Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[CH:3]=1.[Mg].[C:11](=[O:13])=[O:12].Cl>O1CCCC1>[CH2:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:11]([OH:13])=[O:12])[CH3:9]
Reactant: CCc1cccc(Br)c1
Reactant: O=C=O
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCc1cccc(C(=O)O)c1
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Under an argon atmosphere, a solution of 1-bromo-3-ethylbenzene (5.1 g, 28 mmol) in tetrahydrofuran (45 mL) was added dropwise to a mixture of magnesium turnings (0.74 g, 31 mmol) in tetrahydrofuran (5.0 mL), and the mixture was stirred for 30 min. The reaction mixture was added to crushed dry ice and stirred for 1 hr. 1N Hydrochloric acid was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried, filtered and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=5:1) to give the title compound (3.87 g, yield 93%).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH:29]=O>>[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][N:1]1[CH:2]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=2[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]1=[O:8]
Reactant: O=Cc1nc2ccccc2s1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1nc2ccccc2s1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available benzo[d]thiazole-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.82 min.; [M+H]+: 383.14 g/mol.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[C:12]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)([OH:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].Cl>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:10]([O:9][C:7]([C:5]1[S:6][C:2]([C:18]2[CH:19]=[CH:20][C:15]([C:12]([OH:14])=[O:13])=[CH:16][CH:17]=2)=[CH:3][CH:4]=1)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1ccc(Br)s1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccc(C(=O)O)cc2)s1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Ethyl 5-bromothiophene-2-carboxylate (318 mg, 1.35 mmol) and 4-carboxyphenyl boronic acid (203 mg, 1.23 mmol) were suspended in 1 mL of water under nitrogen atmosphere. Tetrabutylammonium bromide (403 mg, 1.25 mmol), palladium acetate (2 mg, 0.009 mmol) and potassium carbonate (422 mg, 3.05 mmol) were added and the mixture stirred at 70° C. for 1 h. The solution was brought to pH 2 by addition of 1M HCl and the product extracted into 10% MeOH in EtOAc. The organic phase was dried and the solvent was removed. The solid was tritured with ethyl acetate, leaving a solid product. 1H-NMR (CDCl3): δ=7.99 (d, J=8.6 Hz, 2H), 7.88 (d, J=8.6 Hz, 2H), 7.83 (d, J=4 Hz, 1H), 7.49 (d, J=4 Hz, 1H), 4.31 (q, J=7.4 Hz, 2H), 1.31 (t, J=7.4 Hz, 3H). MS (EI): cal'd 277 (MH+), exp 277 (MH+).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:13][C@@H:14]([OH:17])[CH2:15]Cl)([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.C(N(C(C)C)C(C)C)C>C(O)C>[CH2:1]([O:3][P:4]([CH2:13][C@@H:14]([OH:17])[CH2:15][NH:24][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=1)([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOP(=O)(Cc1ccccc1)C[C@@H](O)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOP(=O)(Cc1ccccc1)C[C@@H](O)CNCc1ccc(Cl)cc1

Procedure:
A mixture of 2.76 g of (2R)-3-chloro-2-hydroxypropyl(benzyl)phosphinic acid ethyl ester, 3.54 g of p-chlorobenzylamine, 3.25 g of N-ethyl-N,N-diisopropylamine and 20 ml of ethanol is heated under reflux for 48 hours. Removal of the solvent and chromatography yield (2S)-3-(p-chlorobenzylamino)-2-hydroxypropyl(benzyl)phosphinic acid ethyl ester; 1H-NMR spectrum (in CDCl3): δ=7.4-7.17 (9H,m); 4.14-3.83 (3H,m); 3.71 (2H,ABq); 3.20 (2H,d); 2.6-2.5 (2H,m); 1.96-1.62 (2H,m); 1.25 (3H,t); 31P-NMR spectrum (in CDCl3): δ=53.9; 52.7.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13]C3N=CNC=3)[CH2:11][C@@H:10]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:9]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:8][C:7]=2[CH:30]=1.C([C:33]1[NH:34][CH:35]=[CH:36][N:37]=1)=O.Cl.N1C=C(CN2C3C=CC=CC=3CN(C(C3C4C(=CC=CC=4)C=CC=3)=O)CC2)N=C1>>[ClH:1].[ClH:1].[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:33]3[NH:34][CH:35]=[CH:36][N:37]=3)[CH2:11][C@@H:10]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:9]([S:26]([CH3:29])(=[O:27])=[O:28])[CH2:8][C:7]=2[CH:30]=1
Reactant: O=Cc1ncc[nH]1
Reactant: CS(=O)(=O)N1Cc2cc(Br)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Agent: Cl
Agent: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccccc2C1
Product: CS(=O)(=O)N1Cc2cc(Br)ccc2N(Cc2ncc[nH]2)C[C@H]1Cc1ccccc1
Yield: 54 %

