Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[N:7]=[N:6][C:5]([NH:8][C:9]3[CH:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[N:16]4)=[CH:11][CH:10]=3)=[CH:4][C:3]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:33][CH:32]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Nc3ccc4cccnc4c3)nnc2Cl)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nnc(Nc3ccc4cccnc4c3)cc2-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of [6-chloro-5-(4-trifluoromethylphenyl)pyridazin-3-yl]-[quinolin-7-yl]amine, Example 88, (100 mg, 0.3 mmol) in dioxane (2 mL) was added 4-methoxyphenylboronic acid (46 mg, 0.3 mmol, Aldrich), followed by the addition of 2M aq Na2CO3 (0.2 mL, 0.4 mmol) and Pd[PPh3]4 (35 mg, 0.03 mmol, Aldrich). The mixture was flushed with N2 and heated under at 100° C. under N2 atmosphere for 24 h. The reaction mixture was cooled to room temperature, additional amounts of 2M aq Na2CO3 (0.2 mL, 0.4 mmol), 4-methoxyphenylboronic acid (46 mg, 0.3 mmol) and Pd[PPh3]4 (35 mg, 0.03 mmol) were added and the mixture was heated at 100° C. with stirring under N2 atmosphere for 4 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL) and washed with 5% Na2CO3. The organic layer was dried over Na2SO4, filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography, eluting with MeOH:CH2Cl2 (1:19), to give the title compound as a tan crystalline solid. MS (ESI, pos. ion) m/z: 473 (M+1). MP: 215–217° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[C:5]([OH:13])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>CN(C=O)C.C(Cl)Cl>[CH2:27]([O:26][C:24]([N:10]1[CH2:9][CH2:8][C:7]2[C:2]([F:1])=[CH:3][CH:4]=[C:5]([OH:13])[C:6]=2[CH2:12][CH2:11]1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Oc1ccc(F)c2c1CCNCC2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCc2c(O)ccc(F)c2CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of 9-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-ol (550 mg, 3.04 mmol, 1.0 eq.) and DIPEA (1.56 mL, 9.11 mmol, 3.0 eq.) in a mixture of DMF/DCM 1:2 (30 mL), benzyl chloroformate (0.50 mL, 3.34 mmol, 1.1 eq.) was added dropwise. Upon completion of the addition, the cooling bath was removed and the solution was stirred at r.t. for 3 hours. Then 1M aq. NaOH soln. (10 mL) was added ant the reaction mixture was stirred at r.t. for 1 hour. The mixture was extracted with DCM (3×50 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound as a brown solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:38]=[CH:37][C:9]2[N:10]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23](=[O:30])[NH:24][CH:25]([C:27](=[O:29])[NH2:28])[CH3:26])[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])C.N[C@H](C(N)=O)C[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(C(NC(C1C=CC2C(=CC=C(C3N(C4CCCCC4)C4C=CC(C(O)=O)=CC=4N=3)C=2)N=1)=O)C)(=O)N>>[C:27]([CH:25]([NH:24][C:23]([C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:11]3[N:10]([CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[C:9]4[CH:37]=[CH:38][C:6]([C:4]([OH:3])=[O:5])=[CH:7][C:8]=4[N:12]=3)[CH:14]=2)[N:19]=1)=[O:30])[CH2:26][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=[O:29])[NH2:28]
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(C(=O)NC(C)C(N)=O)ccc3c1)n2C1CCCCC1
Agent: CC(NC(=O)c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1)C(N)=O
Product: NC(=O)C(Cc1ccccc1)NC(=O)c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1

Procedure:
The title compound (5 mg yield) was prepared as described for Compound 497a using L-phenylalaninamide in place of L-alaninamide and hydrolyzed as described for Compound 497.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:12][CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:26]([C:29]1[S:33][CH:32]=[N:31][C:30]=1Br)(=O)[CH3:27]>>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[C:26]([CH3:27])=[C:29]3[S:33][CH:32]=[N:31][C:30]3=[N:1][C:2]=2[C:3]=1[O:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:6]
Reactant: CC(=O)c1scnc1Br
Reactant: COC(=O)c1cccc(N)c1OC(c1ccccc1)c1ccccc1
Product: COC(=O)c1ccc2c(C)c3scnc3nc2c1OC(c1ccccc1)c1ccccc1

