Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1N2CCN(CC2)C1.[CH3:9][C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:33]=3[NH:32][CH:31]=[C:30]4[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[N:21]=2)[CH:13]=[N:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18]>C(=O)(OC)OC.CN(C=O)C>[CH3:1][N:32]1[C:33]2[C:29](=[CH:28][CH:27]=[CH:26][C:25]=2[C:22]2[N:21]=[C:20]([C:12]3[CH:13]=[N:14][C:15]([O:16][CH:17]([CH3:19])[CH3:18])=[C:10]([CH3:9])[CH:11]=3)[O:24][N:23]=2)[C:30]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:31]1
Reactant: C1CN2CCN1CC2
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(C)c4)n3)cccc12
Solvent: CN(C)C=O
Solvent: COC(=O)OC
Product: Cc1cc(-c2nc(-c3cccc4c(CCC(=O)O)cn(C)c34)no2)cnc1OC(C)C
Temperature: 70 °C
Yield: 25.3 %

Procedure:
DABCO (20 mg) was added to a solution of ethyl 3-[7-(5-{5-methyl-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D119) (188 mg) in dimethyl carbonate (2 mL) and DMF (0.2 mL). The resulting mixture was stirred at reflux for 1 day. After cooling, the reaction was quenched with water, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was dissolved in iPrOH (8 mL) and water (8 mL). Sodium hydroxide (40 mg) was added to the mixture. The resulting mixture was heated at 70° C. for 30 mins. Then 0.5 M HCl solution was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[1-methyl-7-(5-{5-methyl-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E17) (19 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.35 (6H, d), 2.23 (3H, s), 2.60 (2H, t), 2.96 (2H, t), 3.62 (3H, s), 5.40 (1H, m), 7.16 (1H, d), 7.19 (1H, s), 7.43 (1H, d), 7.79 (1H, d), 8.29 (1H, s), 8.84 (1H, d), 12.12 (1H, br s). MS (ES): C23H24N4O4 requires 420; found 421.2 (M+H+).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C(C[N:11]1[CH:28]=[CH:27][C:15]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[N:14][C:12]1=[O:13])(O)=O>ClCCl>[Cl:4][C:2]([CH2:1][N:11]1[CH:28]=[CH:27][C:15]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])=[N:14][C:12]1=[O:13])=[O:3]
Reactant: O=C(O)Cn1ccc(NC(=O)OCc2ccccc2)nc1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)Cn1ccc(NC(=O)OCc2ccccc2)nc1=O
Reaction time: 2 h

