Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:17]=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:2]1([NH:1][CH2:17][C@@H:16]([NH:15][C:13]([O:12][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:14])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H](CNc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Aniline (3.00 mL, 32.9 mmol) was dissolved in dichloroethane under nitrogen. The product from Step B was added (7.0 g, 29.91) and the reaction stirred for 1 h at room temperature. Sodium triacetoxyborohydride (9.51 g, 44.86 mmol) was added, and the pH adjusted to 5. The reaction was stirred overnight, then quenched with saturated sodium bicarbonate solution. The aqueous layer was removed, the organic phase washed with saturated brine and dried over magnesium sulfate. The title compound was obtained after chromatography on silica get with 8% ethyl acetate in hexane.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:64]=[CH:63][C:53]2[NH:54][C:55]([C@@H:57]([NH2:62])[CH2:58][CH2:59][O:60][CH3:61])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.CO>[Cl:49][C:50]1[CH:64]=[CH:63][C:53]2[NH:54][C:55]([C@@H:57]([NH:62][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][CH2:59][O:60][CH3:61])=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: COCC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COCC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(C)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 77 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methoxypropylamine in tetrahydrofuran. Yield: 77%; Rf value: 0.34 (silica gel; dichloromethane/methanol=9:1); C24H27ClN4O3 (454.96); mass spectrum: (M+H)+=455/457 (chlorine isotope).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:5]=1[C:6]#[N:7])([O-:3])=[O:2].[CH3:15]N>>[CH3:15][NH:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CN
Product: CNc1cccc([N+](=O)[O-])c1C#N
Yield: 79 %

Procedure:
Prepared as in Example 90c from 2,6-dinitrobenzonitrile and methylamine to give 2-methylamino-6-nitrobenzonitrile (0.42 g, 79%). 1H NMR (400 MHz, DMSO-d6) δ 2.85 (d, J=5.2 Hz, 3H), 6.75 (d, J=4.8 Hz, NH), 7.16 (d, J=8.4 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.64 (t, J=8.4 Hz, 1H).
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH3:25]O.C[O-].[Na+]>OCC(CO)O>[CH3:25][O:23][C:1](=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CO
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: OCC(O)CO
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)OC
Reaction time: 0.5 h

Procedure:
Behenic methyl esters are made from hydrogenated high erucic acid rapeseed oil. About 870 grams of hydrogenated high erucic acid rapeseed oil, about 174 grams of methanol, and about 12.2 grams of sodium methoxide solution (25% in methanol) are added to a spherical 3-liter glass reactor. The reactor has a heating mantle, thermometer, temperature controller, reflux condenser, variable speed agitator, vacuum take-off, and bottom outlet. The mixture is reacted at about 65° C. for approximately 1.5 hours,while refluxing the methanol. The agitation is stopped, and the glycerin isallowed to settle for about 30 minutes. The glycerin settles to the bottom of the reactor, and is removed through the bottom outlet. About 30 additional grams of methanol, and about 5.2 grams of sodium methoxide solution (25% in methanol) are added to the glass reactor, and the mixtureis reacted at about 65° C. for about 30 minutes. The agitation is stopped, the glycerin is settled for about 30 minutes, and removed throughthe bottom outlet. About 100 grams of water are added to the mixture, stirred, allowed to settle, and removed through the bottom outlet. The water-washing procedure is repeated two more times. The reflux condenser is removed, and vacuum is broken, and a fractionation column is added to the reactor. The reactor is heated to about 170°-200° C. under a vacuum of about 0.3-1.0 mm Hg. Approximately 50% of the first material to evaporate from the column is collected and discarded. The next40% (approximately) of the material to evaporate from the column is collected as product. This product is approximately 92% by weight methyl behenate.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:11][C:12]([F:22])([F:21])[C@H:13]([CH3:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Br[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH:14]([C@@H:13]([CH3:20])[C:12]([F:21])([F:22])[F:11])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:25]([F:31])[CH:26]=1
Reactant: CCOC(=O)C[C@@H](C)C(F)(F)F
Reactant: Fc1cc(Cl)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(c1ccc(Cl)cc1F)[C@@H](C)C(F)(F)F
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 27.1 %

