Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=[O:17])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.[Br:18]Br.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:18][CH:8]([C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:17])[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: BrBr
Reactant: CCOC(=O)CCCCC(=O)c1ccc(Cl)s1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CCCC(Br)C(=O)c1ccc(Cl)s1
Temperature: 25 °C
Yield: 118.8 %

Procedure:
Ethyl 6-(5-chloro-2-thienyl)-6-oxohexanoate (50.0 g) was dissolved in methylene chloride (150 ml), to which was added dropwise bromine (24.5 g) with stirring at room temperature. The mixture was stirred at room temperature for 1 hour, a 10% aqueous solution of sodium sulfite was then carefully added until disappearance of the red color of bromine, which was extracted with diethyl ether (200 ml×2). The organic layer was washed with a10% aqueous solution of sodium hydrogen carbonate (100 ml), dried over anhydrous magnesium sulfate, and concentrated to give ethyl 5-bromo-6-(5-chloro-2-thienyl)-6-oxohexanoate as an oil (64.4 g, >99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][N:23]=1>CCCCCC.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([C:13]([F:16])([F:15])[F:14])([OH:11])[CH2:12][NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][N:23]=2)[CH:7]=1
Reactant: Nc1nccc2ccccc12
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1nccc2ccccc12)C(F)(F)F
Yield: 21.9 %

Procedure:
Analogously to Example 1, 200 mg (0.68 mmol) of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-(trifluoromethyl)oxirane and 99 mg (0.68 mmol) of 1-aminoisoquinoline are reacted. After chromatography on silica gel with hexane-ethyl acetate (0–60%), 65 mg of product is obtained.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])([CH3:6])([CH3:5])[CH3:4].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>O1CCCC1>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9][C:8]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CBr
Reactant: COCCOc1cc(O)ccc1C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(C(C)(C)C)c(OCCOC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
To a tetrahydrofuran (THF) (10 ml) suspension of sodium hydride (60% in mineral oil) (68 mg, 1.7 mmol) was added a tetrahydrofuran (THF) solution (5 ml) of 4-tert-butyl-3-(2-methoxyethoxy)phenol (320 mg, 1.4 mmol) and the mixture was stirred for 30 minutes at ambient temperature. To the mixture was added ethyl bromoacetate (190 ul, 1.7 mmol) at ambient temperature. The stirred mixture was refluxed for 4 hours. The reaction mixture was then quenched with saturated aqueous solution of ammonium chloride and then crude products were extracted with ethyl acetate The organic layer was then washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with ethyl acetate/hexane=1/9 to furnish 0.26 g (60% yield) of the title compound as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:7]([NH2:16])=[N:6][CH:5]=1.N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>ClCCl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:7]([NH:16][C:24](=[O:26])[CH3:25])=[N:6][CH:5]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cnc(N)c(C#C[Si](C)(C)C)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cnc(NC(C)=O)c(C#C[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 6-amino-5-trimethylsilanylethynyl-nicotinic acid methyl ester (6.05 g, 24.4 mmol) and pyridine (4 mL, 49.4 mmol) in dichloromethane (80 mL) was added acetyl chloride (2.6 mL, 35.6 mmol) at 0° C. The mixture was allowed to warm up to 25° C. and stirred for 12 h. The reaction mixture was extracted with ethyl acetate, washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo to afford 6-acetylamino-5-trimethylsilanylethynyl nicotinic acid methyl ester which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21](=[S:23])[NH2:22])[NH:6]2.Br[CH:25]([CH:28]=O)[CH:26]=[O:27].CN(C)C(=O)C>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]1[S:23][C:25]([CH2:26][OH:27])=[CH:28][N:22]=1)[NH:6]2
Reactant: O=CC(Br)C=O
Reactant: CN(c1ccc(Cl)c2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(c1ccc(Cl)c2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 90 °C
Reaction time: 4 h
Yield: 51.6 %

Procedure:
A mixture of 4-chloro-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.51 g), bromomalonaldehyde (0.30 g) and N,N-dimethylacetamide (15 mL) was stirred at 90° C. for 4 hr. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. To a mixture of the obtained crystals, tetrahydrofuran (5 mL) and methanol (5 mL) was added sodium borohydride (55 mg) at 0° C., and the mixture was stirred at the same temperature for 1 hr. To the reaction mixture was added 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (0.30 g, yield 52%) was obtained as pale-yellow crystals from a fraction eluted with tetrahydrofuran-hexane (2:1, volume ratio). melting point 225-226° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=1>[Cu]>[CH3:8][C:9]1[CH:10]=[C:11]([N:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cccc(Nc2ccccc2)c1
Reactant: Ic1ccccc1
Agent: [Cu]
Product: Cc1cccc(N(c2ccccc2)c2ccccc2)c1
Yield: 75 %

