Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)[OH:10])O)O)=O.C([O-])(=O)CCCCCCCCCCC.[Na+].O.[ClH:29]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)(Cl)Cl>[Cl:29][CH2:11][C:9]1[O:10][C:3]([CH:2]=[O:1])=[CH:5][CH:7]=1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: Cl
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1ccc(CCl)o1
Reaction time: 2.5 h

Procedure:
To the same three-necked flask as in Example 1 were added 5 g (0.028 mole) of a commercially available D-(-)-fructose and two kinds of surface active agent, i.e., 62.2 mg (0.00028 mole) of sodium laurate and 90.2 mg (0.00028 mole) of tetrabutylammonium bromide. Then, 5 ml of water and 30 ml of carbon tetrachloride were added thereto and the mixture was stirred. Thereafter, a molar excess of hydrogen chloride was passed through the mixture at room temperature for about 30 minutes. After stirring was continued at room temperature for a further 2.5 hours, the lower carbon tetrachloride layer was separated from the upper aqueous layer. Thirty milli-liters of carbon tetrachloride and the above two surface active agents of the same amounts as above were then freshly added to the aqueous layer. After stirring was continued at room temperature for 2.5 hours, the lower carbon tetrachloride layer was again separated. This carbon tetrachloride extraction operation was repeated three times in total. All the carbon tetrachloride layers were combined and filtered through Celite. The filtrate was neutralized, dried and concentrated to obtain about 2.0 g of 5-chloromethylfurfural as a crude product.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.Cl.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[CH2:21][CH2:20]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][C:13]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=3)[CH2:21][CH2:20]2)=[O:15])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCCC(=O)O)cc1
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCCC(=O)NC2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)cc1
Reaction time: 12 h
Yield: 60.2 %

Procedure:
3-(4-Acetylphenyloxy)propionic acid (1.0 g) and 4-amino-1-(3,4-dichlorobenzyl)piperidine dihydrochloride (1.6 g) were suspended in DMF (50 mL), and triethylamine (1.3 mL), EDC hydrochloride (1.1 g) and HOBt (0.9 g) were added to the suspension. The suspension was stirred for 12 hrs. The reaction mixture was washed with water and then saturated brine and dried, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to crystallize to give the title compound (1.3 g) as a white solid.
Reaction SMILES: C(O[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])C.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]#[N:20].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.CC(C)([O-])C.[Na+]>CC(O)=O.CC(O)=O.[Pd].C(O)CO.O1CCCC1>[O:8]1[CH2:9][CH2:10][O:7][C:6]1=[C:5]1[C:12]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:18]([C:19]#[N:20])=[CH:4]1
Reactant: CCOC=CC(=O)OCC
Reactant: N#CCc1ccccc1Br
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(C)(C)[O-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: OCCO
Product: N#CC1=CC(=C2OCCO2)c2ccccc21
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
Ethyl 3-ethoxyacrylate (36.9 kg, 255.0 moles), 2-bromophenyl acetonitrile (50 kg, 255. 1 moles), and tetrahydrofuran (57 L) were combined in reactor 1 and the resultant solution was stirred at 25° C. until needed (4 hours.). Palladium II acetate (1.3 kg, 5.7 moles), tricyclohexylphosphine (1.9 kg, 6.7 moles), and tetrahydrofuran (148 L) were combined in reactor 2 and the resultant mixture was stirred for 30 minutes at 25° C. The mixture was then cooled to 5° C. and sodium t-butoxide (61.3 kg, 637.7 moles ) was added to reactor 2 at 5° C. The resulting mixture was warmed to 15° C. and stirred for 15 minutes and then cooled back to 5° C. The contents in reactor 1 were then slowly charged to reactor 2 over 2 hours. at 10° C. and then the contents in reactor 2 were stirred for 15 minutes at 10° C. Reactor 2 