Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C=CC=1Cl)[C:5]([NH:7][CH:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:9]1)=[O:6].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=C=O)=[CH:33][CH:32]=1.C(N(CC)CC)C>C1COCC1>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:5]([NH:7][CH:8]2[C:14](=[O:15])[NH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:9]2)=[O:6])=[CH:33][CH:32]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)cc1)NC1N=C(c2ccccc2)c2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of Intermediate 3 (30 mg) and 4-chloro-1-isocyanato-benzene (0.01 ml) in dry THF (4 ml) was treated with triethylamine (0.05 ml). The mixture was stirred at room temperature for 18 h, and was then partitioned between water and dichloromethane. The organic layer was passed through a hydrophobic frit, and was then evaporated. The residue was triturated with petroleum ether giving the title compound as a beige solid (34 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26]OS(C)(=O)=O)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[CH2:37][OH:38]>CS(C)=O>[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][N:32]4[CH2:36][CH2:35][CH2:34][C@H:33]4[CH2:37][OH:38])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCOS(C)(=O)=O)ccc23)CC1
Reactant: OC[C@@H]1CCCN1
Solvent: CS(C)=O
Product: OC[C@@H]1CCCN1CCOc1ccc2c(C3CCNCC3)ncnc2c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[7-(2-methanesulfonyloxy-ethoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (40.6 mg, 0.09 mmol) in DMSO (0.4 mL) was added (S)-(+)-2-pyrrolidinemethanol (90.9 mg, 0.9 mmol). The mixture was stirred at 120° C. overnight and subsequently partitioned between EtOAc and water. The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was treated with 50% TFA/CH2Cl2 (8 mL) for 2 h, the solvents (TFA/CH2Cl2) were removed under reduced pressure to provide the desired product. LC-MS (ESI) calcd for C20H29N4O2 (MH+) 357.2, found 357.2.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](=O)[CH2:30][C:31]([CH3:36])([CH3:35])[O:32]2)=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CCOCC>[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)=[CH:30][C:31]([CH3:36])([CH3:35])[O:32]2)=[CH:27][CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC1(C)CC(=O)c2ccc(OCc3ccccc3)cc2O1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC1(C)C=C(c2ccc(C(F)(F)F)cc2)c2ccc(OCc3ccccc3)cc2O1
Reaction time: 2 h

Procedure:
n-Butyl-lithium (142 ml of a 2.4 M solution) was added under dry nitrogen to a solution of 4-bromobenzotrifluoride (76.5 g) in dry ether at -50° C. The mixture was left to stir for 2 hours. 7-Benzyloxy-2,2-dimethylchroman-4-one (64g) in dry ether was added dropwise. Water was added and the ether layer washed with 5N.HCl (2×100 ml), and dried (MgSO4). Removal of the solvent under reduced pressure gave an oil (84 g) which was chromatographed on alumina. Elution with petrol-ether (1:1) gave the title compound (52 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[C:12](Br)[N:11]([CH:25]([CH3:27])[CH3:26])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1([OH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C(=O)C>[CH2:1]([O:8][C:9]1[C:13]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[C:12]([O:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:11]([CH:25]([CH3:27])[CH3:26])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: COc1ccc(C(=O)c2c(OCc3ccccc3)nn(C(C)C)c2Br)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(C(=O)c2c(OCc3ccccc3)nn(C(C)C)c2Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 54.1 %

Procedure:
