Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([O:26][CH2:27][C:28]1[C:29]([NH:43][CH2:44][CH3:45])=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([NH:43][CH2:44][CH3:45])=[C:28]([CH2:27][O:26][CH2:24][CH3:25])[CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CCNc1ncc(B2OC(C)(C)C(C)(C)O2)cc1COCC
Product: CCNc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1COCC

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and [3-ethoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-ethyl-amine (Stage 167.1.1) to give the title compound as a white solid. (HPLC: tR 2.30 min (Method A); M+H=472 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.90 (s, 1H), 8.19-8.16 (m, 1H), 8.12 (s, 1H), 8.05-8.01 (m, 1H), 7.87-7.83 (m, 1H), 7.44-7.41 (m, 2H), 6.07 (t, 1H), 4.39 (s, 2H), 3.92 (s, 3H), 3.56 (s, 3H), 3.51 (q, 2H), 3.46-3.37 (m, 2H), 1.95 (s, 3H), 1.19 (t, 3H), 1.15 (t, 3H))
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[S:10].[NH3:11]>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH2:11])=[S:10]
Reactant: N
Reactant: Fc1ccccc1N=C=S
Solvent: CCOCC
Product: NC(=S)Nc1ccccc1F

Procedure:
To a stirred solution of 7.0 g (0.045 mol) of 2-fluorophenyl isothiocyanate in 100 ml of ether, was added ammonia gas over a three minute period. A white solid crystallized and was collected by filtration to yield 5.3 g of N-(2-fluorophenyl)thiourea, melting point 147°-148° C.
Reaction SMILES: C(OCC)(=O)C.[CH3:7][N:8]1[CH:16]=[C:15]2[C:10]([C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14]2)=[N:9]1>[Pd].C1COCC1>[CH3:7][N:8]1[CH:16]=[C:15]2[C:10]([C:11]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:12][C:13]([NH2:17])=[CH:14]2)=[N:9]1
Reactant: Cn1cc2cc([N+](=O)[O-])cc(-c3ccccc3)c2n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cc2cc(N)cc(-c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl acetate (5 mL) and THF (2 mL) were added to 2-methyl-5-nitro-7-phenyl-2H-indazole obtained in the above-described Step 2 (260 mg). Thereafter, 10% palladium on carbon (300 mg) was added under nitrogen atmosphere, and the reaction solution was stirred under hydrogen atmosphere at room temperature overnight. The insolubles were filtrated, and then the solvent was evaporated under vacuum. Subsequently, the resultant residue was purified by column chromatography on basic silica gel (developing solvent:hexane/ethyl acetate) to obtain 2-methyl-7-phenyl-2H-indazol-5-amine as brown amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.[N+:36]([C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1)([O-:38])=[O:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[N:23]([CH2:43][C:42]3[CH:45]=[CH:46][C:39]([N+:36]([O-:38])=[O:37])=[CH:40][CH:41]=3)[C:22]2=[O:35])[CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc([N+](=O)[O-])ccc5n(Cc5ccc([N+](=O)[O-])cc5)c4=O)CC3)c2cc1OC
Yield: 38 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.63 mmol) of Compound 24 was used and 4-nitrobenzyl bromide was used in place of methyl iodide. As a result, 145.0 mg (yield: 38%) of Compound 11 was obtained as pale yellow crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:18]=[C:17]4[C:13]([CH:14]=[N:15][N:16]4[CH3:19])=[C:12]([N+:20]([O-])=O)[CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1>C(OCC)(=O)C.[Pd]>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([NH2:20])[C:13]4[CH:14]=[N:15][N:16]([CH3:19])[C:17]=4[CH:18]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Cn1ncc2c([N+](=O)[O-])cc(-c3cccc4[nH]ccc34)cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1ncc2c(N)cc(-c3cccc4[nH]ccc34)cc21
Reaction time: 2 h
Yield: 157 %

