Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:7]([C:11]([OH:13])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[N+:32]([O-:46])([O:34][CH2:35][C@@H:36]([O:42][N+:43]([O-:45])=[O:44])[CH2:37][CH2:38][CH2:39][CH2:40]O)=[O:33].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:7]([C:11]([O:13][CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]([O:42][N+:43]([O-:45])=[O:44])[CH2:35][O:34][N+:32]([O-:46])=[O:33])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])OC[C@H](CCCCO)O[N+](=O)[O-]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCc1nc(Cl)c(C(=O)OCCCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 12 h

Procedure:
To a dichloromethane (20 mL) solution of 2-butyl-4-chloro-1-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid (1.76 g, 3.72 mmol), (2S)-6-hydroxyhexane-1,2-diyl dinitrate (intermediate 3, 0.83 g, 3.72 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.85 g, 4.46 mmol), and 1-hydroxybenzotriazole (0.68 g, 4.46 mmol) was added N-methylmorpholine (1.84 mL, 16.7 mmol), followed by N,N-dimethylaminopyridine (4.5 mg, 0.04 mmol). After 12 hours, the reaction mixture was washed with saturated sodium bicarbonate solution, brine, dried (magnesium sulfate), filtered, and concentrated in vacuo. Purification of the reaction mixture by reversed-phase mass-directed high-performance liquid chromatography afforded the title compound. 1H NMR (500 MHz, CD3CN) δ 7.69 (d, J=7.6 Hz, 1H), 7.64 (t, J=7.6 Hz, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.50 (d, J=7.8 Hz, 1H), 7.10 (d, J=8.2 Hz, 2H), 7.03 (d, J=8.0 Hz, 2H), 5.63 (s, 2H), 5.34-5.41 (m, 1H), 4.83 (dd, J=2.5, 12.8 Hz, 1H), 4.58 (dd, J=6.2, 13.0 Hz, 1H), 4.25 (t, J=6.2 Hz, 2H), 2.78 (t, J=7.8 Hz, 2H), 1.79 (q, J=7.5 Hz, 2H), 1.71 (quintet, J=6.8 Hz, 2H), 1.48-1.60 (m, 4H), 1.28 (sextet, J=7.4 Hz, 2H), 0.83 (t, J=7.3 Hz, 3H); LC-MS: m/z 643 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][C@H:4]([CH2:8][OH:9])[CH2:3]1.[H-].[Na+].[C:12]1([N:18]2[CH2:23][CH2:22][N:21]([C:24](OC3C=CC([N+]([O-])=O)=CC=3)=[O:25])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[C:12]1([N:18]2[CH2:19][CH2:20][N:21]([C:24]([O:9][CH2:8][C@H:4]3[O:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]3)=[O:25])[CH2:22][CH2:23]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN1CCO[C@H](CO)C1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCO[C@H](COC(=O)N2CCN(c3ccccc3)CC2)C1
Reaction time: 0.5 h
Yield: 20.6 %

