Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH2:3][C@H:4]([N:8]1[CH2:12][C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[CH:10][C:9]1=[O:24])[C:5](O)=[O:6].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:47][C:48]1([CH3:60])[O:52][C@H:51]([CH2:53][N:54]2[CH:58]=[CH:57][C:56]([NH2:59])=[N:55]2)[CH2:50][O:49]1>ClCCl>[CH3:47][C:48]1([CH3:60])[O:52][C@H:51]([CH2:53][N:54]2[CH:58]=[CH:57][C:56]([NH:59][C:5](=[O:6])[C@@H:4]([N:8]3[CH2:12][C:11]([O:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)=[CH:10][C:9]3=[O:24])[CH2:3][CH:2]([CH3:25])[CH3:1])=[N:55]2)[CH2:50][O:49]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(C(F)(F)F)c2)=CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc(C(F)(F)F)c2)=CC1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50.6 %

Procedure:
A solution of (S)-4-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid (0.71 g, 1.99 mmol) in dichloromethane (35 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.38 mL, 2.17 mmol) and 1-hydroxybenzotriazole (0.28 g, 2.07 mmol). The reaction was stirred at 25° C. for 20 min. At this time, the reaction was treated with 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.49 g, 2.48 mmol). The reaction mixture was stirred at 25° C. for 1.5 d. At this time, the reaction was diluted with dichloromethane (50 mL) and was washed with a saturated aqueous ammonium chloride solution (2×50 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 50-100% ethyl acetate/hexanes) afforded (S)-4-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.54 g, 51%) as a light, orange solid: HR-ES-MS m/z calculated for C26H31N4O5F3 [M+H]+ 537.2320, observed 537.2319; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.4 Hz, 3H), 0.95 (d, J=6.4 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.47 (br. s., 1H), 1.54-1.64 (m, 1H), 1.70-1.82 (m, 1H), 3.74 (dd, J=8.4, 5.9 Hz, 1H), 3.94-4.05 (m, 1H), 4.05-4.17 (m, 2H), 4.21 (d, J=18.4 Hz, 1H), 4.35 (quin, J=5.8 Hz, 1H), 4.60 (d, J=18.4 Hz, 1H), 4.84-4.92 (m, 1H), 4.91 (s, 1H), 6.44 (d, J=2.1 Hz, 1H), 7.60 (d, J=2.1 Hz, 1H), 7.65-7.78 (m, 4H), 10.79 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]([NH:20][CH3:21])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1>>[CH3:21][NH:20][C:18]([CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:32]4[CH:33]=[N:28][CH:29]=[N:30][CH:31]=4)[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]=3[CH:10]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: OB(O)c1cncnc1
Reactant: CNC(=O)C1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: CNC(=O)C1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cncnc4)nc3s2)CC1

