Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][NH2:19]>C(O)C>[OH:12][C:11]1[C:10]2[C:9](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:19][N:18]=1
Reactant: NN
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Solvent: CCO
Product: Oc1nnc(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 14.5 h

Procedure:
The mixture of o-benzoyl benzoic acid (11.3 g; 0.05 mol) and hydrazine (0.15 mol) in ethanol (150 ml) is stirred at room temperature for 5-24 hours to give 1-hydroxy-4-phenyl phthalazine as a white precipitate which is filtered off and is washed with ethanol. (12.3 g)(m.p. 240° C.)
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:19]([Si:23]([CH3:33])([CH3:32])[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])([CH3:22])([CH3:21])[CH3:20].[Br:34]NC(=O)CCC(N)=O>C(Cl)(Cl)(Cl)Cl>[Br:34][CH2:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[O:24][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:33])[CH3:32]
Reactant: Cc1ccccc1O[Si](C)(C)C(C)(C)C
Reactant: NC(=O)CCC(=O)NBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1CBr

Procedure:
A catalytic amount of benzoylperoxide (0.5 g) was added to a refluxing solution of an equimolar mixture of Example 1d (30 g, 0.134 mol) and N-bromosuccinamide (24 g, 0.134 mol) in dry CCl4 (175 mL) for 1.5 h. The reaction mixture was filtered, concentrated and purified using flash chromatography (silica gel, PE60-80° C.) to obtain the title compound as an oil. Yield: 36 g, (90%); 1H NMR (CDCl3): δ 0.30 (s, 6H, 2CH3), 1.10 (s, 9H, 3CH3), 4.5 (s, 2H, CH2), 6.8-7.5 (m, 4H, Ar).
Reaction SMILES: [NH:1]1[C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=[N:2]1.C(=O)(O)[O-].[Na+].[Cl:15][CH2:16][C:17](Cl)=[O:18]>CCOC(C)=O>[Cl:15][CH2:16][C:17]([NH:9][NH:8][C:6]([C:5]1[NH:1][N:2]=[CH:3][CH:4]=1)=[O:7])=[O:18]
Reactant: NNC(=O)c1ccn[nH]1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CCl)NNC(=O)c1ccn[nH]1
Yield: 67 %

Procedure:
To a suspension of 1H-pyrazole-5-carbohydrazide (102 mg, 0.81 mmol) in 7 mL AcOEt was added 1.8 mL of 1M sodium bicarbonate solution and the initial white suspension was stirred for a few minutes until it became completely clear two-phase solution. Upon cooling in an ice-water bath to it was added 0.7 ml AcOEt solution of chloroacetyl chloride (110 mg, 0.97 mmol). After stirring overnight, the reaction mixture was poured into a separatory funnel. The organic layer was separated and the aqueous layer was extracted twice with AcOEt. The combined org layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a white solid (110 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][CH:22]([CH3:46])[CH2:23][NH:24][C@H:25]1[CH2:30][C@@H:29]([C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH2:28][N:27]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:26]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.ClC(N(C)C)=[N+](C)C>C(#N)C>[CH3:21][CH:22]([CH3:46])[CH2:23][N:24]([C:18]([C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]2[C:9]=1[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:20])[C@H:25]1[CH2:30][C@@H:29]([C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH2:28][N:27]([C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH2:26]1
Reactant: CC(C)CN[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1nc2ccccn2c1CCc1ccccc1
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)CN(C(=O)c1nc2ccccn2c1CCc1ccccc1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.4 %

