Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH:35]=O)[C:27]3[C:26](=[O:37])[N:25]([CH3:38])[C:24](=[O:39])[N:23]([CH3:40])[C:22]=3[N:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>O1CCCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH:35]=[CH2:1])[C:27]3[C:26](=[O:37])[N:25]([CH3:38])[C:24](=[O:39])[N:23]([CH3:40])[C:22]=3[N:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:9])([CH3:10])[CH3:8]
Reactant: Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2C=O)n(C)c1=O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=Cc1ccccc1-n1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 200.8 %

Procedure:
Potassium tert-butoxide (9 mg) was dissolved in tetrahydrofuran (1 ml), and methyl triphenyl phosphonium bromide (31 mg) was added thereto. The reaction mixture was stirred at room temperature for 30 minutes, and a solution of 4-[7-(2-formylphenyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (20 mg) in tetrahydrofuran (1 ml) was added thereto. The reaction solution was stirred at room temperature for 1 hour, diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 40 mg of 4-[7-(2-vinylphenyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester. This product (12 mg) was dissolved in trifluoroacetic acid, and the solution was concentrated. The residue was purified by reversed phase high performance liquid chromatography to give 4.38 mg of the title compound.
Reaction SMILES: Br[C:2]1[S:27][C:5]2=[N:6][C:7]([CH3:26])=[C:8]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[CH:3]=1.O(C([N:35]1[CH:39]=[C:38](B(O)O)[CH:37]=[N:36]1)=O)C(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[C:8]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:7]([CH3:26])[N:6]=[C:5]3[S:27][C:2]([C:38]4[CH:39]=[N:35][NH:36][CH:37]=4)=[CH:3][C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)n1cc(B(O)O)cn1
Reactant: CCOC(=O)c1c(C)nc2sc(Br)cc2c1NS(=O)(=O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2sc(-c3cn[nH]c3)cc2c1NS(=O)(=O)c1cccc(Cl)c1
Temperature: 100 °C

Procedure:
Alternatively, a mixture of ethyl 2-bromo-4-{[(3-chlorophenyl)sulfonyl]amino}-6-methylthieno[2,3-b]pyridine-5-carboxylate (Description 72) (6.91 g, 14.11 mmol), 1-tert-butoxylcarbonyl-1H-pyrazole-4-boronic acid, pinacol ester (6.22 g, 21.16 mmol), tetrakis(triphenylphosphine)palladium(0) (0.408 g, 0.353 mmol) and potassium carbonate (5.85 g, 42.3 mmol) in 1,4-dioxane (50 mL), DMF (25 mL) and water (12.5 mL) was heated at 100° C. overnight (ca. 20 h). After cooling to RT, the reaction mixture was filtered through celite and the filtrate was concentrated. The residue was purified by chromatography on silica, eluting with a gradient of 0-100% ethyl acetate/DCM. The resulting material was then passed through an SCX cartridge, eluting with MeOH (150 mL) followed by 2M NH3 in MeOH (250 mL) and the basic methanolic fractions concentrated, to give the title compound (6.276 g).
