Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])[C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[CH3:29][C:30]1[N:34]=[CH:33][N:32]([C:35]2[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][C:36]=2[O:37][CH2:38][CH2:39][CH2:40][CH:41]([NH2:43])[CH3:42])[N:31]=1>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:43][CH:41]([CH2:40][CH2:39][CH2:38][O:37][C:36]2[CH:44]=[C:45]([N+:48]([O-:50])=[O:49])[CH:46]=[CH:47][C:35]=2[N:32]2[CH:33]=[N:34][C:30]([CH3:29])=[N:31]2)[CH3:42])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])[C:6]=2[N:7]=1
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCC(C)N)n1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)c(F)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCC(C)Nc2nc(Cl)nc3c2CCC3c2ccc(F)cc2F)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.9 %

Procedure:
To a solution of 2,4-dichloro-7-(2,4-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (907 mg, 3.01 mmol) in acetonitrile (150 mL) was added diisopropylethylamine (1.05 g, 6.03 mmol) followed by 5-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)pentan-2-amine (920 mg, 3.01 mmol) at room temperature. The reaction mixture was stirred at rt for 18 h while monitoring by LC-MS. The solvent was removed under reduced pressure and the residue was purified by column chromatography (60-120 mesh silica) using 2-3% of methanol in chloroform to give 2-chloro-7-(2,4-difluorophenyl)-N-(5-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)pentan-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine as a yellow solid (650 mg, 1.140 mmol, 37.8% yield). LC-MS (M+H)+=570.0. 1H NMR: (400 MHz, CDCl3) δ ppm 8.85 (1H, s), 8.07 (1H, d, J=8.4 Hz), 8.00-7.96 (2H, m), 7.00-6.97 (1H, m), 6.81-6.78 (2H, m), 4.47-4.31 (5H, m), 2.72-2.64 (3H, m), 2.50 (3H, s), 2.04-1.98 (3H, m), 1.78-1.74 (2H, m), 1.32-1.25 (3H, m).
Reaction SMILES: [C:1]12[CH2:9][O:8][CH2:7][C:2]1=[CH:3][CH:4]=[CH:5][CH:6]=2.[N+]([O-])(O)=[O:11].O>C(O)(=O)C>[CH:7](=[O:11])[C:2]1[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]=[O:8]
Reactant: c1ccc2c(c1)COC2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1ccccc1C=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
In a 1000-ml three-neck flask equipped with a thermometer, a reflux condenser and a stirrer were placed 50 g of o-xylylene oxide, 87.5 g of 60% by weight nitric acid, 163.8 g of water, and 198.8 g of acetic acid. The mixture was raised in temperature to 70° C. on an oil bath and was stirred under these conditions for 1 hour. After cooling, the reaction mixture was analyzed by gas chromatography to find that the raw material o-xylylene oxide was completely absent and that phthalaldehyde was formed in a yield of 86%. Phthalide was formed in a yield of 13% as a by-product. The obtained reaction mixture was extracted with two portions of toluene, the organic layer was distilled and thereby yielded phthalaldehyde in a yield of 70% on the basis of o-xylylene glycol. Gas chromatographic analysis revealed that phthalaldehyde had a purity of 99.0%.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:10][CH2:9][CH:8]([C:11](Cl)=O)[CH2:7][CH2:6]1)=O.[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[N:29]=C(N4CCNCC4)[N:27]=[C:26]([O:36]CC)[C:22]=3[NH:23][C:24]=2[CH:25]=1.O>C(Cl)Cl.N1C=CC=CC=1>[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[N:29]=[C:11]([CH:8]4[CH2:7][CH2:6][NH:5][CH2:10][CH2:9]4)[N:27]=[C:26]([OH:36])[C:22]=3[NH:23][C:24]=2[CH:25]=1
Reactant: CCOc1nc(N2CCNCC2)nc2c1[nH]c1cc(Br)ccc12