Procedure:
(S)-(4-Methyl-morpholin-2-yl)-methanol (Intermediate 10; 100 mg, 0.76 mmol) was added to a suspension of NaH (60% dispersion in oil; 90.0 mg, 2.28 mmol,) in anhydrous THF (7 mL) and stirred under nitrogen for 30 min. 4-Nitrophenyl 4-phenylpiperazine-1-carboxylate (Intermediate 2; 300 mg, 0.92 mmol) was added and the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was filtered through celite and the solid washed with THF (10 mL). The filtrates were combined and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase silica, 5 g Isolute-Si column, gradient 1-5% MeOH in DCM) then by reverse phase HPLC(YMC ODS-A 100×20 mm, 5 μm, 25 mL/min, gradient 20% to 100% (over 7 min) then 100% (3 min) MeOH in 10% MeOH/water). The pure product was taken up in DCM (5 mL), filtered, and dried in vacuo to give [(2S)-4-methylmorpholin-2-yl]methyl 4-phenyl-piperazine-1-carboxylate (50 mg, 20%) as a colourless gum.
Reaction SMILES: O.Cl.C[O:4][CH:5](OC)[CH2:6][CH2:7][CH2:8][NH:9][C:10]1[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH:20](OC)[O:21]C)[N:13]=[C:12]([NH:25][CH2:26][CH2:27][CH2:28][CH:29]([O:32]C)OC)[N:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:32][CH:29]1[CH2:28][CH2:27][CH2:26][N:25]1[C:12]1[N:13]=[C:14]([N:16]2[CH2:17][CH2:18][CH2:19][CH:20]2[OH:21])[N:15]=[C:10]([N:9]2[CH2:8][CH2:7][CH2:6][CH:5]2[OH:4])[N:11]=1
Reactant: COC(CCCNc1nc(NCCCC(OC)OC)nc(NCCCC(OC)OC)n1)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: OC1CCCN1c1nc(N2CCCC2O)nc(N2CCCC2O)n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Water (50 ml) containing 37 weight % hydrochloric acid (6 ml) was added in one portion to a stirred solution of the tris-(4,4-dimethoxybutylamino)-1,3,5-triazine of Example 1 (6.0 g; 0.0127 mole) in acetone (50 ml) under nitrogen. The reaction mixture was stirred at room temperature for four days and thereafter neutralized with solid potassium carbonate. The solution was then transferred to a separatory funnel and extracted with ethyl acetate (2×150 ml). The organic layer was separated, dried over anhydrous sodium sulfate and the volatiles were removed under reduced pressure to give 2,4,6-tris-(2-hydroxypyrrolidin-1-yl)-1,3,5-triazine as a solid (2.7 g; 64% isolated yield). The structure of the product was confirmed from the 1H NMR spectrum which exhibited the characteristic absorption for the --NCHO-- group at (δ) 5.6 (m, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([B:14]2[O:18][C:17]([CH3:20])(C)C(C)(C)[O:15]2)=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])C=O)[CH3:2].[N+:23](C)([O-:25])=[O:24]>C1COCC1.[OH-].[Na+]>[CH2:1]([O:3][C:4]1[C:5]2[B:14]([OH:15])[O:18][CH:17]([CH2:20][N+:23]([O-:25])=[O:24])[C:6]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: CCOc1c(OC)ccc(C=O)c1B1OC(C)(C)C(C)(C)O1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1c(OC)ccc2c1B(O)OC2C[N+](=O)[O-]
Yield: 58.5 %

Procedure:
Synthesized according to the methods of general procedure 9 in U.S. Pat. Pub. No. 20090227541 (U.S. patent application Ser. No. 12/142,692) using the following reactants and amounts: [3-ethoxy-4-methoxy-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (1.47 g, 4.80 mmol), nitromethane (0.92 g, 14.4 mmol), CATBr (88 mg, 0.24 mmol) in dry THF (20 mL) and NaOH (0.025 M aqueous solution). Purification by silica gel column chromatography (eluant: 10% EtOAc/hexane to 30% EtOAc/hexane) to obtain the title compound as a yellow solid (0.75 g, 59%). 1H NMR {400 MHz, DMSO-d6+D2O (0.01 ml)} δ (ppm) 9.34 (s, 1H), 7.18 (d, J=8.1 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 5.68 (dd, J=9.2, 2.0 Hz, 1H), 5.29 (dd, J=13.2, 2.8 Hz, 1H), 4.55-4.50 (m, 1H), 4.20 (q, J=7.0 Hz, 2H), 3.77 (s, 3H), 1.27 (t, J=7.0 Hz, 3H); MS (ESI) m/z=261 (M−1, negative).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8](C(OC(C)(C)C)=O)[N:7]=[C:6]2[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1.[C-:26]#[N:27].[Na+].C(OCC)(=O)C>CS(C)=O>[F:25][C:21]1[CH:20]=[C:19]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][C:26]#[N:27])[CH:4]=3)[NH:8][N:7]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(CCl)ccc21
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#CCc1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 8.9 %

Procedure:
To a solution of 1.0 g of tert-butyl 5-(chloromethyl)-3-(3-fluorophenyl)-1H-1-indazolecarboxylate in 5 ml dimethyl sulfoxide was added 204 mg of sodium cyanide, and the mixture was stirred at room temperature for 50 minutes. To the reaction mixture was added 50 ml of ethyl acetate, and after washing with water, the aqueous layer was re-extracted with diethyl ether. The collected organic layer was sequentially washed with water (×2) and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:toluene=1:9), and suspended in diethyl ether-diisopropyl ether, to give 62 mg of the title compound as yellow crystals.
Reaction SMILES: CO[CH2:3][C:4]1[S:5][CH:6]=[N:7][N:8]=1.Cl.[NH2:10][CH2:11][CH2:12][SH:13].Br>>[S:5]1[CH:6]=[N:7][N:8]=[C:4]1[CH2:3][S:13][CH2:12][CH2:11][NH2:10]
Reactant: NCCS
Reactant: COCc1nncs1
Agent: Br
Agent: Cl
Product: NCCSCc1nncs1

