Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[S:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH3:18]>CO>[NH2:18][C:14]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:12][CH:11]=1)=[S:15]
Reactant: N
Reactant: S=C=Nc1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: CO
Product: NC(=S)Nc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
Unless otherwise indicated, all thioureas, isothiocyanates, thioamides and amines were purchased from Maybridge Chemical Co. Ltd.(Cornwall, U.K.), Transworld Chemical Co. (Rockville, Md.), or Aldrich Chemical Co., (Milwaukee, Wis.). (a) 4-Amino-4′-chlorodiphenylether (TCI America, Portland Oreg., 520 mg, 2.03 mmol) was slurried in 10 mL of ether and treated with ca. 1 mL of ether saturated with HCl gas. After 5 min. the solvent was removed in vacuo. To a stirring biphasic solution amine-HCl salt in 20 mL CHCl3-sat'd NaHCO3 (1:1, v/v) at ambient temperature was added thiophosgene (1.2 equiv, 2.4 mmol) in 5 mL of CHCl3 dropwise via an addition funnel. The reaction was vigorously stirred for 1 h (TLC, 50% ethyl acetate-hexanes indicates clean conversion to a higher Rf spot), at which time the layers were separated, the aqueous layer extracted with CHCl3 (1×20 mL), and the combined organic layers washed with brine (1×20 mL) and dried (Na2SO4). Concentration of the solvent in vacuo yielded the crude 4-(4-chlorophenoxy)-phenylisothiocyanate (414 mg). (b) The 4-(4-chlorophenoxy)-phenylisothiocyanate was transferred to an Ace Glass pressure tube equipped with a Teflon coated stir bar and treated with a 2.0 M solution of NH3 in 5 ml methanol (Aldrich Chemical Co., Milwaukee, Wis.)). The tube was sealed and immersed in a 80° C. oil bath. After 2 h, the reaction was cooled to 0° C. in an ice bath. The precipitates were filtered and dried under vacuum to yield amino{[4-(4-chlorophenoxy)phenyl]amino}methane-1-thione (328 mg, 79%). 1H NMR (DMSO-d6, 300 MHz) 7.02 (m, 4H), 7.41 (m, 4H), 9.65 (s, 1H); Mass Spectrum (ESI) m/z calcd. for C13H11ClN2OS, 278.8 (M+H), found 279.4.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][C:13]=1[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][N:23]1[C:32]2[NH:31][C:30]3[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=3[NH:28][CH2:27][C:26]=2[CH:25]=[N:24]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][C:6](=[O:7])[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([N:28]2[CH2:27][C:26]3[CH:25]=[N:24][N:23]([CH3:22])[C:32]=3[NH:31][C:30]3[CH:33]=[CH:34][CH:35]=[CH:36][C:29]2=3)=[O:18])=[CH:14][C:13]=1[CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Reactant: Cc1cc(C(=O)O)ccc1OCCCC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCC(=O)OC(C)(C)C
Yield: 18 %

Procedure:
WSCD (391 mg, 2.06 mmol) and DMAP (133 mg, 1.09 mmol) were added to a solution of 4-(3-tert-butoxycarbonyl-propoxy)-3-methyl-benzoic acid from Example E42 (275 mg, 0.94 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (191 mg, 0.95 mmol) in dichloromethane (30 ml) and triethylamine (0.28 ml, 2.01 mmol). The mixture was heated at reflux for 72 h, washed with 0.3M KHSO4, saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (80 mg, 18%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][CH2:14][CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[CH2:23][CH3:24].[CH:25]1([CH:31]=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:8]=[C:9]([N:13]([CH2:31][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:14][CH:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[CH2:23][CH3:24]
Reactant: CCc1cc(Oc2cccc(NCC(O)C(F)(F)F)c2)ccc1Cl
Reactant: O=CC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCc1cc(Oc2cccc(N(CC3CCCCC3)CC(O)C(F)(F)F)c2)ccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
