Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[C:48]2[C:43](=[C:44]([CH3:49])[CH:45]=[CH:46][CH:47]=2)[NH:42][CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[I:52][C:53]1[CH:60]=[CH:59][C:56]([CH2:57]Br)=[CH:55][CH:54]=1.Cl>CN(C)C=O>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:11][C@H:10]1[C:40]1[C:48]2[C:43](=[C:44]([CH3:49])[CH:45]=[CH:46][CH:47]=2)[N:42]([CH2:57][C:56]2[CH:59]=[CH:60][C:53]([I:52])=[CH:54][CH:55]=2)[CH:41]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2c([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c[nH]c12
Reactant: BrCc1ccc(I)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc2c([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)cn(Cc3ccc(I)cc3)c12
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-7-methyl-1H-indole (1.18 g) in N,N-dimethylformamide (10 mL) was added 55% sodium hydride (87 mg) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. To this mixture was added 4-iodobenzyl bromide (0.62 g) at the same temperature, and the mixture was stirred at the same temperature for 15 minutes, and stirred at room temperature for 1 hour. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1-3/1) to give 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1-(4-iodo-benzyl)-7-methyl-1H-indole (1.48 g). A mixture of 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1-(4-iodobenzyl)-7-methyl-1H-indole (1.06 g), acrylic acid (0.18 g), palladium(II) acetate (14 mg), tris(2-methylphenyl)phosphine (37 mg), triethylamine (2 mL) and acetonitrile (2 mL) was stirred at 80° C. under an argon atmosphere overnight. The reaction mixture was diluted with diethyl ether, and the mixture was stirred at room temperature for 10 minutes. The insoluble material was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1-1/3) to give the title compound (0.85 g).
Reaction SMILES: [Cl:1]Cl.[C:3]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4].O.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Cl:1][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([C:3](=[O:5])[CH3:4])[CH2:7][CH2:8]2
Reactant: ClCl
Reactant: CC(=O)N1CCc2ccccc21
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)N1CCc2cc(Cl)ccc21

Procedure:
74.5 g (1.05 moles) of chlorine were added with stirring at 20° to 30° C. to a mixture of 161 g (1 mole) of 1-acetyl-indoline in 1,050 ml of glacial acetic acid and the mixture was stirred for 15 minutes after which 8500 ml of water were added thereto with stirring. The mixture was stirred for 30 minutes and sodium bisulfite was added to destroy excess chlorine and was then vacuum filtered. The recovered product was dissolved in 250 ml of hot isopropanol and the mixture was cooled with stirring and then vacuum filtered. The product was rinsed with 250 ml of isopropanol to obtain 5-chloro-1-acetyl-indoline which was saponified as in Example 1 to obtain 70 g (45% yield) of 5-chloro-indoline.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]1(O)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:20][CH:19]([CH3:21])[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([O:1][C:37]3[C:38]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:34]=[CH:35][CH:36]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:12]=1)=[O:22]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: Oc1cccc2ccccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3cccc4ccccc34)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.9 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 1-naphthol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (4.30 mg, 66.2% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.72 (d, 1H, J=8.5 Hz), 7.59 (d, 1H, J=8.5 Hz), 7.5 (m, 2H), 7.45-7.30 (m, 6H), 7.25 (m, 3H), 7.17 (apparent dd, 1H, J=2.6, 9.0 Hz), 7.01 (apparent d, 1H, J=2.6 Hz), 6.97 (apparent d, 1H, J=7.9 Hz), 5.46 (apparent dd, 1H, J=4.5, 8.1 Hz), 3.12 (m, 2H), 2.61 (m, 2H), 2.53 (apparent sept, partially hidden, 2H, J=7.9 Hz), 2.30-2.10 (m, 6H), 1.90 (m, 2H), 1.25 (d, 6H, J=7.3 Hz, overlapped); ESMS m/e: 507.2 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[CH2:17][C@H:16]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:15]=[CH:14]2)(=O)=O)=CC=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(Cl)Cl>[O:29]1[CH2:30][CH2:31][N:26]([CH2:12][C@@H:13]2[CH2:17][C@H:16]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH:15]=[CH:14]2)[CH2:27][CH2:28]1
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=C[C@@H](NC(=O)OC(C)(C)C)C2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@H](CN2CCOCC2)C1
Temperature: 0 °C