3-Benzyloxy-5-bromo-1-isopropyl-4-(4-methoxybenzoyl)-1H-pyrazole (43 mg), phenol (14 mg) and potassium carbonate (21 mg) were suspended in N,N-dimethylacetoamide (5 mL) and the mixture was stirred under reflux for 2 hours. The mixture was allowed to cool to room temperature, then 10% citric acid aqueous solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with a saturated sodium hydrogen carbonate and brine. After the solution was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The obtained residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give the title compound, (24 mg).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([Cl:29])=[N:23][C:24]=2Cl)(=[O:3])[CH3:2].[CH2:30]([C:33]1[NH:34][CH:35]=[CH:36][N:37]=1)[CH2:31][CH3:32]>CC#N>[C:1]([O:4][C@@H:5]1[C@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([Cl:29])=[N:23][C:24]=2[N:34]1[CH:35]=[CH:36][N:37]=[C:33]1[CH2:30][CH2:31][CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCCc1ncc[nH]1
Solvent: CC#N
Product: CCCc1nccn1-c1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 65 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A mixture of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloropurine (1.12 g, 2.5 mmol) and 2-propylimidazole (2.20 g, 20 mmol) was dissolved in CH3CN (30 mL) and stirred at 65° C. under N2 for 2 h (reaction complete, TLC). After removal of volatiles, the residue was dissolved in CH2Cl2 (200 mL) and washed (H2O, 3×50 mL). The aqueous phase was extracted with CH2Cl2, and the combined organic phase was dried (Na2SO4) and evaporated to dryness. The residue was chromatographed (MeOH/CH2Cl2, 1:95) to give 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2-chloro-6-(2-propylimidazol-1-yl)purine (977 mg, 93%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:19][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:8][CH2:7][CH:3]2[CH2:4][CH2:5][CH2:6][O:1][CH2:2]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCCOC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCCOC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (tetrahydropyran-3-yl)-methanol (Matrix, 1.67 g, 14.4 mmol) in 15 mL of CH2Cl2 and 15 mL of pyridine was added p-toluenesulfonyl chloride (2.9 g, 15.1 mmol) in portions over 10 minutes. The mixture stirred at ambient temperature for 18 hours and was quenched with 10 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous phase was extracted three 5 mL of portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 70% hexanes in ethyl acetate) afforded the title compound. MS (DCI/NH3) m/z 288 (M+NH4)+.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[C:10]([S:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:9]=[C:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[OH:23])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH2:31]([O:33][C:34]([C:36]1[NH:37][C:38]([CH3:46])=[C:39]([S:42](Cl)(=[O:44])=[O:43])[C:40]=1[CH3:41])=[O:35])[CH3:32]>ClCCl>[CH2:31]([O:33][C:34]([C:36]1[NH:37][C:38]([CH3:46])=[C:39]([S:42]([N:16]2[CH2:17][CH2:18][CH:13]([S:12][C:10]3[CH:9]=[C:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]([OH:23])=[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH:11]=3)[CH2:14][CH2:15]2)(=[O:43])=[O:44])[C:40]=1[CH3:41])=[O:35])[CH3:32]
Reactant: CC(C)(C)c1cc(SC2CCNCC2)cc(C(C)(C)C)c1O
Reactant: CCOC(=O)c1[nH]c(C)c(S(=O)(=O)Cl)c1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c(C)c(S(=O)(=O)N2CCC(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)c1C
Reaction time: 0.05 h
Yield: 80.4 %

Procedure:
To 2,6-di-tert-butyl-4-(piperidin-4-ylsulfanyl)-phenol hydrochloride (Ex. 3c, 500 mg, 1.4 mmol) in 5 mL of dichloromethane was added triethylamine (495 mg, 4.9 mmol). The mixture was stirred for 3 min followed by the addition of 4-chlorosulfonyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (446 mg, 1.68 mmol). The stirring was continued for 3 h at room temperature. The reaction mixture was diluted with Ethyl acetate/hexanes (15 mL, 1:1 v/v), and washed with water (2×20 mL), 0.5 M HCl (2×20 mL) and water (40 mL). It was dried over Na2SO4 and concentrated under reduced pressure to give a brown oil. Chromatography (5-40% Ethyl acetate/hexanes) gave 4-[4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-sulfonyl]-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester as a light-pink foamy solid (620 mg, 80%). ESI/CI-MS m/z 551 ([M+H]+), 549 ([M−H]−).
