Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[Br:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[C:21]1([C:40]3[C:31](=[CH:32][C:33]4[O:38][CH2:37][CH2:36][O:35][C:34]=4[CH:39]=3)[O:30][CH2:29]1)[C:22](=[O:28])[NH:23]2>>[Br:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[C:21]1([C:40]3[C:31](=[CH:32][C:33]4[O:38][CH2:37][CH2:36][O:35][C:34]=4[CH:39]=3)[O:30][CH2:29]1)[C:22](=[O:28])[N:23]2[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCCO3
Reactant: BrCc1ccccn1
Agent: Br
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccn2)c2cccc(Br)c2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 4′-bromo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 4′-bromo-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (75%) as a colorless solid: MS (ES+) m/z 465.7 (M+1), 466.7 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11](Cl)[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)=[C:11]([C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(Cl)c(Cl)c(OCc2ccccc2)nn1Cc1ccccc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=c1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c(OCc2ccccc2)nn1Cc1ccccc1
Temperature: 100 °C
Reaction time: 36 h
Yield: 68.6 %

Procedure:
To a round bottom flask was added 2-benzyl-6-(benzyloxy)-4,5-dichloropyridazin-3(2H)-one (20 gm, 55.4 mmol), 4-chlorophenylboronic acid (19.07 gm, 121.88 mmol), 2N sodium carbonate (124.7 ml, 249.3 mmol), toluene (200 ml) and Pd(PPh3)4 (3.2 gm, 2.77 mmol). The reaction was stirred at 100° C. for 36 hrs. After this time, the solution was cooled to rt and the organic layer was separated. The organic layer was washed with water (100 ml), saturated aqueous NaCl (100 ml). The organic layer was dried (MgSO4), filtered and concentrated. The crude material was recrystallized from methanol (150 ml) at −25° C. The solid was collected by filtration to give the title compound, 2-benzyl-6-(benzyloxy)-4,5-bis(4-chlorophenyl)pyridazin-3(2H)-one, (19.5 gm, 70% yield) as light yellow solid. MS (M+H)=513.1.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=O.[F:21][C:22]([F:39])([F:38])[C:23]1[CH:24]=[C:25]([NH:29][NH:30]C(OC(C)(C)C)=O)[CH:26]=[CH:27][CH:28]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:29]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:39])[F:38])[CH:24]=2)[N:30]=1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Reactant: CC(C)(C)OC(=O)NNc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3cccc(C(F)(F)F)c3)c(=O)[nH]2)c1)C(F)(F)F
Yield: 55.5 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 0.500 g, 1.55 mmol), tert-butyl 2-[3-(trifluoromethyl)phenyl]hydrazinecarboxylate (0.428 g, 1.55 mmol), DCM (20 mL) and trifluoro acetic acid (5.0 mL) to afford 0.400 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=C1Nc2ccc(F)cc2Sc2sc3c(c21)CCCC3
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C2=Nc3ccc(F)cc3Sc3sc4c(c32)CCCC4)CC1

Procedure:
In the same manner as in Example 80 and using 8-fluoro-1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 8-fluoro-1,2,3,4-tetrahydro-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzothiazepine is obtained.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[F:17])[NH:13][CH:12]=[CH:11]2.[OH-].[Na+].CN(C)[CH:22]=[O:23]>>[F:17][C:16]1[CH:15]=[C:14]2[C:10]([C:11]([CH:22]=[O:23])=[CH:12][NH:13]2)=[CH:9][C:8]=1[O:7][CH3:6]
Reactant: COc1cc2cc[nH]c2cc1F
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(C=O)c[nH]c2cc1F
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
POCl3 (10.9 ml, 71 mmol) is added dropwise to 21 ml of dimethylformamide under N2 at 10–20° C., is stirred 15 minutes, then a 13 ml dimethylformamide solution of 5-methoxy-6-fluoro-indole (J. Med. Chem., 22:63–69, 1979; 10.7 g, 64.7 mmol) is added at a rate to keep the reaction temperature between 10 and 20° C. After the addition is complete, the mixture is stirred for 1 hour. Crushed ice and aqeuous NaOH (12.5 g/50 ml H2O) is added to reaction. The resulting mixture is heated to reflux with a heat gun for 1 minute, cooled to 10° C., and is filtered to give 11.8 g of 6-fluoro-5-methoxy-1H-indole-3-carbaldehyde (95%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(O[CH2:13][CH3:14])C>>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:6][C:7]3[C:14]([CH:13]=2)=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CCOCC
Reactant: Cc1cc(C)cc(Br)c1
Product: Cc1cc(C)cc(C2=Cc3ccccc3C2)c1