Procedure:
Ethyl 3-(2-phenylethyl)imidazo[1,2-a]pyridine-2-carboxylate (883 mg) was dissolved in ethanol (50 ml), 2N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, neutralized with 1N hydrochloric acid, subjected to DIAION HP-20 (manufactured by Mitsubishi Chemical), and washed with water. The fraction eluted with acetone was concentrated under reduced pressure to give 3-(2-phenylethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (1.03 g). The obtained 3-(2-phenylethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (341 mg), tert-butyl(3S, 5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (370 mg) and N,N-diisopropylethylamine (862 μl) were dissolved in acetonitrile (20 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (561 mg) was added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (9:1) was concentrated under reduced pressure to give the object product (522 mg).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[CH2:5][NH:6][C:7]#[N:8])[CH3:2].C(N(CC)CC)C.[CH3:19][Si:20](Cl)([CH3:22])[CH3:21]>C1COCC1>[CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[CH2:5][N:6]=[C:7]=[N:8][Si:20]([CH3:22])([CH3:21])[CH3:19])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(CNC#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(CN=C=N[Si](C)(C)C)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2,2-diethoxyethylcyanamide (5.5 g.) in anhydrous THF (100 ml.) at 0° was added triethylamine (6.29 ml.) and trimethylsilyl chloride (5.73 ml.). The reaction mixture was stirred at room temperature for 3 hours, the precipitated triethylamine hydrochloride removed by filtration under nitrogen and the filtrate concentrated. The residue was taken up in CCl4, the solvent evaporated and the residue was distilled at 80°/0.2 mm to give 1-(2,2-diethoxyethyl)-3-trimethylsilylcarbodiimide (6.5 g.) having the following n.m.r. in CDCl3 : 0.219 (s, 9H); 1.244 (t, 6H); 3.256 (d, 2H); 3.486-3.798 (m, 4H); 4.55 (t, 1H).
Reaction SMILES: C([NH:4][C@:5]([CH3:15])([C:12]([OH:14])=[O:13])[CH2:6][S:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=O)N>[OH-].[Li+]>[C:8]([S:7][CH2:6][C@@:5]([CH3:15])([C:12]([OH:14])=[O:13])[NH2:4])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)SC[C@](C)(NC(N)=O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)SC[C@](C)(N)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
N-carbamoyl-S-tert-butyl-α-methyl-L-cysteine (82.4 g, 351.4 mmol) was dissolved in a 18% aqueous lithium hydroxide solution (630 g), and the resultant solution was refluxed in nitrogen for 41 hours. After the solution was allowed to cool down to room temperature, the insoluble substance was filtered off, and the filtrate was adjusted to pH 6 by adding conc. hydrochloric acid (180.1 g). After stirring for about 1 hour, the mixture was cooled to 4° C. to 5° C., and further stirred for 1 hour. The produced crystals were filtered off, washed with water, and then dried under reduced pressure to obtain the title compound as a white solid (53.9 g). As a result of HPLC analysis (column: COSMOSIL 5C18-AR (produced by Nacalai Tesque Inc.), mobile phase: potassium dihydrogen phosphate-phosphoric acid solution (pH 2.0)/acetonitrile=90/10, flow rate: 1.0 ml/min, detection wavelength: 210 nm, column temperature: 40° C.), it was confirmed that the solid was the desired compound (yield 85.7%)
Reaction SMILES: C(O[C:9]([N:11]([CH2:13][CH2:14][NH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)C)=O)C1C=CC=CC=1>CO.[Pd]>[CH3:9][NH:11][CH2:13][CH2:14][NH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(NCCN(C)C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CNCCNc1ccc(C(=O)OC)cc1
Yield: 78.3 %