Procedure:
Equimolar quantities of 2-methoxymethyl(1,3,4)thiadiazole and cysteamine hydrochloride were refluxed under nitrogen for 42 hours in a three-fold excess of hydrobromic acid (48%). The mixture was evaporated to dryness and the residue was dissolved in water. The solution was adjusted to pH 11 by the addition of IRA 400(OH-) and applied to a column of CG50(H+) which was eluted with dilute acetic acid. The eluate was evaporated to give 2-(2-(1,3,4)thiadiazolylmethythio)ethylamine as an oil.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[N:9][NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[OH-].[Na+]>[Br:1][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:4]=1[OH:3])[C:11](=[O:14])[NH:10][N:9]=[CH:8]2
Reactant: O=c1[nH]ncc2ccc(O)cc12
Reactant: BrBr
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]ncc2cc(Br)c(O)cc12
Reaction time: 2 h

Procedure:
Bromine (20 g, 0.25 mole) was added to a stirred solution of 7-hydroxy-1(2H)phthalazinone (10g, 0.062 mole) in aqueous sodium hydroxide (2N, 140 ml), and the stirring was continued for two hours. An excess of sodium metabisulphite was added to the reaction mixture, and the precipitate was filtered off, washed with water and dried. This solid was suspended in acetic anhydride (17 ml) and was heated on a steam-bath for 30 minutes, and the solution was treated with charcoal, filtered and allowed to cool. The cooled mixture was filtered to give 7-acetoxy-6-bromophthalazone, which had m.p. 200°-201° after recrystallisation from ethanol. 7-Acetoxy-6-bromophthalazone was heated with 5% aqueous sodium hydroxide until a clear solution was obtained. The cooled solution was neutralised and the precipitate was filtered off to give 6-bromo-7-hydroxy-1(2H)-phthalazinone, m.p. > 320° (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=1)=O.C(OP([CH2:31][C:32]#[N:33])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=1)=[CH:31][C:32]#[N:33]
Reactant: COc1cc(OC)cc(C(=O)c2cccc(OC)c2OC)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2cccc(OC)c2OC)c1
Yield: 90.5 %

Procedure:
(2,3-Dimethoxyphenyl)-(3,5-dimethoxyphenyl)methanone (1.19 g, 3.94 mmol), cyanomethylphosphonic acid diethyl ester (1.24 ml, 7.87 mmol) in anhydrous THF (20 ml), and lithium bis (trimethylsilyl)amide (1.0 M solution in THF, 7.9 ml, 7.87 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography (5% EtOAc in hexane gradient to 20% EtOAc in hexane in about 40 min.) to give 3-(2,3-Dimethoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile as a clear light pink oil (1.16 g, 91%): 1HNMR (DMSO-d6) δ 7.21-7.08 (m, 2H, Ar), 6.83-6.79 (m, 1H, Ar), 6.62-6.56 (m, 1H, Ar), 6.47-6.46 (m, 2H, Ar), 6.00 (s, 1H, double bond proton), 3.86-3.72 (multiple singlets, 12H, 4OCH3): 13C NMR (CDCl3) δ 161.0, 160.9, 160.7, 160.4, 153.2, 153.1, 147.3, 146.7, 140.5, 140.1, 133.9, 131.7, 124.3, 124.0, 122.5, 122.2, 117.7, 117.5, 114.1, 107.0, 105.7, 102.0, 101.9, 97.8, 97.2, 60.9, 60.7, 56.1, 56.0, 55.7, 55.6; Anal. Calcd. For C19H19NO4: C, 73.20; H, 5.80; N, 4.74. Found: C, 73.10; H, 5.72; N, 4.68.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][CH2:11][C:12](=[O:19])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl[CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[OH:23][CH2:22][CH2:21][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][CH2:11][C:12](=[O:19])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C1=C(Nc2ccccc2O)OCC1=O
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(Nc2ccccc2OCCO)OCC1=O
Temperature: 90 °C
Reaction time: 48 h

Procedure:
A solution of ethyl 2-[(2-hydroxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.38 mmol) which similarly prepared according to the procedure described in the Example 4, First step, 2-chloroethanol (0.038 mL, 0.57 mmol) and potassium carbonate (0.11 g, 0.80 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 90° C. for 2 days. Cooled to ambient temperature, ethyl acetate was added to the reaction mixture, the organic layer was washed with aqueous 5% citric acid solution, water and brine, dried over magnesium sulfate and concentrated. To the residue, tert-butyl methyl ether was added to precipitate the product. The precipitate was collected by filtration, washed with hexane then dried to afford ethyl 2-{[2-(2-hydroxyethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.041 g, y. 35%).
Reaction SMILES: CNN(NC)[C:4]([S:6][C:7]1[C:8]([C:13]([O:15][CH3:16])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=1)=O.CO.C[O-].[Na+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29](CS)=[CH:28][CH:27]=1>CO>[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:4][S:6][C:7]2[C:8]([C:13]([O:15][CH3:16])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:28][CH:27]=1
Reactant: COc1ccc(CS)cc1
Reactant: CNN(NC)C(=O)Sc1cccnc1C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncccc1SCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.2 %

