Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([C:21](OC)=[O:22])=[N:11][C:12]([O:19][CH3:20])=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:26][NH2:27]>CO.O>[NH:26]([C:21]([C:10]1[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:14][C:13]([C:15]([F:18])([F:16])[F:17])=[C:12]([O:19][CH3:20])[N:11]=1)=[O:22])[NH2:27]
Reactant: COC(=O)c1nc(OC)c(C(F)(F)F)cc1NC(=O)OC(C)(C)C
Reactant: NN
Solvent: CO
Solvent: O
Product: COc1nc(C(=O)NN)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Yield: 97.1 %

Procedure:
A suspension of methyl 3-(tert-butoxycarbonylamino)-6-methoxy-5-(trifluoromethyl)picolinate (step 2) (3.1 g, 8.85 mmol) in dry MeOH (20 ml) was treated with hydrazine monohydrate (1.108 g, 22.12 mmol) and the suspension was heated at reflux overnight. The mixture was diluted with water and the resulting precipitate was collected by filtration and dried in a vacuum oven to afford the title compound as a light brown solid (3.01 g). LC-MS Rt=1.27 min [M+H]+ 251 [−minus Boc group] (Method HighpH_v003.).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[C:13]=[S:14]>>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([CH:2]([NH:1][C:13]([NH:12][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]=[CH:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=4)[N:22]=3)=[CH:17][CH:16]=2)=[S:14])[CH2:3][OH:4])=[CH:6][CH:7]=1
Reactant: NC(CO)c1ccc(Br)cc1
Reactant: FC(F)(F)c1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1)c1ccc(Br)cc1

Procedure:
The title compound was prepared with 2-amino-2-(4-bromophenyl)ethanol and 3-(4-isothiocyanatophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole and isolated as a white solid (1.56 g, 99%): 1H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.32-8.22 (m, 2H), 7.92 (d, J=8.0 Hz, 2H), 7.82 (d, J=8.4 Hz, 2H), 7.45-7.28 (m, 8H), 7.20 (d, J=8.0 Hz, 1H), 5.69 (s, 1H), 4.11-3.86 (m, 2H); ESIMS m/z 562 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]([S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH:14][NH:15][C:16](=O)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=O)=[CH:8]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>O1CCCC1>[CH3:1][N:2]([S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:41][C:16]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:15][N:14]=1)=[CH:8]2
Reactant: CCOC(=O)CC(=O)NNC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1nnc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
A mixture of ethyl 3-[2-({7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}carbonyl)hydrazino]-3-oxopropanoate (0.96 g), Lawesson's reagent (0.97 g) and tetrahydrofuran (20 mL) was stirred at 50° C. for 2 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography, and the title compound (0.70 g, yield 71%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 201-202° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:75][CH:76]1[CH2:81][CH2:80][N:79]([CH3:82])[CH2:78][CH2:77]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([CH3:13])([CH3:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:75][CH:76]5[CH2:81][CH2:80][N:79]([CH3:82])[CH2:78][CH2:77]5)=[O:28])=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Reaction time: 0.25 h
Yield: 53.9 %

Procedure:
To a suspension of 0.0226 g (0.00005 mole) of 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoic acid (I-56a) in 3 mL of dimethylformamide was added 0.0121 g (0.00009 mole) of 1-hydroxybenzotriazole, 0.0312 g (0.00008 mole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate and 0.06 mL (0.00035 mole) of ethyldiisopropylamine. The mixture was stirred for 15 minutes and then 0.0091 g (0.00008 mole) of 4-amino-1-methylpiperidine was added. The mixture was stirred for an additional 2.5 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 1 M sodium hydroxide, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol 98:2-85:15) to give 0.0140 g of 4-(9-Cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-N-(1-methyl-piperidin-4-yl)-benzamide (I-56).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:16]=[C:17]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:18]([NH2:21])=[CH:19][CH:20]=3)=[N:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.[C:31](=O)([O-])O.[Na+]>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]4[N:21]=[CH:31][N:22]([C:23]5[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=5)[C:17]=4[CH:16]=3)=[N:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Nc2cc(-c3nnc(CCc4cccc(F)c4)o3)ccc2N)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: COc1ccc(-n2cnc3ccc(-c4nnc(CCc5cccc(F)c5)o4)cc32)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A mixture of 4-[5-[2-(3-fluorophenyl)ethyl]-1,3,4-oxadiazol-2-yl]-N2-(4-methoxyphenyl)benzene-1,2-diamine (0.20 g, 0.49 mmol) and formic acid (1.4 mL) was stirred at 100° C. overnight. After cooling, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=1/1) to give the title compound (0.10 g, yield 49%) as colorless crystals.
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[Br:13].[OH-].[Na+]>C(O)C.[Fe]>[Br:13][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:4]=1[Cl:3])[NH2:10]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Br)c1
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Cl)c(Br)c1
Temperature: 70 °C

