Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CI.[Mg].[Mg].CI.[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][C:33](Cl)=[O:34])[CH2:28][CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CCOCC.C1(C)C=CC=CC=1>[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][C:33]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:34])[CH2:28][CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: c1ccc2[nH]ccc2c1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CI
Product: O=C(CC1CCN(C(=O)OCc2ccccc2)CC1)c1c[nH]c2ccccc12
Temperature: 0 °C
Yield: 55.8 %

Procedure:
17.6 g of indole in solution in 100 ml of ether were added to a magnesium methyl iodide solution prepared from 6.5 g magnesium and 38.6 g methyl iodide in 150 ml ethyl ether. Heating under reflux took place for 2 hours and the solution was cooled to 0° C. before adding, drop by drop while stirring, a solution of 36.3 g of 1-benzyloxycarbonyl-4-piperidyl-acetyl chloride (U.S. Pat. No. 4,064,255) in 300 ml toluene. The solution was stirred for 2 hours at 10° C. and then hydrolyzed with 170 ml of 2 N hydrochloric acid. 25.8 g of 2-(1-benzyloxycarbonyl-4-piperidyl)-1-(3-indolyl)- ethanone melting at 122° C. were obtained and then converted into a tosylated derivative by the action of 15.7 g of tosyl chloride in the presence of 27.8 g potassium carbonate in 400 ml of acetone. 34.5 g of 2-(1-benzyloxycarbonyl- 4-piperidyl)-1-(1-p-toluenesulfonyloxy-3-indolyl)-ethanone were obtained and put into suspension in 600 ml ethyl ether. This suspension was added, little by little, to a magnesium methyl iodide solution prepared from 3.1 g of magnesium and 18.5 g of methyl iodide in 200 ml of ethyl ether. The mixture was stirred over night at the ambient temperature and hydrolyzed at about 5° C. with 650 ml of a 20% by weight aqueous solution of ammonium acetate. 35.5 g of 1-(1-benzyloxycarbonyl-4-piperidyl)-2-(1-tosyl-3-indolyl)-2-propanol were obtained. The piperidine protective group was then eliminated by the action of cyclohexene in the presence of aluminum chloride and 10% palladized carbon; the reagents were added at or near 0° C. in an inert atmosphere. The process was completed by heating under reflux for 4 hours. After filtration, concentration under vacuum and purification by silica gel chromatography (eluant: toluene-ethanol-diethylamine=5-5-1), 10 g of 1-(4-piperidyl)-2-(1-p-toluenesulfonyloxy-3-indolyl)-2-propanol were obtained which were used as such for the preparation of 3-[2-(4-piperidyl)-1-methyl-ethyl]-indole.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17](Cl)(=[O:19])=[O:18])[CH:8]=2)[N:3]=1.[Cl:21][C:22]1[CH:41]=[CH:40][CH:39]=[CH:38][C:23]=1[CH2:24][NH:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([O:34][CH2:35][O:36][CH3:37])[CH2:30][CH2:29]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17]([N:25]([CH2:24][C:23]3[CH:38]=[CH:39][CH:40]=[CH:41][C:22]=3[Cl:21])[CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH:31]([O:34][CH2:35][O:36][CH3:37])[CH2:30][CH2:29]3)(=[O:19])=[O:18])[CH:8]=2)[N:3]=1
Reactant: O=S(=O)(Cl)CCCCOc1ccc2nc(Cl)ccc2c1
Reactant: COCOC1CCN(CCNCc2ccccc2Cl)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOC1CCN(CCN(Cc2ccccc2Cl)S(=O)(=O)CCCCOc2ccc3nc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.2 %

