Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([O:24][CH3:25])[C@@H:19]4[OH:26])[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[Li+].[OH-].Cl.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([O:24][CH3:25])[C@@H:19]4[OH:26])[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CO[C@@H]1CCC[C@H](Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)[C@H]1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: CO[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)[C@H]1O
Temperature: 120 °C
Yield: 95.7 %

Procedure:
In a microwave vial was placed azaindole 51k (0.050 g; 0.092 mmol). To this was added 3 mL of THF and 0.9 mL of 0.8 M LiOH. The vial was sealed and heated to 120° C. for 15 minutes in the microwave. When the reaction is complete, it was neutralized with 9 equivalents of 1N HCl (0.704 mL), then aqueous saturated NaHCO3 solution was added and the organic phase was separated and loaded onto silica gel for purification and eluted w/2% MeOH to 12% gradient over 10 minutes (4 g column) to provide 34.5 mg (91%) desired product 831.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:22][C:23]2[N:24]=[C:25]([CH:36]=[O:37])[N:26]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:27]=2)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[C:17]([O:16][C:15](=[O:21])[N:14]([CH:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]1)[CH2:22][C:23]1[N:24]=[C:25]([CH2:36][OH:37])[N:26]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:27]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N(Cc1cn(COCC[Si](C)(C)C)c(C=O)n1)C1CCN(Cc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N(Cc1cn(COCC[Si](C)(C)C)c(CO)n1)C1CCN(Cc2ccccc2)CC1
Yield: 99.6 %

Procedure:
To a solution of tert-butyl (1-benzyl-4-piperidinyl)((2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)carbamate (1.3 g) obtained in Example 83d) in ethanol (10 ml) was added sodium borohydride (95 mg) at 0° C., and mixed at room temperature for 1 hour. Water (1 ml) was added thereto, the solvent was then distilled off under reduced pressure, and the residue was diluted with ethyl acetate and water. The organic layer was collected by separation, washed with saturated brine and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the title compound as a colorless oil (1.3 g, 98%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]3[C:17]=2[CH2:18][C:19](O)=[O:20])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:29][NH:30][CH3:31].C(N(CC)CC)C.[C:39]([OH:48])(=[O:47])[CH:40]([CH:42]([C:44]([OH:46])=[O:45])[OH:43])[OH:41]>C(Cl)Cl.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[N:11]([CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15]3)[C:17]=2[CH2:18][C:19]([N:30]([CH3:31])[CH3:29])=[O:20])=[CH:6][CH:7]=1.[CH:40]([OH:41])([C:39]([OH:48])=[O:47])[CH:42]([OH:43])[C:44]([OH:46])=[O:45]
Reactant: CNC
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)O)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)N(C)C)cc1
Temperature: 15 °C
Reaction time: 1 h
Yield: 117.2 %

