Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.C1CCC(N=C=NC2CCCCC2)CC1.[C:26]([O:30][C:31]([N:33]1[CH2:36][CH:35]([C:37](O)=[O:38])[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C1CCCCC1>CN(C1C=CN=CC=1)C.ClCCl>[C:26]([O:30][C:31]([N:33]1[CH2:36][CH:35]([C:37]([CH:6]2[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:5])=[O:38])[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)N1CC(C(=O)C2C(=O)OC(C)(C)OC2=O)C1
Reaction time: 8 h

Procedure:
Meldrum's acid (0.85 g, 5.97 mmol), DCC (1.22 g, 5.97 mmol), and DMAP (1.45 g, 11.94 mmol) were successively added to a solution of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (1.2 g, 5.97 mmol) in dichloromethane (25 mL) at room temperature. The reaction mixture was stirred overnight and then diluted by addition of cyclohexane (25 mL). The precipitate of dicyclohexyl urea was then filtered and rinsed with diethyl ether (100 mL). The mother liquors were diluted with DCM (100 mL) and washed with a 1M solution of aqueous HCl (2×30 mL), dried over sodium sulfate, filtered and concentrated to dryness. After trituration in diethyl ether the title compound was obtained as a white solid (1.9 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:15][S:16]([C:19]1[CH:20]=[C:21]([C:31](O)=[O:32])[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)(=[O:18])=[O:17]>>[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:21]([C:31]([N:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:10][CH2:11]2)=[O:32])[CH:20]=1)(=[O:17])=[O:18]
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Product: COc1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3-c3ccccc3)CC2)cc1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from ′1-(4-metoxyphenyl)-piperazine [38212-30-5] and 4-Methanesulfonyl-biphenyl-2-carboxylic acid (Example V). MS (ISP): 451.1 MH+.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)[CH3:7])[C:2]#[CH:3].[CH3:18][O:19][C:20](=[O:26])[C:21](Br)=[CH:22][O:23][CH3:24]>C(N(CC)CC)C.O1CCCC1.[Cu]I>[CH3:18][O:19][C:20](=[O:26])[C:21](=[CH:22][O:23][CH3:24])[C:3]#[C:2][CH2:1][O:4][N:5]=[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=1)[CH3:7]
Reactant: C#CCON=C(C)c1cccc(C(F)(F)F)c1
Reactant: COC=C(Br)C(=O)OC
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC=C(C#CCON=C(C)c1cccc(C(F)(F)F)c1)C(=O)OC
Temperature: 70 °C
Reaction time: 14 h
Yield: 31.2 %

Procedure:
0.25 g of Pd(TPP)2Cl2 and also 0.1 g of copper(I) iodide are added, under an argon atmosphere, to a solution of 10.0 g of 1-(3-trifluoromethylphenyl)ethanone O-prop-2-ynyl-oxime in 150 ml of triethylamine and the mixture is heated to 70° C. 8.9 g of 2-bromo-3-methoxyacrylic acid methyl ester in 30 ml of tetrahydrofuran are then added and the mixture is stirred at 70° C. for 14 h and then filtered. The filtrate is concentrated by evaporation and chromatographed on silica gel (hexane/diethyl ether 2:1) to yield 4.6 g of the product having a melting point of 57-58° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[N:9]2[CH:18]=[CH:19][CH:20]=[C:8]2[C:7]=1[OH:21])=O)C.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([NH2:32])(=[O:31])=[O:30]>C(O)C>[O:30]=[S:29]1(=[O:31])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][C:4]([C:6]2[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[N:9]3[CH:18]=[CH:19][CH:20]=[C:8]3[C:7]=2[OH:21])=[N:32]1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: CCOC(=O)c1c(O)c2cccn2n(CCC(C)C)c1=O
Solvent: CCO
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2cccn21
Temperature: 180 °C
Yield: 50 %

