Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[CH3:22][P:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([CH2:33][CH3:34])[CH:27]=1)([CH3:25])=[O:24].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([P:23]([CH3:25])([CH3:22])=[O:24])=[CH:27][C:28]=2[CH2:33][CH3:34])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Reactant: CCc1cc(P(C)(C)=O)ccc1N
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: CC(C)O
Product: CCc1cc(P(C)(C)=O)ccc1Nc1nnc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 4-(Dimethylphosphoryl)-2-ethylaniline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][C:11]([O:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([N+:23]([O-])=O)=[CH:18][C:17]=1[Cl:26])=[CH:10]2)=[O:4].[NH4+].[Cl-]>CCO.C1COCC1.O.[Fe]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][C:11]([O:15][C:16]1[C:17]([Cl:26])=[CH:18][C:19]([NH2:23])=[CH:20][C:21]=1[Cl:22])=[CH:10]2)=[O:4]
Reactant: COC(=O)c1cccc2cc(Oc3c(Cl)cc([N+](=O)[O-])cc3Cl)cnc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc2cc(Oc3c(Cl)cc(N)cc3Cl)cnc12
Temperature: 25 °C
Yield: 118.7 %

Procedure:
To a solution of 3-(2,6-Dichloro-4-nitro-phenoxy)-quinoline-8-carboxylic acid methyl ester (98) (1.26 mmol) and NH4Cl (370 mg, 6.91 mmol) in EtOH/THF/H2O=8 mL/4 mL/2 mL was added iron powder (386 mg, 6.91 mmol). The reaction mixture was refluxed for 3.5 h. After cooling to room temperature and insoluble materials were filtered by Celite filtration. The filtrate was concentrated and sat NaHCO3 was added to the residue, which was extracted twice with AcOEt. Organic layer was washed by brine, dried over MgSO4, and concentrated. Crude residue was purified by column chromatography (hexane/AcOEt=2/1, 80 g of silica gel) to afford compound 99 (543 mg). 1H NMR (300 MHz, DMSO-d6) δ 3.91 (3H, s), 5.77 (2H, br s), 6.78 (2H, s), 7.50 (1H, d, J=3.0 Hz), 7.61 (1H, dd, J=8.1 Hz), 7.81 (1H, dd, J=1.4, 6.4 Hz), 8.08 (1H, dd, J=1.4 Hz, 6.4 Hz), 8.93 (1H, d, J=3.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([NH2:37])[C:31]=3[CH:30]=[N:29]2)=[CH:24][CH:23]=1>>[F:14][C:13]([F:16])([F:15])[C:10]([CH2:12][NH:37][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:31]=1[CH:30]=[N:29][N:28]2[C:25]1[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=1)([OH:11])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:19][CH3:20])([CH3:18])[CH3:17]
Reactant: Nc1cccc2c1cnn2-c1ccc(F)cc1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F

Procedure:
Prepared similarly to Example 1 from racemic 2-{2-[5-fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane and 1-(4-fluorophenyl)-1H-indazol-4-amine (Intermediate 2).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([CH:39]=[CH:40][CH:41]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:37][CH3:38])=[C:13]([O:16][C@H:17]3[CH2:21][N:20]([C:22](OC(C)(C)C)=O)[C@H:19]([C:29]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[O:30])[CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.C=O>C(O)=O>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([CH:39]=[CH:40][CH:41]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:37][CH3:38])=[C:13]([O:16][C@H:17]3[CH2:21][N:20]([CH3:22])[CH:19]([C:29]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[O:30])[CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1C[C@@H](C(=O)N2CCOCC2)N(C(=O)OC(C)(C)C)C1
Agent: C=O
Solvent: O=CO
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CC(C(=O)N2CCOCC2)N(C)C1
Yield: 22.6 %

