Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:9][CH2:10][CH2:11][CH3:12])[CH:7]=[O:8])(=[O:3])[CH3:2].O[CH:14]([CH:16]=[CH2:17])[CH3:15].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>>[C:1]([S:4][CH2:5][C:6]([CH2:15][CH2:14][CH2:16][CH3:17])([CH2:9]/[CH:10]=[CH:11]/[CH3:12])[CH:7]=[O:8])(=[O:3])[CH3:2]
Reactant: C=CC(C)O
Reactant: CCCCC(C=O)CSC(C)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: C/C=C/CC(C=O)(CCCC)CSC(C)=O
Temperature: 25 °C
Yield: 80.5 %

Procedure:
To a stirred solution of 2-(acetylthiomethyl)hexanal (32.6 g, 0.173 mole) in 325 ml of xylenes in a 500-mL RBF fitted with a Dean-Stark trap is added 2-hydroxy-3-butene (22.5 mL, 0.259 mole), followed by pyridinium p-toluenesulfonate (4.34 g, 0.017 mole) at room temperature under nitrogen. The mixture is heated to reflux overnight. After cooling to room temperature, the xylenes solution is washed with 300 mL of saturated NaHCO3 solution. The aqueous phase is extracted with 300 mL of ethyl acetate. The combined organic extract is washed with 200 mL of brine and 200 mL of water. After removing solvents, the product is obtained by vacuum distillation (157-160° C./1.5 mmHg) in 80.5% yield.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[CH2:4].[Br:11][CH2:12][C:13](Br)=[O:14]>>[CH3:1][N:2]([C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[CH2:4])[C:13](=[O:14])[CH2:12][Br:11]
Reactant: C=C(NC)c1ccccc1
Reactant: O=C(Br)CBr
Product: C=C(c1ccccc1)N(C)C(=O)CBr

Procedure:
N-methyl-N-(1-phenylvinyl)amine and bromoacetyl bromide were used to produce the above compound in the same way as Reference Example 8.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](N)c1ccc(Br)cc1
Solvent: ClCCl
Product: CC(=O)N[C@@H](C)c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To 200 g (1.00 mol) (S)-1-(4-bromophenyl)ethylamine in 800 mL DCM are slowly added 94.5 mL (1.00 mol) acetic anhydride while cooling the mixture to 20-30° C. Then the cooling is removed and the reaction mixture is stirred at r.t. over night. Afterwards the mixture is consecutively washed with water, sat. aq. NaHCO3 solution, water, diluted aq. citric acid solution and again water. The org. layer is dried with MgSO4 and the solvent is removed in vacuo. The crude product is used without further purification.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH:17]1[N:26]=[C:27]=[O:28])[CH2:23]2>>[CH:18]12[CH2:24][CH:22]3[CH2:21][CH:20]([CH2:25][CH:16]([CH2:23]3)[CH:17]1[NH:26][C:27]([NH:2][CH:3]([CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:11](=[O:15])[CH:12]([CH3:13])[CH3:14])=[O:28])[CH2:19]2
Reactant: O=C=NC1C2CC3CC(C2)CC1C3
Reactant: CC(C)C(=O)C(N)Cc1ccccc1
Agent: Cl
Product: CC(C)C(=O)C(Cc1ccccc1)NC(=O)NC1C2CC3CC(C2)CC1C3

Procedure:
This material was obtained in analogy to example 7, step A] from known 2-amino-4-methyl-1-phenyl-pentan-3-one hydrochloride (CAS 472995-82-7, see J. Heterocyclic Chem. 39 (2), 2002, 375-382, 249 mg) and 2-adamantyl isocyanate (194 mg). 1-Adamantan-2-yl-3-(1-benzyl-3-methyl-2-oxo-butyl)-urea was obtained as a white solid (245 mg). MS (ISP): 369.5 (MH+).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[C:8]1([CH:14]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)=O>[CH:5]([N:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:14]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(C2CCCCCN2)cc1
Solvent: O=CO
Product: O=CN1CCCCCC1c1ccccc1
Temperature: 70 °C
Yield: 97 %

