Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][NH2:13].C1([CH:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:21](O)=[O:22])C=CC=CC=1.[CH3:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>>[C:42]1([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:20][C:21]([NH-:1])=[O:22])[CH:41]=[CH:40][CH:45]=[CH:44][CH:43]=1.[C:42]1([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:20][C:21]([NH-:1])=[O:22])[CH:41]=[CH:40][CH:45]=[CH:44][CH:43]=1.[C:42]1([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:20][C:21]([NH-:1])=[O:22])[CH:41]=[CH:40][CH:45]=[CH:44][CH:43]=1.[NH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2][NH2:1]
Reactant: CCCCCCCCCCCCCCCCC(C(=O)O)c1ccccc1
Reactant: CCCCCC
Agent: NCCNCCNCCNCCN
Product: [NH-]C(=O)CCCCCCCCCCCCCCCCCc1ccccc1
Temperature: 175 °C
Reaction time: 2 h

Procedure:
Into a 300 ml reaction flask equipped with a thermometer, an agitator and an addition funnel, 6 g (0.03 mole) tetraethylenepentamine was added and heated to 70°-75° C. with agitation. From the addition funnel, 32.4 g (0.09 mole) phenylstearic acid was added over 10 minutes. To insure complete addition of phenylstearic acid, 15-20 ml hexane was added to the addition funnel and thence into the reaction mixture after hexane was allowed to evaporate away, the contents of the flask was placed under reduced pressure and heated to 175° C. with agitation. Heating was continued at 175° C. for 2 hours allowing the condensation water to distill off. The product, tetraethylenepentamine tris(phenylstearoylamide) was viscous, amber colored liquid.
Reaction SMILES: C[O-].[Na+].C(O[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[N:10][CH:9]=1)C.[C:16]([O:19][CH2:20][CH3:21])(=[O:18])[CH3:17].Cl>O.C1(C)C=CC=CC=1>[CH2:20]([O:19][C:16](=[O:18])[CH2:17][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[N:10][CH:9]=1)[CH3:21]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1ccc(C)nc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)c1ccc(C)nc1
Temperature: 20 °C
Yield: 33.6 %

Procedure:
35.8 g (0.52 mol) of sodium methylate and 200 ml of toluene were put in a 750-ml sulfonation flask. The reaction mixture was heated to reflux temperature. A mixture of 55.7 g (0.33 mol) of 6-methyl nicotinic acid ethyl ester (produced according to Swiss Patent No. 654 577) and 60.3 g (0.68 mol) of ethyl acetate was added drop by drop to the stirred suspension over 7 hour period. The suspension was stirred at reflux temperature for 22 hours and then cooled to 20° C. 200 ml of water and 25 ml of concentrated hydrochloric acid were added and the phases were separated. The water phase was extracted with toluene and the combined organic phases were evaporated. Then the evaporation residue was distilled under vacuum. 25.9 g of 6-methyl nicotinoyl acetic acid ethyl ester, having a boiling point of 112°-130° C./0.2-0.4 mbar and a content according to HPLC of 89.7 percent, was obtained (yield 33.6 percent, in relation to the 6-methyl nicotinic acid ethyl ester).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6][C:7]=1[CH3:8].S(Cl)([Cl:19])=O>>[Cl:19][CH2:2][C:3]1[N:4]=[C:5]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6][C:7]=1[CH3:8]
Reactant: Cc1oc(C=Cc2ccccc2)nc1CO
Reactant: O=S(Cl)Cl
Product: Cc1oc(C=Cc2ccccc2)nc1CCl
Reaction time: 0.5 h

Procedure:
4-Hydroxymethyl-5-methyl-2-styryloxazole (1.0 g) was added to thionyl chloride (3 ml) and the mixture was allowed to stand at room temperature for 30 minutes. The thionyl chloride was distilled off under reduced pressure. The residue was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and isopropyl ether was added to the residue to give 4-chloromethyl-5-methyl-2-styryloxazole as crystals; yield 0.98 g (90.7%). Recrystallization from ether gave light-yellow plates melting at 108°-109° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][NH:5][CH:6]=1.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15](I)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH3:1][C:2]1[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][N:5]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([C:12]([F:21])([F:20])[F:11])[CH:18]=2)[CH:6]=1
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: COC(=O)c1c[nH]cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1cn(-c2cccc(C(F)(F)F)c2)cc1C
Temperature: 170 °C
Reaction time: 1 h
Yield: 43.3 %

