Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([NH2:28])[C:16]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=[CH:17][CH:18]=1.[C:29]1(=[O:39])[C@@H:37]2[C@@H:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[C:31](=O)[O:30]1.CCN(C(C)C)C(C)C.Cl>C(#N)C>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]2[N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([Br:27])=[CH:25][CH:26]=3)[C:31]([C@H:32]3[CH2:33][CH2:34][CH2:35][CH2:36][C@H:37]3[C:29]([OH:39])=[O:30])=[N:28][C:15]=2[CH:14]=1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: Nc1cc(OCc2nc3ccccc3s2)ccc1NCc1ccc(Br)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(O)[C@@H]1CCCC[C@@H]1c1nc2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a 4 mL microwave vial were added 4-(benzo[d]thiazol-2-ylmethoxy)-N1-(4-bromobenzyl)benzene-1,2-diamine hydrochloride (100 mg, 0.21 mmol), cis-hexahydroisobenzofuran-1,3-dione (34 mg, 0.21 mmol), DIPEA (27 mg, 0.21 mmol), and acetonitrile (2 mL). The mixture was irradiated for 1 h at 82° C. in a microwave reactor. The reaction was cooled to RT, HCl (1 mL, 6 N) was added and the reaction was irradiated for 1 h at 82° C. in a microwave reactor. The reaction was cooled to RT and the solid byproducts were removed by filtration and filtrate was purified using reverse phase HPLC to provide the title compound. MS (ESI): mass calcd. for C29H26BrN3O3S, 575.10; m/z found, 576.1 [M+H]+. 1H-NMR (500 MHz, CDCl3) δ 8.03 (d, J=8.0, 1H), 7.89 (d, J=8.0, 1H), 7.56-7.48 (m, 4H), 7.45-7.38 (m, 2H), 7.19-7.16 (m, 1H), 7.16-7.11 (m, 1H), 6.97 (d, J=8.4, 2H), 5.59-5.49 (m, 1H), 5.46 (s, 2H), 3.40-3.24 (m, 1H), 2.93 (d, J=4.5, 1H), 2.39-2.19 (m, 2H), 1.96-1.83 (m, 2H), 1.82-1.69 (m, 1H), 1.65-1.50 (m, 2H), 1.35 (d, J=13.0, 1H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]([C:10]1[N:14]2[CH:15]=[CH:16][N:17]=[C:18]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[O:29][CH3:30])[C:13]2=[C:12]([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[N:11]=1)[C:6]([O:8]C)=O)#[N:2].CO>CCO.[Ni]>[CH3:30][O:29][C:22]1[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=1[CH2:20][NH:19][C:18]1[C:13]2[N:14]([C:10]([CH:5]3[CH2:4][CH2:3][CH2:1][NH:2][C:6]3=[O:8])=[N:11][C:12]=2[C:31]2[CH:32]=[CH:33][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:39][CH:40]=2)[CH:15]=[CH:16][N:17]=1
Reactant: COC(=O)c1ccc(-c2nc(C(CCC#N)C(=O)OC)n3ccnc(NCc4ccc(OC)cc4OC)c23)cc1
Agent: [Ni]
Solvent: CO
Solvent: CCO
Product: COC(=O)c1ccc(-c2nc(C3CCCNC3=O)n3ccnc(NCc4ccc(OC)cc4OC)c23)cc1
Temperature: 75 °C
Reaction time: 7 h
Yield: 40.4 %

Procedure:
To a solution of methyl 4-(3-(4-cyano-1-methoxy-1-oxobutan-2-yl)-8-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrazin-1-yl)benzoate (12 g, 22.1 mmol) in EtOH (350 mL) was added Ra—Ni (24 g) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (50 psi) at 75° C. for 7 hours. The reaction was complete detected by LCMS. The suspension was filtered through a pad of Celite and the pad was washed with EtOH (20 mL×3). The combined filtrates were concentrated. The residue was purified by column chromatography on silica gel eluted with DCM:MeOH=30:1 to give methyl 4-(8-((2,4-dimethoxybenzyl)amino)-3-(2-oxopiperidin-3-yl)imidazo[1,5-a]pyrazin-1-yl)benzoate (4.6 g, yield 40%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH2:19][F:20]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH2:19][F:20])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: FCCBr