Procedure:
For example, methyl 3-amino-2-diphenylmethoxybenzoate A27.12 is reacted with 5-acetyl-4-bromothiazole A27.13 (WO 9317681) to afford after cyclization of the initial displacement product, 5-benzhydryloxy-9-methyl-thiazolo[4,5-b]quinoline-6-carboxylic acid methyl ester A27.14. Reaction with N-bromosuccinimide in hexachloroethane then yields the bromomethyl analog A27.15, and this material is reacted with a trialkyl phosphite in an Arbuzov reaction to give the phosphonate A27.16. The product is then reacted with 3,5-dichlorobenzyl methylamine A27.17 and trimethyl aluminum to afford after deprotection the phosphonate A27.18.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7](=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10].Cl[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CN(C)C=O>[C:21]([O:20][C:18]([CH2:17][O:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[CH:7]=[O:15])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccccc1C=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 51.8 %

Procedure:
366 g of dimethylformamide and 165.9 g (1.2 mol) of potassium carbonate were placed in a flask, followed by dropwise addition of 122 g (1 mol) of salicylaldehyde. 181.2 g (1.2 mol) of t-butyl chloroacetate were added dropwise to the mixture at a temperature of 50° C. for three hours. After the addition, the mixture was stirred for three hours at a temperature of 50° C. The resulting reaction mixture was washed with 122 g of toluene and 662 g of water. 130 g of the solvent was removed from the mixture by distillation and then 122 g of n-heptane were added to the distillation residue to effect crystallization. The resulting crystals were collected by filtration to provide 122.3 g of 2-t-butoxycarbonylmethoxybenzaldehyde having a purity of 98.5% as brown or pale yellow crystals. The filtrate was concentrated and provided 52.6 g of 2-t-butoxycarbonylmethoxybenzaldehyde having a purity of 98.0%. FIG. 1 is an infrared absorption spectrum of the compound. The overall yield was 74%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][N:14]3[C:22]4[C:21]([CH3:23])=[C:20]([CH3:24])[N:19]=[C:18]([N:25](CC5C=CC(OC)=CC=5)CC5C=CC(OC)=CC=5)[C:17]=4[N:16]=[C:15]3[CH3:44])[O:10][N:9]=2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][N:14]3[C:22]4[C:21]([CH3:23])=[C:20]([CH3:24])[N:19]=[C:18]([NH2:25])[C:17]=4[N:16]=[C:15]3[CH3:44])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)c(C)c3c2nc(C)n3Cc2cc(-c3ccc(F)cc3)no2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)c2nc(C)n(Cc3cc(-c4ccc(F)cc4)no3)c2c1C
Yield: 26.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-N,N-bis(4-methoxybenzyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine (1.48 g, 2.50 mmol) in trifluoroacetic acid (20 g) was stirred at room temperature for 24 hours. The solution was then worked-up and the product isolated as described in Part B of Example 21. After the desired product was collected by filtration, it was purified by column chromatography on silica gel (60 g, eluting with 5% to 10% CMA in chloroform) to provide 0.235 g of 1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine as a white powder, mp 278.0-279.0° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C(N(CC)CC)C.[CH3:22][O:23][CH2:24][CH2:25][NH:26][CH3:27].O>CN(C=O)C>[CH3:22][O:23][CH2:24][CH2:25][N:26]([CH3:27])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: CNCCOC
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COCCN(C)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolved 2-fluoro-5-nitrobenzotrifluoride (250 mg, 1.2 mmol) in DMF (4 mL) and added triethylamine (242 mg, 2.39 mmol). N-(2-methoxyethyl)methylamine (179 mg, 1.32 mmol) was added to the reaction mixture and it was stirred overnight at ambient temperature. The reaction mixture was poured into water and extracted with EtOAc (2×). The combined organic washes were washed with brine and dried over Na2SO4. After concentration the remaining residue was purified by column chromatography (100% CHCl3 to 1:1 MeOH:CHCl3) to give the title compound. MS 265 [M−H]−, 267 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][F:17])[N:11]=1)(=O)=O.[CH3:18][NH2:19]>>[F:17][CH2:16][C:12]1[N:11]=[C:10]([C:9]#[C:8][CH2:7][CH2:6][NH:19][CH3:18])[CH:15]=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)OCCC#Cc1cccc(CF)n1
Reactant: CN
Product: CNCCC#Cc1cccc(CF)n1
Yield: 15 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(C), from 4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl methanesulfonate (2.90 g, 11 mmol) and N-methylamine 40% in aqueous solution (20 mL). The crude residue was purified over silicagel chromatography (prepacked 70 g silicagel column, DCM/MeOH: from 90/10 to 90/10 with 1% TEA as eluent) to afford 324 mg of 4-(6-(fluoromethyl)pyridin-2-yl)-N-methylbut-3-yn-1-amine as a pale oil (Yield: 15%).
Reaction SMILES: [NH2:1][CH:2]1[C:22](=[O:23])[N:4]2[C:5]([C:19]([OH:21])=[O:20])=[C:6]([CH:9]([S:13][C:14]3[NH:18][N:17]=[N:16][N:15]=3)[CH2:10][CH2:11][OH:12])[CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.[CH:32]([NH:34][C:35]1[S:36][CH:37]=[C:38]([C:40](=[N:44][O:45][CH2:46][C:47]#[CH:48])[C:41](O)=[O:42])[N:39]=1)=[O:33].P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C.CN(C)C=O>[CH:32]([NH:34][C:35]1[S:36][CH:37]=[C:38]([C:40](=[N:44][O:45][CH2:46][C:47]#[CH:48])[C:41]([NH:1][CH:2]2[C:22](=[O:23])[N:4]3[C:5]([C:19]([OH:21])=[O:20])=[C:6]([CH:9]([S:13][C:14]4[NH:15][N:16]=[N:17][N:18]=4)[CH2:10][CH2:11][OH:12])[CH2:7][S:8][C@H:3]23)=[O:42])[N:39]=1)=[O:33]
Reactant: NC1C(=O)N2C(C(=O)O)=C(C(CCO)Sc3nnn[nH]3)CS[C@H]12
Reactant: C#CCON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[Si](C)(C)CC(N)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(CCO)Sc3nnn[nH]3)CS[C@H]12)c1csc(NC=O)n1
Yield: 60.4 %

