Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1.[CH3:22][O:23][CH2:24][CH2:25][NH2:26].C(NC(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:19])(=[O:18])[NH:26][CH2:25][CH2:24][O:23][CH3:22])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1
Reactant: COCCN
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(Cl)ncn1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COCCNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-(6-chloropyrimidine-4-carboxamido)-3-methylbenzene-1-sulfonyl chloride (Intermediate 30, 400 mg; 1.15 mmol) in THF (20 ml) was treated with 2-methoxyethanamine (125 mL; 1.4 mmol) and diisopropylamine (0.4 ml; 2.9 mmol). After stirring at RT for 18 hours the solvent was removed in vacuo and the residue redissolved in DCM and washed with water. The organic extracts were passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc. The title product was obtained as a white solid.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:22])=[C:14]1[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=[O:5])C.C(O)C.[OH-].[Na+].Cl>O>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:22])=[C:14]1[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)([OH:5])=[O:3]
Reactant: CCOC(=O)CCCCCCCn1c(-n2ccnc2)c(C)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(-n2ccnc2)n(CCCCCCCC(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1-(7-ethoxycarbonylheptyl)-2-(1-imidazolyl)-3-methylindole (0.75 g), absolute ethanol (2 ml), and 3N sodium hydroxide (10 ml) is stirred at room temperature for 18 hours. The resulting clear solution is concentrated in vacuo and the residue obtained is diluted with water (40 ml) and acidified to pH 5.9 with 1N hydrochloric acid. The mixture is extracted with ethyl acetate (3×25 ml) and the extract is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to give an oil which crystallizes on standing. The solid is purified by trituration with ether (10 ml) to give 1-(7-carboxyheptyl)-2-(1-imidazolyl)-3-methylindole; m.p. 101°-103°.
Reaction SMILES: [Cl:1]C(N(C)C)=C(C)C.[Br:9][C:10]1[CH:11]=[C:12]2[C:22](=[CH:23][CH:24]=1)[O:21][C:15]1[CH:16]=[N:17][C:18]([Cl:20])=[CH:19][C:14]=1[C:13]2([NH:28][C:29]([NH:31][C:32](=[O:42])[C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[S:30])[CH2:25][CH2:26]O>C(Cl)Cl>[ClH:1].[Br:9][C:10]1[CH:11]=[C:12]2[C:13]3([CH2:25][CH2:26][S:30][C:29]([NH:31][C:32](=[O:42])[C:33]4[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=4)=[N:28]3)[C:14]3[CH:19]=[C:18]([Cl:20])[N:17]=[CH:16][C:15]=3[O:21][C:22]2=[CH:23][CH:24]=1
Reactant: O=C(NC(=S)NC1(CCO)c2cc(Br)ccc2Oc2cnc(Cl)cc21)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Product: Cl
Product: O=C(NC1=NC2(CCS1)c1cc(Br)ccc1Oc1cnc(Cl)cc12)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
1-Chloro-N,N,2-trimethylprop-1-en-1-amine (2.84 ml, 21.28 mmol) was added to a solution of N-((7-bromo-3-chloro-5-(2-hydroxyethyl)-5H-chromeno[2,3-c]pyridin-5-yl)carbamothioyl)-4-nitrobenzamide (12 g, 21.28 mmol) in DCM (200 ml). The reaction mixture was stirred at RT for 8 hours and then concentrated under reduced pressure to 50% of its original volume. A precipitate formed upon cooling which was filtered off, washed with DCM and then dried under reduced pressure to afford N-(7-bromo-3-chloro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]thiazin]-2′-yl)-4-nitrobenzamide hydrochloride (10.5 g, 18.03 mmol, 85% yield) as an off white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:17][CH2:18][CH:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]2[C:14]=1[N:13]([CH3:15])[C:12](=[O:16])[CH:11]=[CH:10]2.[H][H].[Cl:32]N1C(=O)CCC1=O.Cl>ClCCl.C1COCC1>[Cl:32][C:19]([CH2:18][CH2:17][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12](=[O:16])[N:13]2[CH3:15])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: [H][H]
Reactant: CCOC(=O)C(CCc1ccc(OC)c2c1ccc(=O)n2C)C(=O)OCC
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C(Cl)(CCc1ccc(OC)c2c1ccc(=O)n2C)C(=O)OCC
Yield: 121.8 %

