Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]=[C:8]([C:11]3[N:12]4[CH2:19][CH2:18][N:17]=[C:13]4[S:14][C:15]=3Br)[CH:9]=[CH:10][C:3]1=2.C([Mg]Cl)C.[CH3:24][S:25]SC>O1CCCC1>[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]=[C:8]([C:11]3[N:12]4[CH2:19][CH2:18][N:17]=[C:13]4[S:14][C:15]=3[S:25][CH3:24])[CH:9]=[CH:10][C:3]1=2
Reactant: BrC1=C(c2ccc3sccc3c2)N2CCN=C2S1
Reactant: CSSC
Agent: Br
Agent: CC[Mg]Cl
Solvent: C1CCOC1
Product: CSC1=C(c2ccc3sccc3c2)N2CCN=C2S1
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
3-(Benzo[b]thiophen-5-yl)-2-bromo-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide (0.4 g; prepared as described in Example 28) was added in portions under nitrogen at 0-5° C. over 8 minutes to a stirred solution of ethylmagnesium chloride (2M solution in ether; 1.4 ml) in tetrahydrofuran (10 ml), then the mixture was stirred at 0° C. for 20 minutes and at ambient temperature for 1.25 hours. Dimethyl disulphide (0.14 ml) was added at 0-5° C., the mixture was stirred at this temperature for 10 minutes and at ambient temperature for 4.5 hours, then it was quenched by the addition of saturated aqueous ammonium chloride solution (10 ml) and water (20 ml). The product was extracted into ethyl acetate (30 ml+2×25 ml), the combined extracts were washed with water (2×25 ml) and saturated aqueous sodium chloride solution (25 ml), then they were dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using a 9:1 mixture of ethyl acetate and methanol as eluant. Appropriate fractions were combined and the solvents were removed in vacuo to give 3-(benzo[b]thiophen-5-yl)-2-(methylthio)-5,6-dihydroimidazo[2,1-b]thiazole (2 mg) as a yellow solid, 1H-nmr (DMSO-d6): δH 2.25 (3H, s, —SCH3), 3.68-4.19 (4H, m, —CH2CH2—), 7.36 (1H, d, J 1.7 Hz, ArH), 7.39-7.41 (1H, m, ArH), 7.54 (1H, d, J 5.45 Hz, ArH), 7.87 (1H, d, J 1.4 Hz, ArH), 7.96 (1H, d, J 8.3 Hz, ArH).
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].C[Al](C)C.[O:10]1[CH:14]=[C:13]([C:15]([O:17]C)=O)[N:12]=[CH:11]1.Cl.C(Cl)Cl>ClC(Cl)C>[O:10]1[CH:14]=[C:13]([C:15]([N:4]([CH3:5])[O:3][CH3:2])=[O:17])[N:12]=[CH:11]1
Reactant: CNOC
Reactant: COC(=O)c1cocn1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CON(C)C(=O)c1cocn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 81.1 %

Procedure:
To a suspension of methoxy-methylamine hydrochloride (2.3 g, 23.6 mmol) in 30 ml of dichloroethane at 0° C. was added dropwise 11.8 ml (23.6 mmol) of trimethylaluminum. The mixture was stirred at 0° C. for 20 min, methyl 4-oxazolecarboxylate (1 g, 7.9 mmol) in 20 ml of dichloroethane was added in one portion. The mixture was poured into an ice-cold solution of 0.5N HCl/methylene chloride (2:1) and stirred for 10 min. The aqueous layer was extracted with methylene chloride (2×50 ml), and the combined organic layer was washed with saturated ammonium chloride solution, dried over sodium sulfate, and concentrated in vacuo. The resulting residue was purified by chromatography on silica (methylene chloride/ethyl acetate/methanol 6:3:1) to afford 1.0 g (81.9%) of 4-oxazolyl-N-methyl-N-methoxy-carboxamide.
Reaction SMILES: ON1C(=O)CCC1=O.N1C=CC=CC=1.[CH2:15]([O:22][CH2:23][C@@:24]1([N:49]2[CH:57]=[C:55]([CH3:56])[C:53](=[O:54])[NH:52][C:50]2=[O:51])[O:48][C@H:28]([CH2:29][O:30][Si:31]([C:44]([CH3:47])([CH3:46])[CH3:45])([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:26]([OH:27])[CH2:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH:58]1[CH:63]=[CH:62][C:61]([O:64][C:65](Cl)=[S:66])=[CH:60][CH:59]=1>C1(C)C=CC=CC=1>[CH2:15]([O:22][CH2:23][C@@:24]1([N:49]2[CH:57]=[C:55]([CH3:56])[C:53](=[O:54])[NH:52][C:50]2=[O:51])[O:48][C@H:28]([CH2:29][O:30][Si:31]([C:44]([CH3:47])([CH3:46])[CH3:45])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@@H:26]([O:27][C:65]([O:64][C:61]2[CH:62]=[CH:63][CH:58]=[CH:59][CH:60]=2)=[S:66])[CH2:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Agent: O=C1CCC(=O)N1O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](OC(=S)Oc3ccccc3)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 75.1 %

