Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([OH:14])=O)=[N:10][C:9]2[NH:8][C:7](=[O:15])[CH2:6][S:5][C:4]=2[CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][C:22]([S:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1)=[CH:21]2>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][C:22]([S:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH:34]([NH:37][C:12]([C:11]3[C:2]([Cl:1])=[CH:3][C:4]4[S:5][CH2:6][C:7](=[O:15])[NH:8][C:9]=4[N:10]=3)=[O:14])[CH2:33][CH2:32]1)=[CH:21]2
Reactant: O=C1CSc2cc(Cl)c(C(=O)O)nc2N1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)cc2c1
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)c4nc5c(cc4Cl)SCC(=O)N5)CC3)cc2c1

Procedure:
The title compound is prepared as a light yellow solid (49 mg, 91% yield) following Scheme 3 and in analogy to Example 53 using 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (22 mg, 0.09 mmol, 1.0 eq) and 1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-ylamine (30 mg, 0.09 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH:2]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:15][CH:14]=2)[CH:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)c1ccc(-c2cccnc2)cc1

Procedure:
In a similar manner to Referential Example 12 except for the use of 4-(3-pyridyl)benzoic acid and 1-tert-butoxycarbonyl-3-ethoxycarbonylpiperazine as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@H:4]([CH2:6][S:7][CH3:8])[NH2:5].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:9])[C@H:4]([CH2:6][S:7][CH3:8])[NH:5][C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COC(=O)[C@@H](N)CSC
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CSC)Nc1ncccc1[N+](=O)[O-]
Yield: 54.1 %

Procedure:
In analogy to Example 2, but using only one mole equivalent of triethylamine, 5 g (27 mmol) of (-)-S-methyl-L-cysteine methyl ester were reacted with 3.51 g (22.5 mmol) of 2-chloro-3-nitropyridine (reaction conditions: 5 hours at 80° C.). Working up was followed by chromatography on silica gel (n-heptane/acetone/methyl t-butyl ether=5:1:1). 3.3 g (45%) of N-(3-nitro-2-pyridyl)-(-)-S-methyl-L-cysteine methyl ester, of melting point 95°-97° C., were obtained.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[O:18][CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([Mg]Cl)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.C(Cl)Cl>CCOCC>[C:20]1([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([O:18][CH3:19])=[C:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:17]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: COc1c(Cc2ccccc2)ccc2ccccc12
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COc1c(Cc2ccccc2)cc(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
A solution of the compound of Example 94 Part B (5.00 g, 15.3 mmole) and bis-(1,3-diphenylphosphino)-propane nickel(II) chloride (0.40 g, 0.74 mmole) in dry ether was stirred at 0°. Phenylmagnesium chloride (2.0M in ether; 9.5 mL, 19.0 mmole) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The mixture was then poured into 1.0N hydrochloric acid, and the crude product was isolated by extraction with methylene chloride. This was chromatographed to provide the title product (4.26 g, 86%) as a white solid. A small sample recrystallized from hexane melted at 103°-105°.
Reaction SMILES: [C:1](=[O:16])([O:14][CH3:15])[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][C:4]=1[Br:13].OS(O)(=O)=O.[N+:22]([O-])([O-:24])=[O:23].[K+]>>[C:1](=[O:16])([O:14][CH3:15])[O:2][C:3]1[CH:8]=[C:7]([N+:22]([O-:24])=[O:23])[C:6]([C:9]([CH3:11])([CH3:12])[CH3:10])=[CH:5][C:4]=1[Br:13]
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)Oc1ccc(C(C)(C)C)cc1Br
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)Oc1cc([N+](=O)[O-])c(C(C)(C)C)cc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
2-Bromo-4-tert-butylphenyl methyl carbonate (5.0 g, 17.4 mmol) was added portion-wise to H2SO4 (9.3 mL, 174.1 mmol) to generate a colorless homogeneous solution. This solution was then cooled to 0° C. and treated with KNO3 (2.1 g, 20.9 mmol) portion-wise maintaining the internal temperature below 5° C. The reaction was stirred for 2 h and then poured on ice water. The aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic extracts was dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (10% ethyl acetate/hexane) provided 2-bromo-4-tert-butyl-5-nitrophenyl methyl carbonate (4.4 g, 76% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.92 (s, 1H), 3.90 (s, 3H), 1.34 (d, J=5.4 Hz, 9H).
Reaction SMILES: C(O)C.[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:16])([C:13](=[O:15])[CH3:14])[CH3:12])=[CH:7][CH:6]=1.[O:17]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[K+]>O>[O:17]([C:24]1[CH:25]=[C:26]([CH:27]=[CH:14][C:13](=[O:15])[C:11]([C:8]2[CH:9]=[CH:10][C:5]([CH3:4])=[CH:6][CH:7]=2)([CH3:16])[CH3:12])[CH:29]=[CH:30][CH:31]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CC(=O)C(C)(C)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(C)(C)C(=O)C=Cc2cccc(Oc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97 %

