Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[I-].[K+].[Cl:16][C:17]1[CH:18]=[C:19]([S:24][C:25]2[NH:29][C:28]([CH2:30][O:31]CC3C=CC(OC)=CC=3)=[N:27][C:26]=2[CH:41]([CH3:43])[CH3:42])[CH:20]=[C:21]([Cl:23])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.C(O)C.CN(C)C=O>[Cl:23][C:21]1[CH:20]=[C:19]([S:24][C:25]2[N:29]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:28]([CH2:30][OH:31])=[N:27][C:26]=2[CH:41]([CH3:43])[CH3:42])[CH:18]=[C:17]([Cl:16])[CH:22]=1
Reactant: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)[nH]2)cc1
Reactant: ClCCCCCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: CC(C)c1nc(CO)n(CCCCCCc2ccccc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.1 %

Procedure:
To dimethylformamide was added 99 mg of 1-chloro-6-phenylhexane and 152 mg of potassium iodide under ice-cooling, the mixture was allowed to warm up to room temperature and stirred for 20 minutes. Then, 200 mg of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (101b)was added, followed by addition of 126 mg of potassium carbonate. Then, the mixture was warmed up to 50° C. and allowed to react for 6 hours. After completion of the reaction, the mixture was diluted with water, extracted with diethyl ether, the extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. To thus-obtained oil were added 10 ml of ethanol and 20 ml of 36% hydrochloric acid, and the mixture was stirred at 90° C. for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, an aqueous sodium hydrogen carbonate solution was added, and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1)to give 81 mg of Compound I-125 (yield 37%).
Reaction SMILES: F[C:2](F)(F)[C:3]([NH2:5])=[O:4].[NH:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)C(=O)C2)[CH2:10][CH2:9]1.[OH-].[K+]>CO.O>[O:4]=[C:3]1[CH2:2][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:8][CH2:9][CH2:10]2)[CH2:12][CH2:13][NH:5]1
Reactant: O=C1CC2(CCNCC2)c2ccccc21
Reactant: NC(=O)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1CC2(CCN1)CCNc1ccccc12
Yield: 91.1 %

Procedure:
A solution of 49 mg (0.157 mmol) of the high RF material from Step B in methanol/water 4:1 with excess potasium hydroxide was stirred over night. The solution was concentrated and water and ethyl acetate were added to the residue. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to give 31 mg (0.143 mmol) of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[CH:9][C:10]([OH:12])=O)[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:14][NH:15][O:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([CH:8]=[CH:9][C:10]([N:15]([O:16][CH3:17])[CH3:14])=[O:12])[CH:5]=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)C=Cc1cccc(Br)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C=Cc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.5 %

Procedure:
3-(6-Bromo-pyridin-2-yl)-acrylic acid (4.5 g, 19.5 mmol) prepared in Step 1, N,O-dimethylhydroxylamine hydrochloride (2.3 g, 23.4 mmol), HOBT (5.3 g, 39.1 mmol), EDAC (7.5 g, 39.1 mmol) and triethylamine (5.4 mL, 39.1 mmol) were added to dichloromethane (100.0 mL). The reaction mixture was stirred at room temperature for 18 hours, quenched with a saturated solution of ammonium chloride, and then extracted with dichloromethane. The extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/9) to give 3.2 g of the titled compound as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:6])[CH3:5].Cl[C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[N:11]=[C:10]2[N:20]([CH2:23][CH3:24])[CH:21]=[N:22][C:9]=12>C1C=CC=CC=1>[CH2:23]([N:20]1[C:10]2=[N:11][C:12]([CH3:19])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]([O:6][CH:4]([CH3:5])[CH3:3])=[C:9]2[N:22]=[CH:21]1)[CH3:24]
Reactant: CCOC(=O)c1c(C)nc2c(ncn2CC)c1Cl
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)c1c(C)nc2c(ncn2CC)c1OC(C)C
Reaction time: 10 h

