Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]([C:33]2[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[CH:36]=[CH:35][C:34]=2[O:42][CH3:43])[C:14]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:10])C1C=CC=CC=1.[Li+].[OH-].Cl>C1COCC1.O>[CH2:18]([O:17][C:16]1[CH:15]=[C:14]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:13]([C:33]2[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[CH:36]=[CH:35][C:34]=2[O:42][CH3:43])=[CH:12][C:11]=1[C:9]([OH:10])=[O:8])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc(C(C)C)cc1-c1cc(C(=O)OCc2ccccc2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(C)C)cc1-c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
4,6-Bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-carboxylic acid benzyl ester (573 mg, 1 mmol) was dissolved in a mixture of THF (5 ml) and water (5 ml). LiOH (72 mg, 3 mmol) was added, and the resulting mixture was stirred at 90° C. overnight. After the reaction was complete, the reaction mixture was cooled to r.t., acidified with 1M HCl to pH=1. After extraction with Et2O (25 ml×3), the combined organics were washed with water and brine and dried over Na2SO4. After filtration and concentration, 4,6-bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-carboxylic acid was obtained as a white solid (463 mg, 96%). M.p.: 181-182° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.56-7.53 (m, 2H), 7.43-7.39 (m, 2H), 7.36-7.28 (m, 7H), 7.16 (dd, J=8.4, 2.0 Hz, 1H), 7.03 (d, J=2.0 Hz, 1H), 6.98-6.93 (m, 2H), 5.27 (s, 2H), 5.17 (s, 2H), 3.65 (s, 3H), 2.84 (hept, J=6.8 Hz, 1H), 1.17 (d, J=6.8 Hz, 6H); LCMS: 483 [M+1].
Reaction SMILES: N1[C:9]2[C:4](=[CH:5]C=CC=2)[CH:3]=C1C(O)=O.[Br:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15]=1[C:23]([OH:25])=[O:24].C(OC(OC(C)(C)C)N(C)C)(C)(C)C>C1(C)C=CC=CC=1>[Br:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15]=1[C:23]([O:25][C:4]([CH3:9])([CH3:5])[CH3:3])=[O:24]
Reactant: O=C(O)c1[nH]c2ccccc2c1Br
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1[nH]c2ccccc2c1Br
Temperature: 90 °C

Procedure:
Indole-2-carboxylic acid was converted to 3-bromoindole-2-carboxylic acid using the method described for Example 13. N,N-dimethylformamide di-tert-butyl acetal (35 mL) was added dropwise to a stirring mixture of indole-3-bromo-2-carboxylic acid (14.9 g, 62 mmol) suspended in toluene (100 mL). After the addition was complete, the reaction was heated at 90° C. for 8 h. The reaction mixture was then cooled to room temperature and washed with cold water (2×100 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield the crude tert-butyl 3-bromoindole-2-carboxylate, assume quantitative yield. The crude product was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1[Cl:13].[CH3:14][O-:15].[Na+]>CO>[C:6]([C:5]1[CH:11]=[C:12]([Cl:13])[C:2]([Cl:1])=[CH:3][C:4]=1[C:9]([OH:8])=[O:10])([O:15][CH3:14])=[O:7]
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Cl)c(Cl)cc1C(=O)O
Reaction time: 72 h
Yield: 92.3 %

Procedure:
To a solution of 4,5-dichlorophthalic anhydride (1.0 g, 4.61 mmol) in 15 mL of methanol was added 0.25 g (9.22 mmol, 2.0 eq) of sodium methoxide. The suspension was stirred for 3 days and the methanol was removed in vacuo. The resultant white solid was suspended in 500 mL of CH2Cl2 and washed with 1N HCl. The organic phase was dried over anhydrous Na2SO4, filtered and the volatiles removed in vacuo to yield 1.06 g (92.5%) of the titled compound as a white powder.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C([Mg]Br)C.[CH3:16][N:17]1[C:21]2[CH:22]=[C:23]([CH:26]=[O:27])[CH:24]=[CH:25][C:20]=2[N:19]=[CH:18]1>C1COCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([CH:26]([C:23]3[CH:24]=[CH:25][C:20]4[N:19]=[CH:18][N:17]([CH3:16])[C:21]=4[CH:22]=3)[OH:27])=[CH:3][N:4]=2)[N:7]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: Cn1cnc2ccc(C=O)cc21
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: Cn1cnc2ccc(C(O)c3cnc4ccc(Cl)nn34)cc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-Bromo-6-chloro-imidazo[1,2-b]pyridazine (850 mg, 3.47 mmol) was dissolved in THF (50 mL) under Argon. Ethylmagnesium bromide solution (1 M, 3.47 mL) was added and the mixture was stirred at rt for 20 min. Then 3-methyl-3H-benzoimidazole-5-carbaldehyde in THF (10 mL) was slowly added and the mixture was stirred at rt for 18 h. The mixture was quenched with water and NaHCO3. It was extracted with EtOAc twice and some MeOH to dissolve the solids. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with 40 g RediSep® silica gel column, DCM/MeOH=100:0->94:6 in 25 min then up to 11% MeOH). The collected fractions containing product were evaporated and the residue was dried under vacuum to afford the title compound as a pink foam (tR 1.79 min (conditions 8), MH+=314).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([F:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)#[N:2].Cl[C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][N:31]=1)[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([C:22]2[CH:23]=[C:24]([CH:29]=[CH:30][N:31]=2)[C:25]([O:27][CH3:28])=[O:26])[CH:6]=[C:7]([F:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)#[N:2]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: N#Cc1cc(B(O)O)cc(F)c1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccnc(-c2cc(F)c(OCc3ccccc3)c(C#N)c2)c1

