Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[C:16]1([NH:22]N)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)C.Cl>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:22][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)Cc1ccc(Cl)cc1
Reactant: NNc1ccccc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1[nH]c2ccccc2c1-c1ccc(Cl)cc1
Temperature: 120 °C
Yield: 11.9 %

Procedure:
A mixture of Example 52A (4.75 g, 21.0 mmol) and phenyl hydrazine (2.07 mL, 21.0 mmol) was treated with concentrated sulfuric acid (5 drops), heated to 120° C. for 15 minutes, cooled to room temperature, treated with ethanol (25 mL), treated with bubbling HCl gas for 2 minutes, and heated to reflux for 1 hour. The mixture was poured into water (30 mL) and extracted with diethyl ether. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was recrystallized from ethanol to provide 750 mg (12%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][NH2:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:13]1[N:18]=[C:17](Cl)[C:16]2[N:20]=[CH:21][N:22]([C@@H:23]3[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@H:24]3[OH:31])[C:15]=2[N:14]=1.C(N(CC)CC)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:11][NH:12][C:17]3[C:16]4[N:20]=[CH:21][N:22]([C:15]=4[N:14]=[CH:13][N:18]=3)[C@@H:23]3[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@H:24]3[OH:31])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: NCC1(c2ccc(Cl)cc2)CC1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC4(c5ccc(Cl)cc5)CC4)ncnc32)[C@H](O)[C@@H]1O
Yield: 46.6 %

Procedure:
Reaction of the above amine (1.48 g, 8 mmol) with 6-chloropurine riboside (2.09 g, 7.3 mmol) and triethylamine (1.1 mL, 8 mmol) as prepared in Example 1 and 7 gives N6-((1-(4-chlorophenyl)cyclopropyl)methyl)adenosine (1.47 g, 47%) as a cream colored solid m.p. 132°-8° C. Found: C, 56.16; H, 5.22; N, 15.54; Cl, 9.12%. C20H22N5O4Cl calculated requires: C, 55.62; H, 5.10; N, 16.22; Cl, 8.23%.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([O:33][CH3:34])[CH2:6][C:7]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C1COCC1.CCO>[Cl:32][C:27]1[CH:26]=[C:25]([C:21]2[O:22][C:23]([CH3:24])=[C:19]([CH2:18][CH2:17][O:16][C:10]3[C:11]4[CH:15]=[CH:14][S:13][C:12]=4[C:7]([CH2:6][CH:5]([O:33][CH3:34])[C:4]([OH:35])=[O:3])=[CH:8][CH:9]=3)[N:20]=2)[CH:30]=[C:29]([Cl:31])[CH:28]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3cc(Cl)cc(Cl)c3)oc2C)c2ccsc12)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(Cc1ccc(OCCc2nc(-c3cc(Cl)cc(Cl)c3)oc2C)c2ccsc12)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
0.142 g of the above prepared [rac]-3-(4-{2-[2-(3,5-dichloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-2-methoxy-propionic acid ethyl ester (0.27 mmol) was dissolved in 4 ml of THF/EtOH=1/1 and treated with 0.68 ml of 1N NaOH (2.5 eq.). The reaction mixture was stirred at ambient temperature and progress of the hydrolysis followed by TLC. After 2 h, the reaction mixture was poured onto crashed ice/HCl dil. and extracted twice with AcOEt. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated to dryness. Crystallization from AcOEt/hexane yielded finally 0.107 g of the title product as white crystals of mp. 160-61°.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11]O)=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH3:13].[NH:14]1[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH3:13]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: Cc1cc2cc(CO)ccc2n1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnn(Cc2ccc3c(c2)cc(C)n3C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (1,2-Dimethyl-1H-indol-5-yl)methanol (crude, 250 mg, 76%, 1.084 mmol), Ethyl 1H-pyrazole-4-carboxylate (266 mg, 1.898 mmol) and Triphenylphosphine (341 mg, 1.3 mmol) in toluene (10.5 ml) Diethyl azodicarboxylate (206 ul, 1.3 mmol) was added at rt. The reaction mixture was stirred at rt for 16 hours. The reaction mixture was quenched with brine and extracted twice with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash-chromatography on silica gel (60 g), gradient of cyclohexane/EA (50 ml/min.) from 100/0 (3 min.) to 70/30 (20 min.) to afford pure ethyl 1-((1,2-dimethyl-1H-indol-5-yl)methyl)-1H-pyrazole-4-carboxylate. MS (Method V) [M+H]+=298.4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:22])[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([Cl:20])=[CH:14][C:15]=3[Cl:19])[NH:10][C:9]2=[O:21])=[CH:4][CH:3]=1.