Reaction SMILES: Cl[C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][N:15]3[CH2:18][CH3:19])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[C:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(OC(N1CCN(C2C=CC(C(=O)NC3C=CC(C)=C(I)C=3)=CN=2)CC1)=O)(C)(C)C>>[C:25]([O:24][C:22]([N:29]1[CH2:34][CH2:33][N:32]([C:2]2[CH:21]=[CH:20][C:5]([C:6](=[O:7])[NH:8][C:9]3[CH:17]=[C:16]4[C:12]([CH:13]=[CH:14][N:15]4[CH2:18][CH3:19])=[CH:11][CH:10]=3)=[CH:4][N:3]=2)[CH2:31][CH2:30]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCn1ccc2ccc(NC(=O)c3ccc(Cl)nc3)cc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc1I
Product: CCn1ccc2ccc(NC(=O)c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)cc21

Procedure:
4-[5-(1-Ethyl-1H-indol-6-ylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester was prepared from 6-chloro-N-(1-ethyl-1H-indol-6-yl)-nicotinamide and 1-Boc-piperazine following a method similar to the one described in the synthesis of 4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester above. The product was obtained after silica gel column purification with 10-30% Et2O in toluene gradient. HRMS m/z calcd for C25H31N5O3 [M+H]+: 450.2500. Found: 450.2497.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:35][C:36](=[O:42])[C:37](OCC)=[O:38])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[C:20]([O:33][CH3:34])[CH:19]=3)[S:17][C:10]=12.[CH3:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH2:51][CH2:52][NH2:53]>>[F:1][C:2]1[CH:3]=[C:4]([NH:35][C:36](=[O:42])[C:37]([NH:53][CH2:52][CH2:51][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[O:44][CH3:43])=[O:38])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[C:20]([O:33][CH3:34])[CH:19]=3)[S:17][C:10]=12
Reactant: CCOC(=O)C(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(OCCN5CCOCC5)c(OC)c4)sc23)c(F)c1
Reactant: COc1ccccc1CCN
Product: COc1ccccc1CCNC(=O)C(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(OCCN5CCOCC5)c(OC)c4)sc23)c(F)c1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
Amino ester 140 (80 mg, 0.13 mmol) and 2-(2-methoxyphenyl)ethanamine (0.2 mL, 1.34 mmol) were mixed together and stirred at room temperature until completion of the reaction. The mixture was quenched with a saturated aqueous solution of ammonium chloride and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by flash chromatography (eluent: 3% MeOH/97% DCM to 5% MeOH/95% DCM). This solid product was then triturated with ethyl acetate to afford pure title compound 136 as a white solid (52 mg, 57% yield). 1H NMR (DMSO-d6) 6 (Ppm): 11.03 (s, 1H), 9.04 (t, J=5.9 Hz, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.05-8.01 (m, 2H), 7.82 (d, J=9.0 Hz, 1H), 7.53 (t, J=9.1 Hz, 1H), 7.47 (d, J=2.2 Hz, 1H), 7.38 (dd, J=2.2 and 8.2 Hz, 1H), 7.21 (td, J=1.8 and 7.8 Hz, 1H), 7.14 (dd, J=1.8 and 7.4 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H), 6.97 (d, J=7.4 Hz, 1H), 6.88 (td, J=1.0 and 7.3 Hz, 1H), 6.60 (d, J=5.5 Hz, 1H), 4.14 (t, J=6.0 Hz, 2H), 3.89 (s, 3H), 3.80 (s, 3H), 3.59-3.57 (m, 4H), 3.46-3.41 (m, 2H), 2.83 (t, J=7.0 Hz, 2H), 2.73-2.70 (m, 2H), one peak (4H) did not show, it was probably under H2O or DMSO. MS (m/z): 701.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[Cl:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.ClCCl>C(OCC)(=O)C>[Cl:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cnc2ccccc2c1Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1cnc2ccccc2c1Cl)c1ccccc1
Temperature: 40 °C
Yield: 25.5 %

Procedure:
Under a nitrogen atmosphere, a mixture of 3-amino-4-chloroquinoline (2.50 g, 1 eq), benzoyl chloride (3.0 g, 1.5 eq), and anhydrous dichloromethane (100 mL) was heated at 40° C. After 23 hours additional benzoyl chloride (3.0 g, 1.5 eq) was added and heating was continued for a total of 48 hours. The reaction mixture was diluted with ethyl acetate, washed sequentially with aqueous potassium carbonate (×2), water, and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The crude product was purified by column chromatography (230 g of silica gel eluted initially with a gradient of 20-50% ethyl acetate in hexanes and then with 4/3/3 dichloromethane/ethyl acetate/hexanes) to provide 1.01 g of N-(4-chloroquinolin-3-yl)benzamide as a white solid.