Procedure:
4-Hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (Example 1f, 0.040 g, 0.14 mmol) was mixed with 2-amino-benzenesulfonamide (0.0235 g, 0.14 mmol) and the resulting mixture was heated to 180° C. for 20 min. The resulting crude oil was allowed to cool to 25° C. and ethanol (0.5 mL) was added and sonicated to afford a tan precipitate, which was collected and dried in vacuo. The crude solid was dissolved in 1.0 M aqueous potassium hydroxide solution (0.3 mL) and heated to 110° C. for 20 h. The reaction mixture was allowed to cool to 25° C. and 10% aqueous hydrochloric acid solution (0.5 mL) was added and the resulting white precipitate was collected. The solid was washed with methanol and dried in vacuo to afford the desired product, 3-(1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-4-hydroxy-1-(3-methyl-butyl)-pyrrolo[1,2-b]pyridazin-2-one (0.028 g, 0.07 mmol, 52% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 0.97 (6H, d, J=6.4 Hz), 1.28 (2H, bs), 1.61 (2H, q, J1=15.2 Hz, J2=6.8 Hz), 1.74 (1H, m), 4.43 (2H, t, J=8.0 Hz), 6.71 (1H, dd, J1=4.4 Hz, J2=2.4 Hz), 7.04 (1H, d, J=4.4 Hz), 7.23 (1H, t, J=8.0 Hz), 7.50 (1H, t, J=7.6 Hz), 7.63 (1H, d, J=8.4 Hz), 7.88 (1H, d, J=8.0 Hz), 7.90 (1H, m); LC-MS (ESI) calcd for C19H20N4O4S 400.45. found 401.28 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.[CH:21]1(Br)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:17][CH2:18][CH2:19][CH2:20]2)[N:13]1[CH:21]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: BrC1CCCCCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC2(CCCC2)N1C1CCCCCC1

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was sequentially reacted with SOCl2 and 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cycloheptyl bromide according to Method D2e to give 2-(2-methyl-4-nitrophenylimino)-1-cycloheptyl-3-thia-1-azaspiro [4.4]nonane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]1(=O)[CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C2CCC2)CC1
Reaction time: 3 h

Procedure:
Piperazine-4-carboxylic acid tert-butyl ester (3.74 g), cyclobutanone (3.00 mL), and acetic acid (1.15 mL) were dissolved in methanol (100 mL). To the resultant solution, sodium cyanoborohydride (1.89 g) was added at room temperature, followed by stirring for 3 hours. The solvent was evaporated under reduced pressure, and the residue was partitioned by use of ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as an oily product (4.43 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Br:13]Br>O1CCOCC1>[Br:13][CH2:11][C:10]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=1)=[O:12]
Reactant: BrBr
Reactant: COc1ccc(C(C)=O)cc1F
Solvent: C1COCCO1
Product: COc1ccc(C(=O)CBr)cc1F
Reaction time: 0.17 h
Yield: 62.4 %

Procedure:
To a solution of 3′-fluoro-4′-methoxyacetophenone (1 g, 5.9 mmol) (Aldrich) in dioxane (10 mL) was added dropwise a solution of bromine (1.13 g, 7.1 mmol) in dioxane (30 mL). After stirring for 10 minutes, the mixture was concentrated in vacuo and the residue was purified by flash chromatography, with 10:4 hexanes/dichloromethane as an eluant, to provide 2-bromo-1-(3-fluoro-4-methoxyphenyl)ethanone as a white powder (910 mg, 63% yield).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]1([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH2:25]I>O1CCCC1>[CH3:21][C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH2:25][CH2:24][C:23]([CH3:28])([CH3:27])[CH3:22])[C:18]([OH:20])=[O:19]
Reactant: CC(C(=O)O)c1ccccc1
Reactant: CC(C)(C)CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)CCC(C)(C(=O)O)c1ccccc1
Temperature: 50 °C

