Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[CH:6][C:5]=1Br.[C:29]1(OB(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[CH:6][C:5]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Reactant: OB(O)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1-c1ccccc1
Yield: 120.9 %

Procedure:
In a solution of 0.70 g of 2-bromo-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]benzoic acid methyl ester synthesized similarly to Step 1 of Synthetic Example 10 in 20 ml of tetrahydrofuran and 10 ml of water, 0.18 g of phenyl boric acid, 0.39 g of potassium carbonate and 0.05 g of dichlorobis(triphenylphosphine) palladium (II) were added, and stirred under reflux with heat for 1.5 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was poured in 30 ml of water, then extracted with ethyl acetate (50 ml×1). The organic phase was washed with water, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate, and 0.78 g of the aimed product was obtained as brown resinous substance.
Reaction SMILES: C[CH:2]([C:6]1[O:10][N:9]=[C:8]([CH3:11])[N:7]=1)[C:3]([OH:5])=O.[CH:12]1([O:16][C:17]2[CH:18]=[C:19]([N:25]3[CH2:30][CH2:29][NH:28][C@@H:27]([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:26]3)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:15][CH2:14][CH2:13]1>>[CH:12]1([O:16][C:17]2[CH:18]=[C:19]([N:25]3[CH2:30][CH2:29][N:28]([C:3](=[O:5])[CH2:2][C:6]4[O:10][N:9]=[C:8]([CH3:11])[N:7]=4)[C@@H:27]([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:26]3)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:13][CH2:14][CH2:15]1
Reactant: COc1ccc(N2CCN[C@@H](CC(C)C)C2)cc1OC1CCC1
Reactant: Cc1noc(C(C)C(=O)O)n1
Product: COc1ccc(N2CCN(C(=O)Cc3nc(C)no3)[C@@H](CC(C)C)C2)cc1OC1CCC1
Yield: 4 %

Procedure:
Prepared by the method outlined for Example 275 using methyl-(3-methyl-1,2,4-oxadiazol-5-yl)acetic acid and (S)-1-(3-cyclobutlyoxy-4-methoxy-phenyl)-3-isobutyl-piperazine as starting materials. Product was obtained as an off-white solid (4%). LC/MS (Method B) 3.8 min, [M+1]+ 443.
Reaction SMILES: O/[C:2](/[CH3:12])=[CH:3]\[C:4]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=O.[C:13]([CH2:15][C:16]([NH2:18])=[O:17])#[N:14].N1CCCCC1>CCO>[CH3:12][C:2]1[CH:3]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)[NH:18][C:16](=[O:17])[C:15]=1[C:13]#[N:14]
Reactant: N#CCC(N)=O
Reactant: C/C(O)=C/C(=O)c1ccncc1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(-c2ccncc2)[nH]c(=O)c1C#N
Temperature: 25 °C
Yield: 11.6 %

Procedure:
To a solution of (2Z)-3-hydroxy-1-(4-pyridinyl)-2-buten-1-one (8 g, crude, 49 mmol) and cyanoacetamide (4.12 g, 49 mmol) in anhydrous EtOH (100 mL) was added piperidine (4.17 g, 49 mmol) under N2 at 75° C. The mixture was heated at reflux for 1 h, and then cooled to room temperature. After filtration, the solid was collected and washed with H2O to give the crude product (4 g) as two isomers. After separation by HPLC, 1.8 g of 6-methyl-2-oxo-1,2-dihydro-4,4′-bipyridine-3-carbonitrile and 1.2 g of 4-methyl-6-oxo-1,6-dihydro-2,4′-bipyridine-5-carbonitrile were obtained. The identity of 6-methyl-2-oxo-1,2-dihydro-4,4′-bipyridine-3-carbonitrile was established by nOE analysis. 1H NMR (400 MHz, DMSO-d6) δ 12.79 (br. s., 1H), 8.75 (d, 2H), 7.58 (d, 2H), 6.37 (s, 1H), 2.31 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4]Br.[OH:11][C:12]1[CH:16]=[C:15]([N:17]2[C:21]3[CH:22]=[N:23][CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[S:14][C:13]=1[C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4][O:11][C:12]1[CH:16]=[C:15]([N:17]2[C:21]3[CH:22]=[N:23][CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[S:14][C:13]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1O
Reactant: Clc1cccc(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1c(Cl)cccc1Cl

Procedure:
In a similar manner as described for example B11, 103.5 mg of 2,6-dichlorobenzyl bromide, 100 mg of methyl 3-hydroxy-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate, 59.7 mg of potassium carbonate in 3 ml anhydrous DMF yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:15][CH:14]=[CH2:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCc1cc(C(=O)OC)cc(Cl)c1O
Yield: 83.3 %