Procedure:
N-hydroxysuccinimide (3.9 g, 34 mmol) and pyridine (24.3 mL, 300 mmol) were added to a solution of the alcohol 3 (90.0 g, 150 mmol) in 1 L of toluene. The mixture was warmed up to 80° C. and stirred for 10 min. Phenyl chlorothionoformate (30 g, 174 mmol) was added to the solution and the resultant reaction mixture was stirred at 80° C. for 8 h. The hot toluene solution was decanted from solids. The solids were rinsed with AcOEt (2×30 mL) and the combined toluene solution and AcOEt washes were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes/AcOEt 9:1 then 3:1) to give 83.0 g (75.2%) of the title compound, 17, as a light yellow foam. Rf (hexanes/AcOEt 9:1) 0.24. 13C-NMR (CDCl3): 12.97 (5-CH3), 19.49 (2'-C), 27.16 (Me3C), 38.32 (Me3C), 64.87 (O--C-Ph), 70.75 (N--C--O), 72.28 (5'-C), 84.21 (4'-C), 84.90 (3'-C), 85.39 (1'-C), 110.82 (5-C), 121.95, 126.94, 127.72, 128.27, 128.40, 129.81 (Ar--C), 130.35 (6-C), 131.93, 132.79, 133.76, 135.38, 135.76, 138.30 (Ar--C), 151.05 (2-C), 153.42 (Ar--C), 163.40 (4-C), 194.36 (thioformate-C).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[Br:14]Br>CCOCC>[Br:14][CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13]
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: BrBr
Solvent: CCOCC
Product: COc1ccc2c(c1)CCC(Br)C2=O