Procedure:
1-((2-Chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)-N-methylpiperidine-4-carboxamide was reacted with pyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 269. NMR (CDCl3): 1.71 (s, 3H, CH3), 1.77-1.90 (m, 4H, 2×CH2), 2.10-2.17 (m, 3H, CH2+CH), 2.85 (d, 3H, CH3, J=4.81 Hz), 3.02-3.05 (m, 2H, CH2), 3.78 (s, 2H, CH2), 3.90-3.94 (m, 4H, 2×CH2), 3.97-4.01 (m, 4H, 2×CH2), 5.54 (s, H, NH), 7.18 (s, H, ArH), 9.28 (s, H, ArH), 9.69 (s, 2H, 2×ArH). MS: (ESI+): MH+=454.21
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[C:4]([CH:9]=[C:10]([O:12][CH2:13][CH:14]=[C:15]([Cl:17])[Cl:16])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:19][C:20]([F:33])([F:32])[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH2:30]O)=[N:25][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[C:3]([O:18][CH2:30][CH2:29][CH2:28][O:27][C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:33])([F:19])[F:32])=[CH:26][N:25]=2)=[C:4]([CH:9]=[C:10]([O:12][CH2:13][CH:14]=[C:15]([Cl:16])[Cl:17])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: OCCCOc1ccc(C(F)(F)F)cn1
Reactant: COC(=O)c1cc(OCC=C(Cl)Cl)cc(Cl)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCC=C(Cl)Cl)cc(Cl)c1OCCCOc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an atmosphere of protective gas, 1.85 g of methyl 3-chloro-5-(3,3-dichloroprop-2-enyloxy)-2-hydroxybenzoate, 1.3 g of 3-(5-trifluoromethylpyrid-2-yloxy)-propan-1-ol and 1.64 g of triphenylphosphine were dissolved in 50 ml of dry tetrahydrofuran (THF). With ice-bath cooling, 1.09 g of diethyl azodicarboxylate were added dropwise. After about 30 minutes, the ice-bath was removed, and the mixture was stirred at room temperature for 15 hours. The mixture was then concentrated under reduced pressure and the residue was taken up in a mixture of ethyl acetate and water. After shaking, the organic phase was isolated, dried and concentrated under reduced pressure. The crude product was purified chromatographically. Yield: 1.79 g (59%)
Reaction SMILES: C(OC([P:9]([CH2:14][CH2:15][CH2:16][CH3:17])(=[O:13])[O:10][CH2:11][CH3:12])(OCC)C)C.C(O)C.C[Si](C)(C)Cl>ClCCl>[CH2:14]([PH:9](=[O:13])[O:10][CH2:11][CH3:12])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCP(=O)(OCC)C(C)(OCC)OCC
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCO
Product: CCCC[PH](=O)OCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 176 g of ethyl 1,1-diethoxyethyl(n-butyl)phosphinate in 540 ml of absolute dichloromethane containing 10% of absolute ethanol is treated with 143.6 g of trimethylchlorosilane. After stirring for 48 hours at room temperature, the solvent is removed in vacuo to afford a pale yellow oil. Distillation in vacuo affords ethyl n-butyl-phosphinate, b.p. 27-34° (2×10-2 mbar).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH:16]1([CH2:20]Br)[CH2:19][CH2:18][CH2:17]1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH2:20][CH:16]3[CH2:19][CH2:18][CH2:17]3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: BrCC1CCC1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1CC1CCC1

Procedure:
The title compound, MS: m/e=286.1 (M+H+), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and cydobutyl-methylbromide.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3].[CH3:20][N:21]([CH3:31])[CH2:22][CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1>C(#N)C>[CH3:31][N:21]([CH3:20])[CH2:22][CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7](=[O:15])[C:6]3=[CH:16][S:17][C:18]([CH3:19])=[C:5]23)=[O:3])[CH2:26]1
Reactant: CN(C)CCCC1CCCNC1
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Solvent: CC#N
Product: Cc1scc2c1N(C(=O)N1CCCC(CCCN(C)C)C1)c1ccccc1NC2=O
Yield: 35 %

Procedure:
Prepared analogously to Example 4 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 3-[3-(dimethylamino)propyl]piperidine in a yield of 35% of theory. Colourless crystals, m.p. 137°-139° C. (acetonitrile).
Reaction SMILES: C([O-])=O.[NH4+].[OH:5][C:6]1[CH:29]=[CH:28][C:9](/[CH:10]=[CH:11]/[C:12]([O:14][CH:15]2[CH2:20][CH2:19][C:18]([CH3:27])([C:21]([O:23]CC=C)=[O:22])[CH2:17][CH2:16]2)=[O:13])=[CH:8][C:7]=1[O:30][CH3:31].[Cl-].[Na+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:5][C:6]1[CH:29]=[CH:28][C:9](/[CH:10]=[CH:11]/[C:12]([O:14][CH:15]2[CH2:20][CH2:19][C:18]([CH3:27])([C:21]([OH:23])=[O:22])[CH2:17][CH2:16]2)=[O:13])=[CH:8][C:7]=1[O:30][CH3:31]
Reactant: C=CCOC(=O)C1(C)CCC(OC(=O)/C=C/c2ccc(O)c(OC)c2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1cc(/C=C/C(=O)OC2CCC(C)(C(=O)O)CC2)ccc1O