Procedure:
Sodium hydride (60% in oil) (0.21 g) was added under ice cooling to a THF solution (30 ml) of 1.79 g of diethyl 2-[2-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]malonate, and stirring was carried out until the generation of hydrogen stopped. N-chlorosuccinimide (0.7 g) was added, followed by stirring for 1.5 hours. The reaction mixture was added to cold hydrochloric acid, and extraction with dichloromethane was performed. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to thereby obtain 2.38 g (yield: quantitative) of diethyl 2-chloro-2-[2-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]malonate as a yellow oil.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>>[Cl:10][CH2:11][C:12]1[N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][CH:14]=1
Reactant: NC(=O)c1ccccc1
Reactant: O=C(CCl)CCl
Product: ClCc1coc(-c2ccccc2)n1
Temperature: 130 °C

Procedure:
A 50 mL round bottomed flask equipped with a condenser was charged with benzamide (a compound of formula (b), 363.4 mg, 3.0 mmol) and 1,3-dichloroacetone (457.1 mg, 3.6 mmol, 1.2 equiv.). This mixture was heated at 130° C. for 1 hour under a nitrogen atmosphere. After cooling to room temperature, the resulting mixture was purified by recrystallization from acetonitrile (6 mL). The suspension was heated under reflux reaction condition for 5 minutes and cooled down to ambient temperature. The resulting solid was filtered through a glass filter, and the crystals on the filter were washed with acetonitrile (2 mL). The desired product, 4-(chloromethyl)-2-phenyl-1,3-oxazole, was obtained as a colorless powder.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>O1CCCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:29](=[O:30])[NH:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[C:23]([C:31]([F:32])([F:33])[F:34])[CH:24]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2c(c1)CCCN2Cc1ccccc1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Oc1ccc2c(c1)CCCN2Cc1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of 1-benzyl-1, 2, 3, 4-tetrahydro-quinolin-6-ol (0.239 g., 1 mmol) in dry tetrahydrofuran (5 ml) was added to a stirred suspension of sodium hydride (0.024 g., 1 mmol) in dry tetrahydrofuran (5 ml) at −10° C. during 5 min. The reaction mixture was stirred for 20 min. Then 4-chloro-3-trifluoromethyl-phenyl isocyanate (0.265 g., 1 mmol) was added to the stirring reaction mixture. Stirring was continued for additional 2.5 hours during which the temperature was allowed to rise to room temperature (34° C.). The reaction mixture was quenched with water (0.2 ml), concentrated under vaccum, diluted with water (5 ml), extracted with chloroform (2×5 ml) and dried over sodium sulphate. The combined fractions of chloroform were concentrated under vaccum. The residue was chromatographed on silica gel using chloroform-hexane (20:80) as eluant to give 2k; yield: 0.25 g. (54.2%), m.p. 151° C., C24H20ClF3N2O2; 1H NMR δ ppm (CDCl3): 2.00 (bs, 2H), 2.79 (t, 2H), 3.36 (t, 2H), 4.46 (s, 2H), 6.42-6.46 (m, 1H), 6.70-6.79 (m, 2H), 6.96 (s, 1H), 7.23-7.31 (m, 5H), 7.75-7.82 (m, 2H); IR vmax (KBr) (cm−1): 555, 701, 898, 1027, 1218, 1362, 1509, 1635, 1721, 2375, 2658, 2957, 3028, 3449, 3756; MS: m/z=461 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([F:12])([F:10])[F:11])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Product: CC(=O)Nc1ccc(Br)cc1C(F)(F)F
Yield: 99.7 %

