(C)C=O>[CH3:27][O:26][C:15]1[CH:14]=[C:13]([O:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([O:1][CH2:38][C:39]4[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=4)=[C:3]([O:28][CH3:29])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)[CH:18]=[CH:17][C:16]=1[NH:19][C:20]([NH:22][CH2:23][CH2:24][CH3:25])=[O:21]
Reactant: ClCc1ccncc1
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(OC)cc23)cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCc4ccncc4)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
A starting compound (N-{4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]-2-methoxyphenyl}-N′-propylurea, 80 mg), potassium carbonate (138 mg), and 4-chloromethylpyridine hydrochloride (48 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 65 mg (yield 67%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]([O:14][C:15]1[CH:25]=[CH:24][C:18]([CH:19]=[CH:20][C:21](Cl)=[O:22])=[CH:17][CH:16]=1)(=[O:13])[CH3:12]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:11]([O:14][C:15]1[CH:25]=[CH:24][C:18]([CH:19]=[CH:20][C:21]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[O:22])=[CH:17][CH:16]=1)(=[O:13])[CH3:12]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CC(=O)Oc1ccc(C=CC(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C=CC(=O)Nc2ccc(C(=O)O)cc2)cc1

Procedure:
In a mixture of 20 ml of dry chloroform and 10 ml of dry pyridine were dissolved 2.6 g of 4-aminobenzoic acid. To this mixture were added dropwise under cooling 20 ml of dry chloroform containing 3.2 g of 4-acetoxycinnamoyl chloride. The mixture was heated under reflux for 2 hours and the reaction mixture was concentrated under reduced pressure. The residue was poured into water and hydrochloric acid was then added to make the liquid weakly acidic. The precipitated crystals were collected by filtration and recrystallized from alcohol to yield 2.9 g of 4-(4'-acetoxycinnamoylamino)-benzoic acid. M.P.=305°-307° C. (with decomposition).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:11].Cl.Cl.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[ClH:31].[ClH:11].[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][CH2:15][NH:14][C:9]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:23][CH2:22]2)=[CH:26][CH:27]=1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C=NCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCN1CCN(Cc2ccc(Cl)cc2)CC1)NCc1ccccc1
Yield: 154.1 %

Procedure:
The procedure described in Example 21 was followed, using benzyl isocyanate (1.33 g; 10 mmole), 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (3.77 g; 10 mmole), methylene chloride (250 ml) and triethylamine (4.3 ml; 31 mmole) to provide the title compound (3.65 g; 77% yield) as colorless crystals, m.p. 203°-206° C.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:29])[CH2:15][NH:16][CH2:17][C:18]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH3:3].C(N(CC)CC)C.[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[NH:13][C:14](=[O:29])[CH2:15][N:16]([S:43]([C:40]1[CH:41]=[CH:42][C:37]([CH3:47])=[CH:38][CH:39]=1)(=[O:45])=[O:44])[CH2:17][C:18]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH3:1]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNCC1(c2ccccc2)CCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N(CC(=O)Nc2c(C(C)C)cccc2C(C)C)CC2(c3ccccc3)CCCC2)cc1
Reaction time: 120 h

