Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:10]2[S:11][C:12](/[CH:18]=[CH:19]/[C:20]([O:22]CC)=[O:21])=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[N:1]1([C:10]2[S:11][C:12](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)/C=C/c1sc(-n2cnc3ccccc32)nc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)c1nc(-n2cnc3ccccc32)sc1/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
A mixture of ethyl(2E)-3-[2-(1H-benzimidazol-1-yl)-4-isopropyl-5-thiazolyl]propenoate (1.00 g), 2N aqueous sodium hydroxide solution (5 mL), tetrahydrofuran (5 mL), ethanol (5 mL) was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid and the precipitated solid was collected by filtration, washed with water and dried to give (2E)-3-[2-(1H-benzimidazol-1-yl)-4-isopropyl-5-thiazolyl]propenoic acid (0.90 g, 98%) as crystals. Recrystallization from acetone-hexane gave pale-yellow prism crystals. melting point: 262–264° C.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[N:14]([CH3:40])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[C@H:37]([OH:39])[CH3:38])[N:16]=3)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([CH2:12][C:13]2[N:14]([CH3:40])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[C@H:37]([OH:39])[CH3:38])[N:16]=3)[CH2:9]1
Reactant: C[C@@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-{2-[2-((R)-1-hydroxyethyl)benzoimidazol-1-yl]-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl}azetidine-1-carboxylic acid tert-butyl ester (156 mg, 0.28 mmol) in DCM (5 mL) was added TFA (2 mL) and the resulting mixture stirred at r.t. for 45 min. The reaction mixture was concentrated in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording the title compound (114 mg, 90%). LCMS (method A): RT 1.80 min [M+H]+ 449.4
Reaction SMILES: [CH:1]1([N:4]([CH:34]2[CH2:36][CH2:35]2)[C:5]([C:7]2[N:31]([CH2:32][CH3:33])[C:10]3=[N:11][C:12]([NH:19]/[C:20](/SC)=[CH:21]/[C:22](=O)[CH:23]([O:26]C)OC)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.CN(C(O[N:45]1[N:53]=N[C:47]2C=CC=N[C:46]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:61][NH:62][CH3:63].O>CN(C=O)C>[CH:1]1([N:4]([CH:34]2[CH2:36][CH2:35]2)[C:5]([C:7]2[N:31]([CH2:32][CH3:33])[C:10]3=[N:11][C:12]([NH:19][C:20]4[CH:21]=[C:22]([C:23](=[O:26])[N:62]([CH3:63])[CH3:61])[N:45]([CH2:46][CH3:47])[N:53]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CNC
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N/C(=C/C(=O)C(OC)OC)SC)nc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)cc1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
A mixture of 3-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-1-ethyl-1H-pyrazole-5-carboxylic acid (example 101, 28 mg, 0.059 mmol), HATU (26.8 mg, 0.071 mmol) and dimethylamine (2M in THF, 59 μL, 0.118 mmol) in DMF (1 mL) was stirred at room temperature for 2 h. Water was added and the reaction mixture was extracted with ethyl acetate 3 times. The combined organic layers were washed twice with 10% lithium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude was purified by preparative HPLC (Phenomenex Luna 5u C18 column, 21.2×250 mm column, retention time 15.317 min, 30-100% gradient aqueous methanol over 20 minutes containing 10 mM ammonium acetate, flow rate 20 ml/min and monitoring at 254 nm). N,N-dicyclopropyl-4-(5-(dimethylcarbamoyl)-1-ethyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (20 mg, 66.9% yield) was obtained as an off-white solid.
Reaction SMILES: [O-]I(=O)(=O)=O.[Na+].C[OH:8].O.[Cl:10][C:11]1[CH:12]=[C:13]([C:19]2([C:40]([F:43])([F:42])[F:41])[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4([F:39])[CH2:33][N:32]([C:34](=[O:38])[CH2:35][S:36][CH3:37])[CH2:31]4)=[CH:26][CH:25]=3)[CH2:20]2)[CH:14]=[C:15]([Cl:18])[C:16]=1[F:17]>CO>[Cl:10][C:11]1[CH:12]=[C:13]([C:19]2([C:40]([F:41])([F:42])[F:43])[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]4([F:39])[CH2:33][N:32]([C:34](=[O:38])[CH2:35][S:36]([CH3:37])=[O:8])[CH2:31]4)=[CH:28][CH:29]=3)[CH2:20]2)[CH:14]=[C:15]([Cl:18])[C:16]=1[F:17]
Reactant: CSCC(=O)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Reactant: CO
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: CS(=O)CC(=O)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 0 °C

