Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][CH2:8][CH2:9][S:10]([C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1Cl)(=[O:12])=[O:11].[SH:23][CH2:24][CH2:25][OH:26]>O>[OH:7][CH2:8][CH2:9][S:10]([C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[S:23][CH2:24][CH2:25][OH:26])(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)CCO)c1
Reactant: OCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccc(SCCO)c(S(=O)(=O)CCO)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
58.75 g of potassium carbonate are added at 22° C. to a suspension of 132.85 g of 2-chloro-5-nitrophenyl hydroxyethyl sulfone in 100 ml of water and 80 g of 2-mercaptoethanol in the course of 1.5 hours, and the mixture is stirred at room temperature for 4 hours. The reaction mixture is then filtrated with suction, and the filter residue is washed with water until neutral. Drying these gives 124.3 g of 2-β-hydroxyethylmercapto-5-nitrophenyl hydroxyethyl sulfone having a melting point of 116°-118° C. (purity about 99%), which corresponds to a yield of 81% of theory, relative to starting 2-chloro-5-nitrophenyl hydroxyethyl sulfone.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li]CCCC.CCCCCC.[CH2:21]([O:23][C:24](=[O:31])[CH2:25]/[N:26]=[CH:27]/[N:28]([CH3:30])[CH3:29])[CH3:22].ClC1[CH2:34][N:35]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=2[O:57][CH3:58])[C:36](=[O:47])[C:37]2[CH:43]=[C:42]([CH:44]([CH3:46])[CH3:45])[CH:41]=[CH:40]C=2N=1>C1COCC1.O.C(O)(=O)C>[CH2:21]([O:23][C:24]([C:25]1[N:26]=[CH:27][N:28]2[C:30]=1[CH2:34][N:35]([CH2:48][C:49]1[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=1[O:57][CH3:58])[C:36](=[O:47])[C:37]1[CH:43]=[C:42]([CH:44]([CH3:46])[CH3:45])[CH:41]=[CH:40][C:29]2=1)=[O:31])[CH3:22]
Reactant: COc1ccc(CN2CC(Cl)=Nc3ccc(C(C)C)cc3C2=O)c(OC)c1
Reactant: CCOC(=O)C/N=C/N(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ncn2c1CN(Cc1ccc(OC)cc1OC)C(=O)c1cc(C(C)C)ccc1-2
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Hexamethyldisilazane (2.8 mL, 13.4 mmol) was dissolved in TBF (25 mL), cooled under Argon to −70° C., and treated slowly with a 1.6 M solution of n-BuLi in hexane (8.4 mL, 13.4 mmol). After stirring for 1 h at −70° C., a solution of (E)-(dimethylamino-methyleneamino)-acetic acid ethyl ester (1.28 g, 8.1 mmol) in THF (5 mL) was added, and stirring continued for 1 h at −70° C. Then a solution of 2-chloro-4-(2,4-dimethoxy-benzyl)-7-isopropyl-3,4-dihydro-benzo[e][1,4]diazepin-5-one (1.59 g, 4.1 mmol) (prepared as described above) was added at −70° C., and subsequently allowed to warm up to at 10° C. over 1 h, then cooled again to −30° C. After 30 min, acetic acid (3.0 mL) was added at −30° C. and the suspension was allowed to warm up to room temperature and water (3.0 mL) added and the resulting mixture heated under reflux for 14 h. After cooling, the mixture was evaporated and then dissolved in DCM (30 mL). This solution was then washed with HCl (1 M, 2×15 mL) and sodium hydrogen carbonate (sat., 10 ml), dried (Na2SO4) and evaporated. Chromatography on silica gel eluting with EtOAc:Hexane (19:1). Yield: 1.9 g (99%). m/z 464 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:22](N)[CH2:23][NH2:24].[S]>O>[NH:5]1[CH2:22][CH2:23][N:24]=[C:4]1[C:3]1[C:2]([NH2:1])=[C:9]([O:10][CH3:11])[C:8]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[CH:7][CH:6]=1
Reactant: NCCN
Reactant: COc1c(OCCCN2CCOCC2)ccc(C#N)c1N
Agent: [S]
Solvent: O
Product: COc1c(OCCCN2CCOCC2)ccc(C2=NCCN2)c1N
Yield: 43 %

