Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:9][CH2:10][CH2:11][C:5]2=[N:4][C:3]=1[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1.[CH3:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1.C(=O)([O-])[O-].[Na+].[Na+].N#N>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.O1CCOCC1>[CH3:30][C:31]1[N:32]=[CH:33][C:34]([C:2]2[N:7]=[C:6]3[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:9][CH2:10][CH2:11][C:5]3=[N:4][C:3]=2[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)=[CH:35][CH:36]=1
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccc(C)cc3)c(Cl)nc21
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)nc3)nc21
Temperature: 150 °C

Procedure:
A mixture of step 1 (70 mg), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (73.7 mg, 0.337 mmol) and 2M sodium carbonate (0.252 ml, 0.505 mmol) were combined in a microwave vial. Dioxane (2 ml) was added and the flask was sealed and deoxygenated by evacuation/N2 purge (×3). Pd(Ph3P)4 (38.9 mg, 0.034 mmol) was added and the mixture was de-oxygenated by evacuation/N2 purge (×3) and heated at 150° C. for 3 hours using microwave radiation. The mixture was diluted with water and extracted with EtOAc (×2). The combined organic extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure to a give a brown gum. The crude product was loaded onto an Isolute® SCX-2 cartridge and eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions were concentrated under reduced pressure and further purification by chromatography on silica eluting with 0-100% EtOAc in iso-hexane to afford the titled compound;
Reaction SMILES: OC[C@](N)(C)CCC.CO[C:11](=O)[C@H:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[NH2:13].OCCN.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[S:35])=[C:29]([CH3:36])[CH:28]=1)=[O:26]>>[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]2[NH:13][C@@H:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][S:35]2)=[C:29]([CH3:36])[CH:28]=1)=[O:26]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: COC(=O)c1ccc(N=C=S)c(C)c1
Agent: CCC[C@](C)(N)CO
Solvent: NCCO
Product: COC(=O)c1ccc(N=C2N[C@@H](CC(C)C)CS2)c(C)c1

Procedure:
(1S)-1-(Hydroxymethyl)-1-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4-(Methoxycarbonyl)-2-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-(methoxycarbonyl)-2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-(methoxycarbonyl)-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine. The thiazolidine was saponified according to Method D6a, Step 1 to give (4S)-2-(4-carboxy-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine. The acid was coupled with ammonia as described in Method D6a, Step 2 to afford (4S)-2-(4-carbamoyl-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23]I.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH3:23])[CH2:10][CH:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1C1CC(O)CCN1C(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1C1CC(OC)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-2-(2-methoxyphenyl)-4-hydroxypiperidine (910 mg, 2.94 mmol) in DMF (10 mL) at 0° C. was added methyl iodide (0.92 mL, 14.8 mmol) and NaH (236 mg, 5.9 mmol) and the resulting suspension was stirred at room temperature for 2 hours. The reaction mixutre was quenched with H2O at 0° C., EtOAc was added, and the aqueous layer was extracted with EtOAc (×4). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to provide the title compound as a colorless oil (898 mg). 1H NMR (CDCl3, 400 MHz) δ:3.82 (3H, s, OMe), 3.10 (3H, s, OMe), and 1.22 (9H, s, Bu-t).
Reaction SMILES: C[Al](C)C.[NH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[Br:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]2[C:20]3[C:27]4[CH2:28][CH2:29][CH:30]([C:32](OCC)=[O:33])[CH2:31][C:26]=4[S:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH:15]=[CH:16][CH:17]=1>C1(C)C=CC=CC=1>[Br:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]2[C:20]3[C:27]4[CH2:28][CH2:29][CH:30]([C:32]([N:5]5[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]5)=[O:33])[CH2:31][C:26]=4[S:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: C1CCNCC1
Reactant: CCOC(=O)C1CCc2c(sc3ncnc(Nc4cccc(Br)c4)c23)C1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: O=C(C1CCc2c(sc3ncnc(Nc4cccc(Br)c4)c23)C1)N1CCCCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Anhydrous toluene (2 mL) was added to a 50 mL round bottom flask previously evacuated and refilled with argon or nitrogen gas (3×). This was cooled to 0° C. in an ice-water bath for 5 min. Trimethylaluminum, 0.2 mL (1.8 equiv, 2.0M solution in hexanes) was added and the reaction was stirred at 0° C. for 15 min before piperidine (1.1 equiv, 0.25 mmol) was added to the above solution. It was allowed to stir at 0° C. for 10 min before warming to rt for 20 min. A 3 mL toluene solution of 100 mg (0.23 mmol, 1 equiv) of ethyl 4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylate, 14, was added and the reaction mixture was heated at 100° C. until reaction was complete by TLC. The reaction mixture was cooled to 0° C. and quenched with 1N HCl. The reaction was adjusted to pH 9.0 with 1N NaOH and extracted with EtOAc (3×5 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to give a crude oil which was purified via flash column chromatography MeOH/CH2Cl2 1:9 to provide the required product, 27, as a white solid (100 mg, 92%). 1H-NMR (CD2Cl2-d4) δ 8.49 (s, 1H), 8.05 (d, 1H), 7.62–7.59 (m, 1H), 7.23–7.26 (m, 2H), 7.12 (s, 1H), 3.59 (q, 2H), 3.52 (t, 2H), 3.23–3.10 (m, 3H), 2.94 (dd, 1H), 2.20–2.19 (m, 1H), 2.10–2.08 (m, 1H), 1.71–1.58 (m, 7H); LCMS RT=3.28 min; [M+H]+=473.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.Br[C:10]1[C:11]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])=[N:12][CH:13]=[C:14]([CH3:16])[N:15]=1>>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C:11]1[C:10]([O:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[N:15][C:14]([CH3:16])=[CH:13][N:12]=1)(=[O:19])=[O:20]
Reactant: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(Br)n1
Reactant: OCc1ccncc1
Product: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OCc2ccncc2)n1