Procedure:
6-(1H-Indol-4-yl)-1-methyl-4-nitro-1H-indazole (49 mg, 0.17 mmol) was dissolved in ethyl acetate (10 ml) and treated with 10% Pd/C (5 mg) then stirred under hydrogen for 2 h before stirring under nitrogen over the weekend. The reaction was filtered through a Celite cartridge, washing with ethyl acetate, then evaporated to dryness to give the title compound (70 mg) as a grey solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[C:3]=1[CH3:12].[CH3:13][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[CH3:13][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[C:3]([CH3:12])[C:4]=1[Cl:11]
Reactant: Cc1c(N)ccc(C(=O)O)c1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(N)c(C)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To a suspension of 4-amino-2-chloro-3-methyl-benzoic acid (0.64 g, 3.45 mmol) in toluene (10 mL) and methanol (10 mL) at 0° C. was added drop-wise trimethylsilyldiazomethane (3.45 mL, 2 M in hexane, 6.90 mmol). The reaction mixture was stirred at 0° C. for 30 min during which the reagents dissolved. The reaction mixture was quenched by the addition of acetic acid (1 mL) then washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo to give the title compound as a beige solid (0.66 g, 96%). 1H NMR (CDCl3, 400 MHz) 2.26 (3H, s), 3.86 (3H, s), 6.55 (1H, d, J=8.8 Hz), 7.60 (1H, d, J=8.8 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=O)=[CH:15][CH:14]=1.[K+].[Br-]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]2[NH:11][C:6]3[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=3[N:10]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(O)c1ccc(F)cc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2nc(-c3ccc(F)cc3)[nH]c2c1
Yield: 76 %

Procedure:
Prepared from 4-nitrophenylenediamine and 4-fluorobenzoic acid, in a manner similar to that of Example 9b. Yield: 76%; Rf (7/3 toluene/ethyl acetate): 0.54; IR (KBr): 3312, 1601, 1498, 1333 cm−1.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:6]([N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[N:7]1)[C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:4]=1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc2c1cnn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Nitro-1H-indazole (1.0 g, 6.13 mmol) and potassium carbonate (1.69 g, 12.3 mmol) were added to DMF and stirred at room temperature overnight. Water (50 mL) was added and the product was extracted with ethyl acetate and dried over magnesium sulfate. Crude, brown solid was purified on silica gel using hexanes/ethyl acetate. First isolated peak (730 mg) was the desired 1-benzyl regio-isomer, as confirmed by NMR.
Reaction SMILES: C([O:8][C:9](=[O:20])[NH:10][C:11]([CH3:19])([CH2:13][CH:14](O)[CH2:15][CH2:16][OH:17])[CH3:12])C1C=CC=CC=1.[H-].[Na+].C(O)(=O)C>C1COCC1>[OH:17][CH2:16][CH2:15][CH:14]1[O:20][C:9](=[O:8])[NH:10][C:11]([CH3:12])([CH3:19])[CH2:13]1
Reactant: CC(C)(CC(O)CCO)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1(C)CC(CCO)OC(=O)N1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.8 %

Procedure:
To a cold (0° C.) solution of benzyl(4,6-dihydroxy-2-methylhexan-2-yl)carbamate (460 mg, 1.6 mmol) in 30 mL of anhydrous THF was added sodium hydride (60% dispersion in oil, 128 mg, 3.2 mmol). The reaction was stirred at 0° C. for 15 min then allowed to warm to room temperature and stirred for an additional 4 hours. Acetic acid (ca 3.5 mmol) was added and the mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography (5 to 12% methanol in dichloromethane) to give a white solid (219 mg, 1.26 mmol, 77%). 1H NMR (d6-DMSO, 400 MHz) δ 1.17 (s, 6H), 1.41-1.48 (dd, J=12.3, 13.4 Hz, 1H), 1.64-1.71 (m, 2H), 1.79-1.83 (dt, J=1.8, 13.7 Hz, 1H), 3.49-3.55 (m, 2H), 4.37-4.41 m, 1H), 4.54-4.57 (t, J=5.0 Hz, 1H), 7.2 (br s, 1H). LRMS (ESI/APCI) m/z 174 [M+H]+.
Reaction SMILES: [Cl-].[CH2:2]([N+:6]1[CH:10]=[CH:9][N:8]([CH3:11])[CH:7]=1)[CH2:3][CH2:4][CH3:5].[N+:12]([O-:15])([OH:14])=[O:13]>[OH-].[K+]>[N+:12]([O-:15])([O-:14])=[O:13].[CH2:2]([N+:6]1[CH:10]=[CH:9][N:8]([CH3:11])[CH:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: O=[N+]([O-])O
Agent: CCCC[n+]1ccn(C)c1
Agent: [Cl-]
Agent: [K+]
Product: O=[N+]([O-])[O-]

