Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[O:3]1.[SH:21][CH2:22][CH2:23][OH:24]>>[OH:24][CH2:23][CH2:22][S:21][CH:9]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[CH2:8][C:4]1[O:3][C:2]([CH3:1])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=1
Reactant: CC1(c2ccccc2)OC(/C=C/c2ccsc2)=CC1=O
Reactant: OCCS
Product: CC1(c2ccccc2)OC(CC(SCCO)c2ccsc2)=CC1=O

Procedure:
Following the procedure of Method C, Example 1, (E)-2-methyl-2-phenyl-5-[2-(3-thienyl)ethenyl]-3(2H)-furanone was reacted with 2-mercapto-1-ethanol to provide 5-[2-[(2-hydroxyethyl)thio]-2-(3-thienyl)ethyl]-2-methyl-2-phenylfuran-3(2H)-one: 1H NMR (DMSO-d6) δ1.54 and 1.57 (singlets, 3H), 3.35-3.60 (m ovelapped with DMSO, ˜4H), 4.58 (m, 1H), 5.55 and 5.56 (overlapped singlets, 1H), 7.18-7.37 (m, 6H), 7.40-7.57 (m, 2H); MS(LR-ESI) m/z 361 (M+H calcd. for C19H21O3S2 361).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]([CH3:51])[CH2:44][CH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]([CH3:51])[CH2:44][CH:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CN(CC1CCOCC1)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)CC2CCOCC2)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 57.1 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-methyl-N-(tetrahydropyran-4-ylmethyl)acetamide (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.5 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[CH:11][C:10]=2[C:18]([OH:20])=O)=[C:4]([F:21])[CH:3]=1.[CH:22]([O:24][CH2:25][CH2:26][O:27][NH2:28])=[CH2:23].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:22]([O:24][CH2:25][CH2:26][O:27][NH:28][C:18]([C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:15]=[N:16][CH:17]=2)[C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:21])=[O:20])=[CH2:23]
Reactant: C=COCCON
Reactant: O=C(O)c1ccc2cncn2c1Nc1ccc(Br)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=COCCONC(=O)c1ccc2cncn2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.6 %

Procedure:
To a solution of 5-(4-Bromo-2-fluorophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (2.0 g, 5.7 mmol) and O-(2-vinyloxyethyl)-hydroxylamine (0.71 g, 6.8 mmol) in DMF (44 mL) was added EDCI hydrochloride (1.42 g, 7.41 mmol), HOBt (1.0 g, 7.41 mmol) and DIPEA (0.97 mL, 5.69 mmol). The reaction mixture was stirred at room temperature for 3 hours before being concentrated in vacuo. The resultant residue was dissolved in 1:1 diethylether:ethyl acetate (30 mL) and aqueous saturated sodium hydrogen carbonate solution (30 mL) was added. The resultant mixture was sonicated until a precipitate formed. The precipitate was collected by filtration and washed with 1:1 diethylether:ethyl acetate to yield the title compound as a tan solid (1.33 g, 53%). LCMS (Method B): RT=2.78 min, M+H+=435/437.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:30]=[CH:29][C:12]2[N:13]=[C:14]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[N:15]([CH2:16][CH2:17][CH3:18])[C:11]=2[CH:10]=1.[CH3:31][N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH:37]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][N:7]([CH2:37][C:33]1[N:32]([CH3:31])[CH:36]=[CH:35][N:34]=1)[CH2:8][C:9]1[CH:30]=[CH:29][C:12]2[N:13]=[C:14]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[N:15]([CH2:16][CH2:17][CH3:18])[C:11]=2[CH:10]=1
Reactant: CCCn1c(CCCCN2CCCCC2)nc2ccc(CNCc3ncc[nH]3)cc21
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCn1c(CCCCN2CCCCC2)nc2ccc(CN(Cc3ncc[nH]3)Cc3nccn3C)cc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 105.8 %

Procedure:
The compound (429.5 mg) obtained in Example 61-4 was dissolved in methanol (21.5 ml) and added with 1-methyl-2-imidazole carboxaldehyde (173.6 mg) and sodium cyanoborohydride (132.1 mg). After the solution was adjusted to pH 4 with acetic acid, the whole was stirred at room temperature for 4 days. The reaction solution was concentrated under reduced pressure. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and a saturated saline solution. Then, the resultant was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (559.2 mg) of the subject compound as a pale-yellow solid.
Reaction SMILES: OO.[Cl:3][C:4]1[O:5][C:6]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:7][N:8]=1.C([O-])([O-])=[O:18].[K+].[K+]>CS(C)=O>[Cl:3][C:4]1[O:5][C:6]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]([NH2:13])=[O:18])=[CH:7][N:8]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccc(-c2cnc(Cl)o2)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1cccc(-c2cnc(Cl)o2)c1
Temperature: 25 °C
Yield: 111.7 %