Procedure:
Oxalyl chloride (6.3 g, 50 mmol) is added dropwise over 5 minutes to a solution of 1-(carboxymethyl)-N4-(benzyloxycarbonyl)cytosine (15.3 g, 50 mmol) dissolved in dichloromethane (200 mL). The reaction is stirred until gas evolution has ceased and then for an additional 2 hours. The reaction mixture is evaporated to an oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([NH:34][CH:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)[CH:7]=[CH:6][C:5]=1[C:8]1[O:9][C:10]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:11][N:12]=1
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC2CCN(C)CC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 22.1 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) was converted using 1-methylpiperidin-4-amine (195 mg, 1.71 mmol) and N,N-diisopropylethylamine (147 mg, 1.14 mmol) instead of thiomorpholine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane:methanol 40:40:20:0 to 0:75:20:5, 56 mg, 22%) which was obtained as an off-white solid. MS: m/e=446.2 [M+H]+.
Reaction SMILES: C([O:5][C:6]([CH:8]([N:11]1[C:17](=[O:18])[CH2:16][CH2:15][CH:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:13][CH2:12]1)[CH2:9][CH3:10])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:22]([O:21][C:19]([CH:14]1[CH2:13][CH2:12][N:11]([CH:8]([CH2:9][CH3:10])[C:6]([OH:7])=[O:5])[C:17](=[O:18])[CH2:16][CH2:15]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)C1CCC(=O)N(C(CC)C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCC(=O)N(C(CC)C(=O)O)CC1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
In a 25 ml three necked flask fitted with magnetic stirrer and dropping funnel under inert atmosphere, 1 g (3.1 mmoles) of pure ethyl 1-[1-(tert-butoxycarbonyl)propyl]-7-oxo-4-azepanecarboxylate 29 was dissolved in 5 ml of CH2Cl2. The mixture was cooled down to 0° C., 5 ml of trifluoroacetic acid was added. The mixture was kept at 0° C. under stirring for 24 hours, concentrated to dryness and used as such in the next step.
Reaction SMILES: C(C1OC[C@@H](C2C=CC=CC=2)N=1)(C1OC[C@@H](C2C=CC=CC=2)N=1)(C)C.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:58]2[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=2)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[O:35][CH2:36][C@H:37]2[O:41][C@@H:40]([N:42]3[CH:49]=[CH:48][C:46](=[O:47])[NH:45][C:43]3=[O:44])[C@H:39]([OH:50])[C@@H:38]2[OH:51])=[CH:30][CH:29]=1.[C:66]1([N:72]=[C:73]=[O:74])[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1.COC1C=CC(C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)OC[C@H]2O[C@@H](N3C=CC(=O)NC3=O)[C@H](OC(=O)NC3C=CC=CC=3)[C@@H]2O)=CC=1>C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2].C1COCC1>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([C:58]2[CH:59]=[CH:60][C:61]([O:64][CH3:65])=[CH:62][CH:63]=2)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[O:35][CH2:36][C@H:37]2[O:41][C@@H:40]([N:42]3[CH:49]=[CH:48][C:46](=[O:47])[NH:45][C:43]3=[O:44])[C@H:39]([OH:50])[C@@H:38]2[O:51][C:73](=[O:74])[NH:72][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)=[CH:32][CH:33]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C=Nc1ccccc1
Agent: [Cu+2]
Agent: CC(C)(C1=N[C@H](c2ccccc2)CO1)C1=N[C@H](c2ccccc2)CO1
Agent: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OC(=O)Nc3ccccc3)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2OC(=O)Nc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The THF solution (1 ml) containing 2,2′-isopropylidenebis[(4R)-4-phenyl-2-oxazoline] (0.02 mmol, 7.2 mg) and Cu(OTf)2 (II) (0.02 mmol, 6.7 mg) was stirred for 30 minutes at room temperature. After the reaction mixture was cooled to 0° C., the THF solution (1 ml) of 5′-O-[bis(4-methoxyphenyl)phenylmethyl]uridine (0.2 mmol, 109.3 mg) and the THF solution (1.5 ml) of phenyl isocyanate (0.2 mmol, 23.8 mg) were added thereto. After the mixture was continuously stirred for 1 hour at 0° C. and for 1.5 hours at room temperature, the mixture was analyzed with high-performance liquid chromatography. As a result, it was found that 5′-O-[bis(4-methoxyphenyl)phenylmethyl]-2′-O-phenylcarbamoyl-uridine and 5′-O-[bis(4-methoxyphenyl)phenylmethyl]-3′-O-phenylcarbamoyl-uridine were produced at the ratio of 50:50, and the transformation ratio of the reaction was 87%.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)[C:7]([OH:9])=O)[CH:2]=[CH2:3].P(Cl)(Cl)(Cl)=O.C[Si](CC(N)=O)(C)C.[NH2:29][CH:30]1[C:47](=[O:48])[N:32]2[C:33]([C:44]([OH:46])=[O:45])=[C:34]([CH2:37][S:38][C:39]3[S:40][CH:41]=[N:42][N:43]=3)[CH2:35][S:36][C@H:31]12>O1CCCC1.C(=O)(O)[O-].[Na+].O.CC(C)=O.CN(C)C=O>[CH2:1]([O:4][N:5]=[C:6]([C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)[C:7]([NH:29][CH:30]1[C:47](=[O:48])[N:32]2[C:33]([C:44]([OH:46])=[O:45])=[C:34]([CH2:37][S:38][C:39]3[S:40][CH:41]=[N:42][N:43]=3)[CH2:35][S:36][C@H:31]12)=[O:9])[CH:2]=[CH2:3]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Reactant: C=CCON=C(C(=O)O)c1csc(N)n1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CC(C)=O
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(N)n1
Reaction time: 0.33 h
Yield: 63.3 %

