Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.Cl[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22]C)[N:7]=1.Cl.Cl.[CH3:26][N:27]1[CH2:32][CH2:31][CH2:30][CH:29]([NH2:33])[CH2:28]1.C(N(CC)CC)C>ClCCl.CN(C)C(=O)C>[CH3:26][N:27]1[CH2:32][CH2:31][CH2:30][CH:29]([NH:33][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])[N:7]=2)[CH2:28]1
Reactant: CN1CCCC(N)C1
Reactant: COc1ccccc1-c1nc(Cl)c2ccccc2n1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CN1CCCC(Nc2nc(-c3ccccc3O)nc3ccccc23)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
Boron tribromide (7.4 mL, 1 M solution in dichloromethane, 7.4 mmol) was added to a solution of 4-chloro-2-(2-methoxy-phenyl)-quinazoline (0.200 g, 0.739 mmol) in dichloromethane (5 mL) at 0° C. After 24 hours the solution was poured into ice-water (200 mL) and extracted with dichloromethane (2×100 mL). The organic layers were combined, washed with brine (100 mL), dried (MgSO4) and concentrated to give a yellow solid that was used immediately without further purification. Half of the material (0.370 mmol) was dissolved in N,N-dimethylacetamide and 1-methylpiperidine-3-amine dihydrochloride (0.083 g, 0.444 mmol) was added. Triethylamine (258 μL, 1.850 mmol) was added and the reaction was stirred for 1 hour. The mixture was concentrated and purified by ion exchange chromatography on SCX-2 Isolute acidic resin (2 g), eluting with methanol and then 1 M ammonia in methanol. The basic fractions were combined and purified by silica column chromatography, eluting with 10% methanol in dichloromethane, to give the title compound as a yellow solid (0.103 g, 83%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]3[C:33](=[O:34])[O:32][C:14]4=[N:15][C:16]([N:19]5[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]5)=[CH:17][CH:18]=[C:13]4[CH:12]=3)[N:10]=[C:4]2[CH:3]=1.[ClH:35]>C(Cl)Cl.O1CCOCC1>[ClH:35].[CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]3[C:33](=[O:34])[O:32][C:14]4=[N:15][C:16]([N:19]5[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]5)=[CH:17][CH:18]=[C:13]4[CH:12]=3)[N:10]=[C:4]2[CH:3]=1
Reactant: Cc1ccn2cc(-c3cc4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4oc3=O)nc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccn2cc(-c3cc4ccc(N5CCNCC5)nc4oc3=O)nc2c1
Reaction time: 16 h

Procedure:
To a suspension of t-butyl 4-(3-(7-methylimidazo[1,2-a]pyridin-2-yl)-2-oxo-2H-pyrano[2,3-b]pyridin-7-yl)piperazine-1-carboxylate (112 mg, 0.24 mmol) in CH2Cl2 (3 mL) was added 4N HCl in dioxane (1.5 mL). The mixture was stirred for 16 hours, and filtered. The solid was washed with ether and dried under nitrogen. 3-(7-methylimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-pyrano[2,3-b]pyridin-2-one hydrochloride was obtained quantitatively and used in the next step without further purification. MS m/z 362.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=O)=[C:11]3[N:10]=2)=[CH:4][CH:3]=1.[NH:20]1[CH2:26][C:24](=[O:25])[NH:23][C:21]1=[O:22].N1CCCCC1>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=[C:26]4[NH:20][C:21](=[O:22])[NH:23][C:24]4=[O:25])=[C:11]3[N:10]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1cnn2ccc(Nc3ccc(Cl)cc3)nc12
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cnn3ccc(Nc4ccc(Cl)cc4)nc23)N1
Temperature: 70 °C

