Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Li+].OO.[O-]O.[Li+].C([C@@H]1COC(=O)N1[C:21](=[O:40])[C@@H:22]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31]([Cl:39])[CH:30]=1)[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)C1C=CC=CC=1>O.O1CCCC1>[Cl:39][C:31]1[CH:30]=[C:29]([C@@H:22]([CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[C:21]([OH:40])=[O:1])[CH:34]=[CH:33][C:32]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: [OH-]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1Cl
Agent: OO
Agent: [Li+]
Agent: [O-]O
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reaction time: 1.5 h
Yield: 84.6 %

Procedure:
A solution of lithium hydroxide (215 mg, 9.0 mmol) in water (2.8 mL) was treated with a 30% aqueous hydrogen peroxide solution (2.0 mL, 18 mmol). This freshly prepared lithium hydroperoxide solution was then cooled to 0C and then slowly added to a cooled (0° C.) solution of 4(R)-benzyl-3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionyl]-oxazolidin-2-one (2.20 g, 4.5 mmol) in tetrahydrofuran (18 mL) and water (5.8 mL). After 1.5 h at 0° C., the reaction was quenched with a 1.5N aqueous sodium sulfite solution (25 mL) and was diluted with water (150 mL). The aqueous layer was extracted with diethyl ether (3×50 mL). The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution to pH =2 and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate with 1% acetic acid) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (1.26 g, 85%) as a white solid: mp 106.1-108.8° C.; [α]23589=43.0° (c=0.172, chloroform); EI-HRMS m/e calcd for C15H19ClO4S (M+) 330.0692, found 330.0690.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([Si:8]([CH3:11])([CH3:10])[CH3:9])[O:6][CH:7]=1.N1C=CC=CC=1.[C:18](Cl)(=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O1CCCC1>[C:18]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([Si:8]([CH3:11])([CH3:10])[CH3:9])[O:6][CH:7]=1)(=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: C[Si](C)(C)c1cc(CO)co1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCC(=O)OCc1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-hydroxymethyl-2-trimethylsilylfuran (0.288 g., 1.70 mmol) and pyridine (0.214 g., 2.55 mmol) in 30 ml dry tetrahydrofuran at 0 degrees was added lauroyl chloride (0.408 g., 1.86 mmol). This solution was allowed to warm to room temperature, stirred 30 minutes, and partitioned between ethyl ether and 5% sodium bicarbonate solution The organic portion was washed with aqueous cupric sulfate solution, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to a colorless oil. This material was purified by flash chromatography (silica, 5% ethyl ether/petroleum ether) to give the desired ester.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=[O:24]>ClCCl>[CH3:21][C:22]([CH3:27])([CH3:26])[C:23]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][N:11]=1)=[O:24]
Reactant: Nc1ccc(-c2ccccc2)cn1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
5-phenylpyridin-2-amine (2.4 g, 14.10 mmol) was dissolved in 75 ml of dichloromethane. The solution was treated with triethylamine (1.57 g, 15.51 mmol) and trimethylacetylchloride (1.87 g, 15.51 mmol) and the mixture was stirred at room temperature for 1 hour. Silica gel (9 g) was added and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with hexanes/ethyl acetate (5:1) to afford 2,2-dimethyl-N-(5-phenylpyridin-2-yl)propanamide (2.58 g) as a white solid.
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[CH3:3].[NH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][CH2:8]1>>[OH:14][CH2:13][CH:10]1[CH2:11][CH2:12][N:7]([C:1](=[O:6])[CH:2]([CH3:4])[CH3:3])[CH2:8][CH2:9]1
Reactant: OCC1CCNCC1
Reactant: CC(C)C(=O)O
Product: CC(C)C(=O)N1CCC(CO)CC1

