Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[NH:15][C:14]2=[O:23])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].CI.[C:28](O)(=O)C>COCCOC>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[N:15]([CH3:28])[C:14]2=[O:23])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)ccc1Cl
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: COCCOC
Product: CCOC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)ccc1Cl
Reaction time: 1 h

Procedure:
A solution of 50.2 g of ethyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate in 300 ml of absolute 1,2-dimethoxyethane is added dropwise while stirring at 20° C. during 10 minutes to a suspension of 3.6 g of sodium hydride in 100 ml of absolute 1,2-dimethoxyethane. The reaction mixture is stirred for 1 hour, treated with 21.3 g of methyl iodide and stirred for a further 2 hours. The mixture is subsequently rendered neutral with 0.5 ml of acetic acid and evaporated to dryness under reduced pressure. The residue is dissolved in 500 ml of ethyl acetate, the solution shaken three times with 250 ml of water, and the organic phase is dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is dissolved in 50 ml of hot methylene chloride, seeded, and treated with diethyl ether. There is obtained ethyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d] pyrimidin-3-yl)-benzoate, m.p. 141°-143° C.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][CH:7]=1.S(Cl)(Cl)(=O)=O>CC(C)=O>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:1]=[C:2]([NH2:4])[S:3][CH:13]=2)=[CH:8][CH:7]=1
Reactant: NC(N)=S
Reactant: CC(=O)c1ccc(C)cc1
Solvent: O=S(=O)(Cl)Cl
Solvent: CC(C)=O
Product: Cc1ccc(-c2csc(N)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.7 %

Procedure:
To a mixture of thiourea (2.18 g, 28.6 mmol) and p-methylacetophenone (1.92 ml, 14.3 mmol) was added dropwise sulfuryl chloride (1.264 ml, 15.74 mmol) and the resulting mixture was stirred at room temperature for 10 minutes (until solidification was complete). The reaction mixture was allowed to react at 105° C. for 3 hours and acetone was added thereto. Then insoluble matters were filtered with suction, treated with 300 ml of water and heated at 80° C. Insoluble solids were removed by filtration. After the filtrate was made alkaline (pH 11) with 1N-KOH under ice-cooling, the deposited solids were filtered with suction, washed with water and recrystallized from methanol-water to afford 1.46 g (yield 54%) of 4-(4-methylphenyl)-2-thiazolamine as pale yellowish crystals, m.p.130° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[N:19]=[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]2[CH:26]=1>CN(C=O)C>[N:19]1[C:18]([CH2:17][S:8][C:6]2[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=2)=[CH:26][N:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=12
Reactant: Cc1cc(O)nc(S)n1
Reactant: BrCc1cn2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2cn3ccccc3n2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (638 mg, 4.5 mmol) was dissolved in anhydrous DMF (20 mL), then potassium carbonate (1.86 g, 13.5 mmol) and 2-(bromomethyl)imidazo[1,2-a]pyridine (1.42 g, 6.7 mmol) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, where the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 12% DCM/MeOH to afford 2-({imidazo[1,2-a]pyridin-2-ylmethyl}sulfanyl)-6-methylpyrimidin-4-ol as a white solid (631 mg, 52% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 4.46 (s, 2H), 5.99 (bs, 1H), 6.84 (dt, J=1.7 Hz, J=6.7 Hz, 1H), 7.17-7.22 (m, 1H), 7.45 (dd, J=9.0 Hz, J=0.8 Hz, 1H), 7.86 (s, 1H), 8.46-8.49 (m, 1H); LRMS (ES+) m/z 273 (60%, M+1).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:15]=[C:14]1[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:32][CH:31]=1)=[O:5])C.[OH-].[Na+]>>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:16]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:15]=[C:14]1[C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:34][CH:35]=1)([OH:5])=[O:3]
Reactant: CCCCCCCCOc1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)n2CCCCCCCC(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCOc1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)n2CCCCCCCC(=O)O)cc1
Yield: 55.8 %