Procedure:
A solution of 2-amino-5-bromobenzotrifluoride (1.623 g, 6.76 mmol, Aldrich) in acetic anhydride (10 mL) was stirred at room temperature for 12 h to produce a white needle precipitate. It was filtered to give 1.840 g (99.7%) of title compound. Mp: 140°-2° C., 1HNMR (CDCl3): δ2.212 (s, 3H); 7.358(s, 1H); 7.659(d, 1H, J=8.7 Hz); 7.726(d, 1H, J=1.8 Hz); 8.118 (d, 1H, J=8.4 Hz).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N+:24]([O-])=O)=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([O:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1>C(OCC)(=O)C.Cl.[Pd].ClCCl>[NH2:24][C:5]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:23][C:8]2[C:9]([C:19]([O:21][CH3:22])=[O:20])=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[O:11][C:7]=2[CH:6]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(C3CC3)cc12
Agent: [Pd]
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(C3CC3)cc12

Procedure:
A solution of methyl 5-cyclopropyl-2-(4-fluorophenyl)-6-nitro-1-benzofuran-3-carboxylate (3.175 g, 8.94 mmol) in ethyl acetate (250 mL) containing 2M HCl (17 drops) was stirred with 10% palladium on carbon (0.951 g, 0.894 mmol) under an atmosphere of hydrogen at 21° C. for 16 hours. The reaction mixture was filtered through celite and the filtrate was evaporated under vacuum to give a dark green solid. This was dissolved in dichloromethane, washed with sodium bicarbonate solution, separated by hydrophobic frit, then evaporated to dryness and purified by flash chromatography, eluting over silica gel with a gradient of 0-30% ethyl acetate in cyclohexane. Appropriate fractions were combined and evaporated under vacuum to give the methyl 6-amino-5-cyclopropyl-2-(4-fluorophenyl)-1-benzofuran-3-carboxylate. LCMS (m/z, ES+)=326 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[F:23])[C:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[CH:13]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[NH:12]2)=[O:10])=[CH:4][CH:3]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40].C(N(CC)CC)C>C(Cl)Cl>[C:39]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[F:23])[C:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[CH:13]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[NH:12]2)=[O:10])=[CH:4][CH:3]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(N)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-amino-phenyl)-amide (40 mg, 0.072 mmol) in methylene chloride (5 mL), acetic anhydride (0.072 mmol) was added at room temperature followed by triethylamine (0.10 mL). The mixture was stirred at for 1 hr. and then chromatographed on an ISCO machine (12 g, 40-85% EtOAc/Hexanes) to give a white solid. 34 mg.
Reaction SMILES: Br[CH:2]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][F:6].[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1>CC(C)=O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH:2]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][F:6])=[CH:12][CH:13]=1
Reactant: CC(C)(CF)C(=O)C(Br)Oc1ccc(Cl)cc1
Reactant: c1nc[nH]n1
Solvent: CC(C)=O
Product: CC(C)(CF)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Yield: 89.1 %