Procedure:
A solution of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2S,4R)-1-(tert-butoxycarbonyl)-2-(morpholinocarbonyl)pyrrolidin-4-yloxy]quinazoline (0.3 g), formic acid (3.0 ml) and paraformaldehyde (0.047 mg) was stirred at 80° C. for 8 hours. The reaction was cooled, reduced under vacuum and adsorbed onto silica. The product was eluted with increasingly polar mixtures of methylene chloride/methanol (100/0 to 90/10). The fractions containing the desired product were combined and evaporated under vacuum. The product was then re-purified by preparative HPLC on a reverse phase Hi-Chrom HIRPB column. The product was eluted with decreasingly polar mixtures of acetonitrile/water (0.1% trifluoroacetic acid) (20/80 to 50150). The fractions containing the desired product were combined and evaporated under vacuum and the residue dissolved in methylene chloride/methanol (saturated with ammonia) and adsorbed onto silica. The product was eluted with increasingly polar mixtures of methylene chloride/methanol (saturated with ammonia) (100/0 to 90/10). The fractions containing the desired product were combined and evaporated under vacuum to give the title product as a colourless foam (0.058 g); 1H NMR Spectrum: (DMSO d6) 2.10-2.18 (m, 1H), 2.31 (s, 3H), 2.53-2.60 (m, 1H), 3.44-3.67 (m, 10H), 3.72 (t, 1H), 3.92 (s, 3H), 5.10 (m, 1H), 7.21 (s, 1H), 7.28 (t, 1H), 7467.56 (m, 2H), 7.71 (s, 1H), 8.36 (s, 1H), 9.64 (s, 1H); Mass Spectrum: (M+H)+ 516.
Reaction SMILES: OCC[O:4][C:5]1[CH:24]=[CH:23][C:8]([C:9]2[O:10][C:11]3[C:16]([C:17](=[O:19])[CH:18]=2)=[CH:15][C:14]([C:20]([OH:22])=[O:21])=[CH:13][CH:12]=3)=[CH:7][CH:6]=1.[Na]>>[OH:4][C:5]1[CH:24]=[CH:23][C:8]([C:9]2[O:10][C:11]3[C:16]([C:17](=[O:19])[CH:18]=2)=[CH:15][C:14]([C:20]([OH:22])=[O:21])=[CH:13][CH:12]=3)=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc2oc(-c3ccc(OCCO)cc3)cc(=O)c2c1
Agent: [Na]
Product: O=C(O)c1ccc2oc(-c3ccc(O)cc3)cc(=O)c2c1

Procedure:
4'-(2-hydroxyethoxy)flavone-6-carboxylic acid, m.pt. (sodium salt, 2.5 hydrate) above 360° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:13]2[CH2:18][CH2:17][C:16]([OH:25])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[CH2:10][NH:11][CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.C(OCC)C.CCCCCC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:13]2[CH2:14][CH2:15][C:16]([OH:25])([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]2)[CH2:10][N:11]([CH3:12])[C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cl)c1ccccc1
Reactant: CNCC(c1ccc(Cl)c(Cl)c1)N1CCC(O)(c2ccccc2)CC1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CN(CC(c1ccc(Cl)c(Cl)c1)N1CCC(O)(c2ccccc2)CC1)C(=O)c1ccccc1

Procedure:
N-[2-(3,4-Dichlorophenyl)-2-(4-hydroxy-4-phenylpiperidino)-ethyl]methylamine (450 mg), benzoyl chloride (168 mg), and triethylamine (120 mg) in tetrahydrofuran were stirred at 23° C. for 48 hours. The reaction was filtered concentrated to a gold oil. Chromatography, with chloroform and then methanol:chloroform (5:95) as the eluent, gave a gold oil. Trituration of the oil with diethylether/hexane provided a white solid; MS: m/z=483(M+1); NMR: 1.77 (m,2), 2.4 (m,1), 2.63 (m,1), 2.72 (m,3), 3.2 (m,3), 3.83 (m,1), 4.36 (m,2), 4.93 (m,1), 5.43 (broad s,1), 7.03 (m,2), 7.41 (m,7), 7.83 (m,2). Analysis Calculated: C, 60.28; H, 5.8; N, 5.21; Found: C, 60.25; H, 5.52; N, 5.14.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([NH2:17])[CH3:16]>C(O)C>[CH2:15]([NH:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH3:16]
Reactant: CCN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCO
Product: CCNc1c([N+](=O)[O-])cnc2ccccc12
Yield: 97 %