Procedure:
A suspension of 2-(4-methylphenyl)-6-methylimidazo[1,2-a]-pyridine-3-acetic acid (59.2 g; 0.21 mols) in methylene chloride (820 mL) is added dropwise with oxalyl chloride (29.9 g; 0.23 mols) adjusting the addition according to the gas evolution and keeping the temperature below 35° C. The resulting suspension is added with 2-(4-methylphenyl)-6-methylimidazo[1,2-a]-pyridine-3-acetic acid (59.2 g; 0.21 mols) and oxalyl chloride (29.9 g; 0.23 mols) is added dropwise with the same procedure as in the previous step. The suspension is refluxed for 30 minutes, then cooled to 10÷15° C. and added with N,N-dimethylamine hydrochloride (98% titre, 41 g, 0.49 mols). Keeping the temperature below 15° C., triethylamine (167 g, 1.65 mols) is added dropwise. After one hour at room temperature, water is added (200 mL), the phases are separated and the lower organic phase is washed with a 5% sodium carbonate aqueous solution (200 mL) and subsequently with water (200 mL). The organic phase is concentrated to a residue, which is redissolved in methanol (1100 mL) under reflux, then added with natural tartaric acid (33.0 g, 0.22 mols). The resulting solution is slowly cooled to 0° C. and the precipitated solid is filtered under nitrogen and washed with cold methanol (2×50 mL). The humid solid is taken up in methanol (900 mL), refluxed until dissolution and added with active carbon (5 g). The hot clear solution is filtered, then slowly cooled to 0° C. and the precipitated solid is filtered under nitrogen, washed with cold methanol (2×50 mL) then dried at 50° C. under vacuum to yield Zolpidem tartrate (112.6 g, 100.8% titre, 99.85% HPLC purity, 70.1% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][N:25]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(OCCCN3CCNCC3)cc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(c2cccnc2)=C3c2cc(F)cc(F)c2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
To a 10 mL round-bottomed flask, 6-(3-(piperazin-1-yl)propoxy)-3-(3,5-difluorophenyl)-2-(pyridin-3-yl)-1H-inden-1-one (30 mg, 1.2 eq) obtained in Step 1 of Example 66 and CH2Cl2 (1 mL, 0.05M) were charged. Triethylamine (0.02 mL, 1.5 eq) was added and then the mixture was cooled to 0° C. and treated with a solution of methylsulfonyl chloride (6.2 mg, 0.05 mmol) in CH2Cl2 (1 mL) over 5 min. After being stirred for 3 h, the mixture was diluted with CH2Cl2 and washed with H2O and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH=9:1) and being purified by prep. HPLC (20% H2O/CH3CN) to provide the title compound (19.8 mg, 68%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:17][CH2:16][C:11]3([CH2:14][CH:13]([OH:15])[CH2:12]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCCC1>C(Cl)Cl.O>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:17][CH2:16][C:11]4([CH2:14][CH:13]([OH:15])[CH2:12]4)[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: OC1CC2(CCN(c3ccc(Br)cn3)CC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: OC1CC2(CCN(c3ccc(-c4ccc(F)cc4)cn3)CC2)C1
Yield: 70.3 %

Procedure:
The process is performed according to the procedure described in Example 2 (step 2.7.). Starting with 0.138 g (0.46 mmol) of 7-(5-bromopyridin-2-yl)-7-azaspiro[3.5]nonan-2-ol, obtained in step 10.1., 0.078 g (0.56 mmol) of 4-fluorophenylboronic acid, 0.454 g (1.39 mmol) of caesium carbonate suspended in 3 mL of a 9/1 mixture of tetrahydrofuran and water. 0.038 g (0.05 mmol) of PdCl2dppf.CH2Cl2 is then added. 0.101 g of pure product is thus obtained in the form of a grey powder.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:20][C:21]([C:23]2([NH:38]C(=O)OC(C)(C)C)[CH2:28][CH2:27][N:26]([C:29]3[C:30]4[CH:37]=[CH:36][NH:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:16][CH2:17][CH2:18][OH:19])=[CH:11][CH:10]=1>CO>[NH2:38][C:23]1([C:21]([NH:20][CH:15]([C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=2)[CH2:16][CH2:17][CH2:18][OH:19])=[O:22])[CH2:24][CH2:25][N:26]([C:29]2[C:30]3[CH:37]=[CH:36][NH:35][C:31]=3[N:32]=[CH:33][N:34]=2)[CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(CCCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: NC1(C(=O)NC(CCCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Reaction time: 1 h
Yield: 50.4 %