Procedure:
To a solution of lithium bis(trimethylsilyl)amide in (154.48 g, 0.923 mol) in tetrahydrofuran (350 mL) was added 2-phenyl propionic acid (50.0 g, 0.333 mol) over 27 minutes maintaining the temperature below 25° C. Following a THF rinse (35 mL), the solution was heated to 50° C. for 23 minutes. The solution was then cooled below 25° C. and 3,3-dimethyl-1-iodobutane (110.3 g, 0.416 mol) was added. The reaction mixture was heated to 60° C. for 31 h, then was cooled to RT, and concentrated to a thick oil. Water (500 mL) was added and the solution was cooled to 10-15° C. and the pH was adjusted to <2 by the addition of 6 N HCl (75.59 g). The product was extracted with ethyl acetate (440 mL) and the organic layer was washed with 10% NaCl. The crude ethyl acetate solution (assayed for 66.8 g of 49-1, 85.6%) was concentrated to a thick oil and used in the resolution.
Reaction SMILES: [CH3:1][C:2]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.Cl[C:29]1[CH:34]=[C:33]([N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)[N:32]2[N:40]=[C:41]([NH2:43])[N:42]=[C:31]2[CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[NH2:43][C:41]1[N:42]=[C:31]2[CH:30]=[C:29]([C:11]3[CH:12]=[N:13][C:8]([N:5]4[CH2:4][CH2:3][C:2]([CH3:1])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:7][CH2:6]4)=[N:9][CH:10]=3)[CH:34]=[C:33]([N:35]3[CH:39]=[CH:38][CH:37]=[N:36]3)[N:32]2[N:40]=1
Reactant: Nc1nc2cc(Cl)cc(-n3cccn3)n2n1
Reactant: CCOC(=O)C1(C)CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(-n4cccn4)n4nc(N)nc4c3)cn2)CC1
Temperature: 110 °C
Yield: 55.2 %

Procedure:
A suspension of ethyl 4-methyl-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]piperidine-4-carboxylate (360 mg, 0.97 mmol), 7-chloro-5-(1H-pyrazol-1-yl)[1,2,4]triazolo[1,5-a]pyridin-2-amine (190 mg, 0.81 mmol), cesium carbonate (400 mg, 1.2 mmol) and Pd(dppf)2C12 (60 mg, 0.08 mmol) in 1,4-dioxane (4.5 mL) and water (0.5 mL) was added to a microwave vial and degassed with N2. The vessel was then heated at 110° C. in a microwave reactor for 60 mins. The resultant solution was concentrated in vacuo and the residue purified by flash column chromatography (Biotage SP4, 40 g 0-10% MeOH/DCM) and (Biotage SP4, 12 g 2% MeOH/DCM, then flush with 10% MeOH/DCM) to give the desired product as a cream solid (200 mg, 55%) MS: 448.27 [M+H]+.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[BrH:11]>C1(C)C=CC=CC=1>[Br:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]
Reactant: Br
Reactant: OCCCCCCCCO
Solvent: Cc1ccccc1
Product: OCCCCCCCCBr

Procedure:
In a 6 m3 kettle, 235 kg of octane-1,8-diol were stirred under reflux with 3 m3 of toluene and 440 kg of HBr (48% strength) for 40 hours. The aqueous phase was then separated off. The toluene phase was thoroughly washed with 500 1 of water, then with 500 l of 10% strength sodium carbonate solution and then again with 500 1 of water. A sample was concentrated and was found to contain 92% of bromooctanol in addition to 1.9% of dibromooctane and 2.0% unconverted octanediol. After removal of the toluene by distillation in the reaction kettle and a Sambay distillation of the remaining residue, the yield was 254 kg (76%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)=[O:10].[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:23]2[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=2)=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)=[O:10]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1cc(I)ccc1F
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: O=C(c1cccc([N+](=O)[O-])c1)c1cc(-c2ccncc2)ccc1F
Yield: 56.5 %