Procedure:
To a stirred suspension of 1.40 g of 4-chloro-3-nitroquinoline in 30 ml of dry ethanol is introduced excess amount of gaseous ethylamine at room temperature for 3 hours. Treatment of the reaction mixture as in Example 98 yielded 1.41 g (97%) of 4-ethylamino-3-nitroquinoline. Recrystallization from the ethyl acetate-n-hexane affords yellow crystals melting at 151°-152° C.
Reaction SMILES: [C:1]1([P:7]2(=[O:22])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][N:8]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.F[B-](F)(F)F.[O:31]=[N+:32]=[O:33]>C(OCC)C>[C:1]1([P:7]2(=[O:22])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][N:8]2[C:16]2[CH:17]=[CH:18][C:19]([N+:32]([O-:33])=[O:31])=[CH:20][CH:21]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=P1(c2ccccc2)c2ccccc2CN1c1ccccc1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N2Cc3ccccc3P2(=O)c2ccccc2)cc1
Temperature: 26 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
Under a static nitrogen atmosphere, a solution of 1,2-diphenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (1.0 g, 0.0033 mol) in 10 ml. of methylene chloride was dropwise added to a constantly stirred suspension of nitronium tetrafluoroborate (0.47 g, 0.0035 mol) in 25 ml. of methylene chloride while maintaining the temperature between -5° C. and 5° C. The reaction mixture was stirred for 3 hours at 26° C. and then added to 40 ml. of ice water. The layers were separated and the aqueous layer was extracted with methylene chloride. The methylene chloride layers were combined, dried over magnesium sulfate, and concentrated in vacuo to yield a residue which was purified on a silica gel column using ethyl acetate as the eluant. Fractions containing the benzazaphosphole were combined and concentrated in vacuo to produce a crude product. The crude product was slurried in diethyl ether to yield 1-phenyl-2-(4-nitrophenyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (0.9 g, 78% yield) as a yellow solid having a melting point of 255°-257° C. and the following analysis:
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[CH2:39]([O:46][C:47](Cl)=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:47]([O:46][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:48])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCc2c([nH]c3ccccc23)C1c1ccc2c(c1)OCO2
Reaction time: 16 h

Procedure:
To a solution of 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (9.11 g, 31.1 mmol) (prepared according to the process as disclosed in WO97/43287, Intermediate 7, page 24) in dry dichloromethane (100 mL) were added triethylamine (8.80 mL, 63.1 mmol) and dimethylaminopyridine (5 mg), followed by the dropwise addition of benzylchloroformate (4.60 mL, 30.6 mmol) over a period of 30 min. The reaction mixture was stirred for 16 h, transferred to a separatory funnel, washed with 2N HCl, brine, dried over anhydrous magnesium sulfate and concentration in vacuo. Flash chromatography yielded the product as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:22][CH:23]([OH:26])[CH2:24][OH:25]>O>[OH:26][CH:23]([CH2:24][OH:25])[CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[O:7])=[CH:17][CH:18]=1
Reactant: O=C(c1ccc(O)cc1)c1c[nH]c2ccccc12
Reactant: OCC(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(c1ccc(OCC(O)CO)cc1)c1c[nH]c2ccccc12
Reaction time: 3 h

