Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:14]=[C:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH:16]=[CH:17][CH:18]=2)[CH2:9][CH2:8]1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[C:36]([C:37](Cl)=[O:38])=[C:35]([CH3:40])[O:34][N:33]=1>C1COCC1.C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[C:36]([C:37]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])[CH:14]=3)[CH2:11][CH2:12]2)=[O:38])=[C:35]([CH3:40])[O:34][N:33]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCN)CC2)c1
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)NCCCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-{3-[1-(5-aminopentyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2-chlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 551.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=O)[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19]>CO>[CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH:6]2[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3][C:2]([CH3:11])([CH3:1])[CH2:7]2)[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Reactant: NCCCCCCN
Solvent: CO
Product: CC1(C)CC(NCCCCCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reaction time: 2 h

Procedure:
162.75 g (1.05 moles) of 2,2,6,6-tetramethyl-4-piperidone dissolved in 200 cc of methanol, 58 g (0.5 moles) of hexamethylenediamine dissolved in 70 cc of methanol, and 0.5 g of Pt (at 10% on carbon) were introduced into a 1 liter autocalve. The mixture was hydrogenated at 80° C and 50 atm pressure for 2 hours.
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][NH2:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.[C:15](OCC)(OCC)(OCC)[CH2:16][CH3:17]>>[Cl:1][C:2]1[C:11]2[N:10]([C:15]([CH2:16][CH3:17])=[N:13][N:12]=2)[C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[C:7]([Cl:14])[CH:8]=2
Reactant: CCOC(CC)(OCC)OCC
Reactant: NNc1nc2cc(Cl)ccc2nc1Cl
Product: CCc1nnc2c(Cl)nc3ccc(Cl)cc3n12
Temperature: 25 °C
Yield: 62 %

Procedure:
2,6-Dichloro-3-hydrazinoquinoxaline (1.0 g., 0.0044 mole), the product of Preparation L(a), was refluxed with 15 ml. of triethyl orthopropionate for 4 hours and cooled to room temperature. The precipitate was recovered by filtration, washed with cyclohexane and air dried to afford 730 mg. (62% yield) of 4,8-dichloro-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. >250° C.
Reaction SMILES: [CH2:1]([C:5]1([CH2:21][CH2:22][CH2:23][CH3:24])[C:17]2[CH:16]=[C:15]([C:18](=O)[CH3:19])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4].Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:1]([C:5]1([CH2:21][CH2:22][CH2:23][CH3:24])[C:17]2[CH:16]=[C:15]([C:18](=[N:26][OH:27])[CH3:19])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4]
Reactant: NO
Reactant: CCCCC1(CCCC)c2ccccc2-c2ccc(C(C)=O)cc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCC1(CCCC)c2ccccc2-c2ccc(C(C)=NO)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
After 5.45 g of 1-(9,9-di-n-butylfluorene-2-yl)-ethanone (12) (17 mmol) was dispersed in 50 ml of ethanol and 1.42 g of hydroxylamine hydrochloride (20.4 mmol) and 1.67 g of sodium acetate (20.4 mmol) were added thereto, the reaction mixture was slowly heated and refluxed for 1 hour. The reaction mixture was cooled to room temperature, and 100 ml of distilled water was added thereto and stirred for about 30 minutes. Then, the product was extracted with 200 ml of ethylacetate and sequentially washed with saturated aqueous sodium bicarbonate solution and 100 ml of distilled water, and the recovered organic layer was dried over anhydrous magnesium sulfate, followed by distilling the solvent under reduced pressure. The obtained solid product was dried, thereby obtaining 4.97 g of 1-(9,9-di-n-butylfluorene-2-yl)-ethanone oxime (13) (87.3%) as a light yellow product.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][OH:12])[CH2:7][C:6]=2[CH:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:12][CH2:11][CH:8]2[CH2:7][C:6]3[CH:5]=[C:4]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:3]=[C:2]([Br:1])[C:10]=3[O:9]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1Cc2cc(-c3ccccc3)cc(Br)c2O1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4ccccc4)cc(Br)c3O2)cc1
Yield: 79.1 %