Procedure:
Prepared by the method of Example 20 using pyridine-4-methanol (0.05 g) and N-(3-bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (0.1 g). Yield 0.009 g.
Reaction SMILES: [CH2:1]([O:4][N:5]([CH:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][O:32][Si](C(C)(C)C)(C)C)[CH:20]=[C:19]1[CH2:40][C:41]([NH2:43])=[O:42])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].I([O-])(=O)(=O)=[O:45].[Na+].OS([O-])=O.[Na+]>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:4][N:5]([CH:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[C@H:21]([C:31]([OH:45])=[O:32])[CH:20]=[C:19]1[CH2:40][C:41]([NH2:43])=[O:42])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON(C1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1CC(N)=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CCON(C1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1CC(N)=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 15 h

Procedure:
To the solution of (25)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-4-(2-amino-2-oxoethyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 174, 2.61 g, 4.96 mmol) in acetonitrile (50 mL) was added sodium periodate (4.66 g, 21.81 mmol) and catalytic solution of NaCr2O7/HNO3 solution (6.0 mL) at room temperature and stirred for 15 h. The mixture was diluted with 100 mL ethyl acetate, 25 mL 1M pH 7 buffer, 25 mL 2M NaHSO3. The aqueous solution was extracted with 50 mL ethyl acetate. The ethyl acetate layer was then washed with brine and dried over MgSO4, filtered and concentrated to afford (2S)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-4-(2-amino-2-oxoethyl)-1-(tert-butoxycarbonyl)-1,2,5,6-tetrahydropyridine-2-carboxylic acid, which was used directly in the next step without further purification. Pale yellow solid, crude, 2.79 g, 104%.
Reaction SMILES: [C:1]([C:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1)#N.[OH2:12]>[Ni].C(O)=O>[CH:1]([C:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:12]
Reactant: COC(=O)C1(C#N)CCCC1
Reactant: O
Agent: [Ni]
Solvent: O=CO
Product: COC(=O)C1(C=O)CCCC1
Temperature: 45 °C
Yield: 69 %