Reactant: O=C(Cl)C1CCN(C(=O)C(F)(F)F)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: Oc1nc(C2CCNCC2)nc2c1[nH]c1cc(Br)ccc12
Reaction time: 0.67 h
Yield: 89.4 %

Procedure:
767 mg (3.15 mmol) 1-(2,2,2-trifluoroacetyl)piperidine-4-carboxylic acid chloride dissolved in CH2Cl2 was slowly added drop-wise to 526 mg (2.10 mmol) 3-amino-6-bromo-1H-indole-2-carboxylic acid amide (Example 4) in pyridine at 0° C. Then, stirring was carried out at room temperature for 40 min. After the addition of water, the solvent was removed in vacuo and the residue was taken up in methanol. After the addition of 2 M NaOH (excess), the reaction was kept at reflux for 45 min. Thereafter, the methanol was removed in vacuo, the precipitate was sucked off and washed with water. 652 mg (89%) 7-bromo-2-(4-piperidyl)-5H-pyrimido[5,4-b]indol-4-ol was obtained. ESI-MS [m/z]: 347, 349 [M+H]+
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH:11]2[CH2:14][NH:13][CH2:12]2)=[CH:8][CH:7]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]([NH:26][C:27]([C:29]2[S:33][C:32]([NH:34][C:35](=[O:37])[CH3:36])=[N:31][C:30]=2[CH3:38])=[O:28])[CH3:25])=[CH:20][CH:19]=1.CC([O-])(C)C.[Na+].O1CCOCC1>CO.O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH:11]2[CH2:14][N:13]([C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]([NH:26][C:27]([C:29]4[S:33][C:32]([NH:34][C:35](=[O:37])[CH3:36])=[N:31][C:30]=4[CH3:38])=[O:28])[CH3:25])=[CH:20][CH:19]=3)[CH2:12]2)=[CH:8][CH:7]=1
Reactant: COCCOc1ccc(OC2CNC2)cc1
Reactant: CC(=O)Nc1nc(C)c(C(=O)N[C@@H](C)c2ccc(Br)cc2)s1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: COCCOc1ccc(OC2CN(c3ccc([C@H](C)NC(=O)c4sc(NC(C)=O)nc4C)cc3)C2)cc1
Temperature: 45 °C
Reaction time: 12 h

Procedure:
100 mg (0.39 mmol) 3-[4-(2-Methoxy-ethoxy)-phenoxy]-azetidine (IX.4), 165 mg (0.43 mmol) (S)-2-acetylamino-4-methyl-thiazole-5-carboxylic acid [1-(4-bromo-phenyl)-ethyl]-amide (I.6), 45 mg (0.06 mmol) chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) and 150 mg (1.56 mmol) NaOtBu are combined under an argon atmosphere and 1,4-dioxane (4.0 mL) is added. The mixture is stirred for 12 h at 45° C. Some water and methanol are added and the mixture is filtered and purified by HPLC (Zorbax, acetronitrile/H2O (+0.1% TFA)) to yield the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[CH:13](B(OCCCC)OCCCC)=[CH2:14].[F-].[Cs+]>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.COCCOC.CO>[CH3:8][C:6]1[CH:7]=[C:2]([CH:13]=[CH2:14])[C:3]([CH3:12])=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Br
Reactant: C=CB(OCCCC)OCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: C=Cc1cc(C)c([N+](=O)[O-])cc1C
Temperature: 130 °C

Procedure:
To a microwave reaction vessel was added a mixture of 1-bromo-2,5-dimethyl-4-nitrobenzene (1.15 g, 5.0 mmol), dibutyl vinylboronate (1.16 g, 6.3 mmol), Pd(PPh3)4 (289 mg, 0.25 mmol), CsF (2.28 g, 15 mmol) and a mixed solvent (1,2-dimethoxyethane/MeOH=2:1, 15 mL). The mixture was degassed and sealed with N2. The reaction vessel was then heated to 130° C. in a microwave reactor for 15 min. After opening the reaction vessel, the mixture was poured into saturated NH4Cl aqueous solution (30 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine and dried (MgSO4). After removing the drying agent by filtration, the filtrate was concentrated and purified by flash column chromatography (silica gel, 0-30% EtOAc in hexanes gradient) to provide 1,4-dimethyl-2-nitro-5-vinylbenzene as needlelike crystals; ESMS m/z 178.1 (M+H+).
