Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][CH2:20][CH2:21][OH:22]>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:22][CH2:21][CH2:20][O:19][CH3:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Reactant: COCCO
Product: COCCOc1ccc2c(c1)CN(C(=O)OC(C)(C)C)C2

Procedure:
Prepared in analogy to Example A6(a) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and 2-methoxyethanol. White solid. MS (m/e): 237.9 ([M+H−Me2C═CH2]+, 100%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[C:10]([O-])([O-])=O.[K+].[K+].IC>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:10])=[C:4]([CH3:9])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Br)ccc1O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(Br)cc1C
Temperature: 25 °C
Yield: 67 %

Procedure:
Under nitrogen, to a stirred suspension of 38.9 g (208 mmol) of 4-bromo-2-methylphenol and 43.1 g (312 mmol) of K2CO3 powder in 300 mL of THF was added 39 mL (624 mmol) of iodomethane. The mixture was heated to reflux overnight, and cooled to ambient temperature. The inorganic salts were removed by filtration, and the organic solvent was removed in vacuo. The residue was dissolved in ethyl acetate, washed with water and brine, and dried over MgSO4. Purification by silica gel plug with ethyl acetate/hexane (5:95) gave 28 g (67%) of 4-bromo-2-methylanisole as a colorless solid: mp 65.0-66.0° C.; NMR (CDCl3) δ 2.18 (s, 3H), 3.80 (s, 3H), 6.67 (d, J=9 Hz, 1H), 7.22-7.28 (m, 2H).
Reaction SMILES: [CH:1]12[O:8][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[OH:8][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C1CCC2OC2CC1
Reactant: Nc1ccccc1
Product: OC1CCCCCC1Nc1ccccc1

Procedure:
Reaction of the cycloheptene oxide IIIa with an aniline under conditions well known in the art gives the N-(2-hydroxycycloheptyl)-aniline IX which, when reacted with chlorosulfonic acid in a non-polar organic solvent, e.g., methylene chloride, at 20°-30° C., followed by heating with a selected C1 to C3 -monoalkylamine (aqueous) or ammonium hydroxide (aqueous) at 100°-150° C. for 40-55 hours at elevated pressure (2-10 atm.), gives the diamine VI. Reaction of diamine VI with 2,2,2-trichloroethyl chloroformate, or equivalent N-blocking compound, at 20°-30° C. for 1-5 hours proceeds in the presence of an acid scavenger, e.g., triethylamine, to give the 2-(N-blocked amino) compound XIV. Acylation of the N-blocked compound XIV with the selected acid anhydride, ##STR19## by heating at 90°-120° C. for 12 to 30 hours gives the N-blocked anilide XV. Deprotection of the 2-amino function of the 2-N-blocked anilide XV is then accomplished by reaction with an N-deblocking agent such as metal dust in acid, e.g., zinc in acetic acid, in a polar organic solvent, e.g., methanol, at 20°-100° C. for 2 to 6 hours. Work-up, isolation and purification procedures are those standard in the art of organic chemistry.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].[OH:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:1]([NH:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:33]4[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][OH:27])[CH2:31][CH2:32]4)=[O:23])=[CH:25][CH:26]=3)=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Reactant: OCCN1CCNCC1
Product: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N3CCN(CCO)CC3)cc2)CC1
Yield: 76 %

Procedure:
By the same procedure as described in the example 19, synthesis was carried out starting with 4-[1-[3-(ethylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid and using 1-(2-hydroxyethyl)piperazine. Then, the product was recrystallized using ethyl acetate and hexane to give the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[CH2:60]([N:67]1[CH2:71][CH2:70][CH:69]([CH2:72][NH2:73])[O:68]1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>C(#N)C.C(N(CC)CC)C>[CH2:60]([N:67]1[CH2:71][CH2:70][CH:69]([CH2:72][NH:73][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([C:11]3[CH2:10][C:9]([C:4]4[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=4)([C:24]([F:27])([F:25])[F:26])[O:13][N:12]=3)=[CH:15][C:16]=2[CH3:23])[O:68]1)[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: NCC1CCN(Cc2ccccc2)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC1CCN(Cc2ccccc2)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (1.75 g) (prepared according to WO 2009/080250) in acetonitrile (35 ml) and triethylamine (2.04 ml) were added under nitrogen atmosphere TBTU (1.61 g), AZA.HOBT (0.68 g) and C-(2-Benzyl-isoxazolidin-5-yl)-methylamine (Step B, 1.61 g) were added. The resulting solution was stirred at room temperature for 4 hours, then quenched by addition of aqueous saturated ammonium chloride solution. The mixture was then extracted with ethyl acetate, dried over sodium sulfate, filtered then concentrated in vacuo. The residue purified by column chromatography (ethyl acetate/cyclohexane 1:1) to afford the title compound as a white solid (60 mg, (mixture of diasteroisomers). LCMS (Method F) 2.20 min, M+H 636/638.
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>C(O)C>[CH2:13]([O:9][C:8]1[CH:10]=[CH:11][C:3]([CH2:2][CH2:1][OH:12])=[CH:4][C:5]=1[O:6][CH3:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(CCO)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(CCO)ccc1OCc1ccccc1
Yield: 80 %