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: FCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 84.6 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (100 mg) in N,N-dimethylformamide (0.6 mL) was added cesium carbonate (281 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added 1-bromo-2-fluoroethane (124 mg), and the mixture was stirred at room temperature for 5 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic layer was washed with saturated brine (20 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=90/10→0/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (110 mg) as a colorless transparent oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][S:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:7]=1)[CH3:2].Cl[C:31]([O:33][CH2:34][CH2:35][Cl:36])=[O:32]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:31]([O:33][CH2:34][CH2:35][Cl:36])=[O:32])=[CH:17][C:16]=2[CH2:22][S:23][CH2:24][C:25]([F:26])([F:27])[F:28])[CH:7]=1)[CH3:2]
Reactant: O=C(Cl)OCCCl
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CSCC(F)(F)F)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)OCCCl)cc2CSCC(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 6, using the following starting materials: {3-[4-amino-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and 2-chloroethyl chloroformate.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][CH:6]=1)[CH3:3].[N:14]([N:16]1[CH2:21]CNC[CH2:17]1)=[O:15]>C1(C)C=CC=CC=1>[N:14]([N:16]1[CH2:21][CH2:1][N:2]([CH2:4][C:5]2[C:9]3[C:8](=[CH:13][CH:12]=[CH:11][CH:10]=3)[NH:7][CH:6]=2)[CH2:3][CH2:17]1)=[O:15]
Reactant: CN(C)Cc1c[nH]c2ccccc12
Reactant: O=NN1CCNCC1
Solvent: Cc1ccccc1
Product: O=NN1CCN(Cc2c[nH]c3ccccc23)CC1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
A mixture of 34.8 g (0.22 mol) of gramine and 23.9 g (0.20 mol) of nitrosopiperazine in 700 ml. of toluene is refluxed while stirring under nitrogen for 48 hours. The reaction solution is then concentrated under reduced pressure until a precipitate appears and then is cooled to 0° C. and is filtered. The product is washed with cold toluene and dried to produce crystals of 3-(4-nitrosopiperazin-1-yl)methylindole. This product is recrystallized from toluene to yield pure plates, m.p. 116°-118° C. Analysis: Calculated for C13H16N4O: 63.92% C; 6.60% H; 22.93% N Found: 63.84% C; 6.64% H; 23.06% N.
Reaction SMILES: CO[C:3](=[O:16])[CH2:4][CH2:5][CH:6]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[N+:7]([O-:9])=[O:8].[CH3:17][N:18]1CN(C)CN(C)[CH2:19]1>>[CH:10]1([C:6]2([N+:7]([O-:9])=[O:8])[CH2:17][N:18]([CH3:19])[C:3](=[O:16])[CH2:4][CH2:5]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: COC(=O)CCC(C1CCCCC1)[N+](=O)[O-]
Reactant: CN1CN(C)CN(C)C1
Product: CN1CC(C2CCCCC2)([N+](=O)[O-])CCC1=O
Temperature: 100 °C
Yield: 57.4 %

Procedure:
To 4.25 g (18.5 mmol) rac-4-cyclohexyl-4-nitro-butyric acid methyl ester were added 4.56 ml (32.5 mmol) 1,3,5-trimethylhexahydro-1,3,5-triazine and the mixture heated to 100° C. for 4 hours. The reaction mixture was cooled to ambient temperature and adsorbed on silica gel which was transferred on top of a silica gel column and purified by flash-chromatography with a gradient of heptane and 10 to 75% ethyl acetate: 2.55 g of title compound were isolated as colourless oil: MS (m/e): 240 (MH+).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:19]=1)[CH2:15]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C=O)C>[CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:19]=1)[CH2:15][N:31]=[N+:32]=[N-:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCCC)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1cc(CN=[N+]=[N-])cc(OCCCCCCCCCC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
