Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:12]([C:21]2[CH:26]=[C:25]([C:27]3[N:28]=[N:29][NH:30][N:31]=3)[CH:24]=[CH:23][N:22]=2)[N:11]=[CH:10]1.Br[CH2:33][O:34][C:35](=[O:37])[CH3:36].CC([O-])(C)C.[K+].O>CN(C=O)C>[C:35]([O:34][CH2:33][N:29]1[N:30]=[N:31][C:27]([C:25]2[CH:24]=[CH:23][N:22]=[C:21]([C:12]3[N:11]=[CH:10][N:9]([CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:13]=3[C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[CH:26]=2)=[N:28]1)(=[O:37])[CH3:36]
Reactant: CC(=O)OCBr
Reactant: Fc1ccc(-c2c(-c3cc(-c4nn[nH]n4)ccn3)ncn2Cc2ccccc2Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCn1nnc(-c2ccnc(-c3ncn(Cc4ccccc4Cl)c3-c3ccc(F)cc3)c2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 8.3 %

Procedure:
To a solution of 2-[1-[(2-chlorophenyl)methyl]-5-(4-fluorophenyl)imidazol-4-yl]-4-(2H-tetrazol-5-yl)pyridine (50 mg, 0.12 mmol, Example 137) in DMF (5 mL) was added acetic acid bromomethyl ester (20 mg, 0.12 mmol), t-BuOK (27 mg, 0.24 mmol) and KI (40 mg, 0.24 mmol) at 0° C., then the mixture was stirred for 72 hr at rt, H2O was added, extracted with EA, dried, concentrated and purified by HPLC to give the title compound (5 mg, 8.6%). 1H NMR (300 MHz, CD3OD): δ 2.13 (3H, s), 5.38 (2H, s), 6.55 (2H, s), 6.97-6.98 (1H, m), 7.23-7.49 (7H, m), 7.85 (1H, s), 8.10 (1H, d, J=6.0 Hz), 8.28 (1H, m), 8.64 (1H, m). [M+H] Calc'd for C25H19ClFN7O2, 504. Found, 504.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[O:7][C:8]([C:12](=O)[CH2:13]Cl)=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2].[NH2:16][C:17]([NH2:19])=[S:18]>C(O)C>[C:1]([NH:4][CH2:5][C:6]1[O:7][C:8]([C:12]2[N:16]=[C:17]([NH2:19])[S:18][CH:13]=2)=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1oc(C(=O)CCl)cc1C
Reactant: NC(N)=S
Solvent: CCO
Product: CC(=O)NCc1oc(-c2csc(N)n2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
A suspension of 2-acetamidomethyl-5-chloroacetyl-3-methylfuran (24.8 g) and thiourea (8.2 g) in ethanol (250 ml) was stirred at room temperature for 2 hours. The resulting precipitate was collected by filtration and then dissolved in water (200 ml). The mixture was alkalized with an aqueous potassium carbonate solution. The resulting precipitate was collected by filtration to afford 4-(5-acetylaminomethyl-4-methylfuran-2-yl)-2-aminothiazole (16.7 g).
Reaction SMILES: C(O[K])(C)(C)C.[Cl:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([F:15])[C:9]=1[OH:16].[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24](F)[CH:25]=1)[C:21]#[N:22].C1OCCOCCOCCOCCOCCOC1>CS(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:16][C:9]2[C:10]([F:15])=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=2[Cl:7])[CH:25]=1)[C:21]#[N:22]
Reactant: N#Cc1cc(F)cc(Cl)c1
Reactant: Cc1ccc(F)c(O)c1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)O[K]
Solvent: CS(C)=O
Product: Cc1ccc(F)c(Oc2cc(Cl)cc(C#N)c2)c1Cl
Yield: 79.4 %