Procedure:
The same equipment and conditions as in example I were employed with the following charge: 20.4 grams (0.1 mole) iodobenzene, 27.5 grams (0.15 mole) 3-methyldiphenylamine, 15.0 grams copper powder and 30.0 milliliters of Soltrol® 170. The above-identified intended product was obtained as colorless crystals having a melting point of 69°-70° C. Yield 75%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][C:28]#[N:29])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:30]=[N+:31]=[N-:32].[Na+].Cl>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][C:28]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCC#N)ccc23)CC1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCc4nnn[nH]4)ccc23)CC1
Temperature: 100 °C
Reaction time: 6.5 h
Yield: 44.8 %

Procedure:
A mixture of 4-[7-(3-Cyano-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (24.5 mg, 62 μmol), as prepared in the preceding step, NaN3 (13.4 mg, 206 μmol), TEA.HCl (25.5 mg, 185 μmol), and toluene (100 μL) was tightly capped and stirred at 100° C. for 6.5 hr. The reaction was then allowed to cool to rt, partitioned with EtOAc (1 mL) and 0.1 M HCl (1 mL). The aqueous layer was then extracted with EtOAc (2×1 mL), the organic layers were combined, dried (Na2SO4), and concentrated. The residue was purified via flash silica chromatography (3:2 EtOAc/acetone) to yield the title intermediate as an off-white solid (12.2 mg, 44%). LC/MS (ESI) calcd mass 439.2, found 440.1 (MH)+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:20])[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na]>CO>[C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]([OH:20])[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: [Na]
Solvent: CO
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)OCCC2O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
7-Benzenesulfonyl-chroman-4-one (500 mg, 1.73 mmol) was dissolved in 15 mL MeOH, and sodium borohidride (72 mg, 1.9 mmol) was added. The reaction mixture was stirred at room temperature for one hour, and was then partitioned between water and ethyl acetate. The combined organic layers were dried over MgSO4, and solvent was removed under reduced pressure to give 483 mg of crude 7-benzenesulfonyl-chroman-4-ol. MS: 291 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:6][C:5]2=[O:18].[Cl:19][C:20]1[C:21]([CH3:30])=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1>N1C=CC=CC=1>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[C:21]=3[CH3:30])(=[O:27])=[O:28])=[CH:10][CH:9]=2)[C:5](=[O:18])[NH:6]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc2c(c1)c(=O)[nH]n2Cc1ccccc1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc2c(c1)c(=O)[nH]n2Cc1ccccc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 21 %

Procedure:
To a solution of 5-amino-1-benzyl-1,2-dihydro-indazol-3-one (0.04 g) in pyridine (1 mL) was added 3-chloro-2-methylbenzenesulfonylchoride (0.038 g) in one go. The solution was stirred at 60° C. for 24 hours. The pyridine was then removed in vacuo and the residue was dissolved in EtOAc/water and separated. The aqueous phase was extracted a further two times with EtOAc and the combined organic phases were washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the volatiles were removed in vacuo to afford a crude residue. The crude material was purified via flash column chromatography eluting with EtOAc/nHeptane/1% AcOH) to afford the desired N-(1-benzyl-3-oxo-2,3-dihydro-1H-indazol-5-yl)-3-chloro-2-methyl-benzenesulfonamide (0.015 g) as a pale yellow powder. MS (ESI+): 428.4 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.Cl.[CH2:33]([N:35]=[C:36]=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CNC>O.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([N:35]([CH3:36])[CH3:33])=[O:20])[CH2:15][N:16]=1)=[CH:8]2
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)N(C)C)S3)[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.9 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (500 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (330 mg), 1-hydroxybenzotriazole (230 mg), dimethylamine (2M solution in tetrahydrofuran, 1.1 mL) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 95:5, volume ratio) to give pale yellow crystals. The crystals were recrystallized from acetone-methanol to give the title compound (370 mg, 69%) as pale yellow prisms. MS 489 (MH+). mp 206-207° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1.[CH:16](O)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[C:17]1([CH:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:15][CH2:14][CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCC1CCCNC1
Reactant: OC(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(C(OCC2CCCNC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.6 %

