Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](/[CH:5]=[CH:6]\[C:7]1[CH:8]=[C:9]([CH2:21][C:22]([OH:24])=O)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O:3][CH3:4])=[O:2].[CH3:25][NH:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH3:25][N:26]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:22](=[O:24])[CH2:21][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:7](/[CH:6]=[CH:5]\[C:1]([O:3][CH3:4])=[O:2])[CH:8]=1
Reactant: CNCCc1ccccc1
Reactant: COC(=O)/C=C\c1cc(CC(=O)O)ccc1OCc1ccccc1
Solvent: ClCCl
Product: COC(=O)/C=C\c1cc(CC(=O)N(C)CCc2ccccc2)ccc1OCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of 1.85 g (5.69 mmoles) of cis-3-carbomethoxyvinyl-4-benzyloxyphenylacetic acid in 50 ml of CH2Cl2 is added 1.02 g (6.26 mmoles) if 1,1'-carbonyldiimadazole. After 15 minutes, 827 ml (5.69 mmoles) of N-methyl-N-phenethylamine is added. After 5 hours, the reaction mixture is concentrated in vacuo and is purified flash chromatography to yield cis-N-methyl-N-phenethyl-2-[4-benzyloxy-3-(2-carbomethoxyvinyl)phenyl]acetamide which is used directly in the next step.
Reaction SMILES: C([O:5][C:6](=[O:45])[CH2:7][N:8](C(OC(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([S:29]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[N:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[N:10]=1)(C)(C)C.C(OC(=O)CN(C(OC(C)(C)C)=O)C1C=CC=C(C(CC2C=CC(C3C=CC=CN=3)=CC=2)NS(C2C=NC=CC=2)(=O)=O)N=1)(C)(C)C>>[N:34]1[CH:35]=[CH:36][CH:37]=[C:32]([S:29]([CH:15]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[N:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[C:11]2[N:10]=[C:9]([NH:8][CH2:7][C:6]([OH:45])=[O:5])[CH:14]=[CH:13][CH:12]=2)(=[O:30])=[O:31])[CH:33]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(NCc2ccc(-n3cncn3)cc2)S(=O)(=O)c2cccnc2)n1
Agent: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(Cc2ccc(-c3ccccn3)cc2)NS(=O)(=O)c2cccnc2)n1
Product: O=C(O)CNc1cccc(C(NCc2ccc(-n3cncn3)cc2)S(=O)(=O)c2cccnc2)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
Reaction was carried out in the same manner as in Example 19-(b) except for using tert-butyl[tert-butoxycarbonyl(6-{(pyridin-3-ylsulfonyl)[4-(1,2,4-triazol-1-yl)benzyl]aminomethyl}pyridin-2-yl)amino]acetate (936 mg, 1.47 mmol) obtained in Example 20-(a) in place of tert-butyl[tert-butoxycarbonyl(6-{[4-(pyridin-2-yl)benzyl]-(pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-yl)amino]acetate. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The concentrate was adjusted to pH 4.5 with a 6N aqueous sodium hydroxide solution, and a precipitated solid was collected by filtration. Acetone (1.3 ml) was added to the crude product, followed by stirring at 50° C. for 1 hour, and then at room temperature for 1 hour. A precipitated solid was collected by filtration, and then dried under reduced pressure to afford the title compound (618 mg) as a white solid. (Yield: 88%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:23][C:24](=O)[CH2:25][C:26](=[O:38])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[CH:36][N:35]=[N:34]2)[CH:28]=1)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:15]=[CH:16][CH:17]=[CH:18]2)=[CH:10][C:9]=1[NH:19][C:24](=[O:23])[CH2:25][C:26](=[O:38])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[CH:36][N:35]=[N:34]2)[CH:28]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1

Procedure:
The title compound was prepared from (2-amino-4-pyrrol-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example J2) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example K1) according to the general procedure M. Obtained as a light yellow solid (140 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(F)cc1)N1CCOCC1

