Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C@H:16]([C:20]([S:23][CH2:24][CH2:25][CH2:26][OH:27])([CH3:22])[CH3:21])[C:17]([OH:19])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[C:28](Br)([CH3:31])([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C@H:16]([C:20]([S:23][CH2:24][CH2:25][CH2:26][OH:27])([CH3:21])[CH3:22])[C:17]([O:19][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)(C)SCCCO)cc1
Reactant: CC(C)(C)Br
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Product: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)OC(C)(C)C)C(C)(C)SCCCO)cc1
Temperature: 55 °C
Yield: 52.8 %

Procedure:
To a solution of (2S)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-3-[(3-hydroxypropyl)sulfanyl]-3-methylbutanoic acid from Example 171, (1 g, 2.41 mmol) in dimethylacetamide (6 mL) was added t-butyl bromide (4.16 mL, 36.2 mmol), potassium carbonate (2.66 g, 19.28 mmol), and benzyltriethylammonium chloride (82 mg, 0.36 mmol) and the resulting mixture was heated at 55° C. for 15 h. The solvent was removed and the residue was partitioned with ethylacetate and water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was removed to obtain 600 mg (56%) of tert-butyl (2S)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-3-[(3-hydroxypropyl)sulfanyl]-3-methylbutanoate; 1H NMR (300 MHz, CDCl3) □ 1.22 (s, 9H), 1.35 (s, 3H), 1.39 (s, 3H), 1.76 (m, 2H), 1.80 (m, 3H), 2.41 (m, 1H), 2.68 (m, 2H), 3.71 (m, 3H), 4.69 (m, 2H), 5.74 (d, 1H, J=9.9 Hz), 7.03 (d, 2H, J=7.2 Hz), 7.79 (d, 2H, J=7.2 Hz); HRMS(C22H33NO6S2)(M+Na); cald. 494.1641, found 494.1644.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]=[C:8]([NH:10][N:11]=[C:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=1.[CH3:25]I>CN(C=O)C>[Br:3][C:4]1[N:9]=[C:8]([N:10]([CH3:25])[N:11]=[C:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=NNc2cccc(Br)n2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(N=C1CCN(C(=O)OC(C)(C)C)CC1)c1cccc(Br)n1
Reaction time: 0.33 h
Yield: 99.1 %

Procedure:
Sodium hydride (60% dispersion in oil, 0.72 g, 18 mmol) was added to a solution of tert-butyl 4-(2-(6-bromopyridin-2-yl)hydrazono)piperidine-1-carboxylate (5.5 g, 15 mmol) in DMF (50 mL) at room temperature under N2, and the resulting solution was stirred for 20 min. Methyl iodide (1.0 mL, 17 mmol) was added to the solution, and the resulting solution was stirred for 2 h at ambient temperature. The mixture was quenched with H2O (100 mL) and extracted with EtOAc (4×50 mL). The combined organic extracts were concentrated to an orange oil under reduced pressure. The oil was diluted with EtOAc (100 mL) and washed with brine (7×50 mL). The organics were dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure to provide the title compound (5.7 g, 99%) as an orange oil: 1H NMR (300 MHz, DMSO-d6) δ 7.45 (dd, J=8.1, 7.5 Hz, 1H), 6.91 (d, J=7.5 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 3.56 (t, J=6.0 Hz, 2H), 3.44 (t, J=6.0 Hz, 2H), 3.09 (s, 3H), 2.53-2.46 (m, 4H, overlap with solvent), 1.42 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[CH2:7][OH:8].[C:9](Cl)(=[O:11])[CH3:10].C(N(CC)CC)C.[Cl-].[Na+]>O1CCCC1>[C:9]([O:8][CH2:7][C:6]1[S:5][N:4]=[N:3][C:2]=1[CH3:1])(=[O:11])[CH3:10]
Reactant: Cc1nnsc1CO
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCc1snnc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 107 %

