Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)([OH:11])=[O:10].[NH:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1>C(O)(=O)CC>[C:2]1([C:1]2[C:21]3[CH:22]=[CH:23][C:24]([N:20]=3)=[C:16]([C:15]3[CH:18]=[CH:19][C:12]([C:9]([OH:11])=[O:10])=[CH:13][CH:14]=3)[C:24]3[NH:20][C:21]([C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:24]4[N:20]=[C:21]([C:1]([C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[C:24]5[NH:20][C:21]=2[CH:22]=[CH:23]5)[CH:22]=[CH:23]4)=[CH:22][CH:23]=3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: c1cc[nH]c1
Solvent: CCC(=O)O
Product: O=C(O)c1ccc(-c2c3nc(c(-c4ccccc4)c4ccc([nH]4)c(-c4ccccc4)c4nc(c(-c5ccccc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Temperature: 25 °C

Procedure:
15.2 ml of benzaldehyde and 7.51 g of 4-carboxybenzaldehyde are dissolved in 746 ml of boiling propionic acid, treated dropwise with 13.9 ml of pyrrole, the mixture obtained is subsequently heated under reflux for about 30 minutes and then left to cool to room temperature. The porphine derivative is precipitated by the addition of 0.5 l of water. The filtered-off crude product is pre-purified by two-fold column chromatography on 1.2 kg of silica gel, in each case the elution being carried out with the following solvents in sequence: chloroform/cyclohexane (1:1), chloroform/ethyl acetate (3:2) and (1:1), ethyl acetate and ethyl acetate which contains 2% methanol. For the further purification, the product is suspended in a small amount of methanol and filtered off. This procedure is repeated until the filtrate is only faintly coloured. The thus-obtained product is then chromatographed on a silica gel column using chloroform, chloroform/ethyl acetate (1:1) and ethyl acetate as the elution agent. There are obtained 1.7 g of 4-(10,15,20-triphenyl-21H,23H-porphin- 5-yl)benzoic acid as violet crystals.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH3:31])(=[O:30])=[O:29])(=[O:21])=[O:20])C(OC(C)(C)C)=O)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[S:39]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:31][S:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([NH:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[C:41]1[CH:42]=[CH:43][S:39][CH:40]=1)(=[O:21])=[O:20])(=[O:30])=[O:29]
Reactant: OB(O)c1ccsc1
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3ccsc3)c2c1
Yield: 16.9 %

Procedure:
2-Methylsulfonyl-N-(3-thiophen-3-yl-1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 47 from 1 g of tert-butyl 3-iodo-5-(N-tert-butoxycarbonyl-2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 376 mg of 3-thiopheneboronic acid, 40 ml of dimethylformamide, 3.2 ml of a saturated aqueous sodium hydrogencarbonate solution and 42.7 mg of tetrakis(triphenylphosphine)palladium[0]. 108 mg of 2-methylsulfonyl-N-(3-thiophen-3-yl-1H-indazol-5-yl)benzenesulfonamide are thus obtained in the form of a white solid melting at 249° C. (analysis C18H15N3O4S3 % calculated C, 49.87; H, 3.49; N, 9.69; O, 14.76; S, 22.19. % found C, 49.76; H, 3.53; N, 10.03; S, 21.78).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:16]2[N:20]([CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:19]([CH3:28])=[C:18]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:17]=2)[CH:7]=[C:8]2[C:13]3([CH2:15][CH2:14]3)[CH2:12][CH2:11][O:10][C:9]=12)(=[O:3])[CH3:2].[CH3:33][Mg+].[Br-]>C1COCC1>[CH:22]1([CH2:21][N:20]2[C:16]([C:6]3[CH:7]=[C:8]4[C:13]5([CH2:15][CH2:14]5)[CH2:12][CH2:11][O:10][C:9]4=[C:4]([C:1]([OH:3])([CH3:33])[CH3:2])[CH:5]=3)=[CH:17][C:18]([S:29]([NH2:32])(=[O:30])=[O:31])=[C:19]2[CH3:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(=O)c1cc(-c2cc(S(N)(=O)=O)c(C)n2CC2CCCCC2)cc2c1OCCC21CC1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1c(S(N)(=O)=O)cc(-c2cc(C(C)(C)O)c3c(c2)C2(CCO3)CC2)n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.4 %