Procedure:
6-Methoxytetralone (2.0 g, 11.4 mmol) and bromine (0.6 ml, 11.7 mmol) were refluxed in ether (50 ml) for 30 minutes. The reaction mixture was cooled, concentrated, the residue partitioned between ethyl acetate and dilute NaHSO3. The organic layer was washed with saturated NaHCO3 and water, dried over CaSO4, and concentrated to an oil (2.83 g, 100%); 1H-NMR 8.03 (d, J=9.0Hz, 1H), 6.84 (dd, J1 =9.0 Hz, J2 =2.7 Hz, 1H), 6.69 (d, J=2.3 Hz, 1H), 4.66 (t, J=4.1Hz, 1H), 3.84 (s,3H), 3.20-3.30 (m, 1H), 2.82-2.90 (m, 1H), 2.34-2.50 (m, 2H).
Reaction SMILES: N[C@H](C(O)=O)CCC(=[O:7])N.CC1(C)S[C@@H]2[C@H](NC(CC3C=CC=CC=3)=O)C(=O)N2[C@H]1C([O-])=O.[K+].C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](NC(N)=N)[C@@H](O)[C@@H]2NC(N)=N)[C@H]([O:59][C@@H:60]2[O:65][C@@H:64]([CH2:66][OH:67])[C@H:63]([OH:68])[C@@H:62]([OH:69])[C@@H:61]2NC)[C@@]1(O)C=O>>[O:67]=[CH:66][C@@H:64]([C@H:63]([C@@H:62]([C@@H:61]([CH2:60][OH:59])[OH:7])[OH:69])[OH:68])[OH:65]
Reactant: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: [K+]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Differentiated adipocytes were incubated for a period of 3 days in DMEM (containing 2 mM L-glutamine, 100 iu/ml penicillin, 100 μg/ml streptomycin, 1 nM insulin and 10% FCS) supplemented with or without CLA and/or compound As. The cells were then washed three times with DMEM (containing 1 mM deoxyglucose). Insulin stimulated glucose uptake was carried out according to Iwata et al (Diabetes 2001 50: 1083-1092). Briefly, cells were stimulated with 1 nM insulin in Krebs Ringer Phosphate (KRP) and HEPES buffer [10 mM HEPES, 131.2 mM NaCl, 4.7 mM KCl, 2.5 mM CaCl2, 1.2 mM MgSO4, 2.5 mM sodium phosphate buffer, pH 7.4] with 1% BSA at 37° C. After 1-30 minutes the assay was initiated by addition of 10 μl KRP containing 2.5 μCi [3H]2deoxyglucose and 1 mM deoxyglucose. After 1 hr the reaction was terminated by washing the cells 3× with ice-cold DMEM. Cells were then solubilised with 500 μl/well of 1% Triton X-100, 0.2% SDS and 0.2N NaOH for 20 minutes at 37° C. Radioactive incorporation was measured by scintillation counting of 100 μl of each cell lysate.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:18][C@H:17]([NH:19][C:20](=[O:23])[CH2:21][CH3:22])[C@@H:16]([OH:24])[C@H:15]2[OH:25])=[C:7]([NH:26][CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:6]=1)=O.[CH2:41]([NH2:44])[CH2:42][NH2:43]>>[NH2:43][CH2:42][CH2:41][NH:44][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:18][C@H:17]([NH:19][C:20](=[O:23])[CH2:21][CH3:22])[C@@H:16]([OH:24])[C@H:15]2[OH:25])=[C:7]([NH:26][CH2:27][CH:28]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:6]=1)=[O:2]
Reactant: NCCN
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)[C@H](O)[C@@H]1O
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Temperature: 105 °C
Reaction time: 0.75 h

Procedure:
9-((1R,2S,3R,4S)-2,3-Dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester (62 mg, 1.0 mmol) is dissolved in ethylene diamine (3.4 ml, 51 mmol) and the solution is stirred at 105° C. The reaction is shown to be complete by LCMS after 45 minutes. The reaction mixture is concentrated in vacuo and the title compound is obtained after purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water). MS (ES+) m/e 573.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2oncc2C(=O)O)cc1
Reactant: C1CCNC1
Product: COc1ccc(-c2oncc2C(=O)N2CCCC2)cc1

Procedure:
The title compound was prepared from 5-(4-methoxyphenyl)isoxazole-4-carboxylic acid (11.0 mg, 0.050 mmol) and pyrrolidine (4.3 mg, 0.060 mmol) as described in synthetic method A and thereafter purified, first by preparative HPLC method A and then by method B, to give a solid (15.1 mg). MS (pos) m/z 273.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[CH:4][C:5]2[C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:17][C:3]1[CH:4]=[C:5]2[C:10]([C:9]([CH:12]([CH3:13])[CH3:14])=[CH:8][CH2:7][C:6]2([CH3:15])[CH3:16])=[CH:11][C:2]=1[Br:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)C1=CCC(C)(C)c2cc(O)c(Br)cc21
Product: CC(C)C1=CCC(C)(C)c2cc(OCc3ccccc3)c(Br)cc21
Yield: 100 %