Reaction SMILES: [F:1][C:2]1[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]([F:28])[C:3]=1[CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C@H:9]1[CH2:21][CH3:22])=[O:7].Cl.O.[OH-].[Na+]>CO.O1CCOCC1>[F:1][C:2]1[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]([F:28])[C:3]=1[CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:21][CH3:22])=[O:7]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)ccc(C)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CC[C@@H]1CNCCN1C(=O)OCc1c(F)ccc(C)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.2 %

Procedure:
(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester 1-(2,6-difluoro-3-methyl-benzyl) ester (160 mg) was dissolved in methanol (3 mL), 500 μL 4 N HCl in dioxane was added and the mixture was stirred for 18 h at room temperature. The mixture was added to water (10 mL) made alkaline with 1 N NaOH and extracted with ethylacetate. Organic phases were pooled, dried with Na2SO4 and evaporated to give the product as a yellowish oil (120 mg); MS (ISP): 299.4 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1([OH:28])[C:21]2[O:22][C@@H:18]3[C@@:19]45[CH2:23][CH2:24][N:25]([CH3:26])[C@@H:13]([C@@H:14]4[CH:15]=[CH:16][C@@H:17]3[OH:27])[CH2:12][C:11]([C:20]5=2)=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:36]([C@:17]1([OH:27])[CH:16]=[CH:15][C@@H:14]2[C@@:19]34[CH2:23][CH2:24][N:25]([CH3:26])[C@@H:13]2[CH2:12][C:11]2[C:20]3=[C:21]([O:22][C@@H:18]14)[C:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([OH:28])[CH2:9][CH:10]=2)(=[O:38])[CH3:37]
Reactant: CN1CC[C@]23C4=C5O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1CC4=CCC5(O)Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)[C@]1(O)C=C[C@H]2[C@H]3CC4=CCC(O)(Cc5ccccc5)C5=C4[C@@]2(CCN3C)[C@H]1O5
Temperature: 0 °C
Yield: 97.5 %

Procedure:
To a solution of 3-benzylmorphine (12.7 g, 33.9 mmol) in CH2Cl2 (300 ml), was added triethylamine (10 ml, 99%, 71.2 mmol), acetic anhydride (7.5 ml, 99%, 78.6 mmol), and 4-dimethylaminopyridine (0.3 g). The reaction mixture was heated under reflux for 2 hr, cooled with an ice--H2O bath, then transferred to a separatory funnel, and washed with cold 10% aqueous NaHCO3 solution (3×100 ml). The organic layer was separated and dried over anhydrous Na2SO4. Removal of solvent gave 6-acetyl-3-benzylmorphine (13.87 g, 96% yield). IR (KBr)(ν, cm-1): 2900 (m, sharp), 1727 (s, sharp, AcO); NMR (βH)(CDCl3): 7.47-7.20 (5, m, --C6H5), 6.68 (1, d, J, 8.1, 2-H), 6.48 (1, d, J, 8.2,1-H), 5.63(1, dm, J, 10.1,7-H), 5.43(1, dt, J, 10.1 & 2.3, 8-H), 5.25-5.15(1, m, 6-H), 5.14 (2, s, --OCH2Ph), 5.10 (1, dd, J, 6.7 & 1.1, 5-H), 3.34 (1, dd, J, 6.0 & 3.3, 9-H), 3.01 (1, d, J, 18.6, 10-Hβ), 2.79-2.70 (1, m, 14-H), 2.59(1, dd, J, 12.1 & 3.4, 16-He), 2.43 (3, s, N-CH3), 2.37 (1, td, J, 11.8 & 3.6,16-Ha), 2.27 (1, dd, J, 18.8 & 6.6, 10-Hα), 2.10 (3, s, AcO), 2.04 (1, td, J, 11.9 & 5.1, 15-Ha), 1.86 (1, dm, J, 12.5, 15-He).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].Cl[C:14]1[CH:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=1.[C:21](=[O:24])([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14]2[CH:19]=[C:18]([O:24][C:21]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:9]([F:12])([F:11])[F:10])[CH:4]=3)[N:17]=[CH:16][N:15]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Clc1cc(Cl)ncn1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: FC(F)(F)c1cc(Oc2cc(Oc3ccc(Cl)c(C(F)(F)F)c3)ncn2)ccc1Cl

Procedure:
4-Chloro-3-trifluoromethylphenol (10.0 g, 0.051 mol) and 4,6-dichloropyrimidine (3.7 g, 0.025 mol) were heated to 60° C. in dimethylsulphoxide (75 ml) with potassium carbonate (10 g) under nitrogen for 12 hours. The mixture was then poured into water and the product extracted into diethyl ether. The organic layer was dried using Na2 SO4, filtered and concentrated. The product, 4,6-bis(4-chloro-3-tri-fluoromethylphenoxy)pyrimidine, was obtained by column chromatography (eluting with 5:1, hexane:ethyl acetate) and recrystallization (diethyl ether/hexane). Yield 11.0 g (94%); melting point 111° C.