Procedure:
1-(7-Ethoxycarbonylheptyl)-2-[4-octyloxyphenyl]-4, 5-diphenylimidazole (3.2 g) was reacted with 2N sodium hydroxide in a method similar to Example 9. Column chromatography on silica gel eluted with a dichioro-methane:methanol gradient and recrystallisation from acetonitrile gave 1-(7-carboxyheptyl)-2-[4-octyloxy-phenyl]-4,5-diphenylimidazole (1.7 g, 58.6%) as a white solid, m.p. 114°-115°. Found: C, 78.61; H, 8.23; N, 4.96%; C37H46N2O3 requires: C, 78.41; H, 8.18; N, 4.94%.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[CH:7](O)([CH3:9])[CH3:8].CS(O)(=O)=O>>[C:1]([CH2:3][C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5])#[N:2]
Reactant: CC(C)O
Reactant: N#CCC(=O)O
Agent: CS(=O)(=O)O
Product: CC(C)OC(=O)CC#N
Temperature: 105 °C

Procedure:
Cyanoacetic acid (85.5 g; 1.0 mol), isopropanol (80 g; 1.33 mol) and methanesulfonic acid (1.00 g; 0.01 mol) were introduced into a 500 ml flask. The mixture was slowly heated to a maximum of 105° C. while collecting distillates at 77-80° C. Additional isopropanol (220 g; 3.67 mol) was added to maintain the flask at 105-110° C. and the collection of distillates was continued at 77-80° C. After distilling off the unreacted isopropanol, the isopropyl cyanoacetate (bp 100° C./20 mm Hg) was collected as a clear liquid. The yield was 120 g (94.5% of theoretical and its purity was >99% (GC assay).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17]O)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].S(Cl)([Cl:21])=O.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:21][CH2:17][CH2:16][CH2:15][NH:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, 3-[(3-nitroquinolin-4-yl)amino]propan-1-ol (20.75 g, 83.93 mmol), thionyl chloride (15.0 g, 125.89 mmol), and dichloromethane (420 mL). The bright yellow, homogeneous solution was stirred at ambient temperature for 2 hours at which time the starting material was completely consumed. The volatiles were removed under reduced pressure and he resulting solid stirred in water (400 mL) made basic (pH 10) with solid sodium carbonate. A bright yellow solid was collected by filtration to afford N-(3-chloropropyl)-3-nitroquinolin-4-amine (21.63 g, 81.41 mmol) which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH:14](O)[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:32])CC>ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH:14]([F:32])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CCC1O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CCC1F
Temperature: 25 °C

Procedure:
To a solution of (+/−)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate (1.0 equiv.) in dichloromethane (0.3 M solution) was added DAST at −78° C. The reaction mixture was slowly warmed up to room temperature for 15 h. After quenched with saturated sodium bicarbonate aqueous solution, ethyl acetate and water were added for work-up. The (+/−)-benzyl 3-(tert-butoxycarbonylamino)-4-fluoropiperidine-1-carboxylate was obtained by silica column chromatography (30% EtOAc in hexanes, 40%). LCMS (m/z): 253.1[(M-Boc)H+]; LC Rt=4.08 min. The enantiomerically pure (3R,4R)-benzyl 3-(tert-butoxycarbonylamino)-4-fluoropiperidine-1-carboxylate and (3S,4S)-benzyl 3-(tert-butoxycarbonylamino)-4-fluoropiperidine-1-carboxylate were resolved by chiral HPLC (for analysis: Rt=9.4 min and 12.6 min respectively; n-heptane:isopropanol=90:10 (v:v), Chiralpak AS 250×4.6 mm at 1 mL/min. For preparative separation, n-heptane:isopropanol=90:10 (v:v), Chiralpak AS 50×500 mm. at 90 mL/min)
Reaction SMILES: O[CH:2]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:3]([Cl:6])([Cl:5])[Cl:4].S(Cl)([Cl:19])=O>CN(C)C=O.ClCCl>[Cl:19][CH:2]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:3]([Cl:6])([Cl:5])[Cl:4]
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)c1ccccc1O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NC(Cl)C(Cl)(Cl)Cl)c1ccccc1O
Yield: 99.9 %

Procedure:
To 14.2 g of N-(1-hydroxy-2,2,2-trichloroethyl)-2-hydroxybenzamide were added 100 ml of dichloromethane, 0.1 g of N,N-dimethylformamide and 7.2 g of thionyl chloride, and the reaction was effected while stirring under reflux for three hours. Excess thionyl chloride was distilled off together with the solvent under reduced pressure to obtain 15.1 g of N-(1,2,2,2-tetrachloroethyl)-2-hydroxybenzamide.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[CH:8]=1.O=S(Cl)[Cl:19]>C(Cl)(Cl)Cl>[Cl:19][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cn2cc(CO)ccc2n1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn2cc(CCl)ccc2n1
Yield: 97.8 %

