Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[CH:5]1([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6]1>O1CCCC1>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]([CH:5]2[CH2:6][CH2:7]2)([OH:9])[CH:1]=[CH2:2])=[CH:15][CH:14]=1
Reactant: C=C[Mg]Br
Reactant: O=C(c1ccc(Cl)cc1)C1CC1
Solvent: C1CCOC1
Product: C=CC(O)(c1ccc(Cl)cc1)C1CC1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
A 1.0 M solution of vinylmagnesium bromide in tetrahydrofuran (110 mL, 0.11 mole) was stirred, and a solution of 18.1 grams (0.1 mole) of commercially available 4-chlorophenyl cyclopropyl ketone in 50 mL of dry tetrahydrofuran was added dropwise during a one hour period. The exothermic reaction caused the reaction mixture to warm to 45° C. Upon completion of addition, the reaction mixture was stirred for two hours as it cooled to ambient temperature. The reaction was quenched with the addition of 50 mL of a saturated, aqueous solution of ammonium chloride. The mixture was extracted with two 50 mL portions of diethyl ether. The combined extracts were dried with potassium carbonate and filtered. The filtrate was concentrated under reduced pressure, yielding 20.0 grams of 1-(4-chlorophenyl)-1-cyclopropyl-2-propen-1-ol.
Reaction SMILES: [Br:1][CH2:2][CH:3]=[CH:4][CH2:5]Br.[K].[C:8]1(=[O:18])[NH:12][C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12>CN(C=O)C>[Br:1][CH2:2][CH:3]=[CH:4][CH2:5][N:12]1[C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]2[C:8]1=[O:18]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCC=CCBr
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC=CCBr
Temperature: 40 °C
Reaction time: 16 h
Yield: 38.1 %

Procedure:
To a solution of 1,4-dibromo-2-butene (5 g, 23.37 mmol) in 4 mL DMF was added phthalimide potassium salt (433 mg, 2.34 mmol). The reaction mixture was stirred at 40° C. for 16 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated in vacuo to provide the product (250 mg). 1H NMR (CDCl3) δ3.92 (d, 2H); 4.32 (d, 2H); 5.90 (m, 2H); 7.74 (m, 2H); 7.87 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:3]=1[NH2:16].[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].O>CN(C)C(=O)C>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:16][C:3]1[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=1[NH:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:21]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1c(Cl)ncnc1Nc1ccc(Cl)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(Nc1c(Cl)ncnc1Nc1ccc(Cl)cc1)c1ccccc1Cl
Temperature: 5 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
6-Chloro-N4-(4-chlorophenyl)-pyrimidine-4,5-diamine I-(1A-1)a (1.00 g, 3.92 mmol) was dissolved in 6 ml of N,N-dimethylacetamide giving a clear brown solution. After cooling to 5° C., neat 2-chlorobenzoyl chloride (0.80 g, 4.34 mmol) was added over 1 minute. The solution was warmed to room temperature and stirred for 4 hours. Addition of water (15 ml) caused white precipitate to come out of solution. The mixture was stirred for an additional 30 minutes at room temperature, then the precipitate was collected by vacuum filtration, rinsing with H2O and then hexanes. The solid was further dried under vacuum to give I-(4A-7)a as a colorless solid (1.27 g, 82%): +ACPI MS (M+1) 393.1; 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.11 (s, 1H), 8.40 (s, 1H), 7.93 (dd, J=7.4, 1.6 Hz, 1H), 7.66–7.40 (m, 7H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[N:10]=2)[N:7]=1>C1COCC1.CO.[Pd]>[N:10]1[C:9]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:7]2
Reactant: N#Cc1cccc(-c2cn3nc(Cl)ccc3n2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2cn3ncccc3n2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.5 mg 10% Pd-C were added to the solution of 3-(6-chloroimidazo[1,2-b]pyridazin-2-yl)benzonitrile (50 mg, 0.2 mmol) in THF/MeOH 25 ml. The reaction mixture was stirred vigorously at room temperature for 4 h under hydrogen and the Pd—C was then removed. The filtrate was concentrated in vacuo to give the 3-(imidazo[1,2-b]pyridazin-2-yl)benzonitrile as a yellow-white solid.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[N:5]1)[CH2:2][CH3:3].Cl[C:19]1[N:24]=[N:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([N:31]3[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([F:40])[CH:38]=4)[CH2:33][CH2:32]3)[CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[F:40][C:37]1[CH:38]=[C:39]2[C:34]([CH2:33][CH2:32][N:31]2[CH:28]2[CH2:29][CH2:30][N:25]([C:22]3[N:23]=[N:24][C:19]([C:7]4[CH:6]=[N:5][N:4]([CH2:1][CH2:2][CH3:3])[CH:8]=4)=[CH:20][CH:21]=3)[CH2:26][CH2:27]2)=[CH:35][CH:36]=1
Reactant: CCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Product: CCCn1cc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1