Procedure:
To a solution of methyl 4-methyl-1H-pyrrole-3-carboxylate (3.4 g) synthesized above in N-methyl-2-pyrrolidone (30 mL) were added 3-trifluoromethyliodobenzene (6.7 g), cuprous bromide (0.53 g) and potassium carbonate (4.4 g) at room temperature, and stirred for 1 hr with heating to 170° C. After cooling to room temperature, the reaction mixture was filtered through celite. Water was added to the filtrate and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title compound (3.0 g, 42%) as a slightly yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[C:6]([F:15])[C:5]([OH:16])=[C:4]([CH:17]=[O:18])[CH:3]=1.I[CH:20]([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[C:6]([F:15])[C:5]([O:16][CH:20]([CH3:22])[CH3:21])=[C:4]([CH:17]=[O:18])[CH:3]=1
Reactant: O=Cc1cc(Br)c(-c2ccc(F)cc2)c(F)c1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1c(C=O)cc(Br)c(-c2ccc(F)cc2)c1F
Reaction time: 1 h
Yield: 74 %

Procedure:
A mixture of 6-bromo-2,4′-difluoro-3-hydroxybiphenyl-4-carbaldehyde (3.50 g), 2-iodopropane (5.70 g), potassium carbonate (3.09 g), and DMF (15 mL) was stirred at 50 C for 1 hour. The reaction mixture was poured to water, followed by extraction with ethyl acetate twice. The organic layer was separated, then washed with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.94 g)
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:24])=[N:5]1)([CH3:3])[CH3:2].[NH:25]1[CH2:32][CH2:31][CH2:30][C@H:26]1[C:27]([NH2:29])=[O:28]>>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([N:25]5[CH2:32][CH2:31][CH2:30][C@H:26]5[C:27]([NH2:29])=[O:28])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:24])=[N:5]1)([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(O)cc2OCC3)n(C(C)C)n1
Reactant: NC(=O)[C@@H]1CCCN1
Product: Cc1nc(-c2cn3c(n2)-c2cnc(N4CCC[C@H]4C(N)=O)cc2OCC3)n(C(C)C)n1
Yield: 67 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol and L-prolinamide, were reacted and the crude product recrystallised from IMS to give 369 as a white solid (130 mg, 67%). LCMS: RT=2.48 min, [M+H]+=423. 1H NMR 400 MHz (DMSO-d6) δ: 9.06 (1H, s), 7.80 (1H, s), 7.35 (1H, br), 6.94 (1H, br), 5.96 (1H, s), 5.90-5.88 (1H, m), 4.50 (4 H, d, J=17.28 Hz), 4.32 (1H, m), 3.61 (1H, m), 3.45 (1H, m), 2.26 (2H, s), 2.24-2.15 (1H, m), 1.98-1.97 (3H, m), 1.47 (6H, dd, J=6.59, 3.27 Hz)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=O)[NH:8][C:7]2=O)([O-:3])=[O:2].[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>O>[CH2:16]([NH:20][C:9]1[N:8]=[C:7]([NH:1][CH2:4][CH:5]=[C:6]([CH3:11])[CH3:7])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCN
Reactant: O=c1[nH]c(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Solvent: O
Product: CCCCNc1nc(NCC=C(C)C)c2cc([N+](=O)[O-])ccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.9 %