The 3-[[3-(4-chloro-3-ethylphenoxy)phenyl]amino]-1,1,1-trifluoro-2-propanol product from EX-18C was dissolved in 12 mL of tetrahydrofuran. To this stirred solution was added cyclohexanecarboxaldehyde (0.032 g, 0.285 mmol), followed by sodium tri-acetoxyborohydride (0.079 g, 0.370 mmol and concentrated acetic acid (0.020 g, 0.325 mmol). The resulting mixture was stirred at room temperature for 18 h. Additional cyclohexanecarboxaldehyde (0.032 g, 0.285 mmol) was added and the mixture was allowed to stir at room temperature for another 18 h. The reaction was quenched with saturated sodium bicarbonate and extracted with methylene chloride. The organic layers were combined, dried over MgSO4 and concentrated to an orange/brown oil. The crude product was purified by flash column chromatography on silica gel eluting with 1:4 ethyl acetate in hexane to give 0.080 g (61%) of the desired 3-[[3-(4-chloro-3-ethylphenoxy)phenyl][3-cyclohexylmethyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow-orange oil (>95% pure by HPLC). HRMS calcd.: 456.1917 [M+H]+, found: 456.1942. 1H NMR (CDCl3) δ 0.82-1.01 (m, 2H), 1.22-1.27 (m, 3H), 1.73-1.76 (m, 5H), 2.74 (dd, 2H), 3.15 (dd, 2H), 3.23 (dd, 1H), 3.52 (m, 1H), 3.80 (dd, 1H), 4.28 (m, 1H), 6.34 (d, 2H), 6.42 (d, 1H), 6.83 (dd, 1H), 6.98 (d, 1H), 7.19 (t, 1H), 7.29 (d, 1H). 19F NMR (CDCl3) δ−79.06 (d, 3F).
Reaction SMILES: [Mg].[CH:2]1(Br)[CH2:4][CH2:3]1.[CH:6]([O:9][CH2:10][CH2:11][C:12](=[O:14])[CH3:13])([CH3:8])[CH3:7].[Cl-].[NH4+]>O1CCCC1>[CH:2]1([C:12]([OH:14])([CH2:11][CH2:10][O:9][CH:6]([CH3:8])[CH3:7])[CH3:13])[CH2:4][CH2:3]1
Reactant: BrC1CC1
Reactant: CC(=O)CCOC(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)OCCC(C)(O)C1CC1

Procedure:
To the Grignard reagent [production according to E. Renk et al. J. Am. Chem. Soc. 83, 1987 (1961)], from 9.06 g (0.37 mol) of magnesium and 42.8 g (0.35 mol) of cyclopropyl bromide in 460 cc of absolute tetrahydrofurane, is added dropwise at 5°C over the course of 10 minutes, in an atmosphere of nitrogen and while stirring, a solution of 46 g (0.35 mol) of 4-isopropoxy-2-butanone in 100 cc of absolute tetrahydrofurane. After stirring the reaction mixture at room temperature for 20 hours, saturated ammonium chloride solution and ice are added and the mixture is extracted with ether. The ether extract is washed with saturated salt solution, dried over sodium sulphate and the ether evaporated off. The resulting 2-cyclopropyl-4-isopropoxy-2-butanol is obtained after distillation at 75°-79°/12 mm as a colourless oil.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[F:23][C:24]1[CH:25]=[C:26]([O:30][CH2:31][CH2:32][CH2:33][Br:34])[CH:27]=[CH:28][CH:29]=1>CC#N>[Br-:34].[F:23][C:24]1[CH:25]=[C:26]([O:30][CH2:31][CH2:32][CH2:33][N+:1]23[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)([CH2:3][CH2:2]2)[CH2:7][CH2:8]3)[CH:27]=[CH:28][CH:29]=1
Reactant: Fc1cccc(OCCCBr)c1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCCOc3cccc(F)c3)(CC1)CC2
Product: [Br-]
Yield: 52.9 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0137 g, 0.0467 mmol) and 3-bromopropyl 3-fluorophenyl ether (0.0137 g, 0.0588 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0130 g, 53.1%). EI-MS m/z 446 (M+) Rt (2.03 min).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4]1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:20](O)[CH3:21]>>[OH:1][CH2:2][C:3]1([CH2:6][C:7]([O:9][CH2:20][CH3:21])=[O:8])[CH2:5][CH2:4]1
Reactant: CCO
Reactant: O=C(O)CC1(CO)CC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)CC1(CO)CC1

Procedure:
7.1 g of crude (13) product was dissolved in 150 ml of ethanol. 1 ml of concentrated sulfuric acid was added and the solution was stirred at reflux for 2 hours. 50 ml of saturated aqueous sodium bicarbonate was added to the cooled mixture and the mixture was extracted twice with 100 ml of dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was distilled at 100° C. at a reduced pressure affording a slightly yellow liquid (3.2 g).