Procedure:
To a degassed mixture of 2-amino-3-methoxy-4-(3-morpholin-4-ylpropoxy)benzonitrile (6.5 g, 22.2 mmol) and ethylene diamine (40 mL) was added sulfur (1.8 g, 55.4 mmol). The mixture was stirred at 100° C. for 3 h at which time water was added to the reaction mixture. The precipitate that was formed was collected and washed with water and then dried overnight under vacuum to provide the title compound (3.2 g, 43%): HPLC MS RT=1.25 min, MH+=335.2; 1H NMR (DMSO-d6) δ: 7.15 (1H, d), 6.86 (2H, br s), 6.25 (1H, d), 4.02 (2H, t), 3.66 (3H, s), 3.57 (8H, m), 2.46 (2H, t), 2.44 (4H, m), 1.89 (2H, quint.).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[C:14]([CH2:24][CH:25]4[CH2:27][CH2:26]4)([CH3:23])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH:25]1([CH2:24][C:14]2([CH3:23])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]([OH:22])=[C:12]([C:7]3[NH:6][C:5]4[CH:29]=[CH:30][C:2]([NH:1][S:38]([CH3:37])(=[O:40])=[O:39])=[CH:3][C:4]=4[S:9](=[O:11])(=[O:10])[N:8]=3)[C:13]2=[O:28])[CH2:26][CH2:27]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(CC2CC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(CC2CC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reaction time: 12 h
Yield: 83.3 %

Procedure:
To a stirring solution of Example 165 (0.080 g, 0.189 mmol) and pyridine (0.122 mL, 1.512 mmol) in dichloromethane was added methanesulfonyl chloride (0.017 mL, 0.227 mmol) dropwise over 5 minutes and the resulting reaction mixture stirred for 12 hours. The solution was concentrated in. vacuo and purified by flash chromatography on SiO2 eluting with a 0-100% ethyl acetate/hexane gradient yielding the title compound (0.079 g, 84% yield) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm −0.39 (m, 1 H)-0.13 (m, 1 H) 0.03 (m, 2 H) 0.21 (m, 1 H) 1.24 (m, 1 H) 1.43 (s, 3 H) 1.78 (m, 1 H) 1.99 (m, 1 H) 3.01 (s, 3H) 7.38 (m, 3 H) 7.50 (m, 3 H) 8.07 (d, J=7.35 Hz, 1 H) 9.92 (s, 1 H) 15.36 (s, 1 H).). MS (ESI+) m/z=502 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:6]#[C:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][I:5].[CH3:11][C:12](=[CH2:14])[CH3:13]>>[C:12]([O:1][CH:2]([C:6]#[C:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][I:5])([CH3:14])([CH3:13])[CH3:11]
Reactant: C=C(C)C
Reactant: CCCC#CC(O)CCI
Product: CCCC#CC(CCI)OC(C)(C)C

Procedure:
The subject compound is prepared from 3-hydroxy-1-iodo-4-octyne (Example 498) and isobutylene by the method of Example 492.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4].[N:21]1([CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]2)[CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)(C)C>[N:21]1([CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][N:28]2[CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[CH:20][C:6]2=3)=[O:4])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2ccccc21
Reactant: C1CCC(CN2CCCC2)NC1
Solvent: CC(C)O
Product: O=C1Nc2ccccc2N(C(=O)CN2CCCCC2CN2CCCC2)c2ccccc21

Procedure:
The title compound is prepared analogously to Example 2 from 5-(chloroacetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 2-[(1-pyrrolidinyl)methyl]piperidine to give colorless crystals, mp. 199°-201° C. (isopropanol/activated charcoal).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][CH:20]=2)=[C:13]([C:15](=[O:17])[CH3:16])[CH:14]=1)C1C=CC=CC=1.CS(O)(=O)=O.FC(F)(F)C(O)=O>>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:18][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][C:13]=1[C:15](=[O:17])[CH3:16]
Reactant: COc1cc2nccc(Oc3ccc(OCc4ccccc4)cc3C(C)=O)c2cc1OC
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2nccc(Oc3ccc(O)cc3C(C)=O)c2cc1OC
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 97.6 %

Procedure:
1-[5-Benzyloxy-2-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-ethanone (compound 175) (188 mg) was suspended in a mixed solution composed of methanesulfonic acid (0.3 ml) and trifluoroacetic acid (4 ml) to prepare a suspension which was then stirred at 70° C. for 1.5 hr. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was neutralized with sodium hydrogencarbonate powder and was then extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography using acetone-hexane to give the title compound (145 mg, yield 100%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2Cl)[CH2:6]1)(=[O:3])[CH3:2].[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1.C([O-])([O-])=O.[K+].[K+].CCCCCC.CCOC(C)=O>CN(C=O)C>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2[N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(Cl)=C(C=O)C[C@@H]32)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(n4ccnc4)=C(C=O)C[C@@H]32)C1
Temperature: 80 °C
Yield: 95.8 %