Procedure:
In 10 ml of tetrahydrofuran were dissolved 0.50 g (3.8 mmol) of 4-methyl-1,2,3-thiadiazol-5--ylmethanol, 0.50 g (5.7 numol) of acetyl chloride and 0.80 g (7.6 mmol) of triethylamine. The solution thus obtained was stirred at room temperature for 18 hours. Then, a saturated aqueous solution of sodium chloride was added to the reaction mixture to stop the reaction, the objective product was extracted with ethyl acetate, the organic layer was washed with water and dried, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using 3:1 mixture of n-hexane and ethyl acetate. Thus, 0.70 g of the objective compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[O:9][C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11](O)=[O:12])=[CH:4][CH:3]=1.Cl.[NH2:26][CH2:27][C:28]#[N:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[O:9][C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([NH:29][CH2:28][C:27]#[N:26])=[O:12])=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](OC(c1ccc(F)cc1)c1ccc(Br)cc1)C(=O)O
Reactant: N#CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)C[C@H](OC(c1ccc(F)cc1)c1ccc(Br)cc1)C(=O)NCC#N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (2S)-2-[(4-bromophenyl)(4-fluorophenyl)methoxy]-4-methylpentanoic acid of step 4 (0.35 mmol, 151 mg) in DMF (3 mL) was added aminoacetonitrile hydrochloride (0.38 mmol) and HATU (0.38 mmol, 145 mg). Diisopropylethylamine (0.96 mmol, 123 mg) was added last, the mixture was stirred at r.t. for 3 days. Ether was added, followed by 1 N HCl. The mixture was separated after agitation. The organic extract was washed with 0.1 N HCl, water and brine and dried over anhyd. MgSO4. Concentration of the organic extracts followed by chromatography gave the title amide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=O)[CH2:11][C:12]1[NH:13][C:14](=[O:24])[CH:15]=[C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:17]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]=[C:10]([CH2:11][C:12]3[NH:13][C:14](=[O:24])[CH:15]=[C:16]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[N:17]=3)[O:1][C:2]=2[CH:7]=1
Reactant: Cc1ccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1ccc2nc(Cc3nc(N4CCOCC4)cc(=O)[nH]3)oc2c1

Procedure:
The product is prepared according to the procedure described in Example 2, using 390 mg of N-(2-hydroxy-4-methylphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide and 108 mg of 4-methylbenzenesulphonic acid hydrate, and replacing the toluene with xylene. After recrystallization from 20 ml of ethanol and 5 ml of methanol, 105 mg of 2-[(6-methyl-1,3-benzoxazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:33])[CH:25](Cl)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][CH2:19]1>CN(C=O)C>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:33])[CH:25]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][CH2:19]1
Reactant: COc1ccccc1N1CCN(C(=O)C(Cl)c2ccccc2)CC1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(C(=O)C(Oc2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride 80% dispersion in oil (1.7 g) was added to dry DMF (100 ml) under argon. Phenol (3.76 g; 0.04 m) was added over 20 mins and the resulting grey mixture was stirred a further 20 mins and cooled to 0° C. A solution of 1-(2-methoxyphenyl)-4-(1-oxo-2-chloro-2-phenylethyl)piperazine (13.8 g; 0.04 m) in dry DMF (60 ml) was added over 20 mins. The mixture was heated to 60° C. over a period of about 3 hrs and then maintained at 60° C. for 21/2 hrs and then stirred at ambient temperature overnight. The mix was cooled to 0° C., treated with 10 ml crushed ice and the DMF was vacuumed off. The residue, in methylene chloride, was washed well with water and dried over magnesium sulphate. The oil resulting on evaporation, solidified on standing for a few days to give 1-(2-methoxyphenyl)-4 -(1-oxo-2-phenoxy-2-phenylethyl)piperazine.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1)=[CH2:2].C12BC(CCC1)CCC2.C1C[O:24]CC1>>[S:8]1[CH:9]=[CH:10][C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH2:2][OH:24])=[CH:11][C:7]1=2
Reactant: C=Cc1ccc2ccsc2c1
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Product: OCCc1ccc2ccsc2c1
Temperature: 60 °C
Yield: 99 %

