Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=O)=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12].P(Cl)(Cl)([Cl:19])=O>>[ClH:12].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([Cl:19])(=[O:10])=[O:8])[CH:2]=1
Reactant: O=S(=O)(O)c1cccnc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=P(Cl)(Cl)Cl
Product: Cl
Product: O=S(=O)(Cl)c1cccnc1
Temperature: 130 °C
Reaction time: 3.5 h

Procedure:
A mixture of 3-pyridinesulfonic acid (10.0 g), phosphorous pentachloride (13.1 g) and phosphoryl chloride (10.0 ml) was stirred at 130° C. for 3.5 hours. The solution was evaporated and diluted with acetone. The solution was evaporated and poured into water (200 ml) and isopropyl ether (400 ml). The organic layer was separated, washed with brine twice, saturated sodium bicarbonate aqueous solution and brine and dried over magnesium sulfate. The solution was evaporated, covered with hexane (20 ml) and added hydrogen chloride in ethyl acetate (4N, 20 ml) dropwise with stirring. The resulting solid was collected by filtration and dried to give 3-pyridinesulfonyl chloride hydrochloride (9.49 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].Cl.CN(C)[CH2:15][CH2:16]CN=C=N.O.ON1C2C=CC=CC=2N=N1.C(O)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([O:8][CH2:15][CH3:16])=[O:7]
Reactant: O=C(O)c1ccc(Cl)cc1O
Reactant: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Cl)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
4-Chlorosalicylic acid (344 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (420 mg), 1-hydroxybenzotriazole hydrate (337 mg), and ethanol (2 ml) were dissolved in N,N-dimethylformamide to prepare a solution which was then stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give ethyl 4-chlorosalicylate (174 mg, yield 43%).
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[Cl:31][C:32]1[CH:45]=[CH:44][C:35]([CH:36]([NH2:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([CH:36]([NH:43][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:30])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:44][CH:45]=1
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Yield: 70 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 4-chlorobenzhydrylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 70%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.C[O-].[Na+].Br[CH2:19][C:20]([OH:22])=[O:21]>CO.Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:19][C:20]([OH:22])=[O:21])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CBr
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)c1ccc(OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-t-butylphenol, 37.5 gm, was added to 300 ml of ethanol. 57.2 gm of a 25% solution of sodium methoxide (2 equivalents) in methanol was then added to the system. The system was stirred at room temperature for approximately 0.5 hour. Afterwards, 29.5 ml of bromoacetic acid was added and the system then heated to reflux for 18 hours. The reaction was then stopped and the solvent removed by stripping. The resulting solid was dissolved in methylene chloride; dilute sodium hydroxide was added to give a basic pH. The resulting precipitate was dissolved in hydrochloric acid, and then extracted with methylene chloride. The methylene chloride was stripped and the resulting crude product air dried. Toluene was then added to the product. The toluene was removed by stripping and any remaining water was azeotroped off with the toluene to give 33.3 gm of 4-t-butylphenoxyacetic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[NH2:33][CH2:34][C:35]([OH:37])=[O:36].C([O-])([O-])=O.[K+].[K+]>C(O)CCC>[F:32][C:28]1[CH:27]=[C:26]([S:23]([NH:22][C:18]2[CH:17]=[C:16]([C:9]3[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=3[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:33][CH2:34][C:35]([OH:37])=[O:36])[N:7]=3)[CH:21]=[CH:20][CH:19]=2)(=[O:25])=[O:24])[CH:31]=[CH:30][CH:29]=1
Reactant: NCC(=O)O
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(Cl)n2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(NCC(=O)O)n2)s1
Temperature: 60 °C
Reaction time: 16 h
Yield: 25 %

Procedure:
To a solution of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-3-fluorobenzenesulfonamide (100 mg, 0.20 mmol) in 1-butanol (5 mL) was added glycine (153 mg, 2.0 mmol) and K2CO3 (566 mg, 4.0 mmol). The reaction was stirred at 60° C. for 16 h, then partitioned between water and EtOAc. The pH of the aqueous layer was adjusted to below 4 with 1N HCl, and the aqueous layer was extracted with EtOAc. This organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to generate the title compound as a white powder (24 mg, 0.05 mmol, 22.8% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.04 (d, J=4.5 Hz, 1H), 7.46-7.64 (m, 5H), 7.33 (t, J=8.1 Hz, 1H), 7.18-7.24 (m, 3H), 6.07 (s, 1H), 3.89 (s, 2H), 3.25-3.29 (m, 1H), 1.36 (d, J=6.7 Hz, 6H). MS (ESI): 528.1 [M+H]+.
Reaction SMILES: S([O-])([O-])(=O)=O.[Al+3].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[Al+3].C1(O)C=CC=CC=1.CCCCCCCCCCCCCCCCCC[O:43][C:44]([CH2:46][CH2:47][C:48]1[CH:53]=C(C(C)(C)C)C(O)=C(C(C)(C)C)[CH:49]=1)=[O:45]>>[C:44]([O-:45])(=[O:43])[CH:46]=[CH2:47].[CH2:46]=[CH:47][C:48](=[CH2:49])[CH3:53]
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: Oc1ccccc1
Product: C=CC(=C)C
Product: C=CC(=O)[O-]

