Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12](F)[CH:11]=[C:10]([F:18])[CH:9]=1)[CH3:2].C(N(CC)CC)C.[CH2:28]([NH2:32])[CH2:29][CH2:30][CH3:31]>CN(C=O)C>[CH2:28]([NH:32][C:12]1[CH:11]=[C:10]([F:18])[CH:9]=[C:8]([O:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:19][CH3:20])[CH2:1][CH3:2])[C:13]=1[N+:14]([O-:16])=[O:15])[CH2:29][CH2:30][CH3:31]
Reactant: CCN(CC)CCCOc1cc(F)cc(F)c1[N+](=O)[O-]
Reactant: CCCCN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCNc1cc(F)cc(OCCCN(CC)CC)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a stirred solution of 6-(3-diethylaminopropoxy)-2,4-difluoronitrobenzene (11 mmol) and triethylamine (22 mmol) in DMF (20 mL), a solution of n-butylamine (11 mmol) in DMF (8 mL) was added dropwise at rt, and the mixture was stirred at rt for 10 h. The reaction was quenched by cold H2O (50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with brine (3×50 mL) and dried (anhydrous Na2SO4). The solvent was removed in vacuo to afford the desired 2-n-butylamino-6-(3-diethylaminopropoxy)-4-fluoronitrobenzene which was used for further transformation.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1([CH3:24])[O:13][C:12]2[CH:14]=[CH:15][C:16]([C@H:18]3[O:22][C:21](=[O:23])[NH:20][CH2:19]3)=[CH:17][C:11]=2[CH2:10][O:9]1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][C:37]1[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][C:38]=1[Cl:44]>CN(C=O)C>[Cl:43][C:42]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:44])[C:37]=1[CH2:36][O:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][N:20]1[CH2:19][C@@H:18]([C:16]2[CH:15]=[CH:14][C:12]3[O:13][C:8]([CH3:24])([CH3:7])[O:9][CH2:10][C:11]=3[CH:17]=2)[O:22][C:21]1=[O:23]
Reactant: Clc1cccc(Cl)c1COCCOCCCCCCBr
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4c(Cl)cccc4Cl)C(=O)O3)ccc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
Potassium tert-butoxide (4.38 g, 39 mmol) was added to a solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (9.3 g, 39 mmol) in anhydrous DMF (100 mL) under N2 and the reaction stirred for 1 h at ambient temperature. A solution of 2-[2-(6-bromo-hexyloxy)-ethoxymethyl]-1,3-dichloro-benzene (15 g, 39 mmol) in anhydrous DMF (25 mL) was added and the reaction allowed to stir at ambient temperature for 20 h. The reaction mixture was poured into ice/water (350 mL) and extracted with ethyl acetate (300 mL). The organic layer was separated then washed successively with water/saturated brine (250 mL/25 mL), water/brine (25 mL/10 mL) and finally brine (150 mL), before drying over sodium sulfate. The solution was concentrated to dryness under vacuum to afford the title compound as an oil (21.6 g)—LC RT=6.8 min.
Reaction SMILES: [CH:1]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH2:10]([N:17]=[C:18]=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.[Al]>ClCCl>[CH2:10]([NH:17][C:18](=[O:19])[O:9][CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OC1C=CCCCCC1
Reactant: O=C=NCc1ccccc1
Agent: O=C(NCc1ccccc1)OC1/C=C/CCCCC1
Agent: OC1/C=C/CCCCC1
Agent: [Al]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccccc1)OC1C=CCCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (E)-cyclooct-2-enol 31 (minor isomer 100 mg, 0.792 mmol) in dichloromethane (6 mL) were added benzyl isocyanate (101 μL, 110 mg, 0.826 mmol, 1.04 eq) and a drop of triethylamine. The flask was covered with aluminum foil and the solution was stirred under a nitrogen atmosphere at room temperature overnight. Evaporation of the reaction mixture gave mainly starting material. Benzyl isocyanate (200 μL, 220 mg, 1.65 mmol, 2.08 eq) and a drop of triethylamine in dichloromethane (6 mL) were added and the solution was stirred overnight at room temperature, at 50° C. for 1 hr and at 25-30° C. over the weekend. The volatiles were removed by bulb-to-bulb distillation (50° C., 2 hr). The residue was purified by column chromatography to give carbamate 32 (43 mg, 0.166 mmol, 20.9%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7](C(C2C(O)=CC3C(C)(C)CCC(C)(C)C=3C=2)=O)=[CH:6][CH:5]=1.[OH-].[K+].BrCCC>CS(C)=O>[C:3]([OH:27])(=[O:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)c2cc3c(cc2O)C(C)(C)CCC3(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCBr
Solvent: CS(C)=O
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 233.9 %