Procedure:
1.75 g of 4-(2-chloro-6-quinolyloxy)butylsulfonyl chloride was added, at 0° C., to a solution of 1.6 g of 1-[2-(2-chlorobenzylamino)ethyl]-4-methoxymethoxypiperidine and 1 ml of triethylamine in 25 ml dichloromethane. The mixture was stirred at room temperature for 1 day. The reaction mixture was washed with water and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was purified by a silica gel column chromatography (eluant: 3% methanol/dichloromethane) to obtain 2.63 g of 2-chloro-6-[4-{N-(2-chlorobenzyl)-N-[2-(4-methoxymethoxy-1-piperidinyl)ethyl]aminosulfonyl}butoxy]quinoline.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=O)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[S:33])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(-c2ccc(N3CCCC3=O)cc2C)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc(N3CCCC3=S)cc2C)cc1
Temperature: 75 °C
Yield: 121.4 %

Procedure:
Methyl 2'-methyl-4'-(2-oxo-1-pyrrolidinyl)biphenyl-4-carboxylate (D4, 200 mg, 0.647 mmol) was dissolved in toluene (25 ml) and Lawesson's reagent (130 mg, 0.324 mmol) was added. The solution was heated at 75° C. under argon for 1.5 hrs, then concentrated in vacuo. The resultant pale yellow solid was filtered through a neutral alumina column eluting with ether to remove excess Lawesson's reagent, then purified by column chromatography on silica gel eluting with ether to afford the title compound as a yellow solid (128 mg, 61%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:16]([O:18]C)=[O:17])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.CO.[Li+].[OH-]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:16]([OH:18])=[O:17])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: COCCNc1cc(C(=O)OC)c2ccccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCCNc1cc(C(=O)O)c2ccccc2c1

Procedure:
Methyl 3-{[2-(methyloxy)ethyl]amino}-1-naphthalenecarboxylate (1 eq.) from the previous step was taken up in a 2:1 (v/v) mixture of MeOH:THF (0.08 M). To this solution was then added LiOH (1.0 M aq. solution, 3.4 eq.) and the resulting cloudy solution was vigorously stirred at RT for 16 h. The volatiles were then removed in vacuo and the pH of the residue was carefully adjusted to ˜2 with 1 N aq. HCl before it was extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a yellow solid.
Reaction SMILES: [N:1]1([CH2:6]/[CH:7]=[CH:8]/[CH2:9][NH2:10])[CH:5]=[CH:4][N:3]=[CH:2]1.[IH:11].CS[C:14]1[C:22]2[CH:23]=[CH:24][CH:25]=[C:20]3[C:21]=2[C:16](=[CH:17][CH:18]=[CH:19]3)[N:15]=1>C(O)C>[IH:11].[N:1]1([CH2:6]/[CH:7]=[CH:8]/[CH2:9][NH:10][C:14]2[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]4[C:21]=3[C:16](=[CH:17][CH:18]=[CH:19]4)[N:15]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CSC1=Nc2cccc3cccc1c23
Reactant: NC/C=C/Cn1ccnc1
Agent: I
Solvent: CCO
Product: C(=C/Cn1ccnc1)\CNC1=Nc2cccc3cccc1c23
Temperature: -10 °C
Yield: 63.6 %

Procedure:
A mixture of 5.0 g of (E)-4-(1H-imidazol-1-yl)-2-butenamine, 11.5 g of 2-(methylthio)benz[cd]indole hydroiodide and 400 ml of ethanol was stirred and heated at reflux for 16 hours, then clarified while hot. The filtrate was concentrated to 250 ml, cooled to -10° C. and the resulting solid collected, washed with ethanol, ether and dried at 60° C. in vacuo, giving 9.3 g of the desired product, mp 152°-155° C. (dec.).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](S(C)=O)[CH:9]=[C:8]([CH3:18])[N:7]=1.[H-].[Na+].[F:21][C:22]([F:26])([F:25])[CH2:23][OH:24]>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([O:24][CH2:23][C:22]([F:26])([F:25])[F:21])[CH:9]=[C:8]([CH3:18])[N:7]=1
Reactant: OCC(F)(F)F
Reactant: COCCOc1nc(C)cc(S(C)=O)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Product: COCCOc1nc(C)cc(OCC(F)(F)F)c1[N+](=O)[O-]