Procedure:
A mixture of homovanillyl alcohol (100 mmol, 17.0 g), benzyl bromide (105 mmol, 18.33 g) and 5M aqueous NaOH (24 mL) in ethanol (200 mL) was refluxed for 6 h. The organic solvent was evaporated in vacuo. The residue was partitioned between brine (200 mL) and diethyl ether (200 mL). The aqueous layer was separated from the organic layer and extracted again with ether. The combined organic layers were dried over MgSO4 and the solvent was evaporated in vacuo. Purification by dry-column chromatography with mixtures of ethyl acetate-hexanes (1:4, 1:3, v/v) yielded 20.66 g (80% yield) of (DC-61) as pale yellow oil. Rf 0.25 (EtOAc-hexanes, 1:1, v/v); 1H-NMR (300 MHz, CDCl3) δ 7.44-7.25 (m, 5H, Ar), 6.84-6.67 (m, 3H, Ar), 5.12 (s, 2H, PhCH2O), 3.88 (s, 3H, CH3O), 3.81 (t, 2H, CH2CH2OH), 2.79 (t, 2H, CH2CH2OH), 1.54 (s, 1H, OH); 13C-NMR (75 MHz, CDCl3, APT) δ 149.63 (+), 146.75 (+), 137.21 (+), 131.60 (+), 128.43 (−), 127.70 (−), 127.17 (−), 120.84 (−), 114.25 (−), 112.74 (−), 71.07 (+), 63.58 (+), 55.90 (−), 38.67 (+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([S:35]([C:38]2[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=2)(=[O:37])=[O:36])[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.Cl[Pd]Cl>[F:27][CH:25]([F:26])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([C:41]3[CH:42]=[CH:43][C:38]([S:35]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)(=[O:36])=[O:37])=[CH:39][CH:40]=3)[N:7]=[C:6]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[N:5]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CN1CCN(S(=O)(=O)c2ccc(B(O)O)cc2)CC1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(-c2ccc(S(=O)(=O)N3CCN(C)CC3)cc2)nc(N2CCOCC2)n1
Temperature: 25 °C
Yield: 30.7 %

Procedure:
A mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) (200 mg, 0.504 mmol), 4-[(4-methyl-1-piperazinyl)sulfonyl]phenylboronic acid (186 mg, 0.655 mmol), PdCl2 (dppf) (29 mg, 0.0355 mmol), and aq. K2CO3 (2M, 3 mL) in 1,4-dioxane (20 mL) was refluxed under nitrogen for 1 hr. The mixture was cooled to room temperature and diluted with H2O, and the aqueous phase extracted with CH2Cl2 (9×). The combined organic extracts were dried (Na2SO4), and the solvent was removed under vacuum. Chromatography on alumina, eluting with CH2Cl2/MeOH (100:0 to 99.75:0.25), followed by chromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 98:2), and recrystallization from CH2Cl2/MeOH/hexanes gave 2-(difluoromethyl)-4-methoxy-1-[4-{4-[(4-methyl-1-piperazinyl)sulfonyl]phenyl}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (93 mg, 31%).
Reaction SMILES: Cl.O.[NH2:3]N.Cl.[CH2:6]([O:8][C:9](=[O:22])[C:10](=[CH:18][N:19](C)C)[C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:7]>C(O)C>[CH2:15]([O:14][C:12]([C:11]1[NH:3][N:19]=[CH:18][C:10]=1[C:9]([O:8][CH2:6][CH3:7])=[O:22])=[O:13])[CH3:16]
Reactant: NN
Reactant: CCOC(=O)C(=O)C(=CN(C)C)C(=O)OCC
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cn[nH]c1C(=O)OCC
Temperature: 60 °C
Yield: 31 %