Procedure:
20 g of morpholine were added dropwise to a solution, cooled with ice, of 19.5 g of 4-fluorobenzenesulfonyl chloride in 100 ml of toluene, and the mixture was heated under reflux for 1 hour. After cooling, the mixture was concentrated under reduced pressure, the residue was stirred with water and the precipitate was filtered off with suction, washed with water and recrystallized from isopropanol.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:17][NH:18][C:19]([NH2:21])=[O:20].C([O-])(=O)C.[Na+]>C(O)C.O>[CH:1]1([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[N:17][NH:18][C:19]([NH2:21])=[O:20])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(OC2CCCCC2)cc1
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)NN=Cc1ccc(OC2CCCCC2)cc1
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
To a solution of 4-cyclohexyloxybenzaldehyde (2.1 g) in ethanol (50 mL) was added a solution of semicarbazide hydrochloride (1.24 g) and sodium acetate (0.87 g) in water (20 mL) at room temperature. The mixture was stirred for 30 min, and the resulting solid was collected by filtration, washed with water (3×50 mL) and dried in vacuo to yield the title compound as a white solid (2.2 g, 72%), mp: 215 -217° C. 1H NMR (DMSO-d6): δ 10.08 (s, 1H), 7.61 (d, J=8.5, 2H), 6.92 (d, J=8.5, 2H), 6.41 (s, 2H), 4.38 (m, 1H), 1.91-1.24 (m, 10H).
Reaction SMILES: [CH:1]([CH:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20](=[O:27])[CH2:21][O:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:15]1)([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.[CH3:28]S(O)(=O)=O>CO>[CH:1]([CH:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20](=[O:27])[CH2:21][O:22][CH2:23][C:24]([O:26][CH3:28])=[O:25])[CH2:15]1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)O
Reactant: O=C(O)COCC(=O)N1CCCC(C(c2ccccc2)c2ccccc2)C1
Solvent: CO
Product: COC(=O)COCC(=O)N1CCCC(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a manner similar to that described in Example XXVI, 3.63 grams (10 millimoles) of [2-(3-benzhydrylpiperidino)-2-oxoethoxy]acetic acid (Example VIII), 150 milliliters of methanol and 300 milligrams of methanesulfonic acid are stirred together for about six hours at ambient temperature. Thereafter, the methanol is evaporated, the residue dissolved in ether, the ether solution washed, dried and the solvent evaporated to obtain a methyl [2-(3-benzhydrylpiperidino)-2-oxoethoxy]acetate product as residue.
Reaction SMILES: [CH2:1]=C=O.C(OC([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([O:17]CC2C=CC=C(C#N)C=2)[C@H:12]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O)(C)(C)C.[BH4-].[Na+]>CO>[OH:17][CH:13]1[CH2:14][CH2:15][CH2:16][NH:11][C:12]1([CH3:1])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](OCc2cccc(C#N)c2)[C@H]1c1ccccc1
Reactant: C=C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(c2ccccc2)NCCCC1O
Reaction time: 0.5 h