Procedure:
11 g of 3-(p-hydroxybenzoyl)indole and 7.43 g of sodium hydroxide were dissolved in 10 ml of water. 20.51 g of 3-chloro-1,2-propandiol was added to the solution followed by reflux with stirring for 3 hours in oil bath. After cooling, the solution was evaporated to dryness. The residue was purified by column chromatography on silica gel. After recrystallization from ethyl acetate, 3-[p-(2,3-dihydroxypropoxy)benzoyl]indole (compound 16) was obtained in the form of white crystals. (Yield: 13.8%).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:6]>C1COCC1.CO.O>[C:13]1([N:10]2[CH2:11][CH2:12][CH:7]([C:5]([OH:6])=[O:4])[CH2:8][CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)C1CCN(c2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
LiOH (43 mg, 1.03 mmol) was added at room temperature to a stirred solution of 1-phenyl-piperidine-4-carboxylic acid methyl ester (150 mg, 0.68 mmol) in THF:MeOH:H2O (3:1:1, 3.2 mL). The resulting mixture was stirred at room temperature overnight. The MeOH and THF were evaporated and the residue was diluted with water (2 mL), acidified with citric acid solution and extracted with EtOAc. The organic layer was washed with saturated brine, dried over Na2SO4 and concentrated under reduced pressure to afford 94 mg (67.14% yield) of 1-phenyl-piperidine-4-carboxylic acid. LCMS purity: 95.98%.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4](=[S:7])[NH:5][NH2:6].[CH3:13][O:14][N:15]([CH2:23][CH2:24][C:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>C(O)C>[F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4]1[S:7][C:25]([CH2:24][CH2:23][N:15]([O:14][CH3:13])[C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH:6][N:5]=1
Reactant: CON(CCC(=O)c1ccccc1)C(=O)OC(C)(C)C
Reactant: NNC(=S)c1cc(F)ccc1F
Solvent: CCO
Product: CON(CCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1)C(=O)OC(C)(C)C
Yield: 54.5 %

Procedure:
A mixture of 2,5-difluorobenzothiohydrazide (0.500 g 2.66 mmol) and tert-butyl methoxy(3-oxo-3-phenylpropyl)carbamate (1.11 g, 3.99 mmol) was stirred together in ethanol (5 mL) for 30 hours. The reaction mixture was concentrated under reduced pressure, and the residue was chromatographed (20% ethyl acetate in hexanes) to provide die product (0.650 g, 1.45 mmol) that was used in the next step without further purification.
Reaction SMILES: Br[C:2]([F:15])([F:14])[C:3](F)([F:12])[O:4][C:5]1[CH:6]=[C:7]([Br:11])[CH:8]=[CH:9][CH:10]=1>[Zn].C(#N)C>[F:12][C:3]([O:4][C:5]1[CH:6]=[C:7]([Br:11])[CH:8]=[CH:9][CH:10]=1)=[C:2]([F:14])[F:15]
Reactant: FC(F)(Br)C(F)(F)Oc1cccc(Br)c1
Agent: [Zn]
Solvent: CC#N
Product: FC(F)=C(F)Oc1cccc(Br)c1
Yield: 79.4 %

Procedure:
Acetonitrile (3.5 L) and zinc (Zn) (0.462 mol) were put in a 2-bulb flask and mixed at 80° C. Then, 3-(2-bromotetrafluoroethoxy)bromobenzene prepared in (1) was slowly dropped for 3 hours. The reaction mixture was refluxed for 10 hours and then evaporated. The unpurified product was extracted with hexane. Hexane remaining in the filtrate was removed using a vacuum evaporator to obtain 3-[(trifluorovinyl)oxy]bromobenzene, which is in liquid state at room temperature (yield: 79.4%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[N:9]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9]
Reactant: Nc1ccccc1I
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccccc1I
Temperature: 0 °C
Yield: 44 %