3,5-Didecoxybenzyl chloride (14.4 g, 32.8 mmol) was dissolved in DMF (50 mL) in a 250 mL RBF. Sodium azide (4.26 g, 65.6 mmol) and a magnetic stir bar were added to the RBF. The RBF was heated to just below boiling of the DMF using a heat gun. The reaction mixture was then stirred at room temperature until cool to the touch. Heating and cooling were repeated 3 times. Thin layer chromatography in hexanes showed the presence of a starting material. A heating mantel was used to gently heat the RBF. After 1 hour, thin layer chromatography showed no starting material present. The contents of the RBF were transferred to a separatory funnel. Ether (250 mL) and distilled H2O (250 mL) were added to the funnel. The aqueous layer was washed 2 times with ether (250 mL). The ether layers were combined and washed 2 times with saturated ammonium chloride solution (125 mL) and once with saturated sodium chloride solution (125 mL). The ether layer was then dried with magnesium sulfate, gravity filtered and concentrated using rotary evaporation. High vacuum was then used to remove trace amounts of the ether giving. There was a 13.6 g yield or a 93.1% yield of the derivative. The NMR characterization data for this derivative is as follows. 1NMR (300 MHz, CDCl3): 0.88 (t, J=6.6, 6H, CH2CH3), 1.27-1.43 (m, 28H, CH2(CH2)7), 1.76 (p, J=6.6, 4H, OCH2CH2), 3.92 (t, J=6.6, 4H, OCH2), 4.21 (s, 2H, ArCH2N3), 6.42-6.44 (m, 3H, ArH). 13C NMR (75 MHZ, CDCl3): 14.23, 22.79, 26.13, 29.31, 29.45, 29.49, 29.68, 29.71, 32.01, 55.01, 65.97, 68.19, 101.08, 106.52, 137.45, 160.68.
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH:13]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:14]([F:17])([F:16])[F:15])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:24]1([S:30]([NH2:33])(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CS(C)=O>[F:15][C:14]([F:17])([F:16])[CH:13]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[O:12][C:11]1[C:2]([NH:33][S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: NS(=O)(=O)c1ccccc1
Reactant: FC(F)(F)C(Oc1nc2ccccc2nc1Cl)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=S(=O)(Nc1nc2ccccc2nc1OC(c1cccnc1)C(F)(F)F)c1ccccc1
Temperature: 150 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
2-Chloro-3-[2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy]-quinoxaline (Compound BJ) (73 mg, 0.21 mmol) was dissolved in dimethyl sulfoxide (2 mL). To this, benzenesulfonamide (33 mg, 0.21 mmol) and potassium carbonate (29 mg, 0.21 mmol) were added at room temperature and the mixture was stirred at 150° C. for 2 hours. The reaction mixture was allowed to cool down to room temperature, a 1% aqueous acetic acid solution (20 mL) was added thereto, and the precipitate was collected by filtration. The obtained solid was subjected to slurry purification using methanol, to give N-{3-[2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy]quinoxalin-2-yl}benzenesulfonamide (Compound 137) (31 mg, 320).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].[Li+].[CH3:14]C([N-]C(C)C)C.CI.[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:14])[C:9]([O:11][CH3:12])=[O:10]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)Cc1ccccc1F