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[CH:3][C:4]#[N:5].[C:19](OCC)(=[O:26])[CH2:20][C:21](OCC)=[O:22]>>[OH:26][C:19]1[C:3]([C:4]#[N:5])=[C:2]([C:6]2[CH:11]=[CH:10][C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:7]=2)[NH:1][C:21](=[O:22])[CH:20]=1
Reactant: N#CC=C(N)c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)CC(=O)OCC
Product: N#Cc1c(O)cc(=O)[nH]c1-c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
3-Amino-3-(4-phenoxyphenyl)acrylonitrile (720 mg, 3.05 mmol) in diethyl malonate (9 mL, 59.3 mmol) was microwaved at 250° C. for 10 min. After cooling to room temperature, the solid was collected by filtration, washed with 20% isopropanol in heptanes and dried under vacuum to give 4-hydroxy-6-oxo-2-(4-phenoxyphenyl)-1,6-dihydropyridine-3-carbonitrile (688 mg, 74% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.95 (1H, br. s), 7.67 (2H, δ, J=8.53 Hz), 7.48 (2H, t, J=7.91 Hz), 7.25 (1H, t, J=7.40 Hz), 7.11 (4H, dd, J=19.70, 8.16 Hz), 5.52-5.74 (1H, m); MS (ES+) m/z: 305 (M+H); LC retention time: 3.546 min (analytical HPLC Method A).
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].Br[CH2:18]/[CH:19]=[CH:20]\[CH3:21]>C(O)C>[C:2]([NH:5][C:6]([CH2:18]/[CH:19]=[CH:20]\[CH3:21])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: C/C=C\CBr
Agent: [Na]
Solvent: CCO
Product: C/C=C\CC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Reaction time: 8 h
Yield: 98 %

Procedure:
4.37 g (190 mmol) of sodium metal were dissolved in 110 ml of anhydrous ethanol. 41.14 g (189.6 mmol) of diethyl acetamidomalonate dissolved in 270 ml of anhydrous ethanol were added and the mixture was heated under reflux for 10 minutes. 25.65 g (168 mmol) of (Z)-1-bromo-2-butene were added dropwise at room temperature and the mixture was stirred overnight, then evaporated to dryness under vacuum and the residue was partitioned between ethyl acetate and 0.1 M hydrochloric acid. The organic phase was washed with saturated sodium hydrogen carbonate solution followed by saturated sodium chloride solution and dried over anhydrous magnesium sulphate. After removal of the solvent by evaporation the crude product was chromatographed on silica gel using 66% ethyl acetate in petroleum ether as eluent to obtain 44.69 g of diethyl (Z)-2-acetamido-2-(2-butenyl)malonate as a colourless oil;1H NMR (250 MHz, CDCl3) δ: 1.2 (t, 6H), 1.6 (d, 3H), 2.0 (s, 3H), 3.1 (d, 2H), 4.2 (q, 4H), 5.1(m, 1H), 5.6 (m, 1H), 6.7 (s, 1H).
