Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][C@@H:18]3[CH2:27][CH3:28])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:29]([O:32][CH2:33][C:34]1[C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][C:37]([F:49])=[CH:36][C:35]=1[N:50]1[CH2:62][CH2:61][N:53]2[C:54]3[CH2:55][CH2:56][CH2:57][CH2:58][C:59]=3[CH:60]=[C:52]2[C:51]1=[O:63])(=[O:31])[CH3:30].CC([O-])=O.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[C:29]([O:32][CH2:33][C:34]1[C:35]([N:50]2[CH2:62][CH2:61][N:53]3[C:54]4[CH2:55][CH2:56][CH2:57][CH2:58][C:59]=4[CH:60]=[C:52]3[C:51]2=[O:63])=[CH:36][C:37]([F:49])=[CH:38][C:39]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][C@@H:18]3[CH2:27][CH3:28])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(N4CCn5c(cc6c5CCCC6)C4=O)c3COC(C)=O)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 67.5 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with (S)-5-bromo-3-(5-(2-ethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one (203 mg, 0.45 mmol), 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (216 mg, 0.45 mmol), Pd(dppf)Cl2 (18 mg, 0.0225 mmol), NaOAc (74 mg, 0.90 mmol), K3PO4 (191 mg, 0.90 mmol), and acetonitrile (3 mL). See FIG. 5. After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 1 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (25:1, UV) to afford 105a (220 mg, 87%) as a brown solid. LCMS: [M+H]+ 724
Reaction SMILES: [S:1]([C:4]1[NH:5][CH:6]=[CH:7][CH:8]=1)[C:2]#N.[Br:9][CH2:10]CBr.O=O.C[O-].[Na+]>O.CCOCC.CO>[Br:9][CH2:10][CH2:2][S:1][C:4]1[NH:5][CH:6]=[CH:7][CH:8]=1
Reactant: N#CSc1ccc[nH]1
Reactant: BrCCBr
Agent: C[O-]
Agent: O=O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: BrCCSc1ccc[nH]1

Procedure:
A stirred mixture of 2-thiocyano-pyrrole (8.7 g, 0.07 m; J. Org. Chem., 22 (1957) 1500), 1,2-dibromoethane (155 ml) and methanol (140 ml) was ice-bath cooled in an oxygen-free atmosphere, and sodium methoxide (9.5 g, 0.17 m) added. The resultant highly-colored mixture was allowed to stir cold and then at ambient temperature overnight. The resultant mixture was distributed between ether and water (500 ml), the ether extracts washed, dried and concentrated to a residue which on chromatography on silica gel using a hexane and then 20% ethylacetate/hexane system as eluant yielded 2(2-bromoethylthio)pyrrole (4.6 g). This was dissolved in dry N,N-dimethylformamide (80 ml), covered with an oxygen-free atmosphere, ice-bath cooled, and reacted with sodium hydride (1.2 g of 60% dispersion in mineral oil). After stirring overnight at ambient temperatures the reaction mixture was partitioned between ether and water, the ether layer washed with water until the dimethylformamide was removed, dried and concentrated to 2,3-dihydropyrrolo(2,1-b)thiazole.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH3:13][N:14](C)[CH:15]=[O:16]>>[C:1]1(=[O:11])[N:5]([CH2:3][CH:7]2[O:16][C:15]3=[N:14][CH:13]=[CH:1][CH:2]=[C:10]3[CH2:9][CH2:8]2)[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN(C)C=O
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1CC1CCc2cccnc2O1
Reaction time: 20 h

