Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C2(CO)CCCN2C2C=CC=CC=2)C=CC=CC=1.[N+](C1C=CC=CC=1C(O)=O)([O-])=O.[OH:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=O.[CH2:41]([O:43][C:44](=[O:49])/[CH:45]=[CH:46]/[CH:47]=[O:48])[CH3:42]>C1(C)C=CC=CC=1>[CH2:41]([O:43][C:44]([CH:45]1[C:46]([CH:47]=[O:48])=[CH:35][C:34]2[C:33](=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:32]1)=[O:49])[CH3:42]
Reactant: CCOC(=O)/C=C/C=O
Reactant: O=Cc1ccccc1O
Agent: O=C(O)c1ccccc1[N+](=O)[O-]
Agent: OCC1(c2ccccc2)CCCN1c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1Oc2ccccc2C=C1C=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 29 %

Procedure:
To a stirred mixture of commercially available (S)-(−)-α{tilde over (α)}Diphenyl-2-pyrrolidinemethanol (0.83 g, 3.28 mmol) in toluene (40 mL) was added 2-nitrobenzoic acid (0.55 g, 3.28 mmol), commercially available 2-Hydroxybenzaldehyde (2.00 g, 16.38 mmol) and (E)-4-oxo-but-2-enoic acid ethyl ester (2.51 g, 19.65 mmol). After addition was complete the mixture was stirred at room temperature for 3 days. Upon completion of the reaction the toluene was removed by vacuum distillation. The residue was diluted with ethyl acetate and washed with water, a saturated sodium bicarbonate solution and a saturated sodium chloride solution. The organic fraction was then dried over magnesium sulfate. The crude product obtained was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g; (0% to 100% ethyl acetate/hexane) to afford 3-formyl-2H-chromene-2-carboxylic acid ethyl ester as a yellow oil, 1.09 g (29% yield). (Ref: Chem. Eur. Journal; 2007, 13, pg 574).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[Cl:17])=[C:6]([Cl:18])[N:5]=[CH:4][N:3]=1.[K].[CH2:20]([NH:27][S:28](=[O:31])(=[O:30])[NH2:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Cl:18][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:29][S:28](=[O:30])(=[O:31])[NH:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[Cl:17]
Reactant: NS(=O)(=O)NCc1ccccc1
Reactant: COc1ccc(Cl)c(Oc2c(Cl)ncnc2Cl)c1
Agent: [K]
Product: COc1ccc(Cl)c(Oc2c(Cl)ncnc2NS(=O)(=O)NCc2ccccc2)c1
Yield: 47 %

Procedure:
Benzylsulfamic acid [6-chloro-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin-4-yl]-amide (0.7 g) was prepared from 4,6-dichloro-5-(2-chloro-5-methoxy-phenoxy)-pyrimidine (1 g) and benzylsulfamic acid amide potassium salt (1.21 g) according to the procedure described in Referential Example 15. LC-MS: tR=5.13; [M+H]+=456.91.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:20]I.N1C=CN=C1.[CH3:27][O:28][C:29](=[O:40])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]O)[CH:33]=1>ClCCCl>[CH3:27][O:28][C:29](=[O:40])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][I:20])[CH:33]=1
Reactant: COC(=O)CCc1cccc(CO)c1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: COC(=O)CCc1cccc(CI)c1
Reaction time: 0.25 h
Yield: 77.7 %

Procedure:
A mixture of Ph3P (36 mg, 0.14 mmol), I2 (41 mg, 0.16 mmol) and imidazole (10.5 mg, 0.15 mmol) in 0.40 mL 1,2-dichloroethane was stirred for 15 min. and then a solution of 18 (20.5 mg, 0.11 mmol) in 0.1 mL 1,2-dichloroethane was added by cannula. The resulting mixture was stirred for 1 h and then was filtered through basic alumina, washing with ethyl acetate. The filtrate was evaporated and the residue was purified by flash chromatography on silica gel to give compound 19 (26 mg, 81%).
Reaction SMILES: NC1C=CC(C)=C(C(C2C=CC(NC3C=CC(C(F)(F)F)=CC=3)=CC=2Cl)=O)C=1.[Cl:29][C:30]1[CH:35]=[C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH3:44])[CH:33]=[CH:32][C:31]=1[C:45]([C:47]1[CH:52]=[C:51]([N+:53]([O-])=O)[CH:50]=[CH:49][C:48]=1[CH3:56])=[O:46]>>[NH2:53][C:51]1[CH:50]=[CH:49][C:48]([CH3:56])=[C:47]([C:45]([C:31]2[CH:32]=[CH:33][C:34]([NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])=[CH:35][C:30]=2[Cl:29])=[O:46])[CH:52]=1
Reactant: COc1ccccc1Nc1ccc(C(=O)c2cc([N+](=O)[O-])ccc2C)c(Cl)c1
Agent: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Product: COc1ccccc1Nc1ccc(C(=O)c2cc(N)ccc2C)c(Cl)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 415, using compound 440 (0.28 mmol). The crude product was used without any further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][CH:9]=[N:8][C:7]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])=[O:5])C.[OH-].[Na+]>C(O)C>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:7]1[N:8]=[CH:9][S:10][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1scnc1-c1ccccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1-c1ncsc1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 41 %