Procedure:
0.2 g of bis(triphenylphosphine)palladium dichloride and 4 g of ammonium formate were added to a solution of 1.09 g of white crystal of allyl trans-4-(4-hydroxy-3-methoxycinnamoyloxy)-1-methyl-1-cyclohexanecarboxylate (Example 13) in 70 ml of THF. The solution was reacted for 20 hours under an argon stream, while it was refluxed. After reaction, 150 ml of an aqueous sodium chloride solution was added to the reaction solution. The solution was extracted three times with 50 ml of ethyl acetate. The organic layer obtained was washed three times with an aqueous sodium chloride solution, and was dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo. The oily substance obtained was subjected to column chromatography using 50 g of silica gel. From the fraction eluted with hexane and ethyl acetate=1:2, the solvent was removed in vacuo, yielding 0.7 g of trans-4-(4-hydroxy-3-methoxycinnamoyloxy)-1-methyl-1-cyclohexanecarboxylic acid (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:13]([F:16])([F:15])[F:14])=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([OH:9])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].FC(F)(F)C(O)=O>CN(C)C=O.C(OCC)(=O)C.CC#N.O>[CH3:1][O:2][C:3]1[C:4]([C:13]([F:14])([F:15])[F:16])=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([O:9][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:8]=1
Reactant: CCOC(=O)CBr
Reactant: COc1cc(O)c([N+](=O)[O-])cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(OC)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 104.8 %

Procedure:
5-(methyloxy)-2-nitro-4-(trifluoromethyl)phenol (0.5 g, 2.1 mmol) was dissolved in 1 mL of dimethylformamide under argon. Potassium carbonate was added and the mixture was allowed to stir for 5 minutes before ethyl bromoacetate (2.3 mL, 21.0 mmol) was slowly delivered to the flask. The mixture was warmed to 80° C. and maintained at that temperature for one hour. The reaction was determined to be complete by LCMS (two Aquasil C18, 20×1 mm columns were run in sequence, 4 minutes at 0.1 mL/min, 1-99% CH3CN/H2O with 0.018% trifluoroacetic acid, ES) Rt=2.1 min and m/e 324 [M+1]+. The mixture was allowed to cool to room temperature before it was diluted with 50 mL of ethyl acetate. The organic layer was washed with water (3×20 mL) and brine (3×20 mL). The organic phase was dried over Na2SO4, filtered and concentrated to give ethyl {[5-(methyloxy)-2-nitro-4-(trifluoromethyl)phenyl]oxy}acetate (0.71 g, 2.2 mmol, 95%) as a brown amorphous solid. MS (ES) m/e 324 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][C:10](=[O:23])[C:11]3[CH:17]=[C:16]([CH:18]([CH3:22])[C:19](N)=[O:20])[CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([OH:26])C.[OH-].[K+]>O>[CH3:1][O:2][C:3]1[C:8]2[CH2:9][C:10](=[O:23])[C:11]3[CH:17]=[C:16]([CH:18]([CH3:22])[C:19]([OH:26])=[O:20])[CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CCO
Reactant: COc1cccc2c1CC(=O)c1cc(C(C)C(N)=O)ccc1S2
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cccc2c1CC(=O)c1cc(C(C)C(=O)O)ccc1S2
Temperature: 85 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
To a mixture of 180 mg of 2-(10,11-dihydro-9-methoxy-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide and 5 ml of ethanol was added 700 mg of potassium hydroxide in 5 ml of water, and the resulting mixture was stirred at 75° C. for 1 hour and further at 85° C. for 2 hours. The solvent or ethanol was removed by distillation to obtain a mixture, to which was added water, and the resulting mixture washed with chloroform. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a red oily substance, which was chromatographed over 3 g of silica gel and eluted with chloroform, thereby obtaining 48 mg (yield: 27%) of 2-(10,11-dihydro-9-methoxy-11-oxodibenzo[b,f]thiepin-2-yl)-propionic acid as a yellow oily substance.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])=[CH:7][C:6]=1B1OC(C)(C)C(C)(C)O1.C(S(C1C=CC(OCCC)=C(B2OC(C)(C)C(C)(C)O2)C=1)(=O)=O)C.Br[C:55]1[C:60]2[N:61]=[CH:62][N:63]=[CH:64][C:59]=2[C:58](=[O:65])[N:57]([CH3:66])[CH:56]=1.BrC1C2N=C(C3C=NN(C)C=3)N=CC=2C(=O)N(C)C=1>>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][CH3:15])(=[O:12])=[O:13])=[CH:7][C:6]=1[C:55]1[C:60]2[N:61]=[CH:62][N:63]=[CH:64][C:59]=2[C:58](=[O:65])[N:57]([CH3:66])[CH:56]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cn1cc(Br)c2ncncc2c1=O
Agent: CCCOc1ccc(S(=O)(=O)CC)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cn1cc(-c2ncc3c(=O)n(C)cc(Br)c3n2)cn1
Product: CCS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3cncnc23)c1