Procedure:
21.9 g (100 mmol) o-iodophenyl amine was dissolved in 40 mL concentrated hydrochloric acid. At 0° C., 6.9 g (100 mmol) sodium nitrite (dissolved in 35 mL water) was added dropwise, and stirred at 0° C. for half an hour. Then, SnCl2.2H2O 64.7 g (300 mmol) (dissolved in 70 mL concentrated hydrochloric acid) was added dropwise slowly, and reacted for about 3 h until complete. It was filtered to obtain a white solid, washed with a saturated solution of sodium chloride, and then washed with a mixed solvent of petroleum ether and diethyl ether (1:1). Then, the solid was adjusted to be basic with sodium hydroxide solution. The solid impurity therein was filtered, the aqueous phase was extracted with dichloromethane several times, the organic phases combined, dried, rotate evaporated to dryness to obtain a colorless oil 10.3 g, at a yield of 44.0%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:5]=[C:6]([O:8]CC2C=CC(OC)=CC=2)[CH:7]=1.C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O>O>[Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([NH:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:3]=1
Reactant: COc1ccc(COc2cc(Br)cc(Nc3cccnc3)c2)cc1
Solvent: CSc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Oc1cc(Br)cc(Nc2cccnc2)c1
Reaction time: 1.67 h
Yield: 50.2 %

Procedure:
[3-Bromo-5-(4-methoxy-benzyloxy)-phenyl]-pyridin-3-yl-amine (26.7 g, 69.2 mmol) was dissolved in thioanisole (62 mL, 529 mmol). Trifluoroacetic acid (81 mL, 1.06 mol) was added slowly with the temperature held between 20 and 25° C. over a period of 100 min. The solution was left to stand at room temperature for 2 hours. The reaction solution was diluted with water (100 mL) and concentrated to a small volume (˜30 mL). To the residue were added TBME (250 mL), water (300 mL) and methanol (30 mL). The organic layer was extracted with a mixture of 4N hydrochloric acid and methanol. The combined aqueous layers were diluted with methanol (100 mL), washed with methylene chloride (3×150 mL) and neutralized with 4N NaOH (440 mL) to pH 7. The precipitated white solid was collected, washed with cold water (2×10 mL) and dried in a vacuum oven overnight at 60° C. 3-Bromo-5-(pyridin-3-ylamino)-phenol (9.21 g, 50%) was obtained as an off white solid.
Reaction SMILES: [F:1][C:2]([F:25])([CH:22]([F:24])[F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[N:14]([C@H:17]([CH3:21])[C:18](O)=[O:19])[N:13]=[CH:12]2)=[CH:7][CH:6]=1.S(Cl)([Cl:28])=O>>[F:1][C:2]([F:25])([CH:22]([F:24])[F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[N:14]([C@H:17]([CH3:21])[C:18]([Cl:28])=[O:19])[N:13]=[CH:12]2)=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: C[C@H](C(=O)O)n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Product: C[C@H](C(=O)Cl)n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
To 2.0 g of (2R)-2-[4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]propanoic acid was added 20 ml of thionyl chloride and the mixture was stirred at 80° C. for 40 minutes. The reaction solution was concentrated under reduced pressure to give 2.1 g of (2R)-2-[4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]propanoyl chloride as a pale yellow oil. This product was used for the next step without purification.
Reaction SMILES: [CH2:1]([CH:11]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72]CC)[CH2:12][N:13]=[C:14]([C:16]1[C:25]2[C:24]([C:26]([OH:28])=[O:27])=[C:23]([Br:29])[C:22]([Br:30])=[C:21]([C:31]([OH:33])=[O:32])[C:20]=2[C:19]([C:34](=[N:36][CH2:37][CH:38]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]CC)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]CC)[OH:35])=[C:18]([Br:61])[C:17]=1[Br:62])[OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]CC.C(C(CCCCCCCCCC)CN)CCCCCCC>>[CH2:51]([CH:38]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:37][N:36]=[C:34]([C:19]1[C:20]2[C:21]([C:31]([OH:33])=[O:32])=[C:22]([Br:30])[C:23]([Br:29])=[C:24]([C:26]([OH:28])=[O:27])[C:25]=2[C:16]([C:14](=[N:13][CH2:12][CH:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[OH:15])=[C:17]([Br:62])[C:18]=1[Br:61])[OH:35])[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58]
Reactant: CCCCCCCCCCCCC(CCCCCCCCCC)CN=C(O)c1c(Br)c(Br)c(C(O)=NCC(CCCCCCCCCC)CCCCCCCCCCCC)c2c(C(=O)O)c(Br)c(Br)c(C(=O)O)c12
Agent: CCCCCCCCCCC(CN)CCCCCCCC
Product: CCCCCCCCCCC(CCCCCCCC)CN=C(O)c1c(Br)c(Br)c(C(O)=NCC(CCCCCCCC)CCCCCCCCCC)c2c(C(=O)O)c(Br)c(Br)c(C(=O)O)c12
Yield: 33 %