Procedure:
A solution of sodium (meta)periodate (49 mg, 0.23 mmol) in 1:1 methanol/water (6 mL) was cooled with a ice bath and a solution of 1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidin-1-yl)-2-(methylthio)ethanone (102 mg, 0.19 mmol) in methanol (˜2 mL) was added drop wise via pipette. A precipitate forms and the reaction was allowed to stir with the ice bath in place slowly warming to ambient overnight. When complete, the reaction was partitioned between water (5 mL) and CH2Cl2 (5 mL). Aqueous extracted with additional CH2Cl2 (2×5 mL). Organic phase collected and condensed. The crude material was adsorbed on silica and chromatographed on a 12 g silica column, eluting with a gradient of 0% to 100% ethyl acetate in heptane. Fractions containing the desired material were combined and concentrated. CH2Cl2 (˜100 μL) was added to the resulting film. Placing the flask on high vacuum overnight resulted in formation of a white foam. Yield 90 mg (86%). LC/MS retention time=3.317 minutes, MS calculated for (C22H17Cl2F5N2O3S), 554.03; found 555.0 M+H+.
Reaction SMILES: [H-].[Na+].[Br:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.Cl>O1CCCC1>[Br:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:16][C:15]1[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: OCCCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(COCCCCCCBr)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Sodium hydride (60%, 0.39 g) was added to a mixture of 6-bromohexanol (1.78 g) and 4-chlorobenzyl bromide (2.02 g) in dry tetrahydrofuran (150 ml). The mixture was stirred at 25° C. for 5 h and poured into 1M hydrochloric acid. Extraction with diethyl ether (3×), and washing the combined extracts with water and brine gave a solution that was dried over magnesium sulfate and evaporated under reduced pressure. The residue so obtained was chromatographed on silica gel using 40-60° C. petroleum ether to 10% diethyl ether in 40-60° C. petroleum ether as eluents. This gave 1-bromo-6-(4-chlorobenzyloxy)hexane (1.7 g). 1H-NMR (CDCl3) δ 1.3-1.55 (4H, m), 1.55-1.7 (2H, m), 1.75-1.95 (2H, m), 3.35-3.55 (4H, m), 4.46 (2H, s) and 7.2-7.4 (4H, m).
Reaction SMILES: C([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=CC=1)C.[CH3:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:19][CH2:20][O:21][C:22](C)=[O:23]>>[CH2:20]([O:21][C:22]([C:15]1[CH:14]=[CH:13][C:18]([O:12][C:4]2[O:3][C:9]([CH:8]=[O:11])=[CH:10][CH:5]=2)=[CH:17][CH:16]=1)=[O:23])[CH3:19]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CCCCCC
Reactant: CCOC(C)=O
Product: CCOC(=O)c1ccc(Oc2ccc(C=O)o2)cc1

Procedure:
Using ethyl-4-hydroxybenzoate, the title compound was prepared by the method of Example 52A, except chromatography using 3:1 hexane-EtOAc was used for purification. 1H NMR (CDCl3) δ 9.45 (s, 1H), 8.10 (m, 2H), 7.25 (d, 1H), 7.19 (m, 2H), 5.75 (d, 1H), 4.40 (q, 2H), 1.41 (t, 3H). MS (DCl/NH3) m/e 261 (M+H)+, 278 (M+H+NH3)+.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[NH:8]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9]1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>O>[CH2:32]([N:8]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9]1)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: CCCCCCCCCCCCCCBr
Reactant: CCOC(=O)c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCn1ccc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.3 %