Procedure:
To 50 ml of ethanol were added 5.3 g of 2-(4-methylphenyl)-2-methyl-3-butanone, 6.0 g of 3-phenoxybenzaldehyde and 6.0 g of KOH, and the mixture was stirred at room temperature for one hour and 20 minutes. Then, the reaction mixture was poured into 300 ml of water and extracted with benzene. The benzene extract was washed with water and dried, and the solvent was evaporated under reduced pressure to give 10.4 g of crude 1-(3-phenoxyphenyl)-4-(4-methylphenyl)-4-methyl-1-penten-3-one. Then, the crude product was purified by column chromatography on 250 g of silica gel (eluent:benzene) to give 6.8 g of pure 1-(3-phenoxyphenyl)-4-(4-methylphenyl)-4-methyl-1-penten-3-one.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][C:5]([O:12][CH2:13][O:14][CH3:15])=[CH:4][C:3]=1[CH2:16][OH:17].[H-].[Na+].[CH3:20]I>C1COCC1>[Br:1][C:2]1[C:3]([CH2:16][O:17][CH3:20])=[CH:4][C:5]([O:12][CH2:13][O:14][CH3:15])=[CH:6][C:7]=1[O:8][CH2:9][O:10][CH3:11]
Reactant: CI
Reactant: COCOc1cc(CO)c(Br)c(OCOC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1cc(COC)c(Br)c(OCOC)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
A solution of (2-bromo-3,5-bis-methoxymethoxy-phenyl)-methanol (10.2 g, 33.3 mmol) in THF (60 mL) was treated with NaH (2.67 g, 66.7 mmol) at 0° C. The resulting suspension was stirred at room temperature for 20 min. CH3I was added to the mixture and the reaction was stirred at room temperature for 1 h. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), and concentrated. The residue was purified by flash column chromatography (silica, hexanes/ethyl acetate=5:1) to afford the title compound (10.5 g, 96%). 1H NMR (300 MHz, CDCl3) δ 6.88 (s, 1H), 6.80 (s, 1H), 5.23 (s, 2H), 5.17 (s, 2H), 4.50 (s, 2H), 3.51 (s, 3H), 3.47 (s, 6H).
Reaction SMILES: [CH:1]([N:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)([CH3:3])[CH3:2].[N+:17]([O-])([OH:19])=[O:18].O>CC(O)=O>[CH:1]([N:4]1[C:16]2[CH:15]=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)([CH3:3])[CH3:2]
Reactant: CC(C)n1c2ccccc2c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)n1c2ccccc2c2cc([N+](=O)[O-])ccc21
Reaction time: 0.25 h
Yield: 87 %

Procedure:
A solution of 9-Isopropyl-9H-carbazole (Acros, 1.5 9, 7.2 mmol) in AcOH (50 ml) was treated dropwise with a solution of nitric acid (3.35 ml) in AcOH (10 mL) over 30 minutes. When the reaction was complete the mixture was poured into water and stirred for 15 minutes, then the solid filtered and washed with Et2O to afford the desired product as a solid (1.6 g, 87%).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[SH:16][C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>CCO>[S:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[S:16][CH2:3][C@@H:2]([OH:1])[CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15]
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Reactant: Sc1nc2ccccc2s1
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1C[C@H](O)CSc1nc2ccccc2s1
Yield: 76 %

