Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]3C=CC=CC=3[P+](C)(C3C=CC=CC=3)C3C=CC=CC=3)=[N:10]2)=[CH:5][CH:4]=1.[Li]CCCC.CCCCCC.[CH:44]([C:46]1[CH:47]=[C:48]([CH:52]([S:60][CH2:61][CH2:62][C:63](=[O:67])[N:64]([CH3:66])[CH3:65])[S:53][CH2:54][CH2:55][C:56]([O:58][CH3:59])=[O:57])[CH:49]=[CH:50][CH:51]=1)=O.C([O-])(=O)C.[NH4+]>C1COCC1>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH:13]=[CH:44][C:46]3[CH:47]=[C:48]([CH:52]([S:60][CH2:61][CH2:62][C:63](=[O:67])[N:64]([CH3:66])[CH3:65])[S:53][CH2:54][CH2:55][C:56]([O:58][CH3:59])=[O:57])[CH:49]=[CH:50][CH:51]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1-c1ccc2ccc(Cl)cc2n1
Reactant: COC(=O)CCSC(SCCC(=O)N(C)C)c1cccc(C=O)c1
Agent: CC(=O)[O-]
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CCSC(SCCC(=O)N(C)C)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 7-chloroquinolin-2-yl-methyltriphenylphosphonium bromide (Example 4, Step 2) (809 mg, 1.56 mmol.) in THF (15 mL) at -78° C., was added a soltuion of n-BuLi (1.6M) in hexane (0.89 mL, 1.43 mmol.). The mixture was stirred for 0.5 hrs at -78° C. Then, (+)-methyl 5-(3-formylphenyl)-8-dimethylcarbamyl-4,6-dithiaoctanoate (step 3) (480 mg, 1.3 mmol.) in THF (4 mL) was slowly added. The mixture was stirred for 0.5 hr at -78° C. and then warmed up to room temperature and stirred for an additional 2 hrs. A solution of 25% ammonium acetate was added, the mixture was extracted with ethyl acetate, and the extracts were washed with brine (3×), dried over sodium sulfate, filtered and evaporated to dryness. Purification by flash chromatography afforded the title compound.
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[C:14]([O:16]CC)=[O:15])#[N:2].[OH-:19].[K+]>C(O)C>[C:14]([C:4]1[CH:5]=[N:6][N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[C:1]([NH2:2])=[O:19])([OH:16])=[O:15]
Reactant: [OH-]
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1C#N
Agent: [K+]
Solvent: CCO
Product: NC(=O)c1c(C(=O)O)cnn1-c1ccccc1

Procedure:
A 4 g. portion of ethyl 5-cyano-1-phenyl-4-pyrazolecarboxylate was reacted with 2 g. of potassium hydroxide in 60 ml. of denatured ethanol substantially as described in Example 2, to obtain 2.7 g. of the desired product, m.p. 234°-235°, having the following elemental analysis.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[C:4]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:3]=1.C(N(CC)CC)C.C1(CNC2N=CN=C(C(OC)=O)C=2)CCCCC1.C1(CNC2N=CN=C(C(OCC)=O)C=2)CCCCC1.[OH-].[Li+]>[Pd].CCO.C1COCC1.CCO.O.O>[CH:14]1([CH2:13][NH:12][C:4]2[N:3]=[CH:2][N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: COC(=O)c1cc(NCC2CCCCC2)nc(Cl)n1
Agent: [Pd]
Agent: CCOC(=O)c1cc(NCC2CCCCC2)ncn1
Agent: COC(=O)c1cc(NCC2CCCCC2)ncn1
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cc(NCC2CCCCC2)ncn1

Procedure:
A mixture of methyl 2-chloro-6-[(cyclohexylmethyl)amino]pyrimidine-4-carboxylate (Intermediate 3, 2.25 g; 7.93 mmol), palladium on charcoal and triethylamine (3.32 mL; 23.8 mmol) in EtOH (400 mL) was stirred under an atmosphere of hydrogen. After 2 hours the reaction mixture was filtered on celite and evaporated to give a mixture of methyl 6-[(cyclohexylmethyl)amino]pyrimidine-4-carboxylate and ethyl 6-[(cyclohexylmethyl)amino]pyrimidine-4-carboxylate. The crude mixture was dissolved in a mixture of THF/EtOH/H2O (3/2/1, 84 mL) and treated with an aqueous solution of lithium hydroxide (1N, 16 mL, 16 mmol). The reaction mixture was stirred at RT for 60 minutes. Water was added (50 mL) and the aqueous layer was washed with chloroform. and the aqueous layer was washed with DCM (30 mL). The aqueous layer was acidified to pH 5 by addition of an HCl solution (1N). A precipitate was formed, which was filtered to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([F:11])[F:10])=[CH:6][C:5]([NH:12][NH2:13])=[C:4]([F:14])[CH:3]=1.C1(C)C=CC=CC=1.C([O:24][C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C:28]1=O)=O)C.O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([O:8][CH:9]([F:11])[F:10])=[CH:6][C:5]([N:12]2[C:25](=[O:24])[C:27]3[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=3[NH:13]2)=[C:4]([F:14])[CH:3]=1
Reactant: NNc1cc(OC(F)F)c(Cl)cc1F
Reactant: CCOC(=O)C1CCCCC1=O
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: O=c1c2c([nH]n1-c1cc(OC(F)F)c(Cl)cc1F)CCCC2
Yield: 32.3 %