Procedure:
81.5 ml (81.5 mmol) of a 1 M solution of lithium hexamethyldisilazide in toluene were cooled to −20° C., and a solution of 10.0 g (50.3 mmol) of ethyl (3R)-4,4,4-trifluoro-3-methylbutanoate in 50 ml of abs. toluene was added dropwise. The mixture was stirred for 10 min At −20° C., a solution, prepared beforehand, of 14.8 g (70.6 mmol) of 1-bromo-4-chloro-2-fluorobenzene, 366 mg (1.63 mmol) of palladium(II) acetate and 1.35 g (3.42 mmol) of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl in 50 ml of abs. toluene was then added dropwise. After the addition had ended, cooling was removed and the resulting reaction mixture was initially stirred at RT for 1 h and then at 80° C. overnight. After cooling, the mixture was filtered through celite, the residue was washed repeatedly with toluene and the filtrate obtained was concentrated under reduced pressure. The residue gave, after chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 100:1→100:4), 4.26 g of the title compound (25.1% of theory).
Reaction SMILES: Br[Mg][C:3]#[CH:4].[CH3:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:11](=[O:13])[CH3:12]>O1CCCC1>[CH3:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:11]([OH:13])([C:3]#[CH:4])[CH3:12]
Reactant: CC(=O)c1nccn1C
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(C)(O)c1nccn1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 58 %

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed bromo(ethynyl)magnesium (0.5M in THF, 77 mL, 1.20 equiv). This was followed by the addition of a solution of 1-(1-methyl-1H-imidazol-2-yl)ethan-1-one (4.0 g, 32.22 mmol, 1.00 equiv) in tetrahydrofuran (15 mL) dropwise with stirring at 0° C. in 20 min. The resulting solution was stirred for 20 min at 0° C. The resulting solution was allowed to react with stirring for an additional 5 h at room temperature. The reaction was then quenched by the addition of 50 mL of saturated aqueous NH4Cl. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/hexane (1/3) to give 2.8 g (58%) of 2-(1-methyl-1H-imidazol-2-yl)but-3-yn-2-ol as a off-white solid. 1H-NMR (300 MHz, CDCl3, ppm) δ 7.065 (d, 1H), 6.842 (d, 1H), 3.935 (d, 3H), 3.092 (s, 3H), 1.950 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.CCO.[C-:16]#[N:17].[K+]>O>[CH3:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][C:16]#[N:17]
Reactant: [C-]#N
Reactant: Cc1cccc(CBr)c1[N+](=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cccc(CC#N)c1[N+](=O)[O-]
Temperature: 60 °C
Yield: 93.9 %

Procedure:
A round bottomed flask was charged with 6.51 g (0.028 mol) of 3-methyl-2nitrobenzyl bromide, 120 mL 1:1 EtOH:H2O, and 5.5 g KCN (0.084 mol). The reaction solution was heated to 60° C. for 2 h. The reaction was cooled and the volatiles removed in vacuo. The resulting solid was dissolved in 150 mL water and extracted with 300 mL ethyl acetate. The organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated. This gave 4.63 g (92% yield) of the desired material as a slightly yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.45–7.41 (m, 2H), 7.33–7.31 (m,1H), 3.77 (s, 2H), 2.36 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:26][CH:27]1[CH2:31][CH2:30][CH:29]([CH3:32])[NH:28]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:28]1[CH:29]([CH3:32])[CH2:30][CH2:31][CH:27]1[CH3:26])=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC1CCC(C)N1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2C(C)CCC2C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 2,5-dimethylpyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.53 minutes; C23H24Cl2N4O2 (459.38); mass spectrum: (N−H)−=458/460/462 (chlorine isotope).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[O:11]=[C:12]1[N:18]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C@H:28]([CH2:43][C:44]3[CH:49]=[C:48]([CH3:50])[C:47]([OH:51])=[C:46]([CH3:52])[CH:45]=3)[C:29](=[O:42])[N:30]3[CH2:35][CH2:34][N:33]([CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[CH2:32][CH2:31]3)=[O:26])[CH2:21][CH2:20]2)[CH2:17][CH2:16][C:15]2[CH:53]=[CH:54][CH:55]=[CH:56][C:14]=2[NH:13]1>C(Cl)Cl>[O:11]=[C:12]1[N:18]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C@H:28]([CH2:43][C:44]3[CH:49]=[C:48]([CH3:50])[C:47]([O:51][CH:1]=[O:3])=[C:46]([CH3:52])[CH:45]=3)[C:29](=[O:42])[N:30]3[CH2:31][CH2:32][N:33]([CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[CH2:34][CH2:35]3)=[O:26])[CH2:21][CH2:20]2)[CH2:17][CH2:16][C:15]2[CH:53]=[CH:54][CH:55]=[CH:56][C:14]=2[NH:13]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(C)c1O
Solvent: ClCCl
Solvent: O=CO
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(C)c1OC=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 25 μL acetic anhydride and 0.5 mL formic acid in 1 mL DCM was stirred for 2 h at RT (formation of the mixed anhydride). Then 38 mg (0.06 mmol) (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-[4-(tetrahydropyran-4-yl)-piperazin-1-yl]-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate was added (Example 7i) and the reaction mixture was stirred overnight at RT. The reaction solution was evaporated down and the residue was again added to a solution of the mixed anhydride and stirred overnight at RT. The mixture was evaporated down i.vac. and the residue was purified by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:28])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C:22](=[O:26])[CH2:23]2)[C@:19]2([CH3:20])[C@H:14]([CH2:15][C:16](=[O:27])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)(=O)C.C(=O)(O)[O-].[K+]>CO.O>[OH:4][CH2:5][C:6](=[O:28])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C:22](=[O:26])[CH2:23]2)[C@:19]2([CH3:20])[C@H:14]([CH2:15][C:16](=[O:27])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1
Reactant: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CO)[C@@]3(C)CC(=O)[C@@H]12
Yield: 71 %