Procedure:
To a stirred solution of ((1R,4S)-4-(tert-butoxycarbonylamino)cyclopent-2-enyl)methyl 4-methylbenzenesulfonate (step 1, about 0.5 g) in DCM (50 ml) potassium carbonate (about 0.3 g) was added at room temperature and cooled to about 0° C. After ten minutes, morpholine (3 ml) was added and stirred the reaction at room temperature for about 6 hours then completion of the reaction monitored by TLC. The reaction mixture was neutralized and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (0.5 g) as light yellow liquid. 1H NMR (300 MHz, CDCl3: 1.24-1.29 (m, 1H); 1.39-1.40 (s, 9H); 2.29-2.60 (m, 7H); 2.79-2.80 (m, 1H); 3.70-3.73 (m, 4H); 4.63 (S, 1H); 5.37-5.39 (d, J=6 Hz, 1H); 5.72-5.81 (m, 2H); ES Mass: 283 (100%), [M+1].
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:31]O)[C:27]([O:29][CH3:30])=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:31][N:11]1[C:10](=[O:15])/[C:9](=[CH:8]/[C:7]2[CH:16]=[CH:17][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)/[S:13][C:12]1=[O:14])[C:27]([O:29][CH3:30])=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1ccc(/C=C2\SC(=O)N(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
Compound 2 (285 mg, 1.15 mmol), (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoate (251 mg, 1.15 mmol) and triphenylphosphine (452 mg, 1.72 mmol) were dissolved in 11 mL of anhydrous THF, and stirred at room temperature for 5 min. DIAD (338 μL, 1.72 mmol) was added to the reaction mixture and then stirred overnight at 45° C. The reaction mixture was diluted with ethyl acetate and washed with sat'd NH4Cl aqueous solution. The organic layer was collected, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (30% ethyl acetate in hexanes) to afford compound 21d (99.5%, 517 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](C=O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N+]#[C-])(C)(C)C.C(O)(=O)C>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cn1
Agent: [C-]#[N+]C(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: c1ccc(COc2cccnc2)cc1

Procedure:
A solution of 4.22 g. (0.02 mol) of 5-benzyloxy-2-pyridinecarboxaldehyde in 100 ml. of chloroform is treated with 1.66 g. (0.04 mol) of t-butyl isocyanide and 2.40 g. (0.04 mol) of acetic acid and the solution is refluxed gently for five hours. The reaction mixture is washed with 5% sodium bicarbonate solution, dried and evaporated to dryness to give 2-[α-N-t-butylamido)-acetoxymethyl]-5-benzyloxypyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([Cl:16])=[CH:18][CH:19]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C1CCCc2c1[nH]c1ccc(Cl)cc21
Product: Clc1ccc(NC2CCCc3c2[nH]c2ccc(Cl)cc32)cc1

Procedure:
6-Chloro-N-(4-chlorophenyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-one and 4-chloroaniline in a similar manner as described in Example 13 to give 25-mg (16% yield) of a tan solid. 1H-NMR (CDCl3): δ 8.01 (m, 1H), 7.46 (d, 1H), 7.21-7.14 (m, 3H), 7.11 (dd, 1H), 6.65 (d, 2H), 4.76 (m, 1H), 2.70 (m, 2H), 2.22 (m, 1H), 2.01 (m, 1H), 1.94-1.75 (m, 2H); MS m/z 329 (M−1).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[C:19]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:18]=[CH:17][C:16]=2[O:25][CH3:26])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO[CH:32]1[CH2:36][CH2:35][CH:34](OC)O1.C(O)(=O)C>O>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[C:19]([S:21]([N:22]3[CH:32]=[CH:36][CH:35]=[CH:34]3)(=[O:23])=[O:24])[CH:18]=[CH:17][C:16]=2[O:25][CH3:26])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(S(=O)(=O)n2cccc2)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 88.6 %

Procedure:
A mixture of N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-5-sulfamoyl-benzamide (compound of Example 87(2); 442 mg, 1 mmol), 2,5-dimethoxytetrahydrofuran (159 mg, 1.2 mmol) and acetic acid (5 mL) was refluxed for 2 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=3:2) to give the title compound (436.5 mg, 88.6%) as a white solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]([N+:18]([O-:20])=[O:19])=[CH:13][N:12]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>O1CCOCC1>[Cl:10][C:11]1[N:16]=[C:15]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[C:14]([N+:18]([O-:20])=[O:19])=[CH:13][N:12]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: COc1ccc(N)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2nc(Cl)ncc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.46 g (19.0 mmol) Diisopropylethylamine are added slowly to a solution of 3.36 g (17.3 mmol) 2,4-dichloro-5-nitropyrimidine and 2.13 g (17.3 mmol) p-anisidine in 30 ml dioxane. The mixture is stirred for 3 hours at room temperature. Then it is partitioned between water and dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with ethyl acetate/cyclohexane as eluent giving (2-chloro-5-nitro-pyrimidin-4-yl)-(4-methoxy-phenyl)-amine as orange crystals; HPLC/MS (B): 2.24 min, [M+H] 281;
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH2:17](Br)[CH:18]=[CH2:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:19]([O:16][C:12]1[C:9]2[C:10]([CH3:11])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[O:7][C:8]=2[CH:15]=[CH:14][CH:13]=1)[CH:18]=[CH2:17]
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc2oc(C(=O)OCC)c(C)c12
Yield: 92.2 %