Procedure:
Water (0.05 g) was added to a suspension of 2-allyloxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid (syn isomer)(1.0 g) in tetrahydrofuran (10 ml). Phosphorus oxychloride (0.84 g) was added thereto at 0° to 5° C. and the mixture was stirred for 20 minutes at the same temperature. Trimethylsilylacetamide (0.66 g) was added thereto, the mixture was stirred for 20 minutes at the same temperature, phosphorus oxychloride (0.84 g) was added thereto, the resulting mixture was stirred for 20 minutes at 0° to 5° C., dimethylformamide (0.45 g) was added thereto and the resulting mixture was stirred for 1 hour at the same temperature. The resulting solution was added dropwise at -5° to 5° C. and pH 7.0 to 8.0 to a solution, which was prepared by adding acetone (15 ml) and tetrahydrofuran (15 ml) to a solution of 7-amino-3-(1,3,4-thiadiazol- 2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.45 g) in a mixture of sodium bicarbonate (0.42 g) and water (10 ml). The resulting mixture was stirred for 2 hours under ice-cooling keeping the pH of the mixture at 7.0 to 8.0 and then adjusted to pH 7.5. An insoluble material was filtered off and the filtrate was washed with ethyl acetate. The aqueous layer was adjusted to pH 6.0 and organic solvent in the aqueous layer was distilled off under reduced pressure. The remaining aqueous layer was adjusted to pH 4.0 and an insoluble material was filtered off. The filtrate was adjusted to pH 3.0 and precipitates were collected by filtration and dried to give 7-[2-allyloxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:5]=[CH:6][C:7]=1[C:8]([O:10]C)=[O:9].O.[OH-].[Li+].CO.Cl>C1COCC1.O>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])=[CH:3][C:2]=1[F:1])([OH:10])=[O:9]
Reactant: COC(=O)c1ccc(C2CCCN2C(=O)OC(C)(C)C)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1c1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of EXAMPLE 50C (5.5 g) and lithium hydroxide monohydrate (1.43 g) in THF (50 mL) and water (50 mL) was titrated with methanol until transparent, stirred at ambient temperature for 2 hours, acidified to pH 2 with 2M HCl, concentrated to about 40 mL and filtered.
Reaction SMILES: O[CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[C:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[SH:35])([CH3:28])([CH3:27])[CH3:26].[OH-].[Na+]>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: CC(C)(C)c1ccccc1S
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Sc2ccccc2C(C)(C)C)C1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
To an ice-cold stirred solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (2.20 g, 12.7 mmol) and triethylamine (1.54 g, 15.2 mmol) in THF (60.0 mL) was added methanesulfonyl chloride (1.60 g, 14.0 mmol) and the resulting reaction mixture was warmed to room temperature. After 2 h the reaction mixture was filtered and filtrate concentrated under reduced pressure. The residue was dissolved in toluene (30.0 mL), added to a stirred solution of 80% 2-tert-butylthiophenol (2.12 g, 10.2 mmol), tetrabutylammonium bromide (0.41 g, 1.27 mmol) and sodium hydroxide (4.80 ml of 8.0 M solution in water, 38.4 mmol) in toluene (30.0 mL) and the resulting reaction mixture was heated at 100° C. for 3 h. Then, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and separated. The organic layer was washed with water, saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 95:5 to 80:20 heptane/ethyl acetate) provided tert-butyl 3-(2-tert-butylphenylthio)azetidine-1-carboxylate (1.80 g, 55%) as a pale yellow oil.
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:30])[CH2:10][CH2:11][CH2:12][C:13](=[O:29])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](=[O:28])[CH2:24][C:25](=[O:27])[CH3:26])=[CH:17][CH:16]=1.[C:31]([O:35][C:36](=[O:49])[CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][NH2:48])([CH3:34])([CH3:33])[CH3:32].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:31]([O:35][C:36](=[O:49])[CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][NH:48][C:9](=[O:30])[CH2:10][CH2:11][CH2:12][C:13](=[O:29])[NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23](=[O:28])[CH2:24][C:25](=[O:27])[CH3:26])=[CH:19][CH:20]=1)([CH3:32])([CH3:34])[CH3:33]
Reactant: CC(=O)CC(=O)CCc1ccc(NC(=O)CCCC(=O)ON2C(=O)CCC2=O)cc1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)CC(=O)CCc1ccc(NC(=O)CCCC(=O)NCCOCCOCCOCCC(=O)OC(C)(C)C)cc1