Procedure:
To dry dimethylformamide (DMF) (15 ml) was added 0.84 g (21 mmol) of sodium hydride (60% oil dispersion), and then 2.78 g (20 mmol) of ethyl pyrrole-3-carboxylate was added portionwise thereto under ice-cooling. After stirring at room temperature for 10 minutes, 6.65 g (24 mmol) of bromotetradecane was added dropwise under ice-cooling. The mixture was stirred for 3.5 hours at room temperature, and then 30 ml of water was added thereto. The resulting mixture was extracted with 70 ml of ethyl acetate, washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After removing the solvent, the remaining oil was purified by subjecting it to column chromatography over silica gel (eluent: ethyl acetate/hexane=1/20-1/10) to obtain 6.33 g (89.0% yield) of ethyl 1-tetradecylpyrrole-3-carboxylate as white crystals, m.p. 32°-33° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](O)=[O:21].FC1C=CC(C2(C3C=CC(F)=CC=3)CCN(CC(O)=O)C2=O)=CC=1.O[NH:48]/[C:49](=[N:56]\[H])/[C:50]1[CH:55]=[CH:54][N:53]=[CH:52][CH:51]=1.ON/C(=N\[H])/C1C=CC(C(F)(F)F)=CC=1>>[C:7]1([C:6]2([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:5][CH2:4][N:3]([CH2:19][C:20]3[O:21][N:56]=[C:49]([C:50]4[CH:55]=[CH:54][N:53]=[CH:52][CH:51]=4)[N:48]=3)[C:2]2=[O:1])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [H]/N=C(\NO)c1ccncc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Product: O=C1N(Cc2nc(-c3ccncc3)no2)CCC1(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared using the procedure described in Example 190 substituting 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid from Example 1C for 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid and (Z)—N-hydroxyisonicotinimidamide for (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide. 1H NMR (300 MHz, CDCl3) δ ppm 8.78 (d, J=5.9, 2H), 7.86 (dd, J=1.6, 4.5, 2H), 7.44-7.28 (m, 10H), 4.92 (s, 2H), 3.58 (t, J=6.5, 2H), 2.90 (t, J=6.5, 2H); MS (DCI) m/z 397.1 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:38]([C:41]([CH2:48][CH:49]=[CH2:50])([CH2:45][CH:46]=[CH2:47])[C:42](Cl)=[O:43])[CH:39]=[CH2:40]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:42](=[O:43])[C:41]([CH2:45][CH:46]=[CH2:47])([CH2:48][CH:49]=[CH2:50])[CH2:38][CH:39]=[CH2:40])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C=CCC(CC=C)(CC=C)C(=O)Cl
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: C=CCC(CC=C)(CC=C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 41 %

Procedure:
A procedure similar to that described in Example 6, above, was followed, but using 1.10 g (2.0 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 3, above] and 584 mg (2.9 mmol) of 2,2-diallyl-4-pentenoyl chloride, to provide 585 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.[CH3:8][O:9][C:10]([C@@H:12]([NH:20][C:21]([C@@H:23]([NH2:28])[CH2:24][C:25]([OH:27])=[O:26])=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11].[H][H]>>[CH3:1][C:2]([CH2:3][CH2:4][NH:28][C@H:23]([C:21]([NH:20][C@H:12]([C:10]([O:9][CH3:8])=[O:11])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:22])[CH2:24][C:25]([OH:27])=[O:26])([CH3:7])[CH3:6]
Reactant: [H][H]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Reactant: CC(C)(C)CC=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NCCC(C)(C)C