Reaction SMILES: [N:1]([CH2:10][C:11]([OH:13])=O)([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].C(OC(=O)C)(=O)C.[Br:21][C:22]1[C:23]([CH3:31])=[C:24]([C:26]([CH3:30])=[CH:27][C:28]=1[CH3:29])[NH2:25]>N1C=CC=CC=1>[Br:21][C:22]1[C:23]([CH3:31])=[C:24]([NH:25][C:11](=[O:13])[CH2:10][N:1]([CH2:2][C:3]([OH:5])=[O:4])[CH2:6][C:7]([OH:9])=[O:8])[C:26]([CH3:30])=[CH:27][C:28]=1[CH3:29]
Reactant: Cc1cc(C)c(Br)c(C)c1N
Reactant: O=C(O)CN(CC(=O)O)CC(=O)O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: Cc1cc(C)c(NC(=O)CN(CC(=O)O)CC(=O)O)c(C)c1Br
Temperature: 50 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
A suspension of 9.56 g of nitrilotriacetic acid in pyridine (dried over molecular sieves) is prepared with the exclusion of moisture (CaSO4 drying tube) and heated to 50° C. Acetic anhydride (5.11 g) is added dropwise. The reaction mixture clears and is heated to 100° C. After maintaining the temperature for 40 minutes, the reaction mixture is cooled to 55° C. and a solution of 10.7 g 3-bromo-2,4,6-trimethylaniline in 25 ml of dry pyridine is added slowly. The reaction is heated to 100° C. and after 1.5 hours at this temperature, the solution is cooled in an ice-bath. The reaction mixture is rotary evaporated to a semisolid which is dissolved in 125 ml of 10% sodium hydroxide w/v. The basic layer is then extracted with two 100 ml portions of methylene chloride. Distilled water (100 ml) is added to the basic layer which is then brought to pH 3 with concentrated hydrochloric acid to give a precipitate. After refrigeration for about 16 hours, the crude product is filtered, washed with cold distilled water and dried under vacuum at 40° C. The crude product is dissolved in 100 ml of 60% aqueous ethanol, treated with 3.0 g of Darco and filtered hot through a Hyflo-bed to give a solution. Crystals precipitate and are filtered, washed with three 25 ml portions of 50% aqueous ethanol and dried under vacuum at 40° C. The reaction yields 9.1 g of the title compound, melting point 198°-200° C., dec.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]3[CH2:23][O:22]3)[N:9]=2)=[CH:4][C:3]=1[N+:24]([O-])=O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH3:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>ClCCl.O>[NH2:24][C:3]1[CH:4]=[C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]([OH:22])[CH2:23][N:62]3[CH2:63][CH2:64][N:59]([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=4[CH3:52])[CH2:60][CH2:61]3)[N:9]=2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1ccccc1N1CCNCC1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Cl)c([N+](=O)[O-])c3)nn2CC2CO2)C1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)c(N)c3)nn2CC(O)CN2CCN(c3ccccc3C)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.7 %

Procedure:
A solution of 1-[3-(4-chloro-3-nitro-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (0.754 g, 2.0 mmol) in dichloromethane (10 mL) was treated with ytterbium(III)triflate (0.25 g, 0.40 mmol) and 1-(2-methylphenyl)-piperazine (0.705 g, 4.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h and diluted with dichloromethane (100 mL) and water (50 mL). The organic layer was separated, washed with water (2×50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 5% MeOH/CH2Cl2) to afford 0.98 g (90%) of the desired product as a light yellow solid. MS (electrospray): m/z 553.2 (553.2, calculated for C28H33ClN6O4, [M+H]+). 