Procedure:
In a third example, a three-compartment cell was constructed using a anode, a cation exchange membrane, an anion exchange membrane, and a cathode. 3 Liters of a 2 M solution of 1-butyl-3-methylimidazolium chloride was added to the first compartment, and 3 liters of a 3 M solution of HNO3 was added to the second compartment, and 0.5 liters of 1 M KOH was added to the third compartment. Electricity was applied to the cell, until the pH of the nitric acid-containing solution had risen to 7.0, whereupon the electrolysis was stopped and the second solution was removed from the cell. 85% BMIM Chloride was added continuously to the first compartment to maintain a concentration of 2 M in that compartment during the electrolysis. The second solution was passed through a weakbase ion exchange resin to remove residual nitric acid, then evaporated under rotary vacuum. The product, 1-butyl-3-methylimidazolium nitrate was obtained in 51% yield and contained 418 ppm potassium, 852 ppm chloride,and 3.24% water.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[O:13]=[C:14]1[NH:22][C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[C@@:15]21[CH2:33][C:25]1=[N:26][CH:27]=[C:28]([C:30](O)=[O:31])[CH:29]=[C:24]1[CH2:23]2.Cl.[NH2:35][C@H:36]1[CH2:41][C@@H:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[CH3:48])[C@@H:39]([CH3:49])[N:38]([CH2:50][C:51]([F:54])([F:53])[F:52])[C:37]1=[O:55].N1C2C(=NC=CC=2)N(O)N=1.C(N(CC)CC)C>CN(C=O)C>[CH3:49][C@H:39]1[N:38]([CH2:50][C:51]([F:53])([F:54])[F:52])[C:37](=[O:55])[C@@H:36]([NH:35][C:30]([C:28]2[CH:29]=[C:24]3[CH2:23][C@@:15]4([C:16]5[C:17](=[N:18][CH:19]=[CH:20][CH:21]=5)[NH:22][C:14]4=[O:13])[CH2:33][C:25]3=[N:26][CH:27]=2)=[O:31])[CH2:41][C@H:40]1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH3:48]
Reactant: Cc1ccccc1[C@@H]1C[C@H](N)C(=O)N(CC(F)(F)F)[C@@H]1C
Reactant: O=C(O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1[C@@H]1C[C@H](NC(=O)c2cnc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C(=O)N(CC(F)(F)F)[C@@H]1C
Temperature: 23 °C
Reaction time: 18 h

Procedure:
N1-((Ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.10 g, 0.53 mmol) was added to a solution of (6S)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylic acid (described in Intermediate 1) (111 mg, 0.39 mmol), (3S,5S,6R)-3-amino-6-methyl-5-(2-methylphenyl)-1-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride (described in Intermediate 6) (127 mg, 0.38 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (HOAt, 15 mg, 0.11 mmol), and triethylamine (0.16 mL, 0.91 mmol) in DMF (3 mL), and the resulting mixture was stirred at 23° C. for 18 h. The reaction mixture was then partitioned between saturated aqueous sodium bicarbonate solution (10 mL) and ethyl acetate (2×30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 1% methanol→7% methanol/dichloromethane to afford the title compound. HRMS: m/z=564.2219 (M+1), calculated m/z=564.2234 for C30H28F3N5O3. 1H NMR (500 MHz, CDCl3) δ 8.91 (s, 1H), 8.56 (s, 1H), 8.17 (dd, 1H, J=5.0, 1.5 Hz), 8.05 (s, 1H), 7.30 (d, 1H, J=5.0 Hz), 7.20 (m, 3H), 7.12 (m, 2H), 6.89 (dd, 1H, J=7.5, 5.0 Hz), 5.00-4.94 (m, 1H), 4.55 (m, 1H), 3.93-3.90 (m, 1H), 3.81-3.76 (m, 2H), 3.68 (d, 1H, J=16.5 Hz), 3.31-3.23 (m, 2H), 3.17 (d, 1H, J=16.5 Hz), 2.75-2.67 (m, 2H), 2.41 (s, 3H), 1.11 (d, 3H, J=6.5 Hz).
Reaction SMILES: BrC1C=CC2NC3N=C(C(F)(F)F)C=CC=3CN(S(C3C=CC(C(C)(C)C)=CC=3)(=O)=O)C=2C=1.[I:34][C:35]1[CH:36]=[CH:37][C:38]2[NH:44][C:43]3[N:45]=[C:46]([C:49]([F:52])([F:51])[F:50])[CH:47]=[CH:48][C:42]=3[CH2:41][NH:40][C:39]=2[CH:53]=1.[F:54][C:55]([F:67])([F:66])[C:56]1[CH:61]=[CH:60][C:59]([S:62](Cl)(=[O:64])=[O:63])=[CH:58][CH:57]=1.BrC1C=CC2NC3N=C(C(F)(F)F)C=CC=3CNC=2C=1.C(C1C=CC(S(Cl)(=O)=O)=CC=1)(C)(C)C>>[I:34][C:35]1[CH:36]=[CH:37][C:38]2[NH:44][C:43]3[N:45]=[C:46]([C:49]([F:52])([F:50])[F:51])[CH:47]=[CH:48][C:42]=3[CH2:41][N:40]([S:62]([C:59]3[CH:58]=[CH:57][C:56]([C:55]([F:54])([F:66])[F:67])=[CH:61][CH:60]=3)(=[O:64])=[O:63])[C:39]=2[CH:53]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: FC(F)(F)c1ccc2c(n1)Nc1ccc(I)cc1NC2
Agent: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(Br)cc32)cc1
Agent: FC(F)(F)c1ccc2c(n1)Nc1ccc(Br)cc1NC2
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1Cc2ccc(C(F)(F)F)nc2Nc2ccc(I)cc21