Procedure:
To the crude 4-(2-methoxy-phenyl)-thiazole-5-carboxylic acid ethyl ester (0.88 g) in 95% ethanol (20 ml) was added sodium hydroxide (0.67 g, 16.75 mmol) and the resulting mixture was stirred at room temperature for 5 hours. After acidification with 3N HCl and concentration under vacuum, the remaining residue was taken up with water, and extracted with ethyl acetate (3×50 ml). The combined organics were dried over Na2SO4 and evaporated under reduced pressure to afford the title compound as a yellow solid (0.77 g, 3.28 mmol, a 41% yield). m.p.: 170-172° C.; 1H NMR (200 MHz, DMSO) δ 3.72 (s, 3H, OCH3), 6.99-7.12 (m, 2H, Ar), 7.35-7.46 (m, 2H, Ar), 9.26 (s, 1H, 2-CH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[CH:33][C:32]([C:35](O)=[O:36])=[N:31]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:35]([C:32]4[CH:33]=[CH:34][NH:30][N:31]=4)=[O:36])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: O=C(O)c1cc[nH]n1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cc[nH]n2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 1H-pyrazole-3-carboxylic acid (17 mg, 0.15 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH:5]=[N:4][CH:3]=1.B([C:27]1[CH:38]=[CH:37][C:30]([CH2:31][C@@H:32]([C:34]([OH:36])=[O:35])[NH2:33])=[CH:29][CH:28]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[NH2:33][CH:32]([CH2:31][C:30]1[CH:37]=[CH:38][C:27]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[CH:11]=3)[N:7]=2)=[CH:28][CH:29]=1)[C:34]([OH:36])=[O:35]
Reactant: COc1ccc(CNc2cncc(Cl)n2)cc1OC1CCCC1
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CNc2cncc(-c3ccc(CC(N)C(=O)O)cc3)n2)cc1OC1CCCC1
Temperature: 150 °C
Yield: 7.9 %

Procedure:
An Emrys process vial (2-5 ml) for microwave was charged with (6-chloro-pyrazin-2-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine (50 mg, 0.15 mmol), 4-borono-L-phenylalanine (31 mg, 0.15 mmol) and 2 ml of acetonitrile. Aqueous sodium carbonate (2 ml, 1M) was added to the solution followed by 5 mol percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and the product was purified with Prep-LC to give 5.5 mg of 2-amino-3-{4-[6-(3-cyclopentyloxy-4-methoxy-benzylamino)-pyrazin-2-yl]-phenyl}-propionic acid, yield 6%. 1H-NMR (400 MHz, DMSO-d6): δ 1.46 (m, 2H), 1.62 (m, 4H), 3.01 (m, 2H), 3.08 (m, 2H), 3.65 (s, 3H), 4.0 (m, 1H), 4.45 (d, 2H), 4.65 (m, 1H), 6.90 (s, 2H), 6.95 (s, 1H), 7.32 (d, 2H), 7.60 (t, 1H), 7.90 (s, 1H), 7.95 (d, 2H), 8.25 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:20][CH2:21][CH3:22])[CH2:11][CH2:10][CH:9]2[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]1[CH2:7][CH2:8]2)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O1CCCC1>[C:16]([O:15][C:13]([N:12]1[CH:9]2[CH2:8][CH2:7][CH:6]1[C:5]([CH2:3][OH:2])([CH2:20][CH2:21][CH3:22])[CH2:11][CH2:10]2)=[O:14])([CH3:18])([CH3:19])[CH3:17]
Reactant: CCCC1(C(=O)OC)CCC2CCC1N2C(=O)OC(C)(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCC1(CO)CCC2CCC1N2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 19 %