Procedure:
2-[(2-Methoxyethyl)oxy]-6-methyl-4-methylsulfinyl-3-nitropyridine (1.73 g, 6.31 mmol) was dissolved in 2,2,2-trifluoroethanol (15 mL). Sodium hydride (55% in oil, 600 mg, 13.75 mmol) was added to the solution, followed by refluxing for one hour. The resultant solution was allowed to stand for cooling. Subsequently, the solution was extracted with chloroform-water. The organic layer was washed with saturated brine, followed by drying over sodium sulfate anhydrate and concentration under reduced pressure. The obtained residue was purified through silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1→n-hexane/ethyl acetate=3/1), to thereby yield 2-[(2-methoxyethyl)oxy]-6-methyl-3-nitro-4-[(2,2,2-trifluoroethyl)oxy]pyridine as a pale yellow solid (1.77 g, 91%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.[O:13]=[C:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][N:20]=2)[N:15]1[CH2:24][C:25](O)=[O:26]>>[Br:1][C:2]1[C:3]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[C:4]([NH:7][C:25](=[O:26])[CH2:24][N:15]2[C:16]3[C:21](=[N:20][CH:19]=[CH:18][CH:17]=3)[CH2:22][CH2:23][C:14]2=[O:13])[S:5][CH:6]=1
Reactant: Nc1scc(Br)c1-c1nccs1
Reactant: O=C(O)CN1C(=O)CCc2ncccc21
Product: O=C(CN1C(=O)CCc2ncccc21)Nc1scc(Br)c1-c1nccs1
Yield: 15.3 %

Procedure:
The title compound was prepared from 4-bromo-3-(thiazol-2-yl)thiophen-2-amine (90 mg, 0.35 mmol) and 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid (105 mg, 0.52 mmol) according to protocol A. The crude product was purified by HPLC to give N-(4-bromo-3-(thiazol-2-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide (24 mg) as a white solid. LCMS m/z 449.0/451.0 and retention of 4.019 min using method [7]. 1H-NMR (300 MHz, CDCl3) δ 8.39 (d, J=5.2 Hz, 1H), 7.76 (d, J=3.3 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.51 (dd, J=8.4, 5.3 Hz, 1H), 7.34 (d, J=3.4, 1H), 6.94 (s, 1H), 4.09 (s, 2H), 3.49 (t, J=7.2 Hz, 2H), 3.00 (t, J=7.2 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N+:5]([O-])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>CO.[Ni]>[NH2:9][C:8]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1c[n+]([O-])ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: COc1cnccc1N
Reaction time: 3 h

Procedure:
A solution of 3-methoxy-4-nitropyridine-N-oxide (17.37 g, 0.102 mol) in MeOH (180 ml) was hydrogenated in a 500 ml Parr bottle at 40° C. and 40 psi for 3 hours using Raney Nickel as catalyst. After filtration of the catalyst and evaporation of the solvent, the residue was chromatographed on silica gel using CH2Cl2 /MeOH/NH4OH (90/10/1) as the eluent to give the title compound. The product was recrystallized from toluene to give 10.8 g (65%) of pure product, m.p. 94°-95° C. The structural assignment is supported by the proton NMR spectrum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17]
Reactant: COCCCCOc1cc(C)ccc1C(=O)OC
Reactant: C1CCNC1
Product: COCCCCOc1cc(CN2CCCC2)ccc1C(=O)OC