Procedure:
Prepared as in Example 24a from isobutyric acid and piperidin-4-ylmethanol as a colorless oil (36%). MS 186 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=1)=O.[C:21]([O:28][CH3:29])(=[O:27])[CH2:22][CH2:23][C:24]([CH3:26])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:29][O:28][C:21](=[O:27])[CH2:22][C:23]1[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:24]=1[CH3:26]
Reactant: COC(=O)CCC(C)=O
Reactant: CCc1ccc(C(=O)c2c(N)sc3c2CCCC3)cc1
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: CCc1ccc(-c2c(CC(=O)OC)c(C)nc3sc4c(c23)CCCC4)cc1
Yield: 73.9 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-ethylphenyl)methanone (0.471 g; 1.65 mmol), methyl levulinate (0.233 mL; 1.81 mmol), chlorotrimethylsilane (0.845 mL; 6.6 mmol) in DMF (6.6 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.463 g (74%) of the title compound as a yellow solid.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:8]([O:10]CC1C=CC=CC=1)=[O:9])[CH2:3][CH2:4][C:5](=O)[OH:6].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:40]1[C:45]([S:46]([OH:49])(=[O:48])=[O:47])=[C:44]([OH:50])[C:43]([NH2:51])=[CH:42][C:41]=1Cl.C1COCC1>C(Cl)Cl>[OH:50][C:44]1[C:45]([S:46]([OH:49])(=[O:48])=[O:47])=[CH:40][CH:41]=[CH:42][C:43]=1[NH:51][C:5](=[O:6])[CH2:4][CH2:3][C@@H:2]([C:8]([OH:10])=[O:9])[NH2:1]
Reactant: Nc1cc(Cl)cc(S(=O)(=O)O)c1O
Reactant: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: N[C@@H](CCC(=O)Nc1cccc(S(=O)(=O)O)c1O)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
Z-Glu-OBn (371 mg, 1 mmol) was dissolved in methylene chloride (1 mL), and CDI (180 mg, 1.1 mmol) was added thereto and stirred at room temperature for 30 minutes. Then, 2-amino-4-chlorophenol-6-sulfonic acid (223 mg, 1 mmol) and THF (1 mL) were added thereto and stirred overnight at room temperature. After removing a solvent, purification was conducted in accordance with the purification process A. The obtained intermediate was dissolved in a mixed solvent of methanol and water. Pd/C in catalyst quantity was added thereto and stirred under hydrogen atmosphere overnight at room temperature. After filtering out the catalyst and removing a solvent, purification was conducted in accordance with the purification process A to obtain a title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][CH2:11][CH2:12][CH3:13])=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1>C1C=CC=CC=1.O=[Mn]=O>[Cl:1][C:2]1[C:3]([O:10][CH2:11][CH2:12][CH3:13])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH:8]=[O:9]
Reactant: CCCOc1c(Cl)cccc1CO
Agent: O=[Mn]=O
Solvent: c1ccccc1
Product: CCCOc1c(Cl)cccc1C=O
Reaction time: 48 h
Yield: 37.8 %

Procedure:
MnO2 (3.40 g, 39.2 mmol) was added to a stirring solution of (3-chloro-2-propoxyphenyl)methanol (1.12 g, 5.60 mmol) in benzene (54 mL) under N2. After stirring for 48 h, the solution was filtered over diatomaceous earth, the pad rinsed with CH2Cl2 (100 mL), and the solution concentrated to a clear oil. Purification by column chromatography (silica gel, hexanes/EtOAc, 98:2) gave the title compound (0.42 g, 38%) as a clear oil: 1H NMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.32 (t, J=7.8 Hz, 1H), 4.04 (t, J=6.4 Hz, 2H), 1.85-1.78 (m, 2H), 1.03 (t, J=7.3 Hz, 3H).
Reaction SMILES: [C:1]([O:10]CC)(=[O:9])/[CH:2]=[CH:3]/[C:4]([O:6]CC)=O.[C:13]([O:16]C(=O)C)(=O)[CH3:14].[SH2:20]>>[C:13]([SH:20]=[C:4]([OH:6])[CH2:3][CH2:2][C:1]([OH:10])=[O:9])(=[O:16])[CH3:14]
Reactant: S
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)/C=C/C(=O)OCC
Product: CC(=O)[SH]=C(O)CCC(=O)O

Procedure:
When the alkene-1,2-dicarboxylic acid compound starting material is an ester, such as diethyl fumarate, the addition of acetic anhydride and hydrogen sulfide proceeds to give the diethyl ester of S-acetylthiosuccinic acid, which on selective deacetylation, suitably by means of aqueous alcoholic ammonia, gives diethyl thiomalate according to this invention, as illustrated in SCHEME 2 below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([Cl:1])[CH:7]=1
Reactant: COc1ccc(C)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CBr)cc1Cl

Procedure:
To a solution of 2-chloro-1-methoxy-4-methylbenzene (300 mg, 1.92 mmol) in carbon tetrachloride (10.0 mL) was added N-bromosuccinimide (445 mg, 2.50 mmol) and benzoylperoxide (4.6 mg, 0.0192 mmol) and the reaction heated to reflux for 4.5 hours.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C@@:10]([NH:29][C:30]([CH:32]2[CH2:36][CH2:35][C:34](=[O:37])[CH2:33]2)=[O:31])([C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([F:28])[CH:19]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][CH:9]=1>C1COCC1.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C@@:10]([NH:29][C:30]([CH:32]2[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33]2)=[O:31])([C:18]2[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[C:20]([F:28])[CH:19]=2)[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:8][CH:9]=1
Reactant: O=C1CCC(C(=O)N[C@@](Cc2ccccc2)(c2cc(F)cc(C(F)(F)F)c2)c2ccc(Cl)cn2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1)C1CCC(O)C1
Reaction time: 16 h
Yield: 71 %