1H NMR (CDCl3, 400 MHz, a mixture of two rotamers): 8.25-8.15 (m, 1H), 7.75-7.70 (m, 1H), 7.63-7.55 (m, 1H) 7.20-7.10(m, 2H), 7.05-6.95 (m, 2H), 4.90-4.70 (m, 1H), 4.65 (s, 1H), 4.30-4.15 (m, 2H), 4.10-3.70 (m, 4H), 3.00-2.40 (m, 12H), 2.20(s, 3H), 2.15 (s, 1.5H), 2.10 (s, 1.5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]([NH:17][C@H:18]([C:29]([OH:31])=[O:30])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+]([O-])=O)=[CH:22][CH:21]=3)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.O.O.Cl[Sn]Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:15]([NH:17][C@H:18]([C:29]([OH:31])=[O:30])[CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(C(=O)N[C@@H](Cc3ccc([N+](=O)[O-])cc3)C(=O)O)CCCCC2)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2(C(=O)N[C@@H](Cc3ccccc3)C(=O)O)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL scintillation vial was added Wang resin linked N-[[1-(4-methoxyphenyl)cyclohexyl]carbonyl]-4-nitro-L-phenylalanine (241 mg, 0.14 mmol) prepared in Example 140 and 2 mL of a solution of 2M SnCl2.2H2O in DMF. The reaction mixture was shaken overnight at room temperature. The resulting resin was collected by filtration and was washed with DMF, isopropyl alcohol, dichloromethane, and ether to yield 243 mg (0.14 mmol) of 4-amino-N-[[(1-(4-methoxyphenyl)cyclohexyl]carbonyl]-L-phenylalanine on Wang resin.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]=[C:7]([C:9]([OH:11])=O)[O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:44][CH:45]1[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]1>CN(C)C=O>[OH:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]=[C:7]([C:9]([NH:44][CH:45]3[CH2:46][CH2:47][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:49][CH2:50]3)=[O:11])[O:8][C:4]=2[CH:3]=1
Reactant: O=C(O)c1nc2ccc(O)cc2o1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2nc3ccc(O)cc3o2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
To a stirred mixture of 6-hydroxybenzo[d]oxazole-2-carboxylic acid (0.15 g, 0.86 mmol) in anhydrous N,N-dimethylformamide (2 mL) was added triethylamine (0.10 g, 0.99 mmol), 1-hydroxybenzotriazole hydrate (0.14 g, 0.99 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.20 g, 0.99 mmol), and tert-butyl 4-aminopiperidine-1-carboxylate (0.20 g, 0.99 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography (silica gel, ethyl acetate/hexanes=1/1) to afford tert-butyl 4-(6-hydroxybenzo[d]oxazole-2-carboxamido)piperidine-1-carboxylate as a off-white solid (0.16 g, 52%). 1H-NMR (DMSO-d6, 300 MHz): δ 10.10 (s, 1H), 9.04 (m, 1H), 7.63 (m, 1H), 7.10 (m, 1H), 7.27 (m, 5H), 6.91 (m, 1H), 3.92 (m, 3H), 2.78 (m, 2H), 1.72 (m, 2H), 1.49 (m, 2H), 1.38 (s, 9H); MS (ESI): 362.1 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[H][H]>[Pd]>[CH3:10][CH:4]1[CH2:5][C:6]([CH3:8])([CH3:7])[CH2:9][C:2](=[O:1])[CH2:3]1
Reactant: [H][H]
Reactant: CC1=CC(=O)CC(C)(C)C1
Agent: [Pd]
Product: CC1CC(=O)CC(C)(C)C1
Temperature: 50 °C

Procedure:
2.2 kg of isophorone and 5 g of 5% palladium-on-carbon catalyst are added to a 3 liter autoclave which is fitted with heating means, cooling means and a stirrer. A hydrogen pressure of 8-10 atmospheres is now generated and the mixture is slowly warmed to 30°-35° C. Since the hydrogenation is exothermic, provision is made by cooling that a temperature of 50° C. is not exceeded. After completion of the hydrogen uptake (temperature drop), the catalyst is filtered off. There are thus obtained 2.2 kg of crude dihydroisophorone, which is uniform according to gas chromatography and which is used directly.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14](=[O:18])[NH:15]2)=[CH:10][CH:9]=1.[H-].[Na+].CS(O[CH2:26][CH2:27][CH2:28][C:29]1([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1)(=O)=O>O.C(OCC)(=O)C>[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14](=[O:18])[N:15]2[CH2:26][CH2:27][CH2:28][C:29]2([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:31][CH2:30]2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)C1(CCCOS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccc2ccc(=O)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