Procedure:
A suspension of N-[(2S)-oxiran-2-ylmethyl]-phthalimide (18.4 g, 90.6 mmol) and 2-mercaptobenzothiazole (15.8 g, 94.5 mmol) in EtOH (530 mL) was heated to reflux for 14.5 h. The reaction was then cooled and concentrated under reduced pressure. The crude mixture was crystallized from ethanol and filtered to provide N-[(2S)-3-(1,3-benzothiazol-2-ylthio)-2-hydroxypropyl]-phthalimide (25.5 g, 76%) as a solid. Data for N-[(2S)-3-(1,3-benzothiazol-2-ylthio)-2-hydroxypropyl]-phthalimide: 1H NMR (300 MHz, CDCl3) δ 7.88 (m, 2H), 7.75 (m, 4H), 7.45-7.26 (m, 2H), 5.15 (m, 1H), 4.42 (m, 1H), 4.08-3.88 (m,2H, 3.61 (m, 1H), 3.42 (m, 1H).
Reaction SMILES: Cl.CS[C:4]1[NH:5][CH2:6][CH:7]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:8]=1.[NH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(O)C>[ClH:15].[O:23]1[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][NH:17][C:4]2[NH:5][CH2:6][CH:7]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[N:8]=2)[CH2:21][CH2:22]1
Reactant: NCCN1CCOCC1
Reactant: CSC1=NC(c2c(Cl)cccc2Cl)CN1
Agent: Cl
Solvent: CCO
Product: Clc1cccc(Cl)c1C1CNC(NCCN2CCOCC2)=N1
Temperature: 150 °C

Procedure:
A mixture consisting of 6.0 gm (0.0202 mol) of 2-methylmercapto-4-(2',6'-dichloro-phenyl)-2-imidazoline hydrochloride and 3.25 gm (0.025 mol) of N-(β-amino-ethyl)-morpholine was melted by heating it for 30 minutes at 150° C. Thereafter, while still hot, the molten mass was dissolved in ethanol and reprecipitated from solution by addition of ether. The precipitate, which solidified after some time, was collected and recrystallized from ethanol/acetone and, for further purification, briefly heated in boiling water in the presence of activated charcoal. The mixture was filtered, the filtrate was evaporated to dryness, and the residue was washed with acetone, yielding 3.0 gm (41.8% of theory) of the white crystalline compound of the formula ##STR11## which had a melting point of 225° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[NH2:5].[C:15]([CH2:23][C:24]([CH3:26])=O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[CH3:1][O:2][C:3](=[O:14])[CH:4]([NH:5][C:24]([CH3:26])=[CH:23][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CC(=O)CC(=O)c1ccccc1
Solvent: CO
Product: COC(=O)C(Cc1ccc(O)cc1)NC(C)=CC(=O)c1ccccc1
Yield: 97.7 %

Procedure:
To a solution of L-tyrosine methyl ester (4.00 g, 20.51 mmol) in methanol (150 ml) is added 1-benzoylacetone (3.66 g, 22.56 mmol), then the mixture is heated to reflux for 24 h. The solvent is evaporated under a vacuum. To the residue is added ethanol (50 ml), then the ethanol is distilled off under atmospheric pressure. The crude product is purified by silica gel chromatography using hexane/EtOAc (4:1) as eluent to give the title compound (6.80 g, 98%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15]2[C:16]([Cl:25])=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)(C)(C)C>C(O)C>[Cl:25][C:16]1[C:15]([O:14][C@@H:11]2[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]2)=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][N:20]=[CH:21]2
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Oc2ccc3cnccc3c2Cl)CC1
Solvent: CCO
Product: N[C@H]1CC[C@@H](Oc2ccc3cnccc3c2Cl)CC1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
50 mg (0.13 mmol) cis-[4-(5-Chloro-isoquinolin-6-yloxy)-cyclohexyl]carbamic acid tert-butyl ester (12) were dissolved in ethanol/2N HCl (1:1) and stirred at room temperature until complete conversion could be detected (LCMS). Evaporation of the solvent furnished 36 mg of the title compound as hydrochloride. Rt=0.71 min (Method #1). Detected mass: 277.2/279.2 (M+H+).
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][C:7]=2[O:6][CH:5]=1)(=O)[NH2:2].S(Cl)(Cl)=O>CN(C)C=O>[C:1]([C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][C:7]=2[O:6][CH:5]=1)#[N:2]
Reactant: CS(=O)(=O)Nc1cc2occ(C(N)=O)c(=O)c2cc1Oc1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CS(=O)(=O)Nc1cc2occ(C#N)c(=O)c2cc1Oc1ccccc1