Procedure:
A mixture of 3β-acetoxy-17-chloro-16-formylandrosta-5,16-diene (Compound 3) (500 mg, 1.329 mmol), imidazole (136 mg, 2.0 mmol) and K2CO3 (551 mg, 3.99 mmol) in dry DMF was heated at about 80° C. under N2 for 2 h. After cooling to room temperature, the reaction mixture was poured onto ice-cold water (100 ml), and the resulting white precipitate was filtered, washed with water, and dried to give a white solid. This was titrated with boiling mixture of hexane/EtOAc to give Compound 9 (520 mg, 92%), mp 218-220° C. 1H NMR (300 MHz, CDCl3): δ 1.08 (6H, s, 18 and 19-Me), 2.04 (3H, s, 3β-OAc), 4.61 (1H, m, 3α-H), 5.42 (1H, d, J=4.8 Hz, 6-H), 7.11 (1H, s, 4'-H), 7.23 (1H, s, 5'-H), 7.63 (1H, s, 2'-H) and 9.74 (1H, s, 16-CHO). Analysis calculated for C25H32O3N2 : C, 73.49; H, 7.90; N, 6.88; Found: C, 73.34; H, 8.05; N, 6.65. HRMS calcd. for C25H32O3N2 408.2413, found 408.2426.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:5]#[N:6]
Reactant: C1COCCN1
Reactant: N#Cc1ccc(F)c(Cl)c1
Product: N#Cc1ccc(N2CCOCC2)c(Cl)c1

Procedure:
3-Chloro-4-morpholin-4-yl-benzonitrile is synthesized starting from 3-Chloro-4-fluoro-benzonitrile and morpholine as described in Example 306. LC-MS (m/z, ES+): 223 (MH+), Retention time: 1.11 mins (LC-MS method 7)
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[OH:13][C:14]1[CH:18]=[C:17]([CH3:19])[O:16][N:15]=1.[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>O1CCCC1.CCCCCC>[OH:13][C:14]1[CH:18]=[C:17]([CH2:19][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])[O:16][N:15]=1
Reactant: CCCCCCCCCCCCCCBr
Reactant: Cc1cc(O)no1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCc1cc(O)no1
Reaction time: 0.25 h
Yield: 65.4 %

Procedure:
26(b) 69.1 ml of a 15.13% w/w hexane solution of butyllithium was added dropwise to a solution of 15.42 ml of diisopropylamine in 500 ml of tetrahydrofuran at -10° to -15° C., and the mixture was stirred at the same temperature for 15 minutes. To it was added dropwise a solution of 4.95 g of 3-hydroxy-5-methylisoxazole dissolved in 50 ml of tetrahydrofuran at -10° C., and the mixture was stirred at the same temperature for 30 minutes. It was then cooled to -55° C. after which 41.6 g of tetradecyl bromide were added all at once. After removal from the cooling bath, the mixture was stirred for 3 hours, and then 100 ml of diethyl ether were added. The mixture was washed with 150 ml of 5% w/v aqueous hydrochloric acid, and the organic layer was washed with water, dried and concentrated by evaporation under reduced pressure. 100 ml of hexane were added to the residue, and the precipitated solid was collected by filtration and washed with hexane. It was then dried to give crude crystals (13.65 g) of the title compound. Concentration of the filtered hexane solution gave a residue, which was subjected to column chromatography through 100 g of silica gel. Crude crystals (1.40 g) were obtained from the fractions eluted with a 2:1 by volume mixture of methylene chloride and diethyl ether. The combined crude crystals were recrystallized from methylene chloride to give the pure title compound (9.65 g) melting at 82°-83° C. Further crystals (3.91 g) were obtained by concentration of the mother liquor. The spectra of these compounds were identical with those ofthe compound obtained as described in (a) above.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[S:37](Cl)(=[O:39])=[O:38].N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:37]([C:33]1[O:32][CH:36]=[CH:35][CH:34]=1)(=[O:39])=[O:38]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)c1ccco1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccco1
Temperature: 50 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. furan-2-sulfonyl chloride (12 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 24 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)furan-2-sulfonamide (percentage yield: 94%), was obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:21]=[CH:20][C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[CH:8][CH:7]=1)=[O:5])C>[OH-].[Na+]>[C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[CH:20][CH:21]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(OCc2ccccc2OC)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1COc1ccc(C(=O)O)cc1
Reaction time: 18 h