Reaction SMILES: CS(OCCC[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][C:19]2[N:20]=[C:21](/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:22][CH:23]=2)[CH:10]=1)(=O)=O.[I-:32].[Na+].[CH3:34][C:35]([CH3:37])=O>O>[I:32][CH2:34][CH2:35][CH2:37][C:13]1[C:12]([O:15][CH3:16])=[C:11]([CH:10]=[CH:9][CH:14]=1)[O:17][CH2:18][C:19]1[N:20]=[C:21](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:22][CH:23]=1
Reactant: COc1ccc(CCCOS(C)(=O)=O)cc1OCc1coc(/C=C/c2ccccc2)n1
Reactant: [I-]
Reactant: CC(C)=O
Agent: [Na+]
Solvent: O
Product: COc1c(CCCI)cccc1OCc1coc(/C=C/c2ccccc2)n1
Yield: 95 %

Procedure:
A mixture of 3-[4-methoxy-3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate (900 mg), sodium iodide (3.00 g) and acetone (20 ml) was heated for one hour under reflux. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (1:4, v/v), 4-[3-(3-iodopropyl)-2-methoxyphenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole (905 mg, 95%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless needles, mp 103-104° C.
Reaction SMILES: C[Si]([N-:5][Si](C)(C)C)(C)C.[Li+].[F:11][CH:12]([F:36])[O:13][C:14]1[CH:15]=[C:16]([C:24]([C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)=O)[CH:17]=[CH:18][C:19]=1[O:20][CH:21]([F:23])[F:22].[CH2:37]1[CH2:41]OCC1>>[F:11][CH:12]([F:36])[O:13][C:14]1[CH:15]=[C:16]([C:24]([C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)=[CH:41][C:37]#[N:5])[CH:17]=[CH:18][C:19]=1[O:20][CH:21]([F:23])[F:22]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C1CCOC1
Reactant: COc1cc(OC)cc(C(=O)c2ccc(OC(F)F)c(OC(F)F)c2)c1
Agent: [Li+]
Product: COc1cc(OC)cc(C(=CC#N)c2ccc(OC(F)F)c(OC(F)F)c2)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Lithium bis-(trimethylsilyl)amide (1M, 3.0 mL) was added dropwise to a stirred solution of diethyl cyanomethylphosphate (0.5 g, 3.0 mmol) in THF (10 mL) at 5-8° C. The mixture was stirred at room temperature for 40 min. A solution of (3,4-bis-difluoromethoxy-phenyl)-(3,5-dimethoxy-phenyl)-methanone (0.9 g, 2.5 mmol) in THF (20 mL) was added and the mixture was stirred at room temperature for 17 h. The resulting mixture was poured into ice water (100 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with water (2×40 mL), brine (40 mL) and dried (MgSO4). Solvent was removed and the residue was purified by flash chromatography (Silica gel, Hexane:CH2Cl2 4:6) to afford a mixture of isomers of 3-(3,4-bis-difluoromethxoy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile (0.6 g, 59%) as a white solid: mp 60-62° C.; 1H NMR (CDCl3) δ 7.35-7.22 (m, 3H), 6.90-6.20 (m, 5H), 5.76 (5.70) (s, 1H), 3.77 (3.80) (s, 6H); 13C NMR (CDCl3) δ 160.98 (160.90), 160.65 (160.55), 143.60 (141.87), 139.92, 137.78 (137.06), 135.13, 127.99 (126.83), 123.70 (122.75), 121.84 (121.78), 117.25 (117.05), 115.68 (t, J=1047 Hz), 115.58 (t, J=1047 Hz), 106.80 (107.56), 102.51 (102.37), 96.29 (96.24); Anal Calcd for C19H15NO4F4: C, 75.44; H, 3.81; N, 3.53; F, 19.13. Found: C, 57.82; H, 3.61; N, 3.38; F, 19.39.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[C:8]([O:27][CH3:28])[CH:7]=1)#[N:4].C(O[CH2:33][CH3:34])(=O)C.Cl.O1CCOCC1.[NH2:42][NH2:43]>C1COCC1.C(O)C>[NH2:4][C:3]1[NH:43][N:42]=[C:33]([CH3:34])[C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16][CH2:15]2)=[C:8]([O:27][CH3:28])[CH:7]=1
