Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][CH:12]([C:14](=[O:16])[CH3:15])[CH3:13].C(B(CC)CC)C.[O:24]([C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34]Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1.O>[CH3:11][CH:12]([C:14](=[O:16])[CH2:15][CH2:34][C:33]1[CH:36]=[CH:37][CH:38]=[C:31]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:32]=1)[CH3:13]
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: CC(=O)C(C)C
Agent: CCB(CC)CC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=O)CCc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.6 %

Procedure:
To a solution of potassium bis (trimethylsilyl) amide (20.9 g, 0.105 mol) in 200 ml tetrahydrofuran at 0° C. was added 2-methyl-3-butanone (12 ml, 0.112 mol). After 15 minutes, triethylborane (100 ml of a 1.0M solution in hexanes) was added, followed by 24.8 g (0.094 mole) 3-phenoxybenzyl bromide. The mixture was stirred at 25° C. for 18 hours, poured into 300 ml water and extracted with ether. The organic phase was dried, filtered and concentrated, leaving a yellow oil. The crude ketone product was purified by chromatography over silica gel using 5% ethyl acetate in hexanes, producing 16.8 g of product, a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[CH2:14]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH:9]([N:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: O=C(CCCCl)c1ccc(Br)cc1
Reactant: CCCCCCNCCCCCC
Solvent: Cc1ccccc1
Product: CCCCCCN(CCCCCC)C(CC)C(=O)c1ccc(Br)cc1

Procedure:
To a solution of 5.00 g of 4'-bromo-4-chlorobutyrophenone in 3 ml of toluene was added 11.1 ml of di-n-hexylamine and heated under reflux for 3 hours. After diluting with toluene, the reaction mixture was extracted with a 2N aqueous solution of hydrochloric acid. The extract was neutralized with a mass of sodium hydroxide and extracted with methylene chloride. Next, after drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, thereby giving 4.88 g of crude 4'-bromo-di-n-hexylaminobutyrophenone.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:8]=[C:7]([C:21]#[N:22])[N:6]=1.[CH3:23][C@H:24]([NH2:28])[CH2:25][O:26][CH3:27].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(=O)(O)[O-].[Na+]>[CH3:23][C@H:24]([NH:28][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:8]=[C:7]([C:21]#[N:22])[N:6]=1)[CH2:25][O:26][CH3:27]
Reactant: N#Cc1nc(CCC=O)cc(-c2cccc(C(F)(F)F)c2)n1
Reactant: COC[C@H](C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC[C@H](C)NCCCc1cc(-c2cccc(C(F)(F)F)c2)nc(C#N)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(3-oxo-propyl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile (610 mg) in methanol (8 ml) was added 1-(s)-methyl-2-methoxyethylamine (0.85 mL), acetic acid (0.5 mL), and followed by sodium triacetoxyborohydride (0.82 g). The mixture was stirred at room temperature for 4 hours, then diluted with sodium bicarbonate aqueous solution (5%, 50 ml). The mixture was extracted with ethyl acetate (50 ml plus 3×20 ml). Combined organic layer was dried over sodium sulphate, filtered, solvent removed under vacuum. Residue was columned on silica gel using DCM-MeOH (20:1) as eluant to give 4-[3-(1-(s)-methyl-2-methoxyethylamino)-propyl]-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile (250 mg). The above neutral product was dissolved in DCM and then HCl (1M in ether, 1 ml) added, 4-[3-(1-(s)-methyl-2-methoxyethylamino)-propyl]-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile HCl salt was collected by filtration (180 mg). 1H NMR (MeOD): δ 8.50 (s, 1H), 8.48 (d, 1H), 8.27 (s, 1H), 7.90 (d, 1H), 7.79 (t, 1H), 3.68 (m, 1H), 3.48 (m, 2H), 3.43 (s, 3H), 3.17 (m, 2H), 3.10 (t, 2H), 2.25 (m, 2H), 1.36 (d, 3H). MS m/z 379.5 (M+1), 80%.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@@H:11]([NH:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([Cl:34])[C:27]=1[CH3:35])[C:12]1[O:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)=[N:15][N:16]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[Cl:34][C:28]1[C:27]([CH3:35])=[C:26]([NH:25][C@@H:11]([C:12]2[O:13][C:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=3)=[N:15][N:16]=2)[CH2:10][CH2:9][OH:8])[CH:33]=[CH:32][C:29]=1[C:30]#[N:31]
Reactant: Cc1c(N[C@H](CCO[Si](C)(C)C(C)(C)C)c2nnc(-c3ccc(C#N)cc3)o2)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(N[C@H](CCO)c2nnc(-c3ccc(C#N)cc3)o2)ccc(C#N)c1Cl
Temperature: -40 °C
Yield: 0 %