Procedure:
The title compound was prepared as described herein using tBuOK (4.00 ml, 4.00 mmol), 2-chloro-6-fluoro-3-methylphenol (642 mg, 4.00 mmol), 3-chloro-5-fluorobenzonitrile (622 mg, 4.00 mmol) and 18-crown-6 (211 mg, 0.800 mmol) in dimethyl sulfoxide (16 ml) to give the title compound as a white solid (0.94 g, 79%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.33 (1H, s) 7.12-7.19 (2H, m) 7.07 (1H, t, J=8.9 Hz) 6.98 (1H, s) 2.40 (3H, s). LCMS: m/z 294 (M−1).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])=[CH:19][C:18]=2[OH:29])=[O:16])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].Cl>CC(C)=O>[CH2:37]([O:36][C:34]([CH2:33][O:29][C:18]1[CH:19]=[C:20]([O:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][C:17]=1[C:15](=[O:16])[CH:14]=[CH:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:8][CH:9]=1)=[O:35])[CH3:38]
Reactant: CCOC(=O)CBr
Reactant: CCCCCCc1ccc(C=CC(=O)c2ccc(OCC=C(C)C)cc2O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCCCCc1ccc(C=CC(=O)c2ccc(OCC=C(C)C)cc2OCC(=O)OCC)cc1
Reaction time: 0.08 h
Yield: 85.4 %

Procedure:
To a solution of 5.50 g of 4-n-hexyl-2'-hydroxy-4'-(3-methyl-2-butenyloxy)chalcone in 55 ml of dry acetone was added 1.4 g of crushed potassium hydroxide. After stirring for 5 minutes, 2.40 g of ethyl bromoacetate was added, and the mixture was stirred at room temperature for 40 minutes. After completion of the reaction, the reaction mixture was neutralized by adding dropwise dilute hydrochloric acid with ice cooling. The precipitated solid was collected by filtration, washed with water, dried and recrystallized from ethanol to give 5.73 g of 2'-ethoxycarbonylmethoxy-4-n-hexyl-4'-(3-methyl-2-butenyloxy)chalcone as pale yellow needles.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:22]([C:23]([NH2:25])=[O:24])=[C:21]([NH:26][C:27]([N:29]4[CH2:33][CH2:32][CH2:31][C:30]4=[O:34])=[O:28])[S:20][N:19]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1.Cl.[OH-:36].[Na+]>>[NH2:25][C:23]([C:22]1[C:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[O:10])=[CH:13][CH:14]=2)=[N:19][S:20][C:21]=1[NH:26][C:27]([NH:29][CH2:33][CH2:32][CH2:31][C:30]([OH:34])=[O:36])=[O:28])=[O:24]
Reactant: Cc1ccc(NC(=O)Nc2ccc(-c3nsc(NC(=O)N4CCCC4=O)c3C(N)=O)cc2)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Cc1ccc(NC(=O)Nc2ccc(-c3nsc(NC(=O)NCCCC(=O)O)c3C(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[4-({[(4-methylphenyl)amino]carbonyl}amino)phenyl]-5-{[(2-oxopyrrolidin-1-yl)carbonyl]amino}isothiazole-4-carboxamide (11.8 g,) was added to 1 N sodium hydroxide (100 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for overnight (reaction mixture became clear solution). Reaction mixture acidified with 2 N HCl. The solid which formed was collected by filtration and washed with water then dried in vacuo to give the title compound as off white solid (9.1 g, 75%).
Reaction SMILES: [H-].[Na+].[CH2:3]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10][C:9]=2[CH2:8][CH2:7][CH2:6][S:5](=[O:19])(=[O:18])[CH2:4]1.[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24]Cl>CN(C)C=O>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][N:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[C:17]2[CH2:3][CH2:4][S:5](=[O:18])(=[O:19])[CH2:6][CH2:7][CH2:8][C:9]1=2
Reactant: O=S1(=O)CCCc2[nH]c3ccccc3c2CC1
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCn1c2c(c3ccccc31)CCS(=O)(=O)CCC2
Temperature: 90 °C