Procedure:
87 g (0.27 mol) of 1-bromo-1-(4-chlorophenoxy)-3,3-dimethyl-4-fluoro-2-butanone were dissolved in 200 ml of acetone and the solution was added dropwise to a boiling solution of 46 g (0.66 mol) of 1,2,4-triazole in 200 ml of acetone. After heating the mixture under reflux for one hour, the solvent was removed in vacuo, the residue was taken up in methylene chloride, the methylene chloride mixture was washed several times with water and the organic phase was dried over sodium sulphate. After removing the solvent in vacuo, the residue was crystallized with petroleumm ether. 75 g (89% of theory) of 1-(4-chlorophenoxy)-3,3-dimethyl-4-fluoro-1-(1,2,4-triazol-1-yl)-2-butanone of melting point 60° to 63° C. were obtained.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([N:19]3[C:31]4[CH:30]=[C:29]5[C:32]([CH3:69])([CH3:68])[C:33]6[C:38]([C:28]5=[CH:27][C:26]=4[C:25]4[C:20]3=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:37][CH:36]=[CH:35][C:34]=6[C:39]3[CH:40]=[C:41]4[C:49](=[CH:50][CH:51]=3)[N:48](C(OC(C)(C)C)=O)[C:47]3[CH:46]=[C:45]5[C:59]([CH3:67])([CH3:66])[C:60]6[C:65]([C:44]5=[CH:43][C:42]4=3)=[CH:64][CH:63]=[CH:62][CH:61]=6)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C1(C)C=CC=CC=1.C1(OC)C=CC=CC=1>[C:13]1([C:11]2[N:12]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]([N:19]3[C:31]4[CH:30]=[C:29]5[C:32]([CH3:69])([CH3:68])[C:33]6[C:38]([C:28]5=[CH:27][C:26]=4[C:25]4[C:20]3=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:37][CH:36]=[CH:35][C:34]=6[C:39]3[CH:40]=[C:41]4[C:49](=[CH:50][CH:51]=3)[NH:48][C:47]3[CH:46]=[C:45]5[C:59]([CH3:67])([CH3:66])[C:60]6[C:65]([C:44]5=[CH:43][C:42]4=3)=[CH:64][CH:63]=[CH:62][CH:61]=6)[N:10]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)n1c2ccc(-c3cccc4c3C(C)(C)c3cc5c(cc3-4)c3ccccc3n5-c3nc(-c4ccccc4)nc(-c4ccccc4)n3)cc2c2cc3c(cc21)C(C)(C)c1ccccc1-3
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccc(-c2cccc4c2C(C)(C)c2cc5c(cc2-4)c2ccccc2n5-c2nc(-c4ccccc4)nc(-c4ccccc4)n2)cc13
Temperature: 40 °C
Reaction time: 3 h

Procedure:
30.2 g (34.0 mmol) of tert-butyl 7-{10-(4,6-diphenyl-1,3,5-triazin-2-yl)-12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluorenyl}-12,12-dimethyl-12H-10-azaindeno[2,1-b]fluorene-10-carboxylate are dissolved in 900 ml of toluene and 200 ml of anisole, and 50 ml of trifluoroacetic acid are subsequently added. The mixture is stirred at 40° C. for 3 h and, when the reaction is complete, neutralised by means of ice-water and 20% NaOH solution. The mixture is extracted with dichloromethane, dried and recrystallised from toluene. The yield is 23.6 g (30 mmol, 88%).
Reaction SMILES: II.FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C([I:14])C=CC=1)=O.[CH2:24]([O:26][C:27](=[O:60])[C@H:28]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[C:40]([O:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH:39]=1)[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH3:25]>ClCCl>[CH2:24]([O:26][C:27](=[O:60])[C@H:28]([CH2:37][C:38]1[C:43]([I:14])=[CH:42][C:41]([O:44][C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])=[C:40]([O:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH:39]=1)[NH:29][C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH3:25]
Reactant: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(=O)OC(C)(C)C)c(OC(=O)OC(C)(C)C)c1)NC(=O)OC(C)(C)C
Agent: II
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1cc(OC(=O)OC(C)(C)C)c(OC(=O)OC(C)(C)C)cc1I)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 77 %