Procedure:
A mixture of ethyl-4-hydroxy-3-methylbenzofuran-2-carboxylate (11.0 g, 50 mmol), allyl bromide (4.8 ml, 55 mmol) and potassium carbonate (55 mmol) was refluxed in acetone (300 ml) for 4 hours. The resulting mixture was cooled, filtered and concentrated. The residue was chromatographed (silica gel, eluted with 5% ethyl acetate in hexane) to give 12 g of the title compound, m.p. 64°-65° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[NH:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Br:19]Br.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Br:19][C:12]1[NH:11][C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=2)=[N:14][C:13]=1[C:15]([F:16])([F:17])[F:18]
Reactant: COc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1Cl
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2nc(C(F)(F)F)c(Br)[nH]2)cc1Cl
Reaction time: 72 h
Yield: 68.8 %

Procedure:
To a suspension of 55 (2.56 g, 0.0092 mol) in CHCl3 (75ml) was added dropwise with stirring a solution of bromine (1.55 g, 0.0096 mol) in CHCl3 (75 ml). After stirring for 3 days, saturated NaHCO3 was added, the layers separated and the aqueous layer extracted with CHCl3 (2 x). The organic extracts were dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel and the product eluted with 1.5% CH3OH-CHCl3 to yield 2.25 g (69%) of 56, m.p. 228.30° C. (CHCl3). Analysis calculated for C11H7BrClF3N2O.
Reaction SMILES: C(=O)(O)O.[C:5]1([CH:13]=[CH:12][CH:11]=[C:9]([OH:10])[C:7]=1[OH:8])[OH:6].[CH2:14]([C@H:16]1[O:18][CH2:17]1)Cl.N1C=CC=CC=1>C(OCC)(=O)C>[OH:6][C:5]1[C:7]2[O:8][C@@H:16]([CH2:17][OH:18])[CH2:14][O:10][C:9]=2[CH:11]=[CH:12][CH:13]=1
Reactant: Oc1cccc(O)c1O
Reactant: ClC[C@@H]1CO1
Agent: O=C(O)O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: OC[C@H]1COc2cccc(O)c2O1
Yield: 10.1 %

Procedure:
A mixture of pyrogallol carbonate (8.2 g), (S)-epichlorohydrin (5.0 g) and dry pyridine (0.2 ml) in dry ethyl acetate (50 ml) was heated under reflux for 2 hours. The solvent was removed in vacuo, water (30 ml) was added, and the mixture heated under reflux for 30 minutes. A solution of potassium hydroxide (10 g) in water (20 ml) was added dropwise and the mixture heated under reflux under nitrogen for a further 30 minutes. The cooled mixture was diluted with water (100 ml), acidified with hydrochloric acid (5 M) then extracted with ethyl acetate (3×200 ml). The combined extracts were washed with water (2×100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo and the residue purified by chromatography over silica eluting with a 1:1 mixture of ethyl acetate and petroleum ether (b.p. 60-80° C.) followed by neat ethyl acetate. Appropriate fractions were combined and the solvent removed in vacuo to give (S)-8-hydroxy-1,4-benzodioxan-2-ylmethanol (0.8 g).
Reaction SMILES: [CH:1](N(C(C)C)CC)(C)C.[CH3:10][C:11]([CH3:28])([O:13][C:14]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][C:19]1[CH:24]=CC=C[CH:20]=1)=[O:15])[CH3:12].N[C@H](C(OC)=O)CC(C)C.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:10][C:11]([CH3:28])([O:13][C:14]([NH:16][C@H:17]([C:25]([O:27][CH3:1])=[O:26])[CH2:18][CH:19]([CH3:24])[CH3:20])=[O:15])[CH3:12]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: COC(=O)[C@@H](N)CC(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A solution of diisopropylethylamine (8.7 ml., 50 mmole) in tetrahydrofuran (50 ml.) is added dropwise to a mixture of N-[(1,1-dimethylethoxy) carbonyl]-L-phenylalanine (13.265 g., 50 mmole), L-leucine, methyl ester (9.085 g., 50 mmole) and 1-hydroxybenzotriazole hydrate (7.65 g., 50 mmole) in tetrahydrofuran (100 ml.) at 0°. This is followed by the addition of dicylcohexylcarbodiimide (10.315 g., 50 mmole). The reaction is stirred at 0°for 2 hours and left stirring overnight at room temperature. The nexy day, the precipitated dicyclohexyl urea is filtered off, the solvents are stirred down and the residue is diluted with ethyl acetate (200 ml.). The organic solution is washed sequentially with saturated aqueous sodium bicarbonate solution (2×100 ml.) and saturated aqueous sodium chloride (2×100 ml.), dried over sodium sulfate, filtered, and concentrated to give crude product. Crystallization from ethyl ether gives 7.05 g. of pure product. Concentration of the mother liquor solutions gives 4.57 g. of crystalline product. An additional 1.35 g. of product is obtained by chromatographic purification of the crude product obtained from the left-over mother liquors (40 g. silica gel, eluting with 4:1 hexane:ethyl acetate). Thus, a total of 12.96 g. of N-[N-[(1,1 -dimethylethoxy)carbonyl]-L-leucine, methyl ester is obtained;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([F:20])=[CH:22][CH:23]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NCCc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
2-(4-chlorophenyl)ethanamine (0.321 ml, 2.27 mmol) was diluted with DCM (10 mL) followed by the addition of DIEA (d 0.742) (0.395 ml, 2.27 mmol) and 4-fluorobenzoyl chloride (0.231 ml, 1.89 mmol). After stirring for 30 minutes the reaction was loaded directly onto a biotage 40S cartridge and eluted with hexanes:ethyl acetate (2:1) to yield N-(4-chlorophenethyl)-4-fluorobenzamide (393 mg, 74.8% yield) as a white solid.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[CH3:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([CH3:24])[C:22]=1[OH:23])[CH:18]=[O:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:24][C:21]1[CH:20]=[C:17]([CH:18]=[O:19])[CH:16]=[C:15]([CH3:14])[C:22]=1[O:23][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Br)c1cccc(Cl)c1
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(Oc1c(C)cc(C=O)cc1C)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 94.7 %