Procedure:
To a 12 L flask equipped with a mechanical stirrer, thermometer and condenser containing a nitrogen inlet was added Raney nickel (1 kg, 50% slurry in water, as sold by the Aldrich Chemical Co.). This material was washed with distilled water and decanted (3×0.8 L). Formic acid (88% 7 L) was added (stirring started) followed by a solution of methyl 1-cyanocyclopentanecarboxylate (696 g, 4.54 mol) in formic acid (88%, 1 L). Gas evolved and the exothermic mixture (temperature increased to 45° C.) was stirred at 75° C. for 5 h. After the reaction mixture cooled to room temperature and the catalyst settled, the majority of the solvent was decanted off through a fiberglass filter. The residue was mixed with water (6 L) and filtered. The collected solid was washed with water (1 L) and CH2Cl2 (1 L) and all the filtrates were combined. The aqueous phase was separated and extracted with CH2Cl2 (6 L), and the combined organic phases were washed with saturated aqueous NaHCO3 and brine. Drying (MgSO4), filtering, and concentrating afforded material that was immediately distilled (Vigreux® column, fraction boiling at 93° C., 16 mm Hg collected) to provide methyl 1-formylcyclopentanecarboxylate as a clear colorless liquid (491 g, 69% yield). 1H-NMR (400 MHz, CDCl3) δ 9.65 (s, 1 H), 3.76 (s, 3 H), 2.19-2.04 (m, 4 H), 1.78-1.58 (m, 4 H); 13C NMR (100.6 MHz, CDCl3) δ 197.0, 172.6, 64.3, 51.9, 31.0, 25.3; EI-MS exact mass calcd for: C8H13O3 ; 157.0865; found: 157.0864. This compound has been reported previously by C. R. Davis et al., J. Org. Chem. 1993, 58, 6843.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:21][CH3:22])=[C:12]([C:14](=[O:20])[C:15]([O:17]CC)=[O:16])[CH:13]=2)=[CH:4][CH:3]=1.CO.[OH-].[K+].CCCCCC>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:21][CH3:22])=[C:12]([C:14](=[O:20])[C:15]([OH:17])=[O:16])[CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cc(-c2ccc(Cl)cc2)ccc1CC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCCCCC
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C(=O)C(=O)O
Yield: 82.9 %

Procedure:
To a 50 ml volume three-necked flask, ethyl 2-[5-(4-chlorophenyl)-2-ethylphenyl]-2-oxoacetate (9-c) (1.43 g), methanol (1.9 ml), and potassium hydroxide (600 mg) dissolved in water (3 ml) were added at room temperature, then added methanol (7.6 ml) and water (3 ml), and stirred at 40° C. for 2 hours. To the mixture was added hexane and 2N aqueous potassium hydroxide solution (3 ml), and then the layers were separated. The aqueous layer was washed with hexane again. The organic layers were combined, and extracted with 2N potassium hydroxide. To the resulting aqueous layer, 10 w/w % of hydrochloric acid was added to adjust pH to less than 1, and extracted with ethyl acetate times. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 1.081 g of 2-[5-(4-chlorophenyl)-2-ethylphenyl]-2-oxoacetic acid (8-c).
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[N:26]=[CH:25][NH:24][N:23]=2)=[N:10]1.Cl.[NH:28]1[CH2:33][CH2:32][O:31][C@H:30]([C:34]([OH:37])([CH3:36])[CH3:35])[CH2:29]1>>[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][N:28]2[CH2:33][CH2:32][O:31][C@H:30]([C:34]([OH:37])([CH3:36])[CH3:35])[CH2:29]2)[NH:12][C:11]([C:22]2[N:26]=[CH:25][NH:24][N:23]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Reactant: CC(C)(O)[C@@H]1CNCCO1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCO[C@H](C(C)(C)O)C2)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Yield: 22.5 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (0.75 g, 1.53 mmol) was reacted with (S)-2-(morpholin-2-yl)propan-2-ol hydrochloride (0.28 g, 1.53 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.19 g, 22%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C([NH:4][C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([F:17])[CH:6]=1)(=O)C.Cl>O1CCOCC1>[NH2:4][C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([F:17])[CH:6]=1
Reactant: CC(=O)Nc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]