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Methyl 2-fluorophenylacetate (24.2 g, 0.144 mol) in THF (75 ml) was added dropwise over 20 min to a -78° C. solution of LDA (diisopropylamine (16.0 g, 0.158 mol) and n-butyl lithium (2.5 M, 61 ml)) in THF (300 ml) and stirring was continued for 1 h. Methyl iodide (22.5 g, 0.158 mol) was added dropwise over 15 min and the reaction mixture allowed to warm to room temperature over 1 h. The solution was poured into saturated ammonium chloride solution and extracted with diethyl ether. The extract was washed with brine, dried and evaporated to yield methyl 2-(2-fluorophenyl)propanoate (26.2 g, 100%) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[N:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:21][CH2:20]2)=[O:18])=[C:11]([N+:31]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl>CO>[NH2:31][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([O:15][CH3:16])=[CH:13][C:12]=1[C:17]([N:19]1[CH2:20][CH2:21][N:22]([C:25]2[N:26]=[CH:27][CH:28]=[CH:29][N:30]=2)[CH2:23][CH2:24]1)=[O:18]
Reactant: COc1cc(C(=O)N2CCN(c3ncccn3)CC2)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)N2CCN(c3ncccn3)CC2)c(N)cc1OCc1ccccc1
Yield: 90.2 %

Procedure:
[4-(Benzyloxy)-5-methoxy-2-nitrophenyl][4-(2-pyrimidinyl)piperazino-]methanone (7c) (500 mg, 1.11 mmol) was dissolved in methanol (10 mL), SnCl2.2H2O (751 mg, 3.3 mmol) was added and refluxed until the TLC indicated the completion of the reaction. The methanol was evaporated by vacuum and the aqueous layer was then adjusted to pH 8 with 10% NaHCO3 solution and extracted with ethyl acetate (2×30 mL). The combined organic phase was dried over Na2SO4 and evaporated under vacuum to afford the crude This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (8c) (420 mg, 90% yield). 1H NMR (CDCl3) δ 3.10-3.25 (m, 4H), 3.60-3.80 (m, 4H), 3.95 (s, 3H), 5.20 (s, 2H), 6.20 (s, br), 6.45-6.55 (t, 1H) 6.75 (s, 1H), 7.30-7.55 (m, 5H), 7.80 (s, 1H); FABMS: 419 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[NH:13][C:12](=[O:14])[CH2:11][CH2:10][C:9]2=O)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:17][OH:18]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[NH:13][C:12](=[O:14])[CH2:11][CH2:10][C:9]2=[N:17][OH:18])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)C(c2cccc(Br)c2)N1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(=NO)C(c2cccc(Br)c2)N1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A mixture of 6-(3-bromo-phenyl)-piperidine-2,5-dione (38.2 g) and hydroxylamine hydrochloride (19.8 g) in pyridine (300 ml) was stirred at room temperature under nitrogen. After 4 h the mixture was evaporated in vacuo. The crude mixture was partitioned between chloroform (200 ml) and water (200 ml) then was basified by the addition of 8% sodium bicarbonate solution (~300 ml). The mixture was extracted with chloroform (300 ml×2). The combined organic extracts were washed with saturated brine and evaporated in vacuo. Trituration with ether gave the title compound as a pale yellow solid (34.9 g). T.l.c. (Ethyl acetate) Rf 0.44, 0.28, E/Z mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[O:10][CH3:11].C([Li])CCC.[I:17]I>C1COCC1.C(OCC)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([I:17])=[C:4]([F:9])[C:3]=1[O:10][CH3:11]
Reactant: II
Reactant: COc1c(F)cc(F)cc1Cl
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1c(Cl)cc(F)c(I)c1F
Temperature: -75 °C
Reaction time: 1 h

Procedure:
To a solution of 1-chloro-3,5-difluoro-2-methoxybenzene (2.0 g, 0.01 mol) in THF at −75° C. was added n-butyl lithium (2.5M in hexanes 6.7 mL) and the resulting solution was stirred at −75° C. for 1 hour. A solution of iodine (5.1 g, 0.02 mol) in THF (10 mL) was added and the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was diluted with ethyl ether (50 mL) and aqueous sodium thiosulfate (10%, 50 mL) was added and stirred for 1 hour. After separating the phases, the organic phase was dried (Na2SO4) and concentrated to give 1-chloro-3,5-difluoro-4-iodo-2-methoxybenzene as a white solid: mp 62-64° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH:6]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([NH:16][N:17]=[CH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][C:10]=2[Cl:25])[C:7]#[N:8])=[CH:4][CH:3]=1.[CH3:28][O:29][CH:30]([O:35][CH3:36])[CH2:31][N:32]=[C:33]=[O:34]>C(#N)C.C1CCN2C(=NCCC2)CC1>[CH:18](=[N:17][N:16]([C:12]1[CH:11]=[C:10]([Cl:25])[C:9]([CH:6]([C:7]#[N:8])[C:5]2[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:14]([Cl:15])[CH:13]=1)[C:33]([NH:32][CH2:31][CH:30]([O:35][CH3:36])[O:29][CH3:28])=[O:34])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(CN=C=O)OC
Reactant: N#CC(c1ccc(Cl)cc1)c1c(Cl)cc(NN=Cc2ccccc2)cc1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(CNC(=O)N(N=Cc1ccccc1)c1cc(Cl)c(C(C#N)c2ccc(Cl)cc2)c(Cl)c1)OC
Reaction time: 1 h
Yield: 87.8 %

Procedure:
In 20 ml of acetonitrile was suspended 3.2 g of benzaldehyde 4-(4-chloro-α-cyanobenzyl)-3,5-dichlorophenyl hydrazone. To the suspension were added 1.5 g of 2,2-dimethoxyethyl isocyanate and 20 mg of DBU. The reaction was allowed to proceed for one hour at room temperature, then the resulting crystalline precipitate was collected by filtration, which was washed with hexane, followed by drying to afford 3.7 g of the titled compound as colorless crystals, m.p.190-191° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])[CH3:2].O[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:11]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1)[CH3:12]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCN(CC)CCCCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN(CC)CCCCCCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.3 %

Procedure:
A mixture of 2.17 g of 6-diethylamino-1-hexanol (J. Chem. Soc. 1942, 428), 1.52 g of 4-hydroxy-benzaldehyde and 3.3 g of triphenylphosphine in 100 ml of tetrahydrofuran was treated slowly at 20° with a solution of 1.97 g of diethyl azodicarboxylate. After the dropwise addition the mixture was stirred at room temperature for a further 5 hours. The reaction mixture was then evaporated in a rotary evaporator. The residue was chromatographed on 400 g of neutral aluminium oxide (activity grade III) with hexane:ethyl acetate 7:3). There were obtained 2.22 g (64%) of 4- [[6-(diethylamino)hexyl]oxy]benzaldehyde as a yellowish oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[CH3:21][O:22][C:23](=[O:30])/[CH:24]=[CH:25]/[CH2:26][C:27](O)=[O:28].C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>ClCCl>[CH3:21][O:22][C:23]([CH2:24][CH:25]=[CH:26][C:27]([N:9]([CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])=[O:28])=[O:30]
Reactant: O=C(CNCc1ccccc1Br)OCc1ccccc1
Reactant: COC(=O)/C=C/CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC=CC(=O)N(CC(=O)OCc1ccccc1)Cc1ccccc1Br
Reaction time: 2 h

Procedure:
Benzyl 2-(N-(2-bromophenylmethyl)amino)acetate was dissolved in dichloromethane (0.2 M), followed by addition of trans-glutaconic acid methyl ester (1.2 eq), triethylamine (2 eq), EDAC (1.2 eq), and HOAT (0.1 eq). After stirring for 2 hrs, the solution was washed with 10% HCl, 10% sodium carbonate, water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50% EtOAc/Hex) afforded a viscous oil. EI-MS m/z 460, 462 (M+H)+
