Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].CCN(C(C)C)C(C)C.[CH2:30]([N:37]=[C:38]=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCOCC1>[CH2:30]([NH:37][C:38](=[O:39])[NH:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C=NCc1ccccc1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(CNC(=O)NCc1ccccc1)NC(c1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 93 %

Procedure:
A solution of 0.2 mmol rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 0.28 mmol of DIPEA in 2 ml of dioxane was treated with 0.2 mmol of benzylisocyanate. The mixture was stirred at room temperature for 48 hours, concentrated and diluted with diethyl ether. The solid was filtered off, dissolved in dichloromethane and extracted 2 times with a diluted solution of citric acid. The organic phase was dried and concentrated. The residue was triturated with diethyl ether to give the title compound as a colorless solid. Yield=93%.
Reaction SMILES: [CH2:1]([C:4]1[NH:8][N:7]=[N:6][N:5]=1)[CH2:2][CH3:3].N([CH2:12][C@H:13]1[O:17][C:16](=[O:18])[N:15]([C:19]2[CH:24]=[C:23]([F:25])[C:22]([C:26]3[CH2:27][CH2:28][S:29](=[O:33])(=[O:32])[CH2:30][CH:31]=3)=[C:21]([F:34])[CH:20]=2)[CH2:14]1)=[N+]=[N-]>>[O:33]=[S:29]1(=[O:32])[CH2:28][CH:27]=[C:26]([C:22]2[C:23]([F:25])=[CH:24][C:19]([N:15]3[CH2:14][C@H:13]([CH2:12][N:6]4[N:7]=[N:8][C:4]([CH2:1][CH2:2][CH3:3])=[N:5]4)[O:17][C:16]3=[O:18])=[CH:20][C:21]=2[F:34])[CH2:31][CH2:30]1
Reactant: CCCc1nnn[nH]1
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2cc(F)c(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Product: CCCc1nnn(C[C@H]2CN(c3cc(F)c(C4=CCS(=O)(=O)CC4)c(F)c3)C(=O)O2)n1

Procedure:
This compound was prepared from 5-propyl-1H-tetrazole (0.187 g, 1.67 mmol) and (5R)-3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-(hydroxymethyl)oxazolidin-2-one (WO 01/81350 A1) (0.30 g, 0.84 mmol) as described for Example 29. The title compound was obtained as a colourless solid (0.25 g).
Reaction SMILES: [NH2:1][C:2](=[S:17])[CH2:3][N:4]1[C:8]([O:9][CH2:10][CH3:11])=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[N:5]1.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)=O>>[CH2:10]([O:9][C:8]1[N:4]([CH2:3][C:2]2[S:17][CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=3)[N:1]=2)[N:5]=[CH:6][C:7]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:11]
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cnn(CC(N)=S)c1OCC
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)c1OCC
Yield: 82.9 %

Procedure:
By a reaction in the same manner as in Example 1c and using the compound (200 mg, 0.78 mmol) obtained in Example 8b and 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (0.53 g, 2.0 mmol), the title compound (275 mg, 83%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH3:13])C=2C(=O)[N:4]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[C:3]1=[O:22].[C-:23]#[C-:24].[Li+].[Li+].O.C([O:31][CH2:32][CH3:33])(=O)C>O1CCOCC1>[OH:21][C:19]([CH3:20])([C:23]#[CH:24])[CH2:18][CH2:17][CH2:16][CH2:15][N:4]1[C:32](=[O:31])[C:33]2[N:7]([CH2:11][CH2:12][CH3:13])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:22]
Reactant: CCOC(C)=O
Reactant: CCCn1cnc2c1c(=O)n(CCCCC(C)=O)c(=O)n2C
Reactant: [C-]#[C-]
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Product: C#CC(C)(O)CCCCn1c(=O)c2c(ncn2CCC)n(C)c1=O
Temperature: 25 °C

