Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([C:37]([O:39]C)=[O:38])[CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]#[N:36])[CH:28]=2)=[N:20][N:19]=1)([CH3:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>CO>[C:1]([O:5][C:6]([NH:8][C:9]([C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([C:37]([OH:39])=[O:38])[CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]#[N:36])[CH:28]=2)=[N:20][N:19]=1)([CH3:17])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)cc(-c2ccccc2C#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(C)(Cc1ccccc1)c1nnc(-c2cc(C(=O)O)cc(-c3ccccc3C#N)c2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of methyl 5-(5-{(1R)-1-[(tert-butoxycarbonyl)amino]-1-methyl-2-phenylethyl}-1,3,4-oxadiazol-2-yl)-2′-cyanobiphenyl-3-carboxylate from Step A (780 mg, 1.45 mmole) in methanol (20 mL) at rt was added 0.43 mL of 5 N NaOH aq. The reaction was allowed to stir at rt overnight. The solution was poured into water (100 mL) and acidified by adding 1N HCl (10 mL). The resulting mixture was extracted with ethyl acetate (2×100 mL). The combined organics were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated at reduced pressure to give 5-(5-{1-[(tert-butoxycarbonyl)amino]-1-methyl-2-phenylethyl}-1,3,4-oxadiazol-2-yl)-2′-cyanobiphenyl-3-carboxylic acid (Intermediate XVII). 1H NMR (400 MHz, CDCl3) δ 8.77 (br s, 1H), 8.47 (m, 2H), 7.84 (d, J=7.7 Hz, 1H), 7.72 (t, J=7.7 Hz, 1H), 7.65-7.55 (m, 2H), 7.33-7.25 (m, 3H), 7.13-7.05 (2H, m) 5.25 (br s, 1H), 3.61 (d, J=13.5 Hz, 1H), 3.46 (d, J=13.5 Hz, 1H), 1.76 (s, 3H), 1.42 (s, 9H). LCMS [(M)+H]+=525
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16](Cl)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[NH:19]1[CH2:27][CH2:26][CH:22]([C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]1>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]([N:19]3[CH2:27][CH2:26][CH:22]([C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)C1CCNCC1
Reactant: Clc1cc(-c2ccc(Br)cc2)nc2ccccc12
Solvent: CCO
Product: NC(=O)C1CCN(c2cc(-c3ccc(Br)cc3)nc3ccccc23)CC1

Procedure:
The named compound was made in a manner analogous to that of Example 8(d) using (2-(4-bromophenyl)-4-chloroquinoline and isonipecotamide as starting materials. It was obtained as white needles, mp 247°-249° dec on recrystallization from ethanol.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][C:9]([C:10]#[N:11])([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:20]
Reactant: N#CCc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1cccc(C(F)(F)F)c1

Procedure:
Prepare by the method of example 1.1.2 using 3-trifluoromethyl-phenylacetonitrile (0.161 mol) and ethyl bromoacetate (0.325 mol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6](I)[C:5]([CH3:13])=[N:4]1)[CH3:2].[Cu][C:15]#[N:16].CCOC(C)=O>CN(C=O)C>[C:15]([C:6]1[C:5]([CH3:13])=[N:4][N:3]([CH2:1][CH3:2])[C:7]=1[C:8]([O:10][CH3:11])=[O:9])#[N:16]
Reactant: N#C[Cu]
Reactant: CCn1nc(C)c(I)c1C(=O)OC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1nc(C)c(C#N)c1C(=O)OC
Yield: 91.4 %

Procedure:
To a flask, methyl 1-ethyl-4-iodo-3-methylpyrazol-5-ylcarboxylate (1.00 g, 0.003 mol) was dissolved in 10 mL of DMF and copper (I) cyanide (0.46 g, 0.005 mol) was added in batches. After heating to reflux for 1 h, the mixture was separated by filtration. The filtrate was diluted with 50 mL of water, and then extracted with 50 mL of ethyl acetate. The organic layer was washed with 50 mL of saturated aqueous sodium bicarbonate solution and 50 mL of saturated brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. Column chromatography (EtOAc:P.E.=1:10 as eluent) gave 0.53 g of the title compound as a yellow oil (yield 80%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.[C:25](C1NC=CN=1)(C1NC=CN=1)=[O:26]>O1CCCC1>[F:8][C:7]1[C:2]2[NH:1][C:25](=[O:26])[N:11]([CH:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]3)[C:3]=2[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=1
Reactant: COc1cc(F)c(N)c(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: COc1cc(F)c2[nH]c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 50 °C

