Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25](Br)[CH:26]=4)[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.CN(C)[CH:33]=[O:34].[Cl-].[NH4+]>CCCCCC.O1CCCC1.C(OCC)(=O)C>[F:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([CH2:33][OH:34])[CH:26]=4)[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1
Reactant: Fc1ccc(CCN2CCC(N3CCc4ccc(Br)cc43)CC2)cc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 2.5 M solution (100 ml) of n-butyllithium in hexane was added dropwise at −78° C. into a solution (2 l) of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-bromoindoline (80 g) in tetrahydrofuran over 15 min. After 10 min, dimethylformamide (23.2 ml) was added thereto and the resultant mixture was warmed to room temperature. Next, a saturated aqueous solution of ammonium chloride (400 ml) and ethyl acetate (1 l) were added thereto and the layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the resulting reside were added ethanol (240 ml) and sodium borohydride (7.6 g) and the resultant mixture was stirred at room temperature for 1 hr. After adding ice water (480 ml) to the reaction solution, the resulting crystals were collected by filtration, washed with water and air-dried at 50° C. over day and night to give the title compound (about 71 g) as a yellow powder. A portion of this crude product was purified by silica gel column chromatography (ethyl acetate/methanol system) followed by conversion into a hydrochloride in a conventional manner to give the hydrochloride of the title compound as a pale purple powder.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:31]([Cl:34])=[CH:32][N:33]=1)[C:5]([NH:7][C:8]1[CH:30]=[CH:29][C:11]2[CH2:12][CH2:13][C:14]3[C:15]([C:26]([NH2:28])=[O:27])=[N:16][N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:18]=3[C:10]=2[CH:9]=1)=[O:6].[CH3:35][N:36]1[CH2:42][CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:34][C:31]1[C:4]([C:5]([NH:7][C:8]2[CH:30]=[CH:29][C:11]3[CH2:12][CH2:13][C:14]4[C:15]([C:26]([NH2:28])=[O:27])=[N:16][N:17]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=5)[C:18]=4[C:10]=3[CH:9]=2)=[O:6])=[CH:3][C:2]([N:39]2[CH2:40][CH2:41][CH2:42][N:36]([CH3:35])[CH2:37][CH2:38]2)=[N:33][CH:32]=1
Reactant: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(NC(=O)c3cc(Cl)ncc3Cl)cc1-2
Reactant: CN1CCCNCC1
Product: CN1CCCN(c2cc(C(=O)Nc3ccc4c(c3)-c3c(c(C(N)=O)nn3-c3ccc(F)cc3)CC4)c(Cl)cn2)CC1
Reaction time: 24 h
Yield: 78.3 %