Procedure:
4-Ethoxycarbonylphenoxy-(2'-methoxyphenyl) methane (14.3g.; 0.05 mole) in sodium hydroxide (100ml.; 10N) was heated under reflux with vigorous stirring for 18 hr.
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[NH:8][C:9]([C:11]3[N:16]=[C:15]([C:17]4[C:18]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:40])=[O:39])=[CH:19][C:20]5[O:24][C:23]([C:25]6[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=6)=[C:22]([C:32]([NH:34][CH3:35])=[O:33])[C:21]=5[CH:36]=4)[CH:14]=[CH:13][C:12]=3[OH:43])=[CH:10][C:3]=12.[C:44]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[F:1][C:2]1[C:3]2[CH:10]=[C:9]3[C:11]4[N:16]=[C:15]([C:17]5[C:18]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:39])=[O:40])=[CH:19][C:20]6[O:24][C:23]([C:25]7[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=7)=[C:22]([C:32]([NH:34][CH3:35])=[O:33])[C:21]=6[CH:36]=5)[CH:14]=[CH:13][C:12]=4[O:43][CH2:44][N:8]3[C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(O)c(-c4cc5c(F)cncc5[nH]4)n3)cc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cncc5n3CO4)cc12
Yield: 28.7 %

Procedure:
To a stirring solution of 5-(6-(4-fluoro-1H-pyrrolo[2,3-c]pyridin-2-yl)-5-hydroxypyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (100 mg, 0.17 mmol) and Cs2CO3 (108 mg, 0.33 mmol) in DMF (3 mL) was added chloroidomethane (35 mg, 0.2 mmol) dropwise at 100° C. under N2. The mixture was heated for 8 hours. The mixture was diluted with H2O and extracted with EtOAc. The organics were washed with brine and dried over Na2SO4. The crude product was purified using prep-HPLC to obtain the product of Compound 46 (30 mg, yield: 30%). 1H-NMR (CDCl3, 400 MHz) δ 8.61 (s, 1H), 8.17 (s, 1H), 8.05 (s, 1H), 7.95 (t, J=6.0 Hz, 2H), 7.65 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.53 (d J=8.0 Hz, 1H), 7.25˜7.19 (m, 3H), 6.10 (s, 2H), 5.99 (s, 1H), 3.37 (s, 3H), 3.00 (d, J=4.0 Hz, 3H), 2.80 (s, 3H). MS (M+H)+: 616.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][C:5]=1[NH2:14])([O-])=[O:2].[N:15]#[C:16][NH2:17].[CH]Cl.[OH-].[Na+]>O>[N+:1]1([O-:2])[C:4]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[CH:7]=[CH:6][C:5]=2[N:14]=[C:16]([NH2:17])[N:15]=1
Reactant: Nc1ccc2c(c1[N+](=O)[O-])CCCC2
Reactant: N#CN
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2ccc3c(c2[n+]([O-])n1)CCCC3
Temperature: 50 °C
Reaction time: 3 h
Yield: 15.1 %

Procedure:
A mixture of nitroaniline 169 (0.73 g, 3.8 mmol) and cyanamide (0.63 g, 15.1 mmol) were mixed together at 100° C., cooled to 50° C., cHCl (5 mL) added carefully and the mixture heated at 100° C. for 2 h. The mixture was cooled to 50° C., 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100° C. for 3 h. The mixture was cooled, diluted with water (50 mL), filtered, washed with water (2×25 mL) and dried. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give amine 170 (124 mg, 15%) as a yellow powder: mp (MeOH) 271° C. (dec.); 1H NMR [(CD3)2SO] δ 7.43 (d, J=8.6 Hz, 1H, H-6), 7.26 (d, J=8.6 Hz, 1H, H-5), 7.00 (br s, 2H, NH2), 3.36-3.40 (m, 2H, CH2), 2.75-2.80 (m, 2H, CH2), 1.67-1.75 (m, 4H, 2×CH2); 13C NMR [(CD3)2SO] δ 159.5, 149.5, 137.3, 133.8, 131.1, 129.9, 123.0, 29.8, 28.7, 22.5, 21.0. Anal. calcd for C11H12N4O: C, 61.1; H, 5.6; N, 25.9. Found: C, 61.0; H, 5.6; N, 26.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[C:25]([Cl:34])[CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[C:25]([Cl:34])[CH:24]=2)[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18]([NH2:20])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: NC(=O)[C@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1Cl
Product: NC(=O)[C@H]1CCCC[C@H]1N(Cc1ccc(OC(F)(F)F)c(Cl)c1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 59 %