Procedure:
To a stirred solution of compound 36 (86 mg, 0.19 mmol) in dry THF (2 mL) was added CH3MgBr (3M, 70 μL, 0.21 mmol) and the mixture was stirred at rt for 2 h, quenched with aq. NH4Cl at 0° C. and extracted with EA. The organic layer was concentrated and purified by CC (PE/EE=4/1) to give compound 37 (21 mg, 24%) as a colorless solid. 1H-NMR (CDCl3+D2O, 400 MHz) δ: 0.67-0.72 (2H, m), 0.88-0.91 (2H, m), 1.01-1.05 (5H, m), 1.36-1.44 (3H, m), 1.60 (9H, m), 1.93-1.95 (2H, t, J=10.4 Hz), 2.52 (3H, s), 3.63-3.65 (2H, d, J=7.2 Hz), 4.43-4.45 (2H, t, J=10.4 Hz), 6.35 (1H, s), 6.49 (1H, s), 6.98 (1H, s). MS Calcd.: 472; MS Found: 473 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:21]([OH:23])=O)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C(=O)CCC1=O.[CH2:44]([NH2:47])[CH2:45][NH2:46]>CN(C)C=O.C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:21]([NH:46][CH2:45][CH2:44][NH2:47])=[O:23])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Reactant: NCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NCCNC(=O)c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
80 mg (0.24 mmol) of N-[3-chloro-phenyl]-4-(2-carboxy-4-pyridyl)-2-pyrimidineamine, 70.8 mg (0.36 mmol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride and 42 mg (0.36 mmol) of N-hydroxysuccinimide are dissolved in 3 ml of dimethylformamide and stirred for 2.5 h at RT. The reaction mixture is then added dropwise at 0° within a period of 30 minutes to a solution of 0.77 ml (11.8 mmol) of ethylenediamine in 2 ml of DMF. After stirring for 14 h at RT, the reaction mixture is poured into 50 ml of ethyl acetate and extracted with 30 ml of water. The organic phase is dried (sodium sulfate) and concentrated. Crystallisation from isopropanol/ethanolic hydrochloric acid gives N-[3-chloro-phenyl]-4-[2-(N-{2-amino-ethyl}-aminocarbonyl)-4-pyridyl]-2-pyrimidineamine hydrochloride; m.p. 161°-163°, FAB-MS: 369 (M+ +H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:13]=1[CH2:14][NH2:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.C(O)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:15][CH2:14][C:13]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:12]=2[O:11][CH3:10])[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=Cc1cccc(Br)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(CNCc2cccc(Br)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Bromopicoline aldehyde (0.520 g) and 2,4-dimethoxybenzylamine (0.504 mL) were dissolved in tetrahydrofuran (25 mL), acetic acid (0.176 mL) was added thereto, and the mixture was stirred at room temperature for 1 hr. Sodium triacetoxyborohydride (889 mg) was added thereto, and the mixture was stirred in a second straight night at room temperature. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The 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 (930 mg).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[CH2:16]([CH:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([CH3:25])[C:19]1=[O:26])[CH3:17].Cl[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35]>CCCCCC.O1CCCC1.O>[CH2:16]([C:18]1([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([O:34][CH3:35])[CH:28]=2)[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([CH3:25])[C:19]1=[O:26])[CH3:17]
Reactant: COc1ccccc1Cl
Reactant: CCC1CCCCN(C)C1=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC1(c2cccc(OC)c2)CCCCN(C)C1=O
Temperature: 25 °C

Procedure:
2,2,6,6-tetramethylpiperidine (8.48 g) was added dropwise with cooling and stirring under nitrogen to a solution of butyl lithium (0.05 mole) in hexane (31.25 ml) and tetrahydrofuran (15 ml). 3-Ethylhexahydro-1-methyl-2H-azepin-2-one (7.75 g) in dry tetrahydrofuran (20 ml) was added. On completion of this addition a further portion of butyl lithium (0.06 mole) in hexane (37.5 ml) was added with cooling. After ten minutes o-chloroanisole (8.54 g) was added dropwise in tetrahydrofuran (20 ml). The reaction was then stirred at ambient temperature for c.a. 20 hours. The reaction mixture was poured into water, and the tetrahydrofuran removed under reduced pressure. After acidifying with 5 M hydrochloric acid the mixture was extracted with toluene. Toluene extracts were washed with water, dried (MgSO4) and after removal of the solvent the product distilled affording 2.37 g, b.p. 150°-170° C. at 0.6 mm. Corrected by purity by g.l.c. assay, the yield of the title compound was 15.8%.
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:8]=1)[CH3:5])([OH:3])=O.[C:19](N1C=CN=C1)([N:21]1C=CN=C1)=O.CN>>[Cl:18][C:14]1[CH:13]=[C:12]([N:9]2[CH:10]=[N:11][C:7]([O:6][CH:4]([C:1]([NH:21][CH3:19])=[O:3])[CH3:5])=[N:8]2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(Oc1ncn(-c2cccc(Cl)c2)n1)C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Product: CNC(=O)C(C)Oc1ncn(-c2cccc(Cl)c2)n1
Yield: 73.1 %

