Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[CH2:19]([C@H:21]1[CH2:26][C@H:25]2[C@H:27]3[C@H:36]([CH2:37][CH2:38][C@:23]2([CH3:24])[C@H:22]1[O:40][C:41](=[O:44])[CH2:42]Br)[C@@H:35]1[C:30](=[CH:31][C:32](=[O:39])[CH2:33][CH2:34]1)[CH2:29][CH2:28]3)[CH3:20]>CC(C)=O.O>[CH2:19]([C@H:21]1[CH2:26][C@H:25]2[C@H:27]3[C@H:36]([CH2:37][CH2:38][C@:23]2([CH3:24])[C@H:22]1[O:40][C:41](=[O:44])[CH2:42][O:11][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@@H:35]1[C:30](=[CH:31][C:32](=[O:39])[CH2:33][CH2:34]1)[CH2:29][CH2:28]3)[CH3:20]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)CNC(=O)OC(C)(C)C
Yield: 89.2 %

Procedure:
In a mixture of 40 ml of acetone and 8 ml of water is dissolved 0.7 g of N-t-butoxycarbonylglycine, and 0.42 g of potassium t-butoxide is added to the solution. The mixture is stirred, followed by addition of 1.1 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one. The mixture is refluxed for 12 hours. The solvent is then distilled off under reduced pressure and the residue is extracted with 150 ml of ethyl acetate. The organic layer is washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off and the residue is dissolved in a small amount of diisopropyl ether-n-hexane (1:1) and chromatographed on a silica gel column. Following passage of 100 ml of diisopropyl ether, elution is carried out with 400 ml of ethyl acetate. The eluate is evaporated under reduced pressure to remove the solvent, giving 1.2 g of the above-identified compound as a viscous oil.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][N:18]([CH3:23])[CH:19]=[CH:20][C:21]#[N:22].C(N(CC)CC)C>O1CCOCC1>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([C:20](=[CH:19][N:18]([CH3:23])[CH3:17])[C:21]#[N:22])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=CC#N
Reactant: O=C(Cl)c1cccc(Oc2ccccc2)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(C)C=C(C#N)C(=O)c1cccc(Oc2ccccc2)c1
Reaction time: 8 h
Yield: 36.2 %

Procedure:
A mixture of 3-phenoxybenzoyl chloride (6.9 g), 3-dimethylaminoacrylonitrile (2 g) and triethylamine (4 g) in dry dioxan (50 ml) was refluxed for 6 hours under a nitrogen atmosphere. After standing at room temperature overnight, the dioxan was evaporated in vacuo and dichloromethane added to the residue. The extracts were washed with water, 2N NaOH, brine and finally dried over MgSO4. After filtration and evaporation of the dichloromethane, the residue was purified on a silica gel column using 5% methanol-dichloromethane as eluant to give the title compound (2.2 g, 36%) as a white solid of m.p. 80°-82° C. (identical to that described in Example 46).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>>[CH2:17]([N:11]1[C:12]2[C:7](=[C:6]([OH:31])[C:5]([C:3]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])=[N:14][C:13]=2[C:15]#[N:16])[CH:8]=[C:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:10]1=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCCC(=O)O)c(O)c2cc(-c3ccccc3)c(=O)n(Cc3ccccc3)c12
Temperature: 25 °C
Yield: 81.6 %