Procedure:
The titled compound was prepared in 59% yield from (1S,2R)-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide (75 mg, 0.237 mmol) and 4-bromomethyl-2-chloro-1-trifluoromethoxy-benzene (72 mg, 0.249 mmol) according to the procedure described for Example 3: 1H NMR (500 Mz, DMSO) δ 7.81 (d, 2 H, J=8.5), 7.63 (d, 2 H, J=8.6), 7.48 (br s, 1 H), 7.44–7.35 (m, 4 H), 6.70 (br s, 1 H), 4.56 (ABq, 2 H, Δv=106, Jab=17.1), 3.88 (m, 1 H), 2.82 (m, 1 H), 2.44 (m, 1 H), 1.80 (m, 1 H), 1.67 (m, 2 H), 1.39–1.22 (m, 3 H), 0.89 (m, 1 H); MS m/e 547.2 (M+Na)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[C:23]3[O:25][CH2:26][O:27][C:22]3=[CH:21][C:20]=1[Cl:28])[C:13]([C:29]([O:31]CC)=[O:30])=[C:12]2[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:2]1C=CC=C[CH:3]=1.[Na].[OH-].[Na+]>C(O)C>[Cl:28][C:20]1[CH:21]=[C:22]2[O:27][CH2:26][O:25][C:23]2=[CH:24][C:19]=1[CH2:18][N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:1][CH2:2][CH3:3])=[CH:17][CH:16]=2)[C:12]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[C:13]1[C:29]([OH:31])=[O:30]
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(OCc3ccccc3)ccc2n1Cc1cc2c(cc1Cl)OCO2
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: CCCOc1ccc2c(c1)c(-c1ccccc1)c(C(=O)O)n2Cc1cc2c(cc1Cl)OCO2

Procedure:
Following the procedure of Example 1(d) except substituting ethyl 1-(2-chloro-4,5-methylenedioxybenzyl)-3-phenyl-5-propyloxyindole-2-carboxylate for ethyl 5-benzyloxy-1-(2-chloro-4,5-methylenedioxybenzyl)-3-phenylindole-2-carboxylate, the title compound was prepared as a white solid (0.053 g, 88%). The title compound was converted to the sodium salt using 1.0 eq of 0.1N sodium hydroxide in ethanol. MS (MH+): 464.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=2)[N:13]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](I)=[C:26]([F:31])[CH:25]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][C:26]=3[F:31])=[CH:16][CH:15]=2)[N:13]=1
Reactant: C#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Reactant: Fc1cc(Cl)ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(C#Cc2ccc(Cl)cc2F)cc1
Yield: 31.9 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-2, 0.100 g, 0.319 mmol), 4-chloro-2-fluoro-1-iodobenzene (0.123 g, 0.479 mmol), TBAF (0.201 g, 0.638 mmol), bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.028 mmol) and DMSO (3.0 ml). The obtained crude product was purified with column chromatography on silica gel eluting with 1.0% MeOH:DCM to afford 0.045 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.38 (d, J=8.4 Hz, 1H), 7.50 (t, J=8.7 Hz, 1H), 7.57-7.70 (m, 6H), 8.02 (d, J=8.7 Hz, 2H), 12.74 (br s, 1H). MS (m/z): 442.38 (M+).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)=O>>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:6]1[C:5]([C:3]([OH:2])=[O:4])=[CH:10][C:9]([C:11]2[S:13][CH:24]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[N:12]=2)=[CH:8][CH:7]=1)([O-:22])=[O:21]
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Product: Cc1ccc(-c2csc(-c3ccc(-c4ccccc4[N+](=O)[O-])c(C(=O)O)c3)n2)cc1
Yield: 32 %

Procedure:
2′-Nitro-4-(4-p-tolyl-thiazol-2-yl)-biphenyl-2-carboxylic acid (85 mg, 32%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromo-4′-methylacetophenone (available from ASDI Incorporated) using the procedure described for the preparation of Example 39. 1H NMR (400 MHz, DMSO-d6) δ 13.15 (br s, 1H), 8.57 (d, J=1.9 Hz, 2H), 8.26 (dd, J=8.0, 1.9 Hz, 1H), 8.20 (s, 1H), 8.15 (dd, J=8.1, 0.9 Hz, 1H), 7.97 (d, J=8.1 Hz, 2H), 7.77-7.82 (m, 1H), 7.63-7.69 (m, 1H), 7.42-7.48 (m, 2H), 7.30 (d, J=8.0 Hz, 2H), 2.36 (s, 3H).