Procedure:
A mixture of iron (17.9 g), ethanol (120 ml), water (80 ml) and conc. hydrochloric acid (1.5 ml) was heated to 70° C., this temperature was maintained during the addition of 1-chloro-2-bromo-4-nitrobenzene (21.0 g) in ethanol (100 ml) over 25 min. The mixture was heated to reflux for 11/4 hours before adjusting the pH to 9-10 with sodium hydroxide solution. The mixture was filtered hot through Hyflo™ washing with hot ethanol and water. The mixture was concentrated, dichloromethane added and the organic solution washed with water then dried (MgSO4). The product was purifed by silica gel chromatography then recrystalised from ether/hexane to give the sub-title compound as a solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=3)=[N:8][C:9]3[N:10]([N:12]=[CH:13][CH:14]=3)[CH:11]=2)=[CH:2]1.CC1NN=C(N)[N:25]=1>>[CH3:14][C:13]1[N:25]=[C:9]2[N:8]=[C:7]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=3)[C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[CH:11][N:10]2[N:12]=1
Reactant: O=Cc1ccc(-c2nc3ccnn3cc2-c2ccsc2)cc1
Reactant: Cc1nc(N)n[nH]1
Product: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccsc3)cn2n1

Procedure:
This compound was prepared in a manner according to 4-(6-thiophen-3-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-benzaldehyde by using 5-methyl-1,2,4-triazol-3-amine in the first step.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](Cl)=[O:8].[CH3:19][NH:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24]>>[NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([N:20]([CH3:19])[CH2:21][CH:22]([OH:25])[CH2:23][OH:24])=[O:8]
Reactant: CNCC(O)CO
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)Cl)c1I
Product: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)N(C)CC(O)CO)c1I
Yield: 97 %

Procedure:
5-Amino-3-acetoxymethyl-2,4,6-triiodobenzoyl chloride was reacted with N-methyl-2,3-dihydroxypropanamine according to the conditions in Example 24g. The product was isolated in 97% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1>C1(C)C(C)=CC=CC=1>[N:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:9][CH:10]=1
Reactant: C1CNCCN1
Reactant: Clc1ccncc1
Solvent: Cc1ccccc1C
Product: c1cc(N2CCNCC2)ccn1
Yield: 15.9 %