Procedure:
To a suspension of 2.1g (0.05 mole) of sodium hydride (57% dispersion in mineral oil) in 25 ml of dimethylformamide is added a solution of 12.47g (0.05 mole) of 1,2,4,5,6,7-hexahydrothiocino[5,4-b]indole 3,3-dioxide in 50 ml of dimethylformamide with stirring under nitrogen. The resulting mixture is stirred at 30°-35° C. for one hour. A solution of 6.03g (0.05 mole) of 3-dimethylaminopropyl chloride (freshly distilled) in 25 ml of dimethylformamide is added and the mixture is stirred at room temperature for one hour and then heated in a wax bath at 90° C. for five hours. The dimethylformamide is removed in vacuo. The residue is dissolved in 10% hydrochloric acid and extracted with ether. The aqueous layer is made basic with sodium hydroxide and extracted with ether. The ether layer is washed with water, dried over sodium sulfate and the solvent is removed. Recrystallization from isopropyl ether gives 10.7g (64%) of an analytical sample, m.p. 119°-120° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]2([CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]2)[NH:12][C:11](=[O:21])[C:10]=1[C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=1[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:32][CH:33]1[CH2:35][CH2:34]1.CC(C)([O-])C.[K+]>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:13]2([CH2:14][CH2:15][N:16]([O:19][CH3:20])[CH2:17][CH2:18]2)[N:12]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:11](=[O:21])[C:10]=1[C:22]1[C:23]([CH3:30])=[CH:24][C:25]([CH3:29])=[CH:26][C:27]=1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON1CCC2(CC1)NC(=O)C(c1c(C)cc(C)cc1C)=C2OCc1ccccc1
Reactant: BrCC1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CON1CCC2(CC1)C(OCc1ccccc1)=C(c1c(C)cc(C)cc1C)C(=O)N2CC1CC1
Temperature: 100 °C
Reaction time: 120 h
Yield: 30.9 %

Procedure:
To a solution of 4-benzyloxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound P3.4) (1.0 g, 2.46 mmol) in dioxane (40 ml) was added bromomethyl-cyclopropane (1.257 ml, 1.78 g, 13.16 mmol) and potassium tert-butoxide (1.50 g, 13.37 mmol). The reaction mixture was stirred at 100° C. for 5 days, then poured on water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated. The residue was suspended in ethyl acetate/heptane 1:5, stirred overnight, filtered and dried to afford a first crop of product as a white solid (350 mg). The mother liquor was concentrated, and the residue purified by chromatography on silica gel (dichloromethane/acetone 10:1) to further deliver 205 mg of product. Yield: 555 mg of 4-benzyloxy-1-cyclopropylmethyl-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound P3.8) as a solid, mp 119-121° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10]1=[O:18]>ClCCCl.O>[C:5]([C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[NH:9][C:10](=[O:18])[CH2:11]2)(=[O:7])[CH3:6]
Reactant: O=C1Cc2ccccc2N1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: CC(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
171 g (1.28 mol) aluminium chloride in 500 ml 1,2-dichloroethane are cooled in the ice bath. Then 78 g (1.1 mol) acetylchloride are added dropwise, so that the temperature does not exceed 10° C. After 1 h, 71.3 g (0.53 mol) 2-indolinone (1,3-dihydro-indol-2-one) are added in 4 batches and the temperature is kept at 10–12° C. The reaction mixture is left overnight to warm up slowly to ambient temperature. Then the solution is slowly added to 1 kg ice with vigorous stirring. The slurry is diluted with 1 l water and stirred for another 30 min. Then the precipitate is suction filtered.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1F)([O-:3])=[O:2].CO[C:16]1[C:21]([CH3:22])=[C:20]([CH3:23])[C:19](OC)=[CH:18][C:17]=1[OH:26]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[O:26][C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[C:21]([CH3:22])[CH:16]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc([N+](=O)[O-])c(F)c1
Reactant: COc1cc(O)c(OC)c(C)c1C
Product: Cc1ccc(Oc2cc([N+](=O)[O-])ccc2[N+](=O)[O-])cc1C