Procedure:
Trifluoroacetic acid (20 ml) was added cautiously to a vigorously stirred solution of piperidine-3-methanol (5.75 g, 50 mmol) in dichloromethane (20 ml) and the mixture treated with benzhydrol (9.2 g, 50 mmol) portionwise over 5 minutes, stirred at room temperature for 2 hours and evaporated. The residue was dissolved in dioxane (50 ml) and the solution treated with 4M aqueous sodium hydroxide solution (100 ml), stirred at room temperature for 2 hours, diluted with ether and water and the layers separated. The organic layer was washed with water and extracted into 2M hydrochloric acid. The acidic extract was washed with ether, basified with solid sodium carbonate, extracted into ether, washed with water, dried over magnesium sulphate and evaporated to give the title compound (4.31 g) as a pale yellow oil which was characterised by its 1H-NMR spectrum.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([NH:17][C:18]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[C:34]([Cl:39])[CH:35]=5)[CH:30]=4)(=[O:28])=[O:27])[CH2:22][CH2:21]3)=[O:19])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.[C:44](OCC)(=O)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([N:17]([CH3:44])[C:18]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[C:34]([Cl:39])[CH:35]=5)[CH:30]=4)(=[O:27])=[O:28])[CH2:22][CH2:21]3)=[O:19])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2sc(NC(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2C1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In N,N-dimethylformamide (10 ml), 1-[N-(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbamoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine (147 mg) was dissolved. To the resulting solution, sodium hydride (60% in oil, 22 mg) was added, followed by stirring at room temperature for 30 minutes. After methyl iodide (0.023 ml) was added to the reaction mixture and the resulting mixture was stirred at room temperature for 90 minutes, the residue obtained by the concentration of the reaction mixture under reduced pressure was added with ethyl acetate. The resulting mixture was washed with water and saturated aqueous NaCl solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=2:1), whereby the title compound (43 mg) was obtained.
Reaction SMILES: [CH:1]1([C:7]2[CH:30]=[CH:29][CH:28]=[CH:27][C:8]=2[O:9][C:10]2[CH:11]=[N:12][N:13]([CH:17]([CH2:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:18]([OH:20])=O)[C:14](=[O:16])[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:31][C:32]1[CH:36]=[CH:35][N:34]([CH2:37][C:38]([CH3:41])([OH:40])[CH3:39])[N:33]=1>>[CH:1]1([C:7]2[CH:30]=[CH:29][CH:28]=[CH:27][C:8]=2[O:9][C:10]2[CH:11]=[N:12][N:13]([CH:17]([CH2:21][CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[C:18]([NH:31][C:32]3[CH:36]=[CH:35][N:34]([CH2:37][C:38]([OH:40])([CH3:39])[CH3:41])[N:33]=3)=[O:20])[C:14](=[O:16])[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2C2CCCCC2)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3C3CCCCC3)cc2=O)n1
Yield: 62 %

Procedure:
Using the method described in Example 17, 2-[4-(2-cyclohexyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid (Intermediate 35) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-[4-(2-cyclohexyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (0.82 g, 62%); ES+-HRMS m/e calcd for C31H41N5O4 [M+H+] 548.3232 found 548.3233. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.09 (m, 1H), 1.17-1.84 (m, 18H), 1.94 (m, 1H), 2.27 (m, 1H), 2.61 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.47 (dd, J=4.1, J=10.7 Hz, 1H), 5.61 (d, J=2.7 Hz, 1H), 6.40 (d, J=2.1 Hz, 1H), 7.15-7.24 (m, 1H), 7.27-7.38 (m, 2H), 7.47 (dd, J=3.6, J=5.7 Hz, 1H), 7.52 (d, J=2.1 Hz, 1H), 8.18 (d, J=2.7 Hz, 1H), 10.79 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26]I>>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1F
Reactant: ClCCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: O=C(O)C(CCCCCl)c1ccccc1F
Yield: 89.6 %