Procedure:
The title compound was prepared following the procedure as described in Example 1, Method A, reacting 1-propylpyrazole-4-boronic acid pinacol ester and 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[NH2:14][CH:15]1[CH2:22][CH2:21][CH2:20][NH:19][C:17](=[O:18])[CH2:16]1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([NH:14][CH:15]1[CH2:22][CH2:21][CH2:20][NH:19][C:17](=[O:18])[CH2:16]1)=[O:8]
Reactant: NC1CCCNC(=O)C1
Reactant: COc1ccc(C(=O)O)cc1OC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NC2CCCNC(=O)C2)cc1OC
Reaction time: 0.5 h
Yield: 53 %

Procedure:
N,N'-Carbonyldiimidazole (9.79 g) was added to a solution of 3,4-dimethoxybenzoic acid (10.0 g) in THF (300 ml) and the whole was stirred for 30 mins. at room o temperature. Then, following by addition of 3-amino-ε-caprolactam (7.04 g), the mixture was stirred for 5 hrs. The resultant precipitate was collected by filtration, washed and dried under reduced pressure to give the title compound (8.5 g). This product used in the following reaction without purification. m.p. 190°-191°.
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]1[C:10](=[O:11])[CH:9]=[CH:8]O[C:6]=1[CH3:12])[CH3:3]>C(O)C>[CH2:2]([O:4][C:5]1[C:10](=[O:11])[CH:9]=[CH:8][NH:1][C:6]=1[CH3:12])[CH3:3]
Reactant: CCOc1c(C)occc1=O
Reactant: N
Solvent: CCO
Product: CCOc1c(C)[nH]ccc1=O
Temperature: 25 °C
Yield: 95 %

Procedure:
Ammonia (28% aq. 20 mL) was added to a solution of 3-ethoxy-2-methyl-4H-pyran-4-one (8.5 g, 55 mmol, obtained from Example 4(a)) in ethanol (20 mL) and the mixture was stirred under reflux for 24 h. The reaction mixture was cooled to r.t. and the solution was evaporated in vacuo. The pH was adjusted to pH 1 with 2M HCl, and the aqueous phase was extracted with ethyl acetate. The pH of the water phase was then adjusted to pH 10 with 2M sodium hydroxide. The aqueous phase was extracted with ethyl acetate (3×100 mL) and then saturated with NaCl (s) and extracted with CHCl3. The organic phase was dried (Na2SO4) and evaporated to give the title product (8.0 g, 95%). The crude product was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[CH2:7][C:8]1[CH:9]=[C:10]([CH3:36])[C:11]([O:14][CH2:15][CH2:16][C@@H:17]2[CH2:19][C@@H:18]2[CH:20]2[CH2:25][CH2:24][N:23](C(OCC3C=CC=CC=3)=O)[CH2:22][CH2:21]2)=[N:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CCO.[Pd]>[CH3:36][C:10]1[CH:9]=[C:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:37])[CH:13]=[N:12][C:11]=1[O:14][CH2:15][CH2:16][C@@H:17]1[CH2:19][C@@H:18]1[CH:20]1[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]1
Reactant: Cc1cc(CC(=O)OC(C)(C)C)cnc1OCC[C@@H]1C[C@@H]1C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(CC(=O)OC(C)(C)C)cnc1OCC[C@@H]1C[C@@H]1C1CCNCC1

Procedure:
Benzyl 4-[(1R,2S)-2-(2-{[5-(2-tert-butoxy-2-oxoethyl)-3-methylpyridin-2-yl]oxy}ethyl)cyclopropyl]piperidine-1-carboxylate (2.6 g, 5.1 mmol) in 30 mL of EtOH was treated with 10% palladium on carbon (300 mg) for 2.5 hrs under 1 atm. of hydrogen gas. The suspension was filtered through a celite pad and concentrated in vacuo to give product used for the next reaction without further purification. LCMS (ESI) m/z 375 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][S:9]([CH2:12][C:13]1[CH:26]=[CH:25][C:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:28]1[NH:29][CH2:30][CH2:31][N:32]=1.C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[CH2:1]([NH:8][S:9]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:28]3[NH:32][CH2:31][CH2:30][N:29]=3)=[CH:22][CH:23]=2)=[CH:25][CH:26]=1)(=[O:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClC1=NCCN1
Reactant: Nc1ccc(Cc2ccc(CS(=O)(=O)NCc3ccccc3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=S(=O)(Cc1ccc(Cc2ccc(NC3=NCCN3)cc2)cc1)NCc1ccccc1