Procedure:
By the method of Example 5, the product from Example 10 (2.52 g, 11.4 mmol) dissolved in CHCl3 (100 mL) was reacted with SOCl2 (1.5 g, 12.6 mmol). Final workup provided 2.66 g (98%) of title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(O[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)C>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(=O)Oc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Product: O=C(Oc1ccccc1)c1ccc(O)cc1
Temperature: 180 °C

Procedure:
828 g. (6 moles) of p-hydroxybenzoic acid and 1020 g. (6.5 moles) of phenyl acetate are charged into a four-necked resin kettle equipped as in Example 3. The reaction mixture is stirred constantly under a nitrogen atmosphere throughout the run. The reaction mixture is heated to 180°C, and gaseous HCl is then bubbled through the mixture for 7 hours, the temperature being held at 180°C. Phenyl p-hydroxybenzoate is produced thereby. The HCl flow is discontinued and 660 g. (6 moles) of hydroquinone is added to the charge. The distilling head is heated to 180°C, and the reaction mixture is heated from 180°C to 230°C at a rate of 10°C/hour, held for 4.5 hours at 230+C, and heated to 240°C where the temperature is held for 2 hours. The resulting pasty melt is poured while hot into a tray and allowed to cool and solidify, whereupon it is pulverized. A yield of 1413 g. is obtained. The product consists primarily of an ester, p-hydroxyphenyl p-hydroxybenzoate, having Formula XVII wherein R4 and R9 are each hydrogen, n is 0, and the dioxyarylene moiety is para-dioxyphenylene. The product also contains a linear polyester identical to that produced in Example 6. The desired ester is separable from the linear polyester by virtue of its greater solubility in such solvents as acetone. Accordingly, the product is extracted with hot acetone to obtain a solution of the ester and water is added to the solution to precipitate the ester, which is removed by filtration, dried in vacuum, and crystallized from aqueous isopropyl alcohol. The ester is found to have a melting point of 243°C upon differential thermal analysis.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[O:21]COC)=[CH:10][C:9]=1[NH:25][C:26](=[O:41])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[CH:39][N:38]=[CH:37]2)[CH:31]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([N:36]5[CH:40]=[CH:39][N:38]=[CH:37]5)[CH:31]=4)[CH2:27][C:26](=[O:41])[NH:25][C:9]=3[CH:10]=2)=[C:15]([OH:21])[CH:16]=1
Reactant: COCOc1cc(F)ccc1-c1ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnc3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3ccnc3)c2)=Nc2ccc(-c3ccc(F)cc3O)cc2N1

Procedure:
Prepared from {4′-fluoro-3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-2′-methoxymethoxy-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K51) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (13 mg).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+]>CN(C)C=O.C(O)C>[CH2:14]([N:11]1[CH2:10][CH:9]=[C:8]([CH2:7][CH2:6][CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[CH2:13][CH2:12]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1cc(CCC2CCCO2)ccn1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: C1=C(CCC2CCCO2)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
A solution of 4-(2-[tetrahydrofuran-2-yl]ethyl)pyridine (3.0 g, 16.9 mmol) in anhydrous dimethylformamide (5 ml) was treated with benzyl bromide (2.2 ml, 18.6 mmol) and the mixture was stirred at room temperature for one hour. The reaction was diluted with absolute ethanol (100 ml), treated with sodium borohydride (0.8 g, 21.2 mmol) and stirred at reflux for one hour. The solvent was evaporated in vacuo and the residue partitioned between diethyl ether and water. The organic layer was separated, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed with 3% methanol in dichloromethane as eluant to afford the title compound (3.75 g, 82%) as a colourless oil; δH (DMSO-d6) 1.30-2.08 (8H, m, 4×CH2), 2.45-2.52 (2H, m, tetrahydropyridinyl CH2), 2.52-2.56 (2H, m, CH2), 2.60-2.66 (2H, m, tetrahydropyridinyl CH2), 3.50 (2H, s, PhCH2N), 3.52-3.80 (3H, m, tetrahydrofuranyl CH2 and CH), 5.50-5.55 (1H, m, tetrahydropyridinyl 5-H), and 7.20-7.34 (5H, m, ArH); m/z (CI+, NH3) 272 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:22][O:23][CH:24]=[CH:25][C:26]1[N:31]=[C:30]2[CH2:32][O:33][C:34](=O)[C:29]2=[CH:28][CH:27]=1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:34]1[C:29]2[C:30](=[N:31][C:26]([CH:25]=[CH:24][O:23][CH3:22])=[CH:27][CH:28]=2)[CH2:32][O:33]1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: COC=Cc1ccc2c(n1)COC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COC=Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.6 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (176 mg, 1.16 mmol) in THF (5 mL) is treated with a solution of lithium bis(trimethylsilyl)amide (2.3 mL of a 1M solution in THF, 2.3 mmol) dropwise. The resulting solution is stirred at room temperature for 10 min. A solution of 2-(2-methoxy-vinyl)-7H-furo[3,4-b]pyridin-5-one (111 mg, 0.58 mmol) in THF (2 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 3 h and is poured into cold 10% aqueous HCl solution (30 mL) at 0° C. The resulting mixture is stirred at 50° C. for 1 h and room temperature overnight. The solid which formed is collected by filtration and dried to give the title compound as a light brown solid (65 mg, 35%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19]([NH2:21])=[S:20])=[N:2]1.[C:22](OCCCl)(=[O:24])[CH3:23].N>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19]2[S:20][CH2:23][C:22](=[O:24])[N:21]=2)=[N:2]1
Reactant: NC(=S)Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Reactant: CC(=O)OCCCl
Agent: N
Solvent: CCO
Product: O=C1CSC(Nc2ccccc2/C=C/c2n[nH]c3ccccc23)=N1
Yield: 11.4 %