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])[N:3]=1.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[C:23]2[NH2:29].O.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[C:23]2[NH:29][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])[N:3]=1
Reactant: Cc1cc(Cl)nc(-c2ccccc2C(F)(F)F)n1
Reactant: Nc1n[nH]c2ccc(F)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(Nc2n[nH]c3ccc(F)cc23)nc(-c2ccccc2C(F)(F)F)n1
Temperature: 165 °C
Yield: 56.5 %

Procedure:
A mixture of 4-chloro-6-methyl-2-(2-trifluoromethyl-phenyl)-pyrimidine (0.10 g, 0.37 mmol) and 5-fluoro-1H-indazole-3-ylamine (0.072 g, 0.48 mmol) was heated neat at 160-170° C. for 8 hours. The resulting residue was cooled to ambient temperature then dissolved in N-methyl-pyrrolidinone (2 mL). This mixture was poured into water (20 mL) and sodium bicarbonate (5 mL) was added and the resulting mixture filtered, washing with water. Purification by preparative HPLC provided the title compound (0.081 g, 43% yield) as a tan solid. 1H-NMR (500 MHz, DMSO-d6) δ 12.8 (br s, 1H), 10.6 (br s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.77 (m, 4H), 7.62 (br s, 1H), 7.50 (m, 1H), 7.29 (m, 1H), 2.44 (s, 3H) ppm; LC-MS 388.05 (M+H); Rt (Method A) 2.900 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]([OH:17])(CC=C)[CH2:11][CH:12]=[CH2:13])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH:7]=1.CC(C)([O-])C.[K+].Cl>CN(C)C=O>[CH3:13]/[CH:12]=[CH:11]/[C:10]([CH:3]1[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH:7]=[C:2]1[CH3:1])=[O:17]
Reactant: C=CCC(O)(CC=C)C1C(C)=CCCC1(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C=C/C(=O)C1C(C)=CCCC1(C)C
Reaction time: 0.1 h

Procedure:
100 g of 2,6,6-trimethyl-1-[4-hydroxy-hepta-1,6-dien-4-yl]-cyclohex-2-ene have been added at room temperature and under stirring to a solution of 80 g of potassium tert-butoxide in 180 ml of dimethylformamide, while the temperature raised to 60°. After having been left at this temperature for 6 min., the mixture is put into an aqueous HCl solution (150 ml of conc. HCl/200 ml H2O). A vapour phase distillation has given 4 l of distillate which was then extracted with petrol ether (80°-100°). After the usual treatments of separation, drying and evaporation of the organic extracts, 71 g of a mixture of iso- α-damascone and α-damascone were obtained.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: N#Cc1cc(-c2ccc(CO)cc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, light brown solid (18 mg, 23%), MS (ISN) m/z=318.5 [(M+H)+], mp 257.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-hydroxymethyl-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH:11]2[CH:18]3[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:20][CH:12]2[CH2:13]4)[CH2:17]3)=[O:9])[CH2:4]1.Cl[C:22]([O:24][CH2:25][CH2:26][CH3:27])=[O:23]>>[CH2:25]([O:24][C:22]([NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH:11]2[CH:12]3[CH2:13][CH:14]4[CH2:15][CH:16]([CH2:17][CH:18]2[CH2:19]4)[CH2:20]3)=[O:9])[CH2:4]1)=[O:23])[CH2:26][CH3:27]
Reactant: CCCOC(=O)Cl
Reactant: N[C@@H]1CCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1
Agent: Cl
Product: CCCOC(=O)N[C@@H]1CCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1

Procedure:
The title compound was prepared from (R)-2-adamantyl 3-aminopyrrolidine-1-carboxylate HCl salt and propyl chloroformate following a procedure analogous to that described in Example 3 Step 2. LC-MS Method 1 tR=2.00 min, m/z=351; 1H NMR (CDCl3) 0.97 (t, 3H), 1.50-2.05 (16H), 2.19 (m, 1H), 2.42 (1H), 3.29 (dd, 1H), 3.50 (m, 2H), 3.70 (m, 1H), 4.04 (m, 2H), 4.28 (1H), 4.78 (1H), 4.83 (s, 1H)