Procedure:
The ketene of (a) above (3.2 g) was suspended in methanol under nitrogen and the temperature brought to -40° C. Sodium borohydride (0.3 g) was added portionwise. The mixture was stirred for 30 min and then concentrated in vacuo, azeotroping with tetrahydrofuran. Borane tetrahydrofuran complex (64 ml, 1.0M in tetrahydrofuran) was added and the mixture was heated at reflux overnight. The mixture was cooled and quenched carefully with methanol, and the mixture was then concentrated in vacuo. The resulting residue was dissolved in ethanol (100 ml) and potassium carbonate (4.2 g) was added. The mixture was heated at reflux for 12 h. The mixture was cooled and evaporated and the residue was extracted with ethyl acetate and water. The organic extract was washed with brine, dried (MgSO4) and evaporated to afford 3-hydroxy-2-methyl-2-phenylpiperidine as a white solid. 1H NMR (360 MHz, CDCl3) δ 7.79 (2H, d, ArH), 7.40 (2H, t, ArH), 7.15-7.19 (1H, m, ArH), 3.89 (1H, mc), 2.89-3.01 (2H, m), 1.67-1.91 (4H, m), 1.39 (3H, s, CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:13][C:12]([CH2:14][C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21]C(C)(C)C)=[O:20])=[CH:17][CH:16]=2)=[N:11][N:10]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:13][C:12]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:26][CH:27]=2)=[N:11][N:10]=1
Reactant: COc1ccccc1-c1nnc(Cc2ccc(C(=O)OC(C)(C)C)cc2)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1-c1nnc(Cc2ccc(C(=O)O)cc2)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 4-{[5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}benzoate (86 mg, 0.24 mmol) in methylene chloride (5 mL) was treated with trifluoroacetic acid (3.5 g) and stirred at ambient temperature for 30 minutes. The reaction was evaporated in vacuo to give the title compound as a white solid. 1H NMR (600 MHz, CDCl3) δ 8.09 (d, J=8.5 Hz, 2H), 7.81 (d, J=8.2 Hz, 11H), 7.54 (m, 1H), 7.48 (d, J=8.2 Hz, 2H), 7.06 (m, 2H), 4.41 (s, 2H), 3.93 (s, 3H); ESIMS calcd 311.1 (M++H), found 311.1 (M++H).
Reaction SMILES: Cl[C:2]1[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:18]([N:20]([CH2:21][CH3:22])[C:2]1[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5])[CH3:19]
Reactant: CCNCC
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)c1nc(C(F)(F)F)ccc1C(=O)N(C)OC
Temperature: 110 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
To a suspension of 2-chloro-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (400 mg, 1.489 mmol) and diethylamine (0.773 ml, 7.44 mmol) in DMF (4 ml) was added K2CO3 (1.02 g, 7.44 mmol). The mixture was stirred for 4 hours at 110° C. The reaction mixture was diluted with EtOAc (30 ml) and then washed two times with 1N-HCl (30 ml) and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was chromatographed to yield the 2-diethylamino-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (400 mg, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:9][CH2:8][C:7]=2[C:6]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[N:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:36])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[N+:5]([O-:36])[C:6]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[C:7]2[C:12]=1[C:11](=[O:13])[N:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH2:9][CH2:8]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(CN2CCc3c(C(=O)N(C)C)ncc(OC)c3C2=O)cc1
Solvent: ClCCl
Product: COc1ccc(CN2CCc3c(c(OC)c[n+]([O-])c3C(=O)N(C)C)C2=O)cc1
Temperature: 25 °C

Procedure:
A 100 ml CH2Cl2 solution of 12 g 4-methoxy-6-(4-methoxybenzyl)-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide and 16.8 g mCPBA (maximum 77% purity) was allowed to stir at room temperature until the starting material was consumed (5 hours). The reaction was washed four times with 100 mL sat aqueous NaHCO3 then the organic layer was concentrated. The crude reaction was dissolved in 250 mL CH2Cl2 and the excess mCPBA was then quenched by vigorous stirring with a sat aq sodium sulfite solution for 30 minutes (both organic and aqueous layers were cloudy initially but then turned transparent). The layers were separated and the organic washed twice with sat aqueous NaHCO3. The organic layer was dried over sodium sulfate and concentrated to pure product by HPLC/MS and NMR.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:19](Cl)(=[O:21])=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[NH2:24][C:25]1[CH:29]=[C:28]([Cl:30])[S:27][C:26]=1[Cl:31]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:19]([NH:24][C:25]3[CH:29]=[C:28]([Cl:30])[S:27][C:26]=3[Cl:31])(=[O:21])=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: Nc1cc(Cl)sc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=S(=O)(Nc1cc(Cl)sc1Cl)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Yield: 15 %

Procedure:
3.0 g of 3-chloro-2-(4-chloro-3-chlorosulfonylphenyl)-5-trifluoromethylpyridine and 1.7 g of 3-amino-2,5-dichlorothiophene hydrochloride in a mixture of 100 ml of toluene and 100 ml of pyridine were refluxed for 6 hours. The residue after concentration was dissolved in 100 ml of ethyl acetate. The solution was extracted with 50 ml of dilute hydrochloric acid and 50 ml of water, dried over sodium sulfate and concentrated. Chromatography on silica gel with methylene chloride resulted in 0.6 g of colorless crystals. Yield: 15%, melting point: 106°-108° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[CH3:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([CH3:15])=[CH:17][CH:18]=1)=[O:11]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Cc1ccc(N)cc1
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(C)cc1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 4-methylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(O)cccc1O
Reactant: COC(=O)CBr
Product: COC(=O)COc1cccc(O)c1C(=O)OC