Procedure:
To a stirred solution of methyl 4-[2-(N-benzyloxycarbonyl-N-methylamino)ethylamino]benzoate (1.26 g, 3.68 mmol) in MeOH(20 mL) was added 5 wt. Pd—C (700 mg), and the mixture was hydrogenated (3 atm) for 4 hr at room temp. The mixture was filtered, and the filtrate was evaporated under a reduced pressure to give 600 mg (78%) methyl 4-[2-(N-methylamino) ethylamino]benzoate as a colorless oil. 1H-NMR (CDCl3, 400 MHz) δ 2.46 (s, 3H), 2.88 (t, 2H, J=5.5 Hz), 3.27 (br s, 2H), 3.85 (s, 3H), 6.57 (d, 2H, J=8.8 Hz), 7.85 (d, 2H, J=8.8 Hz); MS (FAB) m/z 209 (M++1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][CH2:33][C@H:34]1[NH:38][C:37](=[O:39])[CH2:36][CH2:35]1.O[C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1>C1COCC1>[O:39]=[C:37]1[NH:38][C@H:34]([CH2:33][O:32][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)[CH2:35][CH2:36]1
Reactant: Oc1cccnc1
Reactant: O=C1CC[C@@H](CO)N1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CC[C@@H](COc2cccnc2)N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
To a solution of triphenylphosphine (52.46 g, 0.20 mol) in 400 mL of anhydrous THF at 0° C. was added diethyl azodicarboxylate (31.49 mL, 0.20 mol) dropwise. The mixture was stirred at 0° C. for 30 minutes, then brought to room temperature. (S)-5-(Hydroxymethyl)-2-pyrrolidinone (Aldrich Chemical Co., 15.19 g, 0.13 mol) and 3-hydroxypyridine (19.02 g, 0.20 mol) were added to the reaction vessel, and stirred for 16 hours. Solvent was removed in vacuo. The residue was diluted with CH2Cl2 and washed with 1N NaOH. After a brine wash (2×), the organic layer was dried over MgSO4. The residue was purified by silica gel flash chromatography using a gradient from 100% CHCl3 to 10% MeOH/CHCl3 (purification system was run twice), then recrystallized with ethyl acetate to give 4.0 g (16%) of the title compound as a white powder, mp.=121-122° C. TLC Rf =0.3 1 (10%MeOH/CHCl3). MS (DCI/NH3) m/e: 193 (M+H)+ and 210 (M+NH4)+. 1H NMR (CDCl3, 300 MHz) δ: 8.32-8.30 (m, 1H), 8.27 (dd, J=4.40, 1.50 Hz, 1H), 7.25-7.16 (m, 2H), 6.17 (br s, 1H), 4.14-4.08 (m, 1H), 4.05 (dd, J=8.80, 3.70 Hz, 1H), 3.89 (dd, J=8.80, 7.70 Hz, 1H), 2.49-2.23 (m, 3H), 1.99-1.87 (m, 1H). Anal. Calc. for C10H12N2O2 : C, 62.49; H, 6.29; N, 14.57; Found C, 62.53; H, 6.25; N, 14.71.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:34][CH2:35][C@H:36]([NH:54][C:55](=[O:63])[CH2:56][N:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1)[C:37]([NH:39][C@@H:40]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[C:47]([OH:53])[CH:46]=1)[C:41](O)=[O:42])=[O:38].[NH2:64][C@@H:65]([CH2:72][C:73]1[CH2:78][CH2:77][CH2:76][CH2:75][CH:74]=1)[C:66]([C@@:68]1([CH3:71])[CH2:70][O:69]1)=[O:67]>CN(C=O)C.O.CCOC(C)=O>[C:73]1([CH2:72][C@H:65]([NH:64][C:41](=[O:42])[C@@H:40]([NH:39][C:37](=[O:38])[C@@H:36]([NH:54][C:55](=[O:63])[CH2:56][N:57]2[CH2:58][CH2:59][O:60][CH2:61][CH2:62]2)[CH2:35][OH:34])[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[C:47]([OH:53])[CH:46]=2)[C:66]([C@@:68]2([CH3:71])[CH2:70][O:69]2)=[O:67])[CH2:78][CH2:77][CH2:76][CH2:75][CH:74]=1
Reactant: C[C@]1(C(=O)[C@@H](N)CC2=CCCCC2)CO1
Reactant: COc1ccc(C[C@H](NC(=O)[C@H](CO)NC(=O)CN2CCOCC2)C(=O)O)cc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](NC(=O)[C@H](CO)NC(=O)CN2CCOCC2)C(=O)N[C@@H](CC2=CCCCC2)C(=O)[C@@]2(C)CO2)cc1O
Temperature: 25 °C
Yield: 35.7 %

Procedure:
HATU (570 mg, 1.5 mmol) and DIPEA (1.48 mL) were added to a solution of (S)-2-((S)-3-hydroxy-2-(2-morpholinoacetamido)propanamido)-3-(3-hydroxy-4-methoxyphenyl)propanoic acid (425 mg, 1 mmol) and (S)-2-amino-3-(cyclohex-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)propan-1-one (TFA salt, 1 mmol) in DMF (20 mL) at 0° C. with stirring. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. EtOAc (100 mL) and water (100 mL) was added and the two layers were separated. The aqueous phase was extracted with EtOAc (50 mL×3) and the combined organic phases were washed with brine (200 mL×3), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (CH2Cl2/EtOAc/MeOH=20:10:0.2) to afford (S)-N-((S)-3-(cyclohex-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-2-((S)-3-hydroxy-2-(2-morpholinoacetamido)propanamido)-3-(3-hydroxy-4-methoxyphenyl)propanamide (220 mg, 35% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.74 (s, 1H), 8.22 (d, J=7.5 Hz, 1H), 8.02 (d, J=8.1 Hz, 1H), 7.78 (m, 1H), 6.73 (d, J=8.4 Hz, 1H), 6.63 (s, 1H), 6.54 (m, 1H), 5.39 (m, 1H), 5.03 (m, 1H), 4.40-4.60 (m, 2H), 4.30 (m, 1H), 3.71 (s, 3H), 3.60 (m, 4H), 3.50 (m, 2H), 3.22 (m, 1H), 2.80-3.10 (m, 3H), 2.40 (m, 3H), 2.20 (m, 2H), 1.90-2.10 (m, 4H), 1.50-1.70 (m, 4H), 1.37 (s, 3H), 1.00-1.30 (m, 3H). MS (EI) for C31H44N4O9, found 617.3 (MH)+.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][C:9]([CH3:22])=[C:8]1[CH2:7][C:6](=[O:23])[CH2:5][CH2:4]2.O[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(CO)C(CC(=O)CC1)=C[C@H]3C>>[CH3:22][C:9]1[CH2:10][C@@H:11]2[C@@H:20]([C@:3]3([CH2:2][OH:1])[C:8]=1[CH2:7][C@H:6]([OH:23])[CH2:5][CH2:4]3)[CH2:19][CH2:18][C@@:16]1([CH3:17])[C@H:12]2[CH2:13][CH2:14][C@@H:15]1[OH:21]
Reactant: CC1=C2CC(=O)CC[C@]2(CO)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@@H]2C1
Agent: C[C@@H]1C=C2CC(=O)CC[C@]2(CO)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Product: CC1=C2C[C@H](O)CC[C@]2(CO)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]2C1

