Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:35])([C:29]2[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=2)[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=[C:13]3[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:5][CH:4]=1.[C-:36]#[N:37].[Na+].O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:28][C:24]1[CH:23]=[C:22]([C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([C:9]([OH:35])([C:29]4[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=4)[C:6]4[CH:5]=[CH:4][C:3]([CH2:2][C:36]#[N:37])=[CH:8][CH:7]=4)[CH:11]=3)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: [C-]#N
Reactant: Cn1cncc1C(O)(c1ccc(CCl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1cncc1C(O)(c1ccc(CC#N)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.3 %

Procedure:
A mixture of (±)-6-[[4-(chloromethyl)phenyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (described in Example B14) (0.000694 mol) and NaCN (0.00139 mol) in DMSO (3.5 ml) was stirred at room temperature for 2 hours, poured out into H2O, basified with K2CO3 (10%) and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (0.2 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH; 95/5/0.1; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.08 g (23%) of (±)-4-[[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]benzeneacetonitrile, as a white foam.
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH2:31][OH:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10]1)[CH3:2].N1C=CN=C1.[CH3:38][C:39]([Si:42](Cl)([CH3:44])[CH3:43])([CH3:41])[CH3:40].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[C:39]([Si:42]([CH3:44])([CH3:43])[O:32][CH2:31][CH2:30][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:17])=[O:18])[CH2:11][CH2:10]1)([CH3:41])([CH3:40])[CH3:38]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCN(CCO)CCCCC[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCN(CCCCC[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1)CCO[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
400 mg (8.4 mmol) trans-N-(4-{5-[Ethyl-(2-hydroxy-ethyl)-amino]-pentyl}-cyclohexyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide were suspended in toluene and evaporated (3×), redissolved in 1 ml DMF and treated with 102.4 mg (1.5 mmol, 1.8 eq) imidazole. At 0° C., 176 mg (11.7 mmol, 1.4 eq) TBDMSCl in 2 ml DMF were added, and the reaction mixture was stirred at 50° C. for 1 h. The solution was added to an aqueous solution of NaHCO3 and extracted with ether. The organic layer was washed with water and brine, and dried over Na2SO4. 509 mg crude trans-N-[4-(5-{[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amino}-pentyl)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide were isolated as light yellow oil.
Reaction SMILES: [CH2:1]([N:3]([CH3:25])[C:4]1[N:24]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21]([OH:23])=O)=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)[CH3:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:1]([N:3]([CH3:25])[C:4]1[N:24]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:23])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)[CH3:2]
Reactant: CCN(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Reactant: C1COCCN1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C)c1nc2cc(NC(=O)c3c(C(=O)N4CCOCC4)cnn3C)ccn2n1
Yield: 81.6 %

Procedure:
A mixture of 5-(2-(ethyl(methyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (144 mg, 419 μmol), morpholine (365 mg, 4.19 mmol), propylphosphonic anhydride (50% in ethyl acetate, 618 μl, 1.05 mmol) and N,N-diisopropylethylamine (214 μL, 1.26 mmol) in tetrahydrofuran (7.00 ml) was refluxed for 2.5 days (weekend). The solvent was evaporated, the residue was triturated with sodium hydrogencarbonate solution. The precipitated solid was filtered off, washed with water and dried affording 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid [2-(ethyl-methyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (141 mg, 81.5%) as a white solid. mp: 167-169° C., MS: m/z=413.4 (M+H+)
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:6])([CH3:5])[CH3:4].[C:19]([N:23]1[CH2:27][CH2:26][O:25][P:24]1Cl)([CH3:22])([CH3:21])[CH3:20]>O1CCCC1>[C:19]([N:23]1[CH2:27][CH2:26][O:25][P:24]1[O:18][C:8]1[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])=[CH:12][C:11]([CH3:13])=[CH:10][C:9]=1[C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)N1CCOP1Cl
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C(C)(C)C)c(OP2OCCN2C(C)(C)C)c(C(C)(C)C)c1
Temperature: 40 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
A 500 ml, three neck flask equipped with a thermometer, an addition funnel and a condenser topped with a nitrogen sweep is charged with 4.4 g (0.11 mol) of sodium hydride. The sodium hydride is washed with two 20 ml portions of hexane and finally suspended in 45 ml of tetrahydrofuran (THF). To the resultant suspension is added dropwise a solution of 22.04 g (0.10 mol) of 2,6-di-tert-butyl-4-methylphenol in 150 ml of THF at such a rate to keep the reaction temperature between 20°-30° C. The resulting yellow solution is warmed to approximately 40° C. for 1 hour and then cooled in an ice bath. A solution of 18.16 g (0.10 mol) of 3-tert-butyl-2-chloro-1,3,2-oxazaphospholidine in 150 ml of THF is added and stirring continued for 16 hours at room temperature. The resulting cloudy mixture is filtered and the solvent evaporated under reduced pressure. The residue is treated with 200 ml of toluene and the resultant suspension filtered. The filtrate is concentrated in vacuo to yield a thick syrup. Triturating with methanol gives 24.5 g (67.0%) of colorless solid: mp 105°-107° C.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:8])([CH3:3])[CH3:2].[CH2:21]=O>C(O)=O>[CH3:21][N:4]([CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:8])[CH:1]([CH3:2])[CH3:3]
Reactant: CC(C)NCCC(C)c1ccccc1-c1ccccc1
Reactant: C=O
Solvent: O=CO
Product: CC(CCN(C)C(C)C)c1ccccc1-c1ccccc1
Reaction time: 12 h