Procedure:
A mixture of 1,1-dimethylethyl 4-[(2-amino-3-fluoro-5-methoxyphenyl)amino]-1-piperidinecarboxylate (D13a) (230 mg, 0.7 mmol), carbonyl diimidazole (150 mg, 1.0 mmol), and tetrahydrofuran (6 ml) was heated 1 h at 50° C. then partitioned between dichloromethane and water. The organic layer was purified by chromatography on silicagel eluting with 0 to 10% methanol in dichloromethane containing 0.2M ammonia to give the title compound as white crystals, 47%, 120 mg, M−−H=364.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5]1)[CH2:2][CH3:3].Cl[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]2[N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH:23]=[N:24][C:13]=12>C1COCC1>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:22]2[C:14]3=[N:15][C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:12]([CH2:11][N:7]4[CH2:8][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][C:6]4=[O:9])=[C:13]3[N:24]=[CH:23]2)=[CH:31][CH:30]=1
Reactant: CCCC1CNC(=O)C1
Reactant: COc1ccc(Cn2cnc3c(CCl)cc(C(F)(F)F)nc32)cc1
Solvent: C1CCOC1
Product: CCCC1CC(=O)N(Cc2cc(C(F)(F)F)nc3c2ncn3Cc2ccc(OC)cc2)C1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 20 %

Procedure:
4-propylpyrrolidin-2-one x1 (0.22 g, 1.1 eq with respect to x199, 1.7 mmol) is dissolved in absolute THF (10 ml). A 1.06 M solution of Li-HMDS in THF (1.76 ml, 1.1 eq, 1.87 mmol) is added at −78° C. in a flow of argon. The reaction mixture is stirred for 15 min at −30° C. and cooled again to −78° C. A solution of 7-(chloromethyl)-3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine x202 in absolute THF (10 ml) is added dropwise at this temperature. The reaction mixture is allowed to heat up slowly to room temperature. In order to complete the reaction, the reaction mixture is refluxed the next morning for 1 h, and then partitioned between saturated aqueous NH4Cl and ethyl acetate. The organic layer is dried with anhydrous sodium sulfate and evaporated. The product is purified by HPLC (water/acetonitrile) to afford 0.14 g of 1-{[3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one x205 (0.14 g).
Reaction SMILES: [BH4-].[Li+].[CH2:3]([N:10]1[C:14](=[O:15])[CH2:13][CH:12]([C:16](OC)=[O:17])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)(=O)C>C1COCC1>[CH2:3]([N:10]1[CH2:11][CH:12]([CH2:16][OH:17])[CH2:13][C:14]1=[O:15])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C1CC(CO)CN1Cc1ccccc1
Temperature: 10 °C
Reaction time: 3 h
Yield: 104.6 %

Procedure:
200 ml of a 2M solution of lithium borohydride in THF were added dropwise to a stirred solution of 100 g of methyl 1-benzyl-5-oxo-3-pyrrolidinecarboxylate in 600 ml of THF under a nitrogen atmosphere. After 3 hours, the mixture was cooled to 10° C. and treated with 200 ml of 50% aqueous acetic acid. The solvents were removed under reduced pressure and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic extracts were dried and evaporated to dryness to give 92 g of 1-benzyl-4-(hydroxymethyl)-2-pyrrolidinone. This was dissolved in 200 ml of pyridine and the solution was treated with 95 g p-toluenesulphonyl chloride. The solution obtained was stirred for 18 hours and then concentrated. The residue was partitioned between dichloromethane and 2M hydrochloric acid. The organic phase was washed with water, dried and evaporated to dryness. Crystallization of the residue from diethyl ether/n-hexane gave 115 g of 1-benzyl-4-(p-toluenesulphonyloxy)-2-pyrrolidinone of melting point 83°-84° C.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[CH2:7]([NH:14][CH2:15][CH2:16][OH:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:7]([N:14]([CH2:15][CH2:16][OH:17])[C:3]([N:2]([CH3:6])[CH3:1])=[O:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(C)C(=O)Cl
Reactant: OCCNCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
N,N-dimethyl carbamoyl chloride (2.55 g, 0.0238 mol) was added drop by drop at 0° C. to a solution of N-benzyl ethanol amine (3 g, 0.0198 mol) and triethylamine (3 g, 0.0298 mol) in 25 ml of DCM (dry) and stirred at RT for 3 h under nitrogen atmosphere. The reaction was quenched with water, extracted with dichloromethane, washed with water, brine and dried over sodium sulfate. Solvent evaporation under reduced pressure followed by column chromatography over silica gel using 3.5% methanol in dichloromethane as eluent afforded 4 g of the sub-title compound as a liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([I:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[CH:19](I)([CH3:21])[CH3:20]>CN(C=O)C>[CH3:11][O:10][C:5]1[CH:6]=[C:7]([I:9])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[O:12][CH:19]([CH3:21])[CH3:20]
Reactant: COc1cc(I)cc(OC)c1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(I)cc(OC)c1OC(C)C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a suspension of 2,6-dimethoxy-4-iodophenol (1.0 g) and potassium carbonate (938 mg) in DMF (10 mL) was added isopropyl iodide (507. L). The mixture was stirred at 60° C. for 3 hours and evaporated. Ethyl acetate and water were added to the residue, the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was applied to a column of silica gel using hexane-ethyl acetate (5:1) as an eluent to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:14](C(OCC)=O)=[C:6]2[C:7]([O:12]C)=[CH:8][C:9]([F:11])=[CH:10][N:5]2[N:4]=1)[CH3:2].B(Br)(Br)Br.O>ClCCl>[CH2:1]([C:3]1[CH:14]=[C:6]2[C:7]([OH:12])=[CH:8][C:9]([F:11])=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCOC(=O)c1c(CC)nn2cc(F)cc(OC)c12
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCc1cc2c(O)cc(F)cn2n1
Reaction time: 1 h
Yield: 94 %