Procedure:
Under an atmosphere of argon, hydrazine monohydrate hydrochloride (1.91 g, 28 mmol) and HCl (36.5% in water, 2.8 ml) were added to a solution of 2-dimethylaminomethylene-3-oxo-succinic acid diethyl ester (6.8 g, 28 mmol, obtained by the method of Hanzlowsky et al., J. Heterocyclic Chem. 2003, 40(3), 487-498) in ethanol (100 ml). The mixture was heated to 60° C. (3 h). The solvent was evaporated, and the residue was taken up in dichloromethane and washed (water). The organic layer was dried (Na2SO4), the solvent was evaporated and the title compound (1.81 mg, 31%) was isolated from the mixture by column chromatography (silica gel, heptane:ethyl acetate=100:0-60:40). MS (m/e)=383.3 [M+H+].
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[C:15]1[C:16]2[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[O:26])[C:17]=2[N:18]=[CH:19][N:20]=1)[CH3:3].[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:13])([F:12])[F:14])=[CH:7][C:6]=1[C:15]1[C:16]2[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]3[CH2:29][CH2:30][N:31]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:32][CH2:33]3)=[O:26])[C:17]=2[N:18]=[CH:19][N:20]=1)[CH3:3]
Reactant: CCOc1ccc(C(F)(F)F)cc1-c1ncnc2c(C(=O)NC3CCNCC3)c(C)[nH]c12
Reactant: COCC(=O)Cl
Agent: Cl
Product: CCOc1ccc(C(F)(F)F)cc1-c1ncnc2c(C(=O)NC3CCN(C(=O)COC)CC3)c(C)[nH]c12

Procedure:
Starting from 4-[2-ethoxy-5-(trifluoromethyl)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f34) and commercially available methoxyacetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[N:12][C:13]([NH:17][CH2:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)([CH3:21])[CH3:20])=[CH:14][C:15]=2[CH3:16])=[CH:6][C:3]=1[C:4]#[N:5].OO.C([O-])([O-])=[O:32].[K+].[K+]>CS(C)=O.CCOC(C)=O>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]([CH3:20])([CH3:21])[CH2:18][NH:17][C:13]2[N:12]=[N:11][C:10]([C:7]3[CH:6]=[C:3]([CH:2]=[CH:9][CH:8]=3)[C:4]([NH2:5])=[O:32])=[C:15]([CH3:16])[CH:14]=2)=[CH:23][CH:24]=1
Reactant: Cc1cc(NCC(C)(C)c2ccc(F)cc2)nnc1-c1ccc(F)c(C#N)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(NCC(C)(C)c2ccc(F)cc2)nnc1-c1cccc(C(N)=O)c1
Yield: 50.4 %

Procedure:
A 0° C. solution of 2-fluoro-5-(6-(2-(4-fluorophenyl)-2-methylpropylamino)-4-methylpyridazin-3-yl)benzonitrile (0.80 g, 2.2 mmol, 1.0 equiv), 30% hydrogen peroxide (0.45 mL, 4.4 mmol, 2.0 equiv), and K2CO3 (600 mg, 4.4 mmol, 2.0 equiv) in DMSO (9.0 mL) was stirred for 1 hour. The mixture was diluted with EtOAc, washed with saturated NaCl, water and saturated NaCl again, and then dried over Na2SO4. Purification by reverse phase HPLC using a gradient of 20-70% CH3CN/water gave the desired product (420 mg, 51%) as a yellow solid. m/z=379.1 [M+H]+.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([CH3:28])[CH:22]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][C:24]1[CH:26]=[CH:27][C:21]([O:20][CH3:19])=[CH:22][C:23]=1[CH3:28])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(N)c(C)c1
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccc(OC)cc1C
Yield: 34.7 %

Procedure:
3-Butyryl-4-chloro-8-methoxyquinoline (5.0 g, 0.019 mol) and 4-methoxy-2-methylaniline (3.0 g, 0.022 mol) were heated under reflux in 1,4-dioxan (50 ml) for 30 minutes. The solvent was evaporated and the residue was dissolved in dichloromethane, washed with dilute hydrochloric acid, sodium bicarbonate solution, water and brine. The solution was dried and evaporated to an oil, which crystallised on standing. The crystals were triturated with ether and recrytallised from ethyl acetate to give 3-butyryl-4-(4- methoxy-2-methylphenylamino)-8-methoxyquinoline (2.4 g, 34.8%), m.p. 161°-3°.
Reaction SMILES: C([N+:8]1[CH:17]=[CH:16][C:15]2[C:14]3[N:18]([CH3:31])[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])=[C:20]([C:21](=[O:23])[NH2:22])[C:13]=3[CH2:12][CH2:11][C:10]=2[CH:9]=1)C1C=CC=CC=1.[Br-].CC(C)([O-])C.[K+]>CS(C)=O.C1COCC1>[CH3:31][N:18]1[C:14]2[C:15]3[CH:16]=[CH:17][N:8]=[CH:9][C:10]=3[CH2:11][CH2:12][C:13]=2[C:20]([C:21]([NH2:22])=[O:23])=[C:19]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30]
Reactant: Cc1ccccc1-c1c(C(N)=O)c2c(n1C)-c1cc[n+](Cc3ccccc3)cc1CC2
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1ccccc1-c1c(C(N)=O)c2c(n1C)-c1ccncc1CC2