Procedure:
A mixture of 2.67 g of 1-isopropylamino-3-p-biphenylylbutane, 12 ml of formic acid and 2 g of 40% formaldehyde solution is heated at 60° for 3 hours and then at 100° for 12 hours and is then evaporated. 1-(N-Methyl-N-isopropylamino)3-p-biphenylyl-butane is obtained after working up in the customary manner.
Reaction SMILES: [Na].[Cl-].[CH3:3][O:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[CH:35]=O>C(O)C>[CH3:3][O:4][CH:5]=[CH:35][C:26]1[CH:27]=[CH:28][C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na]
Solvent: CCO
Product: COC=Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
To the solution produced by reacting sodium (0.92 g) in dry ethanol (60 ml) was added methoxymethyltriphenylphosphonium chloride (15.2 g). After stirring at room temperature for 0.5 hours, 2-naphthaldehyde (5.5 g) was added and the mixture heated at reflux for 5 hours. The mixture was evaporated to dryness and extracted with boiling ether, cooled to precipitate triphenylphosphine oxide, filtered and evaporated. The residue in dichloromethane (5 ml) was passed through a column of alumina and eluted with hexane to give 2-(2-methoxyvinyl) naphthalene (3.6 g), nD20 1.6505, which was hydrolysed in dioxan (50 ml) containing 2N sulphuric acid (5 ml) at 70° for 5 hours. After adding water, the mixture was extracted with ether, and the extract washed, (saturated sodium chloride), dried, (sodium sulphate) and evaporated to give 2-naphthylacetaldehyde (3.25 g) nD20 1.6232.
Reaction SMILES: [C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@H:12]2[C@@H:15]([OH:17])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@H:12]2[C@@H:15]([O:17][S:40]([CH3:39])(=[O:42])=[O:41])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)N/C=C/SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H]([C@H](C)O)[C@H]2C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N/C=C/SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H]([C@H](C)OS(C)(=O)=O)[C@H]2C1
Yield: 91.1 %

Procedure:
p-Nitrobenzyl (5R,6R)-3-[(E)-2-acetamidoethenylthio]-6-[(S)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e4) (100 mg) was suspended in dichloromethane (6 ml) containing triethylamine (45 mg). The mixture was cooled to 0° and methanesulphonyl chloride (38.4 mg in 1.3 ml dichloromethane) was added dropwise over 5 minutes. After 25 minutes at 0° further quantities of triethylamine (15 mg) and methanesulphonyl chloride (13 mg) were added to the solution. After a further 10 minutes the solution was diluted with dichloromethane (10 ml) and was washed with cold water (20 ml), phosphate buffer (pH 3.1) (20 ml) and 5% NaHCO3 solution (20 ml). The organic layer was dried (MgSO4) and evaporated in vacuo to afford p-nitrobenzyl (5R,6R)-3-[(E)-2-acetamidoethenylthio]-6-[(S)-1-methylsulphonyloxyethyl]-7-oxo-1-azabicyclo[3.2.0] hept-2-ene-2-carboxylate (e5) as a yellow foam (107 mg); νmax (CH2Cl2) 1780, 1700, 1625, 1525, 1350, 1330 and 1175 cm-1.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:21]=[CH:20][C:12]([C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Cl.[Cl:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=3)=[CH:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1.O.[BH4-].[Na+]>C1(C)C=CC=CC=1>[ClH:23].[Cl:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[CH:42]=[CH:41][C:38]([CH2:39][NH:1][CH:2]4[CH2:3][CH2:4][N:5]([CH2:8][C:9]5[CH:21]=[CH:20][C:12]([C:13]([N:15]([CH2:16][CH3:17])[CH2:18][CH3:19])=[O:14])=[CH:11][CH:10]=5)[CH2:6][CH2:7]4)=[CH:37][CH:36]=3)=[CH:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1
Reactant: CCN(CC)C(=O)c1ccc(CN2CCC(N)CC2)cc1
Reactant: O=Cc1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)C(=O)c1ccc(CN2CCC(NCc3ccc(Nc4ccnc5cc(Cl)ccc45)cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 168 h
Yield: 42.4 %