Procedure:
0.03 g. of sodium hydride and 0.6 g. of propane-2-ol are refluxed with stirring in 50 ml. dry benzene for 10 hours. After this time, 2.7 g. of 7-chloro-3-ethyl-5-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester obtained in Example 1 d are added and heating is continued for an additional 10 hours. The inorganic precipitate is filtered off and the solvent removed by distillation. The oily residue is distilled to obtain 3-ethyl-5-methyl-7-(1-methylethoxy)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester, b.p. 180°-185°/0.05. Yield 2 g. (69%).
Reaction SMILES: [CH2:1]([C:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[N:12]=[C:13]2[C:18]=1[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:2][CH2:3][CH3:4].[OH:19]OS([O-])=O.[K+].C([O-])(O)=O.[Na+].CO>O>[CH2:1]([C:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[N+:12]([O-:19])=[C:13]2[C:18]=1[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:2][CH2:3][CH3:4]
Reactant: O=S([O-])OO
Reactant: CCCCc1c2c(nc3c1CCCC3)CCCC2
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCc1c2c([n+]([O-])c3c1CCCC3)CCCC2
Temperature: 47.5 °C
Reaction time: 24 h
Yield: 125.3 %

Procedure:
Into a 2L round-bottomed flask equipped with a magnetic stirrer and a reflux condenser fitted with a nitrogen inlet are placed 38.0 g (0.16 mol) of 9-n-butyl-1,2,3,4,5, 6,7,8-octahydroacridine, 72.0 g (0.12 mol) of Oxone (Note 9), 28.5 g (0.34 mol) of NaHCO3, 790 mL of methanol and 240 mL of water. The resulting suspension is stirred at 45-50° C. in an atmosphere of nitrogen for 24 hrs. (Note 10). The cooled reaction mixture is vacuum filtered, washing the residual salts with methanol (2×50 mL). The methanol is removed from the combined filtrates by means of a rotary evaporator and the resulting mixture is extracted with methylene chloride (3× 100 mL). The combined extracts are washed with water (2×50 mL), dried using anhydrous magnesium sulfate and concentrated to dryness by means of a rotary evaporator. Residual solvent is removed at 0.1 mm, yielding 39 g (96%) of 9-n-butyl-1,2,3,4,5,6,7,8-octahydroacridine-N-oxide as a pale yellow solid, mp 89-92° C. (Note 11).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]3[C:15]([CH:16]=[CH:17][NH:18]3)=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([S:28][CH3:29])[N:23]=1.O>CN(C=O)C>[CH3:29][S:28][C:24]1[N:25]=[C:26]([N:18]2[C:19]3[C:15](=[CH:14][CH:13]=[C:12]([C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=4)[CH:20]=3)[CH:16]=[CH:17]2)[CH:27]=[CH:22][N:23]=1
Reactant: O=[N+]([O-])c1cccc(-c2ccc3cc[nH]c3c2)c1
Reactant: CSc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nccc(-n2ccc3ccc(-c4cccc([N+](=O)[O-])c4)cc32)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
Sodium hydride (60% in mineral oil, 40 mg, 0.98 mmol) was added to a mixture solution of 6-(3-nitrophenyl)-1H-indole (117 mg, 0.49 mmol) in DMF (2 mL) at room temperature. 10 minutes later, 4-chloro-2-(methylthio)pyrimidine (68 μL, 0.59 mmol) was added. After stirring at room temperature for 30 minutes, water was added. Thus produced solid was filtered and dried. The target compound (102 mg) was obtained as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[NH2:11])=[O:5])[CH3:2].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH:25]=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH:11][C:10]2[CH:9]=[CH:8][NH:7][C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CCOC(=O)c1[nH]ccc1N
Product: CCOC(=O)c1[nH]ccc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 10 %