[CH:23](=O)[CH3:24].[Na]>>[Cl:19][C:15]1[CH:14]=[C:13]([Cl:20])[CH:12]=[C:11]2[C:16]=1[C:17](=[O:18])[C:8]([CH3:22])([C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:23][CH3:24])=[CH:7][CH:6]=1)[C:9](=[O:21])[NH:10]2
Reactant: CC1(c2ccc(N)cc2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Reactant: CC=O
Agent: [Na]
Product: CCNc1ccc(C2(C)C(=O)Nc3cc(Cl)cc(Cl)c3C2=O)cc1
Yield: 3.9 %

Procedure:
The objective compound was prepared by the same procedure for the example 39 and 40, using a 3-(4-amino-phenyl)-5,7-dichloro-3-methyl-1H-quinoline-2,4-dione (235 mg, 0.70 mmol), acetaldehyde (148 mL, 2.10 mmol), and sodium borocyanohydride (44 mg, 0.70 mmol). After normal workup, The residue was purified by a flash column chromatography (n-hexane:EtOAc=8:1) to give two separable objective chemical compounds of 5,7-dichloro-3-methyl-3-(4-ethylamino-phenyl)-1H-quinoline-2,4-dione (10 mg, 4%, yellow solid) and 5,7-dichloro-3-(4-diethylamino-phenyl)-3-methyl-1H-quinoline-2,4-dione (220 mg, 87%, pale yellow solid:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][C:12]([CH:23]=[CH:24][C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)=[CH:13]3)[CH2:4][CH2:3]1.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][C:12]([CH2:23][CH2:24][C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)=[CH:13]3)[CH2:4][CH2:3]1.[C:30]([O-:35])(=[O:34])[C:31]([O-:33])=[O:32]
Reactant: O=C(O)C(=O)O
Reactant: CN1CCC(OC2c3ccccc3CCn3cc(C=Cc4cccs4)nc32)CC1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: CN1CCC(OC2c3ccccc3CCn3cc(CCc4cccs4)nc32)CC1
Product: O=C([O-])C(=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-methylpiperidin-4-yloxy)-2-(2-thiophen-2-ylvinyl)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 111) (100 mg, 0.247 mmole) in MeOH (10 mL) is added Pd—BaSO4 (100 mg). The flask is evacuated and filled with hydrogen (balloon). The reaction mixture is stirred overnight at room temperature. The mixture is filtered over celite, the cake is washed with MeOH and the filtrate is concentrated under reduced pressure. The residue is dissolved in acetone (1 mL) and oxalic acid (1 equivalent) is added. Acetone is removed under reduced pressure to afford 4-(1-methylpiperidin-4-yloxy)-2-(2-thiophen-2-ylethyl)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene as an oxalate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:6][CH:7]=1.[C:29]([CH2:33][C:34](OC)=[O:35])(=O)[CH2:30][CH3:31].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Si:12]([O:11][CH2:10][CH2:9][O:8][C:5]1[N:6]=[C:7]2[C:2](=[CH:3][CH:4]=1)[NH:1][C:29]([CH2:30][CH3:31])=[CH:33][C:34]2=[O:35])([C:25]([CH3:28])([CH3:27])[CH3:26])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCC(=O)CC(=O)OC
Reactant: CC(C)(C)[Si](OCCOc1ccc(N)cn1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCc1cc(=O)c2nc(OCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc2[nH]1
Yield: 62 %

Procedure:
A solution of compound C (10 g), methyl propionylacetate (11.5 g) and p-toluenesulphonic acid (0.1 g) in benzene (40 ml) was heated under reflux with azeotropic removal of water for 20 hours. Volatile material was removed by evaporation and the residue added to a refluxing eutectic mixture of 26.5% v/v diphenyl and 73.5% v/v diphenyl oxide (30 ml). The solution was heated under reflux for 1 hour, cooled and diluted with hexane (100 ml). The precipitated solid was filtered off and triturated with hot methanol (100 ml) to give 2-ethyl-6-[2-(trimethylsilyl)ethoxy]-1,5-naphthyridin-4-(1H)-one (D) (in 62% yield) as a white solid, m.p. 193° C.; NMR: -0.1(s,9H), 0.85(t,2H), 1.3(t,3H), 2.8(q,2H), 4.1(t,2H), 6.55(s,1H), 6.9(d,1H), 8.2(d,1H).