Procedure:
The 2-(4-methoxybutoxy)-4-(pyrrolidin-1-ylmethyl)-benzoic acid methyl ester that is used is prepared in a manner analogous to that described in Example 30Aa) from 2-(4-methoxybutoxy)-4-methyl-benzoic acid methyl ester and pyrrolidine, with subsequent purification of the crude product by FC (eluants C and M): brown-black oil, Rf (N)=0.22.
Reaction SMILES: C(O[CH:9]([C:11]1([NH:14][C:15]([C:17]2[C:18]([O:35][CH3:36])=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][N:21]=[C:20]3/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[O:16])[CH2:13][CH2:12]1)C)C1C=CC=CC=1.C[Si](I)(C)C.[CH3:42][OH:43]>ClCCl>[OH:43][CH2:42][CH2:9][C:11]1([NH:14][C:15]([C:17]2[C:18]([O:35][CH3:36])=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][N:21]=[C:20]3/[CH:26]=[CH:27]/[C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)=[O:16])[CH2:13][CH2:12]1
Reactant: CO
Reactant: COc1c(C(=O)NC2(C(C)OCc3ccccc3)CC2)ccc2[nH]nc(/C=C/c3ccc(F)cc3)c12
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: COc1c(C(=O)NC2(CCO)CC2)ccc2[nH]nc(/C=C/c3ccc(F)cc3)c12
Reaction time: 2 h

Procedure:
20 mg of 3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic acid (1-benzyloxyethyl-cyclopropyl)-amide obtained by Example 814 was dissolved in 1 mL of dichloromethane, added with 6.4 μl of trimethylsilyliodide at 0° C. under nitrogen atmosphere, and stirred at this temperature for 2 hours. The reaction solution was added with methanol to stop the reaction, and the solvent was concentrated, followed by purification by LC-MS, to afford 1.7 mg of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:10][CH2:11][CH2:12]Cl)(O)C>O>[CH:2]1([CH2:7][O:10][CH2:11][CH2:12][O:1][CH2:2][CH2:7][OH:10])[C:3]2[C:4](=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:5][CH2:6][O:1]1
Reactant: CC(O)(OCCCl)C1CCCCO1
Solvent: O
Product: OCCOCCOCC1OCCc2ccccc21

Procedure:
Furthermore, various 1-hydroxymethylisochromans can be first treated with tetrahydropyranyl chloroethoxyethanol and then with acid and water to yield the corresponding 2-[2-((isochroman-1-yl)methoxy)ethoxy]ethanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][N:9]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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:24]([O:23][C:21]([N:9]1[CH2:10][CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][C@@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:33]2[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=2)=[CH:3][CH:4]=1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(Br)cc2)C1
Reactant: COc1ccc(B(O)O)cc1
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: COCCOC
Solvent: O
Product: COc1ccc(-c2ccc([C@H]3CN(C(=O)OC(C)(C)C)CCN3C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
A mixture of (S)-2-(4-bromophenyl)-1,4-di(t-butoxycarbonyl)piperazine (1.82 g, 4.11 mmol), 4-methoxyphenylboronic acid (937 mg, 6.17 mmol), sodium carbonate (2.18 g, 20.6 mmol), and tetrakis(triphenylphosphine)palladium(0) (238 mg, 0.206 mmol) was dissolved in dimethoxyethane (20 mL) and water (20 mL), and the resulting solution was refluxed for 3 h. After cooling to room temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting solid was washed with ethyl acetate to afford (S)-1,4-di(t-butoxycarbonyl)-2-(4′-methoxybiphen-4-yl)piperazine (1.46 g, 75.9%) as a white solid.
Reaction SMILES: C[C:2]1(C)[O:6][C@H:5]([CH2:7][NH:8]C(=O)OCC2C=CC=CC=2)[C:4](=[O:19])[O:3]1.[ClH:21].[H][H]>CO.CCOCC.[Pd]>[ClH:21].[NH2:8][CH2:7][C@@H:5]([OH:6])[C:4]([O:3][CH3:2])=[O:19]
Reactant: CC1(C)OC(=O)[C@@H](CNC(=O)OCc2ccccc2)O1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)[C@H](O)CN