Reactant: CCOC(C)=O
Reactant: NN
Reactant: COc1cc(CC#N)ccc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1cc(-c2c(C)n[nH]c2N)ccc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
To NaH (60 wt. % dispersion in oil; 0.42 g, 10.5 mmol) suspended in THF (20 mL) was added 1,1-dimethylethyl 4-({[4-(cyanomethyl)-2-(methyloxy)phenyl]oxy}methyl)piperidine-1-carboxylate (1.73 g, 4.81 mmol) and then anhydrous ethyl acetate (0.559 mL, 5.73 mmol). The mixture was stirred at 60° C. for 15 h. The mixture was cooled to room temperature, was acidified with 4 N HCl in dioxane (2 mL, 8 mmol) and was concentrated in vacuo. The residue was partitioned between 1 N hydrochloric acid and ethyl acetate. The organic portion was washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a red oil which was dissolved in ethanol (20 mL) and treated with hydrazine (0.185 mL, 5.84 mmol) at reflux for 1 h. The mixture was concentrated in vacuo and dried in vacuo to afford 1,1-dimethylethyl 4-({[4-(5-amino-3-methyl-1H-pyrazol-4-yl)-2-(methyloxy)phenyl]oxy}methyl)piperidine-1-carboxylate as a red foam (2.00 g, 4.81 mmol, 100% yield). MS (EI) for C22H32N4O4: 417 (MH+), 439 (MNa+).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH2:29][CH2:30][OH:31])[N:17]=2)[CH2:9]1.[OH:33][C:34]1([C:41]2[S:42][C:43]([CH3:46])=[CH:44][N:45]=2)[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1>>[OH:31][CH2:30][CH2:29][N:18]1[C:19]2[C:24](=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[C:16]([NH:15][CH2:14][C:13]([NH:12][CH:10]2[CH2:11][N:8]([CH:37]3[CH2:36][CH2:35][C:34]([OH:33])([C:41]4[S:42][C:43]([CH3:46])=[CH:44][N:45]=4)[CH2:39][CH2:38]3)[CH2:9]2)=[O:32])=[N:17]1
Reactant: Cc1cnc(C2(O)CCC(=O)CC2)s1
Reactant: O=C(CNc1nn(CCO)c2ccc(C(F)(F)F)cc12)NC1CNC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(C2(O)CCC(N3CC(NC(=O)CNc4nn(CCO)c5ccc(C(F)(F)F)cc45)C3)CC2)s1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-[1-(2-hydroxy-ethyl)-5-trifluoromethyl-1H-indazol-3-ylamino]-acetamide TFA salt (as prepared in Example 74, Step A) and 4-hydroxy-4-(5-methyl-thiazol-2-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[CH:11]=[C:12]([NH:15][C:16](OCC3C=CC([N+]([O-])=O)=CC=3)=[O:17])[CH:13]=[CH:14][C:3]1=2.[CH2:30]([NH:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)[CH3:31].C(N(CC)CC)C>CCOC(C)=O.CN(C)C1C=CN=CC=1>[O:29]=[S:2]1(=[O:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[CH:11]=[C:12]([NH:15][C:16]([N:32]([CH2:33][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[CH2:30][CH3:31])=[O:17])[CH:13]=[CH:14][C:3]1=2