Procedure:
21-Acetoxy-5α-pregnane-3,11,20-trione (4.85 g.) in hot methanol (200 ml.) was treated with potassium bicarbonate solution (10%; 20 ml.) and the stirred solution was refluxed under nitrogen for 15 minutes. The cooled reaction mixture was diluted with water and the oily precipitate was extracted into methylene chloride. The extract was washed with water, dried over sodium sulphate and evaporated to a foam (4.3 g.) which was triturated with ether to give title compound (3.07 g.) as white crystals, m.p. 164°-170°.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.BrC1OC(C(Cl)=O)=CC=1.O.[NH2:24][NH2:25]>O>[Br:1][C:2]1[O:6][C:5]([C:7]([NH:24][NH2:25])=[O:9])=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(O)c1ccc(Br)o1
Agent: O=C(Cl)c1ccc(Br)o1
Solvent: O
Solvent: O=S(Cl)Cl
Product: NNC(=O)c1ccc(Br)o1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-furan-2-carboxylic acid (38.2 g, 200 mmol) and thionylchloride (163.1 g, 1.37 mol) was stirred at 70° C. overnight. The mixture of 5-bromo-furan-2-carbonyl chloride was evaporated, solved in tetrahydrofuran (10 ml) and added to a mixture of hydrazine monohydrate (120.1 g, 2.4 mol), followed by stirring for 0.5 hours at <5° C. Water (50 ml) was added followed by filtration. The crystalline product was recrystallized from ethanol (125 ml, 96%). Yield 21.2 g (52%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16]CC3C=CC=CC=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)[CH3:6])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)n1ccc2cc(OCc3ccccc3)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)n1ccc2cc(O)ccc21

Procedure:
A mixture of 2-(5-Benzyloxy-indol-1-yl)-propionic acid ethyl ester (16 g) and Pd/C (5%, 1.93 g) in ethanol (190 mL) is stirred under 60 PSI of hydrogen overnight. Filtration and concentration yields the title compound.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=O)OCC)C.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH:9][C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(Cl)cc2)cc1
Yield: 95 %

Procedure:
Prepared in analogy to example 56b) from (4-nitro-benzyl)-phosphonic acid diethyl ester and 4-chloro-benzaldehyde. Yellow solid. Yield=95%. MS: m/e=259.1 (M+).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5].[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[NH2:10][C:7]1[CH:8]=[CH:9][C:2]([O:26][CH:23]2[CH2:24][CH2:25][N:20]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:21][CH2:22]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: OC1CCN(Cc2ccccc2)CC1
Product: N#Cc1cc(N)ccc1OC1CCN(Cc2ccccc2)CC1
Yield: 41.6 %

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthetic Example 4 using 2-chloro-5-nitrobenzonitrile (10 g) and 1-benzyl-4-hydroxypiperidine (11.5 g), the title compound (7 g) was obtained as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][C:15]([OH:17])=[O:16])=[C:9]([O:23][CH3:24])[CH:8]=1.[O-][CH2:26]C.[Na+].C[O-].[Na+]>>[CH2:1]([O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][C:15]([OH:17])=[O:16])=[C:9]([O:23][CH3:24])[CH:8]=1)[CH3:26]
Reactant: CCCCCC(CC(=O)O)c1ccc(OCCCOC)cc1OC
Reactant: CC[O-]
Agent: C[O-]
Agent: [Na+]
Product: CCCCCC(CC(=O)O)c1ccc(OCCCOCC)cc1OC

Procedure:
Following a similar procedure to that described in Preparation 50A, but using an ethanolic sodium ethoxide solution instead of a methanolic sodium methoxide solution, the title compound was obtained as an oily substance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[CH3:26][S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28]>>[CH3:26][S:27]([N:30]1[CH2:35][CH2:34][N:33]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:9]/[C:10](/[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:11]\[OH:12])=[CH:4][CH:3]=2)[CH2:32][CH2:31]1)(=[O:29])=[O:28]
Reactant: Cc1ccccc1C(C/C(=N\O)c1ccncc1)c1ccc(Br)cc1
Reactant: CS(=O)(=O)N1CCNCC1
Product: Cc1ccccc1C(C/C(=N\O)c1ccncc1)c1ccc(N2CCN(S(C)(=O)=O)CC2)cc1