Procedure:
Following General Procedure O, 3-bromo-5-isopropyl-8,8-dimethyl-7,8-dihydronaphthalen-2-ol (Compound 97, 0.29 g, 0.98 mmol) was reacted with benzylbromide to afford 0.38 g (100%) of the title compound as a yellow oil.
Reaction SMILES: C([O:5][C:6](=[O:38])[C@H:7]([CH3:37])[NH:8][C@H:9]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:10][S:11][CH2:12][C@@H:13]([NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>[CH2:35]([O:34][C:32]([C@@H:9]([NH:8][C@H:7]([C:6]([OH:38])=[O:5])[CH3:37])[CH2:10][S:11][CH2:12][C@@H:13]([NH:21][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:33])[CH3:36]
Reactant: CCOC(=O)[C@H](CSC[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)N[C@@H](C)C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H](CSC[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)N[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a mixture of 50 ml of TFA and 10 ml of anisole was dissolved 20.1 g of β-isomer of N-[(R)-1-ethoxycarbonyl-2-[(S)-2-benzyloxycarbonylamino-3-phenylpropylthio]ethyl]-alanine t-butyl ester prepared in Reference Example 53. The solution was stirred at room temperature for 5 hours. The excess of the solvent was evaporated off. The residue was poured into ice water and the mixture was adjusted to a pH of 4 with a saturated aqueous solution of sodium hydrogencarbonate. Then the mixture was extracted with dichloromethane. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure. To the crystalline residue was added ether to precipitate crystals which were collected by filtration and recrystallized from dichloromethane-ether. Thus the β-isomer of the title compound was obtained. Yield 8.63 g. M.p. 124°-127° C.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:30][C:31]1[CH:32]=[C:33]([C:38]2([CH:41]=O)[CH2:40][CH2:39]2)[CH:34]=[C:35]([F:37])[CH:36]=1>O1CCCC1>[F:37][C:35]1[CH:34]=[C:33]([C:38]2([CH2:41][CH:2]=[O:3])[CH2:39][CH2:40]2)[CH:32]=[C:31]([F:30])[CH:36]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1(c2cc(F)cc(F)c2)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=CCC1(c2cc(F)cc(F)c2)CC1
Reaction time: 8 h
Yield: 37.6 %

Procedure:
To a stirred, cooled (0° C.) solution of (methoxymethyl)triphenylphosphonium chloride (24.9 g) in tetrahydrofuran (190 ml) under an argon atmosphere was added slowly a solution of potassium tert.butoxide in tetrahydrofuran (30 ml) followed (after 30 min stirring) by a solution of 1-(3,5-difluoro-phenyl)-cyclopropanecarbaldehyde (6.3 g) in tetrahydrofuran (40 ml). Stirring was continued overnight, then the reaction mixture was quenched by adding an aqueous sodium chloride solution. The mixture was extracted with ethyl acetate twice and the combined organic layers were dried over MgSO4 and concentrated. The crude enol ether was dissolved in acetone (20 ml) and stirred with 6 M aqueous hydrochloric acid (40 ml) for 6 hours at room temperature. Ethyl acetate was added, the organic layer was separated, washed with brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography (SiO2; heptane/EtOAc=4:1) to give [1-(3,5-difluoro-phenyl)-cyclopropyl]-acetaldehyde as yellow liquid (2.55 g). 1H-NMR (300 MHz, CDCl3, δ): 0.92-0.98 (m, 2H), 1.00-1.06 (m, 2H), 2.65 (d, J=2 Hz, 2H), 6.60-6.67 (m, 1H), 6.75-6.81 (m, 2H), 9.74 (t, J=2 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:17]I.O>CN(C=O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.33 h