Procedure:
To a 25 mL round bottom flask equipped with a magnetic stirrer and a septum was added (R)-4-(3-(tert-butyldimethylsilyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile (900 mg, 177 mmol), which was then dissolved in anhydrous THF (50 mL) under an atmosphere of nitrogen and cooled to −40° C. To this was added the tetrabutylammonium fluoride as a 1 M solution in THF (2.13 mL, 2.13 mmol) producing an instant color change to yellow. The mixture was then allowed to warm to −20° C. over a period of 2 h, at which point TLC analysis suggested the reaction was complete. The solvent was then removed under reduced pressure to yield a dark brown residue. This residue was taken up in EtOAc (40 mL) and washed with water (2×25 mL), brine (1×25 mL) and dried over Na2SO4. The solution was then filtered and concentrated under reduced pressure using rotary evaporation to reveal a yellow solid (1.08 g). Purification by flash column chromatography [EtOAc-hexanes (1:1) as eluent] afforded the title compound as a white crystalline solid (0.605 mg, 87%): 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.21 (d, J=9 Hz, 2H), 7.99 (d, J=9 Hz, 2H), 7.48 (d, J=9 Hz, 1H), 6.92 (d, J=9 Hz, 1H), 6.41 (d, J=9 Hz, 1H), 5.4 (m, 1H), 4.28-4.26 (m, 1H), 3.97-3.77 (m, 1H), 2.58-2.38 (m, 2H), 2.37.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:21][C@H:20]2[C@@H:13]([O:14][Si:15]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[O:16][Si:17]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:18][CH2:19]2)[C@@H:12]1[OH:34].[C:35]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:21][C@H:20]2[C@@H:13]([O:14][Si:15]([CH:28]([CH3:30])[CH3:29])([CH:31]([CH3:33])[CH3:32])[O:16][Si:17]([CH:25]([CH3:26])[CH3:27])([CH:22]([CH3:23])[CH3:24])[O:18][CH2:19]2)[C@@H:12]1[O:34][CH3:35]
Reactant: CC(C)[Si]1(C(C)C)OC[C@H]2O[C@@H](n3cnc4c(Cl)ncnc43)[C@@H](O)[C@@H]2O[Si](C(C)C)(C(C)C)O1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CO[C@H]1[C@@H]2O[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)OC[C@H]2O[C@H]1n1cnc2c(Cl)ncnc21
Reaction time: 3 h
Yield: 71.4 %

Procedure:
To a suspension of (6aR,8R,9S,9aS)-8-(6-chloro-9H-purin-9-yl)-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-ol (300 mg, 0.57 mmol) and Cs2CO3 (1.86 g, 5.7 mmol) in DMF (5.7 mL) at 0° C. was added MeI (350 μL, 5.7 mmol) dropwise. The suspension was stirred for 3 hours, quenched with saturated aqueous NH4Cl and CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 to 20% EtOAc/hexanes) to afford 221 mg (71%) of the title compound.
Reaction SMILES: Cl[CH:2](Cl)[C:3]1[CH:7]=[CH:6][S:5][C:4]=1[N+:8]([O-:10])=[O:9].[OH-:12].[Na+]>C(O)=O>[N+:8]([C:4]1[S:5][CH:6]=[CH:7][C:3]=1[CH:2]=[O:12])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1sccc1C(Cl)Cl
Reactant: [OH-]
Agent: [Na+]
Solvent: O=CO
Product: O=Cc1ccsc1[N+](=O)[O-]
Yield: 41 %

Procedure:
3-Dichloromethyl-2-nitro-thiophene described in Preparation Example T-1 (1.54 g, 7.26 mmol) was dissolved in formic acid (10 mL), and the solution was refluxed for 24 hours under nitrogen atmosphere. An aqueous solution of 5N sodium hydroxide was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), and the title compound (472 mg, 3.00 mmol, 41%) was obtained as a light brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][C:12]([SH:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+].O>CC(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:15][C:12]([CH3:14])([CH3:13])[CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CC(C)(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)Sc1ccc(Br)cc1C=O
Temperature: 25 °C
Yield: 36 %