Procedure:
The title compound was synthesized by the same procedure as in Example 214 starting with the title compound of Example 248 (1 g, 0.0020 mol) and 1-methylhomopiperazine (4.6 g, 0.040 mol). The reaction was run at 95° C. for 24 h. After allowing the reaction mixture to cool, the volatiles were removed under vacuum. The residue was triturated with H2O to yield 0.899 g of the title compound as a tetrahydrate (yield: 71%). 1H NMR (300 MHz, d6-DMSO): δ 1.81–1.83 (m, 2H), 2.21 (s, 3H), 2.41 (t, 2H, J=5.5 Hz), 2.53 (t, 2H, J=4.56 Hz), 2.87–2.93 (m, 4H), 3.53 (t, 2H, J=5.5 Hz), 3.63–3.67 (m, 2H), 6.62 (s, 1H), 7.19 (d, 1H, J=1.9 Hz), 7.27–7.38 (m, 4H), 7.42–7.45 (dd, 1H, J=8.12 Hz, 1.88 Hz), 7.53–7.58 (m, 3H), 8.07 (s, 1H), 10.31 (s, 1H). M+1=575.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].[OH-].[Na+].[BrH:21]>O>[Br:21][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6]
Reactant: Br
Reactant: Nc1cc(C(=O)O)ccc1C(F)(F)F
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(C(F)(F)F)c(Br)c1
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
To a stirred mixture of 3-amino-4-(trifluoromethyl)benzoic acid (Matrix Scientific, 2.05 g, 10 mmol) in aqueous HBr (48% in water, 20 mL) and H2O (67 mL) at 0° C. is added NaNO2 (0.828 g) in small portions over 15 min. After stirring the solution for 30 minutes the mixture is added dropwise to a solution of CuBr (2.5 g) in aqueous HBr (48% in water, 40 mL) and H2O (100 mL). The mixture is stirred at 75° C. for 2 hours, then room temperature for 16 hours. The mixture is treated with 20% NaOH to raise the pH above 10 and then filtered through celite. The resulting solution is acidified with 6 M HCl to pH 1 and extracted with dichloromethane (3×100 mL). Organic layers are collected, dried over Na2SO4, filtered and concentrated to give 3-bromo-4-(trifluoromethyl)benzoic acid (2.30 g, 85.5% yield). LCMS m/z=269.1, 271.1 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[N:10]=[C:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[N:8]=[C:7](C(Cl)(Cl)Cl)[N:6]=1.[NH3:19].O>O1CCCC1>[NH2:19][C:7]1[N:6]=[C:5]([CH2:4][CH2:3][CH2:2][Cl:1])[N:10]=[C:9]([C:11]([Cl:12])([Cl:13])[Cl:14])[N:8]=1
Reactant: ClCCCc1nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n1
Reactant: N
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(CCCCl)nc(C(Cl)(Cl)Cl)n1
Temperature: 25 °C

Procedure:
102.3 g of 2-(3-chloropropyl)-4,6-bis-(trichloromethyl)-1,3,5-triazine are dissolved in 100 ml of tetrahydrofuran, and to this solution are added, whilst it is being stirred at room temperature, 400 ml of concentrated aqueous ammonia solution. After 30 minutes are added 500 ml of water, and the reaction mixture is extracted twice with 100 ml of ether each time. The ether phases are dried over magnesium sulfate, filtered, and concentrated by evaporation to yield 68.3 g of the title product as light-brown oil.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:47]2[C:48]([C:53]#[N:54])=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:46])[N:23]([C@H:34]2[CH2:39][CH2:38][C@H:37]([O:40][CH2:41][C:42]([OH:45])([CH3:44])[CH3:43])[CH2:36][CH2:35]2)[C:24]2[N:25]([N:30]=[C:31]([CH3:33])[N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]>O.C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[C:53]2[NH:3][C:4](=[O:7])[O:5][N:54]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:46])[N:23]([C@H:34]2[CH2:39][CH2:38][C@H:37]([O:40][CH2:41][C:42]([OH:45])([CH3:44])[CH3:43])[CH2:36][CH2:35]2)[C:24]2[N:25]([N:30]=[C:31]([CH3:33])[N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2nc(C)nn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.70 g), sodium hydrogen carbonate (1.1 g) and dimethyl sulfoxide (6 mL) was stirred at 40° C. for 30 min, 3′-fluoro-4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.39 g) was added and the mixture was stirred at 90° C. for 24 hr and then at room temperature for 38 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (4 mL). N,N′-Carbonyldiimidazole (0.13 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL) were added, and the mixture was stirred at room temperature for 1 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.30 g, 69%).
Reaction SMILES: [C:1]([N:3]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]2)=[C:4]1[C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)#[N:2].C1C=CC=CC=1.C(N(CC)CC)C.[C:32](Cl)(Cl)=[S:33]>O1CCCC1>[C:1]([N:3]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]2)=[C:4]1[C:12]1[CH:18]=[CH:17][C:15]([N:16]=[C:32]=[S:33])=[CH:14][CH:13]=1)#[N:2]
Reactant: S=C(Cl)Cl
Reactant: N#Cn1cc2ccccc2c1-c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: N#Cn1cc2ccccc2c1-c1ccc(N=C=S)cc1
Yield: 38.4 %