Procedure:
Iodine (7.4 mmol) and bis(trifluoroacetoxy)iodobenzene (8.16 mmol) were added to a solution of the tri-boc protected dopa ester analog 16 (5.7 mmol) in anhydrous dichloromethane (60 mL) under argon. The reaction mixture was stirred at room temperature for 40 min and then quenched with a saturated solution of sodium thiosulfate. The organic layer was washed with water (3×10 mL), dried with anhydrous sodium sulfate, filtered and evaporated in a rotary evaporator. The product was purified by silica gel column chromatography using 15-20% ethyl acetate in hexane as the mobile phase to give the iodo analog 17 as white foam in 77% yield.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:26][C:27](=[O:29])[CH3:28])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:5][CH:4]=1.[Na].O.C(O)C.C[N:36](C)C=O>Cl.CO>[NH2:36][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:26][C:27](=[O:29])[CH3:28])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(CBr)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Solvent: CO
Product: CC(=O)Nc1nc(CCc2ccc(CN)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-{4-{2-[4-(bromomethyl)phenyl]ethyl}-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide (70 mg) in N,N-dimethylformamide (1 ml) was added diformimide sodium salt (13.5 mg), and the mixture was stirred for 10 min at 20° C. To the reaction mixture was added water, the mixture was extracted with ethyl acetate, washed with water twice, dried over magnesium sulfate, and evaporated to give a crude diformimide compound. The diformimide compound was suspended in conc. hydrocloric acid (200 μl), ethanol (2 ml) and methanol (0.5 ml). The reaction mixture was stirred at 20° C. for 3 hrs., then at 50° C. for 3 hrs. The volatails were evaporated. To the residue was added saturated sodium hydrogen carbonate aqueous solution, the mixture was extracted with chloroform, dried over maganesium sulfate and evaporated to give crude N-{4-(2-{4-[aminomethyl]phenyl}ethyl)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide, that was used as crude in the next reaction.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)[CH:20]=[C:19]([C:32](OC)=[O:33])[N:18]=3)[N:12]=2)[CH:8]=[C:7]([C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=2)[CH:6]=1)=O.OCC1N=C(C2C=CC=C(C3C=C(C4C=CC=CC=4)C=C(CO)N=3)N=2)C=C(C2C=CC=CC=2)C=1>>[OH:2][CH2:3][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:22]=[C:21]([C:23]4[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=4)[CH:20]=[C:19]([CH2:32][OH:33])[N:18]=3)[N:12]=2)[CH:8]=[C:7]([C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=2)[CH:6]=1
Reactant: COC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)cc(-c2cccc(-c3cc(-c4ccc([N+](=O)[O-])cc4)cc(C(=O)OC)n3)n2)n1
Agent: OCc1cc(-c2ccccc2)cc(-c2cccc(-c3cc(-c4ccccc4)cc(CO)n3)n2)n1
Product: O=[N+]([O-])c1ccc(-c2cc(CO)nc(-c3cccc(-c4cc(-c5ccc([N+](=O)[O-])cc5)cc(CO)n4)n3)c2)cc1
Yield: 40 %

Procedure:
Compound 18b was synthesized from 17b using a method analogous to the synthesis described in 18a.
Reaction SMILES: [C:1]1(CC[C@H](C2C=CC=C(OCCCC(=O)NOC(C)(C)C)C=2)O)[CH:6]=CC=C[CH:2]=1.[O:29]=[C:30]([N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][C@H:39]1[C:44]([OH:46])=[O:45])[C:31](=[O:37])[C:32]([CH3:36])([CH3:35])[CH2:33][CH3:34].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:36][C:32]([CH3:35])([CH2:33][CH3:34])[C:31](=[O:37])[C:30]([N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][C@H:39]1[C:44]([O:46][CH2:2][CH2:1][CH3:6])=[O:45])=[O:29]
Reactant: CC(C)(C)ONC(=O)CCCOc1cccc([C@H](O)CCc2ccccc2)c1
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCOC(=O)[C@@H]1CCCCN1C(=O)C(=O)C(C)(C)CC
Reaction time: 8 h
Yield: 176.2 %