Procedure:
A 3-neck 500-mL round-bottomed flask fitted with a condenser and an addition funnel was charged with 1.86 g (77 mmol) of Mg turnings and 15 mL of anhydrous diethyl ether. Slow addition of a solution of 9.9 g (53 mmol) of 3,5-dimethyl-bromobenzene in diethyl ether (60 mL), followed by refluxing for 1 hour, gave an orange solution of the aryl Gnrgnard reagent. The solution was cooled to room temperature, filtered over a plug of Celite and the solvent was removed in vacuo from the filtrate. Toluene (30 mL) was added and the solution cooled to 0° C. whereupon a solution of 2-indanone-(5.67 g, 43 mmol) in toluene (50 mL) was added dropwise to give an orange slurry. This mixture was warmed to room temperature and stirred for an additional 9 hours. After cooling to 0° C., it was quenched with 100 mL of water. Hexane (150 mL) was added and the reaction mixture neutralized with 5M HCl. The organic layer was separated, and the aqueous layer was extracted with two 40-mL portions of hexane. The combined organic layers were washed with two 40-mL portions of brine and dried over anhydrous magnesium sulfate. After filtration over Celite, the solvent was removed in vacuo yielding 2-(3,5-dimethyl)phenylindanol as a very viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]([CH3:34])[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:31][C:30]2[CH:29]=[CH:28][C:27]([O:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:21])[CH3:34])=[CH:33][CH:32]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CN(C)CCCOc1ccc(N)cc1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CN(C)CCCOc1ccc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 4-(3-(dimethylamino)propoxy)aniline (21.6 mg, 0.12 mmol). The title compound was obtained as a solid (17.5 mg, 33% yield). MS m/z: 527.16, 525.16 [M+H]+.
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:18](=[O:28])[C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=[O:23])[CH2:9][C@H:10]([C:12]([O:14]CC)=[O:13])[CH3:11])=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:17][C:18](=[O:28])[C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=[O:23])[CH2:9][C@H:10]([C:12]([OH:14])=[O:13])[CH3:11])=[CH:5][CH:6]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cccc(C(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cccc(C(=O)O)c1)C(=O)O
Temperature: 55 °C
Reaction time: 5 h

Procedure:
To a mixture of (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (70 mg, 0.201 mmol) and 3-chlorocarbonylbenzoic acid methyl ester (0.302 mmol) in methylene chloride (0.5 mL) is added pyridine (0.5 mL) and the mixture is stirred at room temperature for 24 hours. The solvents are removed under reduced pressure and ethyl acetate is added. The solution is washed with aqueous 1M HCl and brine and the organic phase is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by column chromatography using methylene chloride to furnish N-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-butyl)-isophthalamic acid. Next, to a solution of N-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-butyl)-isophthalamic acid (0.287 mmol) in ethanol (10 mL) is added aqueous 1M NaOH (1.2 mL, 1.12 mmol) and the mixture is stirred at 50-60° C. for 5 hours. The ethanol is removed under reduced pressure and water is added. The solution is acidified with 1M HCl and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1% TFA). The proper fractions are lyophilized to furnish N-((1S,3R)-1-biphenyl-4-ylmethyl-3-carboxy-butyl)-isophthalamic acid. HPLC Retention time 1.05 minutes (condition A); MS 432.3 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (d, J=7.07 Hz, 3H), 1.60 (m, 1H), 1.89 (m, 1H), 2.47 (m, 1H), 2.86 (m, 2H), 4.27 (m, 1H), 7.27-7.35 (m, 3H), 7.34 (t, 1H), 7.43 (t, 2H), 7.55-7.66 (m, 5H), 8.01-8.07 (m, 2H), 8.39 (s, 1H), 8.47 (d, J=8.46 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH2:15][CH2:16][CH3:17])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:18]1([C:24]2[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[N:18]1([C:24]2[N:29]=[CH:28][C:27]([NH:30][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[CH2:15][CH2:16][CH3:17])=[O:14])=[CH:26][CH:25]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: CCCc1oc(-c2ccccc2)nc1C(=O)O
Reactant: Nc1ccc(N2CCOCC2)nc1
Product: CCCc1oc(-c2ccccc2)nc1C(=O)Nc1ccc(N2CCOCC2)nc1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-propyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 2-phenyl-5-propyl-oxazole-4-carboxylic acid and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C22H24N4O3 (m/e) 392, obsd 393 (M+H).
Reaction SMILES: C([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17](O)=O)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:32]=[C:31]([NH2:33])[NH:30][N:29]=2)=[CH:24][CH:23]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:32]=[C:31]([NH:33][CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:20])[S:12][CH:13]=3)[NH:30][N:29]=2)=[CH:26][CH:27]=1
Reactant: Nc1cc(-c2ccc(Cl)cc2)n[nH]1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Sc1nc(CCNc2cc(-c3ccc(Cl)cc3)n[nH]2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound obtained using {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid synthesized in Example 3 and 3-(4-chlorophenyl)-1H-pyrazole-5-amine as starting materials and by operations similar to those of Example 242-1 and Example 242-2 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (The objective compound was extracted in the saturated aqueous sodium hydrogen carbonate solution layer). Aqueous 10% citric acid solution was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][O:30][CH:29]([CH2:33][CH2:34][C:35]([NH2:37])=[O:36])[CH2:28]1>>[NH2:37][C:35](=[O:36])[CH2:34][CH2:33][CH:29]1[CH2:28][N:27]([CH2:20][C:13]2[NH:12][C:11]([C:22]3[S:23][CH:24]=[CH:25][N:26]=3)=[N:10][CH:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Br:1])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:32][CH2:31][O:30]1
Reactant: NC(=O)CCC1CNCCO1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCOC(CCC(N)=O)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 86.1 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.51 g, 3 mmol) was reacted with 3-(morpholin-2-yl)propanamide (0.47 g, 3 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (1.5 g, 86%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([N+:19]([O-])=[O:20])([CH3:18])[CH2:13][O:14][C:15](=[O:17])[CH3:16].C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N+:19]([C:12]([CH3:18])([CH3:11])[CH2:13][O:14][C:15](=[O:17])[CH3:16])[O-:20]
Reactant: CC(=O)OCC(C)(C)[N+](=O)[O-]
Reactant: O=Cc1ccc(F)cc1F
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)OCC(C)(C)[N+]([O-])=Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.4 %