Reaction SMILES: [CH:1]1([C:4]2[N:8](CC3C=CC=CC=3F)[N:7]=[C:6]([C:17]3[N:22]=[C:21]([NH:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[C:20]([O:30][CH3:31])=[CH:19][N:18]=3)[C:5]=2[CH3:32])[CH2:3][CH2:2]1.CC([O-])(C)C.[K+].C1COCC1>CS(C)=O.CC(O)(C)C>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([C:17]3[N:22]=[C:21]([NH:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[C:20]([O:30][CH3:31])=[CH:19][N:18]=3)[C:5]=2[CH3:32])[CH2:3][CH2:2]1
Reactant: COc1cnc(-c2nn(Cc3ccccc3F)c(C3CC3)c2C)nc1Nc1ccncc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Product: COc1cnc(-c2n[nH]c(C3CC3)c2C)nc1Nc1ccncc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
410 mg of 2-[5-cyclopropyl-1-(2-fluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine 2-1-10 (0.952 mmol, 1.0 eq.) were dissolved in 1.1 mL of dry dimethyl sulfoxide and 1.4 mL of dry 2-methylpropan-2-ol. 6.56 mL of 1M potassium 2-methylpropan-2-olate in THF (6.56 mmol, 6.9 eq.) were added. The mixture was flushed three times with oxygen and stirred for 5 hours at rt. Then the reaction mixture was partitioned between aqueous saturated ammonium chloride solution and ethyl acetate. The separated aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The purification of the residue by flash chromatography provided 200 mg (0.62 mmol, 65.1%) of analytically pure target compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[OH2:12].[O-:13][Mn](=O)(=O)=O.[K+].C([O-])(O)=O.[Na+]>C(O)(=O)C.CC(C)=O>[OH:12][CH2:3][C:2](=[O:13])[CH2:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Reactant: C=CCc1ccc(OC)cc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(CC(=O)CO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Allylanisole (98%; 3.0 g; 19.86 mmol) was dissolved in glacial acetic acid (180 ml), water (180 ml) and acetone (180 ml). KMnO4 (4.7 g; 29.79 mmol) was added over the course of 1 h. The mixture was then stirred at (RT) for 1 h. It was then decolorized with saturated NaHCO3 solution. The reaction volume was reduced in a rotary evaporator. This was followed by extraction with CH2Cl2, washing of the organic phase with water and drying over Na2SO4. The solvent was then removed in a rotary evaporator. The oily residue was purified by column chromatography (SiO2; EtOAc/n-heptane 1:2). 1-Hydroxy-3-(4-methoxyphenyl)propan-2-one was obtained as a white crystalline powder. MS: 81.20 (M+H); Rt: 0.83 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[C:12]([O:16][CH3:17])(=[O:15])C=C>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]/[C:12]([O:16][CH3:17])=[O:15]
Reactant: C=CC(=O)OC
Reactant: C=CCCCCCCCCCl
Solvent: ClCCl
Product: COC(=O)/C=C/CCCCCCCCCl
Reaction time: 4 h
Yield: 85 %

Procedure:
To a flame-dried round-bottomed flask, evacuated and backfilled with nitrogen (3×), was added 10-chlorodecene (1 equiv, 16 mmol, 2.79 g), methyl acrylate (25 equiv, 395 mmol, 36 mL), and CH2Cl2 (140 mL). Grubbs 2 catalyst (0.031 equiv, 0.48 mmol, 416 mg) was dissolved in CH2Cl2 (15 mL) and added to the reaction mixture in one portion. The reaction was stirred for 4 h, concentrated in vacuo, and purified by flash column chromatography (3% EtOAc/Hex) to afford (E)-methyl 11-chloroundec-2-enoate (3.14 g, 13.6 mmol, 85%). TLC Rf=0.30 (5% EtOAc/Hex); 1HNMR (300 MHz): δ 6.99 (dt, 1H, J=15.6, 7.0 Hz), 5.84 (dt, 1H, J=15.7, 1.5 Hz), 3.75 (s, 3H), 3.55 (t, 2H, J=6.8 Hz), 2.22 (qd, 2H, J=7.3, 1.4 Hz), 1.72-1.85 (m, 2H), 1.26-1.55 (10H); 13CNMR (75 MHz): δ 167.2, 149.6, 120.9, 51.4, 45.1, 32.6, 32.2, 29.2, 29.0, 28.7, 27.9, 26.8; FTIR: 2928, 2856, 1722, 1657, 1435, 1270, 1195, 1174, 1041, 979, 720 cm−1; HRMS-ESI: calc. for C12H21ClNaO2 (M+Na)+: 255.1128. found: 255.1118.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=2)=[C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:6]1(=[O:33])=[O:32])([CH3:4])([CH3:3])[CH3:2].[Li+].[I-]>N1C=CC=CC=1>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:6]1(=[O:32])=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CC(C)(C)N1C(=O)C(NCCCOc2ccc(C(=O)O)cc2)=C(c2ccccc2)S1(=O)=O