Procedure:
2-Propyl-8-aza-bicyclo[3.2.1]octane-2,8-dicarboxylic acid 8-tert-butyl ester 2-methyl ester (mixture of endo and exo isomers from Step 6, 0.98 g, 3.1 mmol) was dissolved in tetrahydrofuran (15 mL), and the resulting mixture was cooled to 0° C. A solution of lithium aluminum hydride in tetrahydrofuran (1 M, 3.3 mL, 3.3 mmol) in tetrahydrofuran was added dropwise over 10 minutes, and stirring was continued at 0° C. for 1.5 hours. A saturated aqueous solution of potassium sodium tartrate (10 mL) was added, and the mixture was warmed to room temperature and stirred for 15 hours. Additional saturated aqueous solution of potassium sodium tartrate (10 mL) was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, ethyl acetate/hexane) to provide 2-hydroxymethyl-2-propyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester as a separable mixture of endo and exo isomers, both as colorless oils (0.68 g and 0.17 g, 76% and 19% yield, respectively).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:34]([O:36][C:37](=[O:42])[C:38](Br)([CH3:40])[CH3:39])[CH3:35]>C1COCC1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH2:22][C:38]([C:37]([O:36][CH2:34][CH3:35])=[O:42])([CH3:40])[CH3:39])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)nc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)CC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)nc1
Reaction time: 0.5 h

Procedure:
To 4-(5-acetyl-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (1.36 g, 4.24 mmol) in THF (15 mL) at −78° C. was added 0.5M potassium bis(trimethylsilyl)amide in toluene (17 mL) and stirred for 30 min before adding 2-bromo-2-methyl-propionic acid ethyl ester (1.25 mL, 8.49 mmol) at −78° C. After overnight stirring at r.t., the reaction was quenched with 1N HCl, extracted with dichloromethane, washed with water/brine, dried over sodium sulfate, and concentrated. The product was purified using a Single Step column (7:3 hexanes:ethyl acetate) to obtain 0.458 g (25%); MS m/z 435 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]=2[S:8][C:7]=1[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42].N>ClCCl>[CH3:16][N:12]1[C:13](=[O:15])[C:14]2[C:6]([S:5][CH2:4][CH2:3][CH2:2][NH:1][S:41]([CH3:40])(=[O:43])=[O:42])=[C:7]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[S:8][C:9]=2[N:10]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:11]1=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCN)c(Cc3cccc4ccccc34)sc21
Agent: N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCNS(C)(=O)=O)c(Cc3cccc4ccccc34)sc21
Reaction time: 1 h

Procedure:
5-[(3-Aminopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (50 mg) and triethylamine (100 μl) were dissolved in dichloromethane (5 ml) and then cooled in ice. Methanesulfonyl chloride (25 μl) was added dropwise and the solution was stirred for 1 h. Aqueous ammonia (dilute) was added and the phases were separated. The aqueous phase was extracted twice with dichloromethane, the organic phases were combined, dried, filtered and evaporated. Purification by HPLC (ethyl acetate:isohexane 20-100:80-0) followed by trituration with methanol gave the title compound (43 mg).
Reaction SMILES: [H-].[Na+].[F:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[C:10]1[C:11]2[S:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][C:12]=2[NH:13][CH:14]=1.Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>CN(C=O)C>[F:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[C:10]1[C:11]2[S:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][C:12]=2[N:13]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:14]=1
Reactant: COC(=O)CBr
Reactant: COC(=O)c1cc2[nH]cc(C3CCCCC3F)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(C2CCCCC2F)c2sc(C(=O)OC)cc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
60% NaH in mineral oil (2 eq.) was added at RT to a 0.25M solution of methyl 6-(2-fluorocyclohexyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate in dry DMF, after few min methyl bromoacetate (3 eq.) was added and the mixture was stirred at 60° C. for 1 h and left overnight at RT. After dilution with EtOAc, the organic layer was washed with 1N HCl, sat. NaHCO3 and brine, dried over Na2SO4 and concentrated. Chromatography (PE/EtOAc) afforded the title compound (53%). 1H-NMR (400 MHz, CDCl3, 300K, δ) 7.60 (s, 1H), 6.92 (s, 1H), 4.74 (s, 2H), 4.50 (dtd, 1H, J 48.9, 10.3, 4.5), 3.88 (s, 3H), 3.77 (s, 3H), 2.85-2.76 (m, 1H), 2.25-2.11 (m, 2H), 1.90-1.74 (m, 2H), 1.68-1.54 (m, 2H), 1.44-1.33 (m, 2H); MS (ES+) m/z 354 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH2:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:16][CH2:17][C:18](Cl)=O>>[Cl:16][CH2:17][C:18]1[N:12]2[N:13]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH:9]=[CH:10][C:11]2=[N:14][N:15]=1
Reactant: O=C(Cl)CCl
Reactant: NNc1ccc(-c2cccc(F)c2)nn1
Product: Fc1cccc(-c2ccc3nnc(CCl)n3n2)c1

