Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2.[C:16]([CH:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)([CH3:19])([CH3:18])[CH3:17].[BH4-].[Na+]>C(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:16]([C@H:20]1[CH2:21][CH2:22][C@H:23]([NH:26][CH:2]2[CH2:11][CH2:10][CH2:9][C:8]3[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]2=3)[CH2:24][CH2:25]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)C1CCC(N)CC1
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: COC(=O)c1ccc2c(c1)CCCC2N[C@H]1CC[C@H](C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (1.0 g, 4.9 mmol), titanium (IV) isopropoxide (2.8 mL, 9.8 mmol), 4-tert-butylcyclohexyl amine (1.5 g, 9.8 mmol) in absolute ethanol (75 mL) was stirred under nitrogen at room temperature for 7 h. Sodium borohydride (0.28 g, 7.4 mmol) was then added and the resulting mixture was stirred for an additional 18 h at room temperature. The reaction was quenched by pouring into aqueous ammonia (2N, 100 mL). The resulting inorganic precipitate was filtered off through Celite and washed with CH2Cl2 (100 mL). The organic layer was separated and the remaining aqueous layer was extracted once with CH2Cl2 (50 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated. Chromatography (15% EtOAc in Hexane) afforded methyl 5-[(trans-4-tert-butylcyclohexyl)amino]-5,6,7,8-tetrahydronaphthalene-2-carboxylate and the corresponding cis product (less polar). HPLC/MS: m/z=344.3 (M+1), Rt=2.84 min. 1H NMR (CDCl3): δ 7.83 (1H, d, J=8.05 Hz), 7.79 (1H, s), 7.47 (1H, d, J=8.5 Hz), 3.94 (3H, s), 2.89 (1H, m), 2.77 (1H, m), 2.62 (1H, m), 2.15 (1H, m), 2.01-1.91 (3H, m), 1.86-1.77 (4H, m), 1.56 (2H, m), 1.23-1.02 (4H, m), 0.90 (9H, s).
Reaction SMILES: [H-].[Na+].[CH3:3]I.[C:5]([O:9][C:10]([NH:12][CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[O:26][CH3:27])[C:15]([OH:17])=[O:16])=[O:11])([CH3:8])([CH3:7])[CH3:6].Cl>C(OCC)(=O)C.O.O1CCCC1>[C:5]([O:9][C:10]([N:12]([CH3:3])[CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[O:26][CH3:27])[C:15]([OH:17])=[O:16])=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: COc1ccc(Cl)cc1C[C@@H](CNC(=O)OC(C)(C)C)C(=O)O
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C[C@@H](CN(C)C(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a 60% mineral oil dispersion of sodium hydride (1.9 g) in a tetrahydrofuran (50 ml) solution, methyl iodide (2.7 ml) was added under ice cooling, then the (2S)-3-[(tert-butoxycarbonyl)amino]-2-(5-chloro-2-methoxybenzyl)propanoic acid (5 g), described in WO 06-059801A, in a tetrahydrofuran (20 ml) solution was slowly added, then the mixture was stirred at room temperature for 72 hours. To the reaction solution, water (50 ml) and ethyl acetate (20 ml) were added and the layers were separated. The organic layer was extracted with water (20 ml) and was combined with the aqueous layer previously obtained, and acidified (pH2) with 6M hydrochloric acid. This aqueous mixture was extracted with ethyl acetate, then the combined extract was washed with water, saturated aqueous sodium thiosulfate solution, and brine. The organic layer was dried over sodium sulfate, then concentrated to obtain (2S)-3-[tert-butoxycarbonyl(methyl)amino]-2-(5-chloro-2-methoxybenzyl)propanoic acid (5.28 g) (compound S17a).
Reaction SMILES: Cl[Si:2](Cl)(Cl)[CH2:3][CH2:4][C:5]([F:16])([F:15])[C:6]([F:14])([F:13])[CH2:7][CH2:8][Si:9](Cl)(Cl)Cl.C([O:22][C:23](=[O:25])[CH3:24])(=O)C>>[C:23]([O:22][Si:2]([O:22][C:23](=[O:25])[CH3:24])([O:25][C:23](=[O:22])[CH3:24])[CH2:3][CH2:4][C:5]([F:16])([F:15])[C:6]([F:14])([F:13])[CH2:7][CH2:8][Si:9]([O:25][C:23](=[O:22])[CH3:24])([O:25][C:23](=[O:22])[CH3:24])[O:25][C:23](=[O:22])[CH3:24])(=[O:25])[CH3:24]
Reactant: FC(F)(CC[Si](Cl)(Cl)Cl)C(F)(F)CC[Si](Cl)(Cl)Cl
Reactant: CC(=O)OC(C)=O
Product: CC(=O)O[Si](CCC(F)(F)C(F)(F)CC[Si](OC(C)=O)(OC(C)=O)OC(C)=O)(OC(C)=O)OC(C)=O
Temperature: 80 °C
Reaction time: 5 h
Yield: 99.6 %