Procedure:
A solution of 4-[4-(3,5-dioxo-hexyl)-phenylcarbamoyl]-butyric acid 2,5-dioxo-pyrrolidin-1-yl ester (1.5 g, 3.6 mmol), 3-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-propionic acid tert-butyl ester (1.0 g, 3.6 mmol) and DIEA (1.3 L, 7.2 mmol) in CH2Cl2 (10 mL) was stirred at rt overnight. The solvent was removed in vacuo and the residual oil purified using column chromatography EtOAc/MeOH (95:5) to give the title compound as a transparent oil, (M+1)=579.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[NH:13][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:3].C1COCC1>[C].[Pd].C(O)C>[NH2:10][C:8]1[CH:7]=[CH:6][C:5]([NH:13][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:4]([C:2]([NH2:1])=[O:3])[CH:9]=1
Reactant: CCOC(=O)C(=O)Nc1ccc([N+](=O)[O-])cc1C(N)=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(=O)Nc1ccc(N)cc1C(N)=O
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a solution of ethyl {[2-(aminocarbonyl)-4-nitrophenyl]amino}(oxo)acetate (2.292 g) in a mixed solvent of THF (100 mL)-ethanol (50 mL) was added 10% palladium carbon (405 mg), and the mixture was subjected to catalytic reduction under hydrogen atmosphere at room temperature for 8 hr. The catalyst was filtered off, and the filtrate was concentrated. The obtained crude crystals were washed with diisopropyl ether to give ethyl {[4-amino-2-(aminocarbonyl)phenyl]amino}(oxo)acetate (1.96 g, 96%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:15])=[C:7]([CH:14]=1)[C:8]([O:10]C(C)C)=[O:9])=[CH2:2].I[C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[OH:15][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[CH:2][C:17]2[CH:18]=[CH:19][C:20]([S:23]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[CH:14][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=S(=O)(Nc1ccccn1)c1ccc(I)cc1
Reactant: C=Cc1ccc(O)c(C(=O)OC(C)C)c1
Product: O=C(O)c1cc(C=Cc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O
Yield: 40 %

Procedure:
Isopropyl 5-ethenyl-2-hydroxybenzoate was reacted with 4-iodo-N-(2-pyridinyl)benzenesulfonamide similarly to the procedure of Example 5c. After the reaction, the solvent was evaporated, toluene was added and the suspension filtered and washed with toluene. After drying on the filter and washing with water the material was hydrolyzed and precipitated similarly to the procedure of Example 3c. Yield 40%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[OH-].[Na+].[O:13](C(OC(C)(C)C)=O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O.C([O-])(O)=O.[Na+]>O1CCOCC1>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:1][C:14](=[O:13])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCCc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Temperature: 22 °C
Reaction time: 2 h

Procedure:
To a solution of 1.00 g (5.75 mmol) of 4-(2-aminoethyl)phenol in 5 mL of dioxane at 22° C. was added 2 mL of 1 N NaOH followed by 1.88 g (8.62 mmol) of BOC2O dissolved in 2 mL of dioxane. The mixture was stirred at 22° C. for 2 h and then neutralized by adding 25 mL of saturated NaHCO3 which resulted in a pH of about 7.5-8. The aqueous layer was separated and extracted with DCM (3×50 mL). The organics were combined, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography on silica gel eluting with a mixture of hexane and ethyl acetate to give tert-butyl 4-hydroxyphenethylcarbamate as a colorless oil.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:27])[NH:17][C@@H:18]3[CH2:22][C@H:21]([CH2:23][OH:24])[C@@H:20]([OH:25])[C@H:19]3[OH:26])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CO[C:30](OC)([CH3:32])[CH3:31].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)(Cl)Cl.CO.C(O)(=O)C>CC(C)=O>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:27])[NH:17][C@H:18]3[C@H:19]4[C@H:20]([O:25][C:30]([CH3:32])([CH3:31])[O:26]4)[C@@H:21]([CH2:23][OH:24])[CH2:22]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(C)(C)OC
Reactant: O=C(N[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O)OCC1c2ccccc2-c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](NC(=O)OCC3c4ccccc4-c4ccccc43)[C@@H]2O1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 91.4 %