Procedure:
The product was prepared as an offwhite solid in 54% yield from Compound C of Example 224 and 2-formyl imidazole as described for Compound D of Example 1.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].CN(C)C=O.[OH:19][CH:20]1[CH2:24][CH2:23][NH:22][C:21]1=[O:25]>O>[Si:10]([O:19][CH:20]1[CH2:24][CH2:23][NH:22][C:21]1=[O:25])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1NCCC1O
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCNC1=O
Reaction time: 1 h
Yield: 11.4 %

Procedure:
In an ice bath, 300 mg of imidazole and 497 mg of tert-butyldimethylchlorosilane were added to a dimethylformamide (2 ml) solution of 255 mg of 3-hydroxypyrrolidin-2-one, and stirred for 1 hour. Water was added to the reaction liquid, extracted with ethyl acetate, and washed with hydrochloric acid (1 N) and saturated saline water. The organic layer was dried to obtain 370 mg of a crude product. 208 g of the product was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=9/1 to 2/8) to obtain 62 mg of the entitled compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][NH:11][C:10](=[O:13])[CH2:9]2)=[CH:4][C:3]=1[I:14].C(N(CC)CC)C.[C:22](=O)([O:28]C(C)(C)C)[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:24]([O:23][C:22]([N:11]1[CH2:12][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([I:14])[CH:4]=2)[CH2:9][C:10]1=[O:13])=[O:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: O=C1C[C@H](c2ccc(Cl)c(I)c2)CN1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](c2ccc(Cl)c(I)c2)CC1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To (4R)-4-(4-chloro-3-iodophenyl)pyrrolidin-2-one (17.4 g, 54.4 mmol) was added 50 mL DCM. The solution was cooled to 0° C. Triethylamine (9.1 mL, 65.25 mmol) was added followed by di-tert butyl carbonate (13.1 g, 59.04 mmol) in 60 mL of DCM. A catalytic amount of DMAP was added, the mixture warmed to room temperature, and then stirred overnight at room temperature. A 5% solution of HCl (50 mL) was added and the organic phase separated. The DCM layers were then washed with brine and evaporated to give the title compound (43a) as a yellowish solid (18.3 g, 80% yield). 1H-NMR (400 MHz, CD3OD): δ 7.83-7.84 d, J=2 Hz, 1H), 7.35-7.46 (m, 1H), 7.31-7.33 (m, 1H), 4.11-4.15 (m, 1H), 3.62-3.67 (m, 2H), 3.45-3.61 (m, 1H), 2.80-2.84 (m, 1H), 2.69-2.74 (m, 1H) 1.52 (s, 9H); MS (ESI) m/z 443.86 (M+Na)+.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:10]([OH:24])[CH2:11][C@@H:12]([C:20]([OH:23])([CH3:22])[CH3:21])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])=O)(C)(C)C.Cl.[C:33]([O:37][C:38]([NH:40][C@H:41]([C:48](O)=[O:49])[CH2:42][C:43]1[N:44]=[CH:45][S:46][CH:47]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34].P(C#N)(OCC)(OCC)=O>O1CCOCC1.O1CCCC1.C(N(CC)CC)C>[C:33]([O:37][C:38]([NH:40][C@H:41]([C:48]([NH:8][C@@H:9]([CH2:25][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)[C@@H:10]([OH:24])[CH2:11][C@@H:12]([C:20]([OH:23])([CH3:21])[CH3:22])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])=[O:49])[CH2:42][C:43]1[N:44]=[CH:45][S:46][CH:47]=1)=[O:39])([CH3:35])([CH3:36])[CH3:34]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Reactant: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)(C)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 309 mg (0.698 mmole) of (2S, 4S, 5S)-5-(t-butoxycarbonylamino)-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-butylhexanamide (prepared as described in Preparation 29) in 6 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes under an atmosphere of nitrogen. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and then benzene was added to the residue. The solvent was removed by distillation under reduced pressure from the resulting solution. The same operation was repeated, in total, three times, and the resulting residue was then dried by evaporation under reduced pressure for 8 hours. At the end of this time, 200.6 mg (0.737 mmole) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine were added to a suspension of the dried material in 15 ml of anhydrous tetrahydrofuran, and then 0.13 ml (0.858 mmole) of 95% diethyl cyanophosphate and 0.3 ml of triethylamine were added to the resulting mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred for 5 hours, after which the solvent was removed by distillation under reduced pressure and the residue was purified by medium pressure silica gel column chromatography (using a 20:1 by volume mixture of methylene chloride and methanol as eluent), followed by recrystallization from a mixture of methylene chloride and diisopropyl ether, to give 457.8 mg or the title compound as white crystals.
Reaction SMILES: O1C=N[C:3]([C:6]([NH:9][C:10]([C:12]2[CH:13]=[C:14]([C:18]3[CH:19]=[C:20]4[C:29]([C:30]([NH:32][CH3:33])=[O:31])=[C:28]([C:34]5[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=5)[O:27][C:21]4=[N:22][C:23]=3/[CH:24]=[CH:25]/[CH3:26])[CH:15]=[CH:16][CH:17]=2)=[O:11])([CH3:8])[CH3:7])=[N:2]1>CO.[Pd]>[C:3]([C:6]([NH:9][C:10]([C:12]1[CH:13]=[C:14]([C:18]2[CH:19]=[C:20]3[C:29]([C:30]([NH:32][CH3:33])=[O:31])=[C:28]([C:34]4[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=4)[O:27][C:21]3=[N:22][C:23]=2[CH2:24][CH2:25][CH3:26])[CH:15]=[CH:16][CH:17]=1)=[O:11])([CH3:7])[CH3:8])#[N:2]
Reactant: C/C=C/c1nc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1-c1cccc(C(=O)NC(C)(C)c2ncon2)c1
Agent: [Pd]
Solvent: CO
Product: CCCc1nc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1-c1cccc(C(=O)NC(C)(C)C#N)c1
Reaction time: 4 h
Yield: 10.9 %