Procedure:
84 mg (0.36 mmol) of 4-(2′-cyanoisoindolyl)aniline was suspended in 40 mL of a mixture of benzene and tetrahydrofuran (1:1, v/v) and refluxed for 1 hour in the presence of 65 mg (0.64 mmol) of triethylamine and 40 mg (0.35 mmol) of thiophosgene. The reaction mixture was concentrated under a vacuum, and then the residue was recrystallized with acetonitrile to obtain 37 mg of the titled 4-(2′-cyanoisoindolyl)phenylisothiocyanate expressed by the following formula in the form of a colorless needle crystal.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[O:22][CH3:23]>C1COCC1>[CH:1]([NH:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[O:22][CH3:23])=[O:2]
Reactant: O=CO
Reactant: COC(=O)c1ccc(N)c(OC)c1
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(NC=O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To formic acid (75 mL) was added dropwise acetic anhydride (50 mL) at room temperature, and the mixture was stirred at room temperature for 40 min. A mixture of methyl 4-amino-3-methoxybenzoate (25 g) in THF (100 mL) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. Ice water (700 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration. The solid was washed with water (400 mL) to give the title compound (25.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH3:12][O-:13].[Na+].CO>C(Cl)Cl>[CH3:12][O:13][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To 4-bromo-2-fluoro-1-nitrobenzene (8.0 g, 36.4 mmol) was added 0.5 N sodium methoxide (105 mL, 52.5 mmol). The mixture was stirred at 60° C. for 1 h. The MeOH was rotovaped down. The crude product was dissolved in DCM (100 mL), washed with H2O, dried (Na2SO4), filtered, and rotovaped down to give the title compound of step A (8.1 g, 34.9 mmol, 96%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.74 (d, J=8.61 Hz, 1H), 7.23 (d, J=2.01 Hz, 1H), 7.16 (dd, J=8.61, 1.83 Hz, 1H), 3.95 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[CH:4][C:3]=1[Cl:12].CCN(C(C)C)C(C)C.[O:22]1[CH2:27][CH2:26][CH:25]([C:28](Cl)=[O:29])[CH2:24][CH2:23]1>C(Cl)Cl>[Cl:12][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:1][C:28]([CH:25]1[CH2:26][CH2:27][O:22][CH2:23][CH2:24]1)=[O:29]
Reactant: O=C(Cl)C1CCOCC1
Reactant: Nc1c(Cl)cc(O)cc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1c(Cl)cc(O)cc1[N+](=O)[O-])C1CCOCC1
Reaction time: 2 h

Procedure:
0.40 g (2.12 mmol) 4-amino-3-chloro-5-nitrophenol were placed in 5 mL DCM. 0.44 mL (2.54 mmol) DIPEA and 0.26 mL (2.54 mmol) tetrahydro-2H-pyran-4-carbonyl chloride were added and at RT the mixture was stirred for 2 h. A further 0.26 mL (2.54 mmol) tetrahydro-2H-pyran-4-carbonyl chloride were added and the mixture was stirred overnight at RT. The reaction mixture was diluted with DCM and washed with water. The organic phase was evaporated down i.vac.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([CH3:12])[CH:3]=1>CCOCC>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[C:4]([CH3:12])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1C
Solvent: CCOCC
Product: Cc1cc(Br)ccc1CO
Reaction time: 3 h

Procedure:
A solution of methyl 4-bromo-2-methyl-benzoate (1.05 g, 4.58 mmols) in 10 mL of Et2O was cooled to 0° C. and treated with LiA1H4 (177.0 mg, 4.58 mmols), stirred for 3 hours, and then carefully quenched with H2O The mixture was extracted with Et2O and the combined organic layers were washed with H2O and saturated aqueous NaCl, dried (MgSO4), and concentrated under reduced pressure. The title compound, 830.0 mg (90%), was isolated by column chromatography (10-30% EtOAc-hexanes) as a colorless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[C:19]2[C:14](=[C:15]([NH:20]C=O)[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8].[OH-].[K+].CCO.CC(O)=O>O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[C:19]2[C:14](=[C:15]([NH2:20])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: O=CNc1cccc2c(S(=O)(=O)Nc3nccs3)cccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cccc2c(S(=O)(=O)Nc3nccs3)cccc12
Temperature: 0 °C
Yield: 91.7 %