Procedure:
4-[(4-Amino-1-piperidinyl)methyl]-N,N-diethylbenzamide (3.81 g, 13.16 mmol) and 4-[(7-chloro-4-quinolinyl)amino]benzaldehyde hydrochloride (13.16 mmol, 4.20 g) are refluxed for 28 hours in 52 mL of toluene under nitrogen with azeotropic removal of water. The toluene is poured off the thick oil, which is then rinsed once with fresh toluene. The remaining traces of solvent are removed in vacuo and the resulting gum is dissolved in 55 mL of ethanol and treated with NaBH4 (14.6 mmol, 552 mg). The reaction mixture is refluxed for 50 minutes, treated with another 200 mg of NaBH4 and refluxed an additional 10 minutes. The reaction mixture is poured over 100 mL of ice, which results in the formation of an orange oil. After stirring rapidly for seven days, the water is decanted and the oil is purified by flash chromatography on silica gel (65 mm column, 5% ammonia saturated methanol in methylene chloride eluent) which affords 1.55 g (2.79 mmol, 21% yield) of the title compound as the free base. Of this, 0.95 g (1.7 mmol) are dissolved in 5 mL of methanol and treated with 1.7 mL of 1N ethereal HCl. The resulting solution is concentrated in vacuo and the residue is triturated with ether for 23 hours. The resulting yellow powder is filtered, washed with ether and dried in vacuo at 60° C. for 16.5 hours, affording 896 mg of the title compound: mp 166°-190° C. (softens slowly over this range); 1H NMR (Me2SO-d6, 400 MHz) δ9.37 (br s, 1H), 8.5 (m, 2H), 7.91 (d,J=2.2 Hz, 1H), 7.6 (m, 3H), 7.28-7.42 (m, 6H), 6.96 (d,J=5.4 Hz, 1H), 4.12 (s, 2H), 2.9-3.6 (m, 10H), 2.1 (m, 4H), 1.7-1.8 (m, 2H), 1-1.2 (m, 6H);
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[C:23]([Si:27]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[O:28][C:29]1[CH:30]=[C:31]([CH:45]=[CH:46][CH:47]=1)[CH2:32][C@:33]1([O:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH2:38][CH2:37][CH2:36][CH2:35][C:34]1=O)([CH3:26])([CH3:25])[CH3:24].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1COCC1.C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]=[C:9]([C:34]3[C@:33]([O:40][Si:41]([CH3:44])([CH3:43])[CH3:42])([CH2:32][C:31]4[CH:45]=[CH:46][CH:47]=[C:29]([O:28][Si:27]([C:23]([CH3:26])([CH3:24])[CH3:25])([C:54]5[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=5)[C:48]5[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=5)[CH:30]=4)[CH2:38][CH2:37][CH2:36][CH:35]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2ncoc2-c2ccccc2)cc1
Reactant: CC(C)(C)[Si](Oc1cccc(C[C@]2(O[Si](C)(C)C)CCCCC2=O)c1)(c1ccccc1)c1ccccc1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [Li]CCCC
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](Oc1cccc(C[C@]2(O[Si](C)(C)C)CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a solution of (4,5-diphenyl)oxazole (17 g) in THF (100 ml) was added n-BuLi (57 ml, 1.6N-solution in hexane) at −78° C. After stirring for 30 minutes, a solution of (R)-1-[3-(tertbutyldiphenyl-silyloxy)benzyl]-1-trimethylsilyoxy-2-cyclohexanone (27 g) in THF (50 ml) was added to the above mixture at the same temperature. After stirring for 1 hour, the reaction mixture was partitioned between EtOAc and water. The organic layer was washed with 1N-HCl solution and brine. The organic solvent was evaporated in vacuo to give a residue. The residue was dissolved in toluene (100 ml) and then added with (methoxycarbonylsulfamoyl)triethyl-ammonium hydroxide, inner salt(20.4 g) at room temperature. After refluxing under stirring for 5 hours, the reaction mixture was evaporated in vacuo. The residue was purified by chromatography on silica gel to give (R)-2-(4,5-diphenyloxazol-2-yl)-1-trimethylsilyloxy-1-[3-(tertbutyldiphenylsiloxy)benzyl]-2-cyclohexene (36 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:24])[N:5]=[N:6][C:7]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[Cl:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[S:36](Cl)(=[O:38])=[O:37]>N1C=CC=CC=1>[Cl:25][C:26]1[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[CH:28][C:27]=1[S:36]([NH:24][C:4]1[N:5]=[N:6][C:7]([S:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)(=[O:16])=[O:17])=[CH:11][CH:10]=2)=[C:2]([CH3:1])[CH:3]=1)(=[O:38])=[O:37]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: Cc1cc(N)nnc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2Cl)nnc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Yield: 10.9 %