Procedure:
To a mixture of, 98-100% formic acid (30 ml) and acetic anhydride (100 ml) was added 2-(R,S)-phenylazacycloheptane (10 g, 57.1 mmol; B. E. Maryanoff et al., J.Med. Chem., 30, 1433, 1987) and the mixture warmed to 70° C. for 2 h. The reaction mixture was then cooled and evaporated to dryness in vacuo and the residue was partitioned between ether and saturated aqueous potassium carbonate. The ether layer was separated and evaporated to dryness in vacuo to afford the title compound (11.24 g; 97%) as a mixture of E/Z isomers.
Reaction SMILES: CC1C([N+]([O-])=O)=CC=CC=1C=O.C(NC(C1CCNCC1)=O)(C)(C)C.[C:26]([NH:30][C:31]([CH:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([N+:46]([O-])=O)[C:41]=2[CH3:49])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][C:31]([CH:33]1[CH2:34][CH2:35][N:36]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([NH2:46])[C:41]=2[CH3:49])[CH2:37][CH2:38]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: Cc1c(CN2CCC(C(=O)NC(C)(C)C)CC2)cccc1[N+](=O)[O-]
Agent: CC(C)(C)NC(=O)C1CCNCC1
Agent: Cc1c(C=O)cccc1[N+](=O)[O-]
Product: Cc1c(N)cccc1CN1CCC(C(=O)NC(C)(C)C)CC1

Procedure:
The title compound is prepared according to the reactions described for BB-5 above starting from 2-methyl-3-nitro-benzaldehyde and piperidine-4-carboxylic acid tert-butylamide yielding after reductive amination 1-(2-methyl-3-nitro-benzyl)-piperidine-4-carboxylic acid tert-butylamide; LC-MS A: tR=0.62 min; [M+H]+=334.32 followed by reduction with stannous chloride the title compound; LC-MS A: tR=0.45 min; [M+H]+=304.32.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:12])[CH2:9][C:10]#[CH:11].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(Cl)Cl>C(OCC)(=O)C>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O:12][CH2:8][CH2:9][C:10]#[CH:11])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: C#CCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 101.7 %

Procedure:
Triethylamine (12.2 mL) was added dropwise to a mixture of 3-butyn-1-ol (5.09 g) and 4-toluenesulfonyl chloride (16.95 g) in 50 nm of CH2Cl2 cooled by an ice bath. The mixture was allowed to warm to room temperature. After 21 hours, the mixture was poured into ethyl acetate (150 mL) and washed with 0.1M HCl (75 mL), saturated NaHCO3 (75 mL), and brine (75 mL) and the organic phase was dried over anhydrous MgSO4 and concentrated in vacuo. Purification by flash chromatography (10% ethyl acetate/hexane) gave 16.57 g of the product as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)=[N:8][NH:9][C:10]2=O)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[N:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(-c3ccc(C(F)(F)F)cc3)n[nH]c(=O)c2c1
Product: COc1ccc2c(-c3ccc(C(F)(F)F)cc3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 7-methoxy-4-(4-trifluoromethylphenyl)-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [C:1]([C:4]1[C:31]([CH3:32])=[CH:30][C:7]2[NH:8][C:9]([S:11][CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH2:22][C:23]4([CH3:29])[CH2:28][O:27][CH2:26][O:25][CH2:24]4)[CH:16]=[CH:15][N:14]=3)=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].C([O-])(O)=[O:34].[Na+].ClC1C=CC=C(C(OO)=O)C=1.[OH-].[Na+]>C(Cl)Cl.O>[C:1]([C:4]1[C:31]([CH3:32])=[CH:30][C:7]2[NH:8][C:9]([S:11]([CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH2:22][C:23]4([CH3:29])[CH2:24][O:25][CH2:26][O:27][CH2:28]4)[CH:16]=[CH:15][N:14]=3)=[O:34])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: COc1c(OCC2(C)COCOC2)ccnc1CSc1nc2cc(C(C)=O)c(C)cc2[nH]1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1c(OCC2(C)COCOC2)ccnc1CS(=O)c1nc2cc(C(C)=O)c(C)cc2[nH]1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A stirred mixture of 5-acetyl-6-methyl-2-[[(3-methoxy-4-(5-methyl-1,3-dioxan-5-yl-methoxy)-2-pyridinyl)methyl]thio]-1H-benzimidazole (87 mg, 0.19 mmol) in 20 ml CH2Cl2 and NaHCO3 (32 mg, 0.38 mmol) in 5 ml H2O was cooled to 0° C. and treated with 3-chloro-perbenzoic acid (47 mg 70%, 0.19 mmol). After reacting for 10 min the layers were separated (the aqueous layer was washed once more with 5 ml CH2Cl2) and the organic layer extracted with 10 ml H2O containing NaOH (15 mg, 38 mmol). The alkaline aqueous layer was collected and treated with several portions of methyl formate (each 23 μl, 38 mmol) until the solution turned opaque. The aqueous layer was extracted with 25+10 ml CH2Cl2. The two latter organic layers were combined, dried over MgSO4 and evaporated. The residue was chromatographed (SiO2, CH2Cl2 /MeOH saturated with NH3(g), 93/7) yielding 40 mg (44%) pure solfoxide.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12](=O)[CH3:13].[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17]>>[F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]([NH:21][S@@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])[CH3:13]
Reactant: CC(=O)c1cccc(C(F)(F)F)c1F
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1cccc(C(F)(F)F)c1F
Yield: 56 %