Procedure:
A 20 mL microwave tube was charged with (2-fluoro-5-iodophenyl)(3-nitrophenyl)methanone (1.1 g), 4-pyridylboronic acid (730 mg), dichlorobis(triphenylphosphine)palladium(II) (420 mg), dimethoxyethane (8 mL), ethanol (4 mL) and a saturated solution of sodium carbonate (2 mL) then heated to 110° C. for 360 s using microwave irradiation. The reaction was concentrated to dryness and the residue was taken up in water then extracted with ethyl acetate. The organic extracts were combined and dried over magnesium sulfate. The drying salts were removed by filtration and the filtrate was concentrated. The residue was purified by silica gel chromatography to provide [2-fluoro-5-(4-pyridinyl)phenyl](3-nitrophenyl)methanone (540 mg) as a solid. H1 NMR (d6-dmso): 8.63 (d, 2H), 8.52 (dd, 1H), 8.48 (s, 1H), 8.21 (d, 1H), 8.15 (m, 1H), 8.06 (dd, 1H), 7.85 (dd, 1H), 7.74 (d, 2H), 7.58 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.C(Cl)(Cl)[Cl:12]>>[Cl:12][C:6](=[N:7][OH:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: ON=Cc1ccc(Cl)cc1
Reactant: ClC(Cl)Cl
Product: ON=C(Cl)c1ccc(Cl)cc1
Yield: 94.7 %

Procedure:
31 g (0.2 mol) of 4-chlorobenzaldoxime was suspended in 200 g of chloroform and chlorine gas was bubbled through the suspension while maintaining the reaction mixture at a temperature of from 5° to 10° C. 3-Chlorobenzaldoxime went into solution while showing a green color upon reaction with chlorine to give a reaction mixture having a deep green color. The reaction mixture turned pale yellowish-brown upon standing; chloroform was then removed from the reaction mixture by distillation under reduced pressure to give 36 g of pale yellowish-brown crystals having a melting point of 75°-80° C. Yield, about 95%.
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:13])[NH:7][C:8](SC)=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].[N:14]1([CH2:20][C:21]2[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=2)[O:24][CH2:25][CH2:26][CH2:27][NH2:28])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH2:1]([C:5]1[C:6](=[O:13])[NH:7][C:8]([NH:28][CH2:27][CH2:26][CH2:25][O:24][C:23]2[CH:29]=[CH:30][CH:31]=[C:21]([CH2:20][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:22]=2)=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CCCCc1cnc(SC)[nH]c1=O
Product: CCCCc1cnc(NCCCOc2cccc(CN3CCCCC3)c2)[nH]c1=O
Yield: 82.5 %

Procedure:
A mixture of 5-butyl-2-(methylthio)-4(3H)-pyrimidinone (0.85 g) and 3-[3-[(1-piperidinyl)methyl]phenoxy]propanamine (1.1 g) was heated at 98°-100° for 6 hours and 140° for 2 hours. The residue was chromatographed (silica/methanol) to give an oil which solidified yielding the title compound (1.41 g) m.p. 105°-105.5°.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]CC)=O.[NH2:13][CH2:14][C:15]([N:17]1[CH2:21][C:20](=[O:22])[NH:19][CH:18]1[CH:23]([CH3:25])[CH3:24])=[O:16]>>[CH:23]([CH:18]1[NH:19][C:20](=[O:22])[CH2:21][N:17]1[C:15](=[O:16])[CH2:14][NH:13][C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])([CH3:25])[CH3:24]
Reactant: CCOC(=O)CN1CCCC1=O
Reactant: CC(C)C1NC(=O)CN1C(=O)CN
Product: CC(C)C1NC(=O)CN1C(=O)CNC(=O)CN1CCCC1=O
Temperature: 110 °C
Yield: 38.8 %