Procedure:
Pd/C (9.0 mg, 8.5 μmol) was added to a stirring solution of (E)-5-(3-((2-(1,2,4-oxadiazol-3-yl)propan-2-yl)carbamoyl)phenyl)-2-(4-fluorophenyl)-N-methyl-6-(prop-1-en-1-yl)furo[2,3-b]pyridine-3-carboxamide (23 mg, 0.043 mmol) in MeOH (853 μl) at room temperature. The reaction mixture was placed in a Parr bomb and charged with 25 PSI of H2 (g) and the reaction mixture was allowed to stir for 4 hours. LCMS indicated no conversion. Pd/C (9.0 mg, 8.5 μmol) was added and the reaction mixture was placed in a Parr bomb and charged with 50 PSI of H2 (g) and the reaction mixture was allowed to stir for 16 hours. The reaction mixture was filtered and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give 5-(3-((2-cyanopropan-2-yl)carbamoyl)phenyl)-2-(4-fluorophenyl)-N-methyl-6-propylfuro[2,3-b]pyridine-3-carboxamide (2.5 mg, 4.7 μmol, 11% yield) consistent by LCMS and NMR. 1H NMR (400 MHz, CDCl3) δ 8.01-7.95 (m, 2H), 7.94 (s, 1H), 7.82 (d, J=7.5 Hz, 1H), 7.70 (s, 1H), 7.56-7.45 (m, 2H), 7.22 (t, J=8.7 Hz, 2H), 6.58 (s, 1H), 6.09-6.01 (m, 1H), 2.99 (d, J=5.0 Hz, 3H), 2.74-2.67 (m, 2H), 1.86 (s, 6H), 1.71-1.65 (m, 2H), 0.85 (t, J=7.4 Hz, 3H). LC-MS retention time: 2.05 min; m/z (M+H)+: 499. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% methanol/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% methanol/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)Cl.[C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22])([CH3:15])([CH3:14])[CH3:13]>C(OCC)(=O)C>[C:12]([C:16]1[CH:21]=[C:20]([C:1](=[O:3])[CH3:2])[CH:19]=[CH:18][C:17]=1[OH:22])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccccc1O
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)c1ccc(O)c(C(C)(C)C)c1
Temperature: 0 °C
Yield: 55 %