Procedure:
A solution of 1.20 g (5 mmol) of methyl 3-(N,N-dimethylaminocarbamoylthio)pyridine-2-carboxylate in 5 mL of methanol and 1.5 mL (6 mmol) of 4.1M sodium methoxide methanol was stirred at room temperature for 10 minutes. Then the solvent was concentrated and the residue was dissolved in 5 mL of N,N-dimethylformamide and 5 mL of tetrahydrofuran. 0.936 g (6 mmol) of p-methoxybenzylmercaptan was added and the solution was stirred at room temperature for 18 hours. The solution was partitioned between ether and water and the aqueous layer was extracted with two portions of ether. The combined extracts were washed with brine, dried and concentrated. Recrystallization from methanol afforded 0.90 g (62%) of pale tan needles, m.p. 99°-100° C.
Reaction SMILES: O1CCCC1.[CH3:6][O:7][C:8](=[O:24])[C@H:9]([CH:21]([CH3:23])C)[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C(Br)[C:26]1[CH:31]=[CH:30]C=[CH:28][CH:27]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH3:6][O:7][C:8](=[O:24])[C@H:9]([CH2:21][C:23]1[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=1)[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12]
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a tetrahydrofuran solution (1 ml) of the compound prepared in Example 6 (174 mg, 0.5 mmol), were succcessively added dropwise at 0° C. in a nitrogen atmosphere benzyl bromide (0.119 ml, 1.0 mmol) and a tetrahydrofuran solution of tetrabutyl ammonium fluoride (0.5 ml, 0.5 mmol). After the mixture was stirred for 1 hour at 0° C., it was poured into water and extracted with ether. The ether layer was dried over anhydrous magnesium sulfate and concentrated under vacuum. The resulting reaction mixture was subjected to column chromatography on silica gel and eluted with a 3:7 mixture of ether and hexane to give the titled compound in an amount of 122 mg (yield, 78% based on the starting materials used in Example 6)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[C:10]1([CH2:16][SH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:16]([S:17][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: SCc1ccccc1
Reactant: COc1ccnc(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccnc(SCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 26 h
Yield: 35.9 %

Procedure:
To a solution of 2-chloro-4-methoxypyridine (786 mg) in toluene (10 mL) were added phenylmethanethiol (683 mg), N,N-diisopropylethylamine (1.56 g), tris(dibenzylideneacetone)dipalladium(0) (202 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (256 mg), and the mixture was stirred at 80° C. for 26 hr under an argon atmosphere. The reaction mixture was filtered through silica gel and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-hexane-ethyl acetate=19:1) to give the title compound as an orange oil (yield 454 mg, 38%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[OH-].[K+].CCO>[CH:20](=[C:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:10]=2)[C:15]1=[O:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 87.8 %

Procedure:
According to the method of Example 8, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.505 g, 1.97 mmol) was reacted with benzaldehyde (0.312 g, 2.94 mmol) in 3.0 mL of 4% KOH in EtOH overnight at room temperature to afford 0.596 g (88%) of the title compound as a cream-colored solid: CI-MS m/e 344 (M+), 345 (M+ +1);
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH2:23]1>>[C:2]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:20])[NH:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:1]
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)NC1CCN(Cc2ccccc2)CC1