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[C:21](Cl)[C:20]([Cl:27])=[CH:19][N:18]=1>C(O)(C)C>[Cl:27][C:20]1[C:21]([N:13]2[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:15][CH2:14]2)=[C:22]([N+:23]([O-:25])=[O:24])[C:17]([NH2:16])=[N:18][CH:19]=1
Reactant: c1ccc(OCCN2CCNCC2)cc1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Product: Nc1ncc(Cl)c(N2CCN(CCOc3ccccc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
A mixture of 1-(2-phenoxy-ethyl)-piperazine (0.047 g, 0.23 mmol), isopropanol (4.0 ml), and 2-amino-4,5-dichloro-3-nitropyridine (0.034 g, 0.16 mmol) was heated at 45° C. for 18 h. The reaction mixture was allowed to cool to room temperature, absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 10% ethyl acetate in dichloromethane, 20% ethyl acetate in dichloromethane and finally 1% methanol in ethyl acetate/dichloromethane (v/v; 1:4). The title compound was obtained as a yellow solid (0.053 g, 88%); 1H-NMR (500 Mz, DMSO-d6) 2.62 (br s, 4H, piperazine N(CH2)2), 2.76 (t, J=5.62 Hz, 2H, NCH2CH2O), 3.06 (br s, 4H, piperazine N(CH2)2), 4.09 (t, J=5.37 Hz, 2H, NCH2CH2O), 6.95 (m, 5H, 2-NH2 and o-ArH and p-ArH), 7.27 (t, J=11.20 Hz, 2H, m-ArH), 8.06 (s, 1H, 6-H); LC-MS (ESI, m/z) 3.79 min—378, 380 [(M+H)+, Cl isotopic pattern].
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Cl:17][C:18]1[CH:19]=[C:20]([CH2:24][C:25](=O)[CH3:26])[CH:21]=[CH:22][CH:23]=1>C1COCC1>[Cl:17][C:18]1[CH:19]=[C:20]([CH2:24][C:25]([CH3:26])=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(=O)Cc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)Cc1cccc(Cl)c1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
At 0° C., a suspension of 60% w/w NaH/mineral oil (7.13 g, 0.176 mol) in THF (250 mL) was treated dropwise with a solution of ethyl 2-(diethoxyphosphoryl)acetate (39.5 g, 0.176 mol) in THF (72 mL) over a 30 min period. The reaction was stirred for another 30 minutes, and a solution of 1-(3-chlorophenyl)propan-2-one (19.7 g, 0.117 mol) in THF (108 mL) was added dropwise over 1 h (reaction was kept at 0° C. during addition). The reaction was allowed to warm to 23° C. overnight and quenched with saturated aqueous NH4Cl (250 mL). After 2 h, the mixture was diluted with water (250 mL) and hexane (100 mL). The organic phase was collected. The aqueous layer was extracted with EtOAc (2×150 mL). Combined organic phases were dried (MgSO4), filtered, and concentrated, giving crude ethyl 4-(3-chlorophenyl)-3-methylbut-2-enoate as a mixture of E and Z isomers. The residue was carried onward without further purification. (˜25 grams). The 1H NMR reported below is from a crude mixture containing both the E and Z isomer. 1H NMR (400 MHz, CDCl3) δ 7.24-7.22 (m, 2H), 7.16 (s, 1H), 7.06-7.04 (m, 1H); 5.67 (s, 1H); 4.18-4.13 (dd, 2H); 3.40 (s, 2H), 2.11 (s, 3H), 1.30-1.26 (t, 3H).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:12][CH2:13][C:14]([O:16]CC1C=CC(OC)=CC=1)=[O:15])[C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[C:1]([O:4][CH:5]([C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)C(CCC(=O)OCc1ccc(OC)cc1)OC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C=CCOC(=O)C(CCC(=O)O)OC(C)=O
Yield: 116.4 %

Procedure:
According to a similar procedure to that described in Example 1-(11), allyl 2-acetoxy-5-[(4-methoxybenzyl)oxy]-5-oxopentanoate (1.36 g, 3.88 mmol) obtained from Example 2-(3), anisole (1.50 g, 13.87 mmol), and trifluoroacetic acid (3 ml) were reacted, and the reaction mixture was worked up to afford the title compound (1.04 g, quantitative yield).