Procedure:
A solution of 5-formylamino-naphthalene-1-sulfonic acid thiazol-2-ylamide (350.0 mg, 1.0 mmol), KOH (168.0 mg, 3.0 mmol), EtOH (1.0 ml) and H2O (0.5 ml) was heated at 60° C. for 6 h. The mixtures was then cooled to 0° C., and neutralized with AcOH (3.0 mmol). The formed precipitate was filtered and dried under vacuum to give 5-amino-naphthalene-1-sulfonic acid thiazol-2-ylamide as a light tan solid (280 mg, 92%). 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J=8.5 Hz, 1H), 8.11 (dd, J=7.2, 1.0 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.45-7.42 (m, 1H), 7.32-7.28 (m, 1H), 7.19 (d, J=4.6 Hz, 1H), 6.77-6.73 (m, 2H), 5.90 (s, 2H). LC/MS (10-99% CH3CN), M/Z: M+1 obs=306.10; tR=1.12 min.
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[CH2:7]([O:10][C:11]([C:13]1[O:20][C:19]2[C:18]([NH2:21])=[N:17][NH:16][C:15]=2[CH:14]=1)=[O:12])[CH2:8][CH3:9].C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:7]([O:10][C:11]([C:13]1[O:20][C:19]2[C:18]([NH2:21])=[N:17][N:16]([C:1]([O:2][CH2:3][CH3:4])=[O:5])[C:15]=2[CH:14]=1)=[O:12])[CH2:8][CH3:9]
Reactant: CCCOC(=O)c1cc2[nH]nc(N)c2o1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCOC(=O)c1cc2c(o1)c(N)nn2C(=O)OCC
Reaction time: 0.08 h
Yield: 97 %

Procedure:
A solution of ethyl chlorocarbonate (4.90 mL, 51.7 mmol) in tetrahydrofuran (THF, 60 mL) was slowly added to a mixture of 3-Amino-1H-furo[3,2-c]pyrazole-5-carboxylic acid propyl ester (12.0 g, 50.2 mmol) and diisopropylethylamine (DIEA, 51.5 mL, 301 mmol) in THF (300 mL), maintaining the temperature between −5 and −10° C. The reaction was kept at the same temperature for 5 minutes then allowed to reach room temperature. The obtained mixture was evaporated to dryness under vacuum and the residue extracted with ethyl acetate (AcOEt) and water. The organic layer was separated, dried over sodium sulphate and evaporated to dryness. The resulting raw material was triturated with diethyl ether to give 13.7 g of the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:9]=[CH:10][N:11](C)C)=[N:5][CH:6]=[CH:7][N:8]=1)#[N:2].N[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(O)(=O)C>C(O)C>[N:9]1[C:4]2[C:3](=[N:8][CH:7]=[CH:6][N:5]=2)[C:1]([NH:2][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[N:11][CH:10]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CN(C)C=Nc1nccnc1C#N
Solvent: CCO
Solvent: CC(=O)O
Product: Oc1ccc(CCNc2ncnc3nccnc23)cc1