Procedure:
30% H2O2 (28.7 mL, 281.0 mmol) was slowly added to a 0° C. mixture of 3-(2-chlorooxazol-5-yl)benzonitrile (8.20 gm, 40.10 mmol) and K2CO3 (3.88 gm, 28.10 mmol) in DMSO (75 mL). The ice bath was removed and the reaction mixture was stirred at rt. After 24 h the reaction mixture was partitioned between EtOAc and water. The organic phase was isolated, washed with saturated aqueous NaCl (2×), dried over MgSO4, filtered and concentrated to give the product, 3-(2-chlorooxazol-5-yl)benzamide, (7.00 gm, 31.40 mmol, 78% yield) as a light yellow solid. Anal. Calcd. for C10H7ClN2O2 m/z 222.0, found: 223.0 (M+H)+. Crude product was used without purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]([CH3:13])([CH3:12])[CH:10]=O)=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[CH3:32][NH:33][CH3:34].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]([CH3:13])([CH3:12])[CH2:10][N:33]([CH3:34])[CH3:32])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CC(C)(C=O)Oc1ccc(Cl)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C)CC(C)(C)Oc1ccc(Cl)nc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a large capacity microwave tube containing 2-(6-chloropyridin-3-yloxy)-2-methylpropanal (354 mg, 1.77 mmol) and sodium triacetoxyborohydride (940 mg, 4.43 mmol) in dry dichloromethane (4 ml) was added glacial acetic acid (0.81 ml, 14.2 mmol) followed by a 2 M solution of dimethylamine (14.2 ml, 28.4 mmol, in tetrahydrofuran). The tube was capped and heated to 50° C. (oil bath) with vigorous stirring for 16 hours. The mixture was cooled to ambient and the contents poured into a separatory funnel containing an aqueous solution of saturated sodium bicarbonate (30 ml). Dichloromethane (30 ml) was added and the mixture was shaken. The contents were filtered through a plug of celite, washing well with dichloromethane. The filtrate was collected and washed with a brine solution (40 ml). The dichloromethane phase was collected and the aqueous phase was back extracted with methylene chloride (2×40 mL). The organic phases were combined, dried over magnesium sulfate, filtered and stripped. The material was purified by preparative thin layer chromatography (2 plates), eluting with 1.8% methanol/dichloromethane. The plates were then re-developed with 2.6% methanol/dichloromethane, and the product band was collected which provided the desired as a light yellow mobile oil, which slowly solidified on standing (255 mg). (M+H)+=229 m/e.
Reaction SMILES: Cl[C:2](=[N:16]OS(C)(=O)=O)[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[S-:22][C:23]#[N:24].[Na+].N1C=CC=CC=1.[CH3:32][C:33]1[C:38]([O:39][C:40]2[C:41]([NH2:53])=[N:42][CH:43]=[C:44]([S:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=3)[CH:45]=2)=[CH:37][CH:36]=[CH:35][N:34]=1>>[CH3:32][C:33]1[C:38]([O:39][C:40]2[C:41]([NH:53][C:23]3[S:22][N:16]=[C:2]([CH:3]4[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:7][CH2:8]4)[N:24]=3)=[N:42][CH:43]=[C:44]([S:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=3)[CH:45]=2)=[CH:37][CH:36]=[CH:35][N:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(Cl)=NOS(C)(=O)=O)CC1
Reactant: N#C[S-]
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1N
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)ns1
Yield: 85.3 %