Procedure:
To 12.7 g of 4-chloro-5-difluoromethoxy-2-fluorophenylhydrazine were added 127 ml of toluene and 9.5 g of 2-ethoxycarbonylcyclohexanone V-1, and the resultant mixture was refluxed for 24 hours. After cooling, the reaction mixture was mixed with water and shaken with chloroform. The chloroform layer was dried and concentrated. The residue was chromatographed on a column of silica gel, eluting with n-hexane-ethyl acetate (1:1 v/v). The elutate was concentrated to give 6,0 g of the titled compound VIII-1 (containing a certain amount of its tautomer 2,3a,4,5,6,7-hexahydro compound).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[N:4]1.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>CN(C=O)C>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:3]2[CH:7]=[CH:6][N:5]=[N:4]2)=[CH:12][CH:11]=1
Reactant: COc1ccc(CCl)cc1
Reactant: c1c[nH]nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To a suspension of 3.5 g (0.139 mol) of sodium hydride in 120 ml of DMF at 0° C. was added 8 g (0.115 mol) of 1,2,3-triazole in 50 ml of DMF dropwise, and the mixture was allowed to warm to room temperature and stirred for 1 h. The above mixture was cooled to 0° C., and 21.8 g (0.139 mol) of p-methoxybenzyl chloride was added, and the mixture was allowed to warm to room temperature and stirred for 20 h. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography on silica (hexane/ethyl acetate) to afford 14 g (64.5%) of 1-(p-methoxybenzyl)-1,2,3-triazole.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:20]2[C:15](=[CH:16][C:17]([CH:21]=O)=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)(=O)C.[Br-].[O:24]1CCO[CH:25]1[CH2:29][P+](CCCC)(CCCC)CCCC.CC(C)([O-])C.[K+].[Cl-].[Na+]>CN(C)C=O.Cl.O>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:20]2[C:15](=[CH:16][C:17]([CH:21]=[CH:29][CH:25]=[O:24])=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: CCCC[P+](CCCC)(CCCC)CC1OCCO1
Reactant: CC(=O)OCCCCCCN1CCCc2cc(C=O)ccc21
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: O
Product: O=CC=Cc1ccc2c(c1)CCCN2CCCCCCO
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a solution 30.3 g (0.1 mole) of N-acetoxyhexyl-1,2,3,4-tetrahydroquinoline-6-carboxaldehyde in dimethylformamide is added 7.4 g (0.2 mole) of 1,3-dioxolan-2-ylmethyltributylphosphonium bromide in dimethylformamide with magnetic stirring, and the mixture is heated at 90° C. Potassium t-butoxide (22.4 g, 0.2 mole) is added, and heating is continued at 90° C. for 16 hours. After cooling to room temperature, the solution is poured into a seven-fold excess of water. The aqueous mixture is saturated with sodium chloride, and the mixture is extracted with three portions of ether. The combined organics are dried over 4A sieves, filtered through cotton, and evaporated. The crude reaction product is then dissolved in 3M HCl, and the reaction is stirred at room temperature for 16 hours. After careful neutralization with saturated sodium bicarbonate, the aqueous mixture is extracted with three portions of ether, and the combined organics are passed through silica gel, dried over 4A sieves, filtered through cotton, and evaporated to yield 3-(N-hydroxyhexyl-1,2,3,4-tetrahydroquinolin-6-yl)acrolein.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.C(O)COCCO.O.CS(C)=O.[Pd](Cl)Cl.C([O-])(=O)C.[Na+]>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: N#Cc1ccccc1Cl
Reactant: Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: OCCOCCO
Solvent: CS(C)=O
Solvent: Cc1ccc(C)cc1
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 87 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 28.9 g of sodium carbonate in 50 ml of p-xylene, 40 ml of diethylene glycol and 10 ml of water were heated to 120° C. At 80° C., a mixture of 19.3 mg of palladium chloride, 17.9 mg of sodium acetate and 0.55 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO was added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 18.3 g of 2-cyano-4'-methylbiphenyl.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[C:5]([F:19])=[CH:4][N:3]=1.[CH:20]1([C:23]2[CH:24]=[C:25]([NH2:34])[CH:26]=[C:27]([N:29]3[CH:33]=[N:32][N:31]=[N:30]3)[CH:28]=2)[CH2:22][CH2:21]1.S(O)(C1C=CC(C)=CC=1)(=O)=O>C(O)(C)C>[CH:20]1([C:23]2[CH:24]=[C:25]([NH:34][C:2]3[N:7]=[C:6]([NH:8][CH:9]4[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]4)[C:5]([F:19])=[CH:4][N:3]=3)[CH:26]=[C:27]([N:29]3[CH:33]=[N:32][N:31]=[N:30]3)[CH:28]=2)[CH2:22][CH2:21]1
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2F)CC(C)(C)N1
Reactant: Nc1cc(C2CC2)cc(-n2cnnn2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CC1(C)CC(Nc2nc(Nc3cc(C4CC4)cc(-n4cnnn4)c3)ncc2F)CC(C)(C)N1
Temperature: 100 °C