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]([CH2:9][OH:10])=[N:5][CH:6]=[CH:7][CH:8]=1.CO.C[O-].[Na+].[CH2:16](Br)[CH:17]=[CH2:18]>O>[CH2:18]([O:2][C:3]1[C:4]([CH2:9][OH:10])=[N:5][CH:6]=[CH:7][CH:8]=1)[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: OCc1ncccc1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=CCOc1cccnc1CO
Temperature: 22 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
Hydroxy-2-(hydroxymethyl)pyridine hydrochloride (50 g, 339.6 mmol) and methanol (250 mL) are combined under nitrogen and cooled to 22° C. To the vigorously stirred mixture is added 4.5 M sodium methoxide in MeOH (170.8 mL, 747.2 mmol). The mixture is stirred at room temperature for 2 h and then the solvent is evaporated. The resulting material is dissolved in DMSO (250 mL), allyl bromide (41 g, 339.6 mmoles) is added, and the mixture stirred for 18 h at room temperature. The reaction mixture is added to water (800 mL) and extracted with methylene chloride (3×80 mL). The organic portions are combined and dried over sodium sulfate, filtered, and the solvent evaporated to afford the title compound (34.4 g, 62%). LC-ES/MS m/z 166.1 [M+H]+.
Reaction SMILES: C([C:3]1[C:7]([C:8]([O-:10])=[O:9])=[CH:6][NH:5][N:4]=1)C.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH3:25][C:26](C)=O>>[CH2:17]([N:4]1[CH:3]=[C:7]([C:8]([O:10][CH2:25][CH3:26])=[O:9])[CH:6]=[N:5]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)=O
Reactant: CCc1n[nH]cc1C(=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cnn(Cc2ccccc2)c1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
To a solution of Ethyl-4-pyrazole-carboxylate (14.0 g, 100 mmol) in Acetone (200 ml) was added potassium carbonate (27.6 g, 200 mmol) and Benzyl Bromide (12 ml, 100 mmol). The mixture was heated to 60° C. and stirred for 14 hours. The reaction mixture was cooled and filtered to remove any solids. The filtrate was concentrated and the residue was purified using column chromatography (3:1 Hexanes:Ethyl Acetate) to yield ethyl 1-benzylpyrazole-4-carboxylate (19.0 g, HNMR)
Reaction SMILES: Cl.[CH3:2][O:3][N:4]1[CH2:10][CH2:9][NH:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.ClC([C:21]1([CH:30]=[C:31]=[O:32])[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][CH:22]1[CH3:29])=O.[OH-].[Na+].[CH2:35]([O:37]CC)C>>[CH3:2][O:3][N:4]1[CH2:10][CH2:9][N:8]2[C:35](=[O:37])[CH:30]([C:21]3[C:22]([CH3:29])=[CH:23][C:24]([CH3:28])=[CH:25][C:26]=3[CH3:27])[C:31](=[O:32])[N:7]2[CH2:6][CH2:5]1
Reactant: CCOCC
Reactant: CON1CCNNCC1
Reactant: CC1=CC(C)C(C=C=O)(C(=O)Cl)C(C)=C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: CON1CCN2C(=O)C(c3c(C)cc(C)cc3C)C(=O)N2CC1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
To a degassed suspension of 5-methoxy-[1,2,5]triazepane hydrochloride salt (408 mg, 2.0 mmol) and triethylamine (1.115 ml, 810 mg, 8.0 mmol) in diethyl ether (1.0 ml) at 0-5° C. was added a solution of 2-(chlorocarbonyl)-2-mesitylketene [prepared according to Nakanishi's method: S. Nakanishi, K. Butler, Org. Prep. Proced. Int. 7, 155-158 (1975)] (891 mg, 4.0 mmol) in diethyl ether (1.0 ml) dropwise. The suspension was stirred at 0-5° C. for 30 minutes, and at room temperature overnight. The reaction mixture was poured on water (5 ml), the pH made alkaline (pH 14) by addition of aqueous sodium hydroxide, the aqueous layer extracted with ethyl acetate (3×10 ml) and the combined organic layers discarded. The aqueous alkaline phase was acidified with cooling to pH 5 by addition of a 4N HCl solution and the product thoroughly extracted with ethyl acetate (3×20 ml) and dichloromethane (3×20 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (gradient ethyl acetate/cyclohexane 5:1→4 ethyl acetate). Yield: 70 mg of 3-methoxy-8-(2,4,6-trimethyl-phenyl)-tetrahydro-pyrazolo[1,2-a][1,2,5]triazepine-7,9-dione (compound P2.1) as a pale beige solid, mp 227-229° C.