Procedure:
The title compound of step 2 was substituted for the title compound of Example 225, step 2 and the title compound of Example 231, step 3 was substituted for the title compound of Example 224, step 4 and reacted in a similar manner as Example 225, step 3. 1H NMR (CDCl3, 400 MHz) δ 9.60 (s, 1H), 9.27 (s, 1H), 8.12 (s, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.94 (dd, J1=8.8 Hz, J2=2.0 Hz, 1H), 7.32-7.25 (m, 1H), 7.15-7.09 (m, 1H), 7.03-6.97 (m, 2H), 3.70 (s, 3H), 3.27 (q, J=7.6 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H). LCMS: 458.0 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:15]1([C:20](=[O:26])[CH2:21][CH2:22][C:23](O)=[O:24])[CH2:19][CH2:18][CH2:17][CH2:16]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:23](=[O:24])[CH2:22][CH2:21][C:20]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)CCC(=O)C1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)CCC(=O)C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a stirred solution of 4-Amino-piperidine-1-carboxylic acid tert-butyl ester (0.3 g, 1.49 mmol) in anhydrous CH2Cl2 under argon and cooled to 0° C., were added 4-Cyclopentyl-4-oxo-butyric acid (0.31 g, 1.79 mmol), EDC.HCl (0.35 g, 1.79 mmol), HOBt (0.24 g, 1.79 mmol), and TEA (0.25 mL, 1.79 mmol). The resulting solution was stirred at 25° C. overnight. CH2Cl2 was evaporate and the residue was partitioned between EtOAc and 1N HCl. The organic layer was washed with H2O, brine and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (80% EtOAc in hexanes) to provide the desired product (0.37 g, 71%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.24–1.32 (m, 2H), 1.45 (s, 9H), 1.60–1.85 (m, 11H), 2.41 (t, J=6.4 Hz, 2H), 2.79–3.04 (m, 5H), 3.85–4.13 (m, 2H), 5.65 (s, 1H). MS(ESI):351 (MH−).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[OH:17].Cl.Cl[CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24]>CN(C=O)C>[Cl:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[O:17][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24]
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1Cl
Temperature: 80 °C
Reaction time: 14 h