Procedure:
The process was carried out as was Example 45, starting with 3 g of the compound of Example 25, 2.7 g of carbonyldiimidazole, and 3 ml of 40% aqueous methylamine. The product was recrystallized from toluene to obtain 2.3 g of the desired product, m.p. 120°-122°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[N:13][S:12][C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].CC1C=C(C)N=C(C)C=1.CC1C([IH+:39])=C(C)N=C(C)C=1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[N:13][S:12][C:9]2=[C:10]([I:39])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2snc(-c3ccc(F)cc3)c2c1O
Reactant: Cc1cc(C)c([IH+])c(C)n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)c1nc(I)c2snc(-c3ccc(F)cc3)c2c1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.8 %

Procedure:
To a solution of 3-(4-fluoro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (400 mg, 1.25 mmol) in CH2Cl2 (12.5 mL) was added bis(2,4,6-trimethylpyridine)iodine(I) hexafluorophosphate (1.29 g, 2.51 mmol). The reaction mixture was allowed to stir at r.t. for 20 h. Then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel. Elution with 0-20% EtOAc/CH2Cl2, gave the title product (382 mg) as a yellow solid: MS (m/z) 442.9 (M−1).
Reaction SMILES: [C:1]([C:10]1[C:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:12][NH:13][CH:14]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:21]SC1C(C2C=NC=CC=2)=NNC=1>>[C:1]([C:10]1[C:11]([C:15]2[CH2:16][N:17]([CH3:21])[CH2:18][CH2:19][CH:20]=2)=[N:12][NH:13][CH:14]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCC#Cc1c[nH]nc1-c1cccnc1
Reactant: CSc1c[nH]nc1-c1cccnc1
Product: CCCCCCCC#Cc1c[nH]nc1C1=CCCN(C)C1
Yield: 79 %

Procedure:
Compound 44C was converted to compound 45C, using the methodology described for the conversion of 21A to 22A (see Scheme 3). Yield: 79% (amorphous). LCMS (method A); Rt: 2.17 min, ([M+H]+=286). 1H-NMR (400 MHz, CDCl3): δ 7.57 (s, 1H), 6.74-6.69 (bs, 1H), 3.40-3.36 (m, 2H), 2.58 (bt, J=7 Hz, 2H), 2.44 (s, 3H), 2.43-2.36 (m, 2H), 1.63-1.55 (m, 2H), 1.48-1.39 (m, 2H), 1.36-1.23 (m, 6H), 0.89 (t, J=7 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]([CH2:13][CH2:14][CH3:15])=[CH2:12])[O:9][CH:8]=[N:7]1)=[O:5])[CH3:2].C(OC(=O)C(NC=O)C(O)C(CCC)=C)C.S(Br)(Br)=O.[P:36]([O:41]C)([O:39][CH3:40])[O:37][CH3:38]>>[CH2:1]([O:3][C:4](=[O:5])[CH:6]([NH:7][CH:8]=[O:9])/[CH:10]=[C:11](\[CH2:13][CH2:14][CH3:15])/[CH2:12][P:36]([O:39][CH3:40])([O:37][CH3:38])=[O:41])[CH3:2]
Reactant: COP(OC)OC
Reactant: C=C(CCC)C1OC=NC1C(=O)OCC
Agent: C=C(CCC)C(O)C(NC=O)C(=O)OCC
Agent: O=S(Br)Br
Product: CCC/C(=C\C(NC=O)C(=O)OCC)CP(=O)(OC)OC