Procedure:
To a vigorously stirred solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (2.07 g, 10.3 mmol) in DMF (25 mL) was added a 60% sodium hydride dispersion in mineral oil (500 mg, 12.5 mmol). After stirring for 20 min, methyl iodide (0.9 mL, 14.5 mmol) was added and the resulting mixture stirred for 48 h before being added to a mixture of water and brine (250 mL, 1:1). Extraction with ethyl acetate (4×50 mL), washing of the combined extracts with brine (100 mL) and drying (MgSO4) gave, after concentration, a residue which was purified via flash chromatography (silica gel, ethyl acetate/hexane, 1:1) to give the title compound as a colourless oil. δH (CDCl3): 1.50 (9H, s), 1.52, 1.88 (4H, 2m) 3.12 (2H, ddd), 3.18 (1H, m), 3.19 (3H, s), 3.77 (2H, m); Rf 0.33 (ethyl acetate/hexane: 1/1).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]1([C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)Cl)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.C(CN)O>C(O)(C)C>[C:11]([NH:4][CH2:3][CH2:1][OH:2])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
A mixture of ethanolamine (2-aminoethanol) (98%, 1.750 kg, 28.0 moles) in isopropanol (7.0 l) was stirred to yield a homogeneous solution. Thereto triphenylchloromethane (97%, 2.020 kg, 7.03 moles) was added slowly within 1 h at room temperature with stirring, whereat the temperature was not to exceed 30° C. After completed dissolution of triphenylchloromethane (whereat ethanolamine hydrochloride separated as a white precipitate) the reaction mixture was stirred for another hour and cooled to room temperature. The precipitate, which separated, was filtered off and the filtrate was poured into ice-cold water (8.0 l). The precipitate, which separated, was filtered off and dried in vacuo at a temperature not exceeding 50° C. Thus there were obtained 2.120 kg (98%) of the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:12]C(F)(F)C(C(F)(F)F)OS(F)(F)OC(C(F)(F)F)C(F)(F)F>C(Cl)Cl>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][F:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: FC(F)(F)C(OS(F)(F)OC(C(F)(F)F)C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CF)cc1
Reaction time: 18 h
Yield: 63.2 %

Procedure:
A solution of 770 mg (5 mmol) of 4-nitrobenzyl alcohol in 15 ml of methylene chloride was added dropwise to a stirred solution of 3.0 g (7.5 mmol) of bis[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]sulfur difluoride in 5 ml of methylene chloride at 25°. The reaction mixture was stirred for 18 hrs, and then evaporated to dryness under reduced pressure. The residue was recrystallized from pentane to give 490 mg (63%) of 4-nitrobenzyl fluoride as colorless needles, mp 33° to 34°. A second recrystallization raised the melting point to 36° to 37°. The 4-nitrobenzyl fluoride is a known compound useful as a chemical intermediate.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)([O-:3])=O.[CH2:13]([O:15][C:16](=[O:26])[C:17]#[C:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[CH3:14].C1(N=C=O)C=CC(N=C=O)=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:13]([O:15][C:16]([C:17]1[C:4]([CH2:5][O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)=[N:1][O:3][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])=[O:26])[CH3:14]
Reactant: O=[N+]([O-])CCOC1CCCCO1
Reactant: CCOC(=O)C#Cc1ccccc1Cl
Agent: O=C=Nc1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(COC2CCCCO2)noc1-c1ccccc1Cl
Temperature: 70 °C
Yield: 94.2 %

Procedure:
Add 2-(2-nitroethoxy)tetrahydropyran (41 mL, 270 mmol) dropwise in toluene (100 mL) to a solution of (2-chloro-phenyl)-propynoic acid ethyl ester (28.3 g, 135 mmol), 1,4-phenylene diisocyanate (67 g, 420 mmol) and triethylamine (15 mL) in toluene (900 mL). Stir at reflux for 10 h. While still warm (˜70° C.), filter the reaction mixture through Celite®, washing the solids with EtOAc. Wash the filtrate with 1N HCl (500 mL) and brine (500 mL). Dry the organics over Na2SO4, filter and concentrate under reduced pressure. Purification by flash chromatography (silica gel, 85:15 Hexanes/EtOAc) gives the title compound (46.5 g, 94%). MS (m/e): 282 (M−C5H8O+H+); 1H NMR (300 MHz, CDCl3) δ 7.35–7.55 (m, 4H), 5.09 (d, J=13 Hz, 1), 4.85–4.91 (m, 2H), 4.15–4.22 (m, 2H), 3.91–4.01 (m, 1H), 3.52–3.61 (m, 1H), 1.49–1.92 (m, 6H), 1.12 (t, J=7 Hz, 3H); TLC Rf=0.53 (7:3 Hexanes/EtOAc).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](Br)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[C:27](B(O)O)=[C:28]2[CH2:33][CH2:32][CH2:31][N:29]2[N:30]=1>C(Cl)Cl>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:27]3[C:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=4)=[N:30][N:29]4[CH2:31][CH2:32][CH2:33][C:28]=34)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2ccccc21
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1cc(-c2c(-c3ccccn3)nn3c2CCC3)c2ccccc21