Procedure:
The title compound was prepared following procedure described for intermediate 53 substituting 8-iodo-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (intermediate 37) and 4-(trifluoromethyl)benzenesulfonyl chloride for 8-bromo-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine and [(4-tert-butylphenyl)-sulfonyl chloride. LC/MS: m/e 599.8 (M+H)+. 1H NMR (500 MHz, acetone-d6): δ 8.56 (1H, s), 7.79-7.82 (2H, m), 7.66 (1H, dd, J=8.5, 2.1 Hz), 7.55 (2H, d, J=8.3 Hz), 7.29 (2H, d, J=8.3 Hz), 7.17 (1H, d, J=7.5 Hz), 7.15 (2H, d, J=8.7 Hz), 4.80-5.10 (2H, br).
Reaction SMILES: [N+](C1C=C(S(CC[O:15][C:16](=[O:78])[CH:17]([NH:37][C:38](=[O:77])[CH2:39][O:40][C:41]2[CH:46]=[C:45]([CH3:47])[C:44]([S:48]([N:51]3[C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=4[N:53]=[C:52]3[S:60]([CH2:62][C:63]3[C:68]([CH3:69])=[C:67]([O:70][CH2:71][C:72]([F:75])([F:74])[F:73])[CH:66]=[CH:65][N:64]=3)=[O:61])(=[O:50])=[O:49])=[C:43]([CH3:76])[CH:42]=2)[CH2:18][CH2:19][C:20]([O:22]CCS(C2C=CC=C([N+]([O-])=O)C=2)(=O)=O)=[O:21])(=O)=O)C=CC=1)([O-])=O.C([O-])(O)=O.[Na+:83]>C1COCC1.O>[Na+:83].[CH3:47][C:45]1[CH:46]=[C:41]([CH:42]=[C:43]([CH3:76])[C:44]=1[S:48]([N:51]1[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=2[N:53]=[C:52]1[S:60]([CH2:62][C:63]1[C:68]([CH3:69])=[C:67]([O:70][CH2:71][C:72]([F:73])([F:74])[F:75])[CH:66]=[CH:65][N:64]=1)=[O:61])(=[O:50])=[O:49])[O:40][CH2:39][C:38]([NH:37][CH:17]([CH2:18][CH2:19][C:20]([O-:22])=[O:21])[C:16]([O-:78])=[O:15])=[O:77].[Na+:83]
Reactant: Cc1cc(OCC(=O)NC(CCC(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)C(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc(C)c1S(=O)(=O)n1c(S(=O)Cc2nccc(OCC(F)(F)F)c2C)nc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCC(=O)NC(CCC(=O)[O-])C(=O)[O-])cc(C)c1S(=O)(=O)n1c(S(=O)Cc2nccc(OCC(F)(F)F)c2C)nc2ccccc21
Yield: 73.9 %