Procedure:
To a 250 mL rb flask equipped with a magnetic stir bar and a reflux condenser was added a solution of 10.33 g (55.4 mmol) of methyl 3-chloro-4-hydroxybenzoate dissolved in 110 mL of acetone and 5.27 mL (60.9 mmol) of allyl bromide and 15.30 g (0.111 mol) of powdered potassium carbonate was added. The reaction was stirred and refluxed for 6 hours, then cooled and filtered. The tiltrate was evaporated in vacuo and the residue was purified on a silica gel flash chromatography column eluted with 10% EtOAc-hexane to afford 10.462 g (84%) of the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.Br[CH2:10][CH2:11][O:12][CH2:13][CH2:14]Br.C(N(CC)CC)C>C(#N)C>[O:12]1[CH2:13][CH2:14][N:1]([C@H:2]2[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]2)[CH2:10][CH2:11]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: BrCCOCCBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O[C@H]1CC[C@H](N2CCOCC2)CC1
Temperature: 60 °C

Procedure:
Trans-4-Aminocyclohexanol (0.5 g), 1-bromo-2-(2-bromoethoxy)ethane (1.07 g) and triethylamine (2.42 mL) were dissolved in anhydrous acetonitrile (20 mL). The reaction mixture was heated at 60° C. overnight. The organic solvent was removed under vacuum. The residue was purified with flash column chromatography on silica gel eluting with 7%-10% methanol in dichloromethane to give the title compound.
Reaction SMILES: CC1C(CCC(O)=O)=C(CC2NC(/C=C3/C(C=C)=C(C)C(N/3)=O)=C(C)C=2CCC(O)=O)NC=1/C=C1/C(C)=C(C=C)C(N/1)=O.[CH3:44][CH2:45][C:46]1[C:68]([CH3:69])=[C:67]2[NH:70][C:47]=1[CH:48]=[C:49]1[N:102]=[C:101]3[C:51]([C:52]([C@H:54]([C:103]([O:105][CH3:106])=[O:104])[C:55]3=[C:56]3[N:60]=[C:59]([CH:61]=[C:62]4[NH:71][C:65](=[CH:66]2)[C:64]([CH:72]=[CH2:73])=[C:63]4[CH3:74])[C@@H:58]([CH3:75])[C@@H:57]3[CH2:76][CH2:77][C:78]([O:80][CH2:81]/C=C(/CCC[C@@H](CCC[C@@H](CCCC(C)C)C)C)\C)=[O:79])=[O:53])=[C:50]1[CH3:107].S(=O)(=O)(O)O.ClCCl>CO>[CH3:44][CH2:45][C:46]1[C:47]2=[N:70][C:67](=[CH:66][C:65]3[NH:71][C:62]([CH:61]=[C:59]4[CH:58]([CH3:75])[CH:57]([CH2:76][CH2:77][C:78]([O:80][CH3:81])=[O:79])[C:56]([C:55]5[CH:54]([C:103]([O:105][CH3:106])=[O:104])[C:52](=[O:53])[C:51]6[C:101]=5[NH:102][C:49]([C:50]=6[CH3:107])=[CH:48]2)=[N:60]4)=[C:63]([CH3:74])[C:64]=3[CH:72]=[CH2:73])[C:68]=1[CH3:69]
Reactant: C=Cc1c(C)c2cc3nc(c4c5nc(cc6[nH]c(cc1[nH]2)c(C)c6CC)C(C)=C5C(=O)[C@@H]4C(=O)OC)[C@@H](CCC(=O)OC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@@H]3C
Agent: C=CC1=C(C)/C(=C/c2[nH]c(Cc3[nH]c(/C=C4\NC(=O)C(C)=C4C=C)c(C)c3CCC(=O)O)c(CCC(=O)O)c2C)NC1=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: ClCCl
Product: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4C(=O)OC)C(CCC(=O)OC)C3C

