Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:45])[CH2:4][NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[C:35]=2[Cl:44])[CH2:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[ClH:44].[Cl:44][C:35]1[C:36]([C:40]([F:41])([F:42])[F:43])=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][N:18]([CH2:19][CH:20]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:17][CH2:16][CH2:15][O:14][C:10]1[CH:9]=[C:8]([CH2:7][CH2:6][NH:5][CH2:4][C:3]([OH:45])=[O:2])[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)CNCCc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CNCCc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of [2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethylamino]-acetic acid methyl ester (70 mg, 0.11 mmol) in THF (10 ml) and water (3.3 ml) was added lithium hydroxide monohydrate (12 mg, 0.28 mmol). The resulting mixture was stirred at room temperature for 18 hours and acidified with HCl (0.5 ml, 1 M in water). The crude mixture was concentrated in vacuo and then extracted with EtOAc (3×). The combined organic layers were washed with brine (1×), dried over sodium sulfate, filtered and concentrated in vacuo. Preparative HPLC (YMC 75×30 mm, 25 ml/min, 25-100% CH3CN) afforded the title compound as the free base. The diamine was treated with 1 M HCl in Et2O (0.11 ml, 0.11 mmol), and the Et2O was evaporated to afford the title compound as an off-white solid, 31 mg (45%). MS(ES) m/e 625.4 (M+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:9][CH:10]=[CH:11][C:4]=12.[H-].[Na+].[CH:16]([Si:19](Cl)([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])([CH3:18])[CH3:17]>O1CCCC1>[F:13][C:2]([F:12])([F:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[N:9]([Si:19]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:16]([CH3:18])[CH3:17])[CH:10]=[CH:11][C:4]=12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: FC(F)(F)c1ccnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(F)(F)F)ccnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
4-Trifluoromethyl-1H-pyrrolo[2,3-b]pyridine (1.5 g, 8 mmol) was suspended in tetrahydrofuran (20 mL) and cooled to 0° C. Sodium hydride (390 mg, 9.7 mmol) was added in small portions and the mixture was stirred at 0° C. for 1 h. Triisopropylsilyl chloride (2.6 mL, 12 mmol) was added and the mixture was stirred at 23° C. for 12 h. The reaction was quenched with saturated ammonium chloride solution (10 mL) and diluted with water (5 mL). The mixture was applied to a Varian chemelut cartridge and eluted with ethyl acetate. Purification by flash silica gel chromatography using a gradient of dichloromethane in hexanes afforded 4-Trifluoromethyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (2.5 g, 7.3 mmol, 90% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.44 (d, J=5 Hz, 1H), 7.76 (d, J=4 Hz, 1H), 7.44 (d, J=5.5 Hz, 1H), 6.74 (m, 1H), 1.88 (septet, J=7.5 Hz, 3H), 1.05 (d, J=7.5 Hz, 18H). MS: m/z 343.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:41][CH3:42])=[C:38]([Pb+3])[CH:39]=1.Cl>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:41][CH3:42])=[C:36]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])[CH:35]=1
Reactant: CCc1ccc(Br)cc1[Pb+3]
Reactant: CC12CCC(C(=O)CC1=O)C2(C)C
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1ccc(Br)cc1C1C(=O)C2CCC(C)(C1=O)C2(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A solution of 1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.22 g, 1.22 mmol) (preparation described by H. Favre et al., Can. J. Chem. (1956), 34 1329-39.) in dry chloroform (10 ml) is stirred at room temperature then thoroughly flushed with nitrogen. To this mixture is then added 4-dimethylaminopyridine (0.744 g, 6.15 mmol) and anhydrous toluene (3 ml), followed by heating to 80° C. 5-Bromo-2-ethylphenyllead triacetate (0.673 g, 1.18 mmol) is added portionwise over 10 minutes, and the mixture is further heated at this temperature for a further 4 hours then left to stand overnight. 2M hydrochloric acid (10 ml) is added, and the resulting biphasic mixture is filtered to remove any inorganic salts (washing with additional dichloromethane, 10 ml). The organic phase separated, and the aqueous phase is extracted again with dichloromethane (10 ml×2). All organic fractions are combined, dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to give an orange gum. This crude product is purified by flash column chromatography on silica gel (100% to 40% hexane/ethyl acetate eluant ratio) to afford rac-3-(5-bromo-2-ethylphenyl)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione as a colourless gum.
Reaction SMILES: [C:1](O)(=[O:3])C.[NH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[N:14]=2)[C:9](=[O:17])[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7]1>C(O)=O>[CH:1]([NH:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[N:14]=2)[C:9](=[O:17])[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7]1)=[O:3]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1cn(N)c2nc(C)ccc2c1=O
Solvent: O=CO
Product: CCOC(=O)c1cn(NC=O)c2nc(C)ccc2c1=O
Temperature: 0 °C