Procedure:
A mixture of ethyl 2-oxo-1-pyrrolidineacetate (7 g) and 1-(2-aminoacetyl)-2-isopropyl-4-imidazolidinone (4 g) was heated at 110° C. for 8 hours. After cooling the oily residue was chromatographed on a silica gel column (eluant dichloromethane/methanol 9:1). The selected fractions were collected, evaporated under vacuum and the residue was triturated with diisopropyl ether to yield 2.6 g of the title compound, m.p. 104°-106° C. Mass spectrum (E.I., 70 eV, 1.5 mA), m/z=310 (M.+), 267 (M.+ --C3H7).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1)[CH:4]=[CH2:5].C[O:16][C:17](=[O:20])[CH2:18]Cl.O>CN(C=O)C>[C:17]([O:20][O:12][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([O:6][CH2:3][CH:4]=[CH2:5])=[CH:8][CH:9]=1)(=[O:16])[CH3:18]
Reactant: C=CCOc1ccc(CO)cc1
Reactant: COC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(COOC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.9 %

Procedure:
Sodium hydride (1.20 g; 60% dispersion in oil) was added over a period of 10 minutes to a stirred solution of 4-allyloxybenzyl alcohol (4.60 g) in DHF (20 ml) at 0° C. under an atmosphere of argon. After 0.5 hours, a solution of methylchloroacetate (3.30 g) in DMF (10 ml) was added over a period of 0.25 hours. The reaction mixture was stirred for 40 hours at ambient temperature. Water (300 ml) was added and the mixture extracted with ethyl acetate (3×100 ml). The ethyl acetate extracts were combined, washed with brine (2×100 ml), dried (MgSO4) and evaporated. The residue was purified by flash column chromatography on silica gel using a 9:1 (v/v) mixture of hexane/ethyl acetate to give 4-allyloxyphenylmethyloxy acetate (2.42 g) as a colourless oil; NMR(CDCl3): 3.75(3H,s), 4.07(2H,s), 4.52(4H,m), 5.36(2H,m), 6.10(1H,m), 6.88(2H,m) and 7.28(2H,m); m/z 236(H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]1[S:7][C:8]([CH3:11])=[CH:9][CH:10]=1.Cl[C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(Cl)Cl>[CH3:5][C:6]1[S:7][C:8]([CH3:11])=[CH:9][C:10]=1[C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Cc1ccc(C)s1
Reactant: CCOC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1cc(C)sc1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of AlCl3 (29.5 g, 221 mmol) in CH2Cl2 (150 mL) was added 2,5-dimethyl thiophene (6.2 g, 55 mmol) followed by ethyl 2-chloro-2-oxoacetate (15.1 g, 110 mmol). The resulting mixture was stirred at room temperature for 12 h at which time the reaction mixture was filtered, diluted carefully with H2O and extracted with EtOAc. Removal of volatiles afforded mostly pure crude material, which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[C:18]([CH3:24])[N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([CH:32]2[CH2:36][CH2:35][CH2:34][NH:33]2)[CH2:28][CH2:27]1.CC([O-])(C)C.[Na+]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1(C)C=CC=CC=1>[CH:21]([N:20]1[C:16]([C:10]2[N:11]=[C:12]3[C:13]4[CH:14]=[N:15][C:2]([N:33]5[CH2:34][CH2:35][CH2:36][CH:32]5[CH:29]5[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]5)=[CH:3][C:4]=4[O:5][CH2:6][CH2:7][N:8]3[CH:9]=2)=[N:17][C:18]([CH3:24])=[N:19]1)([CH3:23])[CH3:22]
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(Cl)cc2OCC3)n(C(C)C)n1