Procedure:
The title compound is prepared in 56% yield (511 mg, a white solid) from 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethanone (600 mg, 2.91 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide (529 mg, 4.37 mmol) by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:14]S(C3C=CC(C)=CC=3)(=O)=O)[N:11]=2)[CH:2]=1.C([O:34][C:35](=[O:57])[C:36]([CH3:56])([O:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:48][CH:47]=1)[CH2:37][C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1)C>C(O)C>[C:1]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:14][C:41]3[CH:40]=[CH:39][C:38]([CH2:37][C:36]([CH3:56])([O:45][C:46]4[CH:51]=[CH:50][C:49]([C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:48][CH:47]=4)[C:35]([OH:57])=[O:34])=[CH:43][CH:42]=3)[N:11]=2)[CH:2]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C(C)(C)C)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccccc3)c2)nc1CCOc1ccc(CC(C)(Oc2ccc(C(C)(C)C)cc2)C(=O)O)cc1
Temperature: 55 °C
Yield: 45 %

Procedure:
Toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethyl ester (0.132 mmol) (see Ex. 2, Part F) was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 3-(4-hydroxyphenyl)-2-methyl-2-(4-tert-butylphenoxy)-propionic acid ethyl ester (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) (see Ex. 15, Part B) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed. The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl) and the vial resealed tightly. The solution was heated in a block heater at 55° C. for 3–16 h, or until MS analysis indicates the completion of the hydrolysis. The solvents are removed with a stream of nitrogen or under reduced pressure and the residue redissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150 μl), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by preparative thin-layer silica chromatography eluting with 95:5 CH2Cl2:MeOH to produce a white solid (45%). MS [EI+] 590 (M+H)+, [EI−] 588 (M−H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[O:9])[S:5][C:6]=1[CH3:7].CC1C=CC(S([CH2:20][N:21]=[CH2:22])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][CH:22]=[N:21][CH:20]=2)[S:5][C:6]=1[CH3:7]
Reactant: Cc1sc(C=O)cc1Br
Reactant: C=NCS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1sc(-c2cnco2)cc1Br
Temperature: 80 °C

Procedure:
To a solution of 4-bromo-5-methylthiophene-2-carbaldehyde (A, 10.5 mmol) and p-tosylmethyl isocyanide (11 mmol) in methanol (80 mL) was added potassium carbonate (13 mmol) and the mixture was heated to 80° C. for 1 h. The solvent was removed in vacuo and diluted in DCM (100 mL) and water (100 mL). The organic layer dried, concentrated and purified by flash chromatography to give 5-(4-bromo-5-methylthiophen-2-yl)oxazole (B, 1.83 g) as yellowish solids.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:13]1[CH:18]=[CH:17][C:16]([CH:19]([NH2:23])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.[OH-].[Na+]>O>[C:2]1([CH2:1][O:8][CH2:9][C:10]([NH:23][CH:19]([C:16]2[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=2)[C:20]([OH:22])=[O:21])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: NC(C(=O)O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(COCc1ccccc1)NC(C(=O)O)c1ccccc1
Reaction time: 8 h