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:22]([O:26][C:27](=[O:37])[CH:28]=[CH:29][C:30]1[CH:31]=[N:32][C:33]([NH2:36])=[CH:34][CH:35]=1)([CH3:25])([CH3:24])[CH3:23].[NH4+].[Cl-]>C1COCC1>[C:22]([O:26][C:27](=[O:37])[CH2:28][C@@H:29]([C:30]1[CH:31]=[N:32][C:33]([NH2:36])=[CH:34][CH:35]=1)[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:16])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(N)nc1
Reactant: C[C@@H](NCc1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N(Cc1ccccc1)[C@@H](CC(=O)OC(C)(C)C)c1ccc(N)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) solution of (R)-(+)-N-benzyl-α-methylbenzylamine (4.0 g, 19 mmol) in 50 mL THF was gradually added n-butyllithium (11.3 mL, 2.5 M, 28.2 mmol) over 5 min. The mixture was stirred for 30 min at 0° C. and cooled to -78° C. A solution of 10-2 (2.0 g, 9.4 mmol) in 20 mL THF was gradually added. After stirring for 40 min at -78° C., it was treated with NH4Cl (sat.) at -78° C., warmed to room temperature and extracted three times with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. After solvent evaporation, the residue was purified using silica gel flash chromatography (EtOAc/hexanes 1:2) to afford the desired product 10-3 as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][N:7]([CH:18]1[CH2:23][CH2:22][N:21]([CH:24]([CH3:38])[CH2:25][CH2:26][NH:27][C:28]([C:30]2[C:31]([CH3:37])=[N:32][CH:33]=[N:34][C:35]=2[CH3:36])=[O:29])[CH2:20][CH2:19]1)[C:8]1[CH:13]=[CH:12][C:11]([O:14]C(=O)C)=[CH:10][CH:9]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:49][C:50]([O:52][CH3:53])=[O:51]>CN(C=O)C>[CH3:53][O:52][C:50](=[O:51])[CH2:49][O:14][C:11]1[CH:10]=[CH:9][C:8]([N:7]([CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:18]2[CH2:23][CH2:22][N:21]([CH:24]([CH3:38])[CH2:25][CH2:26][NH:27][C:28]([C:30]3[C:31]([CH3:37])=[N:32][CH:33]=[N:34][C:35]=3[CH3:36])=[O:29])[CH2:20][CH2:19]2)=[CH:13][CH:12]=1
Reactant: COC(=O)CBr
Reactant: CC(=O)Oc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
To a solution of COMPOUND 138 (105 mg, 0.205 mmol) in DMF (1 mL) were added K2CO3 (87 mg, 0.63 mmol) followed by methyl bromoacetate (40 μL, 0.42 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 148 as a tan solid (81 mg, 66%) following work-up and purification. 1H NMR (CDCl3) δ 0.86-1.03 (m, 5H), 1.52-1.60 (m, 1H), 1.74-1.78 (m, 3H), 2.14 (t, 1H, J=11.4 Hz), 2.51 (s, 6H), 2.51-2.59 (m, 1H), 2.72-2.88 (m, 3H), 3.29-3.48 (m, 2H), 3.78-3.83 (m, 6H), 4.53 (s, 2H), 6.53 (d, 2H, J=8.4 Hz), 6.75 (d, 2H, J=8.1 Hz), 7.40-7.44 (m, 1H), 7.49-7.54 (m, 3H), 8.71 (br s, 1H), 8.84 (s, 1H). 13C NMR (CDCl3) δ 11.37, 19.90, 27.17, 28.32, 28.69, 37.93, 41.60, 46.92, 49.93, 50.15, 55.37, 58.15, 64.12, 110.38, 113.84, 114.32, 116.98, 127.17, 128.17, 128.50, 128.83, 129.20, 139.97, 141.27, 148.72, 155.46, 161.02, 164.27, 167.71. ES-MS m/z 585 (M+H). Anal. Calcd. for C33H40N6O4.0.7H2O: C, 66.36; H, 6.99; N, 14.07. Found. C, 66.32; H, 6.83; N, 13.71.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1.[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1cccc(C(=C/C=C/C(=O)O)c2cccc(OC)c2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccc(OC)c2)c1
Reaction time: 1 h

Procedure:
As in Example 115, (E)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid (49.6) and 4-nitrophenol (25 g) in dichloromethane (600 mL) was treated with 1,3-dicyclohexylcarbodiimide (33 g). The mixture was stirred at 0°-5° C. for 1 hour, then at room temperature for 2 hours. After the usual work up, the crude product (67 g) was crystallized from 2-propanol-ether-hexane to give 61.0 g of (E)-5,5-bis (3-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester mp 95°-97° C. Recrystallization of a portion from dichloromethane-hexane yielded the analytical sample, mp 99°-100° C.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH3:27])[C:24](O)=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CCN(CC)CC>C(Cl)Cl>[C:15]([O:19][C:20](=[O:21])[NH:22][C@H:23]([C:24](=[O:25])[NH:14][C:13]1[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:27])([CH3:16])([CH3:17])[CH3:18]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cccnc1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccnc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 41.5 %