Procedure:
A suspension of 2,4-difluorobenzaldehyde (428.2 mg, 3.01 mmol), 2-methyl-2-nitro-1-acetoxypropane (467.8 mg, 2.90 mmol) and zinc (321.7 mg, 4.92 mmol) in ethanol (5 ml) was cooled to 0° C. in ice-water bath. Acetic acid (0.57 ml, 9.9 mmol) was added dropwise to the mixture and was warmed to room temperature and stirred for 16 hours. The mixture was filtered through Celite® bed and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=2/1) to give the title compound (380.8 mg; 48%).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(=O)([O-])[O-].[K+].[K+].[C:15]1([CH:21](Br)[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[C:15]1([CH:21]([S:1][C:2]2[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=2)[NH2:5])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1cccc(S)c1
Reactant: CC(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Sc1cccc(N)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-mercaptoaniline (1 g) and potassium carbonate (1.21 g) in N,N-dimethylformamide (20 mL) was added 1-phenylethyl bromide (1.2 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=1/1) to give the title compound (1.78 g).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][C:7]#[C:8][CH2:9][OH:10].[CH3:16]C(C)([O-])C.[K+].CI>O1CCCC1>[F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][C:7]#[C:8][CH2:9][O:10][CH3:16]
Reactant: CC(C)(C)[O-]
Reactant: OCC#CCOCc1cc(Br)ccc1F
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COCC#CCOCc1cc(Br)ccc1F
Temperature: -78 °C

Procedure:
A solution of 4-(2-fluoro-5-bromobenzyloxy)-but-2-ynyl alcohol (1.07 g, 3.92 mmol) in tetrahydrofuran (26 ml) was cooled to −40° C. and then treated with potassium t-butoxide (4.31 ml of a 1 M solution in tetrahydrofuran, 4.31 mmol). The resulting dark orange solution was stirred for thirty minutes, cooled to −78° C. and treated with methyl iodide (0.49 ml, 7.84 mmol). The reaction was warmed to 0° C. and stirred for 1.5 hours. The reaction mixture was then partitioned between methylene chloride and saturated sodium bicarbonate. The organic fraction was dried over sodium sulfate, and the solvents were removed in vacuo. The desired title intermediate was further purified by high performance liquid chromatography to yield 790 mg (70%) as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[C:4]([N+:17]([O-])=O)[C:3]=1[NH:20][C:21](=[O:25])[O:22][CH2:23][CH3:24].[Cl-].[NH4+]>CO.O.[Zn]>[NH2:17][C:4]1[CH:5]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:7]=[C:2]([F:1])[C:3]=1[NH:20][C:21](=[O:25])[O:22][CH2:23][CH3:24]
Reactant: CCOC(=O)Nc1c(F)cc(NCc2ccc(F)cc2)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: CCOC(=O)Nc1c(N)cc(NCc2ccc(F)cc2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.8 %