Procedure:
A solution of 7-amino-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (2.0 g) and trimethylsilylacetamide (5.9 g) in dry ethyl acetate (40.0 ml) and a solution of 2-(2-formamidothiazol-4-yl)-2-propargyloxyiminoacetic acid (syn isomer, 1.6 g), dry dimethylformamide (0.5 g) and phosphoryl chloride (1.0 g) in dry ethyl acetate (52.0 ml) were treated in a similar manner to that of Example 1-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer, 2.00 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9]Cl)[CH:5]=[CH:4][N:3]=1.[C:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])[CH3:12]>CS(C)=O>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][N:17]2[CH2:18][CH2:19][N:14]([C:11](=[O:13])[CH3:12])[CH2:15][CH2:16]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1c(CCl)ccnc1Cl
Solvent: CS(C)=O
Product: CC(=O)N1CCN(Cc2ccnc(Cl)c2C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-Chloro-3-methyl-pyridin-4-yl)-methanol (12-4, impure, 0.200 g) was dissolved in 5 mL anhydrous DCM under N2. Anhydrous DMF (0.098 mL, 1.3 mmol) and POCl3 (0.118 mL, 1.27 mmol) were added and the reaction was stirred at RT for 17 h. The reaction was quenched with sat NaHCO3 (aq) and extracted 3× with DCM. The organic phases were dried over Na2SO4, filtered and concentrated to provide 2-chloro-4-chloromethyl-3-methyl-pyridine still contaminated with a major by-product. 2-Chloro-4-chloromethyl-3-methyl-pyridine (impure, 0.215 g) was stirred in 3 mL DMSO. 1-Acetylpiperazine (0.626 g, 4.88 mmol was added and the reaction was stirred at RT overnight. The solution was purified by directly loading onto a preparative reverse phase column to afford an oil which slowly crystallizes. TFA salt: 1H NMR (CD3OD) δ 8.30 (d, 1H, J=5.0 Hz), 7.53 (d, 1H, J=5.0 Hz), 4.48 (s, 2H), 3.84 (bs, 4H), 3.39-3.30 (m, 4H), 2.14 (s, 3H).
Reaction SMILES: [Na].[Br:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5](F)[C:4]=1[CH3:12].[CH3:13][OH:14]>>[Br:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:14][CH3:13])[C:4]=1[CH3:12]
Reactant: CO
Reactant: Cc1c(Br)ccc(C#N)c1F
Agent: [Na]
Product: COc1c(C#N)ccc(Br)c1C
Temperature: 0 °C