Procedure:
The compound of Example 41 (4.53 g) was dissolved in dichloromethane (50 mL). The solution was kept at 0° C. and boron tribromide (21.6 mL, 1.0 mol/L dichloromethane solution) was added. The resulting mixture was stirred for 1 hour. Subsequently, water was added and the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The resulting solid product (4.29 g) was dissolved in ethanol (40 mL). To this solution, water (40 mL) and potassium hydroxide (4.10 g) were added and the mixture was stirred for 2 hours under reflux. This was followed by addition of water and concentrated hydrochloric acid to make the mixture acidic. The resulting mixture was extracted with three times with ethyl acetate and the organic layer was washed with saturated brine, dried over sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The resulting solid product (3.58 g) was dissolved in ethanol (100 mL). To this solution, concentrated sulfuric acid (2 mL) was added and the mixture was refluxed for 7.5 hours. Subsequently, ethanol was evaporated under reduced pressure and the residue was extracted three times with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to afford the title compound as a gray powder (2.88 g) (Process B).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:41]=[CH:40][C:11]([CH2:12][N:13]2[C:17](=[O:18])[C:16]3([CH2:23][CH2:22][N:21](C(OCC4C=CC=CC=4)=O)[CH2:20][CH2:19]3)[N:15]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:14]2)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(OCC)(=O)C.CO>[O:18]=[C:17]1[C:16]2([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:15]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:14][N:13]1[CH2:12][C:11]1[CH:10]=[CH:9][C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)cc1
Yield: 99.5 %

Procedure:
Benzyl 3-(4-(tert-butoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (4.90 g, 8.82 mmol) and palladium on carbon (10 wt. %, wet, Degussa type E101 NE/W,) in ethyl acetate (50 mL) and methanol (50 mL) was stirred at room temperature under hydrogen (balloon) for 3 hours. The catalyst was removed by filtration and the filtrate evaporated and dried under vacuum to give product as foam (3.70 g, 99%); 1H NMR (DMSO-d6); δ1.53 (s, 9H); 2.35-2.48 (m, 2H); 2.85-2.92 (m, 2H); 3.17-3.23 (m, 2H); 3.23-3.43 (m, 2H); 4.58 (s, 2H), 4.62 (s, 2H); 6.74 (t, J=6.8 Hz, 1H); 6.87 (d, J=8.4 Hz, 2H); 7.20 (dd, J=7.6 Hz and 8.8 Hz, 2H); 7.40 (d, J=8.4 Hz, 2H); 7.90 (m, 2H); MS for C25H31N3O3 m/z 422 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1.[CH2:23]=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:23][OH:24])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1
Reactant: C=O
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Product: OCCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
heating 8-chloro-6-phenyl-1-methyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine in an inert organic solvent with paraformaldehyde to 100°-140° C. to give 8-chloro-1-(2-hydroxyethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine; and
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:18])[CH3:17])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].I[CH3:22].O>CN(C=O)C>[CH3:22][N:15]([C@@H:12]1[CH2:13][CH2:14][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11]1)[C:16](=[O:18])[CH3:17]
Reactant: CI
Reactant: CC(=O)N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(C)[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h