Procedure:
NaBH4 (600 μg, 0.015 mmol) was added to a solution of N-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-oxocyclopentanecarboxamide (prepared as described in Example 7, Procedure 12) (7.7 mg, 0.015 mmol) in THF (1 mL) at room temperature. The reaction was monitored by HPLC and after 16 h, the solution was diluted with H2O and extracted with EtOAc (3×). The combined EtOAc layers was further washed with 6N HCl and sat'd aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. Flash chromatography (SiO2, 0-100% EtOAc/hexanes) gave 5.4 mg of N-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-hydroxycyclopentanecarboxamide as a film. 1H NMR (500 MHz, CDCl3, mixture of isomers) δ 8.54 (s, 1H), 8.52 (s, 1H), 8.35-8.29 (m, 2H), 7.72-7.66 (m, 2H), 7.47-7.42 (m, 2H), 7.40-7.32 (m, 2H), 7.25-7.06 (m, 10H), 6.56-6.50 (m, 4H), 4.48-4.38 (m, 2H), 4.30-4.22 (m, 2H), 3.64-3.53 (m, 2H), 2.89-2.80 (m, 2H), 2.10-0.80 (m, 12H); LC/MS (MeOH/H2O/NH4OAc mobile phase) rt=3.91 min; [M+H]=507.3.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Br)[CH:30]=2)[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[NH:52]1[CH2:56][CH2:55][C@@H:54]([NH:57][C:58](=[O:60])[CH3:59])[CH2:53]1>CN(C)C=O.O>[C:58]([NH:57][C@H:54]1[CH2:55][CH2:56][N:52]([CH2:35][C:31]2[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=2)[C:28]([NH:27][C:16]2[CH:17]=[CH:18][C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:20][C:15]=2[C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][N:12]=2)[C:8]([NH:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[C:3]([C:2]([F:43])([F:42])[F:1])[CH:4]=2)=[O:38])=[O:37])[CH2:53]1)(=[O:60])[CH3:59]
Reactant: CC(=O)N[C@@H]1CCNC1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CBr)c2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N[C@H]1CCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)C1
Temperature: 70 °C
Reaction time: 3 h
Yield: 45.8 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(3-(bromomethyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (100 mg, 0.15 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL), potassium carbonate (62 mg, 0.45 mmol, 2.92 equiv), potassium iodide (5 mg, 0.03 mmol, 0.20 equiv), and (R)—N-(pyrrolidin-3-yl)acetamide (38.5 mg, 0.30 mmol, 1.96 equiv). The resulting solution was stirred for 3 h at 70° C. in an oil bath. The resulting solution was diluted with 150 mL of water. The resulting solution was extracted with 4×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×200 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 48 mg (30%) of a light yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.925-8.942 (d, J=5.1 Hz, 1H), 8.642-8.672 (d, J=9.0 Hz, 1H), 8.435 (s, 1H), 8.075-8.141 (m, 3H), 7.863-7.880 (m, 1H), 7.537-7.801 (m, 7H), 4.720 (s, 2H), 4.524-4.594 (m, 2H), 4.374-4.418 (m, 1H), 3.628-3.663 (m, 4H), 2.501 (m, 1H), 2.016-2.031 (m, 5H), 1.947 (m, 3H), 1.810-1.826 (m, 2H). MS (ES, m/z): 699 [M+H]+.
Reaction SMILES: [C:1]([OH:5])(C)([CH3:3])[CH3:2].[C:6]([O:10][O:11]C(C)(C)C)([CH3:9])([CH3:8])[CH3:7]>C(O)(C)(C)C>[CH2:2]1[O:5][CH:1]1[CH3:3].[C:6]([O:10][OH:11])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: CC(C)(C)O
Product: CC(C)(C)OO
Product: CC1CO1