Procedure:
A mixture of 1-benzyl-8-cyano-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (70 mg, 0.17 mmol), beta-alanine (3.64 g, 41 mmol) and NaOMe solution (61 mL, 31 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified with 4 M HCl to pH about 3, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 65 mg of the title compound. MS: (+) m/z 469.13 (M+1).
Reaction SMILES: OS(O)(=O)=O.C(=O)=O.[C:9]([C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15])([CH3:12])([CH3:11])[CH3:10].[N+:20]([O-])([O-:22])=[O:21].[K+]>>[C:9]([C:13]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:14]=1[NH2:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)(C)c1ccccc1N
Agent: O=C=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Concentrated H2SO4 (1 L) was cooled to −10° C. with a dry ice IpOH bath in a 2 L 3-neck round bottom flask fitted with a mechanical stirrer and temperature probe. 2-t-Butylaniline (109 g, 730 mmol) was added, giving a clumpy solid. Once the temperature of the mixture was stabilized at −10° C., KNO3 (101 g, 1001 mmol) was added portion-wise, as the solid, over 4 h, maintaining the temperature between −20 and −5° C. Once all of the KNO3 was added, the reaction was stirred overnight with gradual warming to RT. The reaction was quenched by diluting it with H2O and extracting it 3× with EtOAc. The EtOAc extracts were washed multiple times with saturated NaHCO3(aq), until gas evolution ceased, then with brine. The EtOAc extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure giving a black oil. The oil was eluted through a 36×7 cm column of silica gel with a 5%; 10%; 15%; 25%; and 50% EtOAc:Hexanes step gradient (2 L each step) giving 2-tert-butyl-5-nitro-phenylamine as a red solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:12]([NH2:15])[CH2:13][CH3:14].C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH2:14][CH2:13][CH2:12][NH2:15])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CCCN
Reactant: Clc1nc(Cl)c2sccc2n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NCCCc1nc(Cl)nc2ccsc12
Yield: 91.9 %

Procedure:
3.95 g (19.26 mmol) of 2,4-dichlorothieno[3,2-d]pyrimidine (III), 1.90 mL (23.11 mmol) of propylamine, and 6.71 mL (38.52 mmol) of diisopropylethylamine are stirred for 16 hours in 40 mL of tetrahydrofuran at ambient temperature. Then the reaction mixture is concentrated by evaporation, the residue is combined with water. The precipitate formed is suction filtered and dried. 4.03 g of product IV (92%) is obtained as a powder.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[CH:10]=O)=[N+:2]=[N-:3].[Cl:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:14]=1[NH2:15].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1/[CH:10]=[N:15]/[C:14]1[C:13]([Cl:12])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:20])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccncc1C=O
Reactant: Nc1c(Cl)cccc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=Nc1ccncc1/C=N/c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Titanium tetrachloride (1M, 4.3 mL, 4.3 mmol) was added to a cooled (0° C.) mixture of 4-azidopyridine-3-carbaldehyde (1.06 g, 7.2 mmol), 2,6-dichloroaniline (1.17 g, 7.2 mmol) and triethylamine (3.0 mL, 21.6 mmol) in DCM (24 mL) under nitrogen. The resultant mixture was stirred for 3 hours at 0° C. before warming to room temperature and stirring for a further 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was suspended in toluene and filtered though a pad of Celite®. The filtrate was concentrated to dryness under reduced pressure to afford the title compound as a yellow solid. This crude material was employed in the next step without further purification or analysis.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[Cl:5][C:6]1[CH:7]=[C:8]([S:13](Cl)(=[O:15])=[O:14])[CH:9]=[CH:10][C:11]=1[Cl:12].O>N1C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[C:8]([S:13]([NH:4][O:2][CH3:3])(=[O:14])=[O:15])[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CONS(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 18 h
Yield: 94.6 %

Procedure:
To a suspension of methoxylamine hydrochloride (0.93 g (11.1 mmol)) in pyridine (5.0 ml), 3,4-dichlorobenzenesulfonyl chloride (2.73 g (11.1 mmol)) was added with stirring under cooling with ice and the resulting mixture was stirred for one hour under cooling with ice, and at room temperature for 18 hours. Water (50.0 ml) was then added to the reaction mixture to bring about separation of crystals. The crystals were filtered and washed with water to give 2.69 g (95%) of 3,4-dichloro-N-methoxybenzenesulfonamide as pale yellow crystals.
Reaction SMILES: P(Cl)(Cl)(Cl)=[O:2].[CH3:6][N:7]1[C:12]2[C:13]([CH3:16])=[CH:14][NH:15][C:11]=2[C:10](=[O:17])[N:9]([CH3:18])[C:8]1=[O:19]>CN(C)C=O>[CH3:6][N:7]1[C:12]2[C:13]([CH:16]=[O:2])=[CH:14][NH:15][C:11]=2[C:10](=[O:17])[N:9]([CH3:18])[C:8]1=[O:19]
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cn1c(=O)c2[nH]cc(C=O)c2n(C)c1=O
Reaction time: 2 h
Yield: 43.2 %