Yield: 3.4 %

Procedure:
Methyl 4-{3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propoxy}benzoate (0.90 g, 0.19 mmol) and LiI (0.382 g, 2.86 mmol) was dissolved in dry pyridine (1 mL) and heated at reflux for 4 h and then left at rt over night. The reaction mixture was purified by flash chromatography using first Hexane and EtOAc and then EtOAc and MeOH as eluant giving the title compound (0.003 g, 3.4%). 1H NMR (CD3CN): 7.98 (d, 2H), 7.56-7.48 (m, 5H), 6.90 (d, 2H), 6.02 (t, 1H), 3.90 (t, 2H), 3.12-3.08 (m, 2), 1.82-1.76 (t, 2H), 1.17 (s, 9H); Mass Spectrum: M+H+ 459.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:24][CH2:25][NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[S:37]([C:41]1[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=1)([OH:40])(=[O:39])=O.S(C1C=CC(C)=CC=1)(O)(=O)=O.S(C1C=CC(C)=CC=1)(O)(=O)=O.[NH:70]([CH2:74][CH2:75]O)[CH2:71][CH2:72]O.CO>CN(C)C=O>[CH2:3]([N:10]1[CH2:11][CH2:12][N:13]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:15])=[O:16])[CH2:75][CH2:74][N:70]([S:37]([C:41]2[CH:42]=[CH:43][C:44]([CH3:45])=[CH:46][CH:47]=2)(=[O:39])=[O:40])[CH2:71][CH2:72][N:26]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH2:25][CH2:24]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: OCCNCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)NCCN(CCNS(=O)(=O)c2ccc(C)cc2)Cc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCN(Cc3ccccc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
Into a dry flask under nitrogen was placed about 3.9 g of a 60% sodium hydride dispersion. It was washed twice with hexanes then suspended in 200 ml of dry dimethylformamide. To the mixture was added 20 g (40 mmol) of 4-benzyl-1,7-bis-(p-toluenesulfonyl)-1, 4,7-triazaheptane over 5 minutes. After the initial reaction had subsided, the mixture was heated to 110° C. for 1 hour. To the resulting hot solution was added dropwise 22.6 g (40 mmol) of diethanolamine tritosylate in 100 ml of dry dimethylformamide over 3.5 hours. After an additional 0.5 hours, the solution was allowed to cool and 20 ml of methanol was added. The volatiles were then removed on the rotary evaporator. The residue was dissolved in a mixture of 400 ml of water and 200 ml of dichloromethane. The phases were separated and the aqueous phase washed twice more with dichloromethane. The combined organic fractions were dried (magnesium sulfate), filtered, and evaporated to give a yellow oil. Crystallization was induced by the addition of about 100 ml of methanol. The mixture was kept at -5° C. overnight and the product collected by filtration. After drying, 20.4 g of a colorless solid was obtained; melting point 208°-210° C.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([SH:12])[CH:9]=[C:8]([CH3:13])[C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])(=[O:17])[CH:15]=[CH2:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH2:7][C:6]1[C:8]([CH3:13])=[CH:9][C:10]([S:12][CH2:16][CH2:15][C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:17])=[CH:11][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(S)cc(C(C)(C)C)c1N
Reactant: C=CC(=O)OCCCCCCCCCCCCCCCCCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCSc1cc(C)c(N)c(C(C)(C)C)c1
Yield: 71.9 %

Procedure:
A stirred solution of 4.5 g (23 mmol) of 2-tert-butyl-4-mercapto-6-methylaniline, 7.5 g (23 mmol) of octadecyl acrylate and 0.2 g (2 mmol) of triethylamine in 50 mL of toluene is heated at 50° C. for 18 hrs. The solvent is removed in vacuo and the residue is purified by preparative HPLC (silica gel, 9:1, heptane:ethyl acetate eluent) to give 8.6 g (72%) of the title compound as a colorless liquid.