Procedure:
A solution of alcohol 2 (385 mg, 1.0 mmol) in CH2Cl2 (3 mL) was treated with (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylic acid (23, 255 mg, 1.0 mmol, prepared from L-pipercolic acid in 4 steps following literature procedures by Holt et al. J. Amer. Chem. Soc., 1993, 115, 9925-9938), followed by 1,3-dicyclohexylcarbodiimide (DCC, 247 mg, 1.2 mmol), and 4-(dimethylamino)-pyridine (DMAP, 85 mg, 0.70 mmol) under a nitrogen atmosphere. The resulting bright yellow suspension was allowed to stir overnight. The mixture was then filtered through glass wool and chromatographed (silica gel, 20% EtOAc/hexanes) to give (1R)-3-Phenyl-1-[3-9(3-tert-butyloxycarbamylpropyl)oxy)phenyl]-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarboxylate (524 mg, 84%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) (single diastereomer, mixture of rotamers) 7.35-6.90 (m, 9 H), 5.80 (t, J=5.9 Hz, 1 H), 5.32 (d, J=5.0 Hz, 0.82 H, pipercolate α-H of rotamer A), 4.80 (br. s, 1 H), 4.02 (t, J=6.1 Hz, 2 H), 3.40-3.25 (m, 3 H), 3.12 (td, J=13.0, 3.3 Hz, 1 H), 2.60 (m, 2 H), 2.35 (d, J=14 Hz, 1 H), 2.28 (m, 1 H), 2.07 (m, 1 H), 1.96 (t, J=6.3 Hz, 2 H), 1.80-1.60 (m, 5 H), 1.43 (s, 9 H), 1.22 (s, 3 H), 1.20 (s, 3 H), 0.88 (t, J=7.4 Hz, 3 H); 13C NMR (CDCl3, 75 MHz) (single diastereomer, mixture of rotamers) 208.2, 170.1, 167.6, 159.4, 156.4, 141.7, 141.3, 130.1, 128.9, 128.7, 126.5, 119.4, 114.7, 113.2, 113.0, 66.1, 57.1, 51.7, 47.1, 44.5, 38.3, 32.9, 32.1, 30.0, 28.8, 26.8, 25.4, 24.9, 24.0, 23.8, 23.5, 21.6, 9.1. MS(FAB): (M+Na)+ 645, (M+H)+ 623.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]([CH:35](OC)OC)[CH2:10][CH2:11][CH2:12][C:13]2[CH:34]=[CH:33][C:16]([C:17]([NH:19][C@H:20]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:18])=[CH:15][CH:14]=2)=[C:4]([NH2:40])[N:3]=1.Cl.[NH3:42]>C(O)C.O>[NH2:42][C:2]1[N:7]=[C:6]([NH2:8])[C:5]2[C:9]([CH2:10][CH2:11][CH2:12][C:13]3[CH:34]=[CH:33][C:16]([C:17]([NH:19][C@H:20]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:18])=[CH:15][CH:14]=3)=[CH:35][NH:40][C:4]=2[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCCC(c2c(N)nc(N)nc2N)C(OC)OC)cc1)C(=O)OCC
Reactant: N
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCCc2c[nH]c3nc(N)nc(N)c23)cc1)C(=O)OCC
Temperature: 25 °C

Procedure:
To a suspension of the product of Example 17 (100 mg) in ethyl alcohol (2.0 ml), ethyl alcohol containing 20% (w/w) of hydrogen chloride (2.0 ml) and water (0.02 ml) were added and the mixture was heated at room temperature for 2 hours. The reaction mixture was diluted with water (10 ml), and neutralized by adding aqueous ammonia thereto, followed by removing solvent therefrom by distillation under reduced pressure. The resulting residue was purified by column chromatography (15 g of silica gel; dichloromethane separated from conc. ammonia→dichloromethane separated from conc. ammonia-ethanol=40:1→30:1) to give the subject compound (68 mg).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH:7]([CH2:9][CH:10]=[CH2:11])[OH:8])[CH2:4][O:3]1.Cl.C(Cl)(Cl)Cl>O1CCCC1>[CH2:4]([OH:3])[CH:5]([OH:6])[CH:7]([OH:8])[CH2:9][CH:10]=[CH2:11]
Reactant: C=CCC(O)C1COC(C)(C)O1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: C=CCC(O)C(O)CO

Procedure:
A solution of 11 g of [R-(R*,R*)]-2,2-dimethyl-alpha-2-propenyl-1,3-dioxolane-4-methanol, prepared by the procedure described in J.. Am. Chem. Soc., 1985, 107(26), 8186-8190, in 300 ml of 1:1 tetrahydrofuran: 2N hydrochloric acid is heated at the reflux temperature of the solvents for 2 hours. Chloroform is added and the layers are separated. The aqueous layer is re-extracted 2X with chloroform. The aqueous layer is neutralized with potassium carbonate and exhaustively extracted with 80% chloroform/iso-propanol. The combined organic layers are concentrated in vacuo to give 7.51 g of the desired product.