Procedure:
A solution of 6-vinylbenzo[b]thiophene (2.124 g, 13.3 mmol) in 80 mL THF was added to a solution of 9-borabicyclo[3.3.1]nonane (9-BBN) (5.21 g, 21.3 mmol) in 80 mL THF, rinsing with 5 mL THF. The solution was heated at 60° C. for 2.5 h and then a solution of H2O2 (36 mL, 35%)/NaOH (36 mL. 0.5 M)/H2O (9 mL) was added slowly. The reaction was then heated to 85° C. for 1 h, cooled to room temperature and 50 mL H2O was added. The mixture was extracted with ethyl acetate (3×50 mL), the combined organic solution was washed with brine and then was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (ethyl acetate/hexanes) gave the title compound (2.338 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]2[CH2:13][CH:12]3[NH:14][CH:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:4][CH:3]=1.C[Si](C)(C)CCOC[N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[CH:32]=O.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:13][CH:12]3[N:14]([CH2:32][C:24]4[NH:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[N:23]=4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(CC2CC3CCC(C2)N3)cc1
Reactant: C[Si](C)(C)CCOCn1c(C=O)nc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: Clc1ccc(CC2CC3CCC(C2)N3Cc2nc3ccccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 113.3 %

Procedure:
A mixture of 0.5 g of 3-(4-chloro-benzyl)-8-aza-bicyclo[3.2.1]octane, 0.5 g of 1-(2-trimethylsilylethoxymethyl)-1H-benzimidazole-2-carbaldehyde, 5 mL of 1,2-dichloroethane and 0.5 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was diluted with 50 mL chloroform and 10 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×25 mL of chloroform and the combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The crude SEM ether was heated to reflux in 50 mL of ethanol containing 5 mL of 3N HCl for 2 h, cooled, concentrated and partitioned between 10 ml of saturated aqueous Na2CO3 and 3×25 mL of chloroform. The chloroform extracts were dried over MgSO4 and concentrated. Purification by chromatography eluting with 90:10 CHCl3:MeOH gave 0.75 g of 2-[3-(4-chloro-benzyl)-8-aza-bicyclo[3.2.1]oct-8-ylmethyl]-1H-benzimidazole as a 2:1 mixture of exo:endo isomers. Chromatography on a Chiralpak™ AS column eluting with a 90:10 mixture of hexane with 0.10% diethylamine and isopropanol gave 0.25 g of endo 2-[3-(4-chloro-benzyl)-8-aza-bicyclo[3.2.1]oct-8-ylmethyl]-1H-benzimidazole: RT=5.34 min; MS (m+1)=366; 1H NMR (400 MHz, CDCl3 3.8 (s, 2H), 3.2 (s, 2H), 2.75 (d, 2H), 2.05 (m, 2H), 1.8 (d, 2H).
Reaction SMILES: [Cl:1][C:2]([F:15])([F:14])[C:3](=[O:13])[CH2:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].[CH:16]([O-])([O-])[O:17][CH2:18][CH3:19].C(OC(=O)C)(=O)C>>[Cl:1][C:2]([F:14])([F:15])[C:3](=[O:13])[C:4](=[CH:16][O:17][CH2:18][CH3:19])[C:5]([CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:6]
Reactant: O=C(CC(=O)C(F)(F)Cl)C1CCCCC1
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)C1CCCCC1)C(=O)C(F)(F)Cl
Yield: 96.2 %

Procedure:
A mixture of 235.9 g of 1-chloro-4-cyclohexyl-1,1-difluoro-2,4-butanedione, 266.4 g of ethyl orthoformate and 367.2 g of acetic anhydride was refluxed under heating for 12 hours. The solvent was distilled off under reduced pressure to obtain 280.3 g of the desired product (crude product), which was directly used for the next reaction. A part of the crude product was further purified for measurement of the refractive index. nD20.6 1.4787
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:24](Br)[CH:25]=[CH2:26]>C1COCC1>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([NH:6][C:7](=[O:12])[C:8]([CH3:9])([CH3:11])[CH3:10])[CH2:26][CH:25]=[CH2:24])[CH3:2]
Reactant: C=CCBr
Reactant: CCOC(=O)CNC(=O)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(NC(=O)C(C)(C)C)C(=O)OCC