Procedure:
1,6-Bis(trichlorosilyl)-3,3,4,4-tetrafluorohexane (1 g, 2.35 mmol) and acetic anhydride (4 mL) were added to a 10 mL air-free flask. The reaction solution was stirred at 80° C. for 5 hours. After all the volatiles were removed (120° C. at 5 mtorr), 1.24 g (2.20 mol) of the product were obtained with a yield of 99.6%. 1H NMR (400 Mz, CDCl3): δ 2.4 (m, 4H), 1.3 (m, 4H). 29Si NMR (79.6 Mz, CDCl3): −45.3 (s). 19F NMR (CDCl3): −114.6 (t, J=13 Hz, 4F).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([NH:7][C:8]1[C:9]([N+:19]([O-])=O)=[CH:10][C:11](Br)=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2)=[O:6])C.[H][H]>C(O)(=O)C.[Pd]>[NH:7]1[C:8]2[C:17]3[NH:16][CH2:15][CH2:14][CH2:13][C:12]=3[CH:11]=[CH:10][C:9]=2[NH:19][C:4](=[O:3])[C:5]1=[O:6]
Reactant: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(Br)c2cccnc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc3c(c2[nH]c1=O)NCCC3
Yield: 44.3 %

Procedure:
A solution of the product from Example 83 (1 g, 2.7 mmol) in 250 mL acetic acid was treated with 20% Pd/C (0.1 g) and shaken on a Parr apparatus under 52 psi hydrogen gas for 21 hours. After removal of the catalyst, the solvent was evaporated but gave negligible material. The catalyst/celite was washed two times with 1 N HCl, and the aqueous solution was basified with sodium bicarbonate. The precipitate was collected by filtration, dried and then recrystallized from methanol/dimethylformamide to give the title compound (0.26 g, 44% yield) mp>300° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[NH:11][C:12](=[O:19])[C:13]3[C:18]([C:9]=2[C:8]2[CH:7]=[C:6]([Cl:20])[CH:5]=[CH:4][C:3]1=2)=[CH:17][CH:16]=[CH:15][CH:14]=3.[H-].[Na+].[CH:23](Br)=[CH2:24]>>[CH:23]([O:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:8]3[CH:7]=[C:6]([Cl:20])[CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[C:10]=2[N:11]=1)=[CH2:24]
Reactant: Cn1c2ccc(Cl)cc2c2c3ccccc3c(=O)[nH]c21
Reactant: C=CBr
Agent: [H-]
Agent: [Na+]
Product: C=COc1nc2c(c3ccccc13)c1cc(Cl)ccc1n2C

Procedure:
5-Vinyloxy-7-methyl-10-chloro-7H-indolo(2,3-c)isoquinoline (melting point 121°-124° C.) is prepared from 7-methyl-10-chloro-7H-indolo(2,3-c)isoquinolin-5(6H)-one, sodium hydride and vinyl bromide by the method described in Example 8.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:9]=1[CH2:10][OH:11].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:20]([O:7][C:8]1[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][C:9]=1[CH2:10][OH:11])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: OCc1cc(C(F)(F)F)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCc1cc(C(F)(F)F)ccc1OCc1ccccc1
Temperature: 50 °C
Yield: 100.1 %