Procedure:
Compound 1c was prepared from N-Boc-L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid and 4-amino-1-benzylpiperidine, using the method described in Example 1.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH2:23]([NH2:25])[CH3:24].O>CS(C)=O>[CH2:23]([NH:25][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)[CH3:24]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CCN
Solvent: CS(C)=O
Solvent: O
Product: CCNc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Prepared according to Example 127, using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 40 mg, 0.135 mmol), 70% v/v ethanamine in water (26.1 mg, 0.405 mmol, Sigma Aldrich), and DMSO (1.4 mL) and stirring at 80° C. for 2 h. Purification by high throughput parallel purification (Rilas Technologies, Woburn, Mass.) provided 2-(3-(ethylamino)-2-methyl-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one. 1H NMR (DMSO-d6) δ: 12.23 (br. s, 1H), 7.84-7.89 (m, 1H), 7.50-7.56 (m, 1H), 7.26-7.33 (m, 2H), 7.06-7.11 (m, 1H), 6.93 (br. s, 1H), 3.48-3.58 (m, 2H), 3.38-3.45 (m, 2H), 2.82-2.89 (m, 2H), 2.50 (s, 3H), 1.30 (t, J=1.0 Hz, 3H). m/z (ESI, +ve) 322.1 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(CC)CC>C(Cl)Cl>[CH3:14][O:13][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH2:4]2)=[O:12]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1ccc2c(c1)CCN2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CCN2C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2,3-dihydro-1H-indole-5-carboxylate HCl salt 55a (64.1 mg, 0.3 mmol), and benzoyl chloride 1t (0.042 mL, 0.36 mmol) in CH2Cl2 (1 mL) was added Et3N (0.13 mL, 0.9 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h. The resulting mixture was partitioned between CH2Cl2 and H2O. The organic solution was dried over Na2SO4 and concentrated. Purification of the residue by flash column chromatography (silica gel, 10-20% EtOAc/Heptanes) gave 55 g (88 mg). MS m/z (M+H+) 282.0.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]([O:9][CH3:10])[C:5]([O:7][CH3:8])=[O:6].O[N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.N#N>C(Cl)Cl.O>[O:22]=[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:21])[N:12]1[O:1][CH2:2][CH2:3][C@H:4]([O:9][CH3:10])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)[C@H](CCO)OC
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H](CCON1C(=O)c2ccccc2C1=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.6 %

Procedure:
To a solution of (S)-methyl 4-hydroxy-2-methoxybutanoate (46b, 1.48 g, 10.0 mmol) in CH2Cl2 (25.0 mL) was added 2-hydroxyisoindoline-1,3-dione (1.63 g, 10.0 mmol) and triphenylphosphine (3.93 g, 15.0 mmol). The resultant mixture was cooled to 0° C. and diisopropylazodicarboxylate (2.95 ml, 15.0 mmol) was slowly added drop wise under N2 atmosphere. The reaction mixture was stirred at ambient temperature for 48 h. To the reaction mixture, H2O (100 mL) was added and extracted with CH2Cl2. The organic layers washed with brine. Dried over anhydrous Na2SO4, filtered and concentrated to provide yellow oil, which was purified by flash chromatography (50% EtOAc-hexane) to afford (S)-methyl 4-(1,3-dioxoisoindolin-2-yloxy)-2-methoxybutanoate (46c, 1.25 g, 42%) as light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.98-2.10 (m, 1H) 2.23-2.37 (m, 1H) 3.51 (s, 3H) 3.79 (s, 3H) 4.24 (dd, J=9.47, 3.66 Hz, 1H) 4.31-4.40 (m, 2H) 7.74-7.82 (m, 2H) 7.81-7.90 (m, 2H).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[CH3:12][C:13]1C=C[C:16](S(OCCCC#C)(=O)=O)=[CH:15][CH:14]=1>>[CH3:9][O:8][C:7]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH2:16][CH2:15][CH2:14][C:13]#[CH:12]
Reactant: C#CCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc(C=O)cc1O
Product: C#CCCCOc1cc(C=O)ccc1OC
Yield: 83 %

Procedure:
Isovanillin (0.98 g, 6.4 mmol) was alkylated with pent-4-ynyl 4-methylbenzenesulfonate (2.3 g, 8.3 mmol) according to Procedure 4. The crude product was recystallised from EtOAc/petrol to provide 4-methoxy-3-(pent-4-ynyloxy)benzaldehyde (1.16 g, 83%) as a colourless crystalline solid; mp 73-74° C.; δH (400 MHz, CDCl3) 1.98 (t, J=2.4 Hz, 1H, CCH), 2.06 (p, J=7.0 Hz, 2H, CH2), 2.43 (td, J=7.0, 2.4 Hz, 2H, CH2C≡CH), 3.94 (s, 3H, OCH3), 4.18 (t, J=7.0 Hz, 2H, OCH2), 6.97 (d, J5′,6′=8.0 Hz, 1H, H5), 7.43 (s, 1H, H2), 7.45 (d, J5,6=8.0 Hz, 1H, H6), 9.84 (s, 1H, CHO); δC (100 MHz, CDCl3) 15.1, 27.9, 56.1, 67.3, 69.1, 83.2, 110.6, 110.7, 126.7, 130.0, 148.9, 154.9, 190.9; vmax 1025, 1263, 1584, 1665, 2849, 2936, 3254 cm−1.