Procedure:
2-chloro-4-(3-methyl-2-butenylamino)-6-nitroquinazoline was obtained in accordance with the process described in Example 59, starting from 278 mg (1.45 mmol) of 6-nitroquinazoline-2,4(1H,3H)-dione. After 1.00 ml (10.12 mmol) of butylamine was added to the compound thus obtained and the reaction mixture was stirred at room temperature for 3 hours, water was added to the reaction solution, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 50 mg (11.9%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[CH:19]=O)[CH:11]=1)[CH3:2].C([BH3-])#N.[Na+].[CH2:26]([NH2:28])[CH3:27].C(O)(=O)C>CO>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[CH2:19][NH:28][CH2:26][CH3:27])[CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cncc(-c2ccc(F)cc2C=O)c1
Reactant: CCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNCc1cc(F)ccc1-c1cncc(CC(=O)OCC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To [5-(4-fluoro-2-formyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester (1.2 g, 4.18 mmol) in MeOH was added sodium cyanoborohydride (0.394 g, 6.26 mmol) and ethylamine (2M in THF; 3.13 mL, 6.26 mmol). Acetic acid (0.36 mL, 6.26 mmol) was added, and the reaction was stirred for 2 hours at room temperature. The mixture was concentrated, and the residue was dissolved in CH2Cl2 and washed with saturated aqueous NaHCO3 and H2O. The organic layer was dried over Na2SO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (0-10% MeOH in CH2Cl2) to give [5-(2-ethylaminomethyl-4-fluoro-phenyl)-pyridin-3-yl]-acetic acid ethyl ester.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](O)=[O:46])([CH3:44])[CH3:43])=[CH:33][C:32]=2[CH3:49])=[C:28]([CH:50]([CH3:52])[CH3:51])[NH:27][N:26]=1)(=O)C.[CH3:53][N:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.NC(C)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45]([N:57]4[CH2:58][CH2:59][N:54]([CH3:53])[CH2:55][CH2:56]4)=[O:46])([CH3:43])[CH3:44])=[CH:33][C:32]=3[CH3:49])=[C:28]([CH:50]([CH3:51])[CH3:52])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)NC(C)(C)C(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CN1CCNCC1
Agent: CC(C)(N)C(N)=O
Product: Cc1cc(OCCC(=O)NC(C)(C)C(=O)N2CCN(C)CC2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 78 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole and 1-methylpiperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide, respectively.
Reaction SMILES: [Na].[CH3:2][O:3][CH2:4][CH2:5][OH:6].Cl.Cl[C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[F:27])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[N+:28]([O-:30])=[O:29]>C(O)(=O)C.O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([O:6][CH2:5][CH2:4][O:3][CH3:2])=[C:10]([N+:28]([O-:30])=[O:29])[CH:11]=3)[N:16]=[CH:15][N:14]=2)=[C:21]([F:27])[CH:22]=1
Reactant: COCCO
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1Cl
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: COCCOc1cc2ncnc(Nc3ccc(Cl)cc3F)c2cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 60 %

Procedure:
Sodium (148 mg, 6.4 mmol) was added to 2-methoxyethanol (10 ml), the mixture stirred for 15 minutes to give a complete solution and the volatiles removed by evaporation. The residue was dissolved in DMSO (5 ml) and 7-chloro-4-(4-chloro-2-fluoroanilino)-6-nitroquinazoline hydrochloride (500 mg, 1.3 mmol) was added. The mixture was stirred at ambient temperature for 18 hours then diluted with a solution of acetic acid (1 ml) in water (20 ml). The resulting precipitate was collected by filtration, washed with water, dried and purified by column chromatography eluting with methylene chloride/methanol (96/4). The purified product was recrystallised from methylene chloride/isohexane to give 4-(4-chloro-2-fluoroanilino)-7-(2-methoxyethoxy)-6-nitroquinazoline (304 mg, 60%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][C:9]=1[NH:10]2.[F:23][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C1COCC1.CC#N>[Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[C:6]([F:23])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][C:9]=1[NH:10]2
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2[nH]c3c(C(N)=O)ccc(Br)c3c2cc1F

Procedure:
A mixture of ethyl 5-bromo-8-carbamoyl-9H-carbazole-2-carboxylate [synthesized according to the procedure described in U.S. Pat. No. 8,084,620, Intermediate 48-1] (0.100 g, 0.277 mmol) and 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) [SELECTFLUOR®] (0.100 g, 0.554 mmol) in THF (2 mL) and MeCN (2 mL) was heated at 60° C. overnight. The cooled mixture was filtered and the filtrate was concentrated. The residue was purified using reverse-phase preparative HPLC to give ethyl 5-bromo-8-carbamoyl-3-fluoro-9H-carbazole-2-carboxylate as a tan solid (0.035 g).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([O:12]C)[CH:5]=[CH:4][C:3]=1[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].B(Br)(Br)Br>ClCCl>[F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([OH:12])[CH:5]=[CH:4][C:3]=1[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CCc1ccc(OC)c(C(F)(F)F)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(O)c(C(F)(F)F)c1F
Temperature: -78 °C