was then slowly heated to 60° C. at a rate of 8 to 2° C. per hour (5 hours.) and then held at 60° C. for 4 hours. The reaction was then cooled to 5° C. and ethylene glycol was added at 5° C. The Tetrahydrofuran in the reaction was then distilled off. The reaction was again cooled to 10° C. and sulfuric acid (88.4 kg) added over 1.5 hours at 10° C. The reaction was heated to 40° C. at a rate of 8 to 12° C. per hour (3 hours) and held at 40° C. for 8 hours. The reaction was cooled to 10° C. and ammonium hydroxide (44.8 kg) and water (201 L) were added. The slurry was warmed to 20° C. and granulated for 2 hours. The solid was filtered and washed with water (61 L). The crude solid was recharged to the reactor and water (220 L) added. The slurry was granulated at 20° C. for 4.5 hours and then filtered. The filter cake was washed with water (61 L) and the product dried at 55° C.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](N(OC)C)=[O:14])=[CH:8][CH:7]=1>C1COCC1.CCOCC.[Cl-].[Na+].O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](=[O:14])[CH:1]=[CH2:2])=[CH:8][CH:7]=1
Reactant: CON(C)C(=O)Cc1ccc(F)cc1
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(=O)Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
To a solution of 220 mL (1.0 M, 220 mmol) of vinylmagnesium bromide in 100 mL THF, was added dropwise under nitrogen atmosphere at 0° C. a solution of 21 g (106.6 mmol) 2-(4-fluorophenyl)-N-methoxy-N-methylacetamide (step A) in ˜150 mL dry ether. The reaction mixture was stirred at 0° C. for 0.5 hr then poured slowly into an ice/2N aq HCl mixture. The resulting mixture was diluted with ether and brine, transferred to a separatory funnel and the organic layer separated. The organic layer was washed with brine, dried over drying agent, filtered and the solvent evaporated under vacuum to give 14.2 g of the crude title compound which was used without further purification. 1H-NMR (CDCl3): δ: 7.19 (2 H, m), 7.02 (2 H, t, J=9.5 Hz), 6.42 (1 H, dd, J1=14.2 Hz, J2=11 Hz). 6.34 (1 H, d, J=14.2 Hz), 5.86 (1 H, d, J=11 Hz), 3.87 (2 H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:28]=[CH2:29])=[C:4]([CH:9]=[C:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)=[CH:19][CH:18]=2)[C:11]=1[C:12]([F:15])([F:14])[F:13])[C:5]([O:7]C)=[O:6].ClC1C(C=C)=C(C=C(CC2C=CC(N3C=CC=N3)=CC=2)C=1C(F)(F)F)C(OCC)=O.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[Cl:1][C:2]1[C:3]([CH:28]=[CH2:29])=[C:4]([CH:9]=[C:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)=[CH:19][CH:18]=2)[C:11]=1[C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=[O:6]
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(-n3cccn3)cc2)c(C(F)(F)F)c1Cl
Agent: C=Cc1c(C(=O)OCC)cc(Cc2ccc(-n3cccn3)cc2)c(C(F)(F)F)c1Cl
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1c(C(=O)O)cc(Cc2ccc(-n3cccn3)cc2)c(C(F)(F)F)c1Cl
Temperature: 15 °C
Reaction time: 16 h
Yield: 19.4 %

Procedure:
To a solution of methyl 3-chloro-2-ethenyl-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)benzoate (0.80 g) and ethyl 3-chloro-2-ethenyl-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)benzoate (0.80 g) in THF (5.08 mL)-water (5.08 mL) were added lithium hydroxide monohydrate (0.20 g) and methanol (0.50 mL), and the mixture was stirred at 15° C. for 16 hr. The reaction mixture was poured into 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.15 g).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([NH:14][C@H:15]([C:37]([N:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)=[O:38])[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][S:24]([C:27]4[C:28]5[CH:29]=[CH:30][N:31]=[CH:32][C:33]=5[CH:34]=[CH:35][CH:36]=4)(=[O:26])=[O:25])=[CH:19][CH:18]=3)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.[C:45]1([CH2:51][CH2:52][CH2:53]Br)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[Cl-].[Na+]>CN(C)C=O>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([NH:14][C@H:15]([C:37]([N:39]3[CH2:40][CH2:41][N:42]([CH2:53][CH2:52][CH2:51][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH2:43][CH2:44]3)=[O:38])[CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][S:24]([C:27]4[C:28]5[CH:29]=[CH:30][N:31]=[CH:32][C:33]=5[CH:34]=[CH:35][CH:36]=4)(=[O:26])=[O:25])=[CH:21][CH:22]=3)(=[O:12])=[O:13])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: O=C([C@H](Cc1ccc(OS(=O)(=O)c2cccc3cnccc23)cc1)NS(=O)(=O)c1cccc2cnccc12)N1CCNCC1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=C([C@H](Cc1ccc(OS(=O)(=O)c2cccc3cnccc23)cc1)NS(=O)(=O)c1cccc2cnccc12)N1CCN(CCCc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 7 h