Procedure:
The process was carried out as described in point 5.4 above, using 0.293 g (1.575 mmol) of 2,5-dinitrofluorobenzene and 0.287 g (1.575 mmol) of 2,5-dimethoxy-3,4-dimethylphenol. The title product was obtained in the form of an orange solid (0.415 g, 76%) after column chromatography using, as eluent, an 85:15 mixture of light mineral spirit (60-80° C.):ethyl acetate.
Reaction SMILES: [CH2:1]([CH:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][NH:5][CH2:4]1)[CH3:2].[CH:15]([O:18][C:19]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][C:20]=1[C:21](O)=[O:22])([CH3:17])[CH3:16]>>[CH2:1]([CH:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][N:5]([C:21]([C:20]2[CH:24]=[C:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=[CH:27][C:19]=2[O:18][CH:15]([CH3:17])[CH3:16])=[O:22])[CH2:4]1)[CH3:2]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: CCC1CNCc2cc(OC)ccc21
Product: CCC1CN(C(=O)c2cc(S(C)(=O)=O)ccc2OC(C)C)Cc2cc(OC)ccc21

Procedure:
Prepared in analogy to example 1.1 from 4-ethyl-7-methoxy-1,2,3,4-tetrahydro-isoquinoline and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH:10]12[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[OH-].[Na+].C(=O)=O.CC(C)=O>O.CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:12]2[CH2:13][CH:14]3[CH2:17][CH2:18][CH:10]([CH2:16][CH2:15]3)[CH2:11]2)[N:7]=1
Reactant: C1CC2CCC1CNC2
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Clc1nc(Cl)nc(N2CC3CCC(CC3)C2)n1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
Two hundred and eighty grams (1.5 mole) of cyanuric chloride is dissolved in 1.4 l. of acetone, then 1.8 l. of water is added and the mixture cooled to -10° C. using a dry-ice/acetone bath. 130 g. (1.0 mole) of 3-azabicyclo[3.2.2]nonane slurried in 200 ml. of acetone is then added all at once and the reaction is allowed to stir at -10° C. for 15 minutes. 100 ml. of 10 N NaOH is then added all at once giving rise to a small exotherm. After cooling to -10° C. using the dry-ice/acetone bath, the reaction mixture is stirred without further cooling for 3.8 hours allowing the temperature to rise to about 20° C. Two liters of water is then added, the precipitate filtered off and then washed with water. The precipitate is then dissolved in chloroform, excess water separated, the chloroform solution dried over magnesium sulfate and filtered through Magnesol®. The Magnesol® is then washed with chloroform, solvent removed in vacuo and recrystallized from dichloromethane-hexanes giving 170 g. of needles, m.p. 153°-154° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[C:10](Cl)(=[O:14])[C:11]([CH3:13])=[CH2:12]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])=[CH:4][C:3]=1[CH3:9]
Reactant: C=C(C)C(=O)Cl
Reactant: Cc1cc(N)ccc1F
Product: C=C(C)C(=O)Nc1ccc(F)c(C)c1