Procedure:
15.0 g (70 mmol) of a mixture of the compounds from Example V and VI (ratio 12:5) are heated at 100° C. with 16.0 g (86 mmol) of potassium phthalimide in 150 ml of dimethylformamide under nitrogen with stirring for 20 hours. Dimethylformamide is then distilled off in vacuo and the residue is partitioned between dichloromethane and water. 24.0 g of crystals having a melting range of 152°-158° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:11]([CH3:23])=[C:12]([C:14]([NH:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[N:13]=1.C(N(CC)CC)C.[CH3:38][C:39]([CH3:47])([CH3:46])[CH2:40][CH2:41][S:42](Cl)(=[O:44])=[O:43].O>ClCCl>[CH3:38][C:39]([CH3:47])([CH3:46])[CH2:40][CH2:41][S:42]([O:30][C:27]1[CH:26]=[CH:25][C:24]([N:10]2[C:11]([CH3:23])=[C:12]([C:14]([NH:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:15])[N:13]=[C:9]2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:29][CH:28]=1)(=[O:44])=[O:43]
Reactant: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(O)cc1
Reactant: CC(C)(C)CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(OS(=O)(=O)CCC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
2-(2,4-Dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-N-piperidin-1-yl-1H-imidazole-4-carboxamide, prepared as described in Ex. 2, Step 1 (50 mg, 0.11 mmol) was dissolved in dichloromethane (3.0 ml), cooled to 0° C. and triethylamine (20 μl, 0.13 mmol) was added to the mixture. The resulting mixture was cooled to −78° C. and 3,3-dimethylbutane-1-sulfonyl chloride (25 mg, 0.13 mmol) was carefully added. The reaction was stirred at −78° C. for 2 h. Water was added to the reaction, the product extracted with dichloromethane and dried. The solvent was removed under reduced pressure and separation by preparatory HPLC gave the title compound (46 mg, 69%) as a solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([C:4]2[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)[O:15][CH2:14][CH2:13][O:3]1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(c2ccc([N+](=O)[O-])cc2)OCCO1

Procedure:
33.03 g (200 mmol) of 4-nitroacetophenone, 12.30 mL (220 mmol) of ethylene glycol, and 1.00 g (5 mmol) of p-toluenesulfonic acid are placed in 250 mL of toluene, then refluxed for 16 hours using the water separator. Then the reaction mixture is cooled and extracted with water. The organic phase is dried and evaporated to dryness. The residue is extracted with diisopropyl ether and suction filtered. Yield: 34.45 g (82%).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[C:12]([O:13][CH2:14][CH2:15][F:16])=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].OC1C(O)=CC=CC=1C=O.[BH4-].[Na+]>C(O)C>[F:16][CH2:15][CH2:14][O:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:6]([CH2:7][OH:8])[C:5]=1[O:4][CH2:3][CH2:2][F:1]
Reactant: O=Cc1cccc(OCCF)c1OCCF
Agent: O=Cc1cccc(O)c1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cccc(OCCF)c1OCCF
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.4 %

Procedure:
Under a dry nitrogen atmosphere a mixture of 6.0 grams (0.026 mole) of 2,3-di(2-fluoroethoxy)benzaldehyde (prepared by the method of Example 1 from 2,3-dihydroxybenzaldehyde) and 1.3 gram (0.034 mole) of sodium borohydride in 130 ml of ethanol was stirred at room temperature for approximately 18 hours. The reaction was quenched with dilute hydrochloric acid, and the mixture was extracted with diethyl ether. The extract was washed with dilute hydrochloric acid followed by an aqueous, saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 5.4 grams of 1,2-di-(2-fluoroethoxy)-3-hydroxymethylbenzene as a solid.
Reaction SMILES: F[C:2]1(F)[CH2:4][CH:3]1[CH2:5][N:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]([C:17]([O:19]CC)=[O:18])=[C:14]([CH3:16])[N:15]=2)[C:7]1=[O:22].C1(CN2CCN(C3SC(C(OCC)=O)=C(C)N=3)C2=O)CC1>>[CH:3]1([CH2:5][N:6]2[CH2:10][CH2:9][N:8]([C:11]3[S:12][C:13]([C:17]([OH:19])=[O:18])=[C:14]([CH3:16])[N:15]=3)[C:7]2=[O:22])[CH2:4][CH2:2]1
Reactant: CCOC(=O)c1sc(N2CCN(CC3CC3(F)F)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(CC3CC3)C2=O)nc1C
Product: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Yield: 82 %