Yield: 60.5 %

Procedure:
301 mg of the crude product obtained in Example 28 and 95 mg of 3-phenylpropyl bromide were dissolved in 5 ml of dimethylformamide, and to the solution were added 66 mg of potassium carbonate and 72 mg of sodium iodide. After stirring at 80° C. for 7 hours, 30 ml of saturated sodium chloride was added to the reaction mixture, which was then extracted with 40 ml of ethyl acetate, and the extract was washed with 30 ml of saturated sodium chloride aqueous solution, dried over magnesium sulfate, and concentrated under a reduced pressure. The resulting residue was applied to a silica gel column and eluted with chloroform/methanol (40:1) to obtain 216 mg of the title compound in a yellow amorphous form.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[H-].[Na+].[CH:14]([C:16]1[C:24]2[C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:21]=[CH:20][C:19]=2[NH:18][N:17]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[C@@H:4]([NH:3][CH2:14][C:16]1[C:24]3[C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:21]=[CH:20][C:19]=3[NH:18][N:17]=1)[CH2:5]2
Reactant: COC(=O)c1cccc2[nH]nc(C=O)c12
Reactant: N[C@H]1CN2CCC1CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cccc2[nH]nc(CN[C@H]3CN4CCC3CC4)c12
Reaction time: 1 h
Yield: 180 %

Procedure:
To a stirred suspension of (R)-(+)-3-aminoquinuclidine dihydrochloride (916.0 mg, 4.6 mmol) in dichloromethane (60 mL) was added sodium hydride (368 mg, 9.2 mmol) in portions and the mixture was stirred for 1 h. Acetic acid (0.15 mL) was added dropwise. Then methyl 3-formyl-1H-indazole-4-carboxylate (B1) (776 mg, 3.8 mmol) was added and the mixture continued to stir at room temperature for an additional 2 h. Sodium triacetoxyborohydride (4.2 g, 19.6 mmol) was added in one portion and stirring was continued overnight at room temperature. The solvent was removed under reduced pressure, and the crude material was purified by column chromatography (silica gel, 90:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (R)-methyl 3-((quinuclidin-3-ylamino)methyl)-1H-indazole-4-carboxylate as a brown solid (2.15 g, quant. yield): 1H NMR (500 MHz, CDCl3) δ 7.80 (dd, J=7.2, 0.7 Hz, 1H), 7.68 (dd, J=8.4, 0.7 Hz 1H), 7.36 (dd, J=8.3, 7.3 Hz, 1H), 4.30 (d, J=14.2 Hz, 1H), 4.25 (d, J=14.2 Hz, 1H), 3.96 (s, 3H), 3.28-3.25 (m, 1H), 3.12-3.07 (m, 1H), 2.99-2.91 (m, 4H), 2.73-2.69 (m, 1H), 2.19-2.12 (m, 1H), 2.04-2.00 (m, 1H), 1.80-1.74 (m, 1H), 1.65-1.57 (m, 1H), 1.52-1.46 (m, 1H). MS (ESI+) m/z 315 (M+H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14]Br)[CH3:11].C(N(CC)CC)C.C(O)C>O>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:14][CH:13]([O:16][CH2:17][CH3:18])[O:12][CH2:10][CH3:11])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCOC(CBr)OCC
Reactant: Cc1ccc(N)cc1Br
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CCOC(CNc1ccc(C)c(Br)c1)OCC
Temperature: 150 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
Under a nitrogen stream, a mixture of 3-bromo-4-methyl-phenylamine (4.94 g, 26.55 mmol), bromoacetaldehyde diethyl acetal (6.80 g, 34.50 mmol), triethylamine (5.37 mL, 38.53 mmol) and ethanol (10.3 mL) was stirred for 2 hours at 150° C. using a microwave apparatus. The resultant solution was cooled to room temperature, and then water was added thereto. The resultant mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography (developing solution=ethyl acetate:n-hexane (1:10)), to thereby obtain the titled compound (6.43 g, 80%).