Procedure:
Formic acid (13 ml, 0.33 m) was added to 31.2 ml (0.33 m) of acetic acid stirred in an ice bath. The mixture was stirred 15 minutes at 0° C. and 15 minutes at 55° C. It was then recooled to 0° C. and 8.1 g (0.033 m) of ethyl 1-amino-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate was added. An additional 9.2 ml of formic acid was then added, and the reaction mixture was stirred one hour at 0° C. and two hours at room temperature. The reaction mixture was poured into ice-water, and the solid product collected by filtration, washed with water, tetrahydrofuran and ether, and dried at 75° C. in vacuo to give 4.4 g of ethyl 1-(formylamino)-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate, m.p. 214° C. (decompn), which contained a minor amount of the corresponding N,N-diformyl compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][N:17]3[C:10](=[CH:11][C:12]4[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]=43)[C:9]2=[O:22])[C:3]=1[CH:23]=[O:24].[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([CH:54]4[CH2:57][O:56][CH2:55]4)[CH2:50][CH2:49]3)=[CH:44][N:43]=2)[C:27]1=[O:58].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCCC1>[CH3:25][N:26]1[C:27](=[O:58])[C:28]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([CH:54]4[CH2:55][O:56][CH2:57]4)[CH2:50][CH2:49]3)=[CH:44][N:43]=2)=[CH:29][C:30]([C:2]2[C:3]([CH:23]=[O:24])=[C:4]([N:8]3[CH2:19][CH2:18][N:17]4[C:10](=[CH:11][C:12]5[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]=54)[C:9]3=[O:22])[N:5]=[CH:6][CH:7]=2)=[CH:31]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 25 °C
Yield: 60.4 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 4-chloro-2-{4,4-dimethyl-9-oxo-1,10-diaza-tricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridine-3-carbaldehyde 108a (350 mg, 1.02 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 1011(476 mg, 1.02 mmol), Pd(dppf)Cl2 (83 mg, 0.10 mmol), K3PO4 (526 mg, 3.06 mmol), and tetrahydrofuran (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 4 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (40:1) to afford 108b as white solid (400 mg, 61%). MS: [M+H]+ 649.4.
Reaction SMILES: [CH3:1][C@:2]1([CH2:13][N:14]2[C:18]3[CH:19]=[C:20]([C:23]#[N:24])[CH:21]=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH2:12][CH2:11][CH2:10][C@:4]2([O:8][C:7](=[O:9])[NH:6][CH2:5]2)[CH2:3]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N[C@@H]1CCCC[C@H]1N.Br[C:42]1[N:43]=[CH:44][C:45]([C:48]([OH:51])([CH3:50])[CH3:49])=[N:46][CH:47]=1>O1CCOCC1.[Cu]I.CC#N>[OH:51][C:48]([C:45]1[N:46]=[CH:47][C:42]([N:6]2[CH2:5][C@@:4]3([CH2:10][CH2:11][CH2:12][C@@:2]([CH2:13][N:14]4[C:18]5[CH:19]=[C:20]([C:23]#[N:24])[CH:21]=[CH:22][C:17]=5[N:16]=[CH:15]4)([CH3:1])[CH2:3]3)[O:8][C:7]2=[O:9])=[N:43][CH:44]=1)([CH3:50])[CH3:49]
Reactant: CC(C)(O)c1cnc(Br)cn1
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@]2(CNC(=O)O2)C1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CC#N
Product: CC(C)(O)c1cnc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cn1
Temperature: 100 °C
Yield: 60.6 %