Procedure:
Following the procedure as describe in Preparation 14, making variations as required to replace ethyl 2-(3-((2,2-difluorocyclopropyl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate with ethyl 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a colourless solid in 82% yield: 1H NMR (300 MHz, DMSO-d6) δ 3.96 (t, J=7.8 Hz, 2H), 3.67 (t, J=7.8 Hz, 2H), 3.06 (d, J=6.9 Hz, 2H), 2.52 (s, 3H), 0.97-0.84 (m, 1H), 0.53-0.37 (m, 2H), 0.20-0.11 (m, 2H); MS (ES+) m/z 282.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([C:27]2([O:33][CH3:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([C:27]2([O:33][CH3:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: COC1(c2ccc(I)cc2)CCOCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Product: COC(=O)C(C/C=C/c1ccc(C2(OC)CCOCC2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 79.7 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (2.11 g) was reacted with tetrahydro-4-(4-iodophenyl)-4-methoxy-2H-pyran (2.22 g) in the presence of potassium carbonate (1.45 g), palladium acetate (81.7 mg) and tris(2-methylphenyl)phosphine (106.2 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(4-methoxytetrahydropyran-4-yl)-phenyl]pent-4-enoic acid methyl ester (2.74 g). Column chromatography (silica gel, eluent: cyclohexane/chloroform=2/1→cyclohexane/ethyl acetate=10/1→cyclohexane/ethyl acetate=4/1) was used for purification.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[C:24]([C:28]5[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=5)=[N:25][NH:26][CH:27]=4)[CH:20]=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2].[CH3:35]N(C(OC)OC)C>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[C:24]([C:28]5[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=5)=[N:25][N:26]([CH3:35])[CH:27]=4)[CH:20]=[CH:19][N:18]=3)=[CH:14][CH:15]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CCN1CCN(Cc2ccc(Nc3nccc(-c4c[nH]nc4-c4ccc(C)cc4)n3)cc2)CC1
Solvent: Cc1ccccc1
Product: CCN1CCN(Cc2ccc(Nc3nccc(-c4cn(C)nc4-c4ccc(C)cc4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 61 h

Procedure:
[4-(4-Ethyl-piperazin-1-ylmethyl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine (Example 101) (165 mg; 0.364 mMol) is suspendend in toluene (3 mL) and treated with DMF-DMA (168 mg; 1.32 mMol, 187 μL) at rt. The mixture is stirred at reflux for a total of 102 h whereby additional DMF-DMA is added after 48 h (187 μL), after 61 h (187 μL) and after 82 h (374 μL). Upon completion of the reaction and cooling to rt the solvent is removed under reduced pressure. The crude product mixture is purified by reversed phase chromatography (Lichroprep® RP18 15-25 μM; eluting with 18% CH3CN (0.1% TFA)/82% H2O (0.1% TFA)). The pure fractions 27-34 are combined and evaporated. The residue is dissolved in H2O (2 mL) and neutralized with 1N NaOH. The crystalline product (free base) is filtered off, washed with H2O and dried at 60° C. to obtain the title compound as beige crystalline powder.
Reaction SMILES: C(OC(=O)CC1C=CC(Cl)=C(OC2C=CC(N)=CC=2CSC(C)C)C=1)C.C(Cl)(=O)C(C)(C)C.C([O:36][C:37](=[O:65])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([O:46][C:47]2[CH:52]=[CH:51][C:50]([NH:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])=[CH:49][C:48]=2[CH2:60][S:61][CH:62]([CH3:64])[CH3:63])[CH:40]=1)C>>[Cl:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][C:37]([OH:65])=[O:36])=[CH:40][C:41]=1[O:46][C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:56])[CH3:57])=[CH:49][C:48]=1[CH2:60][S:61][CH:62]([CH3:64])[CH3:63]
Reactant: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc(NC(=O)C(C)(C)C)cc2CSC(C)C)c1
Agent: CC(C)(C)C(=O)Cl
Agent: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc(N)cc2CSC(C)C)c1
Product: CC(C)SCc1cc(NC(=O)C(C)(C)C)ccc1Oc1cc(CC(=O)O)ccc1Cl

Procedure:
[3-(2-Bromomethyl-4-nitro-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester was treated with 2-propanethiol as described in Example 21, Step 8 to provide [4-chloro-3-(2-isopropylsulfanylmethyl-4-nitro-phenoxy)-phenyl]-acetic acid ethyl ester, which was reduced to [3-(4-amino-2-isopropylsulfanylmethyl-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester as described in Example 21, Step 9. Treatment of the amine with pivaloyl chloride as described in Example 21, Step 10 provided {4-chloro-3-[4-(2,2-dimethyl-propionylamino)-2-isopropylsulfanylmethyl-phenoxy]-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester to the acid was carried out as described in Example 21, Step 11.
Reaction SMILES: [Na].Cl[C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2.[CH2:12]([O:15]CC=C)[CH:13]=[CH2:14].[Na]>C(O)C=C>[CH2:12]([O:15][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2)[CH:13]=[CH2:14]
Reactant: Clc1ncnc2nc[nH]c12
Reactant: C=CCOCC=C
Agent: [Na]
Solvent: C=CCO
Product: C=CCOc1ncnc2nc[nH]c12
Temperature: 100 °C
Yield: 48 %