Procedure:
3-Carbamoyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was reacted with thionyl chloride in N,N-dimethylformamide to obtain 3-cyano-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one. The properties (melting point and IR) of this compound were identical with those of the compound obtained in Example 4.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:23]=[CH:22][C:21]3[N:20]4[CH2:24][CH2:25][NH:26][C:27](=[O:28])[C:19]4=[CH:18][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:23]=[CH:22][C:21]3[N:20]4[CH2:24][CH2:25][NH:26][C:27](=[O:28])[C:19]4=[CH:18][C:17]=3[CH:16]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCCn2c1cc1cc(OC3CCNCC3)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
The solution of 0.45 g (1.17 mmol) 4-(1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indol-8-yloxy)-piperidine-1-carboxylic acid tert-butyl ester in 10 mL dichloromethane was cooled to 0° C. and was treated with 5 mL (7.4 g, 65.3 mmol) trifluoroacetic acid. The cooling bath was removed and after stirring at room temperature for 1 h the volatile components were removed at a rotary evaporator. The residue was taken up in dichloromethane and washed with 1 M aqueous sodium hydroxide solution. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 140 mg (42%) of the product as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:8]2[CH:9]([C:13]([O:15][CH3:16])=[O:14])[NH:10][CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:43](Cl)(=[O:45])[CH3:44]>C(Cl)(Cl)Cl>[C:43]([N:10]1[CH2:11][CH2:12][C:7]2[N:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:35][N:34]=[N:33][N:32]=4)=[CH:21][CH:20]=3)[C:8]=2[CH:9]1[C:13]([O:15][CH3:16])=[O:14])(=[O:45])[CH3:44]
Reactant: CC(=O)Cl
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)NCC2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)N(C(C)=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
To a mixture of the compound obtained in Example 3 (296 mg), triethylamine (317 mg) and chloroform (10 ml) is added dropwise a solution of acetyl chloride (148 mg) in chloroform (1 ml) under ice-cooling. The mixture is stirred at room temperature for two hours, and the reaction solution is washed, dried and evaporated to remove the solvent. The resulting residue is purified by silica gel column chromatography (solvent; chloroform/methanol=30:1) to give methyl 5-acetyl-2-n-butyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (158 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:43][CH2:44][CH2:45][CH3:46])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:34]4[CH:35]=[N:36][N:37]([CH2:39][CH2:40][O:41][CH3:42])[CH:38]=4)[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:47]>C(Cl)Cl.O1CCOCC1>[ClH:47].[ClH:47].[CH2:43]([C:18]1[N:17]=[N:16][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:20][C:19]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[C:23]([C:34]2[CH:35]=[N:36][N:37]([CH2:39][CH2:40][O:41][CH3:42])[CH:38]=2)[CH:22]=1)[CH2:44][CH2:45][CH3:46]
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2cnn(CCOC)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(-c2cnn(CCOC)c2)c1
Reaction time: 0.67 h

Procedure:
To a solution of 4-(6-butyl-5-{4-cyclohexyloxy-3-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-phenyl}-pyridazin-3-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (0.107 mmol, 68 mg) in DCM (1.5 mL) was added 4 N HCl in dioxane (0.5 mL) and the reaction mixture was stirred for 40 min. The organic solvents were removed in vacuo and the residue was triturated with anhydrous diethyl ether. The yellow solid was dried overnight under high vacuum to give 3-butyl-4-{4-cyclohexyloxy-3-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-phenyl}-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (59.5 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[C:9]([C:17]([O:19]CC)=[O:18])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Na].O>O1CCOCC1>[CH2:1]([O:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[C:9]([C:17]([OH:19])=[O:18])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=Cc2ccccc2N(C(=O)OCC)CC1
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)N1CCC(C(=O)O)=Cc2ccccc21
Yield: 93.5 %

Procedure:
Compound 9 (5 g, 17.2 mmoles) was dissolved in dioxane (11.5 ml) and a solution of sodium hydroxyde (11.5 ml, 1.5M) was added. The mixture was heated for 2 hours and poured in ice cooled water. The aqueous layer was extracted at pH 12 with Et2O (50 ml), acidified to pH 2 and reextrated with EtOAc (100 ml). This layer was dried (MgSO4), filtered and evaporated to give yellow crystals (4.2 g, 90%), after recrystallization (cyclohexane/CCl4) mp 176° C. 1H NMR (CDCl3) δ=1.25 (3H, t, J=7 Hz) 2.9 (2H, t) 3.5-3.9 (2H, m) 4.2 (2H, q, J=7 Hz) 7-7.6 (4H, m) 7.8 (1H, s). IR (CCl4) 3500-3000 (large signal) 3000 (w) 1695 (s) 1630 (w) 1600 (w) 1575 (w) 1490 (w) 1450 (w) 1410 (m) 1385 (w) 1370 (2) 1340 (w) 1320 (m). Mass spectrum m/z 261.
Reaction SMILES: CC1[N:3]([C:7]2[CH:8]=[C:9]([C:13]3[CH:22]=[N:21][CH:20]=[CH:19][C:14]=3[C:15]([O:17]C)=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH2:4][CH2:5][N:6]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C@H:27]1[O:29][CH2:28]1.[OH-].[Na+].Cl>C1(C)C=CC=CC=1.CO>[Cl:23][C:24]1[CH:25]=[C:26]([C@@H:27]([OH:29])[CH2:28][NH:6][CH2:5][CH2:4][NH:3][C:7]2[CH:8]=[C:9]([C:13]3[CH:22]=[N:21][CH:20]=[CH:19][C:14]=3[C:15]([OH:17])=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)c1ccncc1-c1cccc(N2CCN=C2C)c1
Reactant: Clc1cccc([C@@H]2CO2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(O)c1ccncc1-c1cccc(NCCNC[C@H](O)c2cccc(Cl)c2)c1
Temperature: 110 °C
Yield: 57.7 %