Procedure:
5-Methyl-6-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyridazin-3-ylamine (110 mgs), 2-chloro-4-trifluoromethylbenzenesulfonyl chloride (160 mgs) and pyridine (1 ml) were heated at 50° C. under nitrogen for 72 hours. All volatiles were removed and the residue purified by Preparative HPLC to give 2-chloro-N-{5-methyl-6-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyridazin-3-yl}-4-trifluoromethyl-benzenesulfonamide 20 mg. 1H NMR (CDCl3) 8.25 (1H, d) 7.75 (2H, m) 7.7 (1H, s) 7.6 (3H, m) 6.95 (1H, s) 3.0 (4H, m) 2.3 (3H, s) 1.6 (4H, m) 1.45 (2H, m). LCMS Polarity/Scan type: Negative Q1 Scan. M.wt. 605 (—H), 607 (—H). Retention time 7.05 minutes. HPLC:—MS8. Retention time 4.99 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=[C:16]([OH:29])[CH:15]=2)=[CH:9][C:8]=1[CH3:30])[CH3:2].[N:32]1([CH2:38][CH2:39][CH2:40]O)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=[C:16]([O:29][CH2:40][CH2:39][CH2:38][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:30])[CH3:2]
Reactant: OCCCN1CCOCC1
Reactant: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#CCc3ccccc3)c2)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCc3ccccc3)cc(OCCCN3CCOCC3)c2)cc1C
Reaction time: 1 h

Procedure:
{4-[3-Hydroxy-5-(3-phenyl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (200 mg; 0.46 mmol), 3-morpholin-4-yl-propan-1-ol (101 mg; 0.69 mmol), tributylphosphine (0.28 mL; 1.39 mmol) and 1,1′-(azodicarbonyl)dipiperidine (0.35 g; 1.39 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. After stirring for 1 h the reaction mixture was purified by prep. HPLC (method A). Yield: 200 mg. HPLC-MS: m/z: 560.5 (M+H); Rt: 2.07 min.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.[Cl:17][C:18]1[N:19]=[N:20][C:21](Cl)=[C:22]([CH3:25])[C:23]=1[CH3:24].C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:17][C:18]1[N:19]=[N:20][C:21]([N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][N:7]=3)[CH2:14][CH2:13]2)=[C:22]([CH3:25])[C:23]=1[CH3:24]
Reactant: Cc1c(Cl)nnc(Cl)c1C
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1c(Cl)nnc(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)c1C
Temperature: 180 °C
Yield: 82 %

Procedure:
1-(5-Trifluoromethyl-pyridin-2-yl)-piperazine (10 g, 43.3 mmol) is combined with 3,6-dichloro-4,5-dimethyl-pyridazine (14.4 g, 84.3 mmol), triethylamine (8.25 mL), and NMP (40 mL). The reaction mixture is heated to a temperature of 180° C. for 25 min, and then concentrated in vacuo. The residue is purified by flash chromatography on silica gel (0-8% MeOH/CH2Cl2) to afford the title compound (13.2 g, 82%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6]([SH:11])=[N:5][N:4]=1.IC.[CH2:14](N(CC)CC)C>C(O)C>[OH:1][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6]([S:11][CH3:14])=[N:5][N:4]=1
Reactant: CCCn1c(S)nnc1CO
Reactant: CCN(CC)CC
Solvent: CI
Solvent: CCO
Product: CCCn1c(CO)nnc1SC