Procedure:
112 g (0.81 mol) of potassium carbonate are added to a solution of 35 g (0.202 mol) of 2-chloro-4-nitrophenol in 350 mL of DMF. Then the reaction mixture is combined with 35 g (0.203 mol) of (2-chloroethyl)diethylamine hydrochloride and stirred for 3 hours at 80° C. and 14 hours at ambient temperature. The reaction mixture is evaporated down and the residue is poured onto 1000 mL of water and this mixture is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate, the desiccant is filtered off and the filtrate is evaporated down. Yield: 49.6 g (90% of theory); C12H17ClN2O3 (M=272.73); calc.: molecular ion peak (M+H)+: 273; found: molecular ion peak (M+H)+: 273; Rf value: 0.36 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)(=[O:7])=[O:6]
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)CCCCl
Product: O=S(=O)(CCCCl)N1CCOCC1

Procedure:
The procedure used for the preparation of Intermediate D was used to prepare the title compound from 3-chloropropanesulfonyl chloride and morpholine. High vacuum drying gave the title compound (1.3 g, 104%): 1H NMR (CDCl3) δ: 2.20-2.29 (2H, m), 3.02 (2H, dd), 3.20-3.23 (4H, m), 3.64 (2H, t), 3.68-3.72 (4H, m).
Reaction SMILES: C(O)C(O)C[O:4][CH2:5][CH:6]([OH:9])[CH2:7][OH:8].[C:12]([OH:22])(=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19].O>C1(C)C=CC=CC=1>[C:12]([OH:22])(=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([CH3:19])[CH3:20].[OH:4][CH2:5][CH:6]([CH2:7][OH:8])[OH:9].[OH:4][CH2:5][CH:6]([CH2:7][OH:8])[OH:9]
Reactant: OCC(O)COCC(O)CO
Agent: CC(C)CCCCCC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: OCC(O)CO
Temperature: 200 °C

Procedure:
In a four-neck 1000 mL flask equipped with a stirrer, a thermometer, a gas inlet tube, and a Dean-Stark condenser with a water measuring trap were placed 166.2 g (1.0 mol) of diglycerin, 237.3 g (1.5 mol) of isononanoic acid, and 150 mL of toluene as a solvent. Then, the reaction mixture was heated to 200 degrees C. under a flow of nitrogen gas in a rate of 20 mL/min. At the temperature, the reaction took place while distilling off the produced water with the solvent azeotropically. When the distillation-off water subsided, the temperature was raised to 220 degrees C. to further continue the reaction. When the distillation-off water stopped, the reaction was terminated. It took about 6 hours from the start of the reaction to this point. Diglycerin isononanoate was obtained as a pale yellow viscous oil in an amount of 411.5 g (hydroxyl value: 132, acid value: 0.3).
Reaction SMILES: C[O:2][C:3]([N:5]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:8][C:7](=[O:24])[NH:6]1)=[O:4].[OH-].[Na+]>CO>[CH:19]1([O:18][C:12]2[CH:11]=[C:10]([CH:9]3[N:5]([C:3]([OH:4])=[O:2])[NH:6][C:7](=[O:24])[CH2:8]3)[CH:15]=[CH:14][C:13]=2[O:16][CH3:17])[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COC(=O)N1NC(=O)CC1c1ccc(OC)c(OC2CCCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C2CC(=O)NN2C(=O)O)cc1OC1CCCC1
Reaction time: 8 h
Yield: 45.3 %

Procedure:
A solution of 5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-oxo-l-pyrazolidinecarboxylic acid methyl ester (0.696 g, 2 mmol) in methanol (4 ml) is mixed with 2.5 N sodium hydroxide solution (1.2 ml, 3 mmol). The reaction mixture is kept at 40° overnight. The solvent is removed, and the residue partitioned between ethyl acetate/water, dried and the solvent evaporated. Residue (0.7 g) is allowed to crystallize over ethyl acetate/ether to yield solid (0.29 g) m.p. 137-139°. A crystallization from ethyl acetate/ether gives analytical sample m.p. 136 NMR (Me2SO-d6); δ 9.38 (1H, broad, NH), 7.02 (1H, d, arom), 6.89 (2H, m, arom), 4.75 (1H, m, carbinolic), 4.27 (1H, q, benzylic), 3.72 (3H, s, 0--CH3), 3.60 (1H, d, --CHCO), 3.37 (1H, d, --CHCO), 3.04 (1H, q, --CHCO), 2.25 (1H, q, --CHCO), 1.88 (2H, m, cyclopentyl --CH), 1.70 (4H, m, cyclopentyl --CH), 1.56 (2H, m, cyclopentyl --CH), IR (KBr), 3210, 2940, 2450, 1710, 1630, 1510 cm-1.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CCOCC>[N:25]([CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[N+:26]=[N-:27]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: [Br-]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCCN=[N+]=[N-]
Temperature: 60 °C
Reaction time: 7 h
Yield: 68.9 %