Procedure:
As for Example 2, 6-(3-fluorophenyl)-3-hydrazinopyridazine (prepared in a manner similar to that described in Example 1) is reacted with chloroacetyl chloride to give the product of the Example.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([I:15])[CH:9]=1)[NH2:6].[Cl:17][C:18]1[CH:19]=[C:20]([NH:25][CH:26]([C:28](O)=[O:29])[CH3:27])[CH:21]=[CH:22][C:23]=1[Cl:24].N[C@H](C(O)=O)C>>[CH3:2][O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([I:15])[CH:9]=1)[NH:6][C:28](=[O:29])[CH:26]([CH3:27])[NH:25][C:20]1[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)c(I)c1
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Agent: C[C@H](N)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(O)c(I)c1)NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure D and using 3-iodo-L-tyrosine methyl ester hydrochloride (prepared following General Procedure K and using 3-iodo-L-tyrosine (Aldrich)) and N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above), the title compound was prepared as a mixture of stereoisomers about alanine. The reaction was monitored by tlc (Rf=0.29 in 10% MeOH/CH2Cl2) and purification was by flash chromatography (10% methanol/methylene chloride).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][S:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:22][CH:21]=2)([C:14]([NH:16][OH:17])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:31]O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][S:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:22][CH:21]=2)=[O:31])([C:14]([NH:16][OH:17])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#CCOc1ccc(SCC2(C(=O)NO)CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: OO
Solvent: CO
Product: CC#CCOc1ccc(S(=O)CC2(C(=O)NO)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a slurry of tert-butyl-4-({[4-(2-butynyloxy)phenyl]sulfanyl}methyl)-4-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate (0.24 g, 0.55 mmol) at 0° C. in 7 mL of MeOH was added dropwise 3.5 mL of 30% hydrogen peroxide. The reaction was allowed to warm to room temperature and stirred for 18 h. The reaction was cooled to 0° C. and quenched with 3.5 mL of a saturated solution of Na2SO3. The organics were removed and the aqueous solution was extracted with CH2Cl2. The organics were washed with H2O, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether to provide 0.166 g (67%) of the desired product as an off white solid. Electrospray Mass Spec: 451.3 (M+H)+
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13]([NH:15][C@H:16]([C:18]([NH:20][CH:21]1[CH:25]([O:26]CC2C=CC=CC=2)[O:24][C:23](=[O:34])[CH2:22]1)=[O:19])[CH3:17])=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.[C:35]1([CH2:41][CH2:42][C:43]([OH:45])=O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.OC1C2N=NNC=2C=CC=1.CN1CCOCC1.C(N=C=NCCCN(C)C)C>FC(F)(F)C(O)=O.C(OCC)(=O)C.CN(C)C=O>[C:35]1([CH2:41][CH2:42][C:43]([NH:8][C@H:9]([C:13]([NH:15][C@H:16]([C:18]([NH:20][CH:21]([CH:25]=[O:26])[CH2:22][C:23]([OH:34])=[O:24])=[O:19])[CH3:17])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:45])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)NC1CC(=O)OC1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)CCc1ccccc1)C(=O)N[C@@H](C)C(=O)NC(C=O)CC(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-(Tert-butoxycarbonyl-valinyl-alaninyl)-4-amino-5-benzyloxy-2-oxotetrahydrofuran (590.4 mg) was dissolved in 15 mL of trifluoroacetic acid, aged for 15 minutes, and concentrated. The residue was dissolved in methanol, diluted with toluene and concentrated to give a colorless solid. To 201.9 mg of this solid was added 3-phenylpropionic acid (123 mg, 0. 