Procedure:
A solution of 2-[2-(3,5-dimethyl-4-{2-[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridin-2-ylmethanesulfinyl]-benzimidazole-1-sulfonyl}-phenoxy)acetylamino]-pentanedioic acid bis-[2-(3-nitro-benzenesulfonyl)-ethyl]ester (Intermediate 34, 800 mg, 0.69 mmol) and NaHCO3 (120 mg, 1.41 mmol, 2.05 eq) in THF-H2O (6 mL-3 mL) was heated to 70° C. for 3 h. Thereafter volatile materials were removed by evaporation under reduced pressure, the residual semi-solid was treated with EtOAc, and the mixture was filtered to remove undissolved materials. The filtrate was concentrated to total volume of about 3 mL, and then diethyl ether was added to the mixture. A solid precipitate formed and was collected by filtration to give Compound 13 (400 mg, 73%) as an off-white solid.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:18][CH3:19].[CH2:20](I)[CH3:21].O>C1COCC1>[CH3:19][O:18][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[CH2:20][CH3:21]
Reactant: CCI
Reactant: COc1cc(C=Cc2ccccc2)cc(OC)c1Br
Solvent: C1CCOC1
Solvent: O
Product: CCc1c(OC)cc(C=Cc2ccccc2)cc1OC
Temperature: -78 °C
Yield: 70 %

Procedure:
To a solution of 1-(4-bromo-3,5-dimethoxyphenyl)-2-phenylethene (0.53 g, 1.7 mmol) in THF (10 mL) was added t-Butyl Li (1.1 mL, 1M in THF) at −78° C. After the addition complete, the solution was slowly heated to reflux for 30 min and then cooled down to −78° C. Ethyl iodide (1.2 eq, 0.27 mL) was added to the solution. Water (10 mL) was added after the completion of the reaction. THF was evaporated and the mixture was extracted with CH2Cl2 (3×5 mL). The extract was combined and dried over anhydrous magnesium sulfate. Evaporation of the solution followed by flash chromatography using 20% ether in hexane gave 1,3-dimethoxy-2-ethyl-5-(2-phenylethenyl)benzene in 70% yield.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14][C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:16]=2)[CH:9]=1)(C)(C)C>CO.C(Cl)Cl>[NH2:7][C:8]1[CH:9]=[C:10]([S:14][C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:16]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Sc2cn(C3CCCC3)c3ncnc(N)c23)c1
Solvent: ClCCl
Solvent: CO
Product: Nc1cccc(Sc2cn(C3CCCC3)c3ncnc(N)c23)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of [3-(4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylsulfanyl)-phenyl]-carbamic acid tert-butyl ester (108 mg, 0.25 mmole) in a mixture of MeOH and Methylene Chloride (4 mL/2 mL) was bubbled through HCl gas for 20 minutes. The resulting solution was stirred for 20 minutes at room temperature. Then the reaction mixture was extracted with EtOAc (50 mL) and saturated sodium bicarbonate solution (50 mL). The organic layer was washed with brine, dried over sodium sulfate and concentrated. The title compound was obtained as a yellow solid (79 mg, 96%). MS: 326.2 (MH+); HPLC Rf: 5.332 min.; HPLC purity: 90%.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Cl.[O:21]1[CH2:26][CH2:25][CH2:24][CH:23]([NH2:27])[CH2:22]1>CC(N(C)C)=O>[O:21]1[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:22]1
Reactant: NC1CCCOC1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1ccccc1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: O=C(Nc1nc2cccc(NC3CCCOC3)n2n1)c1ccccc1

