Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:31]2[CH2:43][CH2:42][N:34]3[C:35]4[CH2:36][CH2:37][CH2:38][CH2:39][C:40]=4[CH:41]=[C:33]3[C:32]2=[O:44])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=2)[C:15](=[O:29])[N:14]([CH3:30])[CH:13]=1)(=O)C.O.[Li+].[OH-]>C1COCC1>[OH:4][CH2:5][C:6]1[C:7]([N:31]2[CH2:43][CH2:42][N:34]3[C:35]4[CH2:36][CH2:37][CH2:38][CH2:39][C:40]=4[CH:41]=[C:33]3[C:32]2=[O:44])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=2)[C:15](=[O:29])[N:14]([CH3:30])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(S(C)(=O)=O)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2ccc(S(C)(=O)=O)cn2)c1=O
Yield: 0.1 %

Procedure:
A 100-mL single-neck round-bottomed flask compound was charged with 117e (100 mg, 0.2 mol) in THF/iPA/H2O (5 mL/5 mL/2 mL) and LiOH (50 mg, 2 mmol) while stirring. This mixture was stirred at 50° C. for 0.5 h. Then 20 mL H2O was added and the mixture was extracted with EA (30 mL×3). The combined organic layer was dried over Na2SO4 and concentrated to give a yellow solid, which was further purified by reverse-phase prep-HPLC to afford 117 as a white solid (72 mg, 90% yield). MS: [M+H]+ 575. 1H NMR (500 MHz, CDCl3) δ 9.39 (s, 1H), 8.84 (d, J=2.0, 1H), 8.60 (d, J=2.5, 1H), 8.50 (d, J=2.5, 1H), 7.98 (dd, J=2.5, 4.0, 1H), 7.69 (d, J=2.4, 1H), 7.49-7.47 (d, J=9.0, 1H), 7.38-7.37 (m, 1H), 6.58 (s, 1H), 4.99 (t, J=4.5, 1H), 4.47-4.39 (m, 2H), 4.26-4.11 (m, 3H), 3.88-3.86 (m, 1H), 3.62 (s, 3H), 3.19 (s, 3H), 2.66-2.54 (m, 2H), 2.48-2.46 (m, 2H), 1.79-1.66 (m, 4H)
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][CH:13]([S-:15])[CH3:14].[Na+].O.C(#N)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([S:15][CH:13]([CH3:14])[CH3:12])[CH:3]=1
Reactant: CC(C)[S-]
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CC(C)Sc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
At 0 degree, to a stirring solution of 4-Bromo-2-Floronitrobenzene (2.0 g, 9.1 mmol) in DCM was added Sodium propane-2-thiolate (2.0 g, 20 mmol) in two portions. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was filtered through a syringe filter. The product was isolated by prep-HPLC (water/Acetonitrile) as a bright yellow solid (0.8 g, 2.9 mmol, 32% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[O:19]=[C:20]1[N:24]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([F:38])([F:37])[CH:34]([F:36])[F:35])=[CH:27][CH:26]=2)[CH:23]=[CH:22][N:21]1[C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH:49]=[N:48][NH:47][C:46]2=[O:50])=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:47]1[C:46](=[O:50])[N:45]([C:42]2[CH:41]=[CH:40][C:39]([N:21]3[CH:22]=[CH:23][N:24]([C:25]4[CH:26]=[CH:27][C:28]([O:31][CH2:32][C:33]([F:38])([F:37])[CH:34]([F:36])[F:35])=[CH:29][CH:30]=4)[C:20]3=[O:19])=[CH:44][CH:43]=2)[CH:49]=[N:48]1)[CH3:12]
Reactant: O=c1[nH]ncn1-c1ccc(-n2ccn(-c3ccc(OCC(F)(F)C(F)F)cc3)c2=O)cc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](n1ncn(-c2ccc(-n3ccn(-c4ccc(OCC(F)(F)C(F)F)cc4)c3=O)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 90 °C
Reaction time: 42 h
Yield: 7.8 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (1.2 g), 4-[4-[2-oxo-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1H,3H-imidazol-1-yl]phenyl]-3(2H,4H)-1,2,4-triazolone (2.2 g) and potassium carbonate (powder: 3.5 g) were added to N,N-dimethylformamide (50 ml), and the mixture was heated with stirring at 90° C. for 42 hours. After cooling, the resultant was diluted with ethyl acetate (150 ml) and tetrahydrofuran (50 ml). Ice water (150 ml) was added thereto to separate the ethyl acetate layer. The aqueous layer was extracted with ethyl acetate (100 ml). The ethyl acetate layers were combined and washed with 0.5N-sodium hydroxide (100 ml), 1N-hydrochloric acid (100 ml) and a saturated aqueous solution of sodium chloride (100 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (elute:ethyl acetate/acetone=10/1) and crystallized from tetrahydrofuran-diisopropyl ether to give 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-[2-oxo-3-[4-(2,2,3,3-tetrafluoropropoxy)-phenyl]-1H,3H-imidazol-1-yl]phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 2; 0.26 g) as a colorless crystalline powder.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH3:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH2:38].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH3:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH:38][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:32])([F:1])[F:31])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:29]