Procedure:
(3-Cyano-4-benzyloxy-5-fluorophenyl)boronic acid and methyl 2-chloroisonicotinate were dissolved in a mixed solution of toluene and a 2M aqueous sodium carbonate solution, followed by heating under reflux for 3 hours in the presence of tetrakis(triphenylphosphine)palladium to obtain methyl 2-(3-cyano-4-benzyloxy-5-fluorophenyl)isonicotinate. F: 363.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([OH:31])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O.CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:44](O)[CH2:45][CH2:46][OH:47]>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([O:31][CH2:44][CH2:45][CH2:46][OH:47])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OCCCO
Reactant: COc1ccccc1C(O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccccc1C(OCCCO)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Temperature: 140 °C
Yield: 55.6 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-(hydroxy(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide (41.8 mg, 0.100 mmol) was suspended in 2 mL of toluene containing 4-methylbenzenesulfonic acid hydrate (pTsOH, 23.8 mg, 0.125 mmol) and propane-1,3-diol (9.89 mg, 0.130 mmol). The reaction mixture was then heated to 140° C. for 5 minutes in a microwave reactor. The crude product was then filtered, evaporated to dryness, dissolved in N,N-dimethylformamide (1 mL) and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield the pure product (26.5 mg, 0.0556 mmol, 55.6%). ESI-MS m/z calc. 476.5. found 477.3 (M+1)+. Retention time 2.71 minutes.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:18]=[C:17](I)[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@@H:7]1[F:20])(=[O:3])[CH3:2].[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>C(N(CC)CC)C.[Cu]I>[C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:18]=[C:17]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@@H:7]1[F:20])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(I)c(=O)[nH]c2=O)C[C@@H]1F
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C#C[Si](C)(C)C)c(=O)[nH]c2=O)C[C@@H]1F
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of the product of stage b) (0.7 g, 1.76 mmol), bis-triphenylphosphine palladium (II) chloride (0.036 g) and copper (I) iodide (36 mg) in redistilled triethylamine (35 ml) was degassed with oxygen-free nitrogen. Trimethylsilylacetylene (0.49 ml, 3.52 mmol) was added and the mixture was stirred under a nitrogen atmosphere at room temperature for 60 hours. The solvent was evaporated, the residue dissolved in dichloromethane (30 ml) and the solution washed with a 2% aqueous solution disodium EDTA (2×30 ml), water (40 ml) and dried (Na2SO4). Evaporation of the solvent and purification of the residue by silica gel column chromatography eluting with 40% ethyl acetate/toluene afforded the title compound as a foam.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC1.C1(=O)C2C(CC=CC=2)CCC1.[Br:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27]([CH3:35])([CH3:34])[CH2:28][CH2:29][C:30]2=O)=[CH:25][CH:24]=1.[C:36]1([SH:42])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:34][C:27]1([CH3:35])[C:26]2[C:31](=[CH:32][C:23]([Br:22])=[CH:24][CH:25]=2)[C:30]([S:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:29][CH2:28]1
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Reactant: Sc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C1=Cc2ccccc2CC1
Agent: O=C1CCCC2CC=CC=C12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)CC=C(Sc2ccccc2)c2cc(Br)ccc21