Procedure:
To 5-(4-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (117 mg, 0.430 mmol) in EtOH was added hydantoin (43 mg, 0.430 mmol) and piperidine (43 μL, 0.430 mmol). The mixture was heated at 70° C. overnight. Solvent was removed under reduced pressure and the remaining solid was washed with EtOAc to yield 5-((5-(4-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=355)
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[O:4][CH2:3]1.C(N(CC)CC)C.Cl[C:22]1[N:27]=[C:26]([NH2:28])[C:25]([N+:29]([O-:31])=[O:30])=[CH:24][CH:23]=1>CS(C)=O>[CH3:1][C@H:2]1[CH2:3][O:4][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:6][N:7]1[C:22]1[N:27]=[C:26]([NH2:28])[C:25]([N+:29]([O-:31])=[O:30])=[CH:24][CH:23]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C[C@H]1COC(c2ccccn2)CN1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[C@H]1COC(c2ccccn2)CN1c1ccc([N+](=O)[O-])c(N)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.3 %

Procedure:
To a solution of (5S)-5-methyl-2-(pyridin-2-yl)morpholine (0.7 g, 3.93 mmol) in dimethylsulfoxide (20 mL) was added triethylamine (0.68 g, 7.86 mmol). After 10 min, 6-chloro-3-nitropyridin-2-amine (0.68 g, 3.93 mmol) was added. After 4 h at 110° C., the mixture was cooled to room temperature, and then was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (80% ethyl acetate in petroleum ether) to afford 6-((5S)-5-methyl-2-(pyridin-2-yl)morpholino)-3-nitropyridin-2-amine (0.5 g, 41%).
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][C:3]=1[S:13][CH3:14].C1C=C(Cl)C=C(C(OO)=[O:23])C=1>ClCCl>[CH3:14][S:13]([C:3]1[O:4][C:5]2[C:10]([C:11](=[O:12])[C:2]=1[CH3:1])=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1oc2ccccc2c(=O)c1C
Solvent: ClCCl
Product: Cc1c(S(C)=O)oc2ccccc2c1=O
Reaction time: 2 h
Yield: 82.8 %

Procedure:
To a solution containing 3-methyl-2-methylsulfanyl-chromen-4-one (1.95 g, 9.45 mmol) in dichloromethane (75 mL) at 0° C. was added mCPBA (2 g, 11.82 mmol). The reaction stirred for 2 hours. After consumption of the starting material, the reaction mixture was filtered and the resulting filtrate was washed with cold 5% sodium carbonate, water, and saturated sodium bisulfate. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the desired product as a light yellow solid (1.74 g, 83% yield), which was taken on to the next step without further purification. 1H NMR (600 MHz, DMSO-d6): δ 8.08 (dd, 1H, J=7.8, 1.2 Hz), 7.88 (m, 1H), 7.76 (d, 1H, J=7.8 Hz), 7.55 (m, 1H), 3.01 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:20]([F:23])([F:22])[F:21])[CH:9]=[C:10]([C:11]3[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=3)[C:4]=2[N:3]=1.[Br:24][C:25]1[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][C@H:32]2[CH3:37])=[N:27][CH:28]=[CH:29][CH:30]=1>>[Br:24][C:25]1[C:26]([N:31]2[CH2:36][CH2:35][N:34]([C:2]3[NH:3][C:4]4[C:10]([C:11]5[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=5)=[CH:9][C:8]([C:20]([F:23])([F:22])[F:21])=[CH:7][C:5]=4[N:6]=3)[CH2:33][C@H:32]2[CH3:37])=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(Cl)nc23)cc(F)c1F
Reactant: C[C@@H]1CNCCN1c1ncccc1Br
Product: C[C@@H]1CN(c2nc3cc(C(F)(F)F)cc(-c4cc(F)c(F)c(F)c4)c3[nH]2)CCN1c1ncccc1Br