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (4.06 g) in 2-propanol (20.0 mL) was added 2-methyl-2-propanethiol (2.26 mL) and K2CO3 (3.04 g) and heated overnight. The reaction mixture was cooled to room temperature, poured into 50.0 mL water and extracted with dichloromethane. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was flash chromatographed (3% EtOAc/Haptanes) to obtain 1.97 g (36%) of 5-bromo-2-(tert-butylthio)benzaldehyde as a clear oil. 1H NMR (500 MHz, CDCl3) 8 ppm 1.30 (s, 9 H) 7.51 (d, J=8.05 Hz, 1 H) 7.70 (dd, J=8.29, 2.20 Hz, 1 H) 8.12 (d, J=2.20 Hz, 1 H) 10.70 (s, 1 H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](C3ON=CC=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[CH3:30][C:31]1[N:35](C2C=C(C=CC=2)N)[N:34]=[N:33][N:32]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([N:32]3[C:31]([CH3:30])=[N:35][N:34]=[N:33]3)[CH:21]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: Cc1nnnn1-c1cccc(N)c1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Product: Cc1nnnn1-c1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)ncc2C(N)=O)c1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 3-(5-methyl-1H-tetrazol-1-yl)aniline in step 1. MS: 409.5 (M+H).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].CCOC(C)=O.Cl>O1CCOCC1.O>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CN(c2nc3ccc(O)cc3n2C)C2CCC(C(C)(C)C)CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1c(N(Cc2ccc(C(=O)O)cc2)C2CCC(C(C)(C)C)CC2)nc2ccc(O)cc21
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To the title compound of Example 12 Step A (0.1 mmol, 50 mg) in 800 μL of dioxane was added LiOH (0.4 mmol, 10 mg) in 400 μL of H2O. The resulting solution was stirred at 40° C. overnight. The reaction mixture was taken up in aqueous pH 7 buffer and EtOAc, and acidified with 2 N HCl until two clear layers formed after agitation. The organic layer was collected and the aqueous layer was washed with EtOAc. The combined organic layers were dried with MgSO4 and concentrated under reduced pressure to afford the acid as a white solid, which was used without further purification. (HPLC A: 1.97 min).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[C:3]=1NCC(OCC)=O.C1([NH:23][CH2:24][C:25](OCC)=[O:26])C=CC=CC=1.BrBr.[NH3:32]>O.C(O)(=O)C.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([Br:9])[CH:5]=[C:6]([Br:8])[C:7]=1[NH:32][C:25](=[O:26])[CH2:24][NH2:23]
Reactant: N
Reactant: CCOC(=O)CNc1ccccc1
Reactant: CCOC(=O)CNc1c(Br)cc(Br)cc1Br
Agent: BrBr
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: NCC(=O)Nc1c(Br)cc(Br)cc1Br

Procedure:
The ester required for Id, ethyl N-(2,4,6-tribromophenyl)glycinate (IV), was prepared by the reaction of ethyl N-phenylglycinate with bromine in a mixture of water and acetic acid. IV reacted with ammonia in ethanol solution to form N-(2,4,6-tribromophenyl)glycinamide (V).
Reaction SMILES: Cl[C:2]1[CH:24]=[C:23](Cl)[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:7].O=C1C(C(O)=O)=CC(C2C=CN=CC=2)=NN1.C(Cl)(=O)C(Cl)=O.[F:48][C:49]([F:59])([F:58])C1C=C(C=CC=1)CN>C(N(CC)CC)C.CN(C)C=O.ClCCl>[O:20]=[C:9]1[C:8]([C:6]([NH:5][CH2:4][C:3]2[CH:21]=[CH:22][CH:23]=[C:24]([C:49]([F:59])([F:58])[F:48])[CH:2]=2)=[O:7])=[CH:13][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:11][NH:10]1
Reactant: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccncc2)n[nH]c1=O
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1cc(-c2ccncc2)n[nH]c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1cc(-c2ccncc2)n[nH]c1=O