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: Cc1cccc(CN)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(CNC(=O)c2cnc3cc(NC(=O)c4ccccc4-c4ccc(C(F)(F)F)cc4)ccc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (50 mg, 0.11 mmol) was combined with 3-methylbenzylamine (14 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 1-hydroxybenzotriazole (17 mg, 0.13 mmol), and triethylamine (0.064 ml, 0.46 mmol) in 1 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 30 ml of ethyl acetate, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford 52 mg of the title compound as a colorless solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5]Br.Cl.[Br:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14][NH2:15])=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[Br:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14][N:15]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:11][CH:10]=1
Reactant: BrCCCCBr
Reactant: NCCc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Brc1ccc(CCN2CCCC2)cc1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
0.51 mL (4.23 mmol) 1,4-dibromobutane in 20 mL acetonitrile is added slowly to a solution of 1.0 g (4.23 mmol) 4-bromo-phenethylamine hydrochloride, 1.8 g (13.0 mmol) K2CO3 and 200 mg (1.20 mmol) Kl in 100 mL acetonitrile at 75° C. and the reaction mixture is stirred for a further 4 h at 75° C. The reaction solution is diluted with 100 mL water and the aqueous phase is extracted with 100 mL EtOAc. The combined organic extracts are washed with saturated NaCl solution, the organic phase is dried over Na2SO4 and the solvent is eliminated i.vac. Further purification is carried out by column chromatography on silica gel (EtOAc/MeOH/NH3 9:1:0.1)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([C:35](Cl)=[O:36])[CH2:31][CH2:30]1>C1COCC1>[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([C:35]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([S:8][C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12]/[C:11](=[C:19]4/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/4=[O:24])/[CH:10]=3)=[CH:6][CH:7]=2)=[O:36])[CH2:31][CH2:30]1
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Reactant: CN1CCC(C(=O)Cl)CC1
Solvent: C1CCOC1
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(=O)C3CCN(C)CC3)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and 1-methylpiperidine-4-carbonyl chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.69 (t, J=7.33 Hz, 3H) 1.32 (dq, J=14.84, 7.35 Hz, 2H) 1.79-1.90 (m, 2H) 2.02-2.05 (m, 2H) 2.16-2.18 (m, 2H) 2.58-2.69 (m, 2H) 2.79-2.84 (m, 3H) 2.94-3.06 (m, 2H) 6.73 (s, 1H) 7.57 (t, J=7.45 Hz, 1H) 7.69 (d, J=8.59 Hz, 2H) 7.79-7.91 (m, 4H) 8.09 (d, J=8.08 Hz, 1H) 9.28 (s, 1H) 10.45 (s, 1H); ESI-MS: m/z calc'd for C28H31N5O2S 501.64. found 502.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]=1[CH3:18].C(N(CC)CC)C>[Pd].C(OCC)(=O)C>[CH3:18][C:3]1[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:5][C:6]2[C:11]([CH:2]=1)=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2
Reactant: CCOC(=O)c1nc2ccc(C)cc2c(Cl)c1C
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc2ccc(C)cc2cc1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 4-chloro-3,6-DIMETHYLQUINOLINE-2-carboxylate (3.0 g), triethylamine (2.4 ml) and 10% palladium on carbon (300 mg) in ethyl acetate (30 ml) was stirred for 4 hours at ambient temperature under hydrogen atmosphere. After filtration the filtrate was concentrated in vacuo and diluted with dichloromethane. The mixture was washed with saturated sodium bicarbonate solution and water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (dichloromethane-ethyl acetate) to give ethyl 3,6-dimethylquinoline-2-carboxylate.
Reaction SMILES: [Si](OC1C(F)=C(C=C(CC)C=1)C=O)(C(C)(C)C)(C)C.[CH2:20]([O:22][C:23]1[C:24]([F:33])=[C:25]([CH:28]=[C:29]([CH2:31][CH3:32])[CH:30]=1)[CH:26]=[O:27])C>>[CH2:31]([C:29]1[CH:30]=[C:23]([O:22][CH3:20])[C:24]([F:33])=[C:25]([CH:28]=1)[CH:26]=[O:27])[CH3:32]
Reactant: CCOc1cc(CC)cc(C=O)c1F
Agent: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Product: CCc1cc(C=O)c(F)c(OC)c1