Procedure:
Compound 161 (0.10 g, 0.34 mmol) was added with ethanol (3.0 mL) and chloroethyl acetate (43 μL, 0.41 mmol), and after heating under reflux for 7 hours, the aqueous ammonia was added to stop the reaction. The mixture was extracted with ethyl acetate, concentrated and purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to 1/4), followed by triturating in ethyl acetate to obtain Compound 172 (13 mg, 12%).
Reaction SMILES: CO.C[O-].[Na+].[CH3:6][O:7][C:8]([CH2:10]P(OC)(OC)=O)=[O:9].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[N:31]=[C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:33][CH:34]=1)[CH:23]=O)[CH3:18]>CN(C)C=O>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[N:31]=[C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:33][CH:34]=1)[CH:23]=[CH:10][C:8]([O:7][CH3:6])=[O:9])[CH3:18]
Reactant: CCOc1cc(C=O)ccc1OCc1coc(-c2ccccc2)n1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCOc1cc(C=CC(=O)OC)ccc1OCc1coc(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 91.9 %

Procedure:
A methanol solution of sodium methoxide (28%, 3.4 g) was added dropwise to an ice-cooled solution of trimethyl phosphonoacetate (3.2 g) and 3-ethoxy-4-(2-phenyl-4-oxazolylmethoxy)benzaldehyde (5.1 g) in N,N-dimethylformamide (DMF) (30 ml). The mixture was stirred for 5 minutes under ice-cooling, then for 4 hours at room temperature. The reaction mixture was poured into ice-water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated to yield methyl 3-ethoxy-4-(2-phenyl-4-oxazolylmethoxy)cinnamate (5.5 g, 91%), which was recrystallized from chloroform-ether to give colorless prisms, m.p.125-126° C.
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][S:13]([C:16]2[N:17]=[CH:18][N:19]([CH3:21])[CH:20]=2)(=[O:15])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:22][C:23]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26].C(O)(=O)C>O>[CH3:34][O:33][C:31]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([NH:22][C:2]2[C:3]([NH:12][S:13]([C:16]3[N:17]=[CH:18][N:19]([CH3:21])[CH:20]=3)(=[O:15])=[O:14])=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:11]=2)[CH:32]=1
Reactant: COC(=O)c1ccc(OC)cc1N
Reactant: Cn1cnc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)c1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(OC)cc1Nc1nc2ccccc2nc1NS(=O)(=O)c1cn(C)cn1
Temperature: 170 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
N-(3-chloroquinoxalin-2-yl)-1-methyl-1H-imidazole-4-sulfonamide (2 g; 6.2 mmol; 1 eq) and methyl 2-amino-4-methoxybenzoate (1.2 g; 6.8 mmol; 1.1 eq) are taken up in water (60 mL) and acetic acid (160 μL; 3.65 mmol; 0.6 eq) is added. The suspension is heated up to 170° C. in the microwave under normal absorption for 20 min. The reaction is stopped by filtration of the solid and washing with water until neutral. The orange powder obtained is dried under vacuum at 40° C. overnight then taken up in DCM. Triethylamine (1.72 mL) is added. After sonication, the solvents are removed under reduced pressure and the residue obtained is washed with water then dried under vacuum at 40° C. overnight. The powder is taken up in MeOH and refluxed then the suspension is left at 4° C. for 1 h. The precipitate is filtered and washed with MeOH then dried under vacuum at 40° C. for 2 days, to afford 1.68 g (58%) of the title compound as a yellow powder. 