Procedure:
To a light yellow solution of 1-(((5S,7S)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (0.050 g, 0.154 mmol) in 1,4-dioxane (2.052 mL) was added copper(I) iodide (2.94 mg, 0.015 mmol), potassium phosphate tribasic (0.065 g, 0.308 mmol), trans-1,2-diaminocyclohexane (3.71 μL, 0.031 mmol), and 2-(5-bromopyrazin-2-yl)propan-2-ol (0.040 g, 0.185 mmol). The reaction mixture was heated at 100° C. for 15 h. Then, additional copper(I) iodide (2.94 mg, 0.015 mmol) and trans-1,2-diaminocyclohexane (3.71 μL, 0.031 mmol) were added and stirred for an additional hour at 100° C. Additional copper(I) iodide (2.94 mg, 0.015 mmol) and trans-1,2-diaminocyclohexane (3.71 μL, 0.031 mmol) were then added and stirred for an additional 3 h at 100° C. The reaction was then cooled to RT and CH3CN (5 mL) was added and the mixture vacuum filtered using a Hirsch funnel. The solid was rinsed with CH3CN (3×2 mL) and the filtrate was loaded onto florisil and purified using silica gel chromatography CISCO): 0.5-2% MeOH/DCM (30 min), 12 g silica gel column. The product eluted at 19 minutes to obtain 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile as an orange foam (43 mg, 38% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.59 (s, 1H), 8.47 (s, 1H), 8.37 (s, 1H), 7.82 (d, J=8.28 Hz, 1H), 7.58 (d, J=8.28 Hz, 1H), 5.41 (s, 1H), 4.16 (br. s., 2H), 3.77-3.96 (m, 2H), 1.98 (d, J=7.03 Hz, 1H), 1.82-1.93 (m, 1H), 1.72 (d, J=14.56 Hz, 2H), 1.58-1.67 (m, 2H), 1.28-1.57 (m, 8H), 1.06 (s, 3H). MS (m/z) 461.0 (M+H+).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:32]=[CH:31][C:6]([O:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C@@:18]([OH:30])([CH3:29])[CH2:19][N:20]3[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[N:22]=[C:21]3Cl)=[O:15])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[H-].[Na+]>CN(C=O)C>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:32]=[CH:31][C:6]([O:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C@:18]3([CH3:29])[O:30][C:21]4=[N:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][N:20]4[CH2:19]3)=[O:15])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1
Reactant: C[C@](O)(COC(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]1(COC(=O)N2CCC(Oc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 47.2 %

Procedure:
To the solution of (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-(4-trifluoromethylphenoxy)piperidine-1-carboxylate prepared in Example 104 (0.18 g, 0.36 mmol) in DMF (2 ml), sodium hydride (19 mg, 0.47 mmol) was added followed by stirring for 1.5 hours with cooling on ice-bath. To the reaction mixture, ice-water was added, and the solution was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) and recrystallized from isopropanol to afford (R)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl 4-(4-trifluoromethylphenoxy)piperidine-1-carboxylate (0.08 g, yield 47%) as a white solid.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[C:34]1([C:40]#[C:41][C:42]2[S:43][CH:44]=[C:45]([C:47](O)=[O:48])[N:46]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH:1]1([NH:4][C:47]([C:45]2[N:46]=[C:42]([C:41]#[C:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[S:43][CH:44]=2)=[O:48])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=C(O)c1csc(C#Cc2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CC1)c1csc(C#Cc2ccccc2)n1
Reaction time: 16 h

Procedure:
Cyclopropylamine (2.49 mg, 0.00436 mmol), 1-hydroxybenzotriazole (0.589 mg, 0.00436 mmol), triethylamine (1.82 μL, 0.0131 mmol), N-(3-dimethylaminopropyl-N′-ethylcarbodiimide hydrochloride (2.09 mg, 0.0109 mmol) and CH2Cl2 (2 mL) were combined, and then 2-phenylethynyl-thiazole-4-carboxylic acid (10 mg, 0.004 mmol) was added. The reaction was left standing for about 16 hours and then purified by preparative HPLC. LC/MS (Method 5), RT=1.33 min. Calculated [M+H]+=269; Observed [M+H]+=269.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH:7]([O:11][C:12](=[O:14])[CH3:13])[C:8]([CH3:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH3:22]>CN(C=O)C>[C:1]([O:5][C:6](=[O:15])[C:7]([O:11][C:12](=[O:14])[CH3:13])([C:8](=[O:9])[CH3:10])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCBr
Reactant: CC(=O)OC(C(C)=O)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCC(OC(C)=O)(C(C)=O)C(=O)OC(C)(C)C
Yield: 67.8 %