Procedure:
Acetyl chloride (287 g) was added to a mixture of aluminum chloride (488 g) and methylene chloride (1.8 l) at −60° C. while stirring. 2-tert-Butylphenol (500 g) was added at −70° C. to −50° C. over a period of 1.5 hours, and the temperature was then raised to 0° C. The reaction mixture was poured into ice and extraction was performed with ethyl acetate. The organic layer was washed with brine, the solvent was distilled off under reduced pressure, methanol (1 l) and potassium carbonate (300 g) were added to the residue and the mixture was stirred at room temperature for 2 hours. After adding water to the reaction mixture and neutralizing it with concentrated hydrochloric acid, extraction was performed with ethyl acetate and the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Hexane was added to the residue and the resulting crystals were filtered off to yield the title compound (352 g) as white crystals.
Reaction SMILES: [CH3:1][C:2]([C:5]([C:7]1[CH:12]=[C:11]([C:13](OC)=[O:14])[CH:10]=[CH:9][C:8]=1[C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[F:25])=[CH2:6])([CH3:4])[CH3:3].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[CH3:4][C:2]([C:5]([C:7]1[CH:12]=[C:11]([CH2:13][OH:14])[CH:10]=[CH:9][C:8]=1[C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[F:25])=[CH2:6])([CH3:1])[CH3:3]
Reactant: C=C(c1cc(C(=O)OC)ccc1-c1cc(OC)ccc1F)C(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(c1cc(CO)ccc1-c1cc(OC)ccc1F)C(C)(C)C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a stirred solution of T12.6 (0.400 g, 1 mmol) in THF (6 mL) at 0° C. was added LAH in THF (2 mL, 2 mmol, 1.0M). The resulting mixture was stirred for 2 hours. 1N NaOH(aq) was then added to the mixture, and the resulting mixture was extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-20% EtOAc in hexanes) to yield T12.7 as a colorless oil (0.273 g, 74% yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.Cl.[F:37][C:38]1([F:44])[CH2:43][CH2:42][CH2:41][NH:40][CH2:39]1.C(N(CC)CC)C>C1COCC1.O>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([N:40]4[CH2:41][CH2:42][CH2:43][C:38]([F:44])([F:37])[CH2:39]4)[N:3]=3)[N:25]=2)=[CH:30][CH:31]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: FC1(F)CCCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc(N2CCCC(F)(F)C2)c(C#N)c1-c1ccc(OCCO)cc1

Procedure:
At RT, 150 mg (0.20 mmol, purity about 74%) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A), 64 mg (0.41 mmol) of 3,3-difluoropiperidine hydrochloride and 57 μl (0.41 mmol) of triethylamine were stirred in 3 ml of THF for 2 h. The reaction mixture was then diluted with about 1 ml of water and about 3 ml of THF and purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 90 mg (71% of theory) of the target compound.
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.[NH2:32][CH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH:35]1[C:34]([CH2:33][NH:32][C:3](=[O:5])[CH:2]([OH:1])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]=[C:15]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:18]=4[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=3)=[CH:8][CH:7]=2)=[N:38][N:37]=[N:36]1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCc1nnn[nH]1
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(NCc1nnn[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), 5-(aminomethyl)tetrazole (6.89 mg, 0.070 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were added to DMF (1 mL). This was stirred for 1 h and was then purified by prep HPLC (PHENOMENEX® Luna 5u 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=29.2 min) to provide (R/S)-N-((1H-tetrazol-5-yl)methyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (12 mg, 0.023 mmol, 49.8% yield): LCMS=513.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.11-8.24 (2 H, m), 7.53-7.75 (7 H, m), 5.22 (1 H, s), 4.67-4.81 (2 H, m); HPLC peak RT=8.8 min (Method A).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13]([O:15][CH3:16])=[O:14])([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=O.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[F:28][C:29]([F:42])([F:41])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1NN=[N:38][N:37]=1>C(Cl)Cl>[CH3:1][N:2]1[C:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([F:28])([F:42])[F:41])=[N:37][N:38]=[C:3]1[C:5]12[CH2:12][CH2:11][C:8]([C:13]([O:15][CH3:16])=[O:14])([CH2:9][CH2:10]1)[CH2:7][CH2:6]2
Reactant: CNC(=O)C12CCC(C(=O)OC)(CC1)CC2
Reactant: FC(F)(F)c1ccccc1-c1nnn[nH]1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C12CCC(c3nnc(-c4ccccc4C(F)(F)F)n3C)(CC1)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Carboxylate 1-B (2.76 g, 12.3 mmol) was dissolved in methylene chloride (100 ml). Oxalyl chloride (2.0 M, 15.3 ml) was added to the resulting solution followed by DMF (0.19 ml, 2.45 mmol). The reaction mixture was then stirred at room temperature under a nitrogen atmosphere for 2 hours before it was concentrated and stripped from toluene 3 times. The residue was redissolved in toluene (100 ml), treated with 5-[2-(trifluoromethyl)phenyl]-1H-tetrazole (3.15 g, 14.7 mmol) and heated at 100° C. under nitrogen for 12 hours. The product, 1,2,4-triazole 1-C, which precipitated out of reaction mixture as the HCl salt, was dissolved in methylene chloride, washed twice with saturated aqueous sodium bicarbonate solution, dried (MgSO4) and stripped to yield 1-C as a white solid. MS (ESI+)=394.2 (M+1); 1H NMR (500 MHz, CDCl3): δ 2.00 (6H, m), 2.18 (6H, m), 3.48 (3H, s), 3.72 (3H, s), 7.51 (1H, m), 7.71 (2H, m), 7.85 (1H, m) ppm.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].ClC1C=[CH:20][C:16]([C:17](N)=[O:18])=[C:15](OCCC)N=1.[H-].[Na+]>C(#N)C>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([O:18][CH2:17][CH:16]([CH3:20])[CH3:15])[N:10]=1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: CCCOc1nc(Cl)ccc1C(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)COc1nc(Cl)ccc1C(N)=O
Yield: 66.6 %