Procedure:
To a stirred solution of compound 3 (0.075 g, 0.24 mmol, 1.0 equiv) in methanol (3 mL) was added zinc powder (0.0800 g, 1.22 mmol, 5.00 equiv) followed by ammonium chloride solution (0.065 g, 1.2 mmol, 5.0 equiv) in water (1 mL). The reaction mixture was stirred at RT for 4 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with DCM (10 mL), water (10 mL) and filtered through a pad of celite. The organic layer was separated from filtrate and the aqueous layer was extracted with DCM (2×10 mL). The combined organic extracts were dried over anhydrous Na2SO4, concentrated under vacuum to give crude; which was purified by silica gel column chromatography (EtOAc/Hexane, 1:4) to afford compound 2A (0.050 g, 71%) as an off-white solid. TLC: 40% EtOAc/Hexane (Rf: 0.20); 1H NMR (400 MHz, CDCl3): δ 7.32-7.29 (m, 2H), 7.04 (t, J=8.8 Hz, 2H), 5.84 (d, J=9.6 Hz, 1H), 5.78 (s, 1H), 4.25-4.18 (m, 4H), 4.04-3.96 (m, 3H), 1.30 (t, J=6.8 Hz, 3H); LC-MS: m/z=322 (M++1) at RT 3.38 (99.0% purity); UPLC purity: 99.5%.
Reaction SMILES: C[N:2]1CCOCC1.ClC(OCC)=O.[N:14]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([CH3:34])[C@H:15]([C:31](O)=[O:32])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>C1COCC1>[N:14]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([CH3:34])[C@H:15]([C:31]([NH2:2])=[O:32])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: CN1CCOCC1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(N)=O
Reaction time: 0.25 h
Yield: 97.8 %

Procedure:
Under cooling with ice, NMM (0.463 ml, 4.21 mmol) and ethyl chloroformate (0.403 ml, 4.21 mmol) were added to a solution of Boc-N-Me-Tyr(Bzl)—OH (1.35 g, 3.51 mmol) in THF (35 ml), followed by stirring for 15 min. The reaction mixture was stirred for further 30 min., while bubbling gaseous ammonia therein. The reaction mixture was then left standing at room temperature, diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:1) to give Boc-N-Me-Tyr(Bzl)—NH2 (1.32 g, 98%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][C@@H:4]([OH:7])[C@H:3]1[OH:8].[Cl:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13](Cl)=[CH:12][C:11]=1[Cl:20].C(N(CC)CC)C>C(O)(C)(C)C>[Cl:9][C:10]1[C:11]([Cl:20])=[CH:12][C:13]([NH:1][C@@H:2]2[CH2:6][CH2:5][C@@H:4]([OH:7])[C@H:3]2[OH:8])=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Reactant: N[C@@H]1CC[C@@H](O)[C@H]1O
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1cc(Cl)c(Cl)cc1N[C@@H]1CC[C@@H](O)[C@H]1O

Procedure:
(±)-(1R*,2S*,3R*)-3-Amino-1,2-cyclopentanediol (7.10 g, 50.0 mmol), 1,2,4-trichloro-5-nitrobenzene (11.67 g, 50.0 mmol as 97%, Aldrich), triethylamine (10 mL) and t-butanol (50 mL) were refluxed under nitrogen for 7 hours. Volatiles were removed in vacuo and the black residue chromatographed on silica gel. Title compound was eluted with methanol:chloroform/1:24 as an orange solid (6.45 g, 42%). Crystallization of such a sample from ethanol-water gave title compound as yellow needles, m.p. 137°-140° C.; 1H-NMR (DMSO-d6) δ: 8.26 and 7.49 (both s, 1 each, 2 aromatic CH), 8.06 (d, J=7.0 Hz, 1, NH), 5.04 (d, J=6.1 Hz, 1, OH), 4.65 (d, J=4.1 Hz, 1, OH), 4.0-3.7 (m, 3,2 OCH and NCH), 2.2-2.1, 2.0-1.8, 1.7-1.3 (all m, 4, 4 CH).