Reactant: O=C(Nc1ccc2c(c1)-c1ccccc1S2(=O)=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCNCc1ccncc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCN(Cc1ccncc1)C(=O)Nc1ccc2c(c1)-c1ccccc1S2(=O)=O
Reaction time: 18 h

Procedure:
5,5-Dioxo-2-(4-nitrobenzoxycarbonylamino)dibenzothiophene (Example 24; 0.396 g, 1 mmol) was dissolved in EtOAc (10 ml) and treated with 4-(ethylaminomethyl)pyridine (0.150 g, 1.1 mmol), triethylamine (0.202 g, 2 mmol) and 4-(dimethylamino)pyridine (0.006 mg, 0.05 mmol). The reaction was stirred for 18 hours and the suspended solids collected, washed with 1 M aq. NaOH solution, water and then ether to leave the product as a colourless solid. NMR: 9.00 (s, 1H), 8.54 (m, 2H), 8.27 (s, 1H), 7.93 (m, 2H), 7.81 (m, 1H), 7.75 (m, 2H), 7.65 (m, 1H), 7.28 (m, 2H), 4.63 (s, 2H), 3.43 (q, 2H), 1.12 (t, 3H); m/z 394.42
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][NH:20][C:19](=[O:23])[CH:18]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].[H-].[Na+].Br[CH2:31][CH3:32]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][N:20]([CH2:31][CH3:32])[C:19](=[O:23])[CH:18]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:24]([F:27])([F:25])[F:26]
Reactant: CCBr
Reactant: O=c1cc(OCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)cc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc(OCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)cc1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.5 %

Procedure:
To a solution of 4-{[(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]oxy}-2(1H)-pyridinone (80 mg, 0.202 mmol) in N,N-dimethylformamide (1 mL) was added Sodium hydride (80 mg, 2.00 mmol). After stirring at rt for 10 min, bromoethane (100 μL, 1.34 mmol) was added. The reaction mixture was warmed to 80° C. and stirred for 1 h, then cooled to rt, quenched by addition of methanol, concentrated. Purification via Biotage-Qs system afforded the title product (59.5 mg) as a white solid. LC-MS (ESI): m/z 424 [M+H]+; 3.76 min (ret time).
Reaction SMILES: [Cr]([O-])(OCl)(=O)=O.[NH+]1C=CC=CC=1.[OH:13][CH:14]1[CH2:17][CH:16]([S:18]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:20])=[O:19])[CH2:15]1.C(OCC)(=O)C>C(Cl)Cl.CCCCCC>[O:13]=[C:14]1[CH2:17][CH:16]([S:18]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:20])=[O:19])[CH2:15]1
Reactant: CCCCOS(=O)(=O)C1CC(O)C1
Agent: O=[Cr](=O)([O-])OCl
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCOS(=O)(=O)C1CC(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
Pyridinium chloro chromate (10.3 g, 48.07 mmol) was added to a cooled solution of butyl 3-hydroxycyclobutane-1-sulfonate (5 g, 24.03 mmol) in dry DCM (50 mL) at 0° C. The resulting reaction mixture was stirred at room temperature overnight. The reaction was monitored by TLC (40% ethyl acetate in hexane). The reaction mixture was diluted with DCM, filtered and the filtrate was concentrated to afford the crude product. Purification by column chromatography on silica gel (15% ethyl acetate in hexane) afforded 2.8 g of the product (58% yield).