Procedure:
The title compound (0.156 g, 10%) was prepared in accordance with general method A starting from 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.68 g, 4.4 mmol) and 4-formylpiperidine-1-carboxylic acid tert-butyl ester (P. C. Ting et al., Bioorganic & Medicinal Chemistry Letters, 2001, 11, 491-494) (0.98 g, 4.6 mmol.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([C:19]3[N:20]=[N:21][N:22]([CH3:24])[N:23]=3)=[CH:14][C:13]=2[CH3:25])[N:7]=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[S:28]>C(#N)C.CN(C1C=CN=CC=1)C>[O:29]([C:27]([O:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[C:13]([CH3:25])=[CH:14][C:15]([C:19]3[N:20]=[N:21][N:22]([CH3:24])[N:23]=3)=[CH:16][C:17]=2[CH3:18])[N:7]=1)=[S:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCn1cnc(CO)n1
Reactant: S=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCn1cnc(COC(=S)Oc2ccccc2)n1
Temperature: 20 °C
Reaction time: 7 h

Procedure:
To a mixture of 5-hydroxymethyl-2-[3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethyl-phenoxy]-propyl]-1,2,4-triazole (343 mg, 1 mmol) in 15 ml of acetonitrile was added DMAP (244 mg, 2 mmol) and phenyl chlorothioformate (381 mg, 2.2 mmol). The mixture was stirred at 20° C. for 7 h, an additional phenyl chlorothioformate (1 equiv) was added, and the mixture was stirred for 15 h. The solvent was removed in vacuo and 5-phenoxythiocarbonyloxymethyl-2-[3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-propyl]-1,2,4-triazole was isolated and used without further purification.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C:16]4[C@:28]([CH3:36])([CH2:29][CH2:30][C:31]=32)[C@@H:19]([C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:18][C:17]=4[O:37][Si](C)(C)C)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45].[F-].C([N+](C)(C)C)C1C=CC=CC=1>C1COCC1.CCCCCC>[C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C@@:16]4([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[C@:28]([CH3:36])([CH2:29][CH2:30][C:31]=32)[C@@H:19]([C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:18][C:17]4=[O:37])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CI
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC(O[Si](C)(C)C)=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C[C@@H]1CC3
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C[C@@]12C(=O)C[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CCC1=C2CC[C@H]2C[C@@H](OC(=O)c3ccccc3)CC[C@]12C
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
3β-benzoyloxy-15-trimethylsiloxy-5α-cholest-8,14-diene (1.93 g, 3.35 mmole) in THF (10 mL) and ethyl iodoacetate (0.79 mL, 6.7 mmole) was added at -10° C. to a mixture of benzyl trimethylammonium fluoride (850 mg, 5 mmole) in THF (15 mL). The mixture was stirred at -10° C. for 15 minutes and at ambient temperature for 30 minutes, diluted with hexane, filtered and the filtrate was concentrated. Using the workup described in Example 1(ii), 625 mg of 3β-benzoyloxy-14α-carbethoxymethyl-5α-cholest-8-en-15-one was obtained.
Reaction SMILES: [F:1][C:2]1[C:22]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11](O)=[O:12])[C:7](=[O:18])[CH:6]=1.[CH3:28][C:29]1([CH3:41])[O:33][C@H:32]([CH2:34][N:35]2[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]2)[CH2:31][O:30]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:28][C:29]1([CH3:41])[O:33][C@H:32]([CH2:34][N:35]2[CH:39]=[CH:38][C:37]([NH:40][C:11](=[O:12])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:19]=[CH:20][CH:21]=[C:22]([N:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[C:2]=4[F:1])=[CH:6][C:7]3=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:36]2)[CH2:31][O:30]1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(N3CCCC3)c2F)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc(N3CCCC3)c2F)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
To a solution of (S)-2-[4-(2-fluoro-3-pyrrolidin-1-yl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.140 g, 0.37 mmol) in N,N-dimethylformamide (5 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.090 g, 0.46 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.655 g, 1.48 mmol). The mixture was stirred at room temperature overnight and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 0% to 80% ethyl acetate/hexanes) which afforded (S)-2-[4-(2-fluoro-3-pyrrolidin-1-yl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.110 g, 53%) as a white solid: HR-ES-MS m/z calculated for C29H38FN5O5 [M+H]+ 556.2930, observed 556.2928, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H), 1.25 (s, 3H), 1.29, 1.31 (2×s, 3H), 1.35-1.64 (m, 2H), 1.66-1.83 (m, 1H), 1.84-1.95 (m, 4H), 3.29-3.39 (m, 4H), 3.73 (dd, J=8.3, 5.9 Hz, 1H), 4.00 (dd, J=8.3, 6.5 Hz, 1H), 4.04-4.14 (m, 2H), 4.18 (d, J=18.4 Hz, 1H), 4.25-4.41 (m, 1H), 4.56 (d, J=18.4 Hz, 1H), 4.84-4.93 (m, 2H), 6.43 (d, J=2.1 Hz, 1H), 6.59-6.70 (m, 2H), 7.03 (t, J=8.2 Hz, 1H), 7.60 (br. s., 1H), 10.79 (s, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[S:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:21]Br.O>ClCCl.[Fe]>[Br:21][C:16]1[C:17]([CH3:19])=[CH:18][C:13]2[S:12][CH2:11][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[C:14]=2[C:15]=1[CH3:20]
Reactant: BrBr
Reactant: Cc1cc(C)c2c(c1)SCC2c1ccc(C(C)C)cc1
Agent: [Fe]
Solvent: ClCCl
Solvent: O
Product: Cc1cc2c(c(C)c1Br)C(c1ccc(C(C)C)cc1)CS2
Reaction time: 1 h
Yield: 80 %