Procedure:
The starting material is manufactured as follows: Reaction of 2-methylene-pentanal with isocyanoacetic acid ethyl ester analogously to Example 1 yields 5-(penten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester. By hydrolysis of the 5-(penten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester in a manner analogous to that described in Example 15, 2-formylamino-3-hydroxy-4-propyl-4-pentenoic acid ethyl ester is obtained.Reaction of the 2-formylamino-3-hydroxy-4-propyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with trimethyl phosphite in a manner analogous to that described in Example 1 yields E-2-formylamino-4-propyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15](Cl)=[O:16])[CH:13]=3)[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[N:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:15]([C:12]2[CH:13]=[C:14]3[C:9]([C:8]([CH2:18][CH3:19])=[N:7][N:6]3[CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:10][CH:11]=2)=[O:16])=[CH:23][CH:24]=1
Reactant: NCc1ccncc1
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)Cl)ccc12
Product: CCc1nn(C2CCCC2)c2cc(C(=O)NCc3ccncc3)ccc12
Yield: 20.3 %

Procedure:
This compound was prepared according to the method of Example 15, using 51 mg (0.184 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carbonyl chloride and 20 μL (0.193 mmol, 1.05 equiv) 4-(aminomethyl)pyridine as starting materials, to give 13 mg (20%) of white crystals: mp 147-149° C.; HRMS calcd for C21H24N4O+H: 349.2028. Found: 349.2031.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]3[CH2:15][O:14]3)=[CH:7][C:5]=2[N:6]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(O)C>[OH:14][C@@H:13]([CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=1)[CH2:15][N:19]1[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]1
Reactant: Cc1nc2cc(OCC3CO3)ccc2s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCO
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(C(=O)OC(C)(C)C)CC3)ccc2s1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To 2-methyl-5-(oxiran-2-ylmethoxy)benzothiazole (2.21 g, 10 mmol), a compound of formula (3), was added tert-butyl 1-piperazinecarboxylate (1.86 g, 10 mmol), a compound of formula (4), and ethanol (30 ml). The resulting solution was heated to 85° C. and stirred for 8 hours. The solvent was evaporated under reduced pressure, and the residue was chromatographed on silica gel, eluting with 5% methanol/methylene chloride, to yield tert-butyl 4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinecarboxylate as a clear oil.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][C:8](=[O:14])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[C:4]([C:5]=32)[N:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[NH2:20][C:21]1[CH:22]=[C:23]2[CH2:38][C:28]3([C:36]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[CH2:27][C:24]2=[N:25][CH:26]=1.C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[O:1]=[C:2]1[N:6]2[CH2:7][C:8](=[O:14])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[C:4]([C:5]=32)[N:3]1[CH2:15][C:16]([NH:20][C:21]1[CH:22]=[C:23]2[CH2:38][C:28]3([C:36]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[CH2:27][C:24]2=[N:25][CH:26]=1)=[O:18]
Reactant: O=C([O-])Cn1c(=O)n2c3c(cccc31)NC(=O)C2
Reactant: Nc1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Cn1c(=O)n2c3c(cccc31)NC(=O)C2)Nc1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of sodium (2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)acetate (62 mg, 0.23 mmol, described in Intermediate 9), (±)-3-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (71 mg, 0.28 mmol, described in Intermediate 4), N,N,N′,N′-bis(tetramethylene)chloroformamidinium hexafluorophosphate (153 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) in THF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].O[C:23]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:24]=1[C:25]([O:27][CH2:28][C@@H:29]([CH3:32])[CH2:30][CH3:31])=[O:26].[CH2:38](Cl)[CH2:39]Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][C:23]2[CH:36]=[CH:35][C:34]([O:37][C:17](=[O:18])[C:16]3[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:1](=[O:4])[CH:38]=[CH2:39])=[CH:21][CH:20]=3)=[CH:33][C:24]=2[C:25]([O:27][CH2:28][C@@H:29]([CH3:32])[CH2:30][CH3:31])=[O:26])=[O:18])=[CH:20][CH:21]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: ClCCCl
Reactant: CC[C@H](C)COC(=O)c1cc(O)ccc1O
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(OC(=O)c3ccc(OCCCCCCOC(=O)C=C)cc3)c(C(=O)OC[C@@H](C)CC)c2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture consisting of 4-{[6-(acryloyloxy)hexyl]oxy}benzoic acid (2.92 g), (2S)-2-methylbutyl 2,5-dihydroxybenzoate (1.1 g), DMAP (0.24 g) and EDC (2 g) in CH2Cl2 (30 ml) was stirred for 6 h at room temperature. The yellowish reaction mixture was then evaporated to dryness and the obtained pasty residue was purified by column chromatography over silica to give nearly pure material as transparent oil which becomes pasty upon standing for about 24 h.
Reaction SMILES: COC1C=CC(C[O:8][N:9]([CH2:20][CH2:21][CH2:22][P:23](=[O:34])([O:29]CCCC)[O:24]CCCC)[S:10]([C:13]2[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=CC=1.Cl.C(O)(=[O:40])C.C>O>[C:16]1([CH3:17])[CH:15]=[CH:14][C:13]([S:10]([OH:11])(=[O:12])=[O:40])=[CH:19][CH:18]=1.[OH:8][NH:9][CH2:20][CH2:21][CH2:22][P:23](=[O:24])([OH:34])[OH:29]
Reactant: CC(=O)O
Reactant: CCCCOP(=O)(CCCN(OCc1ccc(OC)cc1)S(=O)(=O)c1ccc(C)cc1)OCCCC
Agent: Cl
Solvent: O
Product: Cc1ccc(S(=O)(=O)O)cc1
Product: O=P(O)(O)CCCNO
Reaction time: 20 h