Procedure:
A mixture of piperazine (67.0 g, 0.78 mol) and 4-chloropyridine (26.1 g, 0.23 mol) in xylene (520 ml) was heated at reflux for 20hr. The reaction mixture was cooled and filtered. The filtrate was evaporated to dryness to give 5.96 g of the title compound as a solid; m.p. 132°-136° C.; NMR(CDCl3) δ1.8(s,1H), 2.9(m,4H), 3.2(m,4H), 6.6(m,2H), 8.2(m,2H).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[N:19]=[C:18]([N:20]2[CH2:24][CH2:23][CH2:22][C:21]2=[O:25])[CH:17]=[CH:16][N:15]=1.IC.[Cl-].[NH4+]>O1CCCC1>[Cl:13][C:14]1[N:19]=[C:18]([N:20]2[CH2:24][CH2:23][CH:22]([CH3:1])[C:21]2=[O:25])[CH:17]=[CH:16][N:15]=1
Reactant: O=C1CCCN1c1ccnc(Cl)n1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1CCN(c2ccnc(Cl)n2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (0.79 mL) in tetrahydrofuran (5 mL) was added dropwise n-butyllithium (1.6 M hexane solution, 3.5 mL) at −78° C. under nitrogen atmosphere, and the mixture was warmed to 0° C., and stirred for 30 min. The reaction mixture was cooled to −78° C., and 1-(2-chloropyrimidin-4-yl)pyrrolidin-2-one (370 mg) obtained in Step A was added thereto. The reaction mixture was stirred at the same temperature for 1 hr, iodomethane (0.35 mL) was added thereto, and the mixture was stirred overnight while it was allowed to be warmed. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (38 mg).
Reaction SMILES: [Li]C(CC)C.[F:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[N:13]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:15][C:8]=12.C(Br)(Br)(Br)[Br:27].[Cl-].[NH4+]>C1COCC1>[Br:27][C:12]1[C:7]([F:6])=[C:8]2[CH:15]=[CH:14][N:13]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:23]([CH3:25])[CH3:24])[CH:17]([CH3:18])[CH3:19])[C:9]2=[N:10][CH:11]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)ccnc21
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)c(Br)cnc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
s-BuLi (53.7 mL, 75.2 mmol, 1.4M in cyclohexane) was added to a solution of 4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (10.0 g, 34.2 mmol, prepared as described in L′Heureux, et al. Org. Lett., 5(26), p. 5023 (2003)) in THF (250 mL) at −78° C., and the reaction was stirred at −78° C. for 30 minutes. A solution of CBr4 (28.3 g, 85.5 mmol) in THF (40 mL) was added next, and the reaction was stirred at this temperature for 1 hour. A saturated ammonium chloride solution (80 mL) was then added, and the reaction was extracted with hexane (200 mL), washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was then purified by column chromatography (hexane) to give 5-bromo-4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (7.8 g, 61.4% yield).
Reaction SMILES: [CH2:1]([O:48][CH:49]1[C@H:53]2[C@H:54](O[Si](C(C)(C)C)(C)C)[N:55](C(OCC(Cl)(Cl)Cl)=O)[C:56]3[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][C:57]=3[C:58](=[O:59])[N:52]2[CH:51]=[C:50]1[C:82]1[CH:91]=[CH:90][C:89]2[C:84](=[CH:85][CH:86]=[CH:87][CH:88]=2)[CH:83]=1)[CH2:2][CH2:3][O:4][CH:5]1[C@H:9]2[C@H:10](O[Si](C(C)(C)C)(C)C)[N:11](C(OCC(Cl)(Cl)Cl)=O)[C:12]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:13]=3[C:14](=[O:15])[N:8]2[CH:7]=[C:6]1[C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=1>C1COCC1>[CH2:1]([O:48][CH:49]1[C@@H:53]2[CH:54]=[N:55][C:56]3[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][C:57]=3[C:58](=[O:59])[N:52]2[CH:51]=[C:50]1[C:82]1[CH:91]=[CH:90][C:89]2[C:84](=[CH:85][CH:86]=[CH:87][CH:88]=2)[CH:83]=1)[CH2:2][CH2:3][O:4][CH:5]1[C@@H:9]2[CH:10]=[N:11][C:12]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:13]=3[C:14](=[O:15])[N:8]2[CH:7]=[C:6]1[C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=1
Reactant: COc1ccc2c(c1)C(=O)N1C=C(c3ccc4ccccc4c3)C(OCCCOC3C(c4ccc5ccccc5c4)=CN4C(=O)c5cc(OC)ccc5N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]34)[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)N2C(=O)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=O)N1C=C(c3ccc4ccccc4c3)C(OCCCOC3C(c4ccc5ccccc5c4)=CN4C(=O)c5cc(OC)ccc5N=C[C@@H]34)[C@@H]1C=N2
Yield: 34.8 %