Procedure:
The green filtrate was evaporated and purified by flash chromatography on Grade V neutral Alumina, eluting first with n-hexane to remove a fast running yellow band and then with dichloromethane to obtain the major blue/gray peak containing pheophytin-a. Treatment of pheophytin-a with 500 ml sulfuric acid in methanol for 12 hours at room temperature in the dark under nitrogen was followed by dilution with dichloromethane. The reaction mixture was rinsed with water and then 10% aqueous sodium bicarbonate and the organic layer was dried, evaporated, and the residue recrystallized from dichloromethane/methanol to obtain 1.8 gm methyl pheophorbide-a. Methyl pheophorbide-a appears to be inactive in the in vivo tumoricidal activity assay when injected at a dose of 5 mg/kg.
Reaction SMILES: N1CCCCC1.O=[CH:8][C:9]1[CH:17]=[CH:16][C:14]([OH:15])=[C:11]([O:12][CH3:13])[CH:10]=1.[CH3:18][O:19][C:20](=[O:24])[CH2:21][C:22]#[N:23]>C(O)C>[CH3:18][O:19][C:20](=[O:24])/[C:21](/[C:22]#[N:23])=[CH:8]/[C:9]1[CH:17]=[CH:16][C:14]([OH:15])=[C:11]([O:12][CH3:13])[CH:10]=1
Reactant: COC(=O)CC#N
Reactant: COc1cc(C=O)ccc1O
Solvent: CCO
Solvent: C1CCNCC1
Product: COC(=O)/C(C#N)=C/c1ccc(O)c(OC)c1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
0.2 ml of piperidine were added carefully to a solution of 4.6 g (30 mmol) of vanillin, 3.4 ml (30.3 mmol) of cyanoacetic acid methyl ester and 0.5 ml of ethanol held at 45° C. The product started to precipitate on cooling to room temperature. The cold reaction mixture was diluted with 8 ml of ethanol, filtered and washed with cold ethanol to give 6.5 g (93%) of 2-cyano-(E)-3-(4-hydroxy-3-methoxyphenyl)acrylic acid methyl ester in form of yellow crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1.Cl.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[O:31][CH3:32]>C(O)C.O>[CH:14]1([N:7]2[CH2:8][CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:19][C:6]2=3)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Temperature: 90 °C

Procedure:
2-Chloro-9-cyclopentyl-8,9-dihydro-5-methyl-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (150 mg, 0.536 mmol) in ethanol (2.25 ml) and water (9 ml) was treated with conc. HCl (0.088 ml) and 4-amino-3-methoxy benzoic acid (134 mg, 0.804 mmol). The mixture was stirred at 90° C. 24 hours, concentrated and the residue triturated with methanol/ether, filtered and the solid washed with ethanol then ether to give 4-(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxo-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as a buff powder (185.5 mg, 84%). NMR DMSO D6 1.51-1.79 (6H, m), 1.82-1.93 (2H, m), 2.70-2.75 (2H m), 3.18 (3H, s), 3.72-3.78 (2H, m), 3.98 (3H, s), 4.81-4.93 (1H, m), 7.57-7.64 (2H, m), 8.15-8.22 (2H, m), 9.46 (1H, br s); HPLC rt(min): 6.57.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Br[C:16]1[CH:20]=[CH:19][S:18][CH:17]=1>CCOCC.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:3]([C:16]1[CH:20]=[CH:19][S:18][CH:17]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCBr
Reactant: Brc1ccsc1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCCCCCCCCc1ccsc1
Yield: 84.9 %

Procedure:
Dried ethyl ether (40 ml) was added to activated magnesium (1.22 g; 50 mmol), and 1-bromododecane (12.46 g; 50 mmol) was added thereto to prepare a Grignard reagent. Then, Ni(dppp)Cl2 (33 mg) was added thereto, and 3-bromothiophene (8 g; 49 mmol) dissolved in 10 ml of ether was slowly added dropwise. The reaction solution was refluxed for one day, and then a mixture of 2N HCl/ice (50 ml) was added to terminate the reaction. The resultant was extracted from ethyl ether, and the solvent was distilled off under reduced pressure. The residue was dissolved in DMF (50 ml) and filtered to remove remaining paraffin. The filtrate was concentrated, and then the residue was distilled off under vacuum to obtain a colorless liquid 3-dodecylthiophene (10.5 g; 85%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[Br:14][C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[Cl:35])=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][C:26]=2[Cl:35])=[CH:20][C:16]=1[C:17]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)=[O:18]
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Br
Reactant: OC1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCOC1)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Br
Reaction time: 8 h