Procedure:
In order to demonstrate the need for obtaining the tertiary butyl alcohol/ditertiary butyl peroxide azeotrope fraction described above, the tertiary butyl alcohol starting material obtained from the reaction of propylene oxide with tertiary butyl hydroperoxide, as described above, was sequentially extracted in a batch water extractor. In each extraction, 15 grams of raffinate or upper layer was extracted with the amount of water as indicated in Table I.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]=O)=[C:2]1[CH:12]=O.C([NH:17][CH:18](P(OC)(OC)=O)[C:19]([O:21][CH3:22])=[O:20])(=O)C.N12CCCN=C1CCCCC2>C(Cl)Cl>[CH:10]1[C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][C:2]=2[CH:12]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[N:17]=1
Reactant: O=Cc1sc2ccccc2c1C=O
Reactant: COC(=O)C(NC(C)=O)P(=O)(OC)OC
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cc2sc3ccccc3c2cn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
1-Benzothiophene-2,3-dicarbaldehyde (C180) (1.91 g, 10.0 mmol) is dissolved in CH2Cl2 (100 ml) and chilled in an ice bath. Methyl (acetylamino)(dimethoxyphosphoryl)acetate (C152) (2.63 g, 11.0 mmol) is dissolved in CH2Cl2 (50 ml) and added to 1,8-diazabicyclo[5.4.0]undec-7-ene (1.65 ml, 11.0 mmol), stirring for 5 minutes. This solution is added dropwise to the chilled thiophene solution. The reaction mixture is stirred in the ice bath for 1 h and then over night at rt. The reaction is concentrated in vacuo and the crude material is chromatographed over 500 g slurry-packed silica eluting with 50% ethyl acetate/hexane to afford methyl benzothieno[3,2-c]pyridine-3-carboxylate (C 181) as a white solid (73% yield). MS for C13H9NO2S, (EI) m/z: 243 (M)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.O>C(#N)C>[CH2:15]([NH:22][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: NCc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1NCc1ccccc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 83.4 %

Procedure:
A solution of 2-chloro-5-nitro-benzenesulfonamide (20 g, 84.52 mmol) in acetonitrile (169 mL) was treated with benzylamine (13.85 mL, 126.78 mmol), diisopropyl ethylamine (29.44 mL, 169.04 mmol) and stirred for 16 h at 55° C. The reaction was cooled to 25° C., poured into water (1.0 L) then placed in an ice bath while stirring. After 4 h a precipitate was filtered off and washed with the mother liquor to afford the desired product, 2-benzylamino-5-nitro-benzenesulfonamide (21.65 g, 70.45 mmol, 83.3% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 6:4.64 (2H, d, J=4.6 Hz), 6.81 (1H, d, J=9.4 Hz), 7.23-7.44 (6H, m), 7.77 (2H, bs), 8.11 (1H, dd, J1=9.4 Hz, J2=2.3 Hz), 8.49 (1H, d, J=3.1 Hz). LC-MS (ESI) calcd for C13H13N3O4S 307.06. found 308.2 [M+H+] (100%), 615.2 [2M+H+] (81%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=O.[Cl-].[OH:16][NH3+:17].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[N:17][OH:16]
Reactant: [NH3+]O
Reactant: CSc1ccc(C(=O)C(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CSc1ccc(C(=NO)C(F)(F)F)cc1
Temperature: 0 °C
Yield: 97 %

Procedure:
49.3 g (0.224 mol) of 2,2,2-trifluoro-1-(4-methylthiophenyl)-ethanone are dissolved in 250 ml of ethanol at 80° C. To the solution are added dropwise 16.3 g (0.235 mol) of hydroxylammonium chloride and 31.2 g (0.381 mol) of sodium acetate dissolved in 125 ml of water. The reaction mixture is refluxed for 6.5 hours, and poured into ice water. Filtration of the precipitate yields 51.1 g of 2,2,2-trifluoro-1-(4-methylthiophenyl)-ethanone oxime, as a yellow solid. The crude product is used in the next reaction step without further purification.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.Cl.[C:17]1([CH:23]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[C:24]([OH:26])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>C1COCC1>[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47]([O:25][C:24](=[O:26])[CH:23]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])[CH2:46]2
Reactant: Cc1ccccc1NC(C(=O)O)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1ccccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103 %