Procedure:
Substituting 17β,19-dihydroxy-4α,17α-dimethyl-5-androsten-3-one and 19-hydroxy-6-methyl-5-androstene-3,17-dione for the 17β,19-dihydroxy-7α-methyl-5-androsten-3-one above results in the preparation of 4,17α-dimethyl-5-androstene-3α,17β,19-triol and 6-methyl-5-androstene-3α,17β,19-triol, respectively.
Reaction SMILES: [C:1]([OH:20])(=[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].C(=O)([O-])[O-].[K+:25].[K+]>>[C:1]([O-:20])(=[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].[K+:25]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]

Procedure:
Alfalfa was sprayed with an aqueous dispersion containing 96 percent water, 0.5 percent decane isomers obtained from the oligomerization of decene-1, 1.5 percent methyl soyate, containing 6.6 percent oleic acid and having an acid value of 20, and 2 percent potassium carbonate. The amount of oleic acid in the methyl ester was calculated to provide approximately 0.11 weight percent potassium oleate. Only 7.25 hours was required to obtain 25 percent residual moisture in the alfalfa using the formulation of this example--an 83 percent reduction in drying time.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1cccc(N2CCN(C)CC2)c1
Temperature: 25 °C
Yield: 63.7 %

Procedure:
A mixture of (S)-[1-(3-bromophenyl)ethyl]carbamic acid tert-butyl ester (5.0 g, 16.7 mmol), 1-methylpiperazine (6.7 g, 67 mmol), Pd2(dba)3 (1.55 g, 10 mol %), di-t-butyl-biphenylphosphine (0.51 g, 10 mol %), potassium phosphate (7.2 g, 34 mmol) in ethylene glycol dimethyl ether (40 ml) was refluxed for 4 hours. After cooling to room temperature, the reaction mixture was diluted with dichloromethane (100 mL) and the precipitate was filtered off. The filtrate was concentrated under vacuum. The crude product was purified by flash chromatography over silica with ethyl acetate/hexanes (1:1) to provide (S)-{1-[3-(4-methylpiperazin-1-yl)phenyl]ethyl}carbamic acid tert-butyl ester as an oil (3.4 g, 64% yield).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:31](Br)(Br)([Br:33])[Br:32]>C(Cl)Cl>[Br:32][C:31]([Br:33])=[CH:7][C:6]1[CH:1]=[CH:2][C:3]2[O:11][CH2:10][O:9][C:4]=2[CH:5]=1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
To a solution of piperonal (4.5 g, 30 mmol) and triphenylphosphine (24 g, 90 mmol) in DCM (120 mL) in an ice-water bath was added a solution of carbontetrabromide (15 g, 45 mmol) over a 10 minutes period. After the addition completed, the ice-water bath was removed, the reaction stirred at ambient temperature for 2 h, and then quenched with saturated NaHCO3. Aqueous was separated, and extracted with dichloromethane (2 times). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to give a redish colored residue, that was filtered through a short path silica gel plug, eluting with DCM/hexane (10% to 20%). Concentration of the filtrate gave the title compound (6.5 g, 74% yield) as a pale yellow liquid. 1H NMR (CDCl3) δ 7.36 (s, 1H), 7.18 (d, 1H, J=1.6 Hz), 6.95 (dd, 1H, J=1.5, 8.1 Hz), 6.79 (d, 1H, J=8.1 Hz), 5.99 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:23])[C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH2:20]NC)[CH:15]=3)[S:11][C:7]=2[C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:5][CH:4]=1.[CH3:30][O-:31].[Na+].ClCCl.CO>O1CCCC1>[CH3:30][O:31][CH2:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][N:17]=1)[C:13]([NH:12][C:10]1[S:11][C:7]2[C:6]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:23]
Reactant: C[O-]
Reactant: CNCc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: COCc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Temperature: 50 °C
Yield: 25 %