Procedure:
A solution of 153.2 g (0.5 mol) of 3-methyl-1-(5-oxohexyl)-7-propylxanthine in 750 ml of dioxane was added dropwise to a suspension of 75.5 g (0.82 mol) of lithium acetylide as ethylenediamine complex in 500 ml of dioxane with exclusion of moisture and stirring at room temperature. The slightly exothermic reaction which started during this was completed by stirring and heating at 70° C. for 6 hours. Subsequently, at room temperature, water was added, the organic solvent was distilled off as far as possible under reduced pressure, the aqueous phase was exhaustively extracted with chloroform, the extract was dried over sodium sulfate and then concentrated under reduced pressure, and the residue was purified by filtration through a silica gel column in chloroform as eluent, resulting in 150.4 g (91% of theory) of oily product which gradually solidified and was recrystallizable from ethyl acetate with the addition of petroleum ether at the boiling point.
Reaction SMILES: C([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][O:16]/[N:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[CH:9][C:8]=1[O:29][C:30](=[O:41])[C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.[Cl-].[Na+].O>[C:25]([C:22]1[CH:23]=[CH:24][C:19](/[CH:18]=[N:17]/[O:16][CH2:15][CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:42])=[O:5])=[C:8]([O:29][C:30](=[O:41])[C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:35][CH:36]=3)[CH:9]=2)=[CH:20][CH:21]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)c1ccc(OCCO/N=C/c2ccc(C(C)(C)C)cc2)cc1OC(=O)c1ccc(C(F)(F)F)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc(/C=N/OCCOc2ccc(C(=O)O)c(OC(=O)c3ccc(C(F)(F)F)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a solution of 4-{2-[({(E)-[4-(tert-butyl)phenyl]methylidene}amino)oxy]ethoxy}-2-{[4-(trifluoromethyl)benzoyl]oxy}benzoic acid tert-butyl ester (0.387 g, 0.66 mmol) in methylene chloride (15 mL) was added trifluoroacetic acid (0.400 mL, 2.83 mmol). The reaction was stirred at room temperature overnight, poured into brine and the aqueous layer extracted with ethyl acetate. The combined organics dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (20/80)+1% formic acid to afford the title compound (0.300 g, 86%) as a white solid. mp=146.3-147.9° C.; mass spectrum (+APCI, M+H) m/z 530. 1H NMR (400 MHz, DMSO-d6); δ 12.70 (bs, 1H), 8.28 (d, 2H), 8.24 (s, 1H), 7.95 (m, 3H), 7.52 (d, 2H), 7.40 (d, 2H), 7.03 (m, 2H), 4.44 (t, 2H), 4.38 (t, 2H), 1.26 (s, 9H). Elemental analysis: Calcd. for C28H26F3NO6: C, 63.51; H, 4.95; N, 2.65, Found: C, 63.15; H, 4.90; N, 2.64.
Reaction SMILES: Cl[C:2]1[C:11]([C@@H:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(O)(O)=[O:37].C(#N)C.O>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>[Cl:25][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[F:26])[C:11]([C@@H:12]([NH:14][C:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=1[C:22]([OH:23])=[O:37])=[O:24])[CH3:13])=[CH:10]2
Reactant: OB(O)c1ccccc1F
Reactant: O=C(O)O
Reactant: C[C@@H](c1cc2cccc(Cl)c2nc1Cl)N1C(=O)c2ccccc2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: C[C@H](NC(=O)c1ccccc1C(=O)O)c1cc2cccc(Cl)c2nc1-c1ccccc1F
Temperature: 85 °C
Reaction time: 28 h

Procedure:
A mixture of (S)-2-(1-(2,8-dichloroquinolin-3-yl)ethyl)isoindoline-1,3-dione (0.5000 g, 1.347 mmol), 2-fluorobenzeneboronic acid (0.2073 g, 1.482 mmol), tetrakis(triphenylphosphine)palladium (0.07782 g, 0.06735 mmol), and sodium carbonate anhydrous (0.7138 g, 6.735 mmol) in acetonitrile-water (3:1) (12.00 mL, 1.346 mmol) was stirred at 85° C. After 28 h, the mixture was cooled to room temperature. The mixture was concentrated under reduced pressure to remove acetonitrile. The mixture was partitioned between CH2Cl2 (50 mL) and water (50 mL). The aqueous layer (pH 10˜11) was washed with CH2Cl2 (50 mL×2) to remove byproducts. The aqueous layer was treated with 2 N HCl (50 mL) and extracted with CH2Cl2 (50 mL×2). The combined organic layers were washed with water (50 mL×1), brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2-(((S)-1-(8-chloro-2-(2-fluoro-phenyl)quinolin-3-yl)ethyl)carbamoyl)benzoic acid as a solid: LC-MS (ESI) m/z 448.9 [M+H]+. The crude product was carried on crude without purification for the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)=[C:17]1[C:32]([NH2:34])=[O:33].CO>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13](=[O:14])[NH:31][C:28]1[CH:27]=[CH:26][C:25]([C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]([CH3:15])[C:17]=2[C:32]([NH2:34])=[O:33])=[CH:30][CH:29]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Cn1c(C(N)=O)c(-c2ccc(N)cc2)c2ccccc21
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(C(N)=O)c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2ccccc21
Reaction time: 1 h
Yield: 59 %