Procedure:
To a mixture of 3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothiophene synthesized in Reference Example 212 (4.45 g, 15.8 mmol) and iron powder (59 mg, 1.05 mmol) in dichloromethane (20 mL) was added bromine (0.81 mL, 15.8 mmol) at 0° C., and the mixture was stirred at the same temperature for 1 hour. Water was poured into the reaction mixture, which was extracted with ethyl acetate. The extract was washed with a saturated sodium hydrogen carbonate solution and water, was dried over magnesium sulfate, was filtered and then was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10) to obtain 4.6 g (yield 80%) of the title compound. Melting point: 98-100° C. (hexane-ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH3:10].[C:11]([C:17](OC)=[O:18])#[C:12][C:13]([O:15][CH3:16])=[O:14]>CO>[CH3:16][O:15][C:13]([C:12]1[CH2:11][C:17](=[O:18])[C:6]2[C:7](=[C:2]([Cl:1])[C:3]([CH3:10])=[C:4]([Cl:9])[CH:5]=2)[N:8]=1)=[O:14]
Reactant: COC(=O)C#CC(=O)OC
Reactant: Cc1c(Cl)ccc(N)c1Cl
Solvent: CO
Product: COC(=O)C1=Nc2c(cc(Cl)c(C)c2Cl)C(=O)C1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
To a solution of 2,6-dichloro-3-aminotoluene (20.5 g, 0.11 mol) in methanol (300 mL) was added dimethyl acetylenedicarboxylate (15 mL, 0.12 mol) and the reaction mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure to a yellow solid. Diphenyl ether (350 mL) was heated to 230–240° C., and the yellow solid was added to it. The temperature was maintained at 230–240° C. for 20 minutes and the reaction mixture was cooled slowly to ambient temperature and diluted with petroleum ether (1L). The solid was filtered and washed with hot ethyl acetate to afford a brown solid, 2-(methoxycarbonyl)-4-oxo-6,8-dichloro-7-methylquinoline (28.5 g, 85%); NMR (CDCl3) 2.62 (s, 3), 4.04 (s, 3), 7.02 (s, 1), 8.24 (s, 1) ppm.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([C:16]([OH:18])=[O:17])=[CH:11][C:12]([F:15])=[N:13][CH:14]=1)=O)(C)(C)C.O.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]1[C:10]([C:16]([OH:18])=[O:17])=[CH:11][C:12]([F:15])=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(F)cc1C(=O)O
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cnc(F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 86.5 %