Procedure:
The benzoimidazole from step (b) above (105 mg, 0.3 mmol) reacted with (2R)-1-(3-bromopyridin-2-yl)-2-methylpiperazine (77 mg, 0.3 mmol, Example 43a) under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 570 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.CN1CCOCC1.[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>C(#N)C>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:6]2[CH:15]=[CH:16][C:3]([CH2:2][NH:1][C:24](=[O:27])[CH2:25][CH3:26])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: NCc1ccc(Oc2ccc(O)cc2)cc1
Reactant: CCC(=O)Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CCC(=O)NCc1ccc(Oc2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4-(4-Aminomethyl-phenoxy)-phenol (0.10 g, 0.47 mmol), MMP-resin (polystyrene bound N-methylmorpholine-type base, 0.30 g, 1.04 mmol) and 1.9 mL of acetonitrile was treated with propionyl chloride (0.086 mL, 1.0 mmol) and shaken for 24 hours at room temperature. After filtration of the resin, the filtrate was diluted with 2 mL of methanol and was treated with 2 mL of 1M lithium hydroxide (LiOH) in water. The mixture was shaken for 24 hours at room temperature, treated with Amberlite IRP-64® resin until neutral, filtered and concentrated in vacuo, affording N-[4-(4-Hydroxy-phenoxy)-benzyl]-propionamide. MS (m/z): 272.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:35])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[CH:22]=[N:21][N:20]=[C:19]1[CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34].C(=O)(O)[O-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:35])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[C:19]([CH2:23][N:24]2[C:25](=[O:34])[C:26]3=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]3[C:28]2=[O:29])=[N:20][N:21]=[C:22]1[CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(c1ccccc1Cl)c1cc([N+](=O)[O-])ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(c1ccccc1Cl)c1cc([N+](=O)[O-])ccc1-n1c(CN2CCCC2)nnc1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 13, 2'-chloro-5-nitro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is reacted with the above suspension then neutralized with sodium bicarbonate to give 2'-chloro-5-nitro-2[3-(pyrrolidinomethyl)-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[C:6]([C:9]1[CH:10]=[CH:11][C:12](Br)=[N:13][CH:14]=1)(=[O:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:6]([C:9]1[CH:10]=[CH:11][C:12]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[N:13][CH:14]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)c1ccc(Br)nc1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(-n2cccn2)nc1
Temperature: 100 °C
Yield: 81.4 %

Procedure:
407.9 mg (corresponding to 5.99 mmol) of pyrazole was dissolved in 10 mL of dimethylformamide. Then, 400.0 mg (corresponding to 1.99 mmol) of 5-acetyl-2-bromopyridine and 827.9 mg (corresponding to 5.99 mmol) of potassium carbonate were added thereto. The resulting solution was heated at 100° C. for 5 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, supplemented with water, and extracted twice with dichloromethane. The combined dichloromethane layer was washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (elution solvent: dichloromethane/ethyl acetate=50/1), to obtain 304.0 mg (corresponding to 1.62 mmol) of 5-acetyl-2-(pyrazole-1-yl)pyridine (FIG. 5, step 1).
Reaction SMILES: [CH3:1][C:2](O)([C:5]([CH3:9])([CH3:8])[CH2:6][CH3:7])[CH:3]=[CH2:4].P(=O)(O)(O)O>>[C:5]([C:2]([CH:3]=[CH2:4])=[CH2:1])([CH2:6][CH3:7])([CH3:9])[CH3:8]
Reactant: C=CC(C)(O)C(C)(C)CC
Agent: O=P(O)(O)O
Product: C=CC(=C)C(C)(C)CC
Yield: 68.7 %

Procedure:
40 g of 3,4,4-trimethylhex-1-en-3-ol were added dropwise to a mixture of 200 g of polyethylene glycol and 3 g of phosphoric acid at from 285° C. to 290° C. in the course of 2 hours. The organic phase of the two-phase mixture discharged was analyzed by means of GC. 24 g (70%) of 2-tert-amylbutadiene were obtained. The organic phase was processed without purification.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:21])=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]([C@@H:13]1[CH2:15][C@@H:14]1[F:16])[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].C(OC([NH:29][C@H:30]1[C:34]2([CH2:36][CH2:35]2)[CH2:33][NH:32][CH2:31]1)=O)(C)(C)C>CS(C)=O>[NH2:29][C@H:30]1[C:34]2([CH2:36][CH2:35]2)[CH2:33][N:32]([C:11]2[CH:10]=[C:9]3[C:4]([C:5](=[O:20])[C:6]([C:17]([OH:19])=[O:18])=[CH:7][N:8]3[C@@H:13]3[CH2:15][C@@H:14]3[F:16])=[C:3]([CH3:21])[C:2]=2[F:1])[CH2:31]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNCC12CC2
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Solvent: CS(C)=O
Product: Cc1c(F)c(N2C[C@@H](N)C3(CC3)C2)cc2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Temperature: 100 °C
Yield: 46.6 %