Procedure:
The subtitle compound was prepared from the product of step (i) (10 g) and methyl bromacetate (5.5 ml) by the method of example 11 step (i). Purified by chromatography eluting with 20% ethyl acetate in isohexane. Yield 3.68 g.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH2:30]([O:37][C:38](=[O:49])[N:39]([C@H:41]1[CH2:46][CH2:45][C@H:44]([CH:47]=O)[CH2:43][CH2:42]1)[CH3:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH2:30]([O:37][C:38](=[O:49])[N:39]([CH:41]1[CH2:46][CH2:45][CH:44]([CH:47]=[CH:2][O:3][CH3:4])[CH2:43][CH2:42]1)[CH3:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CN(C(=O)OCc1ccccc1)[C@H]1CC[C@H](C=O)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=CC1CCC(N(C)C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A supension of 128.6 g (375 mmol) of (methoxymethyl)triphenylphosphonium chloride in 540 ml THF was treated at −8° C. with 43.1 g (375 mmol) potassium tert-butoxide. The red solution was stirred 30 min at 0° C. and cooled (−20° C.), then 82.6 g (300 mmol) of trans-(4-Formyl-cyclohexyl)-methyl-carbamic acid benzyl ester in 240 ml THF were dropped in (60 min). The reaction was warmed to RT and stirred for 2 h, washed with aqueous saturated NaHCO3 (540 ml). The water phase was extracted with 0.5 l TBME, the combined organic phases were oxidized with 16 ml of hydrogen peroxide solution (35%), mixed with water (150 ml). The organic solvent was evaporated, the residue was extracted with MeOH (350 ml)/hexane (2×2000 ml). The hexane was washed twice with 500 ml MeOH/water (7/3), dried (Na2SO4) and evaporated to give 81.7 g (90%) of trans-(2E/Z) [4-(2-Methoxy-vinyl)-cyclohexyl]-methyl-carbamic acid benzyl ester, MS: 303(M).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]([NH:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[NH:8])=[N:4][O:5][N:6]=1.Cl[CH2:15][C:16](=O)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:10]([N:9]1[CH:15]=[C:16]([CH3:17])[N:8]=[C:7]1[C:3]1[C:2]([NH2:1])=[N:6][O:5][N:4]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: CC(=O)CCl
Reactant: CC(C)CNC(=N)c1nonc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cn(CC(C)C)c(-c2nonc2N)n1
Yield: 5.6 %

Procedure:
A mixture of 4-amino-N-isobutyl-1,2,5-oxadiazole-3-carboxamidine (38 mg, 0.2 mmol), 1-chloropropanone (37 mg, 0.4 mmol) and potassium carbonate (55 mg, 0.4 mmol) in DMF (0.5 mL) was microwaved for 20 minutes at 180° C. The crude mixture was purified via Gilson and then a flash pipette column to afford the title compound as a white solid 2.5 mg. HPLC Rt 5.6 min; MS 222.1 as M+1 peak; HPLC Method B Rt 3.4 min. 1HNMR (CDCl3) 6.94 (s, 1H); 5.73 (br, 2H); 4.15 (d, 2H); 2.3 (s, 3H); 2.15 (m, 1H); 0.95 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:40])=[C:4]([S:9]([N:12]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(C(C)C)C(C)C.[O:50]([C:57]1[CH:65]=[CH:64][CH:63]=[CH:62][C:58]=1[C:59]([OH:61])=O)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.CCN=C=NCCCN(C)C>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([OH:40])=[C:4]([S:9]([N:12]([CH2:13][C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[CH2:20][N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:59](=[O:61])[C:58]2[CH:62]=[CH:63][CH:64]=[CH:65][C:57]=2[O:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:31][CH:32]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Reactant: CC(C)CNCc1cccc(CN(Cc2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)CN(Cc1cccc(CN(Cc2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1)C(=O)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.5 %