Procedure:
Trifluoroacetic acid (2 ml, 25.96 mmol) was added to tert-butyl 4-(1-(4-chlorophenyl)-4-hydroxybutylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 17) (140 mg, 0.26 mmol) at 20° C. and the resulting solution stirred for 1 hour. The solution was then diluted with methanol, applied to a 10 g SCX column and eluted with methanol followed by 2N NH3/MeOH. Fractions containing product were combined, concentrated by evaporation and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 μm silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)-4-hydroxybutyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (58.0 mg, 50.8%) as a colourless solid.
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([O:34][CH2:35][CH3:36])[C:29]([O:31]CC)=[O:30])=[CH:23][CH:22]=2)=[CH:14][CH:13]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>O.C1COCC1>[C:4]([O:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][O:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][CH:28]([O:34][CH2:35][CH3:36])[C:29]([OH:31])=[O:30])=[CH:25][CH:26]=2)=[CH:16][CH:17]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
Lithium hydroxide hydrate (77 mg; 1.85 mmole) in water (5.5 ml) was slowly added to a solution of ethyl 3-(4-[2-(4-tert-butoxycarbonylaminophenyl)ethoxy]phenyl}-2-ethoxypropanoate (0.77 g; 1.68 mmole) in THF (7.6 ml). After stirring at room temperature for 4 hours the reaction mixture was kept in a freezer for 4 days. THF was removed by evaporation in vacuo. More water was added and the mixture was acidified with hydrochloric acid to pH 1. The product was extracted with ethyl acetate, washed twice with water, dried (sodium sulfate), filtered and the solvent was evaporated in vacuo to give 0.712 g (98.7% yield) of the desired product.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=CN=[CH:4]1)=[O:2].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:31]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[N:30]=C(N)C=2)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CNC>CN1CCCC1=O.C1COCC1>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:31]([C:32]3[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)[N:30]=[C:12]([NH:8][C:1](=[O:2])[N:3]([CH3:4])[CH3:7])[CH:11]=2)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(-n2nc(N)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Agent: CNC
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(NC(=O)N(C)C)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
Carbonyldiimidazole (1.26 g) was added to a solution of 5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-3-amino-1H-pyrazole (2.4 g) in 1-methyl-2-pyrrolidinone (22 ml). After stirring at ambient temperature for 2 hour, 2M solution of dimethylamine in THF (7.4 ml) was added and the mixture was stirred ambient temperature for 2 hour. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt/n-hexane=80% to give N′-[5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N,N-dimethylurea (2.35 g) as amorphous powder.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][N:9]=[C:8]2[C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:20]1[CH:21]=[C:22]([C:26]2[N:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:28]=[CH:29][N:30]=2)[CH:23]=[CH:24][CH:25]=1.N1C=CC=CC=1C(O)=O.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.O.[Cu]I.CS(C)=O>[O:18]([C:24]1[CH:23]=[C:22]([C:26]2[N:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:28]=[CH:29][N:30]=2)[CH:21]=[CH:20][CH:25]=1)[C:14]1[CH:13]=[C:12]([C:8]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:11]=[CH:10][N:9]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Ic1cccc(-c2nccn2-c2ccccc2)c1
Reactant: Oc1cccc(-c2nccn2-c2ccccc2)c1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc(-n2ccnc2-c2cccc(Oc3cccc(-c4nccn4-c4ccccc4)c3)c2)cc1
Temperature: 200 °C
Yield: 43.1 %

Procedure:
To a 500 mL 3-neck round bottom flask was added 3-(1-phenyl-1H-imidazol-2-yl)phenol (3.05 g, 12.26 mmol), 2-(3-iodophenyl)-1-phenyl-1H-imidazole (4.67 g, 13.49 mmol), picolinic acid (2.27 g, 18.40 mmol), copper(I) iodide (0.70 g, 3.68 mmol), potassium phosphate tribasic monohydrate (9.88 g, 42.9 mmol), and 200 mL DMSO. Nitrogen was bubbled directly into the mixture and was heated to 200° C. for 3 h and then at 120° C. overnight under nitrogen. The cooled reaction mixture was diluted with ethyl acetate and water. The mixture was filtered through Celite® and the Celite® was washed with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, filtered, and evaporated. The residue was purified by column chromatography eluting with ethyl acetate to give pure product (2.4 g, 43%).
Reaction SMILES: [CH:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)=[CH:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+].OO>O1CCCC1.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>[CH:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17](/[CH:6]=[CH:1]/[CH2:2][CH2:3][CH3:4])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)=[CH:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCC=Cc1ccc(C#Cc2ccc(Br)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC=Cc1ccc(C#Cc2ccc(/C=C/CCC)cc2)cc1
Temperature: 25 °C
Yield: 169.6 %