Reaction SMILES: C(O[C:6]([N:8]([CH2:10][C:11]1[C:12]([F:35])=[C:13]([C:28]2[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=2)[N:14]([S:16]([C:19]2[CH:23]=[CH:22][S:21][C:20]=2[C:24]([O:26][CH3:27])=[O:25])(=[O:18])=[O:17])[CH:15]=1)C)=O)(C)(C)C.[C:36]([O:39]CC)(=[O:38])[CH3:37].Cl>C(OCC)(=O)C.CC(O)C>[C:24]([OH:26])(=[O:25])/[CH:20]=[CH:37]/[C:36]([OH:39])=[O:38].[F:35][C:12]1[C:11]([CH2:10][NH:8][CH3:6])=[CH:15][N:14]([S:16]([C:19]2[CH:23]=[CH:22][S:21][C:20]=2[C:24]([O:26][CH3:27])=[O:25])(=[O:18])=[O:17])[C:13]=1[C:28]1[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)c1sccc1S(=O)(=O)n1cc(CN(C)C(=O)OC(C)(C)C)c(F)c1-c1cccnc1F
Agent: Cl
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2ccsc2C(=O)OC)c(-c2cccnc2F)c1F
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of methyl 3-{[4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-3-fluoro-2-(2-fluoropyridin-3-yl)-1H-pyrrol-1-yl]sulfonyl}thiophene-2-carboxylate (155 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a free base of the title compound as a colorless oil (yield 124 mg, 98%). A solution of the obtained free base (124 mg) in ethyl acetate (2 mL) was added dropwise to a solution of fumaric acid (32.9 mg) in ethanol (2 mL) and the mixture was concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and ethanol to give the title compound as a white solid (yield 134 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:3]=1[NH:4][C:5](=[N:19]O)[CH2:6][C:7]([NH:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=1[Cl:18])=[O:8].C(OC(=O)C)(=O)C.CS(O)(=O)=O.C(N(C1CC(=O)N(C2C(Cl)=CC(Cl)=CC=2Cl)N=1)C1C=C([N+]([O-])=O)C=CC=1Cl)(=O)C.C(N(C1C=C(OC(=O)C)N(C2C(Cl)=CC(Cl)=CC=2Cl)N=1)C1C=C([N+]([O-])=O)C=CC=1Cl)(=O)C>O.C(O)(=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:3]=1[NH:4][C:5]1[CH2:6][C:7](=[O:8])[N:9]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[Cl:18])[N:19]=1
Reactant: O=C(CC(=NO)Nc1cc([N+](=O)[O-])ccc1Cl)Nc1c(Cl)cc(Cl)cc1Cl
Agent: CC(=O)N(C1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1)c1cc([N+](=O)[O-])ccc1Cl
Agent: CC(=O)Oc1cc(N(C(C)=O)c2cc([N+](=O)[O-])ccc2Cl)nn1-c1c(Cl)cc(Cl)cc1Cl
Agent: CS(=O)(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC(Nc2cc([N+](=O)[O-])ccc2Cl)=NN1c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.9 %

Procedure:
In a 5 L three-necked flask, equipped with a stirrer, a reflux condenser, and a thermometer, were placed 226 g of 3-(2-chloro-5-nitroanilino)-3-oximino-N-(2,4,6-trichlorophenyl)propionamide, 2 L of glacial acetic acid, and 500 mL of acetic anhydride. The mixture was stirred at room temperature for 18 hours. The yellow color of the slurry turned almost colorless, and thin layer chromatography (TLC) showed that the O-acetyloximino derivative was the sole product. To the reaction mixture was added 50 g of methanesulfonic acid and the mixture was heated as quickly as possible to its boiling point, 117°-120° C., and kept under reflux for 10 minutes. TLC showed that the reaction was essentially complete at that time and gave a mixture of 3-(N-acetyl-2-chloro-5-nitroanilino)-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one and 3-(N-acetyl-2-chloro-5-nitroanilino)-5-acetyloxy-1-(2,4,6-trichlorophenyl)pyrazole. At the end of the heating period, the reflux condenser was quickly replaced with a distillation head, and a water-aspirator vacuum was carefully applied to distill off the solvent as well as to cool down the mixture to 50°-60° C. The distillation of solvent was continued keeping the pot temperature at 50°-60° C. until no more distillate came off. The resulting dark greenish brown viscous oil was dissolved in 2 L of methanol with heat, and 500 mL of concentrated hydrochloric acid in water was added slowly through a dropping funnel. The mixture was heated under reflux for 1 hour, cooled to room temperature, and then allowed to stand at room temperature overnight. The solid was collected, washed with methanol and water, and dried. There was obtained 91 g (42%) of the desired 3-(2-chloro-5-nitroanilino)-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one, having a melting point of 278°-280° C.