Procedure:
According to the general alkylation method, tert-butyl-2-acetoxy-aceto-acetate (219a) (7.12 g, 32.9 mmol), NaH (900 mg, 37.5 mmol) and pentylbromide (4.97 g, 32.9 mmol) were reacted in DMF (64 mL) to give 2-acetoxy-2-acetyl-heptanoic-acid-tert-butylester (250j) (6.40 g, 22.3 mmol, 68%) as a slightly yellow oil after Kugelrohr distillation at 185° C. and 1.0 mbar. Then, 250j (6.40 g, 22.3 mmol) and 402 mg (2.11 mmol) p-TsOH.H2O were stirred in 65 mL benzene according to decarboxylation method A. Kugelrohr distillation at 1.0 mbar and 125° C., followed by column chromatography (ethyl acetate:petroleum ether=1:4) gave 251j (1.6 g, 8.59 mmol, 39%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:18](O)=[O:19])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.[Cl:23][C:24]1[CH:25]=[C:26]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][C@@H:38]([NH2:45])[C:39]3[O:43][N:42]=[C:41]([CH3:44])[N:40]=3)=[CH:33][CH:32]=2)[CH:27]=[CH:28][C:29]=1[F:30]>>[Cl:23][C:24]1[CH:25]=[C:26]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][C@@H:38]([NH:45][C:18]([C:4]3[CH:5]=[C:6]([C:8]4[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=4)[CH:7]=[C:2]([Cl:1])[C:3]=3[O:21][CH3:22])=[O:19])[C:39]3[O:43][N:42]=[C:41]([CH3:44])[N:40]=3)=[CH:33][CH:32]=2)[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: COc1c(Cl)cc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)O
Reactant: Cc1noc([C@H](N)Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)n1
Product: COc1c(Cl)cc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)c1nc(C)no1
Yield: 64.7 %

Procedure:
5-Chloro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (0.5 g) was prepared from 5-Chloro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (0.4 g, 1.2 mmol) and 2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine (0.4 g, 1.2 mmol) according to the general procedure A.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([OH:16])[CH:5]([N:11]1[CH2:14][CH2:13][C:12]1=[O:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[N-:17]=[N+:18]=[N-:19].[Na+]>CS(C)=O.ClCCl>[N:17]([CH2:2][CH2:3][CH:4]([OH:16])[CH:5]([N:11]1[CH2:14][CH2:13][C:12]1=[O:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N+:18]=[N-:19]
Reactant: CCOC(=O)C(C(O)CCCl)N1CCC1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)C(C(O)CCN=[N+]=[N-])N1CCC1=O
Yield: 73 %

Procedure:
A solution of ethyl 5-chloro-3-hydroxy-2-(2-oxoazetidin-1-yl)valerate (3.45 g, 13.8 mmol) and sodium azide (1.1O g, 17 mmol) in dry dimethylsulphoxide (20 ml) was stirred between 55° and 65° C. for 5 hours. The reaction mixture was diluted with dichloromethane and the organic layer was washed three times with water before being dried (MgSO4) and evaporated. The residue was chromatographed on silica gel (Merck Art. 9385), eluting with ethyl acetate/hexane (2:1), to give ethyl 5-azido-3-hydroxy-2-(2-oxoazetidin-1-yl)valerate as a pale yellow oil in 73% yield (2.59 g). Bulb to bulb distillation at 0.2 mmHg between 185°-195° C. further purified the product to a colourless oil. νmax (KBr) 3405, 2102 and 1733 cm-1 ; δH (CHCl3, 250 MHz) 1.31 (3H,t,J 7 Hz), 1.81 (1H,m), 1.87 (1H,m), 3.03 (2H,t,J 3 Hz), 3.40 (2H,m), 3.53 (2H,m), 4.00 (1H,d,J 3.5 Hz), 4.25 (3H,m) and 4.53 (1H,d,J 4.5 Hz, exchangeable). (Found: C, 46.93; H, 6.46; N, 21.83%. C10H16N3O4 requires C, 46.87; H, 6.29; N, 21.86%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)=[O:4].CN(C=O)C.C(Cl)(=O)C(Cl)=O.Cl.[OH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[NH:36][OH:37].C(N(CC)CC)C.OS([O-])(=O)=O.[K+]>C1COCC1.O.C(Cl)Cl>[OH:37][N:36]([C:27]1[CH:28]=[CH:29][C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:26]=1[OH:25])[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)CCCCCC(=O)O
Reactant: ONc1ccc2ccccc2c1O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CCCCCC(=O)N(O)c1ccc2ccccc2c1O
Reaction time: 1 h
Yield: 77.6 %