Procedure:
A solution of the product obtained at 142c (5.95 g, 24.6 mmol) in 100 mL dioxane and 100 mL half-conc. hydrochloric acid was heated to 110° C. for 1.5 h. The mixture was cooled in an ice bath, filtered and washed with water.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.O1CCOCC1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CCNC1
Solvent: C1COCCO1
Solvent: O
Product: Nc1nc(N2CCCC2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
2 g (0.012 mol) of 2-amino-6-chloro-3-nitropyridine, 30 ml of dioxane and 20 ml of water, and 1.8 g of pyrrolidine are charged to a fully equipped round-bottomed flask. The mixture is brought to 70° C. for one hour with stirring and then the mixture is poured onto an ice/water mixture with stirring. The precipitate formed is filtered off and dried. 2.2 g of yellow powder are obtained, Yd=88%.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]([C:12](=[O:14])[CH3:13])[CH2:3]1.[Cl:16][S:17](O)(=[O:19])=[O:18].O>ClCCl>[C:12]([N:4]1[CH2:3][C:2]([CH3:15])([CH3:1])[C:11]2[C:6](=[CH:7][C:8]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:14])[CH3:13]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)N1Cc2ccccc2C(C)(C)C1
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1Cc2cc(S(=O)(=O)Cl)ccc2C(C)(C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
A solution of 1-(4,4-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethanone (D2) (0.5 g, 2.5 mmol) in dry dichloromethane (2 ml) was added over 15 minutes to an ice-cooled, stirred solution of chlorosulfonic acid (1.7 ml, 25 mmol) in dry dichloromethane (6 ml). After stirring the solution at 0° C. for 1 h, it was warmed to ambient temperature and stirred for a further 3 h. The solution was then carefully poured onto a mixture of ice (30 g) and water (30 ml) with stirring. The layers were separated and the aqueous layer was extracted with dichloromethane (30 ml). The combined organic layers were dried (MgSO4) and concentrated in vacuo to an oil which was stirred at room temperature for 15 minutes with diethyl ether (30 ml) to afford the title compound (D3) as a white solid (0.21 g, 27%), δH (CDCl3, rotamers observed)/ppm 1.33, 1.37 (6H, 2×s), 2.21, 2.24 (3H, 2×s), 3.47, 3.66 (2H, 2×s), 4.77, 4.88 (2H, 2×s), 7.55-7.62 (1H, m), 7.77-7.90 (2H, m).
Reaction SMILES: C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:24][C@H:25]([C:36]([O:38][CH3:39])=[O:37])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1.Cl.ON1C2C=CC=CC=2N=N1.[NH:51]([C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:60])[C@H:52]([C:56](O)=[O:57])[CH:53]([CH3:55])[CH3:54]>CN(C)C=O>[NH:51]([C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:60])[C@H:52]([C:56]([NH:24][C@H:25]([C:36]([O:38][CH3:39])=[O:37])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)=[O:57])[CH:53]([CH3:55])[CH3:54]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6.5 ml (approx. 50 mmoles) of N-ethylmorpholine and 11 g of dicyclohexylcarbodiimide are added at 0° C. to a solution in 100 ml of dimethylformamide of 12.64 g (50 mmoles) of H-Trp-OMe.HCl, 6.75 g (50 mmoles) of 1-hydroxybenzotriazole and 12.55 g (50 mmoles) of Z-Val-OH. The mixture is stirred for one hour at 0° C. and is allowed to stand overnight at room temperature. On the following day the precipitate is filtered off and the filtrate is stirred with 50 ml of saturated NaHCO3 solution and 1,000 ml of water. The mixture is cooled to 4° C. and the precipitate is filtered off. While still wet, the precipitate is dissolved in ethyl acetate. The ethyl acetate phase is extracted by shaking with water, saturated NaHCO3 solution, KHSO4 /K2SO4 solution and again with saturated NaHCO3 solution and is dried over Na2SO4 and concentrated to a small residue. The peptide is precipitated from the concentrated solution with petroleum ether. The precipitate is filtered off and dried. Yield 19.1 g (84%), melting point 146°-148°, [α]D22 =-13.9° (c=1, in methanol).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9]C)[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([O:14]C)=[O:13]>Br.O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: COC(=O)Cc1ccc(OC)c(Cl)c1Cl
Agent: Br
Solvent: O
Product: O=C(O)Cc1ccc(O)c(Cl)c1Cl