Procedure:
After completion of the reaction, the obtained latex was coagulated by introduction into a 0.05% by weight aqueous solution of aluminum sulfate. At the time of coagulation, to the aqueous solution of aluminum sulfate was added 0.5 parts by weight of a hindered phenol antioxidant, Irganox 1076 (trade name, produced by Ciba-Geigy AG), based on the amount of the polymer.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:3]=1.ClC(Cl)(O[C:19](=[O:25])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[NH2:34][CH:35]1[N:41]=[C:40]([CH:42]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[C:39]2[CH:49]=[CH:50][CH:51]=[CH:52][C:38]=2[N:37]([CH3:53])[C:36]1=[O:54]>O1CCCC1>[CH:42]1([C:40]2[C:39]3[CH:49]=[CH:50][CH:51]=[CH:52][C:38]=3[N:37]([CH3:53])[C:36](=[O:54])[CH:35]([NH:34][C:19]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([N:8]4[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]4)[CH:3]=3)=[O:25])[N:41]=2)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN1C(=O)C(N)N=C(C2CCCCCC2)c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc(NC(=O)NC3N=C(C4CCCCCC4)c4ccccc4N(C)C3=O)c2)CC1
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 139.7 %

Procedure:
1-Amino-3-(N-methyl-N'-piperazinyl)benzene (197 mg) in anhydrous tetrahydrofuran (30 ml) was cooled to 0° C. whereupon triphosgene (101 mg) was added. The mixture was stirred at 0° C. for 2 min, then triethylamine (430 μl) was added portionwise until pH8. The mixture was then stirred for a further 5 min, allowed to warm to 15° C., and then re-cooled to 0° C. Then a solution 3-amino-5-cycloheptyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (200 mg) (Enantiomer A) in anhydrous tetrahydrofuran (10 ml) was added dropwise over 5 min. The mixture was stirred at 0° C. for 5 min, allowed to warm to room temperature and then stirred for a further 15 min. The undissolved material was removed by filtration. The filtrate was evaporated in vacuo and the residue partitioned between ethyl acetate (50 ml) and water (30 ml). The organic phase was separated, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel with dichloromethane:methanol (9:1) as eluant to afford the title compound (239 mg) as a colourless solid. Mp 160° C. (dec.). 1H NMR (250 MHz, D6-DMSO) δ 1.05-1.87 (11H, m), 1.88-2.04 (1H, m) 2.21 (3H, s), 2.36-2.47 (4H, m), 2.95-3.21 (5H, m), 3.36 (3H, s), 5.05 (1H, d, J=8 Hz), 6.50 (1H, dd, J=8.2 and 2.0 Hz), 6.61 (1H, d, J=8 Hz), 7.04 (1H, t, J=7.5 Hz), 7.13 (1H, s), 7.25 (1H, d, J=7.5 Hz), 7.39 (1H, t, J=7.0 Hz), 7.52-7.70 (2H, m), 7.76 (1H, d, J=8.0 Hz), 8.89 (1H, s).
Reaction SMILES: CN(C)C.[O:5]=O.[CH3:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=1[OH:16]>C(Cl)(Cl)Cl>[CH3:15][C:11]1[C:12](=[O:5])[C:13]([CH3:14])=[C:8]([CH3:7])[C:9](=[O:16])[CH:10]=1
Reactant: O=O
Reactant: Cc1cc(C)c(C)c(O)c1
Agent: CN(C)C
Solvent: ClC(Cl)Cl
Product: CC1=CC(=O)C(C)=C(C)C1=O