Procedure:
The titled intermediate was made via Preparation 33 (General Suzuki Coupling Method D) from 1-benzene-sulfonyl-3-bromo-1H-indole (Maybridge) and 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 5). MS (ESI) m/e 441 (M+1). TLC (SiO2): Rf0.5 (1:1 methylene chloride/[80:18:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:17])[C@H:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH2:12].C(N(CC)CC)C.[Cl:26][CH2:27][C:28]1[N:32]=[C:31](Cl)[S:30][N:29]=1>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:2][O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:17])[C@H:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH:12][C:31]1[S:30][N:29]=[C:28]([CH2:27][Cl:26])[N:32]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC(C)C
Reactant: ClCc1nsc(Cl)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(C)C)Nc1nc(CCl)ns1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.3 %

Procedure:
A solution of N-L-leucyl-L-proline methyl ester hydrochloride (2.22 g, 8 mmol) and triethylamine (2.8 mL, 20 mmol) in DMF (50 mL) was stirred at room temperature for 15 min. Then, a solution of 3-chloromethyl-5-chloro-[1,2,4]thiadiazole (0.34 g, 2 mmol) in DMF (10 mL) and tetra-butylammonium bromide (100 mg) were added and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with water and extracted into ethyl acetate. The organic layer was washed with a saturated ammonium chloride solution, brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by column chromatography on silica gel using a mixture of hexane and ethyl acetate (7/3, 6/4 and 1/1) afforded N-(3-chloromethyl-[1,2,4]thiadiazol-5-yl)-L-leucyl-L-proline methyl ester as a white foam, 0.49 g, 65.3% yield. 1H-NMR (CDCl3) δ 7.56 (d, J=8.2 Hz, 1H, NHCH), 4.78 (m, 1H, NHCH), 4.60 (dd, J=8.5, 4.6 Hz, 1H, CHCO2), 4.46 (s, 2H, CH2Cl), 4.09 (m, 1H), 3.69-3.73 (m, 1H), 3.74 (s, 3H, OMe), 2.25-2.30 (m, 1H), 1.68-2.11 (m, 6H), 0.99-1.03 (2d, 6H, 2Me); MS (m/z) 375 (M++1), 357 305, 246, 218,162,150, 130.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=2[Cl:16])=[C:4]([CH3:17])[N:3]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([NH:15][S:19]([CH3:18])(=[O:21])=[O:20])[CH:12]=[CH:11][C:10]=2[Cl:16])=[C:4]([CH3:17])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1-c1cc(N)ccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1nc(N)nc(N)c1-c1cc(NS(C)(=O)=O)ccc1Cl

Procedure:
This compound was prepared from 2,4-diamino-5-(2-chloro-5-aminophenyl) -6-methylpyrimidine from Example 54 by reaction with methanesulphonylchloride in pyridine, mp. 234°-240° C.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[C:13](Cl)=[N:14][C:15]([Cl:19])=[C:16]([F:18])[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>CC(N(C)C)=O>[CH2:1]([O:8][N:9]1[C:10](=[O:11])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[N:14][C:13]=2[N:31]([C:28]2[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=2)[C:32]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(Cl)nc1Cl
Reactant: COc1ccc(N=C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(Cl)nc32)cc1
Yield: 68.2 %

Procedure:
Using the General Method 5, the reaction of N-benzyloxy-2,6-dichloro-5-fluoro-3-pyridinecarboxamide (Example M-2, 2.00 g, 6.34 mmol) and 60% NaH in oil (300 mg, 7.52 mmol) with 4-methoxyphenyl isocyanate (1.31 mL, 9.51 mmol) in DMA afforded crude product. Recrystallization from chloroform provided 1.85 g of the title compound as a solid. mp 238-240° C.