Procedure:
To a solution of N′-(3-cyanopyrazin-2-yl)-N,N-dimethylformamidine (prepared as in Albert and Ohta, J. Chem. Soc. C 1971, 3727-3730, which is expressly incorporated by reference herein; 2.0 g, 11.4 mmol) in ethyl alcohol (EtOH; 50 mL) was added 4-(2-aminoethyl)-phenol (4.7 g, 34 mmol) and acetic acid (3.9 mL, 4.1 g, 68 mmol). The solution was heated to reflux for 19 h, concentrated in vacuo, and the residue was slurried with H2O and suction filtered. The filter cake was washed with H2O and dried in a vacuum oven (80° C., 0.5 torr) to yield 4-[2-(pteridin-4-ylamino)-ethyl]-phenol (2.7 g) as a white solid: mp>210° C.; 1H NMR (DMSO-d6) δ 9.20 (s, 1H), 9.08 (s, 1H), 8.94 (s, 1H), 8.95 (t, J=6.0 Hz, 1H), 8.82 (s, 1H), 8.64 (s, 1H), 7.06 (d, J=8.5 Hz, 2H), 6.69 (d, J=8.2 Hz, 2H), 3.75 (t, J=6.2 Hz, 2H), 2.85 (t, J=7.6 Hz, 2H); ESIMS m/z 268 (M+).
Reaction SMILES: [BH4-].[Li+].[CH2:3]([N:10]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][C@@H:12]([F:17])[C:13](OC)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1>[CH2:18]([N:10]([CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:11][C@@H:12]([F:17])[CH2:13][OH:14])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)[C@H](F)CN(Cc1ccccc1)Cc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC[C@H](F)CN(Cc1ccccc1)Cc1ccccc1
Temperature: -15 °C
Yield: 92.4 %

Procedure:
Lithium borohydride (5.3 g, 0.24 mol) was suspended in THF (200 mL) under a nitrogen atmosphere and cooled to −15° C. with stirring. Methyl (2R)-3-(dibenzylamino)-2-fluoropropanoate (56.6 g, 0.19 mol) was suspended in THF (250 mL) and added dropwise to the mixture over 1 h; the internal temperature was maintained below −10° C. during the addition. On completion of addition, the reaction mixture was allowed to warm to room temperature and stirred at this temperature for 17 h. The reaction mixture was cooled to 0° C. and cautiously quenched with a saturated aqueous solution of ammonium chloride (300 mL). The reaction mixture was extracted with ethyl acetate (2×200 mL) and the organic phase was concentrated under reduced pressure. The crude residue was dissolved in 2 N hydrochloric acid (200 mL, pH=2 approx.) and the aqueous phase was washed with ether (2×200 mL). The aqueous phase was basified (pH=10 approx.) with 80% ammonium hydroxide in brine, extracted with ethyl acetate (3×200 mL), dried over anhydrous sodium sulfate (10 g), filtered and concentrated under reduced pressure to afford (2R)-3-(dibenzylamino)-2-fluoro-1-propanol (48 g, 93%) as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:28]=[CH:27][C:8]([C:9]([NH:11][C@H:12]([C:23]([O:25][CH3:26])=[O:24])[CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH2:43]([O:50][C:51]1[CH:60]=[CH:59][C:54](/[C:55](=[N:57]/O)/[NH2:56])=[CH:53][CH:52]=1)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>CN(C=O)C>[C:1]([C:5]1[CH:28]=[CH:27][C:8]([C:9]([NH:11][C@@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][NH:57][C:55](=[NH:56])[C:54]3[CH:53]=[CH:52][C:51]([O:50][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[CH:60][CH:59]=3)=[O:19])=[CH:21][CH:22]=2)[C:23]([O:25][CH3:26])=[O:24])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCOc1ccc(/C(N)=N/O)cc1
Reactant: COC(=O)[C@H](Cc1ccc(C(=O)O)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(C(=N)NOC(=O)c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC)cc2)cc1
Reaction time: 2 h