Procedure:
119A was prepared from 118C using a procedure similar to that used in the preparation of 118D. 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (t, J=7.47 Hz, 3H) 2.64 (q, J=7.62 Hz, 2H) 3.92 (s, 3H) 7.02 (dd, J=8.13, 1.98 Hz, 1H) 7.23 (dd, J=5.27, 2.20 Hz, 1H) 10.35 (s, 1H).
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][C:43]([N:46]5[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]5)=[CH:42][CH:41]=4)[C:38]([CH3:52])=[C:37]([OH:53])[C:36]3=[O:54])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:41]=[CH:42][C:43]([N:46]5[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]5)=[CH:44][CH:45]=4)[C:38]([CH3:52])=[C:37]([O:53][CH3:3])[C:36]3=[O:54])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: CC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1c1ccc(N2CCCCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CCOCC
Solvent: CO
Product: COC1=C(C)C(c2ccc(N3CCCCC3)cc2)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (8 eq), ethylene glycol/Et2O (1/2 v/v, 60 ml), 1-(1H-Benzo[d]imidazol-6-yl)-3-hydroxy-4-methyl-5-(4-(piperidin-1-yl)phenyl)-1H-pyrrol-2(5H)-one (0.700 g, 1.88 mmol, 1 eq) and MeOH (20 ml); yield: 0.050 g (7%); MS m/z: 403.1 [M+H]+;1H-NMR: (400 MHz, DMSO-D6) δ: 8.59 (s, 1H), 7.81 (s, 1H), 7.55-7.53 (m, 1H), 7.45-7.42 (m, 1H), 7.06-7.04 (m, 2H), 6.82-6.79 (m, 2H), 5.69 (s, 1H), 3.93 (s, 3H), 3.05-3.02 (m, 4H), 1.70 (s, 3H),1.53-1.46 (m, 6H); HPLC (METHOD [A]): rt 6.03 min (99.04%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[N:8][O:9][N+:10]=2[O-])[N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[N:8][O:9][N:10]=2)[N:7]=1
Reactant: [O-][n+]1onc2nc(Cl)ccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1ccc2nonc2n1
Temperature: 35 °C
Reaction time: 24 h

Procedure:
In a dry flask, 5-chloro[1,2,5]oxadiazolo[3,4-b]pyridine 1-oxide (200 mg, 1.166 mmol) and triphenylphosphine (459 mg, 1.749 mmol) were taken-up in dichloromethane (11.7 ml) under argon. The mixture was stirred at 35° C. for 24 hours. The reaction was quenched with 1.0 M aqueous sodium hydroxide and extracted three times with ethyl acetate. All organic fractions were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by reverse-phase HPLC (20-100% acetonitrile/water with 0.05% trifluoroacetic acid), and then the appropriate fractions were neutralized with aqueous sodium bicarbonate and washed twice with ethyl acetate. All organic fractions were combined, dried over anhydrous magnesium sulfate, and concentrated to afford 5-chloro[1,2,5]oxadiazolo[3,4-b]pyridine. LRMS (APCI) calc'd for (C5H3ClN2O) [M+H]+, 156. found 156.
Reaction SMILES: ClC1C=CC(C2N(C(C3CCCCC3)C(NC[C@H]3CC[C@H](C(O)=O)CC3)=O)C3C=CC(F)=CC=3N=2)=CC=1.[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[N:49]([CH:50]([CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]3)[C:51](O)=[O:52])[C:48]3[CH:60]=[C:61]([F:65])[C:62]([F:64])=[CH:63][C:47]=3[N:46]=2)=[CH:41][CH:40]=1.[NH2:66][C:67]1[CH:76]=[CH:75][C:70]([C:71]([O:73][CH3:74])=[O:72])=[CH:69][N:68]=1>>[CH3:74][O:73][C:71](=[O:72])[C:70]1[CH:75]=[CH:76][C:67]([NH:66][C:51](=[O:52])[CH:50]([N:49]2[C:48]3[CH:60]=[C:61]([F:65])[C:62]([F:64])=[CH:63][C:47]=3[N:46]=[C:45]2[C:42]2[CH:41]=[CH:40][C:39]([Cl:38])=[CH:44][CH:43]=2)[CH:54]2[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59]2)=[N:68][CH:69]=1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: COC(=O)c1ccc(N)nc1
Agent: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)ccc21
Product: COC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)nc1