Procedure:
A mixture of 4-(4-benzylaminosulfonylmethylbenzyl)-phenylamine (39 mg) and 2-chloro-imidazoline base (1 eq) in 2-propanol was heated under reflux for 16 hours. A dilute solution of potassium carbonate was poured into the mixture and extracted with dichloromethane (4×15 mL). Solvents were evaported to give 2-[4-(4-benzylaminosulfonylmethylbenzyl)-phenyl]amino-imidazoline as a solid (41.7 mg), m.p. 115-118° C.; Analysis for C24H25ClN4O2S.H2O: Calc.: C, 58.94; H, 5.98; N, 11.46; Found: C, 59.01; H, 5.91; N, 11.30.
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[C:3](=[O:13])[C:4]1[C:9]([C:10]2=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:14][C:15]([F:29])([F:28])[C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1>C(O)C>[OH:1][C:11]1[C:10](=[O:12])[C:9]2[C:4]([C:3](=[O:13])[C:2]=1[N:25]1[CH2:24][CH2:23][N:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:28])([F:29])[F:14])[CH:17]=3)[CH2:27][CH2:26]1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: O=C1c2ccccc2C(=O)C2OC12
Solvent: CCO
Product: O=C1C(O)=C(N2CCN(c3cccc(C(F)(F)F)c3)CC2)C(=O)c2ccccc21
Reaction time: 20 h
Yield: 29.9 %

Procedure:
A mixture of 1.74 g of 2,3-epoxy-2,3-dihydro-1,4-naphthoquinone and 2.30 g of N-[3-(trifluoromethyl)phenyl]piperazine in 100 ml of absolute ethanol was stirred for 20 hours, then evaporated. The residue was dissolved in dichloromethane, filtered through hydrous magnesium silicate and then chromatographed on silica gel, eluting with hexane:ethyl acetate (4:1), giving 1.2 g of the desired product, mp 167°-169° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:5][C:6]1[CH:30]=[CH:29][C:9]([C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:13]=2)=[O:11])=[CH:8][CH:7]=1.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:31]1([CH:4]([O:5][C:6]2[CH:30]=[CH:29][C:9]([C:10]([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:13]=3)=[O:11])=[CH:8][CH:7]=2)[CH2:3][CH2:2][N:48]2[CH2:47][CH2:46][N:45]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[O:38][CH3:37])[CH2:50][CH2:49]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(OC(CCBr)c3ccccc3)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc(OC(CCN3CCN(c4ccccc4OC)CC3)c3ccccc3)cc2)c2ccccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
Ethyl 4-{3-[4-(3-bromo-1-phenylpropoxy)benzoyl]indol-1-yl}butanoate (1.97 g) obtained in Step 2 was dissolved in N,N-dimethylformamide (20 ml). 1-(2-Methoxyphenyl) piperazine (0.83 g) and potassium carbonate (0.75 g) were added to the resultant solution and stirred overnight at 60° C. After cooling, water was added to the reaction mixture, followed by extraction with ethyl acetate. The resultant extract was washed with brine and then dried. The solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), obtaining 1.95 g of ethyl 4-{3-{4-{1-phenyl-3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy}benzoyl}indol-1-yl}butanoate as a colorless oily substance.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:20][O:21][CH:22]([O:27][CH3:28])[C:23](OC)=[O:24]>O1CCCC1.CCCCCC>[CH3:20][O:21][CH:22]([O:27][CH3:28])[C:23](=[O:24])[CH2:2][C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: COC(=O)C(OC)OC
Reactant: CC(=O)c1ccncc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(OC)C(=O)CC(=O)c1ccncc1
Temperature: -40 °C
Reaction time: 16 h