Procedure:
((1R,2S,3R,4R)-2,3-Dihydroxy-4-hydroxymethyl-cyclopentyl)-carbamic acid 9H-fluoren-9-ylmethyl ester (115 g, 310 mmol), 2,2-dimethoxypropane (360 ml, 3.10 mol) and p-toluenesulfonic acid monohydrate (118 g, 620 mmol) were dissolved in dry acetone (2.00 l). The mixture was stirred for 3.5 h at room temperature to the complete consumption of the starting material according to TLC (Silicagel Merck 60, chloroform/methanol/acetic acid 9:1+0.1% v/v/v). The resulting suspension was stirred 15 min at 0° C. and the precipitate was filtered off and washed with cold acetone. The obtained brown solid was suspended again in diethylether (800 ml) and stirred for 20 min, filtered off, washed with diethylether (400 ml) and dried 8 h under reduced pressure giving 116 g (91%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6]O)#[N:2].P(Br)(Br)[Br:14]>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][Br:14])#[N:2]
Reactant: BrP(Br)Br
Reactant: COc1ccc(CO)cc1C#N
Solvent: ClCCl
Product: COc1ccc(CBr)cc1C#N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 3-cyano-4-methoxybenzyl alcohol (500 mg) in dichloromethane (5 mL) was added phosphorus tribromide (0.146 mL) under ice-water cooling. The mixture was stirred at 0° C. for 3 hours and partitioned between chloroform and water. The separated organic layer was washed successively with water, an aqueous saturated sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residual solid was triturated with diisopropyl ether to give 3-cyano-4-methoxybenzyl bromide as an off-white solid (456.3 mg).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.CCN(CC)CC.Cl[C:17]1[S:21][N:20]=[C:19]([CH3:22])[N:18]=1>CCO>[CH3:22][C:19]1[N:18]=[C:17]([N:2]2[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]2)[S:21][N:20]=1
Reactant: Cc1nsc(Cl)n1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nsc(N2CCC(=O)CC2)n1
Yield: 8.6 %

Procedure:
To a mixture of piperidin-4-one HCl salt (4.08 g, 30 mmol) and Et3N (20 mL, 78.6 mmol) in EtOH (50 mL) was added 5-chloro-3-methyl-1,2,4-thiadiazole (4.05 g, 30 mmol). The mixture was heated to reflux for 1.5 hours and then concentrated to dryness. The residue was dissolved in EtOAc. The solution was washed with water (30 mL×3) and brine (30 mL), dried over Na2SO4, and concentrated to dryness. The residue was recrystalled from ether to give 1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-one (510 mg, 8.6%). 1H-NMR (300 MHz, CDCl3) δ 3.86 (t, J=6.3 Hz, 4H), 2.62 (t, J=6.3, Hz, 4H), 2.44 (s, 3H).
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]2[C:13](=[O:14])[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.O>[C:17]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]2[CH:13]([OH:14])[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1C2CCN(CC2)C1C(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OC1C2CCN(CC2)C1C(c1ccccc1)c1ccccc1
Temperature: -65 °C
Reaction time: 8 h

Procedure:
2-(Diphenylmethyl)-1-azabicyclo[2.2.2]octan-3-one (18.9 g) was dissolved in tetrahydrofuran (350 ml), anhydrous) and cooled to -65° C. under nitrogen. Lithium aluminium hydride (1.0 M solution in THF, 40 ml) was added dropwise to the solution which was stirred at room temperature overnight. Water (2 ml) followed by sodium hydroxide (15% 2 ml) and water (6 ml) were added dropwise to the solution resulting in precipitation of the inorganic salts. Magnesium sulfate (2 g) was added and the mixture filtered through celite. The solvent was removed in vacuo and the residue was recrystallised from isopropanol affording the pure cis isomer. The mother liquors were concentrated and found to be 80:20 cis/trans by 1H NMR; this was used in the examples without further purification.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11](=[O:13])[CH3:12].[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>>[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH:2]([NH:10][C:11](=[O:13])[CH3:12])[CH2:3]2)=[O:20]
Reactant: O=C(Cl)CCCCCl
Reactant: CC(=O)NC1Cc2ccccc2C1
Product: CC(=O)NC1Cc2ccc(C(=O)CCCCCl)cc2C1

Procedure:
Using N-(2,3-dihydro-1H-inden-2-yl)acetamide and 5-chlorovaleryl chloride according to the same method as that of Reference Example 1, the title compound was obtained as colorless crystals having a melting point of 106 to 108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([OH:32])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.O.CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([OH:32])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH2:17][CH2:16]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N2CCC([C@@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(N2CCC([C@@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Yield: 79 %

Procedure:
A solution of (R)-ethyl 4-(4-((4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoate (INTERMEDIATE 11A (First Eluting Compound), 5.37 g, 11.93 mmol) in THF (160 ml), water (40 ml), and methanol (40 ml) was stirred at 50° C. overnight. The volatiles were removed under reduced pressure and the resulting residue was diluted with water (100 ml). The pH of the solution was adjusted to ˜5 with 1N aq. HCl (35 ml) promoting the formation of a precipitate. The white solid was collected via filtration and washed with water (˜150 ml). The filter cake was dried overnight under high vacuum at 50° C. to provide the title product (4.0 g, yield: 79%).