Reactant: CN1CCC(C2CCCN2)CC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cn3c(n2)-c2cnc(N4CCCC4C4CCN(C)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A 10 mL microwave vial was charged with 12-chloro-4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca1(14), 2,4,10,12-Pentaene (160 mg, 0.470 mmol), toluene (4 mL), 1-methyl-4-(pyrrolidin-2-yl)piperidine (156 mg, 0.94 mmol), Pd(PtBu3)2(27 mg, 0.047 mmol), NaOtBu (135 mg, 1.40 mmol). The vial was sealed and degassed with N2 for three times. The resulting mixture was stirred at 110° C. for 1 h. After concentration, the residue was purified by reverse phase Combiflash eluting with a 0-50% gradient of CH3CN in 0.3% NH4HCO3 to give 249, which was separated by chiral HPLC (AD column, 30% EtOH (0.1% DEA) in n-hexane isocratic) to give: 9 mg of one enantiomer and 6 mg of the other (7% total yield)
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].C(N(CC)CC)C.[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:29]([C:21]1[S:20][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=1)(=[O:30])=[O:31])[CH3:4]
Reactant: CCOC(=O)CNCCN
Reactant: O=S(=O)(Cl)c1nc2ccccc2s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a solution of N-(2-aminoethyl)-glycine ethyl ester 2HCl (1.10 g, 5.0 mmol), prepared as described by Will (D. W. Will et al., Tetrahedron, 1995, 51, 12069.), in dichloromethane (50 mL) was slowly added triethylamine (2.02 g, 20 mmol) at room temperature. Then benzothiazole-2-sulfonyl chloride (1.19 g 5.0 mmol) in dichloromethane (10 mL) was added to the reaction mixture at room temperature for 5 min. The resulting reaction mixture was stirred for additional 2 h. at room temperature and washed with water (30 mL). The organic layer was dried over MgSO4 and filtered. The filtrate was evaporated to remove solvent to give desired product (1.60 g, 92%) as a solid. 1H NMR (500 MHz; DMSO-d6) δ 8.28 (d, 1H), 8.19 (d, 1H), 7.69˜7.63 (m, 2H), 4.03 (q, 2H), 3.24 (s, 2H), 3.13 (t, 2H), 2.62 (t, 2H), 1.15 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([CH3:14])[CH:4]=1.[H-].[Na+].[CH3:17]I>CN(C=O)C.Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:17])[S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([CH3:14])[CH:4]=1
Reactant: CI
Reactant: COc1ccc(NS(C)(=O)=O)c(C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)S(C)(=O)=O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 860 mg (4.0 mmol) N-(4-methoxy-2-methyl-phenyl)-methanesulfonamide in 15 ml DMF at ambient temperature was added 192 mg (48 mmol) 60% sodium hydride dispersion and the resulting mixture was treated with 1.14 gm, 0.5 ml (8.0 mmol) methyl iodide. The reaction mixture was stirred at room temperature for 2 hours and 0.5 ml of methyl iodide was introduced and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with 1N HCl and then extracted with ethyl acetate. The organics were washed with brine, dried with sodium sulfate and then evaporated in vacuo to afford 293 mg (X %) of a light purple solid. Mass spectrum APCI (m/z) 230 (p+1).
Reaction SMILES: [C:1]([NH:6][CH2:7][C:8]([NH:10][CH2:11][C:12]([OH:14])=O)=[O:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[SH:15][C:16]1[S:17][CH2:18][CH2:19][N:20]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([NH:6][CH2:7][C:8]([NH:10][CH2:11][C:12]([N:20]1[CH2:19][CH2:18][S:17][C:16]1=[S:15])=[O:14])=[O:9])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: SC1=NCCS1
Reactant: C=C(C)C(=O)NCC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(=O)NCC(=O)NCC(=O)N1CCSC1=S

Procedure:
The synthesis of MA-GG-TT was similar to the synthesis of MA-GFLG-TT in Example 1. N-methacryloylglycylglycine (MA-GG-OH) was coupled with 2-mercaptothiazoline in DCM mediated by EDCI in presence of catalytic amount of DMAP. After reaction, the product was purified by recrystallization from MeOH solution.