Procedure:
A solution of 4-acetylpyridine (12 g) in dry tetrahydrofuran (500 ml), under nitrogen and at −60° C., was treated with a solution of lithium bis(trimethylsilyl)amide in hexane (200 ml, 1M). The mixture was allowed to warm to −40° C. then treated with methyl dimethoxyacetate (12 ml). After standing at room temperature for 16 hours the reaction mixture was evaporated and the residue was triturated with diethyl ether to give the title compound as a yellow solid (22 g).
Reaction SMILES: Cl.N[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[S:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7].N([O-])=[O:16].[Na+]>O>[OH:16][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[S:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(SC)c(N)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(SC)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
A stirred solution of concentrated hydrochloric acid (3.2 mL) in water (3.6 mL) at from 0° C. to 5° C. is treated with methyl 3-amino-4-(methylthio)benzoate (1.97 g), followed by a solution of sodium nitrite (0.82 g) in water (2 mL), at such a rate that the temperature remained from 0° C. to 5° C. The mixture is then allowed to warm to room temperature and it is stirred for a further period of 1 hour. The reaction mixture is treated with water (30 mL) and then heated to 55-60° C., until the evolution of nitrogen ceased (4 hours). The mixture is extracted with dichloromethane (2×100 mL) and the combined organic extracts are dried and concentrated. The resulting brown oil is subjected to flash chromatography, eluting with a mixture of diethyl ether and pentane (1:4 v/v), to give methyl 3-hydroxy-4-(methylthio)benzoate (0.6 g) in the form of a yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[C:23]2[CH:22]=[CH:21][N:20]=[C:19]([Cl:24])[C:18]=2[CH:17]=[C:16]1[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:28][C:27]1=[O:42])=O)(C)(C)C>C(Cl)Cl>[CH2:35]([O:34][C:32]([N:29]1[CH2:30][CH2:31][N:26]([CH2:25][C:16]2[NH:15][C:23]3[CH:22]=[CH:21][N:20]=[C:19]([Cl:24])[C:18]=3[CH:17]=2)[C:27](=[O:42])[CH2:28]1)=[O:33])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)n1c(CN2CCN(C(=O)OCc3ccccc3)CC2=O)cc2c(Cl)nccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1Cc1cc2c(Cl)nccc2[nH]1
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (10 mL) is added to a solution of 2-(4-benzyloxycarbonyl-2-oxo-piperazin-1-ylmethyl)-4-chloro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (5.66 g, 11.3 mmol, prepared in the same manner as described previously) in CH2Cl2 (10 mL). The solution is stirred overnight then diluted with CH2Cl2 and washed with saturated NaHCO3 and brine. The organic layer is dried over MgSO4, filtered and concentrated to dryness. The crude product is chromatographed eluting with 1-5% MeOH/CH2Cl2 to yield the title product (3.81 g, 9.56 mmol) as a foamy yellow solid. 1H NMR (CDCl3, 300 MHz) δ9.43 (bs, 1H), 8.08 (d, 1H), 7.38 (s, 5H), 7.18 (d, 1H), 6.51 (s, 1H), 5.15 (s, 2H), 4.58 (s, 2H), 4.20 (s, 2H), 3.71 (m, 2H), 3.50 (m, 2H). Ion spray [M+H]+=399, 401, Cl pattern.
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([OH:7])[CH3:6])C.[OH-].[Li+]>O1CCCC1.O>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:5]([OH:7])([CH3:6])[C:4]([OH:15])=[O:3])=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(C)(O)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(C(=O)O)c1ccc(Cl)cc1

Procedure:
A solution of 5.72 g of the 2-(4-chlorophenyl)-2-hydroxy propionic acid ethyl ester in 170 ml tetrahydrofurane is hydroysed at 0° C. with a solution of 30.5 ml 1N lithiumhydroxide in 19 ml water. When the reaction is complete, the reaction mixture is diluted with water, washed with diethyl ether, acidified with 1N HCl and extracted with ethyl acetate. The extracts are washed with brine, dried over sodium sulfate and evaporated to give 2-(4-chlorophenyl)-2-hydroxy propionic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]2([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[NH:13][CH3:14].[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[S:32](Cl)(=[O:34])=[O:33]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([S:32]([C:25]1[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:24]=1[O:23][CH3:22])(=[O:34])=[O:33])[C:6](=[O:12])[C:5]2([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[NH:13][CH3:14]
Reactant: CNC1(c2ccccc2Cl)C(=O)Nc2c(F)cc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Product: CNC1(c2ccccc2Cl)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2c(F)cc(Cl)cc21
Yield: 20.5 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 1 from 0.25 g of 5-chloro-3-(2-chlorophenyl)-7-fluoro-1,3-dihydro-3-(methylamino)indol-2-one and 0.165 g of 2,4-dimethoxybenzenesulfonyl chloride. 0.075 g of the expected product is obtained after crystallization and recrystallization from a DCM/iso ether mixture. M.p.=183°-185° C.
Reaction SMILES: [Cl-:1].[NH:2]=[C:3]1[NH:9][CH:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][N+:15](C)=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>>[ClH:1].[N:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][CH:8]2[NH:9][C:3](=[NH:2])[CH2:4][CH2:5][CH2:6][CH2:7]2)=[CH:13][CH:14]=1
Reactant: [Cl-]
Reactant: C[n+]1ccc(CCC2CCCCC(=N)N2)cc1
Agent: Cl
Product: N=C1CCCCC(CCc2ccncc2)N1