8216 mmol), hydroxybenzotriazole (111 mg, 0.8216 mmol), dimethyl formamide (3 mL), and 4-methylmorpholine (45 μl, 0.4108 mmol). Ethyl dimethylaminopropyl carbodiimide (83 mg, 0.4313 mmol) was added and the mixture stirred for 16 hours at ambient temperature. The mixture was diluted with ethyl acetate and washed three times with 2N hydrochloric acid, and twice with dilute sodium bicarbonate. The organics were dried over sodium sulfate, filtered and concentrated to give the title compound as a mixture of two diastereomers: 1H NMR (400 MHz, CD3OD) δ7.4-7.1 (m, 10H, Ar--H), 5.63 (d, 0.5H, J=5.03 Hz, CHOBn), 5.45 (d, 0.5H, J=1.20 Hz, CHOBn), 4.95-4.6 (m, 2.5H, CH2Ph, CHN), 4.4-4.2 (m, 1.5H, CHN), 4.08 (d, 0.5H, J=7.38 Hz, CHN), 4.03 (d, 0.5H, J=7.15 Hz, CH N), 3.03 (dd, 0.5H, J=8.11, 18.3 Hz, CHHCO2), 2.89 (dd, 2H, J=5.49, 8.79 Hz, CH2CON), 2.76 (dd, 0.5H, J=8.76, 17.38 Hz, CHHCO2), 2.7-2.4 (m, 3H, CHHCO2, CH2CH2Ph), 1.98 (m, 1H, CH(CH3)2), 1.31 (d, 1.5H, CHCH3), 1.25 (d, 1.5H, CHCH), 0.87 (m, 6H, CH(CH3)2. ##STR36## N-(3-Phenylpropionyl-valinyl-alaninyl)-3-amino-4-oxobutanoic acid
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)[CH2:16][N:17]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]1.C(N(CC)CC)C>C(Cl)Cl.O>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)[CH2:16][N:17]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]1
Reactant: COc1cccc(CN2CCC(O)C2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: COc1cccc(CN2CCC(=O)C2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
To a solution of oxalyl chloride (14.6 mL, 170 mmol) in methylene chloride (100 mL) at −78° C., was added dimethyl sulfoxide (14.3 mL, 170 mmol). After 15 min, a solution of 1-(3-methoxybenzyl)pyrrolidin-3-ol (11.8 g, 56.8 mmol) from Step A above in methylene chloride (100 mL) was added dropwise. After 4 h, triethylamine (52 mL, 369 mmol) was added and the reaction mixture was warmed to ambient temperature. Water (50 mL) was added and the aqueous layer was separated and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (methylene chloride to 1:1 methylene chloride/ethyl acetate) to provide 1-(3-methoxybenzyl)pyrrolidin-3-one (8.0 g, 68%) as a colorless oil: 1H NMR (CD3OD, 400 MHz) δ 7.26 (t, J=7.9 Hz, 1H), 7.00-6.92 (m, 2H), 6.89-6.81 (m, 1H), 3.81 (s, 3H), 3.72 (s, 2H), 2.99-2.95 (m, 2H), 2.94 (s, 2H), 2.41 (t, J=7.0 Hz, 2H); ESI MS (m/z) 206 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[O:5][CH:6]([CH3:10])[C:7]([OH:9])=O.[N+]([O-])(O)=O.[O:18]([CH2:22][CH2:23][NH2:24])[N+:19]([O-:21])=[O:20].C(OC(C)C)(C)C>>[O:18]([CH2:22][CH2:23][NH:24][C:7](=[O:9])[CH:6]([O:5][C:4]1[CH:11]=[CH:12][CH:13]=[C:2]([Cl:1])[CH:3]=1)[CH3:10])[N+:19]([O-:21])=[O:20]
Reactant: CC(Oc1cccc(Cl)c1)C(=O)O
Reactant: NCCO[N+](=O)[O-]
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: CC(Oc1cccc(Cl)c1)C(=O)NCCO[N+](=O)[O-]
Yield: 56.8 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.71 g of 2-(3-chlorophenoxy)propionic acid and 0.6 g of 2-nitroxyethylamine nitrate, 0.58 g of the title compound was obtained as colorless acicular prisms (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1.C(N(C(C)C)CC)(C)C.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[Br:1][C:2]1[C:3]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[C:6]([CH:10]=1)[C:7]([NH:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)=[O:9]
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(Nc1cccnc1)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1F
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-2-{[(2,4-difluorophenyl)methyl]oxy}-4-(4-morpholinylmethyl)benzoic acid (may be prepared as described in Description 22; 150 mg, 0.34 mmol) in N,N-dimethylformamide (4 ml) was added 3-aminopyridine (38.3 mg, 0.41 mmol), diisopropylethylamine (0.12 ml, 0.68 mmol), 1-hydroxy-7-azabenzotriazole (55.4 mg, 0.41 mmol) and EDC (98 mg, 0.51 mmol). The mixture was stirred overnight and the solvent removed in vacuo to give a residue. Purification by column chromatography (SiO2; 10% 7M NH3 in methanol/dichloromethane) yielded the title compound as a solid. 162 mg.