Procedure:
Sodium (3.00 g, 130 mmol) was added in portions into 80 mL of methanol and the mixture was stirred for 20 min until the sodium was completely dissolved. Then 4-bromo-2-fluoro-3-methylbenzonitrile (8.00 g, 37.3 mmol) was added and the solution was refluxed for 4 hours before cooling down. The reaction mixture was poured into ice/water (300 mL) and the resulting precipitate was collected by filtration. The solid afforded was dried under reduced pressure at 40° C. to give 4-bromo-3-methyl-2-(methyloxy)benzonitrile. 1H-NMR (400 MHz, CDCl3) δ ppm 7.39 (d, J=8.0 Hz, 1 H), 7.28 (d, J=8.0 Hz, 1 H), 4.00 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([OH:11])=[O:10])[C:3]=1[Cl:12].[B-](F)(F)(F)[F:14].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>O>[NH2:1][C:2]1[C:7]([F:14])=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([OH:11])=[O:10])[C:3]=1[Cl:12]
Reactant: F[B-](F)(F)F
Reactant: Nc1cc(Cl)nc(C(=O)O)c1Cl
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Product: Nc1c(F)c(Cl)nc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.5 %

Procedure:
A solution of 4-amino-3,6-dichloropyridine-2-carboxylic acid (1100 g, 5.31 mol), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (2100 g, 5.93 mol) in water (6000 mL) was warmed to 65° C. for six hours. After cooling to ambient temperature, the reaction mixture was stirred an additional 18 hours. The solution was concentrated and the resulting solid washed with 6 N hydrochloric acid (5×1000 mL) and dried to give 4-amino-3,6-dichloro-5-fluoropyridine-2-carboxylic acid (757 g, 3.53 mol. 58% purity). This crude material was added to methanol (3000 mL) which had been saturated with anhydrous hydrogen chloride and the reaction mixture was warmed to 45° C. for 2 hours. The solution was added with vigorous stirring to ice water (4000 mL) and the resulting solid collected. The crude ester was dissolved in ethyl acetate (1000 mL) and washed with saturated sodium bicarbonate solution (2×1000 mL), dried, and concentrated. The resulting solid was recrystallized from ethyl acetate/hexanes to give methyl 4-amino-3,6-dichloro-5-fluoropyridine-2-carboxylate (402.5 g, 1.67 mol), mp 128-131° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH2:3]1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:5]1[C:4]2[CH2:3][N:2]([CH3:1])[CH2:14][CH2:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:27]
Reactant: CCOC(=O)CCCCCBr
Reactant: CN1CCc2c([nH]c3ccccc23)C1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CCCCCn1c2c(c3ccccc31)CCN(C)C2
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 52.6 %