Procedure:
3-Hydroxytetrahydrofuran (0.04 mole), toluene (50 ml) and triethylamine (0.04 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. A solution of 2-bromo-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl chloride (0.04 mole) in toluene (20 ml) is slowly added at room temperature with stirring. After the addition is completed, stirring is continued for a period of about eight hours. After this time, the reaction mixture is washed with water and dried over anhydrous magnesium sulfate. The dried solution is then stripped of solvent under reduced pressure leaving a residue. This residue is purified by silica gel chromatography using toluene and ethyl acetate/toluene mixture as the eluant to yield the desired product 3-tetrahydrofuryl 2-bromo-5-(2-chloro-4-trifluoromethylphenoxy)benzoate.
Reaction SMILES: [CH:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si](C)(C)N[Si](C)(C)C.[Li].[CH2:27](Br)[CH:28]=[CH2:29].Cl>O1CCCC1.O>[CH2:29]([C:1]1([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:28]=[CH2:27]
Reactant: C=CCBr
Reactant: O=C(OCc1ccccc1)C1CCCCC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: C=CCC1(C(=O)OCc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl cyclohexanecarboxylate (1.44 g) in tetrahydrofuran (40 mL) was added a 1M solution of lithium hexamethyldisilazane in tetrahydrofuran (9.9 mL) under ice cooling. The solution was stirred at room temperature for 1 hour under ice cooling, to which hexamethylphosporamide (2.3 mL) was added. The solution was then stirred for additional 10 minutes. To the solution was added allyl bromide (1.4 mL). The solution was stirred under ice cooling for 1 hour, to which allyl bromide (1.4 mL) was further added. The solution was stirred at room temperature for 18 hours. Water and 3N hydrochloric acid were added to the solution, and it was extracted with diethyl ether. The organic layer was washed in turn with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The solution was dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, hexane:ethyl acetate=99:1) to give the title compound (550 mg). This product was subjected to the subsequent step without further purification.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].O=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.C(O)(=O)C.C(O[BH3-])(=O)C.[Na+].[OH-].[Na+]>C(O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCN1CCNCC1
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCN1CCN(C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
29.2 g (256 mmol) of N-ethylpiperazine were introduced with 50.0 g (256 mmol) of tert-butyl 4-oxopiperidine-1-carboxylate (corresponds to 1-Boc-4-piperidone) into 800 ml of ethanol while cooling in ice. 15.4 g (256 mmol) of glacial acetic acid were added. Then 16.1 g (256 mmol) of sodium acetoxyborohydride were added in portions to the cooled reaction mixture. Initially slight gas formation was observed and, after addition of ⅔ of the reducing agent, foam formation was observed. The reaction mixture was stirred at room temperature overnight. The reaction solution was worked up by adding 200 ml of 2N of sodium hydroxide solution while cooling, distilling out the solvent ethanol and diluting the remaining reaction mixture with water. It was extracted with diethyl ether (2×) and was washed with saturated sodium chloride solution (1×), and the combined organic phases were dried over magnesium sulfate and filtered, and the solvent was removed in vacuo. The crude title compound was obtained as a yellow oil which was then chromatographed on a 4 l suction funnel filled with silica gel using dichloromethane and 10% methanol as eluent. In total, 40 g (135 mmol, 53%) of tert-butyl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate were obtained.
Reaction SMILES: C([N:5]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=O)[CH:6]1[CH3:18])(C)(C)C.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.[Cl-].[NH4+]>S(Cl)(Cl)=O>[C:19]([NH:23][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:13]([C:14]([F:15])([F:16])[F:17])=[N:5][C:6]=1[CH3:18])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)N
Reactant: CC1C(C(=O)O)=CC=C(C(F)(F)F)N1C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(C(F)(F)F)ccc1C(=O)NC(C)(C)C
Reaction time: 8 h