Procedure:
10% Cd/Pb couple (455 mg, 3.71 mmol, 26 eq) was added to a rapidly stirring mixture of 17 (190 mg, 0.14 mmol), THF (3.2 mL) and 1 N NH4OAc (3.2 mL). The reaction mixture was allowed to stir for 6.5 hours when TLC showed the incomplete consumption of the starting material and formation of side products. The solids were filtered and rinsed with H2O and MeOH. Excess solvent was removed and the residue was diluted with H2O (25 mL) and DCM (25 mL). The aqueous layer was extracted with DCM (3×25 mL) and the organic extracts were combined, washed with brine (50 mL) and dried (MgSO4). Filtration and evaporation of solvent afforded the crude product which was purified by flash column chromatography (99:1 v/v CHCl3/MeOH then gradient to 98:2 v/v CHCl3/MeOH) to afford 18 as a yellow glass (38 mg, 36%): 1H NMR (400 MHz, CDCl3) δ 7.85 (d, 2H, J=3.9 Hz, H11), 7.77-7.65 (m, 6H, Harom), 7.59-7.50 (m, 6H, H3 and Harom), 7.47 (s, 2H, H6), 7.44-7.33 (m, 4H, Harom), 6.82 (s, 2H, H9), 4.42-4.32 (m, 2H, H11a), 4.31-4.14 (m, 4H, OCH2CH2CH2O), 3.89 (s, 6H, OCH3×2), 3.69-3.56 (m, 2H, H1), 3.50-3.37 (m, 2H, H1), 2.45-2.29 (m, 2H, OCH2CH2CH2O).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]([N:21]1[CH2:25][CH:24]([CH:26]([OH:28])[CH3:27])[CH2:23][N:22]1[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH3:27][C:26]([CH:24]1[CH2:25][N:21]([C:19]([O:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:20])[N:22]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:23]1)=[O:28]
Reactant: CC(O)C1CN(C(=O)OCc2ccccc2)N(C(=O)OCc2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(=O)C1CN(C(=O)OCc2ccccc2)N(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 9.2 %

Procedure:
To a solution of oxalyl chloride (23 ml) in dichloromethane was added dropwise dimethyl sulfoxide (374 ml) while keeping the temperature below -50° C. After the mixture was stirred for 30 minutes at -50° C.~-60° C., 1.2-bis(benzyloxycarbonyl)-4-(1-hydroxyethyl)pyrazolidine (675 g) was added dropwise below -50° C. After the mixture was stirred for 45 minutes at -50° C.~-60° C., triethylamine (122 ml) was added dropwise below -50° C. The reaction mixture was allowed to warm to 0° C. and quenched with water (500 ml). The aqueous layer was separated and extracted twice with dichloromethane (200 ml×2). The combined organic layer was washed with 1N hydrochloric acid (200 ml×2), saturated sodium bicarbonte (200 ml), and 5% sodium chloride (200 ml), dried over magnesium sulfate, and evaporated under reduced pressure. The residue was chromatographed on silica gel (820 ml, hexane:ethyl acetate=2:1~1:1) to give 1,2-bis(benzyloxycarbonyl)pyrazolidin-4-yl methyl ketone (61.5 g).
Reaction SMILES: [C:1]([NH:13][C@H:14]([C:19]([OH:21])=O)[CH2:15][C:16](=[O:18])[NH2:17])(=[O:12])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:22]([N:25]([CH2:34][C@@H:35]([OH:45])[C@@H:36]([NH2:44])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([CH3:24])[CH3:23].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:22]([N:25]([CH2:34][C@@H:35]([OH:45])[C@@H:36]([NH:44][C:19](=[O:21])[C@H:14]([CH2:15][C:16](=[O:18])[NH2:17])[NH:13][C:1](=[O:12])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])([CH3:24])[CH3:23]
Reactant: CC(C)N(C[C@@H](O)[C@@H](N)Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.9 %