Procedure:
To a solution of 7-benzyl-3-carbamoyl-1-methyl-2-o-tolyl-4,5-dihydro-1H-pyrrolo[2,3-f]isoquinolin-7-ium; bromide XXV (1.64 mmol) in dry DMSO (1 mL), 1M potassium tert-butoxide (11.5 mmol) in THF was added. The solution was bubbled with dry air overnight. Volatiles were removed, the residue was suspended in DCM, washed with water, dried (Na2SO4), filtered and the solvent evaporated. Chromatography on silica gel (eluant: DCM/MeOH 20:1) afforded the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.Cl.[CH3:15][O:16][C:17](=[O:24])[CH2:18][CH2:19][C@H:20]([NH2:23])[CH2:21][F:22].CN(C)C.C1(N=C=NC2CCCCC2)CCCCC1>C(O)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:23][C@H:20]([CH2:21][F:22])[CH2:19][CH2:18][C:17]([O:16][CH3:15])=[O:24])=[O:8]
Reactant: COC(=O)CC[C@H](N)CF
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)CC[C@@H](CF)NC(=O)COc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.70 g of 2,4-dichlorophenoxyacetic acid, 0.59 g of 4 and 0.44 ml of trimethylamine were mixed with 75 ml of methylene chloride, and the mixture was stirred at room temperature for 30 minutes. Then, 0.65 g of N,N'-dicyclohexylcarbodiimide was added and the mixture was stirred at room temperature overnight. Several drops of glacial acetic acid were added and the mixture was filtered. The filtrate was washed successively with water, 1N hydrochloric acid, and half-saturated aqueous sodium bicarbonate solution, dried (Na2SO4) and stripped of solvent. The residue was triturated with ethyl acetate, the mixture was filtered and the solvent was evaporated from the filtrate under reduced pressure. The solid residue was triturated with hexane, the mixture was filtered and the solvent was evaporated from the filtrate. The solid residue was chromatographed over silica gel, first with a 1:3 v:v mixture of ethyl acetate and hexane as eluent, then with a 1:1 v:v mixture of ethyl acetate and hexane as eluent. On workup, 16 was obtained, as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([OH:13])=O)[O:8][N:7]=1)=[O:5])[CH3:2].[CH:14]1([NH2:17])[CH2:16][CH2:15]1>C(Cl)Cl>[CH:14]1([NH:17][C:11]([C:9]2[O:8][N:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:10]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1cc(C(=O)O)on1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(=O)NC2CC2)on1
Yield: 43.5 %

Procedure:
The title compound was prepared starting from 3-(ethoxycarbonyl)isoxazole-5-carboxylic acid (3.78 mmol, 0.7 g) and cyclopropyl-amine (2.91 mmol, 0.166 g) using DCM (10 ml) as the solvent. The mixture was diluted with DCM and washed with 1 M Na2CO3 and water. The organic phase was dried, filtered and evaporated. The crude product was purified by flash chromatography. 0.284 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6) δ 0.58-0.64 (m, 2H), 0.70-0.77 (m, 2H), 1.33 (t, 3H), 2.80-2.90 (m, 1H), 4.38 (q, 2H), 7.39 (s, 1H), 9.04 (bs, 1H).
Reaction SMILES: N#N.[Mg].Br[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.II.[CH:22](N1CCCCC1)=[O:23]>C1COCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]#[C:11][C:8]2[CH:9]=[CH:10][C:5]([CH:22]=[O:23])=[CH:6][CH:7]=2)=[CH:14][CH:15]=1
Reactant: Clc1ccc(C#Cc2ccc(Br)cc2)cc1
Reactant: O=CN1CCCCC1
Agent: II
Agent: N#N
Agent: [Mg]
Solvent: C1CCOC1
Product: O=Cc1ccc(C#Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 318.6 %