Procedure:
N-(4-Fluoro-3-methylphenyl)-2-methylacrylamide was prepared as described in Example 1a starting from 4-fluoro-3-methylaniline and methacryloyl chloride. 1H NMR (400 MHz, DMSO-d6): 1.94 (3H, s), 2.21 (3H, s), 5.50 (1H, s), 5.78 (1H, s), 7.05-7.10 (1H, m), 7.48-7.51 (1H, m), 7.57-7.59 (1H, m), 9.75 (1H, s).
Reaction SMILES: [N+:1]([NH:4][C:5]([NH2:7])=[NH:6])([O-:3])=[O:2].[CH:8]([CH:10]([CH2:15][C:16]1[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=1)[C:11](OC)=O)=[O:9]>C(O)C>[CH3:21][N:19]1[CH:20]=[C:16]([CH2:15][C:10]2[C:8](=[O:9])[N:6]=[C:5]([NH:4][N+:1]([O-:3])=[O:2])[NH:7][CH:11]=2)[CH:17]=[N:18]1
Reactant: COC(=O)C(C=O)Cc1cnn(C)c1
Reactant: N=C(N)N[N+](=O)[O-]
Solvent: CCO
Product: Cn1cc(Cc2c[nH]c(N[N+](=O)[O-])nc2=O)cn1
Temperature: 70 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To the solution of N-nitroguanidine (912 mg, 8.76 mmol) in ethanol (50.0 mL) was added methyl 2-formyl-3-(1-methyl-1H-pyrazol-4-yl)propanoate (858 mg, 4.38 mmol). It was stirred at 70° C. overnight. After removing the solvent, 10 mL water was added. Then HCl (conc) was added to adjust pH˜3, and the solution was stirred at 0° C. for 1 h. The solid was collected after filtration. It was dried overnight at 50° C. to get the title compound as an off-white solid (674 mg, 61.5% yield). LCMS: rt=1.17 min, [M+H+]=251.1
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([S:27](=[O:32])(=[O:31])[N:28]([CH3:30])[CH3:29])=[CH:23][C:19]=1[C:20](O)=[O:21]>>[C:14]([C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:20]([C:19]3[CH:23]=[C:24]([S:27]([N:28]([CH3:30])[CH3:29])(=[O:32])=[O:31])[CH:25]=[CH:26][C:18]=3[Cl:17])=[O:21])[CH2:10][CH2:9]2)=[C:2]([F:1])[CH:3]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: CN(C)S(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(=O)(=O)N(C)C)ccc3Cl)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described for example K/step2 from 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone and 2-Chloro-5-dimethylsulfamoyl-benzoic acid (CAS: 37088-27-0; BE 620741) (64%, light yellow foam, MS (m/e): 468.1 (M+H+, 100%)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([CH2:21][O:22][NH2:23])=[CH:19][CH:18]=1)([O-:16])=[O:15].N1C=CC=CC=1>CCO>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22]/[N:23]=[C:10](/[C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([OH:1])[CH:3]=2)\[CH3:11])=[CH:24][CH:25]=1)([O-:16])=[O:15]
Reactant: COc1ccc(C(C)=O)cc1O
Reactant: NOCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: COc1ccc(/C(C)=N/OCc2ccc([N+](=O)[O-])cc2)cc1O
Yield: 89.6 %

Procedure:
A solution of ketone 12 (200 mg, 1.20 mmol) in EtOH (2.0 mL) was treated with compound 19 (0.27 g, 1.32 mmol) and pyridine (0.5 mL) and the resulting mixture heated at reflux for 3 h then cooled and the solvent evaporated under reduced pressure. The ensuing residue was partitioned between CH2Cl2 (10 mL) and H2O (10 mL). The separated aqueous fraction was extracted with CH2Cl2 (1×5.0 ml) and the combined organic fractions were dried (MgSO4) then filtered and concentrated under reduced pressure to give a light-yellow solid. Recrystallisation (isopropanol) of this material afforded the title compound CP30218 (340 mg, 89%) as pale-yellow crystals, m.p. 105.0-105.7° C.
Reaction SMILES: [CH3:1][CH:2]([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:3][CH3:4].C[O-].[Na+].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1.Cl>CO>[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:8][S:5]([CH:2]([CH2:3][CH3:4])[CH3:1])(=[O:7])=[O:6])=[O:21])=[CH:15][CH:14]=1
Reactant: CCC(C)S(N)(=O)=O
Reactant: O=C=Nc1ccc(F)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCC(C)S(=O)(=O)NC(=O)Nc1ccc(F)cc1