Procedure:
A solution of the 4-[(3-hydroxy,5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid methyl ester (from Example 7, 433 mg, 1.18 mmol) in DMSO (2 mL) was treated with KOH (1.5 mmol) at 0° C. and allowed to warm to ambient temperature over 1 h. The yellow solution was cooled again to 0° C., and treated with a solution of bromopropane (118 mL, 1.30 mmol) in DMSO (1mL) and allowed to warm to ambient temperature and stirred for 10 h. The reaction was quenched with saturated aqueous NH4Cl. The aqueous solution was adjusted to pH=3 with 1M HCl and extracted with EtOAc, 3×. The organic layers were combined and washed with water (2×) and brine. The organic solution was dried (NaSO4), filtered, and concentrated. Purification by silica gel radial chromatography (20:1=hexanes:Et2O) gave 4-[2-propoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid 337 mg (75%) as a coloreless oil: 1H NMR (400 MHz, CDCl3) δ8.15 (½ABq, J=8.2 Hz, 2H, ArH), 7.85 (½ABq, J=8.2 Hz, 2H, ArH), 7.46 (s, 1H, ArH), 6.82 (s, 1H, ArH), 3.78 (t, J=6.3 Hz, 2H, OCH2), 1.70 (m, 4H, 2CH2), 1.36 (m, 2H, CH2), 1.32 (s, 6H, 2CH3), 1.28 (s, 6H, 2CH3), 0.62 (t, J=7.4 Hz, 3H, CH3). The propoxyketo acid (1.34 mg, 0.33 mmol) in EtOH (2mL) was converted to the oxime derivative as described in Example 4 to provide, after recrystallization (CH2Cl2/hexanes (4-[(3-propoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid oxime (109) (97%) as a white solid: mp 251-255° C. (d); 1H NMR (400 MHz, CDCl3) δ7.98 (½ABq, J=8.4 Hz, 2H, ArH), 7.54 (½ABq, J=8.4 Hz, 2H, ArH), 7.13 (s, 1H, ArH), 6.86 (s, 1H, ArH), 3.81 (t, J=6.2 Hz, 2H, OCH2), 1.70 (m, 4H, 2CH2), 1.51 (m, 2H, CH2), 1.32 (s, 6H, 2CH3), 1.24 (s, 6H, 2CH3), 0.72 (t, J=7.4 Hz, 3H, CH3).
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:29][CH2:28][C@H:27]4[C@@H:17]([CH2:18][CH2:19][C@@H:20]5[C@:25]4([CH3:26])[C:24](=[CH2:30])[CH2:23][CH2:22][CH2:21]5)[C@@H:6]2[C@H:7]3[CH:15]=[O:16])[CH3:5])[O:2]1.[I-].[CH3:32][S+](C)C.CC([O-])(C)C.[K+]>CN(C)C=O.ClCCl>[CH2:11]1[CH2:10][O:9][C:8]23[O:13][CH2:14][CH2:1][O:2][C:3]2([C@:4]2([CH2:29][CH2:28][C@H:27]4[C@@H:17]([CH2:18][CH2:19][C@@H:20]5[C@:25]4([CH3:26])[C:24](=[CH2:30])[CH2:23][CH2:22][CH2:21]5)[C@@H:6]2[C@H:7]3[CH:15]2[CH2:32][O:16]2)[CH3:5])[O:12]1
Reactant: C[S+](C)C
Reactant: C=C1CCC[C@@H]2CC[C@H]3[C@@H]4[C@@H](C=O)C56OCCOC5(OCCO6)[C@@]4(C)CC[C@@H]3[C@@]12C
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=C1CCC[C@@H]2CC[C@H]3[C@@H]4[C@@H](C5CO5)C56OCCOC5(OCCO6)[C@@]4(C)CC[C@@H]3[C@@]12C
Temperature: 0 °C