Procedure:
Treatment of 3-bromo-4-hydroxybiphenyl (15.7 g, 63.0 mmol) with potassium carbonate (34.84 g, 252.0 mmol) and allyl bromide (9.15 g, 75.63 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-5-bromobiphenyl-4-ol. Treatment of 3-allyl-5-bromobiphenyl-4-ol (17.8 g, 61.5 mmol) with 3-chloroperoxybenzoic acid (31.87 g, 184.67 mmol, 77%) followed by potassium carbonate (21.27 g, 153.89 mmol) generally according to the procedure described for Intermediate 9 afforded 15.8 g (84%) of (±)-(7-bromo-5-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanol (15.8 g, 51.77 mmol) with p-toluenesulfonyl chloride (14.79 g, 77.65 mmol) generally according to the procedure described for Intermediate 10 gave 18.8 g (79%) of (±)-(7-bromo-5-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.26 mmol) and phenylboronic acid (0.59 g, 4.89 mmol) generally according to the procedure described for Intermediate 35 afforded 1.17 g, (78%) of (±)-(5,7-diphenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.342 g, 5.26 mmol) generally according to the procedure described for Intermediate 98 afforded 0.39 g (91%) of (±)-2-(azidomethyl)-5,7-diphenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5,7-diphenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.314 g, 1.21 mmol) according to the procedure described in Example 154 afforded 0.34 g (99%) of (±)-(5,7-diphenyl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a white solid, hydrochloride salt. mp >250° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14]N(C)C=O.C(Cl)(=O)C(Cl)=O.CO>ClCCl>[CH3:14][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[Cl:1]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
A slurry of 20 g (99 mmol) of 2-chloro-3-nitrobenzoic acid in 800 mL dichloromethane was cooled in an ice bath. Dimethylformamide (0.40 ml) was added to the reaction mixture followed by dropwise addition of 13.85 g (109 mmol) of oxalyl chloride. The reaction was allowed to warm to room temperature and was stirred for 6 h. Methanol (200 mL) was added dropwise and the reaction was stirred overnight. The solvent was evaporated in vacuo. The residue was triturated with n-hexane. The resulting solid was collected by filtration, washed with hexane and dried in vacuo to give 21.0 g (98%) of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][NH:7][C:8](=[O:22])[NH:9][C:10]1[CH:15]=[C:14](Cl)[CH:13]=[C:12]([S:17]([OH:20])(=[O:19])=[O:18])[C:11]=1[OH:21])[C:3]([OH:5])=[O:4].[H][H]>O.CO.[Pd]>[NH2:1][C@@H:2]([CH2:6][NH:7][C:8](=[O:22])[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:17]([OH:20])(=[O:18])=[O:19])[C:11]=1[OH:21])[C:3]([OH:5])=[O:4]
Reactant: N[C@@H](CNC(=O)Nc1cc(Cl)cc(S(=O)(=O)O)c1O)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CO
Product: N[C@@H](CNC(=O)Nc1cccc(S(=O)(=O)O)c1O)C(=O)O

Procedure:
The compound obtained in Example 6 was dissolved in water and methanol, to which a catalyst amount of Pd/C was added, and the resultant was stirred for three days in a hydrogen atmosphere. After filtrating the catalyst, the solvent was distilled away, and the resultant was purified using purification step A to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32]C3C4N=C(C5N(C(C)C)N=CN=5)SC=4CCOC=3C=2)C1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:35]1[CH:36]=[CH:37][C:38]2[O:47][CH2:46][CH2:45][C:44]3[S:43][C:42]([C:48]4[N:49]([CH:53]([CH3:55])[CH3:54])[N:50]=[CH:51][N:52]=4)=[N:41][C:40]=3[C:39]=2[CH:56]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][CH:12]([C:35]2[CH:36]=[CH:37][C:38]3[O:47][CH2:46][CH2:45][C:44]4[S:43][C:42]([C:48]5[N:49]([CH:53]([CH3:54])[CH3:55])[N:50]=[CH:51][N:52]=5)=[N:41][C:40]=4[C:39]=3[CH:56]=2)[CH2:33][CH2:32]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)OC(C)(C)C)C3)ccc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc1-2