Procedure:
The general method of procedure B was followed with 2-butanesulfonamide (6.85 g), sodium methoxide (2.7 g), methanol (250 ml), and 4-fluorophenyl isocyanate (6.8 g) except 1N HCl was added to provide the free urea. The solid was recrystallized from benzene to provide 5.2 g of white powder with a melting point of 136-138° C.
Reaction SMILES: [CH3:1][N:2](C=O)C.Br[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH:20]([NH:22][C@@H:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[CH3:24])[CH3:21])=[N:14]2)=[CH:9][CH:8]=1>CCOC(C)=O.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-]#N.[Zn+2].[C-]#N>[Cl:31][C:27]1[CH:26]=[C:25]([C@H:23]([NH:22][CH:20]([C:15]2[CH:16]=[C:17]([O:18][CH3:19])[N:13]([C:10]3[CH:11]=[CH:12][C:7]([C:1]#[N:2])=[CH:8][CH:9]=3)[N:14]=2)[CH3:21])[CH3:24])[CH:30]=[CH:29][CH:28]=1
Reactant: COc1cc(C(C)N[C@H](C)c2cccc(Cl)c2)nn1-c1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1cc(C(C)N[C@H](C)c2cccc(Cl)c2)nn1-c1ccc(C#N)cc1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
A 20 mL vial was charged with Pd(PPh3)4 (0.159 g, 0.138 mmol), zinc cyanide (0.243 g, 2.07 mmol), 3 mL of DMF, and 1-[1-(4-bromophenyl)-5-methoxy-1H-pyrazol-3-yl]-N—[(1R)-1-(3-chlorophenyl)ethyl]ethanamine 85 (0.600 g, 1.38 mmol) as a >20:1 mixture of diastereomers. The reaction mixture was heated to 100° C. After 3 d, an additional 10 mol % of Pd(PPh3)4 and 2 equivalents of ZnCN2 were added. The reaction mixture was heated in a microwave to 180° C. for 15 min. The reaction mixture was cooled to room temperature, dissolved in EtOAc, washed with water and brine, dried, and concentrated. Purification by flash column chromatography on silica gel (2% MeOH in DCM) gave 443-(1-{[(1R)-1-(3-chlorophenyl)ethyl]amino}ethyl)-5-methoxy-1H-pyrazol-1-yl]benzonitrile 96 as a >20:1 mixture of diastereomers. Mass spectrum: calculated for C2H21ClN4O 380.1; found 381.2 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:17]=O.Cl>CO>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCOc1ccc(C=O)cc1OC
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: CO
Product: CCCCCCOc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1OC
Temperature: 25 °C
Yield: 54.6 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-methoxy-4-hexyloxybenzaldehyde 1.88 g were dissolved in methanol 60 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 2.5 hours. After the solution was cooled to room temperature, the precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.34 g.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+].OB(O)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1>C1(C)C=CC=CC=1.CO.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>[N+:21]([C:17]1[CH:16]=[C:15]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:20]=[CH:19][CH:18]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Brc1cccnc1
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: CO
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(-c2cccnc2)c1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a mixture of 3-bromopyridine (2.6 ml) and tetrakis(triphenylphosphine)palladium(0) (0.93 g) in toluene (50 ml) was added 2M aqueous solution of sodium bicarbonate (27 ml) and a solution of dihydroxy(3-nitrophenyl)borane (5.0 g) in methanol (12 ml). The mixture was stirred at 80° C. for 6 hours and cooled. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel (hexane-ethyl acetate (3:7)) to give 3-(3-nitrophenyl)pyridine (3.57 g).
Reaction SMILES: [O:1]=[C:2]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[C:3]([OH:5])=O.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2>>[O:1]=[C:2]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[C:3]([NH:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2)=[O:5]
Reactant: Cc1ccc(OC2CCN(C(=O)C(=O)O)CC2)cc1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Product: Cc1ccc(OC2CCN(C(=O)C(=O)Nc3ccc4c(c3)CC(=O)N4)CC2)cc1

Procedure:
The title compound is prepared from oxo-(4-p-tolyloxy-piperidin-1-yl)-acetic acid and 5-amino-1,3-dihydro-indol-2-one according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 176-178° C. (diethyl ether)