Procedure:
The title compound was prepared according to Example 22, intermediate c), from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid and methyl 6-aminonicotinate.
Reaction SMILES: C([O:5][C:6](=[O:38])[C@@H:7]([NH:30]C(OC(C)(C)C)=O)[CH2:8][CH2:9][CH:10]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][F:29])=[CH:22][CH:21]=1)[C:11]([O:13]C(C)(C)C)=[O:12])(C)(C)C.FC(F)(F)C(O)=O.O.C(#N)C>ClCCl>[NH2:30][C@H:7]([CH2:8][CH2:9][CH:10]([CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][F:29])=[CH:24][CH:25]=1)[C:11]([OH:13])=[O:12])[C:6]([OH:38])=[O:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(CCc1ccc(OCCF)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: N[C@H](CCC(CCc1ccc(OCCF)cc1)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.5 %

Procedure:
20 mg (37 μmol) of (2S)-2-tert.-Butoxycarbonylamino-5-{2-[4-(2-fluoro-ethoxy)-phenyl]-ethyl}-hexanedioic acid di-tert.-butyl ester were dissolved in 2 mL dichloromethane (dried over 4{acute over (Å)} molecular sieve) and 1 mL trifluoroacetic acid were added. The reaction was stirred at room temperature for 30 min, after which the solution was directly applied to reversed phase chromatography on a Biotage system (Flash 12+M cartridge, A=water, B=acetonitrile, A 1 CV, A to 50% B in 10 CV, 2 CV 50% B, 12 mL/min). Fraction 6 was lyophilized to give 2 mg (11%) of (2R,5RS)-2-Amino-5-{2-[4-(2-fluoro-ethoxy)-phenyl]-ethyl}-hexanedioic acid as the Tfa-salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH2:12][N:13]3[CH:17]=[N:16][CH:15]=[N:14]3)[C@H:10]([CH3:11])[O:9]2)=[CH:4][CH:3]=1.[F:18][C:19]([F:36])([O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[CH:33][NH:32][C:31]2=[O:35])=[CH:26][CH:25]=1)[CH:20]([F:22])[F:21].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([OH:9])([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[C@H:10]([N:32]2[CH:33]=[CH:34][N:30]([C:27]3[CH:26]=[CH:25][C:24]([O:23][C:19]([F:36])([F:18])[CH:20]([F:22])[F:21])=[CH:29][CH:28]=3)[C:31]2=[O:35])[CH3:11])=[CH:4][CH:3]=1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1
Reactant: O=c1[nH]ccn1-c1ccc(OC(F)(F)C(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 36.9 %

Procedure:
(2R,3S)-2-(4-Fluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (1.5 g), 2.66 g of 1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone and 6.3 g of cesium carbonate were added to 25 ml of N,N-dimethylformamide. The mixture was stirred at 80° C. for five hours. After cooling, the reaction solution was diluted with 100 ml of ethyl acetate, and washed with water (100 ml×2) and a saturated aqueous solution of sodium chloride (100 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=2/3) to give 1.21 g of 1-[(1R,2R)-2-(4-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone as colorless powdery crystals.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[NH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[N:32]([CH2:35][CH3:36])[CH2:33][CH3:34]>O>[CH2:35]([N:32]([CH2:33][CH3:34])[C:23]1[CH:24]=[CH:25][C:26]([C:28]([F:30])([F:29])[F:31])=[CH:27][C:22]=1[NH:21][C:2](=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:36]
Reactant: O=C(Cl)c1ccncc1
Reactant: CCN(CC)c1ccc(C(F)(F)F)cc1N
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)c1ccc(C(F)(F)F)cc1NC(=O)c1ccncc1
Temperature: 25 °C
Yield: 34.1 %