Procedure:
Following the procedure in Example 51, Step G and using tert-butyl 4-(chloro(methylsulfonyloxyimino)methyl)piperidine-1-carboxylate (34.3 g, 101 mmol), sodium thiocyanate (9.40 g, 116 mmol), pyridine (28.1 ml, 348 mmol), and 3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (24.0 g, 77.3 mmol) provided tert-butyl 4-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate (38.1 g, 65.9 mmol, 85.3% yield).
Reaction SMILES: [OH2:1].O.O.[ClH:4].Cl.Cl.[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH:15]([CH2:21][CH2:22][CH:23]([CH2:40][CH2:41][CH2:42][CH2:43][CH:44]1[C:53]3[C:48](=[CH:49][C:50]([O:56][CH3:57])=[C:51]([O:54][CH3:55])[CH:52]=3)[CH2:47][CH2:46][NH:45]1)[CH2:24][CH2:25][CH:26]1[C:35]3[C:30](=[CH:31][C:32]([O:38][CH3:39])=[C:33]([O:36][CH3:37])[CH:34]=3)[CH2:29][CH2:28][NH:27]1)[NH:14][CH2:13][CH2:12]2>CCOCC.C(Cl)(Cl)Cl>[OH2:8].[OH2:1].[OH2:8].[ClH:4].[ClH:4].[ClH:4].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([CH2:21][CH2:22][CH:23]([CH2:40][CH2:41][CH2:42][CH2:43][C:44]1[C:53]3[C:48](=[CH:49][C:50]([O:56][CH3:57])=[C:51]([O:54][CH3:55])[CH:52]=3)[CH2:47][CH2:46][N:45]=1)[CH2:24][CH2:25][C:26]1[C:35]3[C:30](=[CH:31][C:32]([O:38][CH3:39])=[C:33]([O:36][CH3:37])[CH:34]=3)[CH2:29][CH2:28][N:27]=1)=[N:14][CH2:13][CH2:12]2
Reactant: COc1cc2c(cc1OC)C(CCCCC(CCC1NCCc3cc(OC)c(OC)cc31)CCC1NCCc3cc(OC)c(OC)cc31)NCC2
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COc1cc2c(cc1OC)C(CCCCC(CCC1=NCCc3cc(OC)c(OC)cc31)CCC1=NCCc3cc(OC)c(OC)cc31)=NCC2

Procedure:
To purify the intermediate (1.1a), the crude residue obtained after stripping off the chloroform is converted to the hydrochloride, in ether, and the resulting salt taken up in chloroform. Precipitation with ether, followed by two further reprecipitations from chloroform solution by either yields (1.1a) 1,1'-{3-[2-(3,4-dihydro-6,7-dimethoxy-1-isoquinolinyl)ethyl]heptamethylene}bis[3,4-dihydro-6,7-dimethoxyisoquinoline] trihydrochloride trihydrate, as a yellow solid, m.p. 130-150° (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:12][N:11]([C:13](Cl)=[O:14])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:16][NH2:17]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:12][N:11]([C:13]([NH:17][CH3:16])=[O:14])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=C(Cl)N1CC(Sc2ccc(Cl)cc2)C1
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1CC(Sc2ccc(Cl)cc2)C1
Reaction time: 3 h
Yield: 93.5 %

Procedure:
A stirred solution of 2.6 g (0.01 mole) of 3-[(4-chlorophenyl)thio]-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was cooled in a water bath and treated with 2 ml (0.02 mole) of 40% methylamine in water. After 3 hr, the reaction mixture was diluted with 200 ml of water and the precipitated product collected by filtration (2.6 g). Recrystallization from benzene/methanol yielded 2.4 g (93.8%) of fine white crystals, m.p. 161°-162° C.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=O.Cl.[NH2:18][OH:19].N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[N:18][OH:19]
Reactant: COc1ccc(C(=O)c2sccc2Br)cc1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(C(=NO)c2sccc2Br)cc1
Temperature: 0 °C
Yield: 95.1 %