Procedure:
3.8 g of 3,3;17,17-bis(ethylenedioxy)-1-methylene-5α-androstane-15α-carbaldehyde in 46 ml of dimethylformamide is stirred under argon with 3.0 g of trimethylsulfonium iodide and 2.3 g of potassium tert-butylate at room temperature. After 30 minutes the reaction mixture is added to ice/water. The precipitated product is suctioned off, dissolved in dichloromethane, washed neutral with water. 3.5 g of 3,3;17,17-bis(ethylenedioxy)-1-methylene-15α-(2-oxiranyl)5α-androstane is obtained as foam.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]([OH:26])=[O:25])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.S(Cl)(Cl)=O.[CH3:31]O>>[NH2:1][C:2]1[C:3]([C:24]([O:26][CH3:31])=[O:25])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[CH:15]=2)=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: CC(C)n1cc(-c2nc(C(=O)O)c(N)nc2-c2ccccc2)ccc1=O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1nc(-c2ccc(=O)n(C(C)C)c2)c(-c2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxylic acid (350 mg) in MeOH (7.0 ml), was added thionyl chloride (0.146 m) dropwise under ice-bath cooling. After 1 hour stirring at the same temperature, the mixture was allowed to warm to room temperature. The mixture was stirred for 6 hours and then refluxed with stirring for 15 hours. After cooling, the solvent was removed under reduced pressure. Water was poured into the residue and the pH of the mixture was adjusted to 10 with 1N aq. NaOH. A precipitate was isolated by filtration, washed with water, and dried in vacuo to give methyl 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxylate (244 mg).
Reaction SMILES: [NH:1]1[C:5]2=[N+:6]([O-:10])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.S(=O)(=O)(O)O.O.[N+:17]([O-])([OH:19])=[O:18]>>[N+:17]([C:9]1[CH:8]=[CH:7][N+:6]([O-:10])=[C:5]2[NH:1][CH:2]=[CH:3][C:4]=12)([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: [O-][n+]1cccc2cc[nH]c21
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cc[n+]([O-])c2[nH]ccc12
Temperature: 70 °C

Procedure:
4-Nitro-1H-pyrrolo[2,3-b]pyridine 7-oxide 508 is prepared by dissolving 1H-Pyrrolo[2,3-b]pyridine 7-oxide 507 in nitric acid, followed by the addition of sulfuric acid. Heating (e.g. 70° C.) for one hour, followed by pouring into water provides compound 508, which is isolated by filtration. (Schneller et. al., J. Org. Chem. 1980, 45:4045)
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1.P(Cl)(Cl)([Cl:23])=O.[OH-].[Na+]>CN(C)C=O>[Cl:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccc2nc(-c3ccccc3)cc(O)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2nc(-c3ccccc3)cc(Cl)c2c1
Temperature: 70 °C
Yield: 101.2 %

Procedure:
4-Hydroxy-6-nitro-2-phenylquinoline (10.00 g, 38 mmol) was suspended in phosphorus oxychloride (POCl3) (57.58 g, 380 Mol) at 0° C. Dimethylformamide (DMF) (45 ml) was added dropwise and the resulting mixture heated at 70° C. for 5 hours. The reaction was cooled and then poured onto ice. The pH was adjusted to 6 with aqueous sodium hydroxide and the precipitate collected by vacuum filtration and dried in a vacuum oven to give 4-chloro-6-nitro-2-phenylquinoline (10.95 g, 102%) as a yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([S:19]([CH3:22])(=[O:21])=[O:20])[N:13]=2)[CH2:8][CH2:7]1)[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38]>C(#N)C>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH:18][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][CH:42]=[C:34]([Cl:33])[CH:35]=3)=[CH:16][CH:15]=[C:14]([S:19]([CH3:22])(=[O:21])=[O:20])[N:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)CC1CCN(c2nc(S(C)(=O)=O)ccc2N)CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC1CCN(c2nc(S(C)(=O)=O)ccc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 49.8 %