Procedure:
A mixture of 200 mg of 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 287 mg of 7-(S)-t-butoxycarbonylamino-5-azaspiro[2.4]heptane, and 5 ml of anhydrous dimethyl sulfoxide was heated at 100° C. for 30 minutes with stirring. After allowing to cool, the reaction mixture was concentrated under reduced pressure, and water was added to the residue. The precipitated yellow crystals were collected by filtration and added to 5 ml of trifluoroacetic acid while stirring and cooling with ice, followed by stirring at room temperature for 30 minutes. The reaction mixture was further worked up in the same manner as in Example 7. Recrystallization of the crude crystal from ethanol gave 122 mg of the titled compound as a pale yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[CH:15][S:16][C:10]=2[CH:9]1[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[O:24][CH2:25]C=C)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1C(=O)CC(=O)N(C)C1=O.C1(O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].BrC[C:54]([O:56][CH2:57][CH3:58])=[O:55]>CO.CN(C=O)C.CCOC(C)=O.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[CH:15][S:16][C:10]=2[CH:9]1[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[O:24][CH2:25][C:54]([O:56][CH2:57][CH3:58])=[O:55])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=CCOc1ccc(F)cc1C1c2scnc2CCN1C(=O)OC(C)(C)C
Reactant: CCOC(=O)CBr
Agent: [Pd]
Agent: CN1C(=O)CC(=O)N(C)C1=O
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: Oc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(F)cc1C1c2scnc2CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture under N2 of (±)-4-(2-allyloxy-5-fluoro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester (261 mg, 0.61 mmol, 1.00 eq.), 1,3-dimethylbarbituric acid (191 mg, 1.21 mmol, 2.00 eq.) and tetrakis(triphenylphosphine) palladium (0) (35 mg, 30 μmol, 0.05 eq.) in MeOH (12 mL) was stirred at r.t. for 18 hours. The mixture was partitioned between AcOEt (55 mL) and water (55 mL). The layers were separated and the aq. phase was extracted with AcOEt (2×55 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×55 mL), dried over MgSO4, and concentrated in vacuo. To a solution of the resulting crude phenol and potassium carbonate (252 mg, 1.82 mmol, 3.00 eq.) in DMF (2.1 mL), ethyl bromoacetate (0.1 mL, 0.91 mmol, 1.50 eq.) was added. The mixture was stirred at r.t. for 18 hours. Ethyl bromoacetate (50 μL, 0.46 mmol, 1.33 eq.) was added again and the mixture was stirred at r.t. for 7 hours. LC/MS still showed starting material. Ethyl bromoacetate (67 μL, 0.61 mmol, 1.00 eq.) and potassium carbonate (126 mg, 0.91 mmol, 1.50 eq.) were added again and the mixture was stirred at r.t. for 18 hours. The reaction mixture was diluted with AcOEt and water. The layers were separated and the aq. phase was extracted with AcOEt (2×). The comb. org. extracts were washed with water and sat. aq. NaCl soln., dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 50 g, flow: 30 mL/min, 50 fractions of 30 mL, Heptane to Heptane+40% AcOEt) to yield the title compound as an orange oil.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[C:18]([CH3:37])=[N:19][C:20]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)=[CH:21][C:22]=3[C:23]([F:26])([F:25])[F:24])[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[CH3:37][C:18]1[C:17]([CH2:16][O:15][C:12]2[CH:13]=[C:14]3[C:9]([CH:8]=[CH:7][N:6]3[CH2:5][C:4]([OH:38])=[O:3])=[CH:10][CH:11]=2)=[C:22]([C:23]([F:24])([F:25])[F:26])[CH:21]=[C:20]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:31][CH:32]=2)[N:19]=1
Reactant: CCOC(=O)Cn1ccc2ccc(OCc3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc3C)cc21
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)c1COc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 5 g], {6-[2-methyl-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain the title compound as colorless solid.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13]C)=[C:9]2[C:4]=1[N:5]=[CH:6][CH:7]=[N:8]2.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[OH:13][C:10]1[CH:11]=[CH:12][C:3]([OH:2])=[C:4]2[C:9]=1[N:8]=[CH:7][CH:6]=[N:5]2
Reactant: COc1ccc(OC)c2nccnc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Oc1ccc(O)c2nccnc12
Temperature: 25 °C
Yield: 70.5 %