Procedure:
Sodium (2.0 g, 86.96 mmol) was added to distilled allyl alcohol (35 ml) under nitrogen. 6-Chloropurine (1.0 g, 6.47 mmol) was dissolved in distilled allyl alcohol (35 ml) and the sodium allyloxide solution (33 ml) was added. The reaction was heated to 100° C. for 20 h, under nitrogen. After cooling, neutralisation of the reaction mixture, followed by recrystallisation of the residue from water, gave a white crystalline solid (550 mg, 48%), m.p. 199-200° C.; (Found: C, 54.35; H, 4.49; N. 32.06. Calc. for C8H8N4O: C, 54.54; H, 4.58; N, 31.80%); νmax (cm−1) 3052, 2977, 2811 (NH, C—H) δH (200 MHz, d6-DMSO) 8.526 (1H, s, C(2)H or C(8)H), 8.438 (1H, s, C(2)H or C(8)H). 6.280-6.086 (1H, dddd, CH═CH2), 5.485 (1H, dd, Jgem=1.5Hz, Jtrans=17.2 Hz, ═CH2), 5.325 (1H, dd, Jgem=1.5 Hz, Jcis=10.4 Hz, ═CH2), 5.107 (2H, d, J=5.5 Hz, OCH2); m/z 176 (M+, 43%), 174 (M+, 43%), 161 (31), 147 (39), 136 ([MH—CH2CH═CH2]+, 21%), 120 ([MH—OCH2CH═CH2]+, 49%), 108 (13), 93 (37), 81 (11), 69 (32), 66 (18), 53 (26), 41 ([CH2CH═CH2]+, 63%), 28 (62);
Reaction SMILES: C([O:5][C:6](=[O:36])[C@@H:7]([NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19]([NH:21][C:22]([NH2:24])=[NH:23])=[O:20])=[CH:15][CH:16]=1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:29]([O:28][C:26]([NH:25][C@@H:7]([CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19]([NH:21][C:22]([NH2:24])=[NH:23])=[O:20])=[CH:15][CH:16]=1)=[O:11])[C:6]([OH:36])=[O:5])=[O:27])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC(=N)N)s1)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)NC(=O)CCc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)O)s1
Temperature: 25 °C
Yield: 23.6 %

Procedure:
30 mg of the product obtained in step d) were dissolved in 3 ml of dichloromethane. 0.3 ml of trifluoroacetic acid were added, and the mixture was stirred at room temperature. After 3.5 hours the solution was evaporated, the residue was dissolved in 2 ml of glacial acetic acid and again evaporated in vacuo. This procedure was repeated twice. Then the residue was triturated with diethyl ether to give a suspension which, after filtration, gave 6.3 mg of the title compound as a colourless amorphous solid.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13](O)[CH:12]=[N:11]2>P(Cl)(Cl)(Cl)=O>[Cl:2][C:13]1[CH:12]=[N:11][C:10]2[C:15](=[CH:16][C:17]([Cl:18])=[C:8]([Cl:7])[CH:9]=2)[N:14]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Oc1cnc2cc(Cl)c(Cl)cc2n1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1cnc2cc(Cl)c(Cl)cc2n1
Reaction time: 1 h

Procedure:
Phosphorus oxychloride (50 ml) and phosphorus pentachloride (10 g) were added to 6,7-dichloro-2-hydroxyquinoxaline (6.6 g) and the mixture was stirred for a period of 1 hour. The mixture was then poured onto ice and the precipitate collected by filtration to give 2,6,7-trichloroquinoxaline, mp 137° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:47]=[CH:46][C:45](C4C(C#N)=CSC=4)=[CH:44][CH:43]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19].[CH3:55][N:56]1[CH2:61][CH2:60][N:59](C2C=CC(O)=CC=2)[CH2:58][CH2:57]1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:47]=[CH:46][C:45]([N:59]4[CH2:60][CH2:61][N:56]([CH3:55])[CH2:57][CH2:58]4)=[CH:44][CH:43]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19]
Reactant: CN1CCN(c2ccc(O)cc2)CC1
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(OCCCc3sc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)cc2)CC1