Procedure:
To a mixture of 0.080 g (0.23 mmol) of (3′-amino-6′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester in acetonitrile (5 mL) is added 0.12 mL (0.70 mmol) of N,N-diisopropylethylamine followed by 0.032 mL (0.28 mmol) of 3-chlorobenzoyl chloride. The mixture is heated at 80° C. for 1 h then an additional 0.096 mL (0.84 mmol) of 3-chlorobenzoyl chloride is added. The mixture is stirred at 80° C. for an additional 10 minutes then cooled to room temperature and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide 0.055 g (49%) of [3′-(3-chloro-benzoylamino)-6′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid ethyl ester as a colorless foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7](O)[C:6]=2[CH:17]=1.S(Cl)([Cl:20])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([Cl:20])[C:6]=2[CH:17]=1
Reactant: OC1c2ccccc2C=Cc2ccc(Cl)cc21
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Clc1ccc2c(c1)C(Cl)c1ccccc1C=C2

Procedure:
The thus dried 3-chloro-5H-dibenzo[a,d]cyclohepten-5-ol intermediate was mixed with 10 milliliters of benzene and 10 milliliters of thionyl chloride and the resulting mixture stirred at reflux temperature for 2 hours to obtain 3,5-dichloro-5H-dibenzo[a,d]cycloheptene intermediate in the reaction mixture. The mixture was cooled and evaporated under reduced pressure to recover the chloro intermediate as residue.
Reaction SMILES: [C:1]1([CH2:11][NH:12][C:13](=[O:58])[C@@H:14]([NH:29][C:30]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]([CH2:42][N:43](C(OC(C)(C)C)=O)[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)=[CH:34][CH:33]=2)=[O:31])[CH2:15][CH2:16][CH2:17][NH:18][C@@H:19]2[C:28]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:22][CH2:21][CH2:20]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[ClH:59].O1CCOCC1>CO>[ClH:59].[C:1]1([CH2:11][NH:12][C:13](=[O:58])[C@@H:14]([NH:29][C:30]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]([CH2:42][NH:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)=[CH:34][CH:33]=2)=[O:31])[CH2:15][CH2:16][CH2:17][NH:18][C@@H:19]2[C:28]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:22][CH2:21][CH2:20]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccn1)Cc1ccc(C(=O)N[C@@H](CCCN[C@H]2CCCc3cccnc32)C(=O)NCc2cccc3ccccc23)c2ccccc12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(N[C@@H](CCCN[C@H]1CCCc2cccnc21)C(=O)NCc1cccc2ccccc12)c1ccc(CNCc2ccccn2)c2ccccc12

Procedure:
The compound obtained in Example 90-2 (14.2 mg) was dissolved in methanol (0.3 ml), and 4 mol/l hydrochloric acid/dioxane solution (0.3 ml) was added to the solution. After the reaction for 3.5 hours, the reaction solution was concentrated. The residue obtained was purified by silica gel column chromatography (0.5 g, chloroform/methanol/water=7/3/0.5) and treated with hydrochloric acid to obtain hydrochloride of the title compound (8.1 mg) as a white solid.
Reaction SMILES: C(/[N:14]=[CH:15]/[C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:23]2)=[CH:18][CH:17]=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl[C:33]1[C:38]([Cl:39])=[N:37][CH:36]=[CH:35][N:34]=1>C1COCC1>[Cl:39][C:38]1[C:33]([CH:15]([C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[CH:21][C:22]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[N:23]3)=[CH:18][CH:17]=2)[NH2:14])=[N:34][CH:35]=[CH:36][N:37]=1
Reactant: C(=N/C(c1ccccc1)c1ccccc1)\c1ccc2ccc(-c3ccccc3)nc2c1
Reactant: Clc1nccnc1Cl
Solvent: C1CCOC1
Product: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 91.3 %