Procedure:
PS-DCC (1.15 g, 1.44 mmol, loading: 1.25 mmol/g) is suspended in THF (15 mL). Phenyl-o-methylphenylamino-acetic acid hydrochloride (I38) (200 mg, 0.72 mmol) and HOBT (221 mg, 1.44 mmol) are added, followed by (R)-quinuclidin-3-ol (275 mg, 2.16 mmol) and the mixture is shaken for 16 hours at RT. PS-DCC is filtered off and the filtrate is evaporated. The resulting residue is dissolved in EtOAc and washed sequentially with water, sat. NaHCO3, water and brine. The organic layer is dried over Na2SO4, filtered and evaporated to give the title compound as a colorless oil (260 mg, quantitative yield, mixture of diastereoisomers).
Reaction SMILES: [H-].[Na+].Cl.[OH:4][C@H:5]([CH3:9])[C:6](=[NH:8])[NH2:7].[NH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[C:19]([C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1)=[O:34])[C:20]([C:22]1[CH:23]=[CH:24][C:25]([F:32])=[C:26]([S:28](Cl)(=[O:30])=[O:29])[CH:27]=1)=[O:21]>C1COCC1>[NH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[C:19]([C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1)=[O:34])[C:20]([C:22]1[CH:23]=[CH:24][C:25]([F:32])=[C:26]([S:28]([NH:8][C:6](=[NH:7])[C@H:5]([OH:4])[CH3:9])(=[O:29])=[O:30])[CH:27]=1)=[O:21]
Reactant: C[C@@H](O)C(=N)N
Reactant: O=C(C(C(=O)c1ccc(F)c(S(=O)(=O)Cl)c1)=C1Nc2ccccc2N1)c1cccc(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](O)C(=N)NS(=O)(=O)c1cc(C(=O)C(C(=O)c2cccc(F)c2)=C2Nc3ccccc3N2)ccc1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
At room temperature, sodium hydride (579 mg) was added to a THF (70 mL) suspension of (2R)-2-hydroxypropanimidamide hydrochloride (1.65 g), followed by heating up to 60° C. and stirring for 30 minutes. The reaction mixture was cooled to room temperature, and a THF (35 mL) solution of 5-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]-2-fluorobenzenesulfonyl chloride (2.10 g) was added, followed by stirring for 20 minutes. Then, this was subjected to liquid-liquid separation with water and ethyl acetate added thereto, the organic layer was washed with saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=50/1) to obtain (2R)-N-({5-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxypropanimidamide (1.95 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.[CH3:20][NH:21][CH3:22].O.Cl>O1CCCC1.C(O)C>[CH3:20][N:21]([CH3:22])[CH2:2][CH2:3][CH:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2
Reactant: CNC
Reactant: ClCCC=C1c2ccccc2COc2ccccc21
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCC=C1c2ccccc2COc2ccccc21
Yield: 73.4 %

Procedure:
5.4 g (0.02 mol) of the 11-(3-chloropropylidene)-6,11-dihydrodibenzo-[b,e]-oxepine, prepared according to (c) above, in 20 mL tetrahydrofuran and 5.5 g (0.12 mol) dimethylamine in 20 mL ethanol is heated together for 3 hours using a glass autoclave and a temperature of 95-100° C. (boiling water bath). Water and 6 N hydrochloric acid are added to the contents of the autoclave and the mixture is extracted with ether. The separated, aqueous-acid components are then made alkaline with dilute caustic soda solution, and the oil thereby separated is taken up in ether. The ether residue, after distillation in a high vacuum, produces 4.1 g (73.5% of theory) of 11-(3-dimethylamino-propylidene)-6,11-dihydrodibenzo-[b,e]-oxepine, having a B.P.0.1 147-150° C. The melting point of the hydrochloride is 182-184° C. (recrystallized from isopropanol).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH3:25][C:26]1[C:31]([SH:32])=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:5]2[N:6]([C:8]3[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=3)[CH:7]=[C:3]([CH2:2][S:32][C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:25])[N:4]=2)=[CH:19][CH:20]=1
Reactant: Cc1ccccc1S
Reactant: CS(=O)(=O)c1ccc(-n2cc(CCl)nc2-c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1SCc1cn(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloromethyl-2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (Example 159, Step 1) (250 mg, 0.656 mmol) and o-thiocresol (163 mg, 1.31 mmol) in 5 ml of dry dimethylformamide was added anhydrous potassium carbonate (226 mg, 1.64 mmol). The mixture was stirred rapidly overnight at room temperature. The mixture was then partitioned between ethyl acetate and water. The aqueous layer was further extracted with ethyl acetate, the combined organic extracts washed with brine, and dried over sodium sulfate. The solution was filtered and concentrated. Chromatography of the residue over silica gel using 40% ethyl acetate in hexane gave the title compound as a very pale yellow solid (210 mg): mp (DSC) 51° C. Anal. Calc'd. for C24H21ClN2O2S2 (MW 469.03): C, 61.46; H, 4.51; N, 5.97. Found: C, 61.16; H, 4.50; N, 5.86.