Procedure:
Prepared using General Procedure 5: To a solution of (S)-4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoic acid, INT-1 (10.0 mg, 0.026 mmol) in anhydrous DMF (1 mL) was added HOBt (5.27 mg, 0.39 mmol) and EDC (7.48 mg, 0.39 mmol). After stirring for 2 h, (Z)-4-(heptyloxy)-N′-hydroxybenzimidamide (9.76 mg, 0.39 mmol) was added. The reaction mixture was stirred at RT for 2 h, partitioned between saturated aqueous NaHCO3 (5 ml) and EA (5 mL), and concentrated under reduced pressure to afford the intermediate (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(((4-(heptyloxy)benzimidamido)oxy)carbonyl)phenyl)propanoate. The intermediate was dissolved in DMF (1 mL) and heated to 100° C. for 18 h. The reaction mixture was cooled to RT and partitioned between EA (5 mL) and saturated aqueous NaHCO3 (5 mL). The organic layer was extracted with water (2×5 mL) and brine (5 mL). The organic layer was dried over MgSO4 and concentrated. The brown oil was purified by preparative HPLC to afford 4.5 mg (29%) of (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(3-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-5-yl)phenyl)propanoate. LCMS-ESI (m/z) calculated for C36H43N3O5: 597.3; no m/z observed, tR=12.75 min (Method 2). 1H NMR (400 MHz, DMSO) δ 8.85 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.3 Hz, 2H), 8.00 (d, J=8.9 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.6 Hz, 2H), 7.12 (d, J=8.9 Hz, 2H), 4.87-4.56 (m, 1H), 4.06 (t, J=6.5 Hz, 2H), 3.67 (s, 3H), 3.32-3.13 (m, 4H), 1.74 (dd, J=14.2, 6.5 Hz, 2H), 1.51-1.37 (m, 2H), 1.33 (s, 4H), 1.26 (d, J=20.2 Hz, 9H), 0.88 (t, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 175.00, 171.91, 167.89, 166.27, 161.21, 154.37, 143.68, 130.78, 130.30, 128.76, 127.80, 127.18, 125.07, 121.69, 118.21, 115.07, 67.72, 53.61, 52.05, 36.15, 34.60, 31.20, 30.87, 28.54, 28.39, 25.40, 22.02, 13.93.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH2:17]4)[N:13]([CH3:19])[C:12]=3[CH:20]=2)[C:4](=[O:21])[CH:3]=1.[S:22]1[CH:26]=[CH:25][C:24]2[CH:27]=[C:28]([CH2:31][OH:32])[CH:29]=[CH:30][C:23]1=2.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[S:22]1[C:23]2[CH:30]=[CH:29][C:28]([CH2:31][O:32][C:2]3[CH:7]=[CH:6][N:5]([C:8]4[CH:9]=[CH:10][C:11]5[N:15]=[C:14]([CH:16]6[CH2:18][CH2:17]6)[N:13]([CH3:19])[C:12]=5[CH:20]=4)[C:4](=[O:21])[CH:3]=3)=[CH:27][C:24]=2[CH:25]=[CH:26]1
Reactant: OCc1ccc2sccc2c1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(Cl)cc3=O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc5sccc5c4)cc3=O)cc21
Temperature: 100 °C
Yield: 10.5 %

Procedure:
A mixture of 4-chloro-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), benzo[b]thiophen-5-ylmethanol (110 mg), cesium carbonate (326 mg) and DMF (3 ml) was heated at 100° C. overnight. The mixture was poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (15 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24]Br.C(OCC)(=O)C>CN(C=O)C>[Cl:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24][N:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:16]2[C:11]([C:12]([C:17]([F:18])([F:20])[F:19])=[CH:13][CH:14]=[CH:15]2)=[N:10]1
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: Fc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2ccc(F)cc2Cl)cc1
Temperature: 120 °C
Yield: 42.2 %

Procedure:
To a solution of 3-(4-fluoro-phenyl)-7-trifluoromethyl-1H-indazole (6.43 g, 23 mmol) in 20 mL DMF was added 2-chloro-4-fluoro benzyl bromide (7.0 g, 31 mmol). The reaction mixture was heated overnight at 120° C. After cooling to room temperature, ethyl acetate was added and the solution was washed three times with brine. The organic layer was dried over NaSO4 and concentrated. Flash chromatography (hexane/CH2Cl2, 1:1, as eluent) afforded 4.1 g of pure product. Three grams (3 g) of product were recrystallized from 10 mL of isopropanol to recover 1.98 g of crystalline product, mp 78° C.