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:32]([O:34][C:35]([C@@H:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[C:42](O)=[O:43])=[O:36])[CH3:33].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1CCCC1=O.C(OCC)(=O)C>[CH2:32]([O:34][C:35]([CH:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[C:42]([N:5]1[CH2:6][CH2:7][N:2]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:23])([F:25])[F:24])=[O:16])=[CH:10][CH:9]=2)[CH2:3][CH2:4]1)=[O:43])=[O:36])[CH3:33]
Reactant: CCOC(=O)[C@@H]1CCC[C@H]1C(=O)O
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCCC1C(=O)N1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
To a solution of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl-phenyl)-amide hydrochloride (212 mg, 0.435 mmol), racemic trans-cyclopentane-1,2-dicarboxylic acid monoethyl ester (81 mg, 0.435 mmol) and triethylamine (305 μL, 2.17 mmol) in 5 mL 1-methyl-2-pyrrolidinone was added (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP, 202 mg, 0.456 mmol) in one portion and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography (eluted with ethyl acetate/hexane) to yield rac-2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid ethyl ester as an amorphous solid (236 mg, 93%). ES-MS calcd for C30H31F3N4O5 (m/e) 584.60, obsd 585 (M+H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].[Cl:16][C:17]1[N:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1.C(N(CC)CC)C>C(O)C.C(Cl)Cl>[Cl:16][C:17]1[N:22]=[C:21]([N:13]2[CH2:12][CH2:11][CH:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:15][CH2:14]2)[CH:20]=[CH:19][N:18]=1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: Clc1ccnc(Cl)n1
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC1CCN(c2ccnc(Cl)n2)CC1

Procedure:
A solution of 4-N-Boc-aminomethylpiperidine (4.95 g, 23.1 mmol), 2,4-dichloropyrimidine (3.28 g, 22.0 mmol) and triethyl amine (7.84 g, 77.5 mmol) in ethanol (90 ml) was stirred at 85° C. for 45 minutes. The reaction mixture was concentrated under reduced pressure and the residue obtained was dissolved in CH2Cl2 and filtered. The solvent was removed under reduced pressure to give a crude residue that was purified using normal phase chromatography, eluting with iso-hexane and increasing amounts of ethyl acetate to give tert-butyl (1-(2-chloropyrimidin-4-yl)piperidin-4-yl)methylcarbamate as an off white solid (6.0 g).
Reaction SMILES: C([O-])(O)=O.[Na+].[NH2:6][OH:7].Cl.[Cl:9][C:10]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:11]=1[C:12]([NH:14][C@H:15]([C:33](Cl)=[O:34])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[O:31][CH3:32])=[CH:19][CH:18]=1)=[O:13]>C1COCC1.O.C1COCC1>[OH:7][NH:6][C:33](=[O:34])[C@H:15]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[O:31][CH3:32])=[CH:19][CH:18]=1)[NH:14][C:12](=[O:13])[C:11]1[C:10]([Cl:9])=[CH:39][CH:38]=[CH:37][C:36]=1[Cl:40]
Reactant: NO
Reactant: COc1cccc(OC)c1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(OC)c1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)NO)cc1
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
NaHCO3 (0.21 g) was added to a solution of NH2OH HCl (0.14 g) in THF/water (5 mL each) at 0° C. and the mixture was stirred for ½ h. A solution of N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanyl chloride (0.1 g) in THF (5 mL) was added to the mixture at 0° C. and the mixture was stirred overnight at room temperature. The mixture was partitioned between EtOAc and water. The EtOAc layer was washed successively with 1 N HCl and brine, dried and evaporated. The residue was purified by preparative TLC (silica gel; eluent: CH2Cl2/MeOH 8%) to yield 27 mg of the title compound. ESMS: m/z 489 (MH+).
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7](O)=[O:8])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.C(N1C=CN=C1)([N:22]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1.O>[C:1]1(=[O:19])[N:5]([CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([NH2:22])=[O:8])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)CC(C(=O)O)N1C(=O)c2ccccc2C1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(C(N)=O)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a stirred solution of 2-phthalimido-4-methylpentanoic acid (1.32 g, 5.0 mmol) in tetrahydrofuran (25 mL) are added carbonyldiimidazole (0.81 g, 5.0 mmol) and a few crystals of 4-N,N-dimethylaminopyridine followed by 15 mL of tetrahydrofuran. The reaction mixture is stirred at room temperature for 1 hour, then 1 mL of concentrated ammonium hydroxide is added. After 10 minutes, the reaction mixture is diluted with 50 mL water. The resulting slurry is partially concentrated to remove the tetrahydrofuran and filtered. The solid is washed with water and dried in vacuo (60° C., <1 mm) to afford 1.16 g (89%) of 2-phthalimido-4-methylpentanamide as a white powder: mp 173°-176° C.; 1H NMR (DMSO-d6, 250 MHz) δ 7.95-7.79 (m, 4 H, Ar), 7.61 (br s, 1 H, CONH2), 7.22 (br s, 1 H, CONH2), 4.73-4.60 (m, 1 H), 2.30-2.10 (m, 1 H), 1.95-1.80 (m, 1H), 1.45-1.25 (m, 1H); 13C NMR (DMSO-d6) d: 170.4, 167.7, 134.4, 131.5, 123.1, 51.3, 36.4, 24.7, 23.2, 20.6. Anal. Calculated for C14H16N2O3. Theoretical: C, 64.60; H, 6.20; N, 10.76. Found: C, 64.63; H, 6.11; N, 10.70.