Procedure:
(R)-N-[1-(4-Nitrophenyl)pyrrolidin-3-yl]acetamide (1.3 g) was added in portions to a suspension of sodium hydride (50% in oil; 0.25 g) in DMF (50 ml). After gas evolution had ceased, iodomethane (0.82 g) was added. After one hour, the reaction mixture was cautiously hydrolyzed with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 263.30 (C13H17N3O3); MS (ESI): 264 (M+H+).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([C:21]2[O:25][C:24]([C:26]3[CH:31]=[CH:30][C:29]([C@H:32]([NH:37]S(C(C)(C)C)=O)[C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)=[N:23][N:22]=2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:7][N:8]=1>CO>[NH2:37][C@@H:32]([C:29]1[CH:30]=[CH:31][C:26]([C:24]2[O:25][C:21]([C:4]3[C:3]([NH2:2])=[N:8][CH:7]=[C:6]([C:9]4[CH:14]=[CH:13][C:12]([S:15]([CH:18]([CH3:19])[CH3:20])(=[O:17])=[O:16])=[CH:11][CH:10]=4)[N:5]=3)=[N:22][N:23]=2)=[CH:27][CH:28]=1)[C:33]([F:34])([F:35])[F:36]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccc([C@H](NS(=O)C(C)(C)C)C(F)(F)F)cc4)o3)n2)cc1
Agent: Cl
Solvent: CO
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccc([C@H](N)C(F)(F)F)cc4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
HCl (35.274 of 3 M, 0.1058 mmol) was added to a solution of N-[(1S)-1-[4-[5-[3-amino-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]-2,2,2-trifluoro-ethyl]-2-methyl-propane-2-sulfinamide (253.3 mg, 0.05288 mmol) in MeOH (1 mL) and the resulting solution stirred at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure and the residue triturated with acetonitrile and filtered. The solid was taken up in a mixture of acetonitrile/water/MeOH and passed through the bicarbonate cartridge. The eluent was concentrated in vacuo and then triturated with acetonitrile to give the product as a yellow solid (26 mg, 99% yield); 1H NMR (400.0 MHz, DMSO) d 1.20 (d, 6H), 2.68 (d, 2H), 3.41-3.51 (m, 1H), 4.65-4.75 (m, 1H), 7.81 (d, 2H), 7.98 (d, 2H), 8.20 (d, 2H), 8.41 (d, 2H) and 9.08 (s, 1H) ppm; MS (ES+) 519.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH:7]=1.[F:34]C1C=C(F)C=CC=1CBr>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][C:32]=2[F:34])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH:7]=1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CCOC(=O)c1cccc(-c2ccccc2-c2cc(Cl)ccc2OCc2ccc(F)cc2)n1
Product: CCOC(=O)c1cccc(-c2ccccc2-c2cc(Cl)ccc2OCc2ccc(F)cc2F)n1

Procedure:
Prepared in a similar manner to ethyl 6-(5′-chloro-2′-{[(4-fluorophenyl)methyl]oxy}-2-biphenylyl)-2-pyridinecarboxylate but using 2,4-difluorobenzyl bromide in place of 4-fluorobenzyl bromide. LC/MS t=3.82, [MH+] 480.3
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)[CH2:6][OH:7].[H][H]>[Pd].CO>[NH2:11][C:10]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: [H][H]
Reactant: COc1cc(CO)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1cc(CO)ccc1N
Yield: 108.8 %

Procedure:
A mixture of 3-methoxy-4-nitrobenzyl alcohol (1.0 g) and 10% palladium on carbon (100 mg) in methanol was stirred for 2 hours under 3 atmospheric pressure of hydrogen. After filtration, the filtrate was concentrated in vacuo to give 4-amino-3-methoxybenzyl alcohol (910 mg) as an oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][CH2:9][CH2:10]Br.[CH:12]1([CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]4[CH:33]=[N:34][NH:35][CH:36]=4)[CH:26]=3)=[CH:21][C:18]=2[C:19]#[N:20])[CH2:14][CH2:13]1>CN(C=O)C>[CH:12]1([CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]4[CH:33]=[N:34][N:35]([CH2:10][CH2:9][O:8][CH3:7])[CH:36]=4)[CH:26]=3)=[CH:21][C:18]=2[C:19]#[N:20])[CH2:14][CH2:13]1
Reactant: COCCBr
Reactant: N#Cc1cc(-c2ccnc(Nc3cn[nH]c3)c2)ccc1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCn1cc(Nc2cc(-c3ccc(OCC4CC4)c(C#N)c3)ccn2)cn1
Temperature: 80 °C