Procedure:
In analogy to example 39, from (E)-3-(4-bromo-phenyl)-1-pyridin-4-yl-3-o-tolyl-propan-1-one oxime (example 31) and 1-methanesulfonyl-piperazine (CAS RN: [55276-43-2]) was prepared the title compound as an off-white foam, MS (ESI+): m/z=479.2 ([M+H]+).
Reaction SMILES: [N:1]1([C:5]2[C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:13]([Cl:23])[C:12]3[C:7](=[CH:8][CH:9]=[C:10](Br)[CH:11]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:25][N:26]1[C:30]([C:31]([C:33]2[CH:34]=[N:35][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:38]=2)=[O:32])=[CH:29][N:28]=[CH:27]1>>[N:1]1([C:5]2[C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:13]([Cl:23])[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:31]([C:30]4[N:26]([CH3:25])[CH:27]=[N:28][CH:29]=4)([C:33]4[CH:34]=[N:35][C:36]([C:39]([F:41])([F:40])[F:42])=[CH:37][CH:38]=4)[OH:32])[CH:11]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cn1cncc1C(=O)c1ccc(C(F)(F)F)nc1
Reactant: Clc1ccc(Oc2c(N3CCC3)nc3ccc(Br)cc3c2Cl)cc1
Product: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(N3CCC3)c(Oc3ccc(Cl)cc3)c(Cl)c2c1

Procedure:
The title compound was prepared using 2-(azetidin-1-yl)-6-bromo-4-chloro-3-(4-chlorophenoxy)quinoline (Intermediate 9, step d) and (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (Intermediate 2, step c) according to the procedure of
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>C(Cl)Cl>[CH:1]1([N:6]2[CH2:7][CH2:8][CH:9]([O:12][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCN(C2CCCC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCN(C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
1-Cyclopentyl-4-hydroxypiperidine (1 g, 5.91 mmol), DCM (10 ml) and triethylamine (0.91 ml, 6.5 mmol) were cooled to 0-5° C. and mesyl chloride (0.46 ml, 5.91 mmol) was added dropwise under N2. The reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with sat. NaHCO3 (20 ml) and the aqueous phase extracted with DCM (2×5 ml). The combined organic extracts were dried over MgSO4, filtered, washed with DCM and concentrated in vacuo to give the title compound (1.38 g, 95%) as a pale yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:22]=[C:23]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]4[CH3:37])[C:24]4[CH2:30][CH2:29][NH:28][CH2:27][C:25]=4[N:26]=3)=[CH:17][CH:16]=2)=[O:13])[CH2:10][CH2:9]1.CCN(C(C)C)C(C)C.[CH:47]1([C:50](Cl)=[O:51])[CH2:49][CH2:48]1>C(Cl)Cl>[CH:47]1([C:50]([N:28]2[CH2:29][CH2:30][C:24]3[C:23]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]4[CH3:37])=[N:22][C:21]([C:18]4[CH:17]=[CH:16][C:15]([NH:14][C:12]([NH:11][CH:8]5[CH2:9][CH2:10]5)=[O:13])=[CH:20][CH:19]=4)=[N:26][C:25]=3[CH2:27]2)=[O:51])[CH2:49][CH2:48]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CCNC2
Reactant: O=C(Cl)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CCN(C(=O)C1CC1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.7 %

Procedure:
To a stirred solution of (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea 2,2,2-trifluoroacetate (106 mg, 0.26 mmol) in DCM was added iPr2NEt (91 uL, 0.52 mmol) and cyclopropane carbonyl chloride (26 uL, 0.29 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and triturated from Et2O:MeOH (10:1) to give a white solid (69 mg, 0.15 mmol, 58% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)=[CH:6][N:7]=1
Reactant: OCc1ccc(Cl)nc1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Clc1ccc(COCc2ccc(-c3ccccc3)cc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
To a solution of (6-chloro-3-pyridyl)methanol (0.538 g) in tetrahydrofuran (15 mL), sodium hydride (63% oil, 0.182 g) was added at 0° C., and the mixture was stirred at room temperature for 30 minutes. 1-(Bromomethyl)-4-phenylbenzene (0.932 g) was added to the reaction solution at room temperature, and the mixture was stirred at 50° C. for 3 hours. The reaction solution was cooled to 0° C., and a saturated aqueous ammonium chloride solution was added thereto, followed by extraction with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column (Yamazen Corporation, elution solvent: hexane/ethyl acetate) to obtain the title compound (0.896 g).