Procedure:
Reaction Scheme 3 provides further examples for the synthesis of compounds within the scope of Formula 5 where the linking group between the dihydronaphthalene moiety and the Y group is --CH=CH--. In the sequence of reactions described here the oxo function of a starting tetrahydronaphthalene-one moiety is modified before a Heck coupling reaction is performed. Specifically, in the example shown in the reaction scheme, 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G) is reacted with thiophenol in the presence of titanium tetrachloride and triethylamine in tetrahydrofuran (THF), to provide the intermediate 4,4-dimethyl-7-bromo-1-phenylthio-3,4-dihydronaphthalene (Compound A35). A similar reaction can be performed with ethanethiol as a reagent instead of thiophenol, to yield 2-bromo-5,6-dihydro-5,5-dimethyl-8-ethylthio-naphthalene (Compound A36) and other analogous compounds which are not shown in the reaction scheme. Compound A35 is reacted in the Heck reaction to yield ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-phenylthio-naphthalenyl)ethenyl]benzoate (Compound A16). Compound A16 is saponified to yield the carboxylic acid, (E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(phenylthio)-naphthalen-2-yl)ethenyl]benzoic acid (Compound A18), and is oxidized with m-chloroperoxybenzoic acid (MCPBA) to provide the corresponding phenylsulfonyl compound, ethyl(E)-4-[-2-(5,6-dihydro-5,5-dimethyl-8-(phenylsulfonyl)-naphthalenyl)ethenyl]benzoate (Compound A17). Compound A18 can also be oxidized under similar conditions to provide the free carboxylic acid (or salt thereof) of the phenylsulfonyl compound, (E)-4-[-2-(5,6-dihydro-5,5-dimethyl-8-phenylsulfonyl-naphthalenyl)ethenyl]benzoic acid (Compound A19). ##STR18##
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:15][C:16]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:17]=1[NH2:18].O>C1COCC1>[F:15][C:16]1[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][C:17]=1[NH:18][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1cc(C(F)(F)F)ccc1F
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc2c(Nc3cc(C(F)(F)F)ccc3F)ncnc12
Yield: 98.6 %

Procedure:
A solution of 4-chloro-8-nitroquinazoline (Intermediate-7, step-2, 150 mg, 0.72 mmol) and 2-fluoro-5-(trifluoromethyl)aniline (387 mg, 2.16 mmol) in THF (4 mL) was heated at 50° C. for 2 h. Then water was added to the reaction mixture and it was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 250 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 10.46 (s, 1H), 8.74-8.71 (d, J=8.7 Hz, 1H), 8.63 (s, 1H), 8.43-8.40 (d, J=7.2 Hz, 1H), 8.01 (d, 1H), 7.86-7.81 (m, 2H), 7.66-7.63 (t, J=9.3 Hz, 1H); MS [M+H]+: 353.14.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:15]=[CH:14][CH:13]=[C:7]2[C:8]([O:10][C:11](=O)[C:6]=12)=[O:9]>C(O)C>[Cl:4][C:5]1[CH:15]=[CH:14][CH:13]=[C:7]2[C:6]=1[C:11](=[O:10])[NH:2][NH:3][C:8]2=[O:9]
Reactant: NN
Reactant: O=C1OC(=O)c2c(Cl)cccc21
Solvent: O
Solvent: CCO
Product: O=c1[nH][nH]c(=O)c2c(Cl)cccc12
Yield: 58 %

Procedure:
A mixture of 3-chlorophthalic anyhydride (0.02 mol) and hydrazine hydrate (0.02 mol) in dry ethanol (50 ml) was heated to reflux in a reaction flask. Reflux continued for several hours until the 3-chlorophthalic anhydride disappeared and a white crystalline solid deposited on the walls of the flask. The solid was filtered and recrystallized from ethanol to yield 5-chloro-2,3-dihydrophthalazine1,4-dione in a yield of 58 percent.
Reaction SMILES: Br[CH2:2][C:3]([CH3:5])=[CH2:4].[CH2:6]([O:8][C:9](=[O:16])[C:10]([C:12]([F:15])([F:14])[F:13])=[O:11])[CH3:7].[NH4+].[Cl-]>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH2:6]([O:8][C:9](=[O:16])[C:10]([OH:11])([C:12]([F:13])([F:15])[F:14])[CH:2]=[C:3]([CH3:5])[CH3:4])[CH3:7]
Reactant: CCOC(=O)C(=O)C(F)(F)F
Reactant: C=C(C)CBr
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(C=C(C)C)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 73 %