Procedure:
Benzhydryl-[1-(2-phenyl-quinolin-7-yl)-meth-(E)-ylidene]-amine (12.50 g, 31.4 mmol) was added to a 500 mL rbf fitted with a thermocouple. The flask was degassed and filled with nitrogen. THF (150 mL) was added and the solid dissolved. The mixture was cooled to −5° C. and 1.0 M of HMDS sodium salt in THF (39.2 mL) was added within 5 min. The temperature increased slightly to −3° C. The blue solution was stirred for 20 min at 0° C. and then 2,3-dichloropyrazine (5.61 g, 37.6 mmol) in THF (10 ml) was added within 3 min. The mixture was stirred for 30 min and then quenched with saturated NH4Cl/water (200 mL). EtOAc (200 mL) was added and the aqueous phase was removed. Toluene can also be used. The organic layer was washed with water (200 mL×2) and brine (200 mL). Concentrated HCl (10 mL) and water (200 mL) were added. The phases were separated and the organic layer was extracted with 0.1 M HCl (30 mL). The aqueous was washed with EtOAc (2×) and then saturated K2CO3 was used to adjust to pH 10. The aqueous solution was extracted with EtOAc (2×) and the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to a brown oil which solidified upon standing to yield the title compound as a brown solid (9.94 g, 81% yield). 1H NMR (400 MHz, CDCl3) δ ppm 2.30 (br s, 2H), 5.79 (s, 1H), 7.43-7.56 (m, 3H), 7.62 (dd, J=8.46, 1.89 Hz, 1H), 7.81 (d, J=8.34 Hz, 1H), 7.86 (d, J=8.59 Hz, 1H), 8.07 (d, J=1.01 Hz, 1H), 8.10-8.16 (m, 2H), 8.19 (d, J=8.59 Hz, 1H), 8.31 (d, J=2.27 Hz, 1H), 8.60 (d, J=2.53 Hz, 1H). MS (ES+): m/z=347.01/349.03 (100/68) [MH+].
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:14][CH:15]4[CH2:19][NH:18][CH2:17][CH:16]4[CH:20]=3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22].CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([N:18]1[CH2:17][CH:16]2[CH2:20][C:13]([C:9]3[N:8]=[C:7]4[N:6]([CH3:21])[C:5](=[O:22])[N:4]([CH2:3][C:2]([CH3:24])([CH3:23])[CH3:1])[C:12]4=[CH:11][CH:10]=3)=[CH:14][CH:15]2[CH2:19]1)(=[O:36])[CH3:35]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CNCC4C3)nc21
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CC2C=C(c3ccc4c(n3)n(C)c(=O)n4CC(C)(C)C)CC2C1
Reaction time: 0.08 h

Procedure:
1-(2,2-Dimethylpropyl)-5-(1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (8-4, 100 mg, 0.30 mmol, 1.0 equiv), and DIPEA (0.16 mL, 0.91 mmol, 3.0 equiv) were added to anhydrous methylene chloride (3 mL) Stirred for 5 min and acetyl chloride (26.5 mg, 0.33 mmol, 1.1 equiv) was added. After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 9-1 as a pale yellow oil. MS m/z (M+H): calculated=369.2287; observed=369.2298.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[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][CH3:18].[CH2:21]([OH:26])[CH:22]([OH:25])[CH2:23]O>>[C:1]([O:20][CH2:23][CH:22]([OH:25])[CH2:21][OH:26])(=[O:19])[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][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: OCC(O)CO
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO

Procedure:
Octadecanoic acid, monoester with 1,2,3-propanetriol
Reaction SMILES: [CH3:1][C:2]([CH:4]=O)=O.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([NH2:16])[CH:10]=1)([O-:8])=[O:7].C(O)(C)C>O>[CH3:1][C:2]1[CH:4]=[N:16][C:11]2[C:12](=[CH:13][CH:14]=[C:9]([N+:6]([O-:8])=[O:7])[CH:10]=2)[N:15]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: CC(=O)C=O
Solvent: O
Solvent: CC(C)O
Product: Cc1cnc2cc([N+](=O)[O-])ccc2n1