Procedure:
To a solution of 1.260 g (4.80 mmol) of methyl α-bromo-(3-chlorophenyl)acetate and 0.600 g (4.00 mmol) of 3,5-dimethyl-4-hydroxybenzaldehyde in 16 mL acetone was added 1.10 g (8.00 mmol) of potassium carbonate and the resulting mixture was stirred and heated at reflux for 3.5 hours. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 30% EtOAc-hexane. The purified fractions were combined, evaporated and dried in vacuo to afford 1.260 g (95%) of the title compound.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:15][CH2:16][F:17]>CN(C=O)C>[F:17][CH2:16][CH2:15][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5]1
Reactant: Oc1cccc(N2CCNCC2)c1
Reactant: FCCBr
Solvent: CN(C)C=O
Product: Oc1cccc(N2CCN(CCF)CC2)c1
Yield: 48 %

Procedure:
1 g (5.61 mmol) 3-Piperazin-1-yl-phenol and 0.5 mL (1.25 eq) 1-bromo-2-fluoroethane are stirred 20 h at 60° C. in 5 mL DMF, the reaction mixture allowed to reach room temperature and evaporated, and the residue column chromatographed (silica gel, ethyl acetate/petroleum ether 9:1) to yield 600 mg (48%) of the desired product as a brown oil.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH2:2]1.[NH4+:9].[OH-]>CO>[NH2:9][CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: [NH4+]
Reactant: C1CC2(CCO1)CO2
Agent: [OH-]
Solvent: CO
Product: NCC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The methanol solution of 1,6-dioxaspiro[2.5]octane (3.15 g, 27.6 mmol) was added to the 25% ammonia aqueous solution (50.0 mL, 27.6 mmol) at 0° C. The mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was concentrated in vacuo. The crude product was used for next step reaction without purification.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:19][C:20](=[O:33])[CH:21]=[CH:22][C:23]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=1[O:31][CH3:32])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.Cl.C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[C:42]([NH:1][CH2:2][C@@H:3]([NH:19][C:20](=[O:33])/[CH:21]=[CH:22]/[C:23]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=1[O:31][CH3:32])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[CH2:7][CH2:6]1)(=[O:44])[CH3:43]
Reactant: CC(=O)Cl
Reactant: COc1ccc(C#N)cc1C=CC(=O)N[C@H](CN)CN1CCC(Oc2ccc(F)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C#N)cc1/C=C/C(=O)N[C@H](CNC(C)=O)CN1CCC(Oc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of E)-N-{(R)-1-aminomethyl-2-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-ethyl}-3-(5-cyano-2-methoxy-phenyl)-acrylamide.HCl salt (0.35 g, 0.66 mmol) and triethylamine (0.27 ml, 1.99 mmol) in DCM (5 ml) is treated with acetyl chloride (0.042 ml, 0.6 mmol) at 5° C. The reaction mixture is stirred at ambient temperature for 1 hour then washed with water, saturated aqueous NaHCO3 and brine. The organic phase is dried over MgSO4 and the solvent evaporated. The crude product is purified by flash chromatography (elution methanol:DCM; 4:96) to afford (E)-N-{(R)-1-(acetylamino-methyl)-2-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-ethyl}-3-(5-cyano-2-methoxy-phenyl)-acrylamide. [MH]+ 495.0.