Procedure:
Caesium carbonate (0.17 g, 0.54 mmol) and 2-bromoethyl methyl ether (0.045 g, 0.325 mmol) are added to a solution of the 2-cyclopropylmethoxy-5-[2-(1H-pyrazol-4-ylamino)pyridin-4-yl]benzonitrile prepared above (0.09 g, 0.27 mmol) in dry DMF (2 ml). The reaction mixture is warmed at 80° C. for 8 h. Ice is added, and the mixture is extracted with ethyl acetate (2×50 ml). The organic phase is washed with water (1×25 ml) and dried over sodium sulfate. The mixture is then evaporated in a rotary evaporator. The crude product is purified by chromatography, giving 5.8 mg of the desired product as brown solid;
Reaction SMILES: ClCCl.[CH3:4][C:5]1([CH3:24])[CH2:10][CH:9]([NH:11][CH:12]2[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][C:14]([CH3:21])([CH3:20])[CH2:13]2)[CH2:8][C:7]([CH3:23])([CH3:22])[NH:6]1.[C:25](Cl)(=[O:28])[CH:26]=[CH2:27].[OH-].[Na+]>CN(C)C1C=CN=CC=1.O>[CH3:22][C:7]1([CH3:23])[CH2:8][CH:9]([N:11]([CH:12]2[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][C:14]([CH3:21])([CH3:20])[CH2:13]2)[C:25](=[O:28])[CH:26]=[CH2:27])[CH2:10][C:5]([CH3:24])([CH3:4])[NH:6]1
Reactant: CC1(C)CC(NC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: C=CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)N(C1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1
Yield: 19.3 %

Procedure:
A 2500 ml flask equipped with stirrer, termometer and dropping funnel is charged with 1000 ml of dichloromethane, 147.75 g (500 mmol) N,N-bis-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (prepared as described in EP 838 455 A1) and 1.6 g 4-dimethylaminopyridine. Then, 47.5 g (525 mmol) of acryloylchloride are added during 4 h while keeping the temperature at 0-2° C. After additional 90 minutes of stirring the solution of 21 g (521 mmol) NaOH in 100 ml water is slowly added. The organic layer is separated, dried over MgSO4 and evaporated. The residue (174.55 g) is recrystallized 3× from acetonitrile to afford 33.78 g of the title compound as white crystals, mp 115-118° C.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].CC([O-])(C)C.[K+].[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][C:39]=1[CH3:46]>C1C=CC=CC=1>[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:40][C:39]=1[CH3:46]
Reactant: O=C(O)CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C=O)ccc1F
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: c1ccccc1
Product: Cc1cc(C=CCCCCCC(=O)O)ccc1F
Temperature: 25 °C
Yield: 107 %

Procedure:
To a suspension of 7-Carboxyheptanyltriphenylphosphonium bromide (9.240 g, 19.602 mmol) in 100 mL of benzene, was added t-BuOK (58.8 mL, 58.8 mmol, 1M in THF). The resulting mixture was refluxed for 1 h and then 4-fluoro-3-methylbenzaldehyde (1.43 mL, 11.761 mmol) was added via a syringe. The mixture was continued to reflux under N2 for 63 h. After cooling to room temperature, the reaction mixture was washed with water (80 mL). The aqueous layer was acidified with concentrated HCl to pH=2 and extracted with ethyl acetate (30 mL×3). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-30% ethyl acetate/hexanes to give the title compound as colorless oil (3.150 g, >99% yield). LC-MS: tR=9.6 min, m/z 251 (M+H)+.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:37])[C@@H:15]([O:34][CH2:35][CH3:36])[C@@H:16]([C:18]1[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:20][C:19]=1[CH3:33])[OH:17])C1C=CC=CC=1.[CH3:38][O-:39].[Na+]>CO>[CH3:38][O:39][C:14](=[O:37])[C@@H:15]([O:34][CH2:35][CH3:36])[C@@H:16]([C:18]1[C:19]([CH3:33])=[CH:20][C:21]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][C:23]=1[CH3:24])[OH:17]
Reactant: C[O-]
Reactant: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1c(C)cc(OCc2ccccc2)cc1C
Agent: [Na+]
Solvent: CO
Product: CCO[C@H](C(=O)OC)[C@H](O)c1c(C)cc(OCc2ccccc2)cc1C

Procedure:
In analogy to the procedure described in example 48 e], (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2,6-dimethyl-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one was treated with sodium methoxide in methanol to give (2S,3R)-3-(4-benzyloxy-2,6-dimethyl-phenyl)-2-ethoxy-3-hydroxy-propionic acid methyl ester as colorless liquid. According to 1H-NMR spectroscopy, one single diastereomer was obtained.