Procedure:
4 g (0.021 mol) of 5,8-dimethoxyquinoxaline was refluxed for 2 hours under heating in 50 ml of benzene together with 20 g of aluminum chloride. After allowing to cool to room temperature, the reaction solution was extracted with ethyl acetate, and the extract was dried and concentrated. Recrystallization of the residue from ethyl acetate gave 2.4 g (71%) of the end product. m.p. 234°-236° C.
Reaction SMILES: [N+:1]([C:4]1[CH:45]=[CH:44][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[N+:53]([C:56]1[CH:66]=[CH:65][C:59]([CH2:60][O:61][C:62](Cl)=[O:63])=[CH:58][CH:57]=1)([O-:55])=[O:54]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:14][C@H:13]2[CH2:37][N:38]2[CH2:43][CH2:42][N:41]([C:62]([O:61][CH2:60][C:59]3[CH:58]=[CH:57][C:56]([N+:53]([O-:55])=[O:54])=[CH:66][CH:65]=3)=[O:63])[CH2:40][CH2:39]2)=[O:11])=[CH:44][CH:45]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCN(C[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a solution of (2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-(piperazin-1-yl)methyl-4-(triphenylmethylthio)-pyrrolidine (2.51 g) and triethylamine (0.73 ml) in dichloromethane (25 ml) was added 4-nitrobenzyloxycarbonyl chloride (0.91 g) under ice-cooling and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (20:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-[4-(4-nitrobenzyloxycarbonyl)-piperazin-1-yl]methyl-4-(triphenylmethylthio)pyrrolidine (2.77 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=O)=[O:7].[C:17]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33][NH2:34])[CH2:29][CH2:28]1)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.C(Cl)(Cl)Cl>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:9]=[C:10]([C:11]([NH:34][CH2:33][CH:30]2[CH2:31][CH2:32][N:27]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:28][CH2:29]2)=[O:13])[CH:14]=[CH:15][CH:16]=1)=[O:7]
Reactant: O=C(O)c1cccc(C(=O)CCCCO)c1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(CCCCO)c1cccc(C(=O)NCC2CCN(C(=O)OCc3ccccc3)CC2)c1
Reaction time: 16 h

Procedure:
A solution of 8-2 (0.44 g, 2 mmoles) in DMF (25 ml) was treated with N-(CBZ-4-piperidinyl)methyl amine (0.53 g, 2 mmoles) (8-3), HOBT (0.3 g, 2.2 mmoles) EDC (0.44 g, 2.3 mmoles) followed by NMM (0.4 g, 4 mmoles) and the resulting solution was stirred for 16 hours. The solvent was removed and the residue was taken up in H2O and extracted with EtOAc. The organic extract was washed with 10% KHSO4 solution, brine, saturated NaHCO3 solution, brine and dried (Na2SO4). Solvent removal gave a residue that was purified by flash chromatography on silica gel eluting with CHCl3 (97)/MeOH(3) to give pure 8-4. Rf 0.35 (silica, CHCl3 (95)/MeOH(5). ##STR55##
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH2:8][Cl:9])=[O:7])(=[O:3])[CH3:2].C[Si](C)(C)[O:12][CH2:13][CH2:14]O[Si](C)(C)C.C(=O)=O.CC(C)=O>C(Cl)Cl.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>[C:1]([O:4][CH2:5][C:6]1([CH2:8][Cl:9])[O:12][CH2:13][CH2:14][O:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)CCl
Reactant: C[Si](C)(C)OCCO[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(=O)OCC1(CCl)OCCO1
Temperature: 25 °C
Reaction time: 120 h
Yield: 73.6 %