Procedure:
Benzyl [(4R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]methylcarbamate (7.76 g) prepared by the method described in Step B above was dissolve in methanol (70 mL) with 0.62 g 10% Pd/C. A 1 M HCl in ether solution was added (25 mL). This mixture was hydrogenated using a hydrogen balloon for 22 hours. The reaction mixture was purged with nitrogen, filtered though a pad of Celite, and evaporated under vacuum to give the title compound as a yellowish solid. 1H NMR (CD3OD, 500 MHz) δ 4.45 (dd, J=4 and 8 Hz, 1H), 3.82 (s, 3H), 3.31 (dd, 1H), 3.15 (dd, J=8 and 13 Hz, 1H).
Reaction SMILES: [C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:22]([N-]C1CCCCC1)(C)C.[Li+].CI.Cl>O1CCCC1>[CH3:22][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:1]([O:20][CH3:21])=[O:19]
Reactant: CC(C)[N-]C1CCCCC1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCCCCCCC/C=C\CCCCCCC(C)C(=O)OC

Procedure:
A solution of methyl oleoate (0.054 mole) in tetrahydrofuran (100 ml) was added dropwise to a freshly prepared cold solution of lithium isopropyl cyclohexyl amide (1.2 eq.) in tetrahydrofuran (400 ml) over 4.75 hrs. Methyl iodide (1.5 eq.) was added dropwise rapidly and the reaction was allowed to come to room temperature. The reaction was stripped of solvent to give an orange oil. The material was added to 1N hydrochloric acid (100 ml) and extracted into ethyl ether. The ethyl ether was washed with water (100 ml), dried over sodium sulfate, filtered and stripped to an oil which was identified as the title compound by spectral analysis and used in Example 67.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=2[C:23]([O:25][CH3:26])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[C:23]([O:25][CH3:26])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(2-methoxycarbonyl-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 2.7 mmol) in MeOH (30 mL) was added 10 wt % Pd/C (0.1 equiv by wt) under argon atmosphere. The mixture was evacuated and then refilled with hydrogen (3 cycles) and stirred at room temperature for 2 h. The heterogeneous reaction mixture was filtered through a pad of Celite, washed with MeOH and concentrated in vacuo. The crude amino-compound was used in the next step without purification. MS (ES+): m/z 336 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:7]=1)=[O:5])[CH3:2].[Br:26]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][Br:26])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:7]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1C
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1CBr
Temperature: 25 °C
Yield: 64 %

Procedure:
A mixture of 1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester I-4a (2.8 g, 7.46 mmol), N-bromosuccinimide (1.6 g, 8.95 mmol), AlBN (245 mg, 1.49 mmol) in CCl4 (60 ml) was heated under reflux for 17 hours. The reaction was cooled to room temperature, filtered to remove any solids, and concentrated under vacuum. The crude residue was purified via silica gel chromatorgraphy (Flash 40) using a solvent gradient of 10% EtOAc/hexanes to 20% EtOAc/hexanes to give the desired product (I-4b) as an amorphous solid (2.2 g, 64%): +APCI MS (M+1) 455.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]C(C)C)=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]2[O:23][CH2:24][CH2:25][CH3:26])=[C:4]([F:27])[CH:3]=1.S(=O)(=O)(O)O>>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[N:14]=[C:13]2[O:23][CH2:24][CH2:25][CH3:26])=[C:4]([F:27])[CH:3]=1
Reactant: CCCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(OC(C)C)c(Cl)cc1F
Agent: O=S(=O)(O)O
Product: CCCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F

Procedure:
using 1-(4-chloro-2-fluoro-5-isopropoxyphenyl)-2-propoxy-4-trifluoromethyl-6(1H)-pyrimidinone with concentrated sulphuric acid during 2 minutes at 0° C. there is obtained 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-2-propoxy-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 122°-123° C.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]([C:13]1[S:14][C:15]2[N:20](C(OC(C)(C)C)=O)[N:19]=[C:18]([NH:28][C:29]([C:31]3[CH:35]=[CH:34][S:33][CH:32]=3)=[O:30])[C:16]=2[N:17]=1)=[O:12])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].Cl.[Cl-].[Na+]>C(O)C.O1CCOCC1>[CH3:3][C:2]([NH:10][C:11]([C:13]1[S:14][C:15]2[NH:20][N:19]=[C:18]([NH:28][C:29]([C:31]3[CH:35]=[CH:34][S:33][CH:32]=3)=[O:30])[C:16]=2[N:17]=1)=[O:12])([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:1]
Reactant: CC(C)(C)OC(=O)n1nc(NC(=O)c2ccsc2)c2nc(C(=O)NC(C)(C)c3ccccc3)sc21
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)(NC(=O)c1nc2c(NC(=O)c3ccsc3)n[nH]c2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79 %