Procedure:
A suspension of 0.27 mol Mn and 0.01 mol ZnCl2 in 105 ml THF is heated to reflux. 0.01 mol 3-bromo-2-methyl-1-propene is added to the boiling mixture and after 30 minutes a solution of 0.11 mmol ethyl-trifluoropyruvate and 0.18 mol 2-bromo-2-methyl-1-propene in 90 ml THF is dropped to the reaction mixture within 2.5 hours. After 3 hours under reflux the mixture is stirred for 19 hours at room temperature. The reaction mixture is poured on 90 ml of a saturated NH4Cl and ice mixture. After vigorous stirring for 30 minutes the mixture is extracted four times with 110 ml of MTBE each. The combined organic extracts are washed with 30 ml of brine, dried over magnesiumsulfate and concentrated in vacuo. The residue is destined under reduced pressure. ethyl-2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoate is obtained in 73% yield.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:17][CH:18]([OH:25])[C:19]2[N:20]=[C:21]([NH2:24])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([O:5]C)=[O:4].O.Cl>O1CCOCC1.CO>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:17][CH:18]([OH:25])[C:19]2[N:20]=[C:21]([NH2:24])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([OH:5])=[O:4]
Reactant: COC(=O)c1ccc(CC(C)N(Cc2ccccc2)CC(O)c2csc(N)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CC(Cc1ccc(C(=O)O)cc1)N(Cc1ccccc1)CC(O)c1csc(N)n1

Procedure:
13.6 ml (0.0136 mol) of 1N sodium hydroxide solution are added dropwise at room temperature to a solution of 1.5 g (0.0034 mol) of N-[2-(4-carbomethoxyphenyl)-1-methyl-ethyl]-N-benzyl-2-hydroxy-2-(2-aminothiazol-4-yl)ethanamine in dioxan/methanol=1:1 within 10 minutes, with stirring. After 1 hour 20 ml of water are added dropwise sufficiently slowly that a solution is always maintained. After 16 hours 13.5 ml (0.0136 mol) of 1N hydrochloric acid are added, and the mixture is extracted with methylene chloride which is dried over sodium sulphate and evaporated to dryness, and the resulting base is purified on a silica gel column using ethyl acetate/methanol=9:1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]([OH:16])=O.[Cl:17][C:18]1[CH:19]=[C:20]([NH2:33])[CH:21]=[CH:22][C:23]=1[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([CH3:32])[CH2:28][CH2:27]1>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:33][C:14](=[O:16])/[CH:13]=[CH:12]/[C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])[CH:21]=[CH:22][C:23]=1[CH2:24][CH2:25][N:26]1[CH2:27][CH2:28][CH:29]([CH3:32])[CH2:30][CH2:31]1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1Cl
Reactant: CC1CCN(CCc2ccc(N)cc2Cl)CC1
Solvent: CN(C)C=O
Product: CC1CCN(CCc2ccc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3Cl)cc2Cl)CC1

Procedure:
Prepared in DMF analogously to Example 143 starting from (E)-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylic acid (Z37b) and 3-chloro-4-[2-(4-methyl-piperidin-1-yl)-ethyl]-phenylamine (Z46c). The crude product was purified by column chromatography (Alox, neutral, act. II-III, gradient petroleum ether/EtOAc 3:1→2:1) and then triturated with petroleum ether.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(C(=O)O)ccc1C(F)(F)F
Product: CC(=O)Nc1cc(C(=O)O)ccc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
3 g. of 2-amino-α,α,α-trifluoro-p-toluic acid is dissolved in 20 ml. of acetic anhydride and the resultant solution is heated to 80° C. After 30 minutes at a temperature of 80° C., the excess acetic anhydride is removed from the reaction mixture on a rotary evaporator and water is added to the residue. The resultant precipitate is filtered, washed with water and dried to yield 2-acetamido-α,α,α-trifluoro-p-toluic acid (N-acetyl-4-trifluoromethylanthranilic acid), m.p. 195°-197° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1.[F:29][C:30]([F:59])([F:58])[C:31]1[C:35](B(O)O)=[CH:34][N:33]([C:39]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:32]=1>>[CH3:28][S:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][CH:15]2[CH2:16][CH2:17][N:12]([C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:35]5[C:31]([C:30]([F:58])([F:59])[F:29])=[N:32][N:33]([C:39]([C:46]6[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=6)([C:52]6[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=6)[C:40]6[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=6)[CH:34]=5)[CH:3]=4)[N:8]=[CH:7][CH:6]=3)[CH2:13][CH2:14]2)=[CH:20][CH:21]=1)(=[O:27])=[O:26]
Reactant: OB(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(OC2CCN(c3ccnc4ccc(Br)cc34)CC2)cc1
Product: CS(=O)(=O)c1ccc(OC2CCN(c3ccnc4ccc(-c5cn(C(c6ccccc6)(c6ccccc6)c6ccccc6)nc5C(F)(F)F)cc34)CC2)cc1
Yield: 98.9 %