Procedure:
In a four necked flask equipped with a stirrer, a reflux condenser and a thermometer which had been replaced by a nitrogen atmosphere, 1-[4-(1-pentenyl)phenyl]-2-(4-bromophenyl)acetylene (3.9 g, 12 mmol), tetrakis(triphenylphosphine)palladium (0.23 g, 0.2 mmol), sodium hydroxide (2.4 g, 60 mmol) and tetrahydrofuran (60 ml) were charged. Then, to the mixture, a solution of E-1-pentenylcatecholborane (20 mmol) in tetrahydrofuran (50 ml) was dropwise added at room temperature, followed by heat refluxing for 6 hours while stirring. After cooling the reaction mixture to room temperature, 10% aqueous solution of sodium hydroxide (5 ml) and 30% aqueous hydrogen peroxide (2 ml) were added to the mixture, followed by stirring for 1 hour. The mixture was extracted with ethyl ether. The organic layer was washed with saturated aqueous solution of sodium chloride (20 ml each) twice and dried over anhydrous magnesium sulfate. After evaporating the solvent off, the residue was purified by silica gel column chromatography to obtain 1-[4-(1-pentenyl)phenyl]-2-[4-(1-trans-pentenyl)phenyl]acetylene (3.2 g). Yield: 84%.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][O:7][CH:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1.Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>C(#N)C>[C:30]([O:29][C:27](=[O:28])[CH2:26][N:12]1[CH:13]=[CH:14][N:10]([CH2:9][CH:8]([O:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH2:11]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: Clc1ccc(COC(Cn2ccnc2)c2ccc(Cl)cc2Cl)cc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1C=CN(CC(OCc2ccc(Cl)cc2)c2ccc(Cl)cc2Cl)C1

Procedure:
1-[2-(4-chloro-benzyloxy)-2-(2,4-dichloro-phenyl)-ethyl]-1H-imidazole (1 g, 2.25 mmol) and tert-butyl bromoacetate (1 ml, 6.8 mmol) were dissolved in 15 ml acetonitrile and heated to reflux overnight. TLC showed full conversion of the starting material. The solvent was cooled, evaporated in vacuo, and the residual oil was dissolved in chloroform and triturated with ether. The product was identified by Maldi mass spectrometry, and used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:19])[C:6]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[NH:11][CH:10]=1)([CH3:8])[CH3:7].C[N:21](C=O)C>>[CH3:3][O:4][C:5](=[O:19])[C:6]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[N:11]([NH2:21])[CH:10]=1)([CH3:8])[CH3:7]
Reactant: CN(C)C=O
Reactant: COC(=O)C(C)(C)c1c[nH]c2ccc(F)cc12
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C(C)(C)c1cn(N)c2ccc(F)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of NaH (1.02 g, 25.5 mmol, 60% in mineral oil) in DMF (25 mL) at 0° C. is treated with 2-(5-fluoro-1H-indol-3-yl)-2-methyl-propionic acid methyl ester (400 mg, 1.7 mmol) and stirred at 0° C. for 0.5 h. The mixture is treated with HOSA (960 mg, 8.5 mmol) portion wise and warmed to rt over 2 h. The mixture is then poured over ice, filtered through a pad of Celite, and extracted with EtOAc (3×100 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo to afford 2-(1-amino-5-fluoro-1H-indol-3-yl)-2-methyl-propionic acid methyl ester, which is used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH2:7][CH2:6][C:5](=[O:8])[C:4]=1[O:9]C)[CH3:2].Cl>>[CH2:1]([C:3]1[CH2:7][CH2:6][C:5](=[O:8])[C:4]=1[OH:9])[CH3:2]
Reactant: CCC1=C(OC)C(=O)CC1
Agent: Cl
Product: CCC1=C(O)C(=O)CC1
Yield: 65.6 %