To 7 mL of an N,N-dimethylformamide solution containing 0.64 g of 7-methoxyquinolin-2(1H)-one, 0.15 g of 60% sodium hydride was added at room temperature, and the mixture was stirred at 60° C. for 20 minutes. Thereto was added 1.50 g of 1-tert-butyl 4-ethyl 4-(3-((methanesulfonyl)oxy)propyl)piperidine-1,4-dicarboxylate, the mixture was stirred at 70 to 80° C. for 1 hour and 30 minutes, and thereto was further added 75 mg of 60% sodium hydride, and the mixture was stirred for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then ethyl acetate and water were added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=1:1] to obtain 0.72 g of a yellow oily substance, 1-tert-butyl 4-ethyl 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-1,4-dicarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N+:9]([O-])=[CH:8][CH:7]=[CH:6]2.ClC(OC)=O.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[CH:25][CH:26]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[CH:26]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2c(ccc[n+]2[O-])c1
Reactant: COc1cccc([Mg]Br)c1
Agent: COC(=O)Cl
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc3cc(OC)ccc3n2)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 46.4 %

Procedure:
To a solution of 6-methoxyquinoline-N-oxide (175 mg, 1.0 mmol) in THF (3 mL) at room temperature is added methyl chloroformate (77 uL, 1.0 mmol). The mixture is cooled to 0° C. and 3-methoxyphenylmagnesium bromide (2 mL of 1M, 2 mmol) is added dropwise. The mixture is stirred for 16 h while warming to room temperature. The solvent is removed in vacuo and the resulting residue is partitioned between water and CH2Cl2. The organic phase is washed with water and brine, dried over MgSO4, filtered and concentrated. Flash chromotography (0-20% EtOAc/hexanes) yields 6-methoxy-2-(3-methoxy-phenyl)-quinoline (123 mg, 46% yield).
Reaction SMILES: [H-].[Na+].C(=N[OH:11])C1C=CC=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:29])[C:20]2[CH:25]=[CH:24][C:23]([N+]([O-])=O)=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.O>CS(C)=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:29])[C:20]2[CH:25]=[CH:24][C:23]([OH:11])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Reactant: ON=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
250 cc of DMSO and 4.8 g sodium hydride are placed in a 500 cc flask and heated at 70° C for 1 hour, by which time the solution has become clear. A solution of 24.2 g (0.2 mole) of benzaldoxime in 100 cc of DMSO is then added drop by drop. The solution is maintained at 70° C for 1 hour, then allowed to cool to 15° C. A solution of 26 g (0.1 mole) of 4'-chloro-4-nitrobenzophenone in 150 cc of DMSO is then added. The reaction mixture is stirred for 20 hours at ambient temperature and then poured into acidulated water. The mixture is extracted with ether and then with ether containing 2N caustic soda. On acidification the product is precipitated. Yield 15 g (65%). Melting point 178° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][NH2:9])[N:5]=[CH:4][N:3]=1.Cl.[F:11][C:12]1([F:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(C(C)C)C(C)C)C.FC(F)(F)C(O)=O.CN([CH:38]=[C:39]([N:45]1[CH:49]=[C:48]([C:50]#[N:51])[N:47]=[CH:46]1)[C:40](OCC)=[O:41])C>O>[F:11][C:12]1([F:18])[CH2:17][CH2:16][N:15]([C:2]2[N:3]=[CH:4][N:5]=[C:6]([N:8]3[C:40](=[O:41])[C:39]([N:45]4[CH:49]=[C:48]([C:50]#[N:51])[N:47]=[CH:46]4)=[CH:38][NH:9]3)[CH:7]=2)[CH2:14][CH2:13]1