Reaction SMILES: [NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:13]N)=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].N(OCCC(C)C)=O.N[C@H:34]([C:42]([NH:44][C@H:45]([C:50]([NH:52][C@H:53]([C:59]([NH:61][C@H:62]([C:80]([NH:82][C@H:83]([C:86]([NH:88][C@H:89]([C:92]([OH:94])=[O:93])[CH2:90][OH:91])=[O:87])[CH2:84][OH:85])=[O:81])[CH2:63][CH2:64][CH2:65][NH:66][C:67](=[NH:79])[NH:68][S:69]([C:72]1[CH:78]=[CH:77][C:75]([CH3:76])=[CH:74][CH:73]=1)(=[O:71])=[O:70])=[O:60])[CH2:54][CH2:55][C:56](=[O:58])[NH2:57])=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.N(C(OCC1C=CC=CC=1)=O)[C@H](C(NCC(N=[N+]=[N-])=O)=O)CC(C)C>CN(C)C=O.Cl.O1CCOCC1.C(N(CC)CC)C>[NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:13][C@H:34]([C:42]([NH:44][C@H:45]([C:50]([NH:52][C@H:53]([C:59]([NH:61][C@H:62]([C:80]([NH:82][C@H:83]([C:86]([NH:88][C@H:89]([C:92]([OH:94])=[O:93])[CH2:90][OH:91])=[O:87])[CH2:84][OH:85])=[O:81])[CH2:63][CH2:64][CH2:65][NH:66][C:67](=[NH:79])[NH:68][S:69]([C:72]1[CH:73]=[CH:74][C:75]([CH3:76])=[CH:77][CH:78]=1)(=[O:71])=[O:70])=[O:60])[CH2:54][CH2:55][C:56](=[O:58])[NH2:57])=[O:51])[CH2:46][CH:47]([CH3:48])[CH3:49])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc2ccccc2)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)cc1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)NN
Agent: CC(C)CCON=O
Agent: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)N=[N+]=[N-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)OCc2ccccc2)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)cc1

Procedure:
0.39 Gram of Z-Leu-Gly-NHNH2 was dissolved in 5 ml of dimethylformamide and 0.58 ml of 6N HCl/dioxane, then a reaction similar to that described in Reference example 1 was carried out by using 10 ml of a dimethylformamide solution containing 0.15 ml of isoamyl nitrite, 0.49 ml of triethylamine and 1.00 g of H-Phe-Leu-Gln-Arg(Tos)-Ser-Ser-OH, further an equivalent amount of Z-Leu-Gly-N3 was added to the reaction mixture and reacted at 4° C. for 20 hours. The reaction mixture was extracted with butanol, the extract was washed with 2%-acetic acid, then butanol and acetic acid were removed by sistillation, the residue was crystallized from ether. The crystals were collected by filtration and washed with a hot methanol to obtain 0.65 g of Z-Leu-Gly-Phe-Leu-Gln-Arg(Tos)-Ser-Ser-OH.
Reaction SMILES: S(Cl)(Cl)=O.[O:5]=[C:6]1[CH:15]=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1.[CH3:20]COCC>CO>[O:5]=[C:6]1[CH:15]=[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1
Reactant: CCOCC
Reactant: O=C(O)Cc1cc(=O)[nH]c2ccccc12
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)Cc1cc(=O)[nH]c2ccccc12
Reaction time: 8 h
Yield: 80 %

Procedure:
95 g (0.8 mol) of thionyl chloride are added dropwise in the course of approximately 1 h to a stirred suspension of 60 g (0.295 mol) of 2-oxo-1,2-dihydro-4-quinolineacetic acid in 1 1 of methanol. The mixture is left overnight. The solvent is driven off and the residue obtained is dissolved in 300 ml of boiling methanol. After the mixture is cooled, 300 ml of ether are added. The solid is drained and then recrystallized in methanol. 51.5 g (80%) of methyl 2-oxo-1,2-dihydro-4-quinolineacetate, melting point 209°-210° C., are obtained