Procedure:
150 mg 6-bromo-4-{4-[4-(methylsulfonyl)phenoxy]piperidino}quinoline (compound in Production Example 89) and 180 mg 3-trifluoromethyl-1-trityl-1H-4-pyrazolylboronic acid (compound in Production Example 31) were reacted in the same manner as in Example 9, to give 244 mg 4-[4-(4-methylsulfonylphenoxy)piperidin-1-yl]-6-(3-trifluoromethyl-1-trityl-1H-pyrazol-4-yl) quinoline. This product was reacted in the same manner as in Example 67, to give 130 mg of the title compound as pale yellow crystals.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[C:37]1([S:43]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[C:37]1([S:43]([N:46]2[CH2:51][CH2:50][N:49]([CH2:6][C:7]3[N:12]=[CH:11][C:10]4[N:13]=[CH:14][N:15]([C:16]5[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=6[C:30]([F:31])([F:32])[F:33])[CH3:23])[CH:20]=5)[C:9]=4[CH:8]=3)[CH2:48][CH2:47]2)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=S(=O)(c1ccccc1)N1CCNCC1
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CN4CCN(S(=O)(=O)c5ccccc5)CC4)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Temperature: 40 °C
Reaction time: 1 h

Procedure:
100 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate are dissolved in 2.5 ml dichloromethane. Under N2 atmosphere benzenesulfonyl piperazine (209 mg) is added. The reaction mixture is stirred at 40° C. for 1 hour and then concentrated to dryness under vacuum. The residue is purified by preparative HPLC (ammonium formate buffer/acetonitrile, elution gradient 97/3 to 0/100 (v/v)) to obtain the title product.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:15]=[C:14](Cl)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:17]C)[CH:12]=2)[N:7]=1)=[O:5])C.[CH2:19]([S-:21])[CH3:20].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.CCOC(C)=O>[CH2:19]([S:21][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[CH:12]=2)[N:7]=[C:6]([C:4]([OH:3])=[O:5])[N:15]=1)[CH3:20]
Reactant: CC[S-]
Reactant: CCOC(=O)c1nc(Cl)c2cc(OC)ccc2n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCSc1nc(C(=O)O)nc2ccc(O)cc12
Temperature: 140 °C
Yield: 67.3 %

Procedure:
To a solution of 4-chloro-6-methoxy-quinazoline-2-carboxylic acid ethyl ester (1.22 g, 4.574 mmol) in anhydrous DMF (4.0 mL) was added sodium ethanethiolate (3.07 g, 36.59 mmol) and the reaction mixture was heated at 140° C. for 3 h. Water and EtOAc was added . The pH of the aq. layer was adjusted to 6 with citric acid. The organic layer was separated and the aq. layer was extracted with EtOAc. The combined organic layer was washed with water, brine, dried (Na2SO4) and concentrated under reduced pressure to give 0.770 g of 4-ethylsulfanyl-6-hydroxy-quinazoline-2-carboxylic acid.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@:15]3([O:33][CH3:34])[CH2:16][CH2:17][C@@H:18]2[C:28]2[CH:32]=[CH:31][O:30][CH:29]=2)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+]>>[CH3:34][O:33][C@@:15]12[C@H:14]3[C@@H:23]([C@:24]4([CH3:27])[C@H:11]([CH2:12][CH2:13]3)[CH2:10][C@@H:9]([OH:8])[CH2:26][CH2:25]4)[CH2:22][CH2:21][C@:19]1([CH3:20])[C@@H:18]([C:28]1[CH:32]=[CH:31][O:30][CH:29]=1)[CH2:17][CH2:16]2
Reactant: CO[C@]12CC[C@H](c3ccoc3)[C@@]1(C)CC[C@H]1[C@H]2CC[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@]21C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Product: CO[C@]12CC[C@H](c3ccoc3)[C@@]1(C)CC[C@H]1[C@H]2CC[C@@H]2C[C@@H](O)CC[C@@]21C
Yield: 87.1 %

Procedure:
A solution of 3.0 g of 3β-tert-butyldimethylsilyloxy-14β-methoxy-17β-(3-furyl)-5β-androstane in 57 ml of a 1.0 M solution of tetrabutylammonium fluoride was heated at 70° C. under nitrogen for an hr and then poured into a saturated solution of sodium chloride. The mixture was extracted with ethyl acetate and the organic layer was dried over sodium sulfate, evaporated to dryness under reduced pressure and purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 80/20 as eluant to give 2.0 g of the title compound (II-c) as a white solid.