Procedure:
The title compound 82 was prepared as a TFA salt in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 82A: 1H NMR (DMSO-d6): δ 12.90 (s, 1H), 9.58 (s, 1H), 8.04 (d, J=7.63 Hz, 2H), 7.80 (d, J=7.93 Hz, 2H), 7.67 (d, J=7.63 Hz, 1H), 7.35-7.50 (m, 4H), 6.90-6.92 (m, 2H), 6.82-6.85 (m, 2H), 4.83 (s, 2H), 3.91 (t, J=6.26 Hz, 2H), 3.14-3.17 (m, 2H), 3.03 (t, J=5.95 Hz, 2.82-2.86 (m, 5H), 1.94-2.00 (m, 2H). ESI (+)/MS: 669 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20]C(C)(C)C)=[O:19])=[C:16]([NH:27][C:28]([C:30]3[CH:31]=[N:32][CH:33]=[C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:35]=3)=[O:29])[CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([C:14]2[CH:26]=[CH:25][C:17]([C:18]([OH:20])=[O:19])=[C:16]([NH:27][C:28]([C:30]3[CH:31]=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:35]=3)=[O:29])[CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cncc(-c2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cncc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (5 mL) was added to the obtained tert-butyl 4-phenyl-2-(5-phenylpyridine-3-carboxamido)benzoate, followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and ethyl acetate was added to the obtained residue. The solid substance was collected by filtration to obtain 40 mg of 4-phenyl-2-(5-phenylpyridine-3-carboxamido)benzoic acid as a white solid.
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH:19]([NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:33][O:34][CH3:35])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1)=[O:20].[Br:36]N1C(=O)CCC1=O>C1C=CC=CC=1>[CH:19]([NH:21][C:22]1[S:23][C:24]([Br:36])=[C:25]([C:27](=[N:33][O:34][CH3:35])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1)=[O:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(=NOC)c1csc(NC=O)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)C(=NOC)c1nc(NC=O)sc1Br
Yield: 94.3 %

Procedure:
A small amount of benzoyl peroxide was added to a suspension of ethyl 2(2-formamidothiazol-4-yl)-2-methoxyiminoacetate (syn isomer, 7.55 g.) and N-bromosuccinimide (5.75 g.) in dry benzene (150 ml.) and refluxed under heating for an hour. After cooling, the reaction mixture was washed with water three times, dried over magnesium sulfate, treated with activated charcoal and then evaporated in vacuo. The residue was pulverized with n-hexane, and the precipitates were collected by filtration, washed with n-hexane and water successively and dried to give ethyl 2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetate (syn isomer, 9.3 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][OH:14])=[CH:5][CH:4]=1>C(Cl)Cl.[O-2].[Mn+2]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH:13]=[O:14])=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(CO)c2c1
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc2cccc(C=O)c2c1

Procedure:
19.2 g (0.1 mol) of the compound obtained in Step B are dissolved in 300 ml of CH2Cl2. Under argon, 65 g (7.5 eq) of manganese oxide are added in three stages (t═0: 25 g, t=3 h :25 g, and t=24 h: 15 g). The alcohol is totally oxidised after a further 24 hours. The mixture is then filtered over Celite in order to remove the mineral compounds, rinsed with CH2Cl2 and then filtered over silica to yield an oil which solidifies on cooling.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[C@@H:6]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:8]([C:18]([O:20][CH3:21])=[O:19])[CH2:7]1>CN(C)C=O>[N:1]([C@H:6]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:8]([C:18]([O:20][CH3:21])=[O:19])[CH2:7]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@@H]1C[C@H](Br)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 100.5 %

Procedure:
A dispersion of sodium azide (0.90 g, 13.84 mmol) and 1-(tert-butyl)-2-methyl (2S,4S)-4-bromotetrahydro-1H-1,2-pyrroledicarboxylate (4) (1.0 g, 3.24 mmol) in anhydrous dimethylformamide (32 mL) was heated for 64 h under an atmosphere of nitrogen. The mixture was cooled to room temperature, poured into ice-cold water and extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with hexane-ethyl acetate (3:1 to 1:1, v/v) to give the title azide (5) (0.88 g, 93%) as a pale yellow oil:
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:12]([C:15]1[CH:16]=[C:17]([OH:24])[CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)([O-:14])=[O:13].N1C=CC=CC=1>CC(C)=O>[C:1]([O:24][C:17]1[CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cc(O)cc([N+](=O)[O-])c1
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(C=Cc1ccccc1)Oc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
66.64 g (0.4 mole) of cinnamoyl chloride and 300 g of methyl ketone (hereinafter referred to as MEK) were placed in a reaction vessel to be stirred by heating at 60° C. under a nitrogen current. 73.64 g (0.4 mole) of 3,5-dinitrophenol, 50 g of pyridine, and 500 g of MEK were added dropwise to the above reaction vessel using a dropping funnel. After that, reflux stirring was conducted for approximately 2 hours under a nitrogen current. After the completion of the reaction, the precipitate was separated by filtration. The filtrate was concentrated until crystals separated out and poured into methanol. 90 g of light yellow colored needle-like crystals (2, 4-dinitrophenyl cinnamate) were yielded.