Procedure:
Stir a solution of (3-bromothiophen-2-yl)-(4-methoxyphenyl)methanone (19.65 g, 0.066 mol), hydroxylamine hydrochloride (6.89 g, 0.099 mol), and pyridine (30 mL) at 85° C. under nitrogen for five hours. Pour the reaction mixture into a mixture of water (120 mL) and toluene (180 mL), and chill to 0° C. Add concentrated hydrochloric acid (approximately 30 mL) dropwise with cooling to adjust to pH 1–2. Filter the mixture and wash the solid with toluene and water. Separate the phases and extract the acidic aqueous phase with toluene. Wash the combined toluene phases twice with water, dry (Na2SO4), filter and evaporate. Combine the residue from the toluene extracts with the previously obtained solid filter cake, and triturate the mixture with petroleum ether. Filter the mixture and dry in vacuo at 60° C. to give the title compound as a white solid (19.6 g, 95% yield).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH:17](O)[CH2:18][CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])(=[O:12])[CH3:11]>C(Cl)Cl.C(OCC)(=O)C>[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH:17]([F:7])[CH2:18][CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])(=[O:12])[CH3:11]
Reactant: CC(=O)OCCCC(O)CCCOC(C)=O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)OCCCC(F)CCCOC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
To a solution of (diethylamino)-sulfur trifluoride (571 mg, 3.54 mmol) in CH2Cl2 was added the solution of acetic acid, 7-acetoxy-4-hydroxy-heptyl ester (403 mg, 1.74 mmol) in CH2Cl2 (10 ml) at −78° C. The resulting mixture was allowed to stir for 15 minutes −78° C., 30 minutes at room temperature and then diluted with ethyl acetate (300 ml). The organic solution was washed with sat. NaHCO3, brine and dried over Na2SO4. Evaporation of the solvent and purification of the residue by column chromatography on silica gel, using 15% ethyl acetate in hexanes, gave the title compound (386 mg, 94%) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][CH2:11][CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[ClH:22].C(OC(C)C)(C)C>O1CCOCC1.O>[N+:1]([C:4]1[C:5]([NH:10][CH2:11][CH2:12][CH2:13][NH2:14])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[ClH:22]
Reactant: CC(C)(C)OC(=O)NCCCNc1ncccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Solvent: O
Product: NCCCNc1ncccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To tert-butyl (3-((3-nitropyridin-2-yl)amino)propyl)carbamate (C42, 53 mg), a 4.0 mol/L solution of hydrochloric acid in dioxane (2 mL) and water (100 μL) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, diisopropyl ether were added, the solvent was removed by decantation, and then the residue was dried under reduced pressure to obtain N1-(3-nitropyridin-2-yl)propane-1,3-diamine (C43) hydrochloride (113 mg).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1([CH3:29])[C:19]([S:24]([O:27]C)(=[O:26])=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=1>CCOCC>[C:18]1([CH3:29])[C:19]([S:24]([O-:27])(=[O:26])=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=1.[C:1]1([C:7]2[O:8][C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][N+:11]=2[CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2cnc(-c3ccccc3)o2)cc1
Reactant: COS(=O)(=O)c1ccccc1C
Solvent: CCOCC
Product: C[n+]1cc(-c2ccccc2)oc1-c1ccccc1
Product: Cc1ccccc1S(=O)(=O)[O-]
Yield: 95 %

Procedure:
10 g of 2,5-Diphenyloxazole was heated at 125° C. for 5-10 minutes with 30 g of methyl toluenesulfonate, both commercially available compounds. The solution was cooled, and anhydrous ether was added to precipitate the product. The product was recrystallized by dissolving in absolute ethanol and then adding ethyl acetate. The product was obtained in 95% yield, and had a melting point of 167°-168° C.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)[CH:2]([CH3:4])[CH3:3].C(O)=O.C(OCC)C.C([NH2:22])=O>O>[CH3:3][CH:2]([CH3:4])[CH:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH2:22]
Reactant: CC(C)C(=O)c1ccccc1
Reactant: NC=O
Solvent: O
Solvent: CCOCC
Solvent: O=CO
Product: CC(C)C(N)c1ccccc1
Reaction time: 48 h
Yield: 61 %