Procedure:
Isonicotinoyl chloride hydrochloride (88.2 mg, 0.495 mmol, commercially available product) and triethylamine (140 μL, 1.00 mmol) were sequentially added at 0° C. to a dichloromethane (3 ml) solution of 2-amino-1-diethylamino-4-(trifluoromethyl)benzene (103 mg, 0.443 mmol), obtained as described in Referential Example 6-2. The resulting mixture was warmed to room temperature and stirred for one and a half hours. Water was added to the mixture, and the resulting mixture was extracted three times with dichloromethane. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 g, hexane/ethyl acetate=2/1). Thus, N-[2-diethylamino-5-(trifluoromethyl)phenyl]isonicotinamide (GIF-0347) (51.0 mg, 34.1%) was yielded as a colorless solid.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]([O:24][CH3:25])(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[OH:18].O[CH2:27][CH:28]1[O:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:37]([O:36][C:34]([N:30]1[CH2:31][CH2:32][O:33][CH:28]([CH2:27][O:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[C:15]([O:24][CH3:25])=[O:23])[CH2:29]1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Reactant: COC(=O)c1ccccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1OCC1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of diisopropyl azodicarboxylate (776 μL; 3.94 mmol; 2 eq.) in THF (5 mL) was added to a cold (0° C.) solution of methyl salicylate (1 g; 6.57 mmol; 1 eq.) and tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (641 mg; 2.95 mmol; 1.5 eq.) and triphenylphosphine (1.03 g; 3.94 mmol; 2 eq.) in THF (15 mL) and the reaction mixture was stirred at room temperature for 16 hours then concentrated in vacuo. Purification by column chromatography (EA/heptane) afforded 2-(2-methoxycarbonyl-phenoxymethyl)-morpholine-4-carboxylic acid tert-butyl ester which was dissolved in THF (10 mL) and MeOH (10 mL). 5M NaOH (1.97 mL; 9.86 mmol; 5 eq.) was added and the resulting mixture was stirred at room temperature for 16 hours then concentrated in vacuo. The residue was partitioned between 1M NaOH and DCM and the aqueous layer was washed with DCM. The aqueous phase was made acidic and extracted with DCM (3×). The combined organic phase was dried over magnesium sulfate and concentrated in vacuo to afford the title compound (411 mg, 34%) as an orange oil which was used without further purification. HPLC (max plot) 89.4%; Rt 3.73 min. UPLC/MS: (MS−) 336.1 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([OH:13])=O.C(Cl)(=O)C([Cl:17])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([Cl:17])=[O:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCc1ccc(F)cc1Cl
Solvent: ClCCl
Product: O=C(Cl)CCc1ccc(F)cc1Cl
Temperature: 25 °C

Procedure:
To a mixture of 3-(2-chloro-4-fluorophenyl)propanoic acid (21.6 g, 0.11 mol) and dichloromethane at room temperature was added dropwise oxalyl chloride (19.2 ml). The mixture was stirred at room temperature until gas evolution had ceased. The excess oxalyl chloride was removed by distillation to give 3-(2-chloro-4-fluorophenyl)propionyl chloride. A solution of the 3-(2-chloro-4-fluorophenyl) propionyl chloride in dichloromethane (100 ml) was added dropwise to a mixture of aluminium chloride (17.3 g, 0.13 mol, Aldrich) in dichloromethane (100 ml) at room temperature. After the addition was completed, the mixture was refluxed for 2.5 h. The reaction mixture was poured into ice water (1.5 L). The two phases were separated and the dichloromethane phase was washed with 0.1N aqueous sodium hydroxide, dried (Na2SO4), and concentrated to give crude 4-chloro-6-fluoro-1-indanone. Chromatography on silica gel with hexanes:dichloromethane (1:1) as eluent gave 11.1 g (55%) of 4-chloro-6-fluoro-1-indanone as a white solid: mp 94°-96° C.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16]OS(C)(=O)=O)[CH2:10][C@H:9]1[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)=[O:7].[NH:42]1[CH2:47][CH2:46][S:45][CH2:44][CH2:43]1.C(N(CC)CC)C.[ClH:55]>CO.C(OCC)(=O)C>[ClH:55].[ClH:55].[F:40][C:2]([F:41])([F:1])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:37])([F:39])[F:38])[CH:35]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:42]2[CH2:47][CH2:46][S:45][CH2:44][CH2:43]2)[CH2:10][C@H:9]1[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)=[O:7]
Reactant: CS(=O)(=O)OCCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc3ccccc3c2)C1
Reactant: C1CSCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCCN2CCSCC2)C[C@H]1Cc1ccc2ccccc2c1

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (250 mg), thiomorpholine (43 mg) and triethylamine (46 mg) in dry methanol (5 ml) was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel using ethyl acetate as an eluent. The product obtained was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-(3-thiomorpholinopropyl)piperazine dihydrochloride (195 mg).