Procedure:
A solution of methyl 3-[3-(2-methyl-4,5-dihydro-1H-imidazol-1-yl)phenyl]isonicotinate (0.25 g) and (R)-3-chlorostyrene oxide (0.13 g) in anhydrous toluene (2 ml) was heated at reflux (ca. 110° C.) for 18 h. The mixture was cooled to ca. 50° C., 1M sodium hydroxide solution (4.8 ml) and methanol (3 ml) were added over 5-10 min. The apparatus was configured to distill out 4 ml of solvents under atmospheric pressure. The homogeneous mixture obtained was heated at reflux for 2 h. The mixture was cooled to <50° C., and concentrated hydrochloric acid (36%, 0.3 ml) was added dropwise to adjust pH to 7. The aqueous solution was loaded on to silica gel column and eluted with a mixture of dichloromethane and methanol (8/2, v/v). The product was isolated as 0.2 g (57%) of hygroscopic brown solid.
Reaction SMILES: [CH2:1]([OH:19])[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].[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl>>[CH2:20]([O:19][CH2:1][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])[CH:22]1[O:24][CH2:23]1
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: ClCC1CO1
Product: CCCCCCCC/C=C\CCCCCCCCOCC1CO1

Procedure:
reacting oleyl alcohol with epichlorohydrin in a molar ratio of 1:1 to give oleyl glycidyl ether,
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C(Cl)(Cl)Cl.Cl.[CH2:19]([OH:21])C>C1(C)C=CC=CC=1>[OH:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]([CH:19]=[O:21])=[CH:3][CH:2]=1
Reactant: Oc1cccc2c1CCCC2
Reactant: CCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: O=Cc1ccc(O)c2c1CCCC2
Reaction time: 0.25 h

Procedure:
5,6,7,8-Tetrahydro-naphthalen-1-ol (108, 20 g, 135 mmol) was stirred in 100 mL of ethanol, and potassium hydroxide (7.57 g, 135 mmol) as an aqueous solution was added. The mixture was stirred for 15 minutes and went clear. Solvents were removed and dried. PEG (MW 380-420, 53 mL) was added, followed by chloroform (32.3 mL, 405 mmol) and toluene (34 mL). An aqueous potassium hydroxide solution (50% by weight, 54.4 mL) was introduced dropwise with stirring over 15 minutes. The stirring was continued for another 30 minutes. 1M HCl was added to acidify the reaction mixture and it was extracted with EtOAc three times. The combined organic layers were washed with water and brine The combined organic layers were dried over MgSO4, filtered, concentrated, and purified by flash chromatography (0-40% EtOAc/hexane) to give 4-hydroxy-5,6,7,8-tetrahydro-naphthalene-1-carbaldehyde (109, 4.7 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:28][C:29]1[CH:30]=[C:31]([S:35]([NH:38][CH:39]2[CH2:41][CH2:40]2)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[CH:39]1([NH:38][S:35]([C:31]2[CH:30]=[C:29]([NH:28][C:25]([C:24]3[CH:23]=[N:22][N:15]4[C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:12]([C:4]5[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:9])[F:10])=[C:2]([CH3:1])[CH:3]=5)=[N:13][C:14]=34)=[O:26])[CH:34]=[CH:33][CH:32]=2)(=[O:37])=[O:36])[CH2:41][CH2:40]1
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: Nc1cccc(S(=O)(=O)NC2CC2)c1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)NC5CC5)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) and 3-amino-N-cyclopropyl-benzenesulfonamide [CAS 459434-39-0] according to general procedure II. Yellow solid. MS (ISP) 582.0 [(M−H)−]; mp 201° C.