Procedure:
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-methylaminomethyl-isonicotinamide (200 mg, 0.48 mmol, dissolved in tetrahydrofurane (5.0 ml), is treated with sodium methoxide (81 mg, 1.4 mmol) at 0° C. and the mixture heated to 50° C. for 15 h. The mixture is quenched with saturated sodium carbonate (4.0 ml), extracted four times with each 15 ml dichloromethane and the combined organic phases dryed and evaporated. Flash chromatography (first SiO2, eluent: dichloromethane/methanol 0 to 5% and second dichloromethane/ethyl acetae 30% to 60%) afforded the title compound as light yellow crystals (49 mg, 25% yield). MS: m/e=415 (M+H+).
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.N(C(C)(C)C#N)=NC(C)(C)C#N.[OH-].[Na+].O>C(OCCCC)(=O)C.CCCCCC>[CH:10]#[C:9][C:8]1[CH:11]=[CH:12][C:5]([OH:4])=[CH:6][CH:7]=1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCOC(C)=O
Solvent: CCCCCC
Product: C#Cc1ccc(O)cc1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
p-Acetoxystyrene (32.4 g (0.2 mol)) was dissolved in 120 ml of butyl acetate, 0.066 g of azobisisobutyronitrile (AIBN) was added thereto with stirring at 80° C. three times every 2.5 hours in a nitrogen stream, and the stirring was further continued for 5 hours, thereby performing the polymerization reaction. The reaction solution was poured in 1,200 ml of hexane to precipitate a white resin, and the obtained resin was dried and then dissolved in 150 ml of methanol. An aqueous solution containing 7.7 g (0.19 mol) of sodium hydroxide/50 ml of water was added thereto, and the resulting solution was refluxed under heating for 3 hours to effect hydrolysis. The resulting reaction solution was diluted by adding 200 ml of water and neutralized with hydrochloric acid to precipitate a white resin. The precipitated resin was separated by filtration, washed with water, dried and further dissolved in 200 ml of tetrahydrofuran, and the resulting solution was added dropwise to 5 L of ultrapure water with vigorous stirring, thereby effecting reprecipitation. This reprecipitation operation was repeated three times. The obtained resin was dried in a vacuum drier at 120° C. for 12 hours to obtain poly(p-hydroxystyrene) Alkali-Soluble Resin R-1. The weight average molecular weight of the obtained resin was 3,000.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:27]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1cccc(N2CCCC2)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(N2CCCC2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 3-(pyrrolidin-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.82 min.; [M+H]+: 395.20 g/mol.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:6](Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[K+]>C1COCC1>[CH2:6]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClCc1ccccc1
Reactant: c1c[nH]cn1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: c1ccc(Cn2ccnc2)cc1
Temperature: 25 °C
Yield: 65.2 %

Procedure:
According to the selected experimental protocol, 44 g of imidazole (0.65 mol.), 100 g of benzyl chloride (0.78 mol.), and 60 g of KOH (1.07 mol.) in 700 ml of THF are placed in a 1-liter balloon flask. The reaction mixture is brought to reflux for 120 h, then cooled at ambient temperature. The organic phase is filtered and the solvent is evaporated under reduced pressure. The obtained solid product is dissolved in 500 ml of CH2Cl2, then washed with water (3×100 ml). The organic phase is dried on Na2SO4, filtered, then evaporated under reduced pressure. The collected solid is recrystallized in toluene to yield 67 g of desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])=[C:5]2Cl.[NH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])=[C:5]2[NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CC(C)CC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CC(C)CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure B, 1-(6-bromo-4-chloroquinolin-3-yl)-3-methylbutan-1-one (309 mg, 0.950 mmol) was reacted with tert-butyl trans-4-aminocyclohexylcarbamate (407 mg, 1.90 mmol) to afford the desired product (267 mg, 56%) as a yellow solid: ESI MS m/z 504 [C20H26BrN3O+H]+.