Procedure:
Benzyloxyacetyl chloride (6.3 mL, 40 mmol) is added to a solution of DL-phenylglycine (3.00 g, 19.8 mmol) and NaOH (2.32 g, 58.0 mmol) in 100 mL H2O and allowed to stir overnight. The reaction pH is adjusted to 11 with 3M NaOH 5 and washed with (3×50 mL) Et2O, then brought to pH=3 with concentrated HCl. The resulting precipitate is collected, washed with H2O and dried to obtain the title compound as an off-white solid. mp 127°-30° C.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[NH:7][CH:8]=[C:9]([C:11]([CH3:22])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[CH3:12])[N:10]=1)([CH3:5])[CH3:4].I[CH3:24]>C1COCC1>[CH:3]([C:6]1[N:10]([CH3:24])[C:9]([C:11]([CH3:12])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[CH3:22])=[CH:8][N:7]=1)([CH3:5])[CH3:4]
Reactant: CC(C)c1nc(C(C)(C)c2cccc([N+](=O)[O-])c2)c[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1ncc(C(C)(C)c2cccc([N+](=O)[O-])c2)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
To a cold (0° C.) slurry of 50% sodium hydride (84 mg, 1.75 mmol) in THF (3 mL) was added 2-isopropyl-4-[1-methyl-1-(3-nitro-phenyl)-ethyl]-1H-imidazole (0.4 g, 1.46 mmol). The mixture was warmed to r.t. and stirred for 30 min. Iodomethane (0.13 mL, 2.1 mmol) was added and the reaction maintained for 2 h. The solvent was evaporated under reduced pressure and the residue partitioned between DCM and water. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (60-120 mesh), eluting with 25% ethyl acetate/hexane to obtain 2-isopropyl-1-methyl-5-[1-methyl-1-(3-nitro-phenyl)-ethyl]-1H-imidazole (0.148 g, 35%) as a colourless semisolid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH2:14]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][CH:34]([NH:1][CH2:2][C@H:3]([OH:13])[CH2:4][O:5][C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=3)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)(=[O:23])=[O:24])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1CCN(c2ccc(S(=O)(=O)NCc3ccccc3)cc2)CC1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Product: O=S(=O)(NCc1ccccc1)c1ccc(N2CCC(NC[C@H](O)COc3ccc(O)cc3)CC2)cc1

Procedure:
The title compound was prepared from 4-((2S)-3-Amino-2-hydroxy-propoxy)-phenol and Reference Example 70, N-benzyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as a tan solid. 1H NMR (DMSO) δ 1.27 (m, 2H), 1.86 (m, 2H), 2.75(m, 3H), 2.91(t, 2H, J=8.4 Hz), 3.82(m, 5H), 3.89(s, 2H), 4.89(m, 1H), 6.67 (d, J=6.6 Hz), 6.76(d, 2H, J=6.6 Hz), 7.02 (d, 2H, J=6.6 Hz), 7.26 (m, 5H), 7.57 (d, 2H, J=6.6 Hz), 7.78)bs, 1H), 8.87(bs, 1H); MS (ES) m/z: 512.1 (MH+); HRMS for C27H33N3O5S: 511.2215 (MH+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N+:17]([O-])([OH:19])=[O:18].S(=O)(=O)(O)O>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([F:12])([F:13])([F:16])([F:14])[F:15])=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(S(F)(F)(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(S(F)(F)(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
4-Acetamidophenylsulphur pentafluoride (27.0 g) was added during 5 minutes to a stirred mixture of concentrated nitric acid and concentrated sulphuric acid (1 part:2 parts by volume) at 0-5° C. After 5 minutes acetic acid (1 part) was added and stirring continued at 5° C. for 1.5 hours. The mixture was added to ice/water, extracted (ethyl acetate) and the extract washed (sodium carbonate solution), dried (magnesium sulphate) and evaporated. The residue was triturated with ether to give 4-acetamido-3-nitrophenylsulphur pentafluoride (30.0 g), m.p.135-138° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].I.[CH3:9][C:10]1[N:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=2)[C:12]([CH3:15])=[CH:13][CH:14]=1>[OH-].[Na+]>[C:1]([C:13]1[CH:14]=[C:10]([CH3:9])[N:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=2)[C:12]=1[CH3:15])(=[O:3])[CH3:2]
Reactant: CCOc1ccc(-n2c(C)ccc2C)cc1
Reactant: CC(=O)OC(C)=O
Agent: I
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccc(-n2c(C)cc(C(C)=O)c2C)cc1
Temperature: 100 °C

Procedure:
Acetic anhydride (8.5 mL, 89 mmol) and hydriodic acid (0.48 mL, 6.3 mmol) were added to 2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (8.0 g, 37 mmol) under nitrogen and the resulting mixture maintained at 100° C. overnight. After cooling to rt, the mixture was diluted with 1N NaOH (200 mL), extracted with EtOAc (2×200 mL), and the combined extracts washed with brine (200 mL), dried (MgSO4), filtered, concentrated in vacuo, and purified by flash chromatography on silica gel (15% EtOAc/hexanes) to give 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole as a tan solid: 1H NM (CDCl3, 500 MHz) δ 7.08-7.04 (m, 2H), 6.99-6.96 (m, 2H), 6.30 (s, 1H), 4.08 (q, 2H), 2.41 (s, 3H), 2.29 (s, 3H), 1.97 (s, 3H), 1.45 (t, 3H); MS (ESI) 258 (M+H)+.
Reaction SMILES: [OH-:1].[Na+].[OH:3][CH:4]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6][CH2:7][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:20])[C:17]([OH:19])=[O:18])[C:9]#[N:10].OO.Cl>O.C(O)C>[OH:3][CH:4]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6][CH2:7][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:20])[C:17]([OH:19])=[O:18])[C:9]([NH2:10])=[O:1]
Reactant: CCCCCC(O)CCCN(C#N)CCCCCC(C)C(=O)O
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCC(O)CCCN(CCCCCC(C)C(=O)O)C(N)=O