Procedure:
In a 100 mL round bottom flask to a solution of 2-chloro-5-fluoro-N-(2,2,6,6,-tetramethylpiperidin-4-yl)pyrimidin-4-amine (Compound 11; 0.16 g, 0.56 mmol) in 10 mL isopropanol, 3-cyclopropyl-5-(1H-tetrazol-1-yl)benzenamine (0.125 g, 0.622 mmol) and TosOH (0.085 g, 0.448 mmol) were added. The reaction mixture was heated at 100° C. for 3 hours. LCMS analysis indicated the complete consumption of the mono-SNAr product and appearance of Compound III-116. The reaction mixture was then cooled to room temperature and volatiles were removed under reduced pressure. The crude reaction mixture was purified by column chromatography using DCM/2 M NH3 in MeOH to obtain Compound III-116 as a tan solid that was further purified by trituration using DCM/hexanes.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH2:18](Br)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:16]([O:15][C:7]([CH:8]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:14])[CH3:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCc1ccccc1)C(=O)OCC
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
123.4 g of potassium tert-butoxide were added in portions, at a temperature of 15° C., to a solution of 160.1 g of diethyl malonate in one litre of dimethylformamide. The reaction mixture was stirred for 30 minutes and a solution of 207.7 g of phenethyl bromide in 200 ml of dimethylformamide was then added dropwise at room temperature. The reaction mixture was subsequently heated at 60° C. for one hour and then allowed to cool down once again. The dimethylformamide was evaporated off under reduced pressure and the remaining residue was taken up in a mixture of methyl tert-butyl ether and water. The organic phase was separated, washed with water, dried over sodium sulfate and evaporated. The crude product, which remained as an oily residue, was purified by distillation under reduced pressure. 202.5 g of ethyl 2-ethoxycarbonyl-4-phenylbutanoate were obtained, b.p.1.5 =148°-153° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[CH:10][CH2:11][O:12]C(=O)C)=[C:5]([N+:16]([O-])=O)[CH:4]=1>CO.[Pd].ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([NH:9][CH2:10][C:11](=[O:12])[NH:16]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N=CCOC(C)=O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2c(c1)NC(=O)CN2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The obtained [(4-methoxy-2-nitrophenyl)imino]ethyl-acetate crude product was dissolved in methanol (30 ml) and 10% palladium on carbon (50% wet, 1.20 g) was added thereto and the mixture was stirred at room temperature for 3 hours under a hydrogen gas atmosphere. The catalyst was removed by filtration using celite and the filtrate was concentrated under reduced pressure to yield 1.733 g of a crude product of 7-methoxy-3,4-dihydroquinoxalin-2(1H)-one. In dichloromethane (12 ml) was dissolved 518 mg of the obtained crude product of 7-methoxy-3,4-dihydroquinoxalin-2(1H)-one, and under a nitrogen gas atmosphere in an ice bath, N,N-diisopropylethylamine (0.604 ml, 3.47 mmol) and subsequently benzyl chloroformate (0.408 ml, 2.77 mmol) were added thereto. Then, the mixture was stirred at room temperature for 17 hours, a saturated sodium hydrogen carbonate aqueous solution was added thereto and the resultant was extracted with dichloromethane. The extract was combined, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to yield 291 mg (40%) of the title compound in the form of a light red solid.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[N:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20][CH:19]=1>>[N:18]1[CH:23]=[C:22]([C:2]2[C:10]3[NH:9][C:8]4[CH:11]5[CH2:17][CH2:16][N:14]([CH2:15][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]5)[CH:21]=[N:20][CH:19]=1
Reactant: OB(O)c1cncnc1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Product: c1cc(-c2cncnc2)c2[nH]c3c(c2c1)CN1CCC3CC1