Procedure:
Working as in example 2 for the preparation of N-(2,4-dichlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide, but starting with 0.3 g of 3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxylic acid, 10 cm3 of dichloromethane, 0.02 cm3 of dimethylformamide, 0.12 cm3 of oxalyl chloride, 0.21 cm3 of 3-(trifluoromethyl)benzylamine and 0.19 cm3 of triethylamine, 0.22 g of 3-oxo-6-pyridin-4-yl-N-[3-(trifluoromethyl)benzyl]-2,3-dihydropyridazine-4-carboxamide was obtained in the form of a cream-colored solid melting at 224° C.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([O:13]C(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[C:21]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:24](C(Cl)=O)=[CH:23][CH:22]=1.[CH2:36]([N:38]1[C:50]2[CH:49]=[CH:48][C:47]([NH2:51])=[CH:46][C:45]=2[C:44]2[C:39]1=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH3:37]>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([C:33]2[CH:34]=[CH:35][C:30]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:31][CH:32]=2)=[O:13])[C@H:8]([C:18]([NH:51][C:47]2[CH:48]=[CH:49][C:50]3[N:38]([CH2:36][CH3:37])[C:39]4[C:44]([C:45]=3[CH:46]=2)=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: C=CCON=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 51% purity by LC/MS. MS(ESI+): m/z=557.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:5]([CH2:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41])=[C:6]([C:8]([N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@H:11]2[CH2:16][C@@H:15]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]2)=[O:9])[N:7]=1.[C:48](=[O:51])([O-:50])[O-].[K+].[K+].FC(F)(F)C(O)=[O:57]>>[C:39]([OH:40])(=[O:57])/[CH:38]=[CH:37]/[C:48]([OH:50])=[O:51].[CH3:1][O:2][C:3]1[N:4]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:5]([CH2:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41])=[C:6]([C:8]([N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@H:11]2[CH2:16][C@@H:15]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:14][NH:13][CH2:12]2)=[O:9])[N:7]=1
Reactant: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc(OC)n1-c1ccccc1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: COCCCCc1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)nc(OC)n1-c1ccccc1
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl (3S,5R)-3-[{[2-methoxy-5-(4-methoxybutyl)-1-phenyl-1H-imidazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (110 mg) was dissolved in trifluoroacetic acid (25% toluene solution, 4 ml), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was basified with saturated aqueous potassium carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane-methanol (50:50:0-100:0:0-85:0:15) was concentrated under reduced pressure. The residue was dissolved in methanol (2 ml), fumaric acid (15 mg) was added and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure to give the object product (86 mg).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[CH:4]([CH3:6])[CH3:5].[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH:35]2[CH2:37][CH2:36]2)[C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=3)=[N:20][CH:19]=2)[CH2:12][CH2:11]1)#N>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH:35]1([N:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:8]3[O:1][N:2]=[C:3]([CH:4]([CH3:6])[CH3:5])[N:7]=3)[CH2:11][CH2:12]2)[C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:28][CH:29]=3)=[N:20][CH:19]=2)[CH2:37][CH2:36]1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(C(=O)N(C3CC3)C3CCN(C#N)CC3)cn2)cc1
Reactant: CC(C)C(=N)NO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1noc(N2CCC(N(C(=O)c3ccc(-c4ccc(S(C)(=O)=O)cc4)nc3)C3CC3)CC2)n1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
0.5 M solution of zinc chloride in tetrahydrofuran (4.52 mL) is added dropwise at room temperature to a mixture of N-hydroxy-isobutyramidine (58 mg) and N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-6-(4-methanesulfonyl-phenyl)-nicotinamide (160 mg) in ethyl acetate (8 mL). The reaction mixture is stirred at 50° C. for two days and cooled to room temperature. The precipitate is filtered off and heated to 100° C. for 1 h in a mixture of ethanol (6 mL) and glacial acetic acid (3 mL). The solvents are evaporated in vacuo and dichloromethane and 10% aqueous K2CO3 solution are added to the residue. The organic phase is separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue is triturated with diethyl ether to give the title compound. LC (method 8): tR=1.51 min; Mass spectrum (ESI+): m/z=510 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1Br.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:10][O:11][C:12]1[C:13]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccccc1B(O)O
Reactant: Clc1cccc(Cl)c1Br
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1c(Cl)cccc1Cl
Yield: 77.2 %