Procedure:
To a dry 100 mL three-necked flask under a flow of N2 containing magnesium turnings (0.595 g; 24.50 mmol) in dry THF (10 mL) at reflux, an activating, small amount of 1-bromo-4-[(4-chlorophenyl) ethynyl] benzene (VIId) (0.39 g; 1.33 mmol) was added in one portion. N2 flow and stirring were stopped. Reaction mixture was heated at reflux for 5 minutes then iodine crystal was added keeping vigorous reflux to start the reaction. The reaction mixture went colourless after 5minutes and reaction mixture turned black-blue after an additional minute. A solution of the remaining amount of 1-bromo-4-[(4-chlorophenyl) ethynyl] benzene (VIId) (6.104 g; 20.93 mmol) in dry THF (35 mL) at 55° C. was added drop wise into the reaction mixture while keeping gentle reflux. Reflux was maintained for 15minutes then temperature was allowed to cool to RT under stirring for 1 h. The reaction mixture was cooled to 3° C. and a solution of dry 1-formyl-piperidine (3.71 mL; 33.40 mmol) in dry THF (10 mL) was added drop wise maintaining temperature at 5° C. The reaction mixture was then allowed to warm to RT and it was stirred overnight. Protocol and work-up was then similar with those described above. Purification was performed by flash chromatography (SiO2) using (cyclohexane 9-ethyl acetate 1). The title compound (m=1.02 g) was obtained as a white solid in a19% yield. Melting point: 164° C.
Reaction SMILES: C(=O)(O)[O-].[Na+].[F:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1.Cl[CH2:22][CH2:23][CH2:24][N:25]1[C:38]2[CH:37]=[C:36]([S:39][CH3:40])[CH:35]=[CH:34][C:33]=2[S:32][C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2>CN(C)C=O>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:22][CH2:23][CH2:24][N:25]3[C:38]4[CH:37]=[C:36]([S:39][CH3:40])[CH:35]=[CH:34][C:33]=4[S:32][C:31]4[C:26]3=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:15][CH2:14]2)=[O:12])=[CH:19][CH:20]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CSc1ccc2c(c1)N(CCCCl)c1ccccc1S2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc2c(c1)N(CCCN1CCC(C(=O)c3ccc(F)cc3)CC1)c1ccccc1S2
Temperature: 78 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To a stirred solution of sodium bicarbonate (10 g) in 40 ml of dimethylformamide was added 2.5 g of 4-(4-fluorobenzoyl)piperidine in 40 ml of dimethylformamide, and 4.5 g of 10-(3-chloropropyl)-2-methylthiophenothiazine in 20 ml of dimethylformamide. The reaction mixture was stirred at 78° C. for four hours, cooled, and filtered. The filtrate was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, filtred and concentrated to an oil. The oil was purified by high pressure liquid chromatography on a silica gel column, utilizing ethyl acetate as the eluent. Concentration of the appropriate fractions yielded 2.97 g (36%) of 4-(4-fluorobenzoyl)-1-[3-(2-methylthio-10H-phenothiazin-10-yl)propyl]piperidine as an oil.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH:12]=[CH:11]2>>[CH3:22][CH:18]([C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:9]=2)[CH:14]=1)[C:19]([OH:21])=[O:20]
Reactant: CCCCCI
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Product: CCCCCOc1ccc2cc(C(C)C(=O)O)ccc2c1

Procedure:
The title compound is prepared according to the method of Example 7 using 1-iodopentane and racemic 6-hydroxy-α-methyl-2-naphthaleneacetic acid. White crystals are obtained having a melting point of 97°-99° C.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28](OCC)=O)[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[NH2:34].C[Al](C)C.C(O)(=O)C>C1C=CC=CC=1>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28]#[N:34])[N:27]=2)[CH2:22]1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: CCOC(=O)c1coc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: C[Al](C)C
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CC(C)(C)[Si](OC1CN(c2nc(C#N)co2)C1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 41 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-oxazol-2-yl)azetidine (357 g, 0.79 mmol) (obtained as described in Reference Example 21(3)) in benzene (8 ml) was added a solution of 0.67M methylamine-trimethylaluminium in benzene (2.8 ml) at room temperature under an atmosphere of nitrogen. The mixture was stirred in a water bath (60° C.) for 7 hours. After checking the completion of the reaction, 10% aqueous acetic acid solution (10 ml) was added to the reaction mixture in an ice bath, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (5:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-cyano-1,3-oxazol-2-yl)azetidine (130 mg, yield 41%) as a colorless oil.