Procedure:
0.4 g of cobalt di-(5-methylsalcylal)-3,3'-diimino-di-n-propylamine (0.0001 mole) was dissolved in chloroform. To this was added 0.2 ml of an aqueous solution of 30% trimethylamine (0.0001 mole), which had been dissolved in 20 ml of chloroform, followed by the introduction of oxygen thereinto, but very little oxygen was absorbed. Upon adding a solution of 1.36 g of 2,3,5-trimethylphenol (0.01 mole) in 200 ml of chloroform to the above solution, the absorption of oxygen started, and in 5 hours the theoretical amount of oxygen was absorbed (224 ml). After the reaction was completed, the chloroform was distilled off and the residue was subjected to steam-distillation. The distillate was extracted with ether and the ether was then distilled off to give 1.5 g of pseudocumoquinone, (0.01 mole), that is, the yield was quantitative.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.C([O:40][C:41](=O)[C:42]1[C:47]([CH2:48]Br)=[CH:46][CH:45]=[CH:44][C:43]=1[O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])C>C(#N)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:18]3[CH2:48][C:47]4[C:42](=[C:43]([O:50][Si:51]([C:54]([CH3:56])([CH3:55])[CH3:57])([CH3:52])[CH3:53])[CH:44]=[CH:45][CH:46]=4)[C:41]3=[O:40])[N:13]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CN)cc1
Reactant: CCOC(=O)c1c(CBr)cccc1O[Si](C)(C)C(C)(C)C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CN2Cc3cccc(O[Si](C)(C)C(C)(C)C)c3C2=O)cc1
Reaction time: 12 h
Yield: 66.1 %

Procedure:
To a solution of 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (3.00 g, 7.45 mmol) and diisopropyl ethylamine (1.93 ml, 11.2 mmol) in acetonitrile at room temperature was added a solution of 6-bromomethyl-2-(tert-butyl-dimethyl-silanyloxy)-benzoic acid ethyl ester (2.78 g, 7.45 mmol) in acetonitril over 48 hours. The solution was stirred for 12 hours after the addition was complete. The volatiles were evaporated in vacuo and the residue was taken into ethyl acetate (50 ml) and washed with water, 1 N hydrochloric acid, brine, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was chromatographed on silica gel column eluted with a mixture of 20% ethyl acetate/Hexane, which afforded 3.2 g (66%) of 2-amino-5-(7-(tert-butyl-dimethyl-silanyloxy)-1-oxo-1,3-dihydro-isoindol-2-ylmethyl]-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: C[C:2]1([CH2:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][C:14]#N)[O:6]CC[O:3]1.N.[OH2:17].[CH3:18]CO>[OH-].[Na+]>[O:17]=[C:14]([CH3:18])[CH2:13][CH2:12][C:11]#[C:10][CH2:9][CH2:8][CH2:7][C:2]([OH:3])=[O:6]
Reactant: CCO
Reactant: CC1(CCC#CCCCC#N)OCCO1
Reactant: O
Agent: N
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)CCC#CCCCC(=O)O
Yield: 85 %

Procedure:
The 2-(methyl)-2-(7-cyano-3-heptynyl)-1,3-dioxolane (20 g, 0.1 mol) was dissolved in 200 ml EtOH and 200 ml 10N NaOH. The reaction was stirred at reflux until no more NH3 was evolved (20 hours). The cooled reaction was then poured into 500 ml H2O and extracted with 3-200 ml portions of ether. The aqueous phase was acidified with concentrated HCl and allowed to stir 2 hours at room temperature. The acid solution was extracted with ethyl acetate and the combined organic extracts were washed with H2O, brine, and dried over anhydrous MgSO4. Evaporation of the solvent gave 15.5 g (85%) of 9-oxo-5-decynoic acid as a red oil. NMR (CDCl3): 1.6-2.8(m, 11HO; 2.17(s, 3H); and 10.4(s, 1H). IR (CHCl3): 2400-3400, 1710 cm-1.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:7]=1[CH3:20].[Cl:21][C:22]1[S:26][C:25]([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:1].[ClH:21].[ClH:1].[Cl:21][C:22]1[S:26][C:25]([CH2:27][N:28]2[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][S:5][C:6]3[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)[C:7]=3[CH3:20])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1
Reactant: Cc1c(SCCCCl)ccnc1CSc1ccncc1
Reactant: Clc1ccc(CN2CCNCC2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1c(SCCCN2CCN(Cc3ccc(Cl)s3)CC2)ccnc1CSc1ccncc1
Product: Cl
Yield: 79 %