Procedure:
0.075 g of 2-fluoro-5-trifluoromethylphenyl isocyanate is added to a solution of 0.086 g of 1-methyl-3-(4-aminophenyl)-1H-indole-2-carboxamide in 18 ml of tetrahydrofuran and the stirring is continued for 1 hour. 5 ml of methanol are added, the reaction mixture is then concentrated under reduced pressure, and the residue is purified by chromatography on a silica column, elution being carried out with a mixture of cyclohexane and ethyl acetate (20/80 by volume), to give 90 mg of 3-{4-[3-(2-fluoro-5-trifluoromethyl-phenyl)ureido]phenyl}-1-methyl-1H-indole-2-carboxamide, the characteristics of which are as follows:
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[CH:29]2.[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CCOCC.O>[CH2:35]([N:31]1[C:32]2[C:28](=[CH:27][C:26]([Cl:25])=[CH:34][CH:33]=2)[CH:29]=[CH:30]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCc1ccccc1
Reactant: Clc1ccc2[nH]ccc2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: Clc1ccc2c(ccn2Cc2ccccc2)c1
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a solution of 0.8 g (3.03 mmoles) of 18-crown-6 in 100 mL of dry ether was added 4.39 g (39.12 mmoles) potassium tert-butoxide. The mixture was stirred while 5.08 g (33.51 mmoles) of 5-chloroindole was added. The stirring was continued for 0.5 hour. Most of the solid dissolved. Then 6.69 g (39.11 mmoles) of benzyl bromide in 40 mL of ether was added during 0.5 hours. The stirring was continued for 27 hours. Water (100 mL) was added. The layers were separated. The aqueous layer was extracted with ether (2×75 mL). The combined ether phases were washed with 50 mL of brine and dried over MgSO4. Evaporation of the solvent left 9.17 g of orange oil. The oil was chromatographed on a 700 g column of silica gel. The column was eluted with 1:2 CH2Cl2 -Skellysolve B and 200 mL fractions were collected. The fractions were assayed by silica gel tlc (2×8") (1:2 CH2Cl2 -Skellysolve B). Fractions 10-14 were combined giving 7.26 g (90%) of 1-benzyl-5-chloroindole as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[C:23]=1[N:31]=[C:32]=[O:33])([CH3:21])[CH3:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)[C:32]([NH:31][C:23]2[C:22]([CH:19]([CH3:20])[CH3:21])=[CH:27][CH:26]=[CH:25][C:24]=2[CH:28]([CH3:30])[CH3:29])=[O:33])=[CH:6][CH:7]=1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CN(C)c1ccc(CNc2ccc(Cl)cc2)cc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(Cl)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 1 using (4-chlorophenyl)[(4-dimethylaminophenyl)methyl]amine (0.70 g) and 2,6-diisopropylphenyl isocyanate (0.64 mL) as starting materials, N-(4-chlorophenyl)-N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]urea (0.48 g) was obtained. melting point: 151–152° C.
Reaction SMILES: C(O[K])(C)(C)C.O1CCCC1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21]Cl)=[CH:15][CH:14]=1>O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]=[CH2:21])=[CH:15][CH:14]=1
Reactant: ClCCOc1ccc(Br)cc1
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: C1CCOC1
Product: C=COc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 78.7 %

Procedure:
Tert-Butoxypotassium (33.7 g, 300 mmol) was added to a solution of tetrahydrofuran (hereinafter THF) (250 mL) containing 1-bromo-4-(2-chloroethoxy)benzene (58.6 g, 249 mmol) prepared in Example 6 (6a) over 10 minutes at −10° C. The mixture was stirred at room temperature for 21 hours, and water (500 mL) was added thereto. The resulting mixture was extracted with methyl tert-butyl ether (200 mL, 150 mL) twice. The organic layers were combined, washed with saturated brine (100 mL) twice, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated. The resulting residue was dissolved in hexane (100 mL), and the precipitated insoluble substance was removed by filtration. The insoluble substance was further washed with hexane (5 mL) five times. The filtrates were combined, concentrated, and purified by silica gel column chromatography (hexane) to give 39.0 g of the title compound (colorless oil, yield: 79%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:7]=1.[C:19](OC(=O)CC)(=O)[CH2:20][CH3:21].Cl>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:18][C:19]([CH2:20][CH3:21])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:8]2=[O:17]
Reactant: CCC(=O)OC(=O)CC
Reactant: O=C(Cc1ccccc1F)c1cc(Br)ccc1O
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1oc2ccc(Br)cc2c(=O)c1-c1ccccc1F
Temperature: 25 °C
Yield: 64.9 %