Reactant: NNc1cc(Cl)ncn1
Reactant: FC1(F)CCNCC1
Reactant: CCOC(=O)C(=CN(C)C)n1cnc(C#N)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N#Cc1cn(-c2c[nH]n(-c3cc(N4CCC(F)(F)CC4)ncn3)c2=O)cn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 200 mg (1.4 mmol) of the compound from Example 11A, 262 mg (1.7 mmol) of 4,4-difluoropiperidine hydrochloride and 289 μl (215 mg, 1.7 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine in 3 ml of water is stirred at 100° C. for 16 h. Following the addition of 53 μl (79 mg, 0.7 mmol) of trifluoroacetic acid and 324 mg (1.4 mmol) of the compound from Example 6A, the reaction mixture is stirred at 100° C. for 16 h. The precipitated solid is filtered off and washed first with water and then with diethyl ether. The product is dried under reduced pressure. Yield: 111 mg (21% of theory)
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1([CH3:24])[C:13]([CH3:15])([CH3:14])[O:12][B:11]([C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[CH:18]=O)[O:10]1.[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.[BH4-].[Na+]>CCOCC.C(O)=O>[CH3:8][C:9]1([CH3:24])[C:13]([CH3:15])([CH3:14])[O:12][B:11]([C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[CH2:18][NH:31][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[O:10]1
Reactant: NC1CCCCC1
Reactant: CC1(C)OB(c2ccccc2C=O)OC1(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O=CO
Product: CC1(C)OB(c2ccccc2CNC2CCCCC2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Toluene (250 mL) was added to 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (5.0 g, 21.54 mmol) followed by cyclohexylamine (2.37 g, 23.89 mmol) and formic acid (˜1.0 mL of 88%) to form a clear solution. The mixture was allowed to reflux using a Dean-Stark trap and the toluene/water mixture collected till clear. Upon completion, the mixture was cooled to room temperature and the solution evaporated to 100 mL. MeOH (200 mL) was then added to the reaction mixture followed by NaBH4 (1.63 g, 43.08 mmol) portion wise. The mixture was stirred for 20 min and quenched with water (5 mL). The solution was evaporated to 100 mL and EtOAc (50 mL) was added. The solution was dried with Na2SO4 and the solvent removed by reduced pressure, yielding a white solid. Et2O (200 mL) was then added dissolving half of the white solid. The remaining solid was collected and dried under reduced pressure offering compound 7. Yield: 6.3 g, 46.4%. 1H NMR (CD2Cl2): δ 7.52-7.50 (d, 1H), 7.28-7.27 (m, 2H), 7.15-7.13 (d, 1H), 4.02 (s, 2H), 3.42 (s, 1H), 3.15-3.07 (m, 1H), 1.74-1.61 (m, 5H), 1.29 (s, 12H), 1.19-1.05 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH2:23](I)[CH3:24].O>CN(C)C=O>[CH2:23]([N:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)[C:18](=[O:20])[CH3:19])[CH3:24]
Reactant: CCI
Reactant: CC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(C)=O)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 1 h

Procedure:
To 12.5 g of N-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl]phenyl]acetamide (U.S. Pat. No. 4,112,095) in 500 ml of dimethylformamide under argon, was added 2.47 g of sodium hydride (50% in oil). The mixture was stirred for one hour, then 4.1 ml of ethyl iodide was added. This mixture was stirred for 2.5 days, then poured into 1.5 liters of water and extracted with 150 ml portions of dichloromethane. The extracts were combined, dried and evaporated in vacuo. The residue was chromatographed on a Waters Prep 500 silica gel column, eluting with dichloromethane:methanol (97:3). Fractions 8-13 were combined, evaporated in vacuo and the solid recrystallized from dichloromethane-hexane, giving 6.54 g of the desired product, mp 180°-185° C.