Procedure:
A mixture of dibutyl 3-[N-(p-methoxybenzyloxy)-N- tosylamino]propylphosphonate (28.4 g), 6N hydrochloric acid (280 ml) and acetic acid (280 ml) was refluxed with stirring for 20 hours. The resultant mixture was concentrated under reduced pressure to give a residue, and then water was added thereto. The mixture was treated with an activated charcoal, whereafter the mixture was concentrated under reduced pressure to give an oily residue. The oily residue was washed with ether and dried under reduced pressure. The solid was washed with acetonitrile and ethyl ether to give p-toluenesulfonic acid salt of 3-(N-hydroxyamino)propylphosphonic acid (12.4 g) in the form of crystals. MP: 129°~135° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].N1C=CN=C1.[C:13]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[Si:17]([O:5][CH2:4][C:3]([CH3:7])([CH3:6])[CH2:2][NH2:1])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(CN)CO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(CN)CO[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
2 g of 3-amino2,2-dimethylpropan-1-ol (19.39 mmol) are placed in 40 ml of DCM. 2.56 g of imidazole (38.77 mmol) are added and the solution is cooled to +4° C. in an ice bath, followed by dropwise addition of 3.36 ml of tert-butyl(chloro)dimethylsilane (19.39 mmol). The medium is stirred for 30 minutes at +4° C., and the ice bath is then removed and the mixture is stirred at room temperature for 18 hours. The medium is then washed with water, and then with brine. The organic phase is dried over Na2SO4, filtered and concentrated to give 4.02 g of 3-(tert-butyldimethylsilanyloxy)-2,2-dimethylpropylamine.
Reaction SMILES: C[Si](C)(C)C(=[C:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[C:13]1C=CN=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])C#CC.O.[F-].[CH2:26]([N+:30](CCCC)(CCCC)CCCC)[CH2:27]CC.O.[CH2:44]1[CH2:48]OC[CH2:45]1>>[N+:19]([C:14]1[C:13]([N:8]2[CH2:7][CH2:12][C:11](=[CH:48][C:44]#[CH:45])[CH2:10][CH2:9]2)=[N:30][CH:26]=[CH:27][CH:15]=1)([O-:21])=[O:20]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C1CCOC1
Reactant: CC#CC(=C1CCCCN1c1ccncc1[N+](=O)[O-])[Si](C)(C)C
Agent: [F-]
Solvent: O
Product: C#CC=C1CCN(c2ncccc2[N+](=O)[O-])CC1

Procedure:
A solution of Compound 1b (0.57 g, 1.81 mmol), tetra-n-butylammonium fluoride hydrate (0.57 g, 2.03 mmol) in 38 mL of THF was stirred at r.t. for 2 h. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography (EtOAc—Petroleum Ether 1:9) giving the title product (0.21 g).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32].CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:2]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[N:7][CH:6]=[N:5][C:4]=3[O:8][C:9]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:13]=1
Reactant: NCCCCCC(=O)O
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCC(=O)O)c23)cc1

Procedure:
Stir 1.0 g (3.0 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine, 0.78 g (5.94 mmol) 6-aminohexanoic acid and 1.5 ml DIEA in 10 ml DMF overnight at 120° C. Add the reaction mixture to water and extract three times with ethyl acetate. Combine the organic phases and wash with saturated sodium chloride solution, dry over magnesium sulphate and concentrate by vacuum evaporation. Chromatograph the residue on silica gel (solvent: cyclohexane/ethyl acetate 2:1→1:2). 560 mg (43.7% of theor.) of the target compound is obtained.