Procedure:
To a mixture of the product of Example 6 (0.45 g) and excess triethylamine at room temperature was added 0.22 g p-toluene sulfonyl chloride. This mixture was diluted with ethyl acetate, concentrated, and triethylamine and ethyl acetate added a second time. The reaction mixture was then concentrated to a brown oil. After sitting 5 days at room temperature, the oil was taken up in ethyl acetate, washed with NaHCO3 and NaCl solutions, dried over MgSO4, filtered, and concentrated to an oil. The oil was purified by chromatography on silica gel using hexane/EtoAc, 8/21 as eluant. The appropriate fractions were concentrated to an oil which crystallized upon trituration with hexane. 0.44 g (69%). NMR (CDCl3) δ 1.17 (6H, d), δ 1.64-1.82 (4H, m), δ 2.03 (4H, m), δ 2.42 (3H, s), δ 2.97 (2H, m), δ 3.42 (2H, s), δ 3.55 (2H, s), δ 7.13-7.65 (12H, m). IR (KBr) 3370, 2965, 2870, 1673, 1497, 1328, 1158, 1092, 755, 550 cm-1.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:34])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH:31]([F:33])[F:32])[CH:21]=1)[CH2:16][C:17](O)=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2].[C:35](N1C=CN=C1)([N:37]1C=CN=[CH:38]1)=O.CNC.O>O1CCCC1>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:34])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH:31]([F:32])[F:33])[CH:21]=1)[CH2:16][C:17]([N:37]([CH3:38])[CH3:35])=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)Nc1cccc2c1C(=O)N(C(CC(=O)O)c1ccc(OC(F)F)c(OC(F)F)c1)C2=O
Agent: CNC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cccc2c1C(=O)N(C(CC(=O)N(C)C)c1ccc(OC(F)F)c(OC(F)F)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
To a solution of 3-(4-acetylamino-1 ,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3,4-bis-difluoromethoxy-phenyl)-propionic acid (350 mg, 0.72 mmol) in tetrahydrofurane was added carbonyldiimidazole (175 mg, 1.08 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added dimethylamine in THF (0.73 ml, 1.45 mmol). The resulted mixture was stirred at room temperature for 2 hours. Water (5 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was taken up in ethyl acetate (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×10 ml), water (10 ml), brine (10 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was purified by HPLC (acetonitrile:water=45:55) to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3,4-bis-difluoromethoxy-phenyl)-N,N-dimethyl-propionamide as a white solid (200 mg, 55%): mp, 83–85° C.; 1HNMR (CDCl3): 2.25 (s, 3H, CH3CO), 2.91 (s, 3H, NCH3), 3.06–3.13 (m, 4H, CHHCO+NCH3), 3.85 (dd, J=10, 15 Hz, 1H, CHHCO), 5.85–5.91 (m, 1H, CHN), 6.80 (t, JH-F=75 Hz, 1H, OCF2H), 6.84 (t, JH-F=75 Hz, 1H, OCF2H), 7.23 (d, J=7.5 Hz, 1H, Ar), 7.41–7.47 (m, 3H, Ar), 7.63 (t, J=7.5 Hz, 1H, Ar), 8.72 (d, J=7.5 Hz, 1H, Ar), 9.51 (s, 1H, NHCO). 13C NMR (CDCl3): 24.8, 34.5, 35.4, 36.9, 50.5, 111.4, 111.5, 115.2, 115.6, 115.7, 117.9, 119.8, 119.9, 122.0, 122.4, 124.7, 126.1, 131.1, 135.8, 137.4, 138.2, 141.9, 142.2, 167.7, 168.8, 169.1, 169.7; Anal. Calcd. for C23H21F4N3O6: C, 54.02; H, 4.14; N, 8.22. Found: C, 53.89; H, 3.88; N, 8.13.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.C(N(CC)C(C)C)(C)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([NH:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1coc(N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1coc(NS(C)(=O)=O)n1
Reaction time: 14 h

Procedure:
To a 20 ml screw cap vial was added (1 g, 5.8069 mmoles) ethyl 2-amino-1,3-oxazole-4-carboxylate, (10 ml) dichloromethane and (1.39 ml, 7.9797 mmoles, 1.25 eq.) N,N-diisopropylethylamine. To the reaction was then added (0.545 ml, 7.0415 mmoles, 1.1 eq.) methanesulfonyl chloride, and the reaction was agitated for 14 hours. The reaction was then evaporated to dryness and purified using a Biotage silica gel column, resulting in (272 mg) of ethyl 2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[NH2:19][CH2:20][CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22]1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:19][CH2:20][CH:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22]2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCC1CCc2ccccc2N1
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(NCC2CCc3ccccc3N2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-(aminomethyl)-1,2,3,4-tetrahydroquinoline hydrochloride and DBU in DME. ES-MS m/e (%): 347 (M+H+, 100).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH2:11])[N:7]([C:12]2[CH:17]=[CH:16][C:15](F)=[C:14]([Cl:19])[CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].ClC(N(C)C)=C(C)C.[F:28][C:29]1[CH:30]=[C:31]([CH:39]([CH3:43])[C:40](O)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11][C:40](=[O:41])[CH:39]([C:31]2[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:29]([F:28])[CH:30]=2)[CH3:43])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:19])[CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C(=O)O)c1ccc(S(C)(=O)=O)c(F)c1
Reactant: CC(C)(C)c1cc(CN)n(-c2ccc(F)c(Cl)c2)n1
Agent: CC(C)=C(Cl)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C(=O)NCc1cc(C(C)(C)C)nn1-c1cccc(Cl)c1)c1ccc(S(C)(=O)=O)c(F)c1
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of (3-tert-butyl-1-(3-chloro-4-fluorophenyl)-1H-pyrazol-5-yl)methanamine (49 mg, 0.189 mmol) in DCM (1.3 mL) at room temperature and under nitrogen atmosphere was added 1-chloro-N,N,2-trimethyl-1-propenylamine (48 μL, 0.369 mmol), After 1 h of stirring were added 2-(3-fluoro-4-(methylsulfonyl)phenyl)propanoic acid (93 mg, 0.378 mmol) and N-ethyldiisopropylamine (0.11 mL, 0.662 mmol). The reaction mixture was stirred overnight at room temperature, washed with NaHCO3 solution (2×10 mL), dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (eluent: ethyl acetate/cyclohexane (2:1)) to give pure N-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-(3-fluoro-4-methylsulfonyl-phenyl)-propionamide (example compound D1) (66 mg, 71%).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11].C[O:13][C:14](=[O:29])[CH:15]([O:27][CH3:28])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25]Br)[CH:18]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:28][O:27][CH:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][O:11][C:2]2[CH:3]=[CH:4][C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=3[CH:1]=2)[CH:18]=1)[C:14]([OH:29])=[O:13]
Reactant: COC(=O)C(Cc1cccc(OCCBr)c1)OC
Reactant: Oc1ccc2c(c1)CCCC2
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCCOc2ccc3c(c2)CCCC3)c1)C(=O)O