Procedure:
The product of Example 1B (100 mg, 0.32 mmol) and pyrimidine-5-boronic acid (64 mg, 0.52 mmol; MayBridge) were processed as described in Example 4 to provide the title compound: 1H NMR (500 MHz, methanol-d4) δ ppm 2.01-2.17 (m, 4 H), 2.60 (s, 3 H), 3.03-3.14 (m, 3 H), 3.20-3.29 (m, 2 H), 4.27 (s, 2 H), 7.03-7.06 (m, 1 H), 7.10 (t, J=7.6 Hz, 1 H), 7.34 (dd, J=7.6, 1.2 Hz, 1 H), 7.42 (d, J=8.2 Hz, 1 H), 7.96 (dd, J=7.9, 2.4 Hz, 1 H), 8.63 (d, J=2.1 Hz, 1 H); MS (ESI+) m/z 291 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:34]=[C:35]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:36]=[CH:37][CH:38]=1>>[Cl:32][C:33]1[CH:34]=[C:35]([N:39]2[CH2:44][CH2:43][N:42]([C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[C:18]([C:16]4[CH:15]=[N:14][C:10]5[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]6[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=6[C:28]([F:31])([F:30])[F:29])[C:9]=5[CH:17]=4)[CH:19]=3)=[O:23])[CH2:41][CH2:40]2)[CH:36]=[CH:37][CH:38]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(c2cccc(Cl)c2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(3-chlorophenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=625.97 (M+H+); retention time=1.05 minutes.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][CH:5]([OH:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>[OH-].[Na+].CO>[CH:3]#[C:4][CH:5]([OH:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCC(O)C#C[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#CC(O)CCCCCCCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
10 g of (3RS)-1-(trimethylsilyl)-1-undecin-3-ol is dissolved in a mixture of 420 ml of 0.1 n sodium hydroxide solution and 420 ml of methanol and stirred for 3 hours at room temperature. Then, the methanol is removed in a vacuum, shaken with diethyl ether, dried (Na2SO4) and concentrated by evaporation. 6.46 g of (3RS)-1-undecin-3-ol is obtained as a yellow oil, which is further reacted as a crude product.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: CC(=O)c1ccc(C)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Cc2ccc(S(C)(=O)=O)cc2)cn1
Temperature: 25 °C

Procedure:
1-(6-methylpyridin-3-yl)ethanone 1 (50 g, 370 mmol), 1-bromo-4-(methylsulfonyl)benzene 2 (87 g, 370 mmol), potassium phosphate (235.6 g, 3 equiv, 1.11 mol), palladium(II) acetate (125 mg, 0.15mol, 557 μmol), Xantphos (161 mg, 0.075% mol, 278 μmol) and N,N′-dimethylformamide (300 ml, 6 vol) were introduced in the order into a 2000 ml flask provided with mechanical stirring, thermometer and coolant, at 25° C. and under a nitrogen atmosphere. The reaction mixture was stirred at 25° C. and subject to three cycles of vacuum and nitrogen, then it was heated to 85° C. and stirred at such temperature for 27 h. The reaction mixture was then quenched to 45° C. and the stirring was stopped, promoting the separation of an aqueous phase that was removed by suction siphoning with the aid of vacuum. The resulting higher mixture was diluted with water (600 ml, 12 vol) and was quenched to 3° C. After 2 h stirring at such temperature, the resulting suspension was filtered and the product was washed with water (4×200 ml, 4×4 vol) and dried at 60° C. in vacuum, yielding the raw 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone of formula (I) (89.1 g, 83.2%) as a yellow solid.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:21][C@H:22]([C:25]([OH:27])=[O:26])[CH2:23][OH:24].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[C:1]([NH:21][C@H:22]([C:25]([OH:27])=[O:26])[CH2:23][OH:24])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: N[C@@H](CO)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@@H](CO)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of hydroxysuccinimide ester of oleic acid (395 mg, 1 mmole) in tetrahydrofuran (10 ml) was added to a solution of L-serine (105 mg, 1 mmole) and sodium bicarbonate 84 mg, 1 mmole) in water (10 ml). The reaction mixture was let stirring overnight at room temperature, evaporated down to 10 ml, and acidified to pH 1 with 1 N HCl. The product was extracted with methylene chloride (2×20 mL) and dried (MgSO4) and the solvent evaporated under reduced pressure. The crude material was chromatographed on silica gel (eluting with chloroform:methanol) to give 221.7 mg (60%) as a white powder, m.p. 118 C, NMR (CD3OH, ppm): 5.35-5.32 (m, 2H), 4.57-4.36 (m, 1H), 3.90-3.85 (dd, J=12 Hz, 6 Hz, 1H), 3.82-3.78 (dd, J=12Hz, 6 Hz, 1H), 2.29-2.24 (t, 2H), 2.03-1.98 m, 4H), 1.68-1.58 (m, 2H), 1.32-1.29 (m, 22H), 0.91-0.87 (t, 3H). GC-MS (dTMS): 513, 498, 250, 132 m/z; LC-MS(−p): (M-H)+=368 m/z.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[O:13][C:14]([C:18]([O:20]C)=[O:19])=[CH:15][C:16](=[O:17])[C:11]=2[CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH2:8]2)[CH3:2].C(=O)(O)[O-].[Na+]>O>[CH2:1]([C:3]1[C:12]2[O:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][C:16](=[O:17])[C:11]=2[CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH2:8]2)[CH3:2]
Reactant: CCc1c2c(cc3c(=O)cc(C(=O)OC)oc13)CCCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCc1c2c(cc3c(=O)cc(C(=O)O)oc13)CCCC2
Yield: 84.1 %