Procedure:
A suspension of 36.6 g (140 mM) of 5-[N-(tert-butoxycarbonyl) amino]-2-fluoropyridine-4-carboxylic acid hydrated with 0.3 equivalents of water in 280 mL of dichloromethane was cooled in an ice bath then treated dropwise over 15 minutes with 140 mL of trifluoroacetic acid. The bath was removed, and the resultant mixture was stirred at room temperature for 14 hours, then concentrated. The yellow-orange solids were triturated in 125 mL of warm 1:1 diethyl ether:dichloromethane. After cooling, the yellow solids were collected, washed with 100 mL of the diethyl ether:dichloromethane mixture, and dried to afford 19.3 g of product. Processing of the filtrate afforded 1.7 g of a second crop. Total yield=21 g (94%). Recrystallization of a small sample from ethyl acetate provided product of mp 259° C. (dec). 1H NMR [(CD3)2SO]: δ8.86 (m, 3H), 7.81 (d, JH-F=1.1 Hz, 1H), 7.20 (d, JH-F=2.3 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O.O>CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 85.2 %

Procedure:
Treat a slurry of 2-chloro-3-methyl-5-nitro-pyridine (27.00 g, 0.156 mol) and piperazine-1-carboxylic acid tert-butyl ester (32.03 g, 0.172 mol) in anhydrous DMF (270 mL) with K2CO3 (34.55 g, 0.250 mol), then heat the reaction mixture at 80° C. under N2 overnight. Pour the resulting reaction mixture into 1/1 EtOAc/H2O (3,000 mL), separate the layers, then extract the aqueous layer with EtOAc (1,000 mL). Wash the combined organics with saturated aq. sodium chloride (3×1,000 mL each), dry over MgSO4, filter, then concentrate under reduced pressure to give a yellow solid. Slurry the yellow solid in hexanes/EtOAc, then recover the resulting solid by vacuum filtration. Wash with hexanes and vacuum filter to give (42.84 g) of 4-(3-methyl-5-nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid. Concentrate the filtrate under reduced pressure to give a yellow solid. Slurry the yellow solid in hexanes, then recover the resulting solid by vacuum filtration, washing with hexane and drying under vacuum filtration to give an additional (5.38 g) of 4-(3-methyl-5-nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester compound as a yellow solid (48.22 g, 95.9% yield). 1H NMR (400 MHz, CDCl3) δ 8.96 (d, 1H), 8.14 (d, 1H), 3.57 (m, 4H), 3.41 (m, 4H), 2.36 (s, 3H), 1.48 (s, 9H); TOF-MS [ES+, M+H] Obs. m/z 323.1723, Calc. m/z 323.1719; Anal. Calcd. For C15H22N4O4: C, 55.88; H, 6.87; N, 17.37. Found C, 55.94; H, 6.87; N, 17.14.
Reaction SMILES: [CH2:1]([C:3]1[C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[C:24]([CH2:26][OH:27])[C:23]([CH3:28])=[N:22]3)=[CH:17][CH:16]=2)=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[N:5]2[N:4]=1)[CH3:2]>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:3]1[C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[C:24]([CH:26]=[O:27])[C:23]([CH3:28])=[N:22]3)=[CH:17][CH:16]=2)=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(-n2cc(CO)c(C)n2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(-n2cc(C=O)c(C)n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
{1-[4-(2-Ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-ylmethyl)-phenyl]-3-methyl-1H-pyrazol-4-yl}-methanol (18) (500 mg, 1.38 mmol) was dissolved in 10 ml of dichloromethane and after addition of manganese dioxide (1.2 g, 13.8 mmol) the reaction mixture was stirred for 3 h at rt. The mixture was filtrated though celite and evaporated under reduced pressure. The product was used in the next step without further purification.