Procedure:
The title compound was prepared following procedure and work up described for example 30 but starting from N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 100 mg; 0.37 mmol; 1.0 eq.) and tetrahydro-pyran-3-ylamine hydrochloride (CBI, 257 mg; 1.87 mmol; 5 eq.) in DMA (1 mL) as a white powder (32 mg, 26%). 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.00 (d, J=6.8 Hz, 2H), 7.48-7.63 (m, 4H), 6.91 (d, J=8.3 Hz, 1H), 6.46 (d, J=9.0 Hz, 1H), 6.36 (d, J=7.9 Hz, 1H), 3.86 (m, 1H), 3.71 (m, 2H), 3.50 (m, 2H), 2.06 (m, 1H), 1.22-1.97 (m, 3H). HPLC, Rt: 2.27 min. (purity 99.6%). LC/MS, M+(ESI): 338.1, M−(ESI): 336.0.
Reaction SMILES: [OH-].[Na+].[C:3]([OH:13])(=[O:12])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[Eu+3:15].[Cl-].[Cl-]>O>[C:3]([O-:13])(=[O:12])[CH:4]=[CH:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1.[Eu+3:15].[C:3]([O-:13])(=[O:12])[CH:4]=[CH:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1.[C:3]([O-:13])(=[O:12])[CH:4]=[CH:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)C=Cc1ccccc1
Agent: [Cl-]
Agent: [Eu+3]
Agent: [Na+]
Solvent: O
Product: O=C([O-])C=Cc1ccccc1

Procedure:
Then a sodium cinnamate aqueous solution obtained in advance by dissolving 1.64 g of sodium hydroxide in 300 ml of purified water and thereafter dissolving 6.06 g of cinnamic acid (purity 99.9%, conjugate number 4) thoroughly in the resultant solution was gradually added with continued stirring into the aforementioned aqueous europium chloride solution. Consequently, a white salt of europium cinnamate was produced in the form of a precipitate. Thereafter, the reaction solution was adjusted to pH 6.5 with a 0.1N sodium hydroxide aqueous solution added under thorough stirring.
Reaction SMILES: ClCC([O:5][C:6]1[CH:14]=[CH:13][C:12]2[N:11]([CH3:15])[C:10]3[C:16](=[O:19])[CH2:17][CH2:18][C:9]=3[C:8]=2[CH:7]=1)=O.[OH-].[Na+]>CCO>[OH:5][C:6]1[CH:14]=[CH:13][C:12]2[N:11]([CH3:15])[C:10]3[C:16](=[O:19])[CH2:17][CH2:18][C:9]=3[C:8]=2[CH:7]=1
Reactant: Cn1c2c(c3cc(OC(=O)CCl)ccc31)CCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c2c(c3cc(O)ccc31)CCC2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7-Chloroacetyloxy-1,4-dihydro-4-methylcyclopent[b]indol- 3(2H)-one (5.0 g) was suspended in EtOH (100 ml), and thereafter 10% NaOH solution (50 ml) was added and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo, CH2Cl2 (100 ml) was added followed by 10% HCl until the aqueous layer was neutralized. The layers were separated and the aqueous phase extracted with CH2Cl2 (2×100 ml). The organic portion was dried (Na2SO4) and concentrated and the residue was recrystallized from 95% EtOH to provide 1,4-dihydro-7-hydroxy-4-methylcyclopent[b]indol-3(2H)-one as an off-white solid. The phenol was dissolved in CH2Cl2 (100 ml), and thereafter 1,8-diazabicyclo[5.4.0]undec-7-ene (0.4 g) was added followed by methyl isocyanate (1.4 g) and the mixture was stirred overnight. The mixture was concentrated in vacuo to afford an oily solid which was crystallized from EtOH to provide 1,4-dihydro-7 -methylaminocarbonyloxy-4-methylcyclopent[b]indol-3(2H)-one (1.1 g).
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[C:3]([O:5]CC)=[O:4].[ClH:16]>O>[ClH:16].[CH3:1][CH:2]([CH2:8][CH2:9][N:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)CCN1CCCCC1
Agent: Cl
Solvent: O
Product: CC(CCN1CCCCC1)C(=O)O

Procedure:
6.5 g. (0.030 mole) of ethyl 2-methyl-4-piperidinobutyrate was combined with a mixture of 45 ml. of water and 45 ml. of concentrated hydrochloric acid and heated at reflux for 16 hours. The solution was concentrated under reduced pressure (water aspirator) to give a residue which crystallized upon addition of 50 ml. of diethyl ether. The ether was decanted, and the solid was triturated with acetone and filtered. Recrystallization from acetic acid/acetone gave 3.38 g. of colorless crystals, m.p. 166°-168°C. and a second crop of 1.27 g. of solid, m.p. 165°-168°C. The total yield for both batches was 69%.