Procedure:
A mixture of the product of step (b) (3.0 g) and sodium bicarbonate (3.0 g) in water (100 ml) was heated at reflux for 3 hours. The solution was cooled and acidified and the resulting white solid was filtered and dried to give the title compound 2.4 g (84%), mp 269°-271°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[OH:23][CH2:24][CH2:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>>[OH:23][CH2:24][CH2:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:22])=[CH:28][CH:27]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: NCc1ccc(CCO)cc1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccc(CCO)cc4)cc3)c2)o1

Procedure:
N-[4-(2-Hydroxyethyl)benzyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-(2-hydroxyethyl)benzylamine using method H. NMR; δH [2H6]—DMSO 9.11,(1H, t), 7.99,(2H, d), 7.89,(1H, dd), 7.76,(1H, d), 7.56-7.51,(3H, m), 7.24,(2H, d), 7.16,(2H, d), 4.62,(1H, t), 4.46,(2H, d), 3.55,(2H, q), 2.69,(2H, t), 2.56,(3H, s), 2.31,(3H, s). LCMS; retention time 3.00 min, MH+ 428.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[C:25]12([O:35][C:36](F)=[O:37])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2.CN(C1C=CC=CN=1)C.C(N(CC)CC)C>C(Cl)Cl>[C:25]12([O:35][C:36]([N:10]3[C:9](=[O:24])[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[C:13]([C:14]4[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=4)[CH:12]=[N:11]3)=[O:37])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2ccc(F)cc2)cc1
Reactant: O=C(F)OC12CC3CC(CC(C3)C1)C2
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2cnn(C(=O)OC34CC5CC(CC(C5)C3)C4)c(=O)c2-c2ccc(F)cc2)cc1
Yield: 18 %

Procedure:
A solution of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared according to the procedure of Example 11 (200 mg, 0.58 mmol) in CH2Cl2 (8 ml) was prepared and stirred. 1-Adamantylfluoroformate (172 mg, 0.87 mmol), dimethylaminopyridine (14 mg, 0.011 mmol) and triethylamine (0.12 ml, 0.87 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 (50 ml) and washed with 10% citric acid (50 ml), brine (50 ml) and dried over MgSO4, and concentrated in vacuo. The resulting crude residue was purified using flash chromatography (SiO2, eluting with 15:1 CH2Cl2:diethyl ether) to provide the desired product (yield: 55 mg, 18%). 1H NMR (300 MHz, DMSO-d6) δ 1.66 (bs, 6H), 2.25 (bd, 10H), 3.21 (s, 3H), 7.15 (t, 2H), 7.24 (m, 2H), 7.6 (dd, 2H), 7.88 (d, J=9 Hz, 2H), 8.15 (s, 1H). MS (ESI) m/z 521 (M−H)+. Anal. calc. for C21H15F N2O3S2: C, 64.35; H, 5.20; N, 5.36.