Procedure:
A solution of 3-hydroxymethyl-4-propyl-5-mercapto-4H-1,2,4-triazole (2.0 g), iodo methane (1.1 ml) and triethylamine (2.5 ml) in ethanol (20 ml) was stirred for 2 days at 50° C. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:5→1:4), to give 3-hydroxymethyl-5-methylthio-4-propyl-4H-1,2,4-triazole (2.13 g) as pale yellow oil. To a solution of 3-hydroxymethyl-5-methylthio-4-propyl-4H-1,2,4-triazole (2.13 g) in chloroform (6 ml), thionyl chloride (16 ml) was slowly added at 0° C. The mixture was heated to reflux for 2 hours, and concentrated under reduced pressure. To the residue were added small amount of ethanol and ethyl acetate, and the precipitated crystals were collected by filtration. The crystals were washed with ethyl acetate and diethylether, to give 3-chloromethyl-5-methylthio-4-propyl-4H-1,2,4-triazole hydrochloride (1.06 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)=[O:7].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)=[O:7]
Reactant: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)c2cccc(N)c2)cc1OC
Yield: 38.9 %

Procedure:
To a solution of 3,4-dimethoxy-3'-nitrobenzophenone (0.5 g, 1.7 mmol) in 40 mL of ethyl acetate was added 0.05 g of 10% palladium on carbon catalyst. The mixture was hydrogenated in a Parr-Shaker apparatus at 55-60 psi of hydrogen for 1.5 hours. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford the crude product. The crude product was purified by flash column chromatography (silica gel, 10% ethyl acetate/methylene chloride) to afford 0.17 g (38%) of the product as a yellow solid: mp 157-175° C.; 1H NMR (CDCl3) δ 7.56-6.80 (m, 7 H); 3.95 (s, 3 H), 3.94 (s, 3 H); 13C NMR (CDCl3) δ 195.7, 152.9, 148.9, 146.4, 139.3, 130.3, 128.9, 125.4, 120.1, 118.4, 115.6, 112.1, 109.7, 56.0, 56.0; Anal. Calcd for C15H15NO3. Theoretical: C, 70.02; H, 5.88; N, 5.44. Found: C, 70.00; H, 6.10; N, 5.13.
Reaction SMILES: C(CCC1C(CCCCCCOC2C=C(C3C=CC(F)=C(F)C=3)C=C(C(=O)N(C)C)C=2)=CC=CC=1OCCCC(O)=O)(O)=O.C([O:47][C:48](=[O:92])[CH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][O:65][C:66]2[CH:67]=[C:68]([C:77]3[CH:82]=[CH:81][C:80]([F:83])=[C:79]([OH:84])[CH:78]=3)[CH:69]=[C:70]([C:72](=[O:76])[N:73]([CH3:75])[CH3:74])[CH:71]=2)[C:54]=1[CH2:85][CH2:86][C:87]([O:89]CC)=[O:88])C.[OH-].[Na+]>C1COCC1.CCO>[C:87]([CH2:86][CH2:85][C:54]1[C:55]([CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][O:65][C:66]2[CH:67]=[C:68]([C:77]3[CH:82]=[CH:81][C:80]([F:83])=[C:79]([OH:84])[CH:78]=3)[CH:69]=[C:70]([C:72](=[O:76])[N:73]([CH3:75])[CH3:74])[CH:71]=2)=[CH:56][CH:57]=[CH:58][C:53]=1[O:52][CH2:51][CH2:50][CH2:49][C:48]([OH:92])=[O:47])([OH:89])=[O:88]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N(C)C)cc(-c3ccc(F)c(O)c3)c2)c1CCC(=O)OCC
Agent: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)c(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)c(O)c2)c1
Yield: 92.4 %

Procedure:
The title compound was prepared by the same method as 4-{2-(2-carboxy-ethyl)-3-[6-(5-dimethylcarbamoyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid starting from 4-{3-[6-(5-dimethylcarbamoyl-4′-fluoro-3′-hydroxy-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (142 mg, 0.213 mmol) and 1.0 N aqueous NaOH (5 mL) in THF (5 mL) and EtOH (5 mL) to afford 4-{2-(2-carboxy-ethyl)-3-[6-(5-dimethylcarbamoyl-4′-fluoro-3′-hydroxy-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid (120 mg, 92%) as a white amorphous solid.