Procedure:
Into a 25 ml methylene chloride solution of 500 mg (2.87 mmol) of 6-methoxycarbonylhexanoic acid and 222 μl (2.87 mmol) of DMF was added 564 μl (6.46 mmol) of oxalyl chloride at 0° C., and the mixture was stirred as such for one hour. The mixture was then added to a solution of 3.17 g (15 mmol) of 1-hydroxy-2-naphthylhydroxylamine hydrochloride, 3.1 ml (23 mmol) of triethylamine in THF (25 ml), and water (5 ml), at 0° C., and after stirring at 0° C. for one hour and at room temperature for one hour, the reaction was completed with aqueous KHSO4, and the mixture was extracted with methylene chloride. The organic layer was washed with 4N HCl and with saturated aqueous NaCl, and then dried over anhydrous magnesium sulfate, and after evaporation of the solvent under a reduced pressure, the residue was subjected to silica gel column chromatography to give 738 mg (78%) of the desired product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][C:14]=1[CH3:20])[CH2:11][F:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[B:26](OC)([O:29]C)[O:27]C.Cl>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][CH2:9][C@@H:10]([C:13]1[CH:18]=[CH:17][C:16]([B:26]([OH:29])[OH:27])=[CH:15][C:14]=1[CH3:20])[CH2:11][F:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COB(OC)OC
Reactant: Cc1cc(Br)ccc1[C@@H](CF)COCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(B(O)O)ccc1[C@@H](CF)COCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 48.5 %

Procedure:
To a solution of 24B (0.46 g, 1.364 mmol) in THF (7 mL) at −78° C., was added a solution of n-BuLi (2.2 mL, 3.52 mmol) dropwise. The mixture was stirred at −78° C. for 15 min, then was treated with trimethyl borate (0.456 mL, 4.09 mmol). The reaction was stirred at −78° C. for 15 min, then was allowed to warm to rt and stir for 3 h. The reaction mixture was diluted with EtOAc (30 mL), treated with 1N HCl (20 mL). The mixture was stirred at rt for 1 h. The phases were separated, then the aqueous layer was extracted with EtOAc. The combined organic phase was washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 80% EtOAc/hexanes) to give 24C (0.2 g, 0.662 mmol, 48.5% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.97-8.10 (m, 2H) 7.28-7.44 (m, 6H) 4.82 (d, J=5.56 Hz, 1H) 4.71 (d, J=5.56 Hz, 1H) 4.53-4.59 (m, 2H) 3.56-3.90 (m, 3H) 2.47 (s, 3H); 19F NMR (376 MHz, chloroform-d) δ ppm −223.99 (s, 1F).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:19]1[S:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=1>CN(C)C=O.C(OCC)(=O)C>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:19]2[S:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(O)cc1
Reactant: N#Cc1cnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Oc2ncc(C#N)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 1A (1.18 g, 7.75 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (1.1 g, 7.96 mmol), 2-chlorothiazole-5-carbonitrile (CAS 51640-36-9, 1.12 g, 7.75 mmol) and then the reaction was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (3×50 mL) and brine (50 mL). The organics were dried over magnesium sulfate, filtered, and evaporated. The product was purified via silica-gel column chromatography using dichloromethane as the eluent. The title compound was obtained as white solid (2.0 g), 1H NMR (300 MHz, CDCl3) δ ppm 7.76 (s, 1H) 7.12-7.23 (m, 2H) 6.87-7.00 (m, 2H) 4.44-4.65 (heptet, J=6.25 Hz, 1H) 1.36 (d, J=6.25 Hz, 6H), MS (DCI): m/z 261 (M+H)+.