Procedure:
To a solution of sodium hydroxide (0.4 g., excess) in water (50 ml.) and ethanol (50 ml.) is added 7-[N-(4-hydroxynonyl)-cyanamido]-2-methylheptanoic acid (1.5 g., 0.005 mole). The clear solution that is obtained is treated with 30% hydrogen peroxide (1.25 ml., excess). After two hours the reaction is poured into water (125 ml.), acidified with 5% hydrochloric acid and extracted with ethyl acetate (3 × 75 ml.). The organic phase is washed with brine, then dried over sodium sulfate. Evaporation of the solvent yields 7-[1-(4-hydroxynonyl)ureido]-2-methyl-heptanoic acid as a viscous oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C:14](=[O:15])[O:13][CH2:12][CH2:11][N:10]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.COC(=O)C(N)C1C=CC(F)=CC=1>>[CH2:16]([N:10]1[CH:11]=[CH:12][O:13][C:14](=[O:15])[C@@H:9]1[C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1OCCN(Cc2ccccc2)[C@H]1c1ccc(F)cc1
Agent: COC(=O)C(N)c1ccc(F)cc1
Agent: Cl
Product: O=C1OC=CN(Cc2ccccc2)[C@H]1c1ccc(F)cc1
Temperature: 65 °C
Reaction time: 72 h

Procedure:
To a solution of 3-(4-fluorophenyl)-4-phenylmethyl-2-morpholinone (i.e. N-benzyl-4-fluorophenyl-1,4-oxazin-2-one) (10 g) in isopropyl acetate (110 ml) at room temperature was added a solution of (−)-3-bromocamphor-8-sulphonic acid ((−)-3BCS) (12 g) in acetonitrile (24 ml). Crystallisation began after 2-3 min. The slurry was stirred for 1 h at room temperature. Trifluoroacetic acid (7 ml) was added and the mixture stirred at 65° C. for 3 days. The mixture was cooled to 0-5° C., aged for 1 h. and the solid collected, washed with isopropyl acetate and dried in vacuo at 40° C., to give the N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (−)-3BCS salt: yield 17.24 g, ee 98.6% (S) isomer. The chiral composition of the remaining liquors was determined as 79%(R), 21%(S). The liquors were stirred at 65° C. for 3 days, then cooled to 0-5° C. The solid was collected, washed with isopropyl acetate and dried in vacuo to give a further batch of the N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (−)-3BCS salt: yield 0.84 g, ee 98.6% (S) isomer. The chiral composition of the remaining liquors was determined as 64%(R), 36%(S). The liquors were stripped in vacuo and the residue was dissolved in isopropyl acetate (20 ml) containing trifluoroacetic acid (1 ml) and stirred at 65° C. for 20 h. The mixture was cooled to 0-5° C. for 1 h and the solid collected, washed with isopropyl acetate and dried in vacuo to give a further batch of the N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (−)-3BCS salt: yield 2.2 g, ee 99.2% (S) isomer. Total weight of (−)-3BCS salt: 20.28 g, 97% yield. A sample (0.5 g) of the (−)-3BCS salt was retained and the remainder converted back to free base. The salt was partitioned between isopropyl acetate (50 ml) and water (100 ml) containing 0.88 ammonia soln. (3 ml). The layers were separated and the aqueous phase extracted with isopropyl acetate (25 ml). The combined organic phases were washed with water (25 ml). The organic phase was concentrated to residue and flushed with isopropyl acetate to give the 3-(S)-(4-fluorophenyl)-4-phenylmethyl-2-morpholinone (i.e. N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one) as the free base: yield 8.7 g, 93% recovery, ee 98.4% (S) isomer.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[S:2].[CH:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([P:1]([Cl:5])([Cl:3])=[S:2])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: S=P(Cl)(Cl)Cl
Reactant: c1ccccc1
Product: S=P(Cl)(Cl)c1ccccc1
Temperature: 200 °C
Reaction time: 4 h

Procedure:
In a 100 cc autoclave, 42.35 g (0.25 mole) of thiophosphoryl trichloride, 19.53 g (0.25 mole) of benzene were charged, and the mixture was heated with stirring at 200° C for 4 hours. The reaction mixture was treated in accordance with the process of Example 1. No phenylphosphonothioic dichloride was produced.