Procedure:
According to the procedure indicated in Example 7, reaction of 4-(3-chloropropylthio)-3-methyl-2-[(4-pyridinylthio)methyl]pyridine with [1-(5-chlorothiophen-2-yl)methyl]piperazine and potassium carbonate gives, after crystallization from isopropanol/acetone/conc. hydrochloric acid, the title compound; m.p. 160-162° C., dec.; yield 79% of theory.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Br[CH:10]1[CH2:13][CH2:12][CH2:11]1.[C:14]12([C:24](O)=[O:25])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>>[CH:10]1([N:3]2[C:2]([CH3:1])=[C:6]([CH3:7])[S:5]/[C:4]/2=[N:8]\[C:24]([C:14]23[CH2:23][CH:18]4[CH2:17][CH:16]([CH2:22][CH:20]([CH2:19]4)[CH2:21]2)[CH2:15]3)=[O:25])[CH2:13][CH2:12][CH2:11]1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1nc(N)sc1C
Reactant: BrC1CCC1
Product: Cc1s/c(=N\C(=O)C23CC4CC(CC(C4)C2)C3)n(C2CCC2)c1C

Procedure:
4,5-Dimethylthiazol-2-ylamine, bromocyclobutane and 1-adamantane carboxylic acid were processed according to the method of Example 47 to afford the title compound. 1H NMR (CDCl3, 500 MHz) δ ppm 0.43-0.53 (m, 3 H) 1.21-1.29 (m, J=7.18, 7.18 Hz, 1 H) 1.60-1.74 (m, J=15.60 Hz, 7 H) 1.82 (d, J=2.81 Hz, 6 H) 1.94-2.03 (m, 3 H) 2.17 (s, 3 H) 2.24 (s, 3 H) 4.06 (d, J=7.18 Hz, 2 H); MS (ESI) m/z 345 (M+H)+.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:21](=[O:40])[N:22]([C@@H:24]([CH2:32][NH:33][C:34]([NH:36][CH:37]1[CH2:39][CH2:38]1)=[S:35])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:23])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:25]([C@@H:24]([N:22]([CH3:23])[C:21](=[O:40])[C@H:9]([NH:7][CH3:6])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[CH2:32][NH:33][C:34]([NH:36][CH:37]1[CH2:38][CH2:39]1)=[S:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN(C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C)[C@@H](CNC(=S)NC1CC1)Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@@H](CNC(=S)NC1CC1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 41.9 %

Procedure:
N-((1R)-1-(N-((1R)-1-((3-Cyclopropylthioureido)methyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butylester (579 mg, 1.01 mmol) was dissolved in dichloromethane (2 ml). The solution was cooled to 0° C. Trifluoroacetic acid (2 ml) was added. The solution was stirred for 5 min. The solvents were removed in vacuo without warming. The residue was dissolved in dichloromethane (100 ml) and the solvent was removed in vacuo. This latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (45 g) using dichloromethanelmethanol/25% aqueous ammonia 100:10:1 as eluent to give 201 mg of (2R)-N-((1R)-1-benzyl-2-(3-cyclopropylthioureido)ethyl)-N-methyl-2-methylamino-3-(2-napthyl)propionamide.
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](=O)[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=O)OC.O.[NH2:28][NH2:29]>>[CH3:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:20]1[CH:19]=[C:4]2[C:3]([C@:2]3([CH3:1])[C:8]([CH3:10])([CH3:9])[C@H:5]2[CH2:6][CH2:7]3)=[N:29][N:28]=1
Reactant: COP(=O)(CC(=O)CC(C)(C)C)OC
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Reactant: NN
Solvent: O
Product: CC(C)(C)Cc1cc2c(nn1)[C@@]1(C)CC[C@@H]2C1(C)C

Procedure:
light-yellow solid. MS (ESI): 258.9 (MH+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, (4,4-dimethyl-2-oxo-pentyl)-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:15]([C:17]1[C:29]([O:30][CH3:31])=[CH:28][C:20]([O:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[C:19]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)[CH:18]=1)=O.C[O-].[Li+]>CN(C=O)C.CO.O>[CH3:14][S:11]([NH:10][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])/[CH:2]=[CH:15]/[C:17]2[C:29]([O:30][CH3:31])=[CH:28][C:20]([O:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[C:19]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[CH:18]=2)=[CH:9][CH:8]=1)(=[O:12])=[O:13]
Reactant: COc1cc(OC(C)(C)C(=O)O)c(-c2cccs2)cc1C=O
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: COc1cc(OC(C)(C)C(=O)O)c(-c2cccs2)cc1/C=C/C(=O)c1ccc(NS(C)(=O)=O)cc1
Reaction time: 5 h
Yield: 15.5 %