Reaction SMILES: [CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2/[C:17](=[N:19]/[OH:20])/[NH2:18])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:21]([O:28][C:29]([NH:31][C@@H:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:33](O)=[O:34])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[NH2:18]/[C:17](=[N:19]\[O:20][C:33](=[O:34])[C@@H:32]([NH:31][C:29](=[O:30])[O:28][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)/[C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][N:11]1[S:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)(=[O:9])=[O:10]
Reactant: N/C(=N\O)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1
Reactant: O=C(N[C@H](C(=O)O)c1ccccc1)OCc1ccccc1
Product: N/C(=N\OC(=O)[C@@H](NC(=O)OCc1ccccc1)c1ccccc1)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1

Procedure:
The title compound was prepared by a similar method to Preparation 5 from (Z)-(2S)-1-[cyclohexylmethylsulfonyl]-N′2-hydroxy-2-piperidinecarboximidamide [see Preparation 28] and (2S)-2-{[(benzyloxy)carbonyl]amino}-2-phenylethanoic acid to afford benzyl N-[(1S)-2-{[((Z)-amino{(2S)-1-[(cyclohexylmethyl)sulfonyl]piperidyl}methylidene)amino]oxy}-2-oxo-1-phenylethyl]carbamate as an oil.
Reaction SMILES: [CH:1]([OH:3])=O.OO.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2C[CH2:16][CH2:15][CH:14]=2)=[CH:9][CH:8]=1>>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:14][CH2:15][CH2:16][C:1]2=[O:3])=[CH:9][CH:8]=1
Reactant: O=CO
Reactant: Clc1ccc(C2=CCCC2)cc1
Agent: OO
Product: O=C1CCCC1c1ccc(Cl)cc1
Temperature: 40 °C
Yield: 34.9 %

Procedure:
A mixture of formic acid (60 mL, 84 mmol) and hydrogen peroxide (15 mL, 84 mmol) was warmed at 40° C. for 10 min. The resulting solution was carefully added to 1-chloro-4-cyclopentenylbenzene (15 g, 84 mmol) under stirring. The two-phase system was initially stirred at room temperature. After a certain period of time, a spontaneous exothermic reaction took place, and the temperature rose to about 50° C. The reaction mixture was stirred at room temperature for 1 h. The LC/MS analysis of the reaction mixture shows the disappearance of the starting material and the formation of the product. The reaction mixture was quenched by careful addition of a saturated sodium bicarbonate solution. Ether was added and the reaction mixture was vigorously shaken. The organic layer was separated and the aqueous layer was extracted with ether. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 2-(4-chlorophenyl)cyclopentanone (5.7 g, 29.3 mmol, 34.9% yield) as a colorless oil. LC-MS (M+H)+=195.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.21-7.37 (2H, m), 7.11 (2H, d, J=8.5 Hz), 3.25 (1H, dd, J=11.6, 8.5 Hz), 2.44 (2H, d, J=6.1 Hz), 2.15-2.31 (1H, m), 1.96-2.15 (3H, m), 1.78-1.95 (1H, m).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]2[N:12]=[N:13][N:14]=[C:10]2[C:9]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[N:8][CH:7]=1.C1COCC1.[ClH:33]>CO.C(Cl)Cl>[ClH:33].[N:15]1([C:9]2[C:10]3[N:11]([N:12]=[N:13][N:14]=3)[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[CH:7][N:8]=2)[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cccs3)n3nnnc23)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: c1csc(-c2cnc(N3CCNCC3)c3nnnn23)c1
Yield: 79 %

Procedure:
A 1 L round bottom flask was charged with tert-butyl 4-(5-(thiophen-2-yl)tetrazolo[1,5-a]pyrazin-8-yl)piperazine-1-carboxylate (210 g, 0.54 mol) and THF (400 mL). To this solution was added concentrated HCl (40 mL) dropwise in an ice-water bath. The resulting solution was stirred at reflux for 0.5 h. Reaction progress was monitored by TLC (MeOH/CH2Cl2=1:10). Work-up: the resulting crystalline solid was collected by filtration, washed with EtOH (200 mL), and dried to afford 139 g (79%) of the product as a yellow solid. MS m/z: 288 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][CH2:25][C:24]1[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][CH:23]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: NCc1ccc(Cl)cc1
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1ccc(Cl)cc1
Yield: 85 %

Procedure:
The compound prepared in Example 3 was reacted with 4-chloro-benzylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 85%).