Procedure:
0.16 g (0.32 mmol) of tert-butyl 5-(1-methyl-1-phenylethylcarbamoyl)-3-[(thiophene-3-carbonyl)amino]-1H-pyrazolo[4,3-d]thiazole-1-carboxylate dissolved in 7 ml of ethanol is placed in a 100 ml round-bottomed flask. 1.6 ml (6.4 mmol) of a 4M solution of hydrochloric acid in dioxane are then added and the reaction mixture is stirred for 15 hours at 25° C. A further 1.6 ml (6.4 mmol) of 4M solution of hydrochloric acid in dioxane are then added and the mixture is stirred for 15 hours at 25° C. The reaction medium is then concentrated to dryness under reduced pressure (40° C.) and the residue is taken up in 30 ml of dichloromethane and 30 ml of water, and basified with 0.1N sodium hydroxide solution. The emulsion obtained is resorbed by saturation with sodium chloride. After separation of the phases by settling, the organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure (40° C.). The residue is purified by flash chromatography (msilica=30 g; eluent: 95/5 dichloromethane/methanol). 0.104 g of N-(1-methyl-1-phenylethyl)-3-[(thiophene-3-carbonyl)amino]-1H-pyrazolo[4,3-d]thiazole-5-carboxamide is thus obtained in the form of a cream-coloured foam. m.p.K=221° C. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.70 (s, 6H); 7.20 (t, J=7.5 Hz, 1H); 7.31 (t, J=7.5 Hz, 2H); 7.41 (d, J=7.5 Hz, 2H); 7.69 (m, 2H); 8.46 (broad s, 1H); 8.53 (broad s, 1H); from 10.0 to 15.0 (very broad m, 2H).
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]2[CH:10]=[CH:11][O:12][C:6]=2[C:5]=1[OH:13])([O-])=O.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([C@@H:24](O)[CH3:25])=[N:22][N:23]=2)[N:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>Cl.[Fe].CCO.C1COCC1>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([C@H:24]([O:13][C:5]3[C:6]4[O:12][CH:11]=[CH:10][C:7]=4[CH:8]=[N:9][C:4]=3[NH2:1])[CH3:25])=[N:22][N:23]=2)[N:20]=1
Reactant: O=[N+]([O-])c1ncc2ccoc2c1O
Reactant: C[C@H](O)c1nnc2ccc(Cl)nn12
Agent: [Fe]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](Oc1c(N)ncc2ccoc12)c1nnc2ccc(Cl)nn12
Temperature: 40 °C

Procedure:
To a mixture of 6-nitrofuro[3,2-c]pyridin-7-ol (50.0 mg, 0.278 mmol), (S)-1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-ethanol (110 mg, 0.555 mmol), triphenylphosphine (191 mg, 1.11 mmol) and THF (10 mL) under nitrogen at rt was added diisopropyl azodicarboxylate (0.219 mL, 1.11 mmol) dropwise. The solution was heated to 40° C. for 2 h. The solvent was removed in vacuo, and EtOH (20 mL), iron powder (200 mg, 3 mmol) and conc. HCl (8 drops) were added. The mixture was heated to 75° C. for 1 h. The material was loaded into a SCX cartridge, washed with MeOH and ejected with 2M NH3 in MeOH. The filtrate was concentrated in vacuo to afford the title compound as a dark orange solid, and was used in the next step without further purification. MS (ES+): m/z 331.02 (100) [MH+]. HPLC: tR=1.92 min (ZQ3, polar—5 min).