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[CH2:7]([CH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[Se:26][C:25]([CH:27]=O)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[CH2:8][CH3:9].Cl>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1.CC(OC)(C)C.[Cl-].[NH4+]>[CH:27]([C:25]1[Se:26][C:22]([C:19]2[CH:20]=[CH:21][C:16]([CH:13]3[CH2:14][CH2:15][CH:10]([CH2:7][CH2:8][CH3:9])[CH2:11][CH2:12]3)=[CH:17][CH:18]=2)=[CH:23][CH:24]=1)=[CH:1][CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CCCC1CCC(c2ccc(-c3ccc(C=O)[se]3)cc2)CC1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC=Cc1ccc(-c2ccc(C3CCC(CCC)CC3)cc2)[se]1
Reaction time: 1.5 h

Procedure:
1.80 g (4.85 mmol) of ethyltriphenylphosphonium bromide are initially introduced in 8 ml of THF at 0° C., and 533 mg (4.75 mmol) of potassium tert-butoxide are added. After 1.5 h at RT, a solution of 1.16 g (3.23 mmol) of 5-[4-(4-propylcyclohexyl)phenyl]selenophene-2-carbaldehyde in 7 ml of THF is added, and the batch is stirred for 2.5 h. The mixture is diluted with MTBE, and sat. ammonium chloride soln. and 2 N hydrochloric acid are added. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane→n-heptane:EtOAc=20:1). 2-(Propenyl)-5-[4-(4-propylcyclohexyl)phenyl]selenophene is obtained as an E/Z isomer mixture.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=1.Cl.Cl.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C@H:15]1[CH3:20].C(N(CC)CC)C.CO>C1COCC1>[Cl:9][C:6]1[C:7]([F:8])=[C:2]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[C@H:15]([CH3:20])[CH2:16]2)[N:3]=[C:4]([CH3:10])[N:5]=1
Reactant: C[C@@H]1CNCCN1C
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c(F)c(N2CCN(C)[C@H](C)C2)n1
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a solution of 4,6-dichloro-5-fluoro-2-methylpyrimidine (0.181 g, 1.0 mmol) and (2R)-1,2-dimethylpiperazine dihydrochloride (0.189 g, 1.0 mmol) in THF (10 mL) was added triethylamine (0.42 mL, 3.0 mmol). MeOH (1 mL) was added to improve solubility. Reaction left to stir overnight. The solvent was removed in vacuo, and THF and ether were added to the resulting residue, which was washed with water. The organics were dried (Na2SO4) and concentrated in vacuo to provide 4-chloro-6-[(3R)-3,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine as a yellow oil (0.242 g, 94%). LCMS: (M+H)+=259.3.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH:13]2[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]2)[CH2:4][C@H:3]1[NH:19]C(OCCCC)=O.[N+](C1C=CC=CC=1)([O-])=O.Cl.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1.[C].[Pd].O.CO>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:4][C@H:3]1[NH2:19]
Reactant: CCCCOC(=O)N[C@@H]1CN(C2C=CCCC2)c2ccccc2NC1=O
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: O=[N+]([O-])c1ccccc1
Solvent: Cc1ccccc1C
Solvent: CO
Product: N[C@@H]1CN(c2ccccc2)c2ccccc2NC1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
To a solution of (3R)-2-oxo-3-butoxycarbonylamino-5-(2-cyclohexen-1-yl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin e (12.87 g) in xylene (200 mL), nitrobenzene (22.16 g) and 10% palladium carbon (6 g) were added, followed by refluxing for 1 hour and 30 minutes. The reaction mixture was allowed to cool down and then filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (30mL), and a 4 N hydrochloric acid-dioxane solution (20 mL) was added, followed by stirring at 50° C. for 1 hour. After the reaction mixture was allowed to cool down, crystals so precipitated were collected by filtration and washed with 2-propanol, whereby the hydrochloride of the title compound was obtained. The hydrochloride was then dissolved under heat in a mixed solution of methanol and water. After the reaction mixture was allowed to cool down, a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture for neutralization. Crystals so precipitated were collected by filtration, washed with water and then dried, whereby the title compound (5.55 g) was obtained.