Procedure:
To a solution of 1,1-dimethylethyl (3-hydroxypropyl)carbamate (1.612 g, 9.2 mmol) in toluene (40 mL) cooled with an ice bath was added triethylamine (1.282 mL, 9.20 mmol) then methanesulfonyl chloride (0.717 mL, 9.20 mmol) and the resulting mixture was stirred for 15 min. Tetrabutylammonium bromide (0.297 g, 0.920 mmol) was then added followed by a solution of sodium azide (5 g, 77 mmol) in water (20 mL) and the resulting mixture was stirred at 60° C. for 7 h then cooled to room temperature and diluted with Et2O (150 mL). The two layers were separated and the organic phase was washed with water then brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 25 G silica cartridge gave 1,1-dimethylethyl (3-azidopropyl)carbamate (1.27 g, 6.34 mmol, 68.9% yield) as a colourless oil.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][OH:33])[CH:26]=1)[CH2:10][NH:11][C:12]([CH3:24])([CH3:23])[CH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:34][O:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=1)[CH2:39][CH2:40][NH2:41]>>[Si:1]([O:8][C@H:9]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][OH:33])[CH:26]=1)[CH2:10][NH:11][C:12]([CH3:24])([CH3:23])[CH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([NH:41][CH2:40][CH2:39][C:38]1[CH:42]=[CH:43][CH:44]=[C:36]([O:35][CH3:34])[CH:37]=1)=[O:19])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: COc1cccc(CCN)c1
Reactant: CC(C)(Cc1cccc(C(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Product: COc1cccc(CCNC(=O)c2cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(CO)c3)c2)c1
Yield: 98 %

Procedure:
The title compound was prepared from 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxy methyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid (preparation 37) and 3-methoxyphenethylamine, using a similar method to that of preparation 158, in 98% yield.
Reaction SMILES: [CH3:1][S-:2].[Na+].FC(F)(F)CO[C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[C:15]([S:17]([NH:20][C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])(=[O:19])=[O:18])[N:16]=[C:10]2[N:9]=1>CS(C)=O.Cl>[CH3:1][S:2][C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[C:15]([S:17]([NH:20][C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])(=[O:19])=[O:18])[N:16]=[C:10]2[N:9]=1
Reactant: O=S(=O)(Nc1c(Cl)cccc1Cl)c1nc2nc(OCC(F)(F)F)ccn2n1
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1ccn2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Temperature: 25 °C
Reaction time: 25 h
Yield: 66 %

Procedure:
To 25 ml (13 mmol) of a 0.52M solution of sodium methyl mercaptide in DMSO prepared by bubbling methyl mercaptan into a suspension of sodium hydride in DMSO, was added 2.6 g (5.9 mmol) of 5-(2,2,2-trifluoroethoxy)-N-(2,6-dichlorophenyl)-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide. The solution was stirred at room temperature for 25 hours, diluted with 100 ml of ice water and neutralized with 3N aqueous HCl. The gummy solid which separated was collected and taken up in 0.5N aqueous NaOH. The mixture was filtered to remove insoluble material, and the filtrate was acidified with 6N aqueous HCl. The solid which separated was collected by filtration and dried to yield 1.5 g (66%) of the desired product as a pale yellow solid, mp 239°-243° C. IR and 1H NMR spectra were in agreement with the assigned structure.