1H NMR (DMSO-d6) δ 11.77 (s, 1H), 9.05 (d, J=2.3 Hz, 1H), 8.10-7.95 (m, 2H), 7.90 (s, 1H), 7.85-7.76 (m, 1H), 7.73-7.60 (m, 1H), 7.55-7.35 (m, 2H), 6.73 (dd, J=8.6, 2.2 Hz, 1H), 3.91 (s, 6H), 3.72 (s, 3H). HPLC (max plot) 100%; Rt 4.12 min. LC/MS: (ES+): 469.0, (ES−): 467.1.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[NH2:16][C@H:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:18]([CH2:20][CH3:21])[CH3:19].Cl.[NH:30]([C:42]([O:44][CH2:45][CH:46]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:52]2[C:47]1=[CH:48][CH:49]=[CH:50][CH:51]=2)=[O:43])[C@H:31]([C:39](O)=[O:40])[CH2:32][CH2:33][CH2:34][NH:35][C:36](=[NH:38])[NH2:37].C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[NH:30]([C:42]([O:44][CH2:45][CH:46]1[C:47]2[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:53]2[C:58]1=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:43])[C@H:31]([C:39]([NH:16][C@H:17]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C@H:18]([CH2:20][CH3:21])[CH3:19])=[O:40])[CH2:32][CH2:33][CH2:34][NH:35][C:36](=[NH:37])[NH2:38]
Reactant: N=C(N)NCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC[C@H](C)[C@H](N)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C

Procedure:
2.2 g of DCC are added, at 0° C., to a stirred solution of 2.23 g of H-Ile-OtBu.HCl, 4 g (10 mmol) of Fmoc-Arg-OH and 1.35 g of HOBt in 80 ml of dimethylformamide. The working-up is carried out in analogy to Example 2b.
Reaction SMILES: [CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[CH:21]=4)[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2].[CH:30](=O)[CH2:31][CH2:32]C>>[CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[C:21]=4[CH2:30][CH2:31][CH3:32])[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2]
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3c(F)cc(F)cc3nc2-1
Reactant: CCCC=O
Product: CCCc1c2c(nc3cc(F)cc(F)c13)-c1cc3c(c(=O)n1C2)COC(=O)C[C@]3(O)CC

Procedure:
The product of Example 100 is treated with butyraldehyde according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: [H-].[Na+].CS(O[CH2:8][CH2:9][N:10]1[CH2:14][C@@H:13]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:12][C@H:11]1[C:25](=[O:28])[NH:26][CH3:27])(=O)=O.[Cl-].[Na+]>CN(C)C=O>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][S:15][C@@H:13]2[CH2:14][N:10]3[C@H:11]([C:25](=[O:28])[N:26]([CH3:27])[CH2:8][CH2:9]3)[CH2:12]2)=[CH:18][CH:19]=1
Reactant: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1CCOS(C)(=O)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CS[C@H]2C[C@H]3C(=O)N(C)CCN3C2)cc1
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
347 mg of sodium hydride (as a 55% w/w suspension in mineral oil) was added, whilst ice-cooling, to a solution of 2.64 g of (2S. 4S)-1-(2-methanesulfonyloxyethyl)-4-(4-methoxybenzylthio)-2-methylcarbamoylpyrrolidine dissolved in 30 ml of dry dimethylformamide, and the mixture was stirred at 0° to 5° C. for 30 minutes and then at 30° C. for 2 hours. The reaction mixture was then poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and freed from the solvent by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluted with a 5:1 by volume mixture of acetonitrile and methanol), to afford 1.75 g of the title compound as an oil.