Procedure:
2,3-Dichloro-4-methoxybenzeneacetic acid, methyl ester, 46 gm, was refluxed for 18 hours in concentrated HBr, 350 mL. The reaction mixture was poured in water, 1.4 L, and the solution was extracted with EtOAc, 2×500 mL. The organic layers were washed with water, dried (Na2SO4) and concentrated to dryness. The residue was slurried in 20% EtOAc-hexane to yield 2,3-dichloro-4-hydroxybenzeneacetic acid, mp 189-190° C. The acid was stirred at room temperature in methanolic HCl, 100 mL, for 30 minutes. The volatiles were removed in vacuo and the residue was slurried in hexane, filtered and air-dried to yield 17.6 gm of the title compound, mp 105-106° C., analysis, calculated: C, 45.98; H, 3.43; Cl, 30.16; obtained: C, 46.10; H, 3.65; Cl, 30.31.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=[O:9])[CH:2]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:26][C:27]([CH3:29])=[CH2:28].O>O1CCCC1.CO.ClCCl>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[CH:26][CH:27]([CH3:29])[CH3:28])[C:8]([OH:10])=[O:9])[CH:2]=1
Reactant: O=C(O)Cc1cccc(-c2ccccc2)c1
Reactant: C=C(C)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C=C(C(=O)O)c1cccc(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A solution of biphenyl-3-yl acetic acid (7.0 g, 33 mmol) in anhydrous tetrahydrofuran (84 mL) was added dropwise to a solution of lithium diisopropyl amide (36.4 mL, 2M solution in hexanes) in anhydrous tetrahydrofuran (84 mL) at −78° C. The mixture was allowed to warm to 0° C. and stirred for 40 min. The mixture was then cooled to −78° C. and 3-bromo-2-methylpropene (4.97 mL) rapidly added. The mixture was stirred for 1 h at −78° C. then water (28 mL) added and the organics removed under reduced pressure. The mixture was then acidified with hydrochloric acid (6M, 14 ml), extracted with ethyl acetate (3×100 ml), dried (MgSO4) and evaporated under reduced pressure to afford a residue. Flash chromatography of the residue over silica (400 g) using methanol:dichloromethane (3:97) as the eluent afforded impure 2-biphenyl-3-yl-4-methylpentenoic acid (8.3 g). Flash chromatography over silica (400 g) using methanol:dichloromethane (1.5:98.5) afforded pure 2-biphenyl-3-yl-4-methylpent-4-enoic acid, yield 5.27 g, (60%), TLC (single UV spot, Rf=0.28, 5% methanol in dichloromethane), analytical HPLC Rt=19.99 min, HPLC-MS (single main UV peak with Rt=9.57 min, 267.1 [M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:8]([CH2:22][C:23]#[N:24])[C:7]=2[CH:25]=1.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=3)[N:8]([CH2:22][CH2:23][NH:24][C:29]([CH:26]3[CH2:28][CH2:27]3)=[O:30])[C:7]=2[CH:25]=1
Reactant: COc1ccc2c(c1)N(CC#N)C(c1cccc(C(F)(F)F)c1)CO2
Reactant: O=C(Cl)C1CC1
Product: COc1ccc2c(c1)N(CCNC(=O)C1CC1)C(c1cccc(C(F)(F)F)c1)CO2

Procedure:
The procedure is as in Example 15, starting from the compound obtained in Step A and with the replacement of benzoyl chloride with cyclopropylcarbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[CH2:11][N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]1=[O:23].S(OC)(O[CH3:28])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[CH2:11][N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[N:14]([CH3:28])[C:13]1=[O:23]
Reactant: COc1cc(Cl)cc(Cn2c(=O)cc(C(F)(F)F)[nH]c2=O)c1Cl
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(Cl)cc(Cn2c(=O)cc(C(F)(F)F)n(C)c2=O)c1Cl
Yield: 65.2 %

Procedure:
By the method of Example 1, Step H, 8.95 grams (0.024 mole) of 3-(2,5-dichloro-3-methoxyphenylmethyl)-6-trifluoromethyluracil, 5.03 grams (0.036 mole) of dimethyl sulfate, and 8.99 grams (0.048 mole) of potassium carbonate were reacted in 800 mL of acetone, yielding 6.0 grams of 3-(2,5-dichloro-3-methoxyphenylmethyl)- 1 -methyl-6-trifluoromethyluracil as a viscous, yellow oil, which became a glass upon cooling. This glass crystallized after standing for a period of time, m.p. 117°-123° C. The NMR spectrum was consistent with the proposed structure.