Procedure:
Intermediate 23 (1.1 g, 3.55 mmoles) was taken in a RB flask and to this triethylamine (10 ml) and propionic anhydride (1.44 g, 11.13 mmoles) were added and the mixture was refluxed for 22 h. After cooling to RT, the reaction mixture was acidified by the addition of 1N HCl solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried with sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as off-white solid (0.800 g, 65% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.10(d, J=2.5Hz, 1H), 8.00(dd, J=9.0,2.5 Hz, 1H), 7.71(d, J=9.0Hz, 1H), 7.51(m, 1H), 7.36(m, 3H), 2.54(m, 2H), 1.19(t, J=7.6Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:14]([F:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=2)=[CH:4][C:3]=1[OH:20].[CH2:21](Br)[C:22]#[CH:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:23]([O:20][C:3]1[CH:4]=[C:5]([C:9]2[C:14]([F:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=2)[C:6]([F:8])=[CH:7][C:2]=1[Cl:1])[C:22]#[CH:21]
Reactant: Oc1cc(-c2ncc(C(F)(F)F)cc2F)c(F)cc1Cl
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc(-c2ncc(C(F)(F)F)cc2F)c(F)cc1Cl
Temperature: 67.5 °C
Reaction time: 2 h

Procedure:
A mixture of 0.25 g (0.808 mmol) of the compound of Example 7, 0.12 g (0.97 mmol) of propargyl bromide and 0.22 g (1.62 mmol) of potassium carbonate powder in 10 ml of DMF was stirred for 2 h at 65-70° C. After cooling, 50 ml of water were added and the mixture was extracted 3 times with methyl tert-butyl ether, and the extracts were dried and concentrated, affording 0.28 g (100% of theory) of the title compound of mp. 68-70° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([C:8](=[O:12])[CH2:9][CH2:10][I:11])[CH:5]=[CH:6][CH:7]=1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]([OH:12])[CH2:9][CH2:10][I:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCI)c1cccc(Cl)c1F
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: OC(CCI)c1cccc(Cl)c1F
Reaction time: 0.25 h

Procedure:
1-(3-Chloro-2-fluorophenyl)-3-iodopropan-1-one: To a solution of sodium iodide (165 mg, 1.099 mmol) in ACN (1 mL) was added chlorotrimethylsilane (0.139 mL, 1.099 mmol) dropwise. To the mixture was added water (0.016 mL, 0.916 mmol), followed by Intermediate 16B (169 mg, 0.916 mmol) in 1 mL ACN. After 15 min, the reaction mixture was diluted with EtOAc and washed with water followed by 10% Na2S2O3. The organic layer was then washed with brine and dried over MgSO4. The desired product was isolated as a yellow solid (286 mg, 100%). MS (ESI) m/z: 312.9 (M+2+H)+.
Reaction SMILES: [CH3:1][S:2]([CH3:4])=O.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[NH2:20][C:21]1[C:26]([Cl:27])=[N:25][CH:24]=[CH:23][N:22]=1>C(Cl)Cl>[CH3:1][S:2]([CH3:4])=[N:20][C:21]1[C:26]([Cl:27])=[N:25][CH:24]=[CH:23][N:22]=1
Reactant: Nc1nccnc1Cl
Reactant: CS(C)=O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CS(C)=Nc1nccnc1Cl
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a mechanically stirred solution of 3.9 g (0.05 mol) dimethyl sulfoxide in 30 ml dry methylene chloride at -78° under nitrogen is added 13.1 g (0.046 mol) trifluoromethanesulfonic anhydride dropwise to afford a white precipitate. To this is added a solution of 5.0 g (0.039 mol) 2-amino-3-chloropyrazine (1) in 30 ml methylene chloride/15 ml dimethyl sulfoxide and the resulting solution is stirred at -78° for 2 hours and at -55° for 1 hour. The reaction mixture is then quenched with 50 ml of 5% aqueous sodium bicarbonate solution and stirred at -5° for 5 minutes. The reaction mixture is diluted with 200 ml methylene chloride and the phases are separated. The aqueous phase is extracted with 250 ml methylene chloride and the combined organic phases are washed with 3×75 ml portions of water and dried over anhydrous sodium sulfate. The solvent is removed from the rotary evaporator to give 5.8 g (79%) of 2 as yellow crystals, m.p. 106°-108°.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[C@@H:3]([NH:23]C(=O)OC(C)(C)C)[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([O:21][CH3:22])[CH:15]=2)=[CH:9][CH:8]=1)=[O:5].C(O)(C(F)(F)F)=O>ClCCl>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:10]2[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C@@H:3]([CH:2]([CH3:31])[CH3:1])[NH2:23])=[CH:8][CH:9]=2)=[CH:15][C:16]=1[O:21][CH3:22]
Reactant: COc1cc(Oc2ccc(NC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)cc2)ccc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Oc2ccc(NC(=O)[C@H](N)C(C)C)cc2)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a solution of 1,1-dimethylethyl ((1R)-2-methyl-1-{[(4-{[4-methyl-3-(methyloxy)phenyl]oxy}phenyl)amino]carbonyl}propyl)carbamate (Intermediate 82, 110 mg) in dry dichloromethane (3 mL), TFA (1 mL, 12.98 mmol) was added and the reaction mixture was stirred for 1 hour at room temperature. The solvent and the excess of TFA were evaporated and the residue was purified by SCX cartridge (5 g) to afford the title compound as a yellow pale solid (68 mg).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13](=[O:16])([O-])[O-:14].[Na+].[Na+].C(=O)([O-])ON1C(=O)CC([CH2:27][CH:28]2[C:40]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:34]3[C:29]2=[CH:30][CH:31]=[CH:32][CH:33]=3)C1=O>O.O1CCOCC1>[CH:30]1[C:29]2[CH:28]([CH2:27][O:14][C:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[O:16])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]=2[CH:33]=[CH:32][CH:31]=1
Reactant: O=C([O-])[O-]
Reactant: O=C([O-])ON1C(=O)CC(CC2c3ccccc3-c3ccccc32)C1=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 31 %