Procedure:
3.08 g (22 mmol) of 3-ethyl-2-methoxy-2-cyclopenten-1-one are held at reflux temperature for 5 hours with 30.80 g of 5N hydrochloric acid. After cooling the reaction mixture is extracted 3 times with 50 ml of CH2Cl2 each time. The combined organic phases are dried over magnesium sulphate and concentrated on a rotary evaporator. The crude product is bulb-tube distilled at 0.1 mbar/110° C. and gives 1.82 g (65.7%) of 3-ethyl-2-hydroxy-2-cyclopenten-1-one (melting point 39°-41° C.).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.O>C1COCC1>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([N:3]2[CH:7]=[CH:6][CH:5]=[CH:4]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cccc2)cc1
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To a suspension of 60% NaH (3.13 g) in THF (20 mL) was added dropwise a solution of pyrrole (5.00 g) in THF (20 mL). The mixture was stirred for 30 minutes, and thereto was added a solution of p-toluene sulfonylchloride (14.2 g) in THF (20 mL), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the organic layer was separated, dried, filtered, and concentrated. The residue was recrystallized from a mixed solvent of methanol and water (each 35 mL), and the resulting crystals were collected by filtration, and dried to give 1-p-toluenesulfonyl-1H-pyrrole (16.3 g, 99%).
Reaction SMILES: ClC(OCC)=O.[O:7]1[C:11]([C:12](O)=O)=[CH:10][CH:9]=[N:8]1.C(N(CC)CC)C.[NH2:22][C:23]1[C:31]([NH2:32])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>O1CCCC1>[O:7]1[C:11]([C:12]2[NH:22][C:23]3[C:24]([C:25]([NH2:27])=[O:26])=[CH:28][CH:29]=[CH:30][C:31]=3[N:32]=2)=[CH:10][CH:9]=[N:8]1
Reactant: NC(=O)c1cccc(N)c1N
Reactant: O=C(O)c1ccno1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)c1cccc2nc(-c3ccno3)[nH]c12
Temperature: -10 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
A solution of 0.81 g (7.5 mmol) of ethyl chloroformate in 5 ml of tetrahydrofuran was added dropwise to a solution of 0.85 g (7.5 mmol) of isoxazole-5-carboxylic acid and 3.79 g (37.5 mmol) of triethylamine in 50 ml of tetrahydrofuran at −10° C. After stirring at −10° C. for 1 hour, 1.68 g (7.5 mmol) of 2,3-diaminobenzamide were added. The reaction mixture was stirred at room temp. for 16 hours. The reaction mixture was then concentrated in vacuo. The residue was partitioned between methylene chloride and saturated sodium bicarbonate solution. The aqueous phase was extracted with methylene chloride. The combined organic phases were dried over magnesium sulfate. The residue obtained after concentration in vacuo was taken up in 10 ml of glacial acetic acid and stirred at 100° C. for 60 minutes. The reaction mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was taken up in isopropanol, and the precipitate produced with petroleum ether was filtered off, washed with petroleum ether and dried in vacuo at 35° C. 120 mg of yellow crystals were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[C:7](=[O:11])[NH:8]2)=[C:4](NC(=O)C)[CH:3]=1.Cl.[NH:18]([C:20]1[CH:31]=[CH:30][C:23]([CH2:24][S:25]([NH:28][CH3:29])(=[O:27])=[O:26])=[CH:22][CH:21]=1)[NH2:19]>>[OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[N:19][NH:18][C:20]3[CH:31]=[CH:30][C:23]([CH2:24][S:25](=[O:27])(=[O:26])[NH:28][CH3:29])=[CH:22][CH:21]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[NH:8][C:7](=[O:11])[CH3:6]
Reactant: CC(=O)Nc1cc(O)cc2c1C(=O)C(=O)N2
Reactant: CNS(=O)(=O)Cc1ccc(NN)cc1
Agent: Cl
Product: CNS(=O)(=O)Cc1ccc(NN=C2C(=O)Nc3cc(O)c(NC(C)=O)cc32)cc1
Yield: 4 %

Procedure:
Condensation of N-(6-hydroxy-2,3-dioxo-2,3-dihydro-1H-indol-4-yl)acetamide and 4-hydrazino-N-methyl-benzylsulfonamide hydrochloride according to Procedure G gave the title compound in 4% yield: 1H NMR (DMSO-d6): δ 2.04 (s, 3H), 2.51 (d, J=4.8 Hz, 3H), 4.24 (s, 2H), 6.45 (s, 1H), 6.84 (t, J=4.8 Hz), 1H), 7.30 (s, 4H), 7.82 (s, 1H), 9.12 (s, 1H), 10.20 (s, 1H), 10.77 (s, 1H), 12.50 (s, 1H); APCI−MS m/z 416 (M−H)−.