Procedure:
At a temperature of 5-10° C., phosphorous oxychloride (1.84 ml, 20.087 mmol) was mixed with N,N-dimethylformamide (2 mL). Then a solution of Intermediate 1 (600 mg, 3.348 mmol) in N,N-dimethylformamide (3 mL) was added while stirring. The reaction mixture was held for 2 h at 95° C., cooled and poured onto ice (10 g). The precipitate formed was filtered off and recrystallised from water to give 300 mg of the product as an off-white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 3.25 (s, 3H), 3.75 (s, 3H), 8.06 (s, 1H), 9.79 (s, 1H), 13.15 (br s, 1H); APCI-MS (m/z) 208.20 (M+H)+.
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1([CH3:23])[NH:11][CH2:10][CH2:9][N:8]([C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=O)=[CH:14][CH:13]=2)[CH2:7]1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][O:35][C:36]2[CH:37]=[C:38]([NH2:41])[NH:39][N:40]=2)[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1.S([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CC(C)=O>[CH3:33][O:32][C:30]1[CH:29]=[C:28]([CH2:34][O:35][C:36]2[CH:37]=[C:38]([NH:41][C:16](=[O:18])[C:15]3[CH:14]=[CH:13][C:12]([N:8]4[CH2:9][CH2:10][NH:11][C:6]([CH3:5])([CH3:23])[CH2:7]4)=[CH:22][CH:21]=3)[NH:39][N:40]=2)[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=1
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Reactant: CCOC(=O)c1ccc(N2CCNC(C)(C)C2)cc1
Agent: C[Al](C)C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: COc1cc(COc2cc(NC(=O)c3ccc(N4CCNC(C)(C)C4)cc3)[nH]n2)cc(OC)c1
Temperature: 20 °C
Reaction time: 24 h
Yield: 10.5 %

Procedure:
A 2M solution of trimethylaluminium in toluene (0.691 mL, 1.38 mmol) was added dropwise to a stirred solution of ethyl 4-(3,3-dimethylpiperazin-1-yl)benzoate (145 mg, 0.55 mmol) and 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (138 mg, 0.55 mmol) in toluene (5 mL) at 20° C., over a period of 5 mins under nitrogen. The resulting solution was stirred at 20° C. for 24 h. This was diluted with acetone (25 ml) and an excess of damp solid sodium sulphite was added. The mixture was stirred for 1 h and the solid filtered off. The solid was washed with 10% MeOH/DCM and the combined organics evaporated to dryness. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (27.0 mg, 10.49%) as a colourless gum.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:15][N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[S:24]([CH3:23])(=[O:26])=[O:25]
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C1CCNCC1)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 150.1 %

Procedure:
To a solution of 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester (1.20 g, 5.58 mmole, Astatech) and triethylamine (3.2 mL, 22.95 mmole) in dichloromethane (70 mL) at 0° C. was added methanesulfonyl chloride (724 mg, 6.287 mmole, Aldrich). The mixture was allowed to stir for 30 min before washed successively with aqueous sodium bicarbonate and water and concentrated to dryness. The residue was taken up in dichloromethane (20 mL), treated with trifluoroacetic acid (20 mL) and allowed to stir for 3 h before it was concentrated to dryness. The residue was dissolved in dichloromethane, washes with aqueous sodium bicarbonate and concentrated to give N-methyl-N-piperidin-4-yl-methanesulfonamide (1.61 g) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[C:11]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])=[N:12][O:13][C:14]=2[CH:15]([CH3:17])[CH3:16])[CH:5]=[CH:4][C:3]=1[C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32]([C:36]([O:38]C)=[O:37])=[CH:31][CH:30]=[CH:29]2.C1COCC1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[C:11]([C:18]3[C:19]([Cl:25])=[CH:20][CH:21]=[CH:22][C:23]=3[Cl:24])=[N:12][O:13][C:14]=2[CH:15]([CH3:17])[CH3:16])[CH:5]=[CH:4][C:3]=1[C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32]([C:36]([OH:38])=[O:37])=[CH:31][CH:30]=[CH:29]2
Reactant: COC(=O)c1cccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3Cl)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C(=O)O)cccc3c2)c(Cl)c1
Temperature: 65 °C
Yield: 42.7 %