Procedure:
N-tert-Butyl-2-methyl-6-trifluoromethyl-nicotinic acid (5.0 g, 24 mmol) is refluxed in 10 mL of thionyl chloride for 3 h and is then concentrated under reduced pressure. The residue is dissolved in toluene and the solvent is removed under reduced pressure. The residue is again dissolved in toluene and the solvent is removed under reduced pressure. The resultant residue is dissolved in 50 mL of dichloromethane and to the solution is added tert-butyl amine (3.8 mL, 49 mmol) and triethylamine (6.8 mL, 49 mmol) and the reaction is allowed to stir overnight. The reaction is then poured into sat. ammonium chloride and extracted three times with dichloromethane. The combined organic phases are then washed with sat. NaHCO3, and brine. The organic layer is then dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound. Further purification is achieved by trituration from diethyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:30]2[CH2:29][CH2:28][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=3)[CH2:32][CH2:31]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 87 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 87%). 1H NMR (300 MHz, CDCl3): δ 2.46 (s, 3H), 3.19-3.33 (m, 4H), 3.72-3.77 (m, 4H), 4.13 (s, 3H), 6.79-7.66 (m, 7H), 7.71 (d, J=8.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]3[CH:15](O)[CH2:16][CH2:17][C:13]=3[N:12]=[C:11]2[CH:19]([CH3:21])[CH3:20])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:22]([O:24][C:25]([CH:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:26])[CH3:23].CP(C)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]3[CH:15]([C:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:25]([O:24][CH2:22][CH3:23])=[O:26])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:16][CH2:17][C:13]=3[N:12]=[C:11]2[CH:19]([CH3:21])[CH3:20])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(O)CC2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CP(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCc2nc(C(C)C)n(Cc3ccc(Cl)c(Cl)c3)c21
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of Intermediate 22 (660 mg) and triethylmethanetricarboxylate (0.86 ml) in toluene (1.5 ml) and tetrahydrofuran (1.5 ml), stirred at RT under an inert atmosphere of nitrogen, was added dropwise trimethylphosphine, 1M in toluene (4.06 ml). The resulting solution was cooled to −78° C. and diisopropyl azodicarboxylate (0.799 ml) was added dropwise via syringe and the reaction was stirred at −78° C. for 2 hours. The reaction mixture was removed from the cold bath and allowed to warm to RT and stirred under N2 atmosphere for 30 mins. Reaction mixture concentrated in vacuo. The residue was taken up in DCM (40 ml) and washed with water (40 mL). The 2 phases were separated; the organic extract was dried (hydrophobic frit) and concentrated under vacuum. The residue was purified on silica using a cyclohexane:ethyl acetate 0-100% gradient. The desired fractions were combined and concentrated under vacuum to give the title compound (750 mg). LC/MS MH+ 539, 541, Rt 2.19 min (5 minute run).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:22]=[CH:21][C:14]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:13][C:12]=2[O:23][CH3:24])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)=[O:36]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:24][O:23][C:12]1[CH:13]=[C:14]([CH:21]=[CH:22][C:11]=1[N:10]=[N:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:1][C:35]([O:37][C:38]2[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=2)=[O:36])=[CH:4][CH:5]=1)[O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)COc1ccc(N=Nc2ccc(CO)cc2)c(OC)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)COc1ccc(N=Nc2ccc(COC(=O)Oc3ccc([N+](=O)[O-])cc3)cc2)c(OC)c1
Reaction time: 0.17 h

Procedure:
Compound 4 (0.1 g, 0.0302 mmol) was dissolved in DCM (15 mL) and freshly activated 4° A M.S (0.15 g) was added and reaction mixture stirred for 10 minutes. DIPEA (0.215 mL, 1.2 mmol) and DMAP (0.05 g) were added and reaction mixture cooled to 0° C. p-Nitrophenyl chloroformate (0.15 g, 0.0757 mmol) in DCM was added slowly and reaction mixture stirred at 0° C. for 1 hour, followed by an additional 4 hours at room temperature. The remaining procedure was followed as described for compound 5 to obtain compound 6 (E:Z isomers). Yield: 0.11 g (76%). 1H NMR (500 MHz, CDCl3) δ 3.79 (s, 3H, Hn (OMe), for Z), 3.82 (s, 3H, Hn (OMe), for E), 3.99 (s, 3H, aromatic-OMe for Z), 4.00 (s, 3H, aromatic-OMe for E), 4.58 (s, 2H, Hf for Z), 4.71 (s, 2H, Hf for E), 5.21 (s, 2H, Hl for Z), 5.34 (s, 2H, Hi for E), 6.22-6.28 (m, 1H, Hb for Z), 6.44-6.50 (m, 2H, Hb for E), 6.52-6.60 (m, 1H, He for Z), 6.64-6.70 (m, 1H, He for E), 6.84-6.95 (m, 2H, He for Z), 7.30-7.40 (m, 2H, He for E), 7.42-7.50 (m, 1H, Ha for Z), 7.50-7.54 (m, 1H, Ha for E), 7.54-7.58 (m, 2H, Hn for Z), 7.68-7.75 (m, 2H, Hn for E), 7.80-7.90 (m, 4H, Hd for Z and E), 8.08-8.14 (m, 2H, Ho for Z), 8.22-8.30 (m, 2H, Ho for E). 13C NMR (125 MHz, CD3SOCD3) δ 52.3, 52.44 (Cn), 55.4, 56.34 (aromatic-OMe), 65.2, 65.2 (Cf), 67.3, 67.4 (Cl), 70.1, 70.4, 100.2 (Cc), 104.2, 105.3 (Cb), 115.62, 116.9 (Ci), 118.0, 120.04, 121.5, 121.7, 121.75, 122.8, 122.9, 125.3, 126.0, 128.7, 128.9, 129.2, 135.9, 137.3, 145.3, 152.3, 154.4, 155.4, 158.7, 161.7, 168.7 (CO). ESI-MS: [M+H]+ C24H22N3O9 calcd 496.1356, obsd 496.12.