Procedure:
The title compound was prepared by a similar procedure to 3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylic acid tert-butyl ester using 9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 instead of 8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 27 and 4-piperidine-1-carboxylic acid tert-butyl ester zinc iodide instead of 3-azetidine-1-carboxylic acid tert-butyl ester zinc iodide. LCMS: RT=5.12 min, [M+H]+=496
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[C:10]([CH3:18])([CH2:12][CH2:13][C:14]([CH3:17])(Cl)[CH3:15])[CH3:11].[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl>[Br:1][C:2]1[C:3]([OH:8])=[CH:4][C:5]2[C:14]([CH3:17])([CH3:15])[CH2:13][CH2:12][C:10]([CH3:18])([CH3:11])[C:6]=2[CH:7]=1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: Oc1ccccc1Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(Br)c(O)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
To a solution of 2-bromophenol (10 g, 57.8 mmol) and 2,5-dichloro-dimethyl hexane (13.04 g, 69.36 mmol) in 160 mL anhydrous CH2Cl2 at 5° C. was added, portionwise, AlCl3 (2.31 g, 17.34 mmol). Upon addition of AlCl3, HCl gas evolution was observed. The solution changed from yellow to reddish orange. The reaction solution was kept at 5-20° C. for two hours and then allowed to stir at room temperature overnight. The reaction mixture was poured into 160 g of ice and extracted with 160 mL CHCl3). The organic phase was washed with water, aqueous, saturated NaHCO3, saturated NaCl and dried (Na2SO4). The organic solution was then concentrated in vacuo and chromatographed (5 to 10% EtOAc/hexane) to provide 12.83 g of 2-bromo-3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene as a white solid in 80% yield. 1H NMR (400 MHz, CDCl3) δ 7.34(s, 1H, aromatic), 6.93(s, 1H, aromatic), 5.24(s, 1H, phenolic OH), 1.64(s; 4H, 2CH2), 1.23(s, 6H, 2CH3), 1.22(s, 6H, 2CH3).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][NH:6][C:7](=[O:32])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22][C:23]2[CH:28]=[C:27]([CH3:29])[C:26](Br)=[C:25]([CH3:31])[CH:24]=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.[CH:34]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)([CH3:36])[CH3:35]>>[F:20][C:18]([F:19])([F:21])[CH2:17][CH2:16][CH2:15][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:33])=[O:32])=[CH:9][CH:10]=1)[O:22][C:23]1[CH:24]=[C:25]([CH3:31])[C:26]([C:40]2[CH:41]=[CH:42][C:37]([CH:34]([CH3:36])[CH3:35])=[CH:38][CH:39]=2)=[C:27]([CH3:29])[CH:28]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2cc(C)c(Br)c(C)c2)cc1
Reactant: CC(C)c1ccc(B(O)O)cc1
Product: Cc1cc(OC(CCCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(C(C)C)cc1

Procedure:
The title compounds are prepared in a manner substantially similar to Example 128 starting from 3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic acid methyl ester and 4-isopropyl phenyl boronic acid. Isomer 1 MS: 554.2 [M−H]−; Isomer 2 MS: 554.2 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]([C@@H:13]1[CH2:15][C@@H:14]1[F:16])[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[CH:21]1([NH:24][CH2:25][C@@H:26]2[C@H:30]([F:31])[CH2:29][NH:28][CH2:27]2)[CH2:23][CH2:22]1>>[CH:21]1([NH:24][CH2:25][C@@H:26]2[C@H:30]([F:31])[CH2:29][N:28]([C:11]3[CH:10]=[C:9]4[C:4]([C:5](=[O:20])[C:6]([C:17]([OH:19])=[O:18])=[CH:7][N:8]4[C@@H:13]4[CH2:15][C@@H:14]4[F:16])=[CH:3][C:2]=3[F:1])[CH2:27]2)[CH2:23][CH2:22]1
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Reactant: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2cc(F)c(F)cc2c1=O
Product: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2cc(N3C[C@H](CNC4CC4)[C@H](F)C3)c(F)cc2c1=O
Yield: 48.2 %