Procedure:
Into a 8-mL sealed tube (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 3-[2-fluoro-4-methoxy-3-(trifluoromethyl)phenyl]propanoate (200 mg, 0.68 mmol, 1.00 equiv), dichloromethane (1.0 mL). This was followed by the addition of BBr3 (1N in dichloromethane) (1.36 mL, 2.00 equiv) dropwise with stirring at −78° C. The resulting solution was warmed to room temperature and stirred for 2 h at 30° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 3×10 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by TLC-Plate with petroleum ether/EtOAc=3:1. This resulted in 85 mg (45%) of ethyl 3-[2-fluoro-4-hydroxy-3-(trifluoromethyl)phenyl]propanoate as a light yellow solid. Mass spectrum (ESI, m/z): Calcd. for C12H12F4O3, 279.1 (M−H). found 279.1.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([N:12]3[CH2:17][CH2:16][CH2:15][CH:14]([N:18]([CH3:20])[CH3:19])[CH2:13]3)=[N:9]2)=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:45]1[CH:46]=[C:47]([NH:52][S:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)(=[O:55])=[O:54])[C:48]([Cl:51])=[N:49][CH:50]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:51][C:48]1[C:47]([NH:52][S:53]([C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)(=[O:55])=[O:54])=[CH:46][C:45]([C:2]2[CH:11]=[C:10]3[C:5](=[CH:4][CH:3]=2)[N:6]=[CH:7][C:8]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([N:18]([CH3:20])[CH3:19])[CH2:13]2)=[N:9]3)=[CH:50][N:49]=1
Reactant: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccccc1
Reactant: CN(C)C1CCCN(c2cnc3ccc(Br)cc3n2)C1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CN(C)C1CCCN(c2cnc3ccc(-c4cnc(Cl)c(NS(=O)(=O)c5ccccc5)c4)cc3n2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 8.3 %

Procedure:
A slurry of 1-(7-bromo-2-quinoxalinyl)-N,N-dimethyl-3-piperidinamine (1.2 mmol), bis(pinacolato)diboron (1.30 mmol), potassium acetate (4.80 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.09 mmol) in 1,4-dioxane (5 ml) was heated at 100° C. After the reaction stirred for 2.5 hours, N-(5-bromo-2-chloro-3-pyridinyl)benzenesulfonamide (1.20 mmol) and 2M solution potassium carbonate (5 ml) was added and continued to stir for 18 hours. The reaction was cooled to ambient temperature, concentrated, redissolved in methanol and purified on reverse phase HPLC (0.1% trifluoracetic acid/water in acetonitrile). The desired fractions were combined, neutralized with saturated sodium bicarbonate, extracted with ethyl acetate (3×20 ml). Combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give the title compound (52 mg, 10%) as a yellow solid. MS(ES)+ m/e 524.2 [M+H]+.
Reaction SMILES: C1(N=C=O)C=CC=CC=1.[Cl:10][C:11]1[C:19]([O:20][CH3:21])=[C:18]([Cl:22])[C:17]([O:23][CH3:24])=[C:13]([CH:14]=[N:15]O)[C:12]=1[OH:25].O>O1CCCC1>[Cl:22][C:18]1[C:19]([O:20][CH3:21])=[C:11]([Cl:10])[C:12]2[O:25][N:15]=[CH:14][C:13]=2[C:17]=1[O:23][CH3:24]
Reactant: COc1c(Cl)c(O)c(C=NO)c(OC)c1Cl
Solvent: O=C=Nc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1c(Cl)c(OC)c2cnoc2c1Cl
Reaction time: 16 h
Yield: 56.5 %

Procedure:
Phenylisocyanate (1.19 g) is added slowly to a solution of 2.66 g of 3,5-dichloro-4,6,-dimethoxysalicylaldoxime in 20 ml of tetrahydrofuran. The clear solution is allowed to stand at room temperature for 16 hours. It is poured into 250 ml of water and the resulting precipitate is filtered, washed with water, and recrystallized from ethanol to give 1.4 g (56.5%) of 5,7-dichloro-4,6-dimethoxy-1,2-benzisoxazole, m.p. 138°-140° C.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C.C([O:41][C:42]1[CH:47]=[C:46]([CH2:48]Br)[CH:45]=[CH:44][C:43]=1[C:50]#[N:51])(=O)C>CC#N>[NH2:51][CH2:50][C:43]1[CH:44]=[CH:45][C:46]([CH2:48][N:18]([CH2:17][C:9]2[NH:8][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH:19]2[C:28]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:22][CH2:21][CH2:20]2)=[CH:47][C:42]=1[OH:41]
Reactant: CC(=O)Oc1cc(CBr)ccc1C#N
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1O
Temperature: 25 °C
Yield: 68.4 %