Procedure:
Step AQ (1): 2-(2-Fluorophenyl)acetic acid (5 g, 32.4 mmol) was deprotonated with NaHMDS (2.0 M in THF, 32.4 mL, 64.9 mmol) and reacted with 1-chloro-4-iodobutane (3.97 mL, 32.4 mmol) using a procedure analogous to Step AC (1) to afford 6-chloro-2-(2-fluorophenyl)hexanoic acid (7.10 g, 89% yield). LC-MS (M−H)− 243.1. The crude product was used for subsequent chemistry without purification.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](CCN)=[CH:22][CH:21]=1.C(OCC)(=O)C>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])=[CH:22][CH:21]=1
Reactant: S=C(Nc1nc2ccccc2[nH]1)n1ccnc1
Reactant: COc1ccc(CCN)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CCNC(=S)Nc2nc3ccccc3[nH]2)cc1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
A solution of 1-[(2-benzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(4-methoxyphenyl)ethylamine (0.77 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was purified by chromatography on silica gel to provide 1.1 g (67%) of the titled product as a white solid:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[OH:21][CH2:22][CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][C:27](=[O:33])[NH:28]2>>[OH:21][CH2:22][CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[C:26](=[CH:19][C:3]1[NH:4][C:5]3[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]4[CH2:14][CH2:15][CH2:16][CH2:17]4)[C:7](=[O:18])[C:6]=3[C:2]=1[CH3:1])[C:27](=[O:33])[NH:28]2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Reactant: O=C1Cc2c(CCO)cccc2N1
Product: Cc1c(C=C2C(=O)Nc3cccc(CCO)c32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Yield: 30 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (prepared according to US2004186160) as starting materials to give 2-[4-(2-hydroxy-ethyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (30 mg, 30.0%) as a yellow solid.
Reaction SMILES: Br[C:2](=[CH:4][CH3:5])[CH3:3].[Li].C(O[C:10](=[O:16])[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])C.O>C(OCC)C>[OH:16][C:10]([CH2:11][CH2:12][N:13]([CH3:14])[CH3:15])([C:2]([CH3:3])=[CH:4][CH3:5])[C:4]([CH3:5])=[CH:2][CH3:3]
Reactant: CCOC(=O)CCN(C)C
Reactant: CC=C(C)Br
Agent: [Li]
Solvent: O
Solvent: CCOCC
Product: CC=C(C)C(O)(CCN(C)C)C(C)=CC

Procedure:
2-bromo-2-butene (108 g; 0.800 mol) was added to 10.0 g of lithium (1.43 mol) in diethyl ether (300 ml) in about 30 minutes with reflux. After stirring overnight (17 hours), ethyl-3-(N,N-dimethylamino)propionate (52.0 g; 0.359 mol) was added to the reaction mixture in about 15 minutes. After stirring for 30 minutes at room temperature 200 ml of water was added dropwise. After separation the water phase was extracted two times with 50 ml of CH2Cl2. The organic phase was reduced by evaporation and the residue was distilled at reduced pressure. The yield was 51.0 g (67%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][CH:8]=1.[C:17](Cl)(=[O:19])[CH3:18].Cl>C(Cl)Cl>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:8]=1[C:17](=[O:19])[CH3:18]
Reactant: COc1ccc(OC)c(OC)c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(OC)c(C(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 50 %

Procedure:
To methylene chloride, 47.5 g of aluminum chloride were added, followed by the addition of 30 g of 2,4,5-trimethoxybenzene and then 13 ml of acetyl chloride under ice cooling. The resulting mixture was stirred at room temperature for 6 hours. After the completion of the reaction, 1N hydrochloric acid was added to the reaction mixture under ice cooling. The resulting mixture was then extracted with methylene chloride. The extract so obtained was washed successively with 1N hydrochloric acid, a 1N aqueous solution of sodium hydrochloride and saturated saline and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The crude product so obtained was washed with ethanol, whereby 18.6 g of 2',4',5'-trimethoxyacetophenone were obtained (yield: 50%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[N:4]([CH2:6][C:7]#[C:8][CH2:9]N(CC)CC)[CH3:5].N#C[Br:18]>C(OCC)C>[Br:18][CH2:9][C:8]#[C:7][CH2:6][N:4]([CH3:5])[C:3](=[O:15])[O:2][CH3:1]
Reactant: N#CBr
Reactant: CCN(CC)CC#CCN(C)C(=O)OC
Solvent: CCOCC
Product: COC(=O)N(C)CC#CCBr
Reaction time: 12 h

Procedure:
A solution of methyl[4-(diethylamino)-2-butynyl]- methyl-carbamate (4.2 g, 0.02 mol) (Example 1i) in anhydrous diethyl ether (50 ml) is added dropwise at room temperature to a stirred solution of cyanogen bromide in anhydrous diethyl ether (40 ml). The mixture is allowed to stand for 12 hours and the diethyl ether layer is separated, washed with water (40 ml), dried over magnesium sulfate, and concentrated. The resulting oil is then purified by bulb to bulb distillation under high vacuum to give methyl N-(4-bromo-2-butynyl)-N-methylcarbamate as a ight yellow oil. Azetidine (2 g, 0.032 mol) is added to a stirred solution of methyl N-(4-bromo-2-butynyl)-N-methylcarbamate (3.6 g, 0.016 mol). The mixture is kept at room temperature for one hour and then filtered. The filtrate is concentrated and the resulting oil purified by bulb to bulb distillation under high vacuum to give a light yellow oil. NMR(CDCl3): 4.10 (brs, 2H); 3.7 (s, 3H); 3.39 (brs, 2H); 2.94 (s, 3H); 2.45 (brs, 4H).