Procedure:
Using 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (283 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (190 mg), the same procedure was followed as in Example 23 to give 7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as pale yellow crystals (203 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1)([O-])=O.I[CH3:25].[H-].[Na+]>CN(C=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:25])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccncc2[N+](=O)[O-])CC1
Reactant: CI
Agent: [Pd]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccncc2N)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl N-[1-(3-nitro-4-pyridyl)-4-piperidyl]carbamate (2100 mg, 6.514 mmol) (prepared according to methods similar to the one depicted in Step 1 of Preparation N-1) and iodomethane (4.623 g, 2.028 mL, 32.57 mmol) in DMF at 0° C. was added portionwise sodium hydride (312.7 mg, 7.817 mmol). The reaction was stirred at 0° C. for 1 h, and at room temperature for 1 h. The reaction was quenched by pouring the reaction mixture onto a saturated aqueous solution of ammonium chloride, then extracted with ethyl acetate (2×50 mL). The combined organics was washed with brine (2×50 mL), dried and evaporated to leave an orange solid. To the crude solid dissolved in MeOH (50 mL) was added Pd/C (10%) (346 mg) and the mixture was stirred under a hydrogen atmosphere for 4 h. The reaction was filtered through celite and evaporated to leave tert-butyl (1-(3-aminopyridin-4-yl)piperidin-4-yl)(methyl)carbamate as a yellow oil. (600 mg, 20%) MS (ES+-tBu) 251.1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[N+:23]([O-])=O)[C:4]=1[OH:26].[OH-].[Na+].C(S(O)=O)(N)=N>O.C(O)CC>[OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([N:11]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]3=[N:23]2)[C:4]=1[OH:26]
Reactant: COc1cc(CO)c(O)c(N=Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])c1
Agent: N=C(N)S(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Solvent: O
Product: COc1cc(CO)c(O)c(-n2nc3ccc(C(F)(F)F)cc3n2)c1
Temperature: 80 °C
Yield: 31.3 %

Procedure:
In a 250 ml round bottom flask equipped with a magnetic stirrer was added 7.70 g (20.7 mmol) 2-(hydroxymethyl)-4-methoxy-6-((2-nitro-4-(trifluoromethyl)phenyl)diazenyl)-phenol from Example 2 part 1, 25 ml deionized water, 1.85 g sodium hydroxide, and 80 ml 1-propanol. The mixture was heated to 80° C. and 6.55 g (60.6 mmol) formamidine sulfinic acid (Aldrich) was added slowly and concurrently with a solution of 3.0 g NaOH in 50 ml deionized water. The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was cooled at −20° C. for 2 hours and filtered. The solid was dissolved in 2.5 L deionized water containing 4 grams NaOH. The pH was adjusted to 2.0 using 1 N HCl. The resultant solid was filtered, washed with ample amounts of deionized water, filtered and dried to give 2.2 g (31%) of a yellow solid. 1H NMR (CDCl3) delta: 11.03 (s, 1H, Ar—OH), 8.30 (s, 1H, Ar—H benzotriazole 4-position), 8.07 (d, 1H, Ar—H benzotriazole 6-position), 7.88 (s, 1H, Ar—H phenol), 7.69 (d, 1H, Ar—H benzotriazole), 7.08 (s, 1H, Ar—H phenol), 4.84 (s, 2H, Ar—CH2), 3.90 (s, 3H, Ar—OCH3).
Reaction SMILES: N[C:2]1[N:3]=[C:4]([O:11][CH3:12])[C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1.N([O-])=O.[Na+].C(Cl)(Cl)Cl.[FH:21].N1C=CC=CC=1>>[F:21][C:2]1[N:3]=[C:4]([O:11][CH3:12])[C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1
Reactant: F
Reactant: COc1nc(N)cnc1C(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1nc(F)cnc1C(N)=O
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
In a nitrogen atmosphere, 0.5 g of 5-amino-3-methoxy-2-pyrazinecarboxamide is dissolved in 9 mL of 70% pyridine hydrofluoride under ice-cooling. Then, 0.23 g of sodium nitrite is added thereto at −70° C., and the resulting solution is heated to a temperature of −10° C. in 30 minutes. Further, the solution is stirred at ambient temperature for 30 minutes. A mixture of 30 mL of ice water and 100 mL of chloroform is added thereto and the resulting mixture is separated into layers. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue thus obtained is purified by column chromatography (eluent: chloroform:methanol =10:1) to obtain 0.37 q of 5-fluoro-3-methoxy-2-pyrazinecarboxamide.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][N:17]=[C:18]2[C:21]2([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:24][CH2:23][CH2:22]2)=[CH:13][CH:12]=1)(C)(C)C.Cl>ClCCl.C(O)(C)C>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:21]2([C:18]3[C:19]4[C:14](=[CH:13][CH:12]=[C:11]([O:10][CH2:9][CH2:8][NH2:7])[CH:20]=4)[CH2:15][CH2:16][N:17]=3)[CH2:24][CH2:23][CH2:22]2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)=NCC2
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)=NCC2
Temperature: 25 °C