Procedure:
13.06 g of the above prepared (2,2-dimethyl-propionylamino)-acetic acid ethyl ester (69.75 mmol) was dissolved in 350 ml of abs. THF and cooled down to −78°. 146 ml of 1M lithium hexamethyldisilazide in THF (2.1 eq.) were slowly added via dropping funnel. After keeping the yellow suspension for 30 Min. at −78°, 6.491 ml of allyl bromide (1.1 eq.) was added and stirring continued for 15 Min. at the same temperature and for 40 Min. at 0°. Pouring of the homogeneous reaction mixture onto crashed ice/HCl, twofold extraction with AcOEt, twofold washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=8/2) afforded 10.50 g of the title compound as colorless solid. In addition, 2.70 g of the di-allylated product (2-allyl-2-(2,2-dimethyl-propionylamino)-pent-4-enoic acid ethyl ester) was obtained from the less polar fractions.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:7][N:8]2[CH2:11][C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([OH:31])=[O:30]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]3[CH2:18][CH2:19][N:20]([CH2:24][CH2:25][O:26][C:27]4[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=4[C:29]([OH:31])=[O:30])[CH2:21][CH2:22]3)=[CH:7][N:8]2[CH2:11][C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)cn(Cc3cccs3)c2c1
Reactant: O=C(O)c1ccccc1OCCCl
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(Cc3cccs3)c3cc(F)ccc23)CC1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 0.1 g (0.33 mmol) of 6-fluoro-3-piperidin-4-yl-1-thiophen-2-ylmethyl-1H-indole (example 82, part B) and 0.092 g (0.42 mmol) 2-(2-chloro-ethoxy)-benzoic acid acid methyl ester. The crude mixture was purified by HPLC-MS using a C-18 column.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:20]=[C:21]([CH3:23])[CH:22]=2)[O:15][CH2:16][CH2:17][CH2:18][OH:19])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:20]=[C:21]([CH3:23])[CH:22]=2)[O:15][CH2:16][CH2:17][CH:18]=[O:19])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc(F)c2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2cccc(F)c2)c1
Temperature: 0 °C
Reaction time: 2.75 h
Yield: 56 %

Procedure:
A solution of 3-[3-(3-fluorophenylsulfonyloxy)-5-methylphenoxy]-propanol (840 mg, 2.5 mmol, as prepared in the preceding step), N,N-diisopropylethylamine (0.90 mL, 25.2 mmol), anhydrous dimethyl sulfoxide (0.52 mL, 27.4 mmol), and anhydrous dichloromethane (25.9 mL) was cooled to 0° C. under nitrogen. Sulfur trioxide pyridine complex (830 mg, 5.2 mmol) was added in portions over 13 minutes. The solution was stirred at 0° C. for 2.75 hours, then the reaction was quenched with 10% aqueous citric acid (60 mL). Diethyl ether (60 mL) was added, and the mixture was extracted. The aqueous layer was extracted with diethyl ether (30 mL), and the combined organic layers were washed with 5% aqueous citric acid (100 mL). The aqueous layer was extracted with diethyl ether (30 mL), and the combined organic layers were washed with pH 7 buffer (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to an oil. The crude product was purified by flash column chromatography through silica gel (40% diethyl ether in hexane) to give the title compound as a pale yellow oil (468 mg, 56%). 1H-NMR (300 MHz, CDCl3) δ 9.84 (t, 1H, J=1.4 Hz), 7.51-7.68 (m, 3H), 7.35-7.42 (m, 1H), 6.63 (br s, 1H), 6.44 (br s, 1H), 6.37 (br t, 1H, J=2.2 Hz), 4.20 (t, 2H, J=6.1 Hz), 2.87 (td, 2H, J=1.4, 6.1 Hz), 2.26 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C16H15FO5S: 361.1 (M+Na). Found: 361.3.
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][C:8]3[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH2:3]1.[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:20][C:21]1[N:22]=[C:23]([C:28]([NH:1][CH:2]2[CH2:5][N:4]([C:6]3[S:7][C:8]4[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=[CH:11][C:9]=4[N:10]=3)[CH2:3]2)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27]
Reactant: CCOC(=O)c1cccc2nc(N3CC(N)C3)sc12
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCOC(=O)c1cccc2nc(N3CC(NC(=O)c4nc(Cl)c(CC)[nH]4)C3)sc12
Yield: 85.4 %

Procedure:
The same operation as in Example (217c) was performed using ethyl 2-(3-aminoazetidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained in Example (224b) (273 mg, 0.98 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (166 mg, 0.95 mmol), WSC hydrochloride (547 mg, 2.85 mmol), 1-hydroxybenzotriazole (128 mg, 0.95 mmol) and N-methylmorpholine (0.21 mL, 1.90 mmol), to obtain 352 mg of the title compound as a pale yellow solid (85%).
Reaction SMILES: [NH2:1]OS(O)(=O)=O.[CH:7]([CH:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1)([CH3:9])[CH3:8].[OH-].[Na+]>C(O)=O>[CH:7]([CH:10]1[CH2:15][CH2:14][NH:1][C:13](=[O:16])[CH2:12][CH2:11]1)([CH3:9])[CH3:8]
Reactant: NOS(=O)(=O)O
Reactant: CC(C)C1CCC(=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CC(C)C1CCNC(=O)CC1
Temperature: 25 °C