Procedure:
According to the second and third steps of the present invention, 3,3-dimethylbutyraldehyde is added to the mixture and reacted with aspartame in the presence of the catalyst and in the presence of hydrogen for a time and at a temperature sufficient to produce neotame. 3,3-Dimethylbutyraldehyde can be added slowly or all at once to the reaction mixture. When the aldehyde is gradually added, typically it is added over the course of about 2 to 8 hours, preferably from about 4 to 6 hours. It is important to note that the reactants, i.e., aspartame, catalyst, aldehyde, can be added in any order.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([NH2:25])=[CH:20][C:19]=2[O:26][CH3:27])=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.C(OCC)C>[NH2:25][C:21]1[C:22]([Cl:24])=[CH:23][C:18]([C:16]([NH:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:17])=[C:19]([O:26][CH3:27])[CH:20]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a solution of N-tert-butyloxycarbonyl-4-(4-amino-5-chloro-2-methoxyphenylcarbonylaminomethyl)piperidine (500 mg, 1.26 mmol) in methanol solution (30 ml) was added an ethereal 1N hydrogen chloride solution (12.6 ml, 12.6 mmol). The solution was heated at 50° C. The reaction mixture became heterogeneous within 5 min. After 1.5 h, the reaction mixture was concentrated to give a white solid which was suspended in diethylether and filtered to give 4-(4-amino-5-chloro-2-methoxyphenylcarbonylamino-methyl)piperidine as a bis-hydrochloride salt (433 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:22][CH2:23][CH:24]=[C:25]([Cl:27])[Cl:26])[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12]C(=O)C1C=CC=CC=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([O:22][CH2:23][CH:24]=[C:25]([Cl:27])[Cl:26])[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: O=C(OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.1 %

Procedure:
A reaction vessel was charged with 11.6 g of 3,5-dichloro-4-(3-benzoyloxypropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene, 15.2 g of 10% aqueous potassium hydroxide solution and 300 ml of methanol. After stirring at room temperature for 24 hours, and the reaction mixture was concentrated. The concentrate was poured into water, and extracted twice with 150 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 7.41 g of 3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)-1-propyl alcohol (83%o yield), m.p. 56.6° C.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6]C=[CH:4][CH:3]=1.CI.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.[CH3:22][N:23]([CH3:26])[CH:24]=O>>[CH3:22][N:23]([CH3:26])[C:24]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: Nc1ccccc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN(C)c1ccccc1
Reaction time: 8 h

Procedure:
The aniline derivative (1.4 g, 7.3 mmol) obtained in Step 1 was dissolved in dimethylformamide (50 ml), methyl iodide (1.4 ml, 22 mmol) and potassium carbonate (3.0 g, 22 mmol) were added, and the mixture was stirred overnight. A treatment according to a conventional method using ethyl acetate as an extraction solvent gave a crude product, which was successively purified by silica gel column chromatography to give a dimethylaniline derivative (1.1 g, 5.0 mmol).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[O:51][C:52]2[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=2[N:54]=1.N1C=CC=CC=1>C(Cl)Cl.O>[O:51]1[C:52]2[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=2[N:54]=[C:50]1[NH:49][C:40](=[O:42])[CH:39]([C:31]1[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:29]([Cl:28])[CH:30]=1)[CH2:43][CH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: Nc1nc2ccccc2o1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3o2)cc1Cl
Temperature: 0 °C
Yield: 60.9 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it became homogeneous. The resulting light purple reaction mixture was then treated with 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (200 mg, 0.61 mmol). The resulting reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminobenzoxazole (121 mg, 0.91 mmol) and pyridine (0.15 mL, 1.8 mmol) and was stirred at 25° C. for 16 h. The reaction was then diluted with water (15 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 60/40 hexanes/ethyl acetate) afforded N-benzooxazol-2-yl-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (166 mg, 61%) as a light pink foam: EI-HRMS m/e calcd for C22H23ClN2O4S (M+) 446.1067, found 446.1077.
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20]([C:22]1[C:23]([CH3:28])=[N:24][N:25]([CH3:27])[CH:26]=1)=O)(=O)OC.O.[NH2:30][NH2:31]>>[CH3:27][N:25]1[CH:26]=[C:22]([C:20]2[CH:19]=[C:4]3[C:3]([C@:2]4([CH3:1])[C:8]([CH3:10])([CH3:9])[C@H:5]3[CH2:6][CH2:7]4)=[N:31][N:30]=2)[C:23]([CH3:28])=[N:24]1
Reactant: COP(=O)(CC(=O)c1cn(C)nc1C)OC
Reactant: NN
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Solvent: O
Product: Cc1nn(C)cc1-c1cc2c(nn1)[C@@]1(C)CC[C@@H]2C1(C)C