Procedure:
A solution of isobutyrophenone (5.1 mL, 33.7 mmol) and formic acid (1.3 mL, 33.7 mmol) in formamide was stirred at 165-180° C. for 20 h. The mixture was cooled, diluted with water, and extracted with benzene. The benzene was concentrated down and the residue was boiled in 3 M HCl (10 mL) for 48 h. The cooled reaction mixture was added to diethyl ether and extracted with water. The combined water extracts were basified with 20% NaOH, and extracted with dichloromethane. The combined extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to yield 3.09 g (61%) of the desired amine: 1H NMR (400 MHz, CD3OD): δ 7.33-7.23 (m, 4H), 7.22-7.20 (m, 1H), 3.49 (d, 1H), 1.87 (m, 1H), 1.00 (d, 3H), 0.73 (d, 3H). MS (ESI) m/z: Calculated: 149.12; Observed: 149.9 (M++1).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)C(C)C)(C)C.[CH2:41]([O:48][P:49]([O-:58])[O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C([O-])(O)=O.[Na+]>C(#N)C.CN(C1C=CN=CC=1)C>[CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][P:49](=[O:58])([O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:48][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: O=S(=O)(CCN1CC[C@H](Cc2ccccc2)[C@H](O)C1)c1ccc(O)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=P(OCc1ccccc1)(OCc1ccccc1)Oc1ccc(S(=O)(=O)CCN2CC[C@H](Cc3ccccc3)[C@H](O)C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
To a solution of 500 mg (133 mmol) (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenol in 20 ml acetonitrile were added 0.64 ml (6.7 mmol) CCl4, 16.3 mg (0.13 mmol) DMAP and 0.48 ml (2.9 mmol) N,N-diisopropylethylamine. The reaction mixture was stirred for 15 min at room temperature and 0.43 ml (1.9 mnmol) dibenzylphosphite were added dropwise. After 20 min. 20 ml sat. NaHCO3 solution was added and the aqueous phase was extracted with ethylacetate (3×30 ml) and the combined organic layers were washed with water, dried over MgSO4, filtrated and the solvent was removed under reduced pressure. Purification of the crude product by chromatography over silica gel (ethylacetate/hexane 2/1) yielded 700 mg (11 mmol, 83%) phosphoric acid dibenzyl ester (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl ester as a colorless solid.
Reaction SMILES: CS([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)=O.[C-:30]#[N:31].[K+]>C1C=CC=CC=1.CCCCC[N+](CCCCC)(CCCCC)CCCCC.[Br-].O>[C:30]([CH:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:31]
Reactant: CS(=O)(=O)[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [C-]#N
Agent: CCCCC[N+](CCCCC)(CCCCC)CCCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: N#CC1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h

Procedure:
In 2 ml of benzene are dissolved 0.5 mmol of (3R,4R)-4-methylsulfonyl-3-tritylamino-2-azetidinone and 0.1 mmol of tetra-n-amylammonium bromide, and a solution of 0.55 mmol of potassium cyanide in 0.55 ml of water is added at 15° C. The mixture is stirred vigorously for 15 minutes and treated in the same manner as Example 20 to give (3S,4RS)-4-cyano-3-tritylamino-2-azetidinone with the (3S,4R):(3S,4S) ratio of 1:4.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.C([Mg]Br)C.[CH2:18]=[O:19].Cl>C1COCC1.CCN(CC)CC.C(OCC)C>[OH:13][C:9]1[CH:8]=[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH:12]=[CH:11][C:10]=1[CH:18]=[O:19]
Reactant: Oc1cccc(N2CCOCC2)c1
Reactant: C=O
Agent: CC[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=Cc1ccc(N2CCOCC2)cc1O
Temperature: 30 °C
Reaction time: 1.5 h

Procedure:
After slowly adding a solution of 3-morpholinophenol (5.0 g) in THF (100 ml) to a 3 M diethyl ether solution (10 ml) of ethylmagnesium bromide, the mixture was stirred at 30° C. for 1.5 hours. Paraformaldehyde (3.0 g) and Et3N (3.0 g) were added to the reaction solution and the mixture was stirred at 80° C. for 4 hours. After cooling, a 6 N hydrochloric acid aqueous solution (20 ml) was added, the mixture was stirred for an hour, and then the organic layer and aqueous layer were separated and the aqueous layer was rendered weakly alkaline prior to extraction with AcOEt. The organic layers were combined and dried with MgSO4, and then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=3/1) to obtain 2-hydroxy-4-morpholinobenzaldehyde.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:8])[CH:5]([CH3:7])[NH2:6].C(N(CC)CC)C.[CH2:16]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][C:21]=1Cl)[CH:17]=[CH2:18].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:8])[CH:5]([CH2:7][Cl:1])[NH:6][C:27](=[O:28])[CH2:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:16][CH:17]=[CH2:18])=[CH:25][CH:24]=1
Reactant: COC(=O)C(C)N
Reactant: C=CCOc1ccc(CC(=O)O)cc1Cl
Reactant: Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOc1ccc(CC(=O)NC(CCl)C(=O)OC)cc1
Temperature: 25 °C

Procedure:
A suspension of (DL)-alanine methyl ester hydrochloride (2.8 g) in dry methylene chloride (10 ml) containing dry triethylamine (2.8 ml) was added to a solution of 4-allyloxy-3-chloro-phenylacetic acid (4.3 g) in dry methylene chloride (30 ml). N,N'-dicyclohexyl-carbodiimide (DCC; 4.1 g) was added and the reaction mixture was stirred at room temperature.