Procedure:
A round bottom flask fitted with reflux condenser containing 2-methyl-2,3,4,9-tetrahydro-1H-β-carboline (16) (0.20 g, 1.1 mmol), and sodium hydride (60% by wt. in mineral oil, 0.055 g, 1.35 mmol) was vacuum purged and filled with argon, followed by addition of DMF (4 mL). After stirring at 60° C. for 20 min, ethyl 6-bromo-hexanoate (0.24 g, 1.1 mmol) was added and the mixture was stirred at 60° C. for 6 h. The reaction was quenched by addition of water (30 mL), transferred to a separatory funnel and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (2×20 mL), dried (Na2SO4) and concentrated. The product was purified by MPCC (0-10% gradient of MeOH in CH2Cl2), giving 190 mg of 6-(2-methyl-1,2,3,4-tetrahydro-b-carbolin-9-yl)hexanoic acid ethyl ester.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[CH2:41][NH2:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[NH:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[CH2:41][NH:42][C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:30])([F:29])[F:31])[O:14][N:13]=2)=[CH:8][CH:7]=1
Reactant: NCc1nc2ccccc2[nH]1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCc1nc2ccccc2[nH]1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 50 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol), (1H-benzo[d]imidazol-2-yl)methanamine (10.24 mg, 0.070 mmol), HATU (22.92 mg, 0.060 mmol), and 4-methylmorpholine (18.76 mg, 0.185 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-N-((1H-benzo[d]imidazol-2-yl)methyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (12.8 mg, 0.023 mmol, 49.3% yield): LCMS=561.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.19 (2 H, d, J=8.58 Hz), 7.51-7.79 (10 H, m), 7.34 (2 H, dd, J=6.05, 3.19 Hz), 5.27 (1 H, s), 4.76-4.94 (2 H, m); HPLC peak RT=2.6 min (Method E).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][N+:5]([O-:7])=[O:6].[CH:9](OCC)(OCC)[O:10][CH2:11][CH3:12].C(OC(=O)C)(=O)C>>[CH3:1][O:2][C:3](=[O:8])[C:4]([N+:5]([O-:7])=[O:6])=[CH:9][O:10][CH2:11][CH3:12]
Reactant: COC(=O)C[N+](=O)[O-]
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OC)[N+](=O)[O-]
Yield: 84.5 %

Procedure:
A 12-l. three-necked flask, equippedewith a thermometer, mechanical stirrer and a reflux condenser was charged under an atmosphere of nitrogen with 746 g (6.26 moles) of nitroacetic acid methylester, 1392 g (9.4 moles) of triethyl orthoformate and 1.92 l of acetic anhydride. The mixture was stirred and heated at reflux for 23 hours. The volatile components were distilled off first at atmospheric pressure (pot temperature up to 100° C, then at aspirator; vacuum and finally at 0.17 mmHg, (pot temperature up to 70°), leaving 926 g (84%) of crude alpha-nitro-beta-ethoxyacrylic acid methylester as an orange oil.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:15]1[C:20]([Cl:21])=[CH:19][C:18]([CH3:22])=[CH:17][N:16]=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([CH3:22])=[CH:17][N:16]=2)[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cnc(Cl)c(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Yield: 93.5 %

Procedure:
To a mixture of 1-Boc-piperazine (7.2 g), 2,3-dichloro-5-methylpyridine (5 g), palladium(II) acetate (179 mg), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (499 mg) and sodium tert-butoxide (4.1 g) was added toluene (30 mL), and the mixture was stirred with heating under reflux for 5 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-chloro-5-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g). To a mixture of the obtained 4-(3-chloro-5-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g),
Reaction SMILES: N#N.[Cl:3][CH2:4][C:5]1[O:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=1.[CH2:12](I)[CH3:13]>C(Cl)Cl>[Cl:3][CH2:4][C:5]1[O:6][CH:7]=[C:8]([CH2:10][O:11][CH2:12][CH3:13])[N:9]=1
Reactant: OCc1coc(CCl)n1
Reactant: CCI
Agent: N#N
Solvent: ClCCl
Product: CCOCc1coc(CCl)n1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-(chloromethyl)oxazol-4-yl)methanol (500 mg, 3.39 mmol) in CH2Cl2 (2.0 mL) was treated with EtI (0.28 mL, 3.39 mmol) followed by Ag2O (1.18 g, 5.08 mmol) and the resulting mixture (protected from light) was stirred overnight at 40° C. The reaction mixture was filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (7:3 hept-EA) gave the title compound as a yellow oil: TLC: rf (7:3 hept-EA)=0.29. LC-MS-conditions 07: tR=0.62 min, [M+H]+=176.26.