Procedure:
A solution of 1-acetoxy-3-chloroacetone (20.0 g, 133 mmol, TCI America) and 1,2-bis(trimethylsilyloxy)ethane (30.2 g, 146 mmol, Aldrich) in anhydrous CH2Cl2 and under N2 atmosphere was cooled (−78° C., dry ice/acetone) and trimethylsilyl trifluoromethanesulfonate (1.2 mL, 6.6 mmol, Aldrich) was added. The reaction was warmed to room temperature and stirred for 5 days, with monitoring by 1H-NMR. The crude reaction solution was separated by silica gel column, and eluted with CH2Cl2, then 5% Et2O in CH2Cl2. Product fractions were pooled and concentrated in-vacuo giving the title compound (19.05 g) as a yellow oil, contaminated with 1-acetoxy-3-chloroacetone (2.93 g) and CH2Cl2 (1.0 g): 1H NMR (500 MHz, CDCl3) δ ppm 4.17 (2H, s), 4.03-4.11 (4H, m), 3.60 (2H, s), 2.09 (3H, s).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][O:8][CH2:9][C:10]([CH3:14])([OH:13])[C:11]#[CH:12].CI>O1CCCC1.CCOCC.O>[CH3:1][O:13][C:10]([CH3:14])([CH2:9][O:8][CH3:7])[C:11]#[CH:12]
Reactant: C#CC(C)(O)COC
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: C#CC(C)(COC)OC
Reaction time: 0.5 h

Procedure:
17.5 ml of the 1.0M solution of potassium tert-butoxide in tetrahydrofuran (Aldrich; 17.52 mmol) are added to a solution, cooled with an ice bath, of 2 g of (±)-1-methoxy-2-methyl-3-butyn-2-ol (17.52 mmol) in 6 ml of tetrahydrofuran. Stirring is carried out at ambient temperature for 30 minutes and then 0.55 ml of methyl iodide (35.04 mmol) is added. The reaction mixture is stirred at ambient temperature for 3 hours and then is diluted with ether and water. After separation by settling, the organic phase is washed with water, dried over sodium sulfate, filtered and concentrated under limited vacuum. 2.4 g of the expected product are obtained in the form of a yellow oil comprising residual ether and residual tetrahydrofuran. The (±)-3,4-dimethoxy-3-methylbut-1-yne obtained is used in the following stage without subsequent purification.
Reaction SMILES: C([O-])(O)=O.[Na+].[Br:6][C:7]1[CH:23]=[CH:22][C:10]2[NH:11][C:12](=[O:21])[CH2:13][C:14](=[CH:17]N(C)C)[C:15](=O)[C:9]=2[CH:8]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([NH:34][C:35]([NH2:37])=[NH:36])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]>>[Br:6][C:7]1[CH:23]=[CH:22][C:10]2[NH:11][C:12](=[O:21])[CH2:13][C:14]3[CH:17]=[N:37][C:35]([NH:34][C:28]4[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[CH:27]=4)=[N:36][C:15]=3[C:9]=2[CH:8]=1
Reactant: COc1ccc(NC(=N)N)cc1OC
Reactant: CN(C)C=C1CC(=O)Nc2ccc(Br)cc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(Nc2ncc3c(n2)-c2cc(Br)ccc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to method I (NaHCO3 used instead of K2CO3), 7-bromo-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-k) and 1-(3,4-dimethoxyphenyl)-guanidine were converted to I-18 (74%): HRMS Calcd. for C20H17BrN4O3: 441.0562, Found 441.0548.