Procedure:
To a solution of (1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.375 g, 0.99 mmol) in CH3CN (5 mL) was added N,N-diisopropylethylamine (0.35 mL, 2.00 mmol) followed by a solution of (5-bromomethyl-2-cyano-phenyl) acetate (0.318 g, 1.25 mmol) in CH3CN (5 mL). The resultant mixture was heated to 60° C. for 15 hours then cooled to room temperature. The mixture was concentrated and the residue was partitioned between CH2Cl2 (40 mL) and brine (10 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1 CH2Cl2—CH30H) followed by radial chromatography on silica gel (2 mm plate, 2:1 hexanes-EtOAc) provided 0.28 g (51%) of a tan foam.
Reaction SMILES: [NH2:1][C@H:2]([CH2:25][CH3:26])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[C:18]3[C:19]([CH3:23])([CH3:22])[CH2:20][O:21][C:17]=3[C:16]([CH3:24])=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)=[O:4].C(N(CC)CC)C.Cl[C:35](Cl)([O:37]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH2:25]([C@H:2]1[NH:1][C:35](=[O:37])[N:5]([C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[C:18]4[C:19]([CH3:22])([CH3:23])[CH2:20][O:21][C:17]=4[C:16]([CH3:24])=[CH:15][CH:14]=3)=[CH:10][CH:11]=2)[C:3]1=[O:4])[CH3:26]
Reactant: CC[C@@H](N)C(=O)Nc1ccc(Oc2ccc(C)c3c2C(C)(C)CO3)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC[C@H]1NC(=O)N(c2ccc(Oc3ccc(C)c4c3C(C)(C)CO4)nc2)C1=O
Temperature: 0 °C
Yield: 128 %

Procedure:
(2R)-2-amino-N-{6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}butanamide (Intermediate 188, 300 mg, 0.84 mmol) was dissolved in ethyl acetate (6 mL). Triethylamine (0.47 ml, 3.36 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (100 mg, 0.34 mmol) in ethyl acetate (6 mL) was slowly added. At the end of addition the mixture was treated with an aqueous saturated solution of NaHCO3 and two phases were separated. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness to obtain a waxy solid. The residue was purified by flash chromatography on silica gel using cyclohexane/ethyl acetate 70:30 to cyclohexane/ethyl acetate 50:50 as eluents affording the title compound (166 mg) as a white foam.
Reaction SMILES: [N+](C1C=CC=CC=1N=NC1C=C(C(CC)(C)C)C=C(C(CC)(C)C)C=1O)([O-])=O.[N+:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]=[N:39][C:40]1[CH:45]=[C:44]([C:46]([CH2:49][C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:48])[CH3:47])[CH:43]=[CH:42][C:41]=1[OH:54])([O-])=[O:30]>>[OH:54][C:41]1[CH:42]=[CH:43][C:44]([C:46]([CH2:49][C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:48])[CH3:47])=[CH:45][C:40]=1[N:39]1[N+:29]([O-:30])=[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]2=[N:38]1
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: CCC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC)c1
Product: CC(C)(C)CC(C)(C)c1ccc(O)c(-n2nc3ccccc3[n+]2[O-])c1
Yield: 89.7 %

Procedure:
The same procedure as in Example 1 was repeated, except that 2-nitro-2'-hydroxy-3',5'-di-t-amylazobenzene 25.5 g was replaced by 2-nitro-2'-hydroxy-5'-t-octylazobenzene 23.7 g, thus producing 20.3 g of 2-(2-hydroxy-5-t-octylphenyl)benzotriazole-N-oxide having a melting point of 106° to 110° C. at the yield of 90.0%.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][C:10]=3[O:20][CH3:21])[NH:8][C:4]=2[CH:3]=1.[O-:24][C:25]#[N:26].[K+].C(O)(=O)C>O1CCCC1>[NH2:26][C:25]([NH:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][C:10]=3[O:20][CH3:21])[NH:8][C:4]=2[CH:3]=1)=[O:24]
Reactant: N#C[O-]
Reactant: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(N)cc2[nH]1
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(NC(N)=O)cc2[nH]1

Procedure:
One gram (3.0 mmol) of 5-amino-2-(2'-methoxy-4'-methanesulfonyloxy-phenyl)-benzimidazole were dissolved in 20 ml of pure tetrahydrofuran, and then 2.0 gm of potassium cyanate and 5 ml of 2M acetic acid were added successively. After the mixture refluxed for eight hours, the solvent was evaporated off in vacuo, and the residue was mixed with 10 ml of water and neutralized with 5% sodium bicarbonate solution. The crude product precipitated was subjected to suction filtration and chromatographed over 200 gm of silica gel (eluant: methylene chloride with 8% ethanol).