Procedure:
15.3 ml (0.1 mol) of a 40% w/v aqueous solution of pyruvic aldehyde were added to a suspension of 15.3 g (0.1 mol) of 4-nitro-1,2-phenylenediamine in 800 ml of a 1:1 by volume mixture of isopropanol and water, and the resulting mixture was heated under reflux for 3 hours. At the end of this time, the mixture was cooled, and the crystals which had precipitated were collected by filtration and recrystallized from ethanol. The filtrate was concentrated by distillation under reduced pressure, and the concentrate was triturated with ethanol to cause crystallization. A total of 15.5 g of 2-methyl-6-nitroquinoxaline were obtained as crude yellow-brown crystals. 12.5 g (0.066 mol) of this crude 2-methyl-6-nitroquinoxaline were suspended in 200 ml of toluene, and 13.2 g of selenium dioxide were added to the suspension. The resulting mixture was then heated under reflux for 4 hours. It was then cooled, after which insoluble materials were filtered off and the filtrate was freed from the solvent by distillation under reduced pressure. The residue was mixed with 400 ml of acetone. 420 ml (0.13 mol) of a 5% aqueous solution of potassium permanganate were then slowly added at room temperature and with stirring to the resulting mixture, which was then stirred at room temperature for 2.5 hours. At the end of this time, insoluble materials were filtered off and the filtrate was freed from acetone by distillation under reduced pressure. The aqueous layer thus obtained was washed with diethyl ether and then acidified with concentrated hydrochloric acid to precipitate crystals. These crystals were dissolved in a 1N aqueous solution of sodium hydroxide, and insoluble materials were filtered off. The filtrate was again acidified with concentrated hydrochloric acid to precipitate crystals, which were recrystallized from a mixture of acetone and diethyl ether, to give 9.9 g of the title compound as pale yellow-brown crystals, melting at 208°-210° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]#[N:21])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:30]>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10]([F:30])=[O:11])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]#[N:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C#N)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C#N)C(=O)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-(2-cyano-phenyl)-propionic acid (2.5 g, 8.6 mmol) and pyridine (0.68 g, 8.6 mmol) were dissolved in dichloromethane (50 mL) at 0° C. Cyanuric fluoride (1.74 mL, 12.9 mmol) was added dropwise. The mixture was stirred at 0° C. for 1 hour and then ice-water was added. The mixture was extracted with dichloromethane (2×). The organic extracts were washed with water, brine, and dried over sodium sulfate. Evaporation of the solvents gave crude [(S)-2-(2-cyano-phenyl)-1-fluorocarbonyl-ethyl]-carbamic acid tert-butyl ester as a yellow solid which was used without further purification in the next step (2.4 g).
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][NH2:13])[N:7]=1.[C:14](#[N:18])/[CH:15]=[CH:16]/[CH3:17]>CCOCC>[NH2:18][C:14]1[CH2:15][CH:16]([CH3:17])[N:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[N:7]=2)[N:13]=1
Reactant: NNc1cccc(Cl)n1
Reactant: C/C=C/C#N
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CC1CC(N)=NN1c1cccc(Cl)n1

Procedure:
A 0.23 g. amount of sodium metal is dissolved in 75 ml. of absolute ethanol, then 7.2 g of 2-chloro-6-hydrazinopyridine is added followed by 3.4 g. of distilled crotononitrile. The reaction mixture is refluxed for 18 hours and the procedure of Example 5 is followed through the anhydrous magnesium silicate filtration step. The filtrate is evaporated to give a dark orange gum which crystallizes on standing. The residue is dissolved in ether, treated with activated charcoal and filtered through diatomaceous earth. The filtrate is concentrated while adding hexane at reflux to yield an oil. The oil is seeded and cooled. Ether is added and continued cooling provides light yellow crystals. The mixture is filtered to give 5.2 g. of the desired product as pale yellow crystals, m.p. 105°-107° C.