Procedure:
To a solution of hydroxylamine-O-sulfonic acid (60.5 g, 535 mmol) in formic acid (320 ml) was added dropwise a solution of 4-isopropyl cyclohexanone (50.0 g, 357 mmol) in formic acid (110 ml) at r.t. under an argon atmosphere. The reaction mixture was refluxed for 3 h, cooled to r.t. and slowly treated with ice-water (550 ml). 10 N NaOH (1.1 liter) was added to adjust the pH to 8 and the resultant mixture was extracted with CHCl3 (4×). The combined organic extracts were washed with water, brine, dried (MgSO4), filtered and concentrated under reduced pressure. The light-brown solid was crystallized from n-heptane: 42.4 g (75%);
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1.C([O-])(=O)C.[Na+]>CN(C=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(Br)cc1
Reactant: C1=CCCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(C2=CCCCC2)cc1
Temperature: 140 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
2 ml of the stock solution described in Example 23 are added to 18 ml of DMF. 9.26 g (50 mmols) of 4-bromobenzaldehyde, 5.58 ml (55 mmols) of cyclohexene and 4.52 g (55 mmols) of anhydrous sodium acetate are then added and the reaction mixture is stirred for 8 hours at 140° C. in a pressure tube. After working up as described in Example 1, the crude product is distilled in vacuo. 2.05 g (11.0 mmols) of 4-formylphenylcyclohexene are obtained in the form of a yellow liquid of boiling point 140°-150° C./2400 Pa; yield 22% of theory (conversion figure 2200; Pd content 0.01 mol %). The product is a mixture of isomers.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[CH:11][C:12]([Cl:21])=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[C:7]=2[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:21][C:12]1[CH:11]=[CH:10][C:8]2[CH2:9][CH:5]([CH2:4][NH2:1])[O:6][C:7]=2[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]
Reactant: Cc1ccccc1-c1c(Cl)ccc2c1OC(CN=[N+]=[N-])C2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccccc1-c1c(Cl)ccc2c1OC(CN)C2
Yield: 21.9 %

Procedure:
Treatment of 1-bromo-2-methylbenzene (5.0 g, 26.88 mmol) with (2-chloro-6-methyoxyphenyl)boronic acid (13.8 g, 80.6 mol) generally according to the procedure described for Intermediate 37 afforded 3.85 g (62%) of 6-chloro-2′-methylbiphenyl-2-yl methyl ether. Treatment of 6-chloro-2′-methylbiphenyl-2-yl methyl ether with hydrogen bromide (100 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 395 afforded brown oil. The oil was reacted with sodium hydride (0.61 g, 25.38 mmol) and allyl bromide (3.07 g, 25.38 mmol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-6-chloro-2′-methylbiphenyl-2-ol. Treatment of 3-allyl-6-chloro-2′-methylbiphenyl-2-ol (4.38 g, 16.92 mmol) with m-chloroperoxybenzoic acid (4.38 g, 25.38 mmol, 77%) and potassium carbonate (2.81 g, 20.30 mmol) generally according to the procedure described for Intermediate 9 afforded 2.4 g (52%) of (±)-[7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment (±)-[7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol (2.4 g, 8.73 mmol) with p-toluenesulfonyl chloride (2.50 g, 13.1 mmol) generally according to the procedure described for Intermediate 10 gave 3.2 g (85%) of (±)-[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.21 g, 0.49 mmol) with sodium azide (0.35 g, 5.38 mmol) generally according to the procedure described for Intermediate 98 afforded 0.14 g, (99%) of (±)-2-(azidomethyl)-7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran (0.14 g, 0.468 mmol) in tetrahydrofuran (10 m]L) with polymer-supported triphenylphosphine (0.24 g, 0.936 mmol) generally according to the procedure described for Example 154 provided 0.028 g (18%) of (±)-{[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 204-206° C.