Procedure:
A solution of methyl 6-[2-chloro-4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylate (0.36 g, 0.62 mmol), 6.5 mL of THF, 3.5 mL of methanol and 1.3 mL of 1 N NaOH was stirred for 18 h at rt. The reaction mixture was heated to 65° C. for 2 hours. The solution was allowed to cool to room temperature and the pH was adjusted with 1N HCl. The solution was concentrated and the residue was extracted with ethyl acetate. The organic layer was dried with MgSO4, filtered, and the filtrate was concentrated to give the crude product as oil. The crude material was purified by flash chromatography (silica gel, gradient hexane to hexanes/ethyl acetate, 1:1) to afford the title compound as a white foam (0.15 g, 67%). 1H NMR (DMSO-d6): δ 13.13 (s, 1H), 8.87 (d, J=9 Hz, 1H), 8.19-8.14 (m, 2H), 7.97 (m, 1H), 7.64-7.53 (m, 5H), 7.36 (d, J=9 Hz, 1H), 7.04 (m, 1H), 6.86-6.84 (m, 1H), 4.92 (s, 2H), 3.48 (septet, J=7 Hz, 1H), 1.33 (d, J=7 Hz, 6 H). HRMS C30H22Cl3NO4 m/z 566.0693 (M+H)+Cal; 566.0687 (M+H)+Obs.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:12]([O:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([CH:6]=[O:7])=[C:8]([CH3:10])[CH:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(O)cc(C)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(OCc2ccccc2)cc(C)c1C=O

Procedure:
In analogy to the procedure described in example 23 a], 4-hydroxy-2,6-dimethyl-benzaldehyde was reacted with benzyl bromide in the presence of potassium carbonate to yield 4-benzyloxy-2,6-dimethyl-benzaldehyde as orange liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: Fc1ccc(C(OCCCl)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: Fc1ccc(C(OCCN2CCCCC2)c2ccc(F)cc2)cc1
Yield: 26.4 %

Procedure:
1-[Bis(4-fluorophenyl)methoxy]-2-chloroethane (3) (1.03 g, 3.6 mmol) was added to a flask containing acetonitrile (70 ml) and potassium carbonate (1.54 g, 11.1 mmol). This was followed by addition of piperidine (0.69 g, 8.1 mmol). The resulting mixture was heated to reflux for 48 hours under an atmosphere of nitrogen. At the end of this time, the solution was added to ether (75 ml), washed with water (100 ml) followed by brine (100 ml). The solution was then dried over magnesium sulfate, filtered and the solvents were evaporated under reduced pressure. The resulting clear yellow oil was then chromatographed on silica gel and eluted with 3:1 ethyl acetate/methanol to afford the desired product (5) (315 mg, 26.1%) as a clear and colorless oil.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[N:31]=[C:32]=[O:33]>>[N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH:23][C:32]([NH:31][C:27]4[S:26][CH:30]=[CH:29][CH:28]=4)=[O:33])=[CH:21][CH:20]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: O=C=Nc1cccs1
Product: O=C(Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1)Nc1cccs1