Procedure:
To a stirred solution of the product of Step A (0.111 g; 0.386 mmol), the product of Example 2, Step B (0.13022 g; 0.386 mmol), benzotriazol- 1 -yloxytris (dimethylamino)phosphonium hexafluorophosphate (0.205 g; 0.46 mmol) and 1-hydroxybenzotriazole (0.052 g; 0.384 mmol) in 1 ml of anhydrous DMF was added, N,N-diisopropylethylamine (0.24 ml; 1.38 mmol). After stirring for 12 hours at room temperature the reaction was diluted to 30 ml with ethyl acetate and washed with water, 2% potassium bisulfate, 5% sodium bicarbonate and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure and purification of the residue by column chromatography (silica gel, ethyl acetate) gave 0.152 g (65% yield) of the title product melting at 109°-114° C.; Rf (C)=0.36; Rf (D)=0.37; NMR (CDCl3) 1.0 (m, 6H, val, isopropyl CH3); 1.42 (s, 9H, t-butyl CH3); 2.5-3.1 (m, 7H, asn CH2, butyl CH2 -1,-4, CH-3); 3.44 (m, 1 H, isopropyl CH); 4.21 (m, 1 H, butyl CH-2); 4.55 (s, 1 H, OH); 4.94 (m, 1H, asn CH-α); 5.4-6.2 (m, 3H, amide); 6.7-8.4 (m, 11H, aromatic); 9.25 (m, 1H, NH).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[NH:7][C:8](=O)[N:9]([CH3:12])[C:10](=[O:11])[C:5]=2[N:4]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=2[Cl:22])[N:3]=1.P(Cl)(Cl)([Cl:25])=O.C(N(CC)C(C)C)(C)C>>[Cl:25][C:8]1[N:9]([CH3:12])[C:10](=[O:11])[C:5]2[N:4]([C:14]3[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=3[Cl:22])[N:3]=[C:2]([CH3:1])[C:6]=2[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nn(-c2c(Cl)cc(Cl)cc2Cl)c2c(=O)n(C)c(=O)[nH]c12
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(-c2c(Cl)cc(Cl)cc2Cl)c2c(=O)n(C)c(Cl)nc12
Temperature: 100 °C
Reaction time: 60 h

Procedure:
A mixture of 3,6-dimethyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[4,3-d]pyrimidine-5,7(4H,6H)-dione (20 mg, 0.0556 mmol), phosphorus oxychloride (0.52 ml) and N,N-diisopropylethylamine (0.21 ml) was stirred at 100° C. for 60 h. The solvent was evaporated under vacuum to give the title compound, which was used for the next step without further purification.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[CH2:13][C:14]([OH:16])=[O:15].[CH3:17]O>>[Br:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: O=C(O)Cc1ccc(F)cc1Br
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (6 mL) was added dropwise to a solution of 2-bromo-4-fluorophenylacetic acid (5.0 g) in methanol (50 mL), and the reaction solution was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, and then the residue was dissolved in ethyl acetate. The solution was filtered through a silica gel pad (carrier: Chromatorex NH), and the filtrate was concentrated under reduced pressure to obtain methyl 2-bromo-4-fluorophenylacetate (5.53 g). A solution of methyl 2-bromo-4-fluorophenylacetate (2.0 g) in DMF (5 mL) was added to a suspension of sodium hydride (containing mineral oil at 40%, 356 mg) in DMF (20 mL) under ice-cooling. The reaction solution was stirred for 10 minutes, further stirred at room temperature for 30 minutes and then ice-cooled again. A solution of 1-chloro-3-iodopropane (1.82 g) in DMF (5 mL) was added to the reaction mixture, and the reaction solution was stirred at room temperature for three hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The resulting organic layer washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Hydrazine monohydrate (8 mL) was added to a solution of the resulting crude purified methyl 5-chloro-2-(2-bromo-4-fluoro)phenylpentanoate (2.75 g) in ethanol (20 mL), and the reaction solution was heated under reflux for 3.5 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Saturated sodium bicarbonate water and ethyl acetate and were added to the residue, and the organic layer was separated. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-methanol system) to obtain 1.157 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1/[CH:29]=[CH:30]/[C:31](O)=[O:32]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:31](=[O:32])/[CH:30]=[CH:29]/[C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=3[O:20][CH3:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COc1cccc(/C=C/C(=O)O)c1OC
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: COc1cccc(/C=C/C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)c2)c1OC

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2,3-dimethoxy-phenyl)-acrylic acid.