Procedure:
The same synthetic method for compound 22 was used except using 2-octyldodecyl amine instead of 2-decyltetradecyl amine, and the yield was 33% (calculated based on the TBNDA as a starting material).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([NH:16][C@H:17]1[C@@H:24]2[C@@H:20]([CH2:21][N:22]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[CH2:23]2)[CH2:19][CH2:18]1)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=O)(C)(C)C>CCOCC>[F:34][C:32]([F:33])([F:35])[C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][N:22]1[CH2:23][C@H:24]2[C@@H:17]([NH:16][C:14](=[O:15])[C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[NH2:8])[CH2:18][CH2:19][C@H:20]2[CH2:21]1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H]1CC[C@@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@@H]21
Solvent: CCOCC
Product: CC(C)C[C@H](N)C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N2-(tert-butyloxycarbonyl)-N1-{(3aR*,4R*,6aS*)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide (140 mg, 0.281 mmol) from Example 137 and 2 NHCl (2.5 mL, 5.00 mmol) were combined in ether, and the reaction was stirred at room temperature overnight. The solids were collected and dried to give the title compound as the hydrochloride salt: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.59 (s, 0.5H), 8.48 (s, 0.5H), 7.89 (s, 0.5H), 7.83 (s, 0.5H), 7.69 (t, J=6.8, 1H), 7.60 (d, J=7.8, 1H), 7.50-7.44 (m, 1H), 4.96 (br s, 2H), 4.57-4.48 (m, 1H), 3.73 (d, J=13.2, 0.5H), 3.67 (s, 1H), 3.64 (d, J=13.2, 1H), 3.39 (d, J=13.1, 0.5H), 3.35 (d, J=13.2, 0.5H), 2.81-2.70 (m, 2H), 2.45 (dd, J=7.5, 15.3, 1H), 2.39-2.31 (m, 1H), 2.27-2.14 (m, 2H), 1.95-1.79 (m, 2.5H), 1.72-1.56 (m, 2H), 1.53-1.46 (m, 0.5H), 1.33-1.23 (m, 1.5H), 0.90 (dt, J=6.2, 14.1, 6H); MS (ESI+) m/z 398 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:8]=1[Cl:34])[CH3:6])=[O:4].[CH3:35][NH:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][C:47](O)=[O:48])[CH2:41][CH2:40]1)=[O:38]>>[Cl:34][C:8]1[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:47](=[O:48])[CH2:46][CH2:45][N:42]1[CH2:43][CH2:44][N:39]([C:37]([NH:36][CH3:35])=[O:38])[CH2:40][CH2:41]1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Reactant: CNC(=O)N1CCN(CCC(=O)O)CC1
Product: CNC(=O)N1CCN(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)CC1

Procedure:
A mixture of 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide and 3-(4-(methylcarbamoyl)piperazin-1-yl)propanoic acid was coupled as described for the preparation of 2 to give 4-(3-((2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)-N-methylpiperazine-1-carboxamide (7).