Procedure:
yellow solid. MS (EI): 282.3 (M+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, [2-(1,3-Dimethyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: CN1CCOCC1.[NH:8]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].O.[NH2:32][C@H:33]([C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[CH:34]([CH3:36])[CH3:35].S(O)(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C>[NH:8]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C@H:9]([C:18]([NH:32][C@H:33]([C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[CH:34]([CH3:36])[CH3:35])=[O:20])[CH2:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 85.4 %

Procedure:
15.83 g of 1-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate and 9 ml of N-methylmorpholine were added to a solution of 13.65 g of Z-Asp(OBut)-OH.H2O and 15.9 g of Val-OBzl.TosOH in 250 ml of DMF. After stirring for 2 hours the reaction mixture was evaporated in a vacuum and the residue was partitioned between ethyl acetate and water. The organic phase was washed with 5% KHSO4 /10% K2SO4 solution, water, saturated NaHCO3 solution, water and saturated NaCl solution, dried over Na2SO4, filtered and evaporated. The residue was crystallized from diethyl ether/hexane and there were obtained 17.5 g of Z-Asp(OBut)-Val-OBzl of m.p. 99°; [a]D20 -27.7° (c=1, MeOH).
Reaction SMILES: [Cl:1][C:2]1[C:6]([N+:7]([O-])=O)=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.C(O)(=O)C.C(O)C>O.[Fe]>[Cl:1][C:2]1[C:6]([NH2:7])=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cn(-c2cccnc2)nc1Cl
Agent: [Fe]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cn(-c2cccnc2)nc1Cl
Temperature: 5 °C
Reaction time: 18 h

Procedure:
To a 100 mL, 3-neck round bottom flask was charged 3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine (2.40 g, 10.7 mmol), acetic acid (4 mL), ethanol (4.8 mL) and water (4.8 mL). The mixture was cooled to 5° C. and iron powder (2.98 g, 53.4 mmol) was added portionwise over ˜15 minutes. The reaction was allowed to stir at 20° C. for 18 hours and diluted to 50 mL with water. The mixture was filtered through Celite® and the filtrate was carefully basified with 50% sodium hydroxide solution. The resulting suspension was filtered through Celite® and the filtrate was extracted with ethyl acetate (3×20 mL). The organics were dried over sodium sulfate and concentrated to dryness to afford a tan colored solid, which was further dried under vacuum for 18 hours (2.2 g, quantitative): mp 145-147° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.95 (dd, J=2.6, 0.8 Hz, 1H), 8.45 (dd, J=4.7, 1.4 Hz, 1H), 8.08 (ddd, J=8.4, 2.7, 1.4 Hz, 1H), 7.91 (s, 1H), 7.49 (ddd, J=8.3, 4.7, 0.8 Hz, 1H), 4.43 (s, 2H); 13C NMR (101 MHz, DMSO-d6) δ 146.35, 138.53, 135.72, 132.09, 130.09, 124.29, 124.11, 114.09; EIMS m/z 194 ([M]+).