Procedure:
A solution of N-(4-acetyl-phenyl)-methanesulfonamide (Ex-100A, 279.6 mg, 1.31 mmol) and 2-(4-formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-propionic acid (Ex-47D, 400 mg, 1.20 mmol) in DMF (5.25 mL) and MeOH (2.25 mL) was treated with lithium methoxide (182.2 mg, 4.8 mmol) and stirred for 5 hours at room temp. under nitrogen atmosphere. The reaction mixture was diluted with water (25 mL) which was then extracted with isopropyl acetate (2×50 mL). The aqueous portion was collected and acidified to a pH of 3 with 3N HCl. The aqueous solution was then extracted with isopropyl acetate (2×50 mL). The organic was collected, dried over sodium sulfate, and concentrated to a green solid. Attempted to recrystallize crude material from ethanol/hexanes; however, this mixture was concentrated and stirred with ethyl acetate (3 mL) to give 95.6 mg (14%) of the title compound as a yellow solid, mp 181–183° C. 1H-NMR (DMSO-d6) δ 10.31 (br s, 1H), 8.24 (s, 1H), 8.12 (d, 2H), 7.95 (d, 1H), 7.87 (d, 1H), 7.67 (d, 1H), 7.50 (d, 1H), 7.30 (d, 2H), 7.09 (t, 1H), 6.45 (s, 1H), 3.81 (s, 3H), 3.08 (s, 3H), 1.65 (s, 6H). MS m/z=516 ([M+H]+, 100%). HRMS m/z: calc. 516.1150, found 516.1165.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[C:16]([CH2:17][CH:18]=[CH2:19])=[CH:15][C:14]([Cl:20])=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(BCCC(C)C)CC(C)C.[OH-:32].[Na+].OO>C1COCC1>[CH2:1]([C:8]1[O:9][C:10]2[C:16]([CH2:17][CH2:18][CH2:19][OH:32])=[CH:15][C:14]([Cl:20])=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCc1cc(Cl)cc2nc(Cc3ccccc3)oc12
Reactant: [OH-]
Agent: CC(C)CCBCCC(C)C
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCCc1cc(Cl)cc2nc(Cc3ccccc3)oc12
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A solution of 2-benzyl-5-chloro-7-allylbenzoxazole (2.2 g, 8 mmol) in THF (12 ml) was added to a solution of di-iso-amylborane (1.13 g, 8 mmol) in THF. The reaction was allowed to stir at room temperature for 21 hours and then 3 N sodium hydroxide solution (4 ml) was added followed by 30% hydrogen peroxide (4 ml). After 3 hours, the reaction mixture was partitioned between dichloromethane and water. The dichloromethane solution was washed with water (3×100 ml) and the solvent was evaporated under reduced pressure. The residue was purified over flash chromatographic silica gel to give the title compound (600 mg) eluted with 1:1 dichloromethane/hexane. The material was recrystallized three times from toluene to give the title compound (200 mg), trip 78-80° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:27]([CH3:31])[C:28]([OH:30])=[O:29].C1(O)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCOCC1>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:27]([CH3:31])[C:28]([OH:30])=[O:29])=[CH:9][CH:10]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Reactant: CC(Cl)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: Oc1ccccc1
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1)C(=O)O
Reaction time: 4 h

Procedure:
28.9 g of 4-(2-chloro-4-trifluoromethylphenoxy)phenol was added to 50 ml of dioxane, and with stirring at 30° to 40° C., 13.8 g of potassium carbonate was added. The mixture was heated to 40° to 60° C., and 10.8 g of α-chloropropionic acid was added. The reaction was performed for 4 hours. The disappearance of the starting phenol was confirmed by gas chromatography, and the reaction product was poured into a suitable amount of water. Sodium carbonate was added to transfer the final product into the aqueous phase. The oily phase was separated and removed, and then hydrochloric acid was added to afford 20 g of a solid precipitate. The final product obtained had a melting point of 90° to 92° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)[CH3:2].[N+:11]([O-])([OH:13])=[O:12].S(=O)(=O)(O)[OH:16].Cl>>[OH:16][CH2:2][CH2:1][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccccc1
Agent: Cl
Product: O=[N+]([O-])c1ccc(NCCO)cc1

Procedure:
The above acetanilide (11.05 g, 0.05 mol) is treated with nitric acid-sulfuric acid mixture and hydrolyzed with 2.5N hydrochloric acid, in the manner as set forth subsequently herein in Example to provide N-(2-hydroxyethyl)-4-nitrobenzenamine.