Procedure:
Phenylalanine (27.25 g, 0.165 mole) was dissolved in a solution of sodium carbonate (31.8 g, 0.3 mole) in 320 ml of water. This mixture was added to a solution of 9-fluorenylmethylsuccinimidyl carbonate (50.8 g, 0.15 mole) dissolved in a minimum amount of dioxane (approximately 90 ml being required). The mixture was stirred vigorously (mechanical stirring) at room temperature for 22 hours and then diluted with water. The reaction mixture was extracted twice with ethyl ether and then acidified to pH 2 with concentrated hydrochloric acid in the presence of 750 ml of ethyl acetate. The organic layer was separated, washed twice with 1 N hydrochloric acid, twice with water, once with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The product was crystallized by addition of hexane to the boiling ethyl acetate solution, to give 18 g of N-[(9H-fluoren-9ylmethyloxy)carbonyl]-L-phenylalanine, mp 179°-181° C.
Reaction SMILES: C([N:20]1[C:24]([CH2:25]/[CH:26]=[CH:27]/[C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH:29]=2)=[CH:23][N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.C(O)(=O)C>CO>[NH:20]1[C:24]([CH2:25]/[CH:26]=[CH:27]/[C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[CH:29]=2)=[CH:23][N:22]=[CH:21]1
Reactant: COC(=O)c1ccc(/C=C/Cc2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(F)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(/C=C/Cc2cnc[nH]2)cc1-c1ccc(F)cc1
Yield: 20 %

Procedure:
A solution of methyl 4-[(E)-3-(1-tritylimidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate (7.8 g; 10 mmol), 12N HCl (7.5 ml) and acetic acid (7.5 ml) in methanol (150 ml) was refluxed for 1 hour 30 minutes. After evaporation to dryness and neutralisation with an aqueous solution of ammonium hydroxide, the residue was extracted with dichloromethane and purified by flash chromatography, eluting with a gradient 2-5% ethanol/dichloromethane to give methyl 4-[(E)-3-(imidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate. Yield: 20%.
Reaction SMILES: C(O)C#C.[CH2:5]([OH:15])[C:6]#[C:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].COCCO[AlH2-]OCCOC.[Na+]>CCOCC>[CH2:5]([OH:15])/[CH:6]=[CH:7]/[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCC#CCO
Agent: C#CCO
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCCC/C=C/CO

Procedure:
trans-2-Decen-1-ol was prepared by reduction of the propargyl alcohol by the method described by Jones and Denmark (Org. Syn., 1985, 64, 182-8) using 15 g (97 mmole) of 2-decyn-1-ol in 40 ml of ether and 48 ml (162 mmole) of Red-Al (sodium bis(2-methoxyethoxy)aluminum hybride) in 50 ml of ether. Kugelrohr distillation afforded 11.59 g of a clear oil. 1H NMR δ5.66 (m, 2), 4.07 (d, 2, J=5 Hz), 20.3 (dd, 2, J=6, 13 hz), 1.68 (br, 1), 1.4-1.2 (m, 10), 0.88 (t, 3, J=7 Hz).