Procedure:
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (60 mg, 0.17 mmoles) and 2-thienyl isocyanate (18 mg, 0.14 mmoles), the title compound was isolated as a grey solid after Silica gel column chromatography by eluting with 5% ethyl acetate:methanol. Yield: 12 mg (14%); (M+H)=470.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=O.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[N:43]1([C:51]2[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=2)[CH2:48][CH2:47][CH:46]([CH2:49][NH2:50])[CH2:45][CH2:44]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH:50][CH2:49][CH:46]1[CH2:45][CH2:44][N:43]([C:51]2[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=2)[CH2:48][CH2:47]1)=[O:17]
Reactant: NCC1CCN(c2ccncc2)CC1
Reactant: O=C(O)c1cccc(OCCc2ccc(Cl)cc2Cl)c1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCC1CCN(c2ccncc2)CC1)c1cccc(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.100 g (0.321 mmol) of 3-[2-(2,4-Dichlorophenyl)-ethoxy]-benzoic acid was dissolved in 2 ml of DMF and treated with 0.148 g (1.28 mmol) of N-NEM and 0.105 g (0.321 mmol) of TOTU and 0.123 g (0.64 mmol) of C-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylamine. The solution was stirred for 16 h at RT. The solvent was removed under reduced pressure, the residue was taken-up in ethyl acetate and the solution was washed twice with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with a gradient of 0 to 17% MeOH in DCM.
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:32][C:33]([C:35]1[CH:40]=[CH:39][C:38](N)=[CH:37][CH:36]=1)=[O:34]>CN(C=O)C>[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:34])[CH3:32].[OH:3][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:1]
Reactant: CC(=O)c1ccc(N)cc1
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The D-biotin (1 g, 4.1 mmol) is solubilized in 45 ml of anhydrous DMF in the hot state. The mixture is cooled to 0° C. under argon, and then N-methylmorpholine (590 μl, 5.33 mmol) and isobutyl chloroformate (840 μl, 6.60 mmol) are successively added. The mixture is kept stirred for 30 min, and then 4-aminoacetophenone (824 mg, 6.10 mmol) is added. The solution is maintained stirred at 0° C. for 2 h, and then evaporated to dryness. The residue is taken up in 50 ml of water. The precipitate obtained is filtered, washed with water and then with 50 ml of MeOH in the hot state. The white precipitate is dissolved in DMF while heating and then the solution obtained is filtered and washed to with MnOH. The filtrate is recovered and evaporated to dryness to give 888 mg of 1b (2.46 mmol, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:23])=[O:22])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[N:10]=[N:11][C:12](Cl)=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=1.C([O-])(=[O:26])C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:23])=[O:22])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:26])[NH:11][N:10]=1
Reactant: CC(=O)[O-]
Reactant: CC(C)c1cc(Sc2c(Cl)cc(CC(=O)O)cc2Cl)nnc1Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1cc(Sc2c(Cl)cc(CC(=O)O)cc2Cl)n[nH]c1=O
Temperature: 100 °C
Yield: 47.8 %

Procedure:
A mixture of [3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-ylsulfanyl)-phenyl]-acetic acid (75) (90 mg, 0.23 mmol) and sodium acetate (66 mg, 0.80 mmol) in glacial acetic acid (2.5 mL) was heated to 100° C. for 7 h. At this time, the reaction was concentrated in vacuo. The residue was slurried three times in a 1:1 solution of methylene chloride:hexanes followed by concentration under vacuum. The resulting solid was diluted with water (100 mL) and was then treated with a 1N aqueous sodium hydroxide solution to adjust the pH between 10-11. This solution was extracted with ethyl acetate. The organics were discarded. The aqueous layer was then acidified to pH=2-3 with a 1N aqueous hydrochloric acid solution. This solution was then extracted with ethyl acetate (2×100 mL). The organics were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried with magnesium sulfate, filtered, and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70:30 hexanes/ethyl acetate with 2% glacial acetic acid) afforded [3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylsulfanyl)-phenyl]acetic acid (76) (41 mg, 17.5%) as a white solid; EI(+)-HRMS m/e calcd for C15H14Cl2N2O3S (M+H)+ 373.0175, found 373.0175. Exact Mass=372.0102; Molecular Weight=373.26