Procedure:
3,5-Dichloro-N-((4′-fluorobiphenyl-4-yl)methyl)-2-hydroxy-N-(3-((isobutyl amino)methyl)benzyl)benzene sulfonamide (0.04 g, 0.066 mmol, 1 eq) was dissolved in acetonitrile. DIPEA (0.034 mL, 0.198 mmol, 3 eq) was added to the solution followed by 2-phenoxy benzoic acid (0.014 g, 0.066 mmol, 1 eq), EDCI (0.018 g, 0.099 mmol, 1.5 eq) and HOIST (0.013 g, 0.099 mmol, 1.5 eq). The reaction mixture was stirred at ambient temperature for 12 h and concentrated to remove all the volatiles. The residue obtained was dissolved in ethyl acetate and the organic layer was washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford the title compound (0.025 g, 50%). 1H NMR (400 MHz, DMSO-d6) δ 0.64-0.65 (d, 3H), 0.74-0.78 (t, 3H), 1.74 (s, 1H), 1.9 (t, 1H), 3.6 (t, 1H), 3.8 (t, 1H), 4.2 (m, 2H), 4.41-4.45 (m, 4H), 6.86-6.93 (m, 3H), 6.92-6.99 (m, 3H), 7.00-7.13 (m, 7H), 7.14-7.26 (m, 3H), 7.28-7.39 (m, 5H), 7.44-7.47 (d, 1H), 7.54-7.61 (m, 3H), 7.73-7.74 (d, 1H), 7.83-7.84 (d, 1H). MS (ESI): 798.7 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][OH:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Cl:11][CH2:12][C:13]#[C:14][CH2:15]Cl.[H-].[Na+].[Cl-].[NH4+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH2:1]([O:3][P:4]([CH2:9][O:10][CH2:15][C:14]#[C:13][CH2:12][Cl:11])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: ClCC#CCCl
Reactant: CCOP(=O)(CO)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCOP(=O)(COCC#CCCl)OCC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of hydroxymethylphosphonic acid diethylester (3.35 g, 20 mmol), 1,4-dichloro-2-butyne (3.8 g, 30 mmol) and tetra-n-butylammonium iodide (0.75 g, 2 mmol) in anhydrous tetrahydrofuran (100 ml), sodium hydride (0.95 g, 24 mmol, 60% in oil) is added in portions at 0° C. The resulting mixture is stirred overnight at 0° C. Then the reaction mixture is stirred overnight at 20° C., hydrolyzed with a saturated solution of ammonium chloride and extracted with diethylether. The title product is obtained by flash chromatography on silica gel (2.3 g, 30%).
Reaction SMILES: S(=O)(=O)(O)O.C=O.[CH:8]1([CH2:14][CH:15]=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH2:17](NCC)C>>[CH:8]1([C:14](=[CH2:17])[CH:15]=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCNCC
Reactant: O=CCC1CCCCC1
Agent: C=O
Agent: O=S(=O)(O)O
Product: C=C(C=O)C1CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
Successively, sulfuric acid 62% (79.4 g, 0.5 mol), aqueous formaldehyde 35% (82 g, 1.0 mol) and cyclohexyl acetaldehyde (100.8 g, 0.8 mol) were added slowly to diethylamine (73 g, 1.0 mol) at 0° C. After stirring at 80° C. overnight, the reaction mixture was extracted with MTBE. The combined organic phases were washed with H2O until neutral pH was achieved, dried (MgSO4) and concentrated in vacuo. The crude product was distilled under reduced pressure using a Widmer column (10 Torr, 80° C.) yielding 89.5 g (81%) of pure product as colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5]([CH3:34])([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:17]=[C:16]([NH2:26])[N:15]=2)=[CH:9][CH:8]=1)[CH3:2].[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH:42]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl>[CH2:1]([O:3][C:4](=[O:35])[C:5]([CH3:34])([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([N:20]3[CH2:21][CH2:22][N:23]([CH2:42][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=4)[CH2:24][CH2:25]3)[N:17]=[C:16]([NH2:26])[N:15]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: O=Cc1ccccn1
Reactant: CCOC(=O)C(C)(Cc1ccc(Oc2cc(N3CCNCC3)nc(N)n2)cc1)Oc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C)(Cc1ccc(Oc2cc(N3CCN(Cc4ccccn4)CC3)nc(N)n2)cc1)Oc1ccccc1
Temperature: 25 °C

Procedure:
To a stirring solution of 3-[4-(2-Amino-6-piperazin-1-yl-pyrimidin-4-yloxy)-phenyl]-2-methyl-2-phenoxy-propionic acid ethyl ester (1 mmol) in dry dichloromethane (20 ml) under N2 was added pyridine-2-carbaldehyde (1.1 mmol). The reaction was stirred at room temperature for half an hour, then Sodium triacetoxyborohydride (1.3 mmol) was then added and stirred over night. Water (10 mL), the biphasic mixture was diluted with dichloromethane and partitioned, and the organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified in silica to provide yellow solid.