Procedure:
Treatment of 2,6-dichlorobromobenzene (25.0 g, 0.110 mol) with 2-methoxybenzeneboronic acid (25.22 g, 0.166 mol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (2.33 g, 2.96 mmol), and potassium carbonate (34.15 g, 0.247 mmol) generally according to the procedure described for Intermediate 37 provided 21.5 g (77%) of 2′,6′-dichloro-1,1′-biphenyl-2-yl methyl ether. Treatment of 2′,6′-dichloro-1,1′-biphenyl-2-yl methyl ether (19.0 g, 75.06 mmol) with boron tribromide (18.78 g, 1.0 M in dichloromethane) generally according to the procedure described for Intermediate 163 provided 17.89 g (99%) of 2′,6′-dichloro-111′-biphenyl-2-ol as a light yellow solid. mp 100-103° C.; Anal. calcd. for C12H8Cl2O: C, 60.28H, 3.37. Found: C, 60.29; H, 3.13.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:7][C:6]2[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:5]=2[O:4]1.[CH2:13]([O:15][C:16](=[O:37])[C:17]1[C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]3[O:30][CH2:31][O:32][C:26]=3[C:25]=2C=CC)=[CH:21][CH:20]=[CH:19][C:18]=1F)[CH3:14].O.[CH2:39]1[CH2:43]OC[CH2:40]1>CS(C)=O.C(OCC)(=O)C>[CH2:31]1[O:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:12][C:9]4[CH:8]=[C:6]5[O:7][CH2:3][O:4][C:5]5=[CH:11][C:10]=4[CH:40]=[CH:39][CH3:43])[C:17]=3[C:16]([O:15][CH2:13][CH3:14])=[O:37])=[CH:25][C:26]=2[O:32]1
Reactant: CC=Cc1c(Oc2cccc(F)c2C(=O)OCC)ccc2c1OCO2
Reactant: C1CCOC1
Reactant: Oc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC=Cc1cc2c(cc1Oc1cccc(Oc3ccc4c(c3)OCO4)c1C(=O)OCC)OCO2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (308 mg, 7.69 mmol) was added to a solution of sesamol (967 mg, 6.99 mmol) in dry THF (5 ml), and the solution was stirred at room temperature for 20 minutes. The THF was then removed under pressure and the remaining sodium salt of sesamol was placed under vacuum for 10 minutes. Dry DMSO (8 ml) followed immediately by ethyl-2-fluoro-6-[2-(1-propenyl)-3,4 (methylenedioxy)phenoxy]benzoate (2.41 g, 6.99 mmol) in dry DMSO were added. The resulting dark brown mixture was heated at 80° C. for 18 h. Water (30 ml) followed by ethyl acetate (50 ml) was added to the reaction mixture upon cooling and the layers were separated. The aqueous layer was extracted with an additional 50 ml of EtOAC. The combined organic fractions was then washed with brine and dried over MgSO4. Evaporation of solvents yielded an oil which was purified by flash column chromatography using 5-10%-ethyl acetate-hexanes giving 1.4 g (43%) of the unsaturated ester as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]([CH3:32])[C:9](=[O:31])[NH:10][C:11]2[CH:12]=[C:13]([NH:18][C:19](=[O:30])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[CH:14]=[CH:15][C:16]=2[CH3:17])[CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[N:44]1([C:50]2[CH:55]=[CH:54][C:53]([NH2:56])=[CH:52][CH:51]=2)[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>CN(C=O)C>[CH3:17][C:16]1[CH:15]=[CH:14][C:13]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[CH:12][C:11]=1[NH:10][C:9]([N:8]([CH3:32])[C:4]1[CH:3]=[C:2]([NH:56][C:53]2[CH:52]=[CH:51][C:50]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:55][CH:54]=2)[N:7]=[CH:6][N:5]=1)=[O:31]
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)N(C)c1cc(Cl)ncn1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)N(C)c1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
N-{3-[3-(6-Chloro-pyrimidin-4-yl)-3-methyl-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamide (50 mg, 0.107 mmol) and p-toluenesulfonic acid (20 mg, 0.105 mmol) were mixed and dissolved in 1 ml DMF. Then 4-Morpholin-4-yl-phenylamine (22 mg, 0.11 mmol) was added to it. The reaction was stirred at 80° C. for 10 hours. The crude product was purified by reverse phase HPLC to give final product N-(4-Methyl-3-{3-methyl-3-[6-(4-morpholin-4-yl-phenylamino)-pyrimidin-4-yl]-ureido}-phenyl)-3-trifluoromethyl-benzamide as grey solid, 48 mg; 1H NMR 600 MHz (DMSO) δ 12.74 (s, 1H), 10.46 (s, 1H), 9.53 (s, 1H), 8.47 (s, 1H), 8.41 (m, 1H), 8.31 (s, 1H), 8.28 (d, 1H, J=7.8 Hz), 7.97 (d, 1H, J=7.2 Hz), 7.79 (t, 1H, J=4.2 Hz), 7.52 (d, 1H, J=7.8 Hz), 7.47 (d, 2H, J=8.4 Hz), 7.22 (d, 1H, J=8.4 Hz), 6.99 (s, 1H), 6.98 (s, 1H), 6.34 (s, 1H), 4.15 (m, 4H), 3.76 (m, 4H), 3.10 (m, 3H), 2.32 (s, 3H); MS m/z 606.2 (M+1).