Procedure:
The title compound was prepared from 5,6,7,8-tetrahydro-naphthalen-2-ol and 3-[3-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 351, Step 1) via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) for C22H26O5 [M−H]−: 369.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]([CH:14]3[CH2:16][CH2:15]3)=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=2)[CH2:25][CH2:24]1>O1CCOCC1.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>[CH:14]1([C:11]2[O:10][C:9]([C:4]3[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:32]4[CH:33]=[CH:34][CH:35]=[C:30]([CH2:29][N:26]5[CH2:27][CH2:28][O:23][CH2:24][CH2:25]5)[CH:31]=4)[CH:3]=3)=[N:13][N:12]=2)[CH2:16][CH2:15]1
Reactant: OB(O)c1cccc(CN2CCOCC2)c1
Reactant: Nc1ncc(Br)cc1-c1nnc(C2CC2)o1
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: C1COCCO1
Product: Nc1ncc(-c2cccc(CN3CCOCC3)c2)cc1-c1nnc(C2CC2)o1
Temperature: 100 °C
Reaction time: 18 h
Yield: 16.8 %

Procedure:
To a solution of 5-bromo-3-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-pyridin-2-ylamine (400 mg; 1.42 mmol) in dioxane (10 mL) and water (6 mL) were added K2CO3 (587 mg; 4.26 mmol), (3-(morpholinomethyl)phenyl)boronic acid (348 mg; 1.56 mmol) in a sealed tube. The reaction mixture was degassed with argon for 30 min, then added Pd(PPh3)4 (82.0 mg; 0.07 mmol) to the reaction mixture. The reaction mixture was stirred for 18 h at 100° C. The reaction mixture was diluted with water (50 mL) extracted with ethyl acetate (2×50 mL) and organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Crude compound was purified by column chromatography using 100-200 mesh silica gel and eluted with 100% ethyl acetate, which is further purified by washing with 30% chloroform in hexane to afford 90 mg (Yield: 16.7%) of the title compound, as a yellow colour solid.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[N:22]=[C:23](/[CH:26]=[CH:27]/[C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)[O:24][CH:25]=2)[CH:16]=[CH:15][C:14]=1[CH2:39][S:40]([CH2:42][CH2:43][N:44]1[CH:48]=[CH:47][N:46]=[N:45]1)=[O:41]>C(OCC)(=O)C.ClCCl>[CH3:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[N:22]=[C:23](/[CH:26]=[CH:27]/[C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]([F:37])([F:36])[F:38])=[CH:32][CH:33]=3)[O:24][CH:25]=2)[CH:16]=[CH:15][C:14]=1[CH2:39][S:40]([CH2:42][CH2:43][N:44]1[CH:48]=[CH:47][N:46]=[N:45]1)(=[O:6])=[O:41]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(OCc2coc(/C=C/c3ccc(OC(F)(F)F)cc3)n2)ccc1CS(=O)CCn1ccnn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(OCc2coc(/C=C/c3ccc(OC(F)(F)F)cc3)n2)ccc1CS(=O)(=O)CCn1ccnn1
Reaction time: 48 h
Yield: 52.9 %

Procedure:
35 mg (0.15 mmol) 75% 3-chloroperoxybenzoic acid dissolved in 5 ml ethyl acetate were given at −30° C. to solution of 52 mg (0.10 mmol) 1-[2-(2-methyl-4-{2-[2-(E)-(4-trifluoromethoxy-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl-methanesulfinyl)-ethyl]-1H[1,2,3]triazole in 25 ml dichloromethane. The mixture was stirred for 48 h and slowly allowed to reach room temperature. Additional 20 ml dichloromethane were added, washed with conc. sodium carbonate solution, water, dried and evaporated to give 29 mg (53%) of the title compound.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=1>>[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:2]2[N:7]3[CH:8]=[C:9]([CH2:11][O:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=[C:6]3[C:5]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[N:4][CH:3]=2)[CH:30]=1
Reactant: Brc1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Product: c1cncc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)c1

Procedure:
Compound 15a (150.0 mg, 0.34 mmol) was subjected to Suzuki coupling conditions with 3-pyridineboronic acid pinacol ester using the methods described in Example 1, Step G to obtain compound 46a. Mass Spectrum (LCMS, ESI pos.) Calcd. for C25H22N6O2: 439.1 (M+H). Found 439.1.