Procedure:
To a solution of 2,6-dichloro-nicotinamide (1) (3 g, 15.7 mmol) in acetonitrile (anhydrous, 30 mL) were added 2-methyl-propan-1-ol (2) (1.22 g, 16.5 mmol) and NaH (0.42 g, 16.5 mmol). The reaction was kept at r.t. O/N. The suspension was filtered and the filtrate was concentrated in vacuo. The residue was purified by Biotage silica gel chromatography with 10%-80% EtOAc/hexanes gradient elution to afford 2.39 g (66% yield) of the title compound.
Reaction SMILES: O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[C:47]3[C:42](=[CH:43][C:44]([O:48][CH2:49][O:50][CH3:51])=[CH:45][CH:46]=3)[S:41][CH2:40][C:39]2([C:53]2[CH:58]=[CH:57][C:56]([O:59][CH2:60][O:61][CH3:62])=[CH:55][CH:54]=2)[CH3:52])=[CH:34][CH:33]=1)(C(C)(C)C)(C)C>O>[OH:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[C:47]3[C:42](=[CH:43][C:44]([O:48][CH2:49][O:50][CH3:51])=[CH:45][CH:46]=3)[S:41][CH2:40][C:39]2([C:53]2[CH:54]=[CH:55][C:56]([O:59][CH2:60][O:61][CH3:62])=[CH:57][CH:58]=2)[CH3:52])=[CH:34][CH:33]=1
Reactant: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2c2ccc(O)cc2)cc1
Reaction time: 2 h
Yield: 99.8 %

Procedure:
Under argon atmosphere, tetrahydrofuran solution of tetrabutylammonium fluoride (1.0M, 2.27 ml, 2.27 mmol) was added dropwise to tetrahydrofuran solution (35 ml) of (3RS,4RS)-4-(4-t-butyldimethylsilyloxyphenyl)-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methylthiochroman (856 mg, 1.51 mmol) at 0° C. and the resulting mixture was stirred for 2 hours. After adding water, the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent. The crude product thus obtained was purified with silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 682 mg (yield: 100%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:17]1[CH2:22][CH2:21][S:20][CH2:19][CH2:18]1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:17]2[CH2:22][CH2:21][S:20][CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C1CSCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Brc1ccc(CN2CCSCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.8 %

Procedure:
A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine (0.84 mL, 6.0 mmol) and thiomorpholine (0.82 mL, 8.0 mmol) in THF (10 mL) was stirred at ambient temperature for 16 h. The solvent was evaporated and the resultant residue diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound as an off-white solid (1.13 g, quantitative yield). 1H NMR (CDCl3, 300 MHz): 7.46-7.40 (m, 2H), 7.21-7.16 (m, 2H), 3.45 (s, 2H), 3.15-3.09 (m, 1H), 2.76-2.60 (m, 6H), 2.62-2.57 (m, 1H).