Procedure:
4-[2-(hexahydro-7-imino-1H-azepin-2-yl)ethyl]-1-methylpyridinium chloride, monohydrochloride salt;
Reaction SMILES: I[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[I:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[N:14]=[CH:13][C:12]=1[OH:19]>CC(C)=O>[CH2:2]([O:19][C:12]1[C:11]([I:10])=[CH:16][C:15]([O:17][CH3:18])=[N:14][CH:13]=1)[CH3:3]
Reactant: COc1cc(I)c(O)cn1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cnc(OC)cc1I
Temperature: 80 °C
Reaction time: 8 h

Procedure:
At 0° C., 304 mg (1.95 mmol, 1.3 eq.) of iodoethane and 415 mg (3.0 mmol, 2.0 eq.) of potassium carbonate were added to a solution of 405 mg (1.5 mmol) of 4-iodo-6-methoxypyridin-3-ol in 10 ml of acetone and the mixture was stirred at 80° C. overnight and concentrated under reduced pressure. The residue was triturated with water, filtered and dried under reduced pressure. Yield: 322 mg (purity 93%, 72% of theory)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:39][CH2:40][CH2:41][CH3:42])=[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[O:35][CH:36]=[CH:37][N:38]=4)[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)[Cl:44]>Cl.O1CCOCC1>[ClH:44].[ClH:44].[CH2:39]([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[O:35][CH:36]=[CH:37][N:38]=2)[CH:22]=1)[CH2:40][CH2:41][CH3:42]
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2ncco2)c1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(-c2ncco2)c1
Reaction time: 0.5 h

Procedure:
To a stirring solution of 4-[6-Butyl-5-(4-cyclohexyloxy-3-oxazol-2-yl-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.08 g, 0.13 mmol) in DCM, 2.0 mL of 4.0 M HCl in dioxane was added and stirring continued for 30 min. Solvent evaporated, resulting solid was washed with ether, dried to get 3-butyl-4-(4-cyclohexyloxy-3-oxazol-2-yl-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride salt (60 mg)
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[NH2:25][C@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[OH:32]>>[OH:32][C@H:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:26]1[NH:25][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: N[C@H]1CCCC[C@@H]1O
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N[C@H]2CCCC[C@@H]2O)cn1
Yield: 91 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using (1S,2S)-2-amino-cyclohexanol hydrochloride (1:1) instead of 2-aminoethyl isopropylether, to the title compound (240 mg, 91%) which was obtained as a white solid. MS: m/e=408.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH3:10][OH:11]>[Pd]>[CH3:9][C:4]1[N:1]=[CH:10][O:11][C:5]=1[C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:1]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CO
Agent: [Pd]
Product: Cc1ncoc1-c1cccc(N)c1
Reaction time: 20 h

Procedure:
A solution of the nitrobenzene adduct (50 g) produced in the previous step C in MeOH (600 mL) was prepared in parr-shaker bottle; Pd/C (5 g) was transferred carefully and hydrogenated at 3.5 kg pressure for 20 h. The reaction mixture was filtered over celite bed and the filtrate was concentrated. The residue was purified by silica gel column chromatograph using 40% EtOAc in pet.ether to get yellow color solid. Yield 18 g (42%). 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 7.08 (t, J=8.0 Hz, 1H), 6.82 (s, 1H), 6.71 (d, J=7.9 Hz, 1H), 6.52 (d, J=8.2 Hz, 1H), 5.24 (s, 2H), 2.29 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([N:16]3[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]3)=[O:12])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc3cc[nH]c3c2)CC1

Procedure:
Prepared from 1H-indole-6-carboxylic acid (4.0 g, 24.84 mmol, 1.0 eq) and tert-butyl piperazine-1-carboxylate (4.6 g, 24.84 mmol, 1.0 eq) in an analogous manner as described under procedure 1a). White solid. Yield: 5.0 g (61% of theory)