Procedure:
To a mixture of N2-phenylpyridine-2,3-diamine (2.00 g, 0.011 mol), (S)-2-tertbutoxycarbonylaminopropionic acid (3.06 g, 0.0162 mol), HOBt (2.19 g, 0.0162 mol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.10 g, 0.0162 mol) in DCM (80 mL) cooled to 0° C. under a nitrogen atmosphere was added Et3N (4.5 mL, 0.0324 mol). The reaction mixture was stirred at 0° C. for 5 min, then slowly warmed to RT and stirring was continued for 20 h. The resulting mixture was partitioned between EtOAc and a saturated solution of NaHCO3. The aqueous phase was further extracted with EtOAc and the combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The residue thus obtained was purified column chromatography (Si—PCC, gradient 0-5% 2M NH3/MeOH in DCM) affording [(S)-1-(2-phenylaminopyridin-3-ylcarbamoyl)ethyl]carbamic acid tertbutyl ester as a pale pink solid (2.05 g, 4.56 mmol). LCMS: RT 3.75 min [M+H]+ 390.2
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][CH2:6][N:7]([C:17](=[O:43])[CH2:18][N:19]([C:21](=[O:42])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])=[O:31])=[C:25]([O:40][CH3:41])[CH:24]=1)[CH3:20])[CH2:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16])C.O.[OH-].[Li+]>O1CCCC1.O>[CH3:41][O:40][C:25]1[CH:24]=[C:23]([CH2:22][C:21]([N:19]([CH2:18][C:17]([N:7]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH2:6][CH2:5][C:4]([OH:44])=[O:3])=[O:43])[CH3:20])=[O:42])[CH:28]=[CH:27][C:26]=1[NH:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39])=[O:31]
Reactant: CCOC(=O)CCN(CCCN1CCCC1=O)C(=O)CN(C)C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CC(=O)N(C)CC(=O)N(CCCN2CCCC2=O)CCC(=O)O)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetic acid [0.80 g, Reference Example 1] and 3-[3-(2-oxo-pyrrolidin-1-yl)-prop-l1ylamino]-propionic acid ethyl ester (0.51 g, Reference Example 2(c)] in dimethylformamide (25 ml) was treated with [O-(7-azabenzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate (0.80 g) and diisopropylethylamine (0.75 ml). After stirring at room temperature for 2 hours the reaction mixture was treated with water (100 ml) then extracted three times with ethyl acetate. The combined organic extracts were washed with hydrochloric acid (1M), then with brine, then dried over magnesium sulphate and then evaporated. The residual oil was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (25:1, v/v) to give 3-{[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-[3-(2-oxo-pyrrolidin-1-yl)-prop-1-yl]-amino}-propionic acid ethyl ester as a colourless oil (0.76 g). The ester was dissolved in tetrahydrofuran (50 ml) and then treated with lithium hydroxide hydrate (0.065 g) in water (10 ml). After stirring at room temperature for 2 hours the mixture was concentrated to remove the tetrahydrofuran. The residual aqueous residue was washed with ethyl acetate then acidified by addition of hydrochloric acid (1M) and then extracted three times with dichloromethane. The combined organic extracts were washed with brine, then dried over magnesium sulphate and then evaporated to give 3-{[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-[3-(2-oxo-pyrrolidin-1-yl)-prop-1-yl]-amino}-propionic acid as a white solid (0.58 g, Compound A), m.p.73-76° C. [Elemental analysis:- C,60.69; H,6.85; N,11.79% Calculated for C30H39N5O7.0.67H2O:- C,60.69; H,6.69; N,11.58%]. MS: 580 [MH]−. HPLC: RT=9.72 minutes (gradient elution using a mixture of acetonitrile and water 1:4 to 4:1).