Procedure:
tert-Butyl[2-({1-[1-(4-fluorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-yl}oxy)ethyl]carbamate (2.5 g, 5.7 mmol) was dissolved in dichloromethane (30 mL) and 5N hydrochloric acid in isopropanol (20 mL) was added. After stirring over night at room temperature the solvent was evaporated in vacuo. Water (30 mL) was added and the aqueous phase was neutralized with saturated aqueous NaHCO3 and extracted with dichloromethane. The combined organic layers were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The crude product (1.76 g) was used without purification for the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=1[O:18][CH3:19])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[C:30]([C:33](O)=[O:34])[NH:31][CH:32]=2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[C:30]([C:33]([NH:17][C:14]3[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][NH:7][C:6](=[O:20])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[C:12]([O:18][CH3:19])[CH:13]=3)=[O:34])[NH:31][CH:32]=2)=[CH:24][CH:23]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Reactant: COc1cc(N)ccc1OCCNC(=O)OC(C)(C)C
Product: COc1cc(NC(=O)c2cc(-c3ccc(Cl)cc3)c[nH]2)ccc1OCCNC(=O)OC(C)(C)C

Procedure:
tert-Butyl-(4-amino-2-methoxyphenoxy)ethylcarbamate was converted to the title compound (80 mg) by acylation with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid (25 mg) following the procedure described in step C of Example 1. MS (ESI) 386 (M-Boc)+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[NH2:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([C:26](=[O:30])[C:27]([NH2:29])=[O:28])=[C:11]([CH2:24][CH3:25])[N:12]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.O>[CH3:6][O:5][C:3](=[O:4])[CH2:2][NH:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([C:26](=[O:30])[C:27]([NH2:29])=[O:28])=[C:11]([CH2:24][CH3:25])[N:12]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CBr
Reactant: CCc1c(C(=O)C(N)=O)c2c(N)cccc2n1Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(C(=O)C(N)=O)c2c(NCC(=O)OC)cccc2n1Cc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
Methyl bromoacetate (0.07 ml, 0.78 mmol) was added to 250 mg (0.78 mmol) of 4-Amino-2-Ethyl-α-oxo-1-(phenylmethyl)-1H-indole-3-Acetamide in 4 ml of DMF, stirred at 60° C. for 0.5 hour, and then at room temperature for 20 hours. The mixture was diluted with water and extracted with EtOAc. The EtOAC solution was washed with brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed over silica gel eluting with Hexane/50 to 100% EtOAc to give 196 mg (64%) of [[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]amino]acetic acid methyl ester melting at 188-193° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]([O:18]C)=[O:17])[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.C(O)(=O)C.Cl>O>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]([OH:18])=[O:17])[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccccc1-c1cc(-c2cccc(C(F)(F)F)c2)no1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccccc1-c1cc(-c2cccc(C(F)(F)F)c2)no1
Yield: 65 %

Procedure:
A solution of 6.20 g of methyl 2-[3-(3-trifluoromethylphenyl)-5-isoxazolyl]benzoate, 75 ml. of acetic acid, and 50 ml. of concentrated HCl was held at reflux for 4 hours, cooled, and poured into 450 ml. of cold water. The resultant solid was recrystallized from CH3CN to give 3.87 g of solid, mp 176°-177° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[CH:6][C:5]([NH:16][C:17](=[O:19])[CH3:18])=[C:4]([F:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].O>CN(C)C=O>[C:17]([NH:16][C:5]1[C:4]([F:20])=[CH:3][C:2]([Cl:1])=[C:7]([CH:6]=1)[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])(=[O:19])[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)Nc1cc(Oc2ccccc2O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1Cl
Temperature: 25 °C

Procedure:
N-[4-chloro-2-fluoro-5-(2-hydroxyphenoxy)phenyl]acetamide is dissolved in N,N-dimethylformamide, then, potassium carbonate is added and the mixture is stirred at room temperature. Then, ethyl bromoacetate is added at room temperature. The mixture is stirred under the same temperature, poured into water, extracted with ethyl acetate, the organic layer is washed with dilute hydrochloric acid, washed with water, dried over magnesium sulfate and concentrated, and the resulted crystal is washed with t-butyl methyl ether to obtain ethyl [2-(5-acetylamino-2-chloro-4-fluorophenoxy)phenoxy]acetate.