Procedure:
Cesium carbonate (2.24 g, 6.9 mmol) was added to a solution of 2-hydroxy-5-trifluoromethyl-benzyl alcohol (885 mg, 4.6 mmol) and benzyl bromide (547 μL, 4.6 mmol) in anhydrous DMF (8 mL) at room temperature. The reaction was heated to 50° C. for 2 hours, cooled, diluted with ethyl acetate (25 mL) and washed with water (3×25 mL), brine (1×25 mL), and dried (Na2SO4), filtered and concentrated to afford 1.3 g of the title compound as a colorless solid. 1H NMR (400 MHz. CDCl3) δ 7.6-7.3 (m, 7H); 7.01 (d, 1H, J=9.1 Hz); 5.18 (s, 2H); 4.79 (s, 2H); 2.8 (bs, 1H).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH:26]4[CH2:28][CH2:27]4)[NH:23][N:22]=3)[C:17]([C:29]#[C:30][CH2:31][OH:32])=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH:26]4[CH2:28][CH2:27]4)[NH:23][N:22]=3)[C:17](/[CH:29]=[CH:30]/[CH2:31][OH:32])=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:7])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(C#CCO)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(/C=C/CO)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 0 °C
Yield: 39.8 %

Procedure:
A solution of N-tert-butyl-5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(3-hydroxyprop-1-ynyl) pyrimidin-2-yl)thiophene-2-sulfonamide (250 mg, 0.53 mmol, 1.0 eq) in dry THF (2 mL) was added dropwise over 10 min to a mixture of LiAlH4 (250 mg, 6.58 mmol, 12.4 eq) in THF (20 mL) under nitrogen. The reaction mixture was maintained 0° C. during the addition. The reaction mixture was heated to reflux for 10 min. Then the reaction mixture was cooled to 0° C., while vigorous stirring was maintained, carefully treated with Na2SO4.10H2O (10 g) in portion and then stirred at room temperature for 10 min. The reaction mixture was filtered. The filtrate was concentrated and purified by silica gel chromatography (EtOAc/MeOH/THF from 10:0:0 to 20:1:2) to afford (E)-N-tert-butyl-5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(3-hydroxyprop-1-enyl)pyrimidin-2-yl)thiophene-2-sulfonamide (Compound 218) (100 mg, 40.0%). LC-MS (m/z)=475 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.74-0.75 (m, 2H), 0.96-0.97 (m, 2H), 1.20 (s, 9H), 1.90-1.95 (m, 1H), 4.16 (m, 2H), 4.85 (s, 1H), 6.38 (d, J=16.0 Hz, 1H), 6.46 (s, 1H), 6.89 (d, J=15.2 Hz, 1H), 7.59 (d, J=3.6 Hz, 1H), 7.73 (d, J=4.0 Hz, 1H), 7.87 (bs, 1H), 8.42 (s, 1H), 9.26 (bs, 1H), 12.18 (bs, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:20])([F:19])[C:9]1[S:10][C:11]([C:14](OCC)=[O:15])=[CH:12][N:13]=1.O.[OH-].[Na+]>O1CCCC1>[F:20][C:8]([F:7])([F:19])[C:9]1[S:10][C:11]([CH2:14][OH:15])=[CH:12][N:13]=1
Reactant: CCOC(=O)c1cnc(C(F)(F)F)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cnc(C(F)(F)F)s1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of lithium aluminum hydride (2.17 g, 57.1 mmol) in tetrahydrofuran (80 ml) was dropwise added a solution of ethyl 2-(trifluoromethyl)-1,3-thiazole-5-carboxylate (8.579 g, 38.10 mmol) in tetrahydrofuran (40 ml) under ice-cooling and the mixture was stirred at 0° C. 1 hr. The reaction solution was ice-cooled and water (2 ml), 15% aqueous sodium hydroxide solution (2 ml) and water (5 ml) were dropwise added successively to decompose excess lithium aluminum hydride. The mixture was stirred at room temperature as it was for 2 hrs. The resulting precipitate was removed by filtration and the precipitate was washed with ethyl acetate. The solvent of the collected filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1−1/1) to give the objective substance.
Reaction SMILES: [CH:1](=O)[CH3:2].[NH:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH:13][C:14]([C:16]1[NH:20][CH:19]=[N:18][C:17]=1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:26][C:25]=1[CH3:37])=[O:22])=[O:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>CN(C=O)C>[NH:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH:13][C:14]([C:16]1[NH:20][CH:19]=[N:18][C:17]=1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([CH2:1][CH3:2])[CH2:33][CH2:32]2)=[CH:26][C:25]=1[CH3:37])=[O:22])=[O:15]
Reactant: CC=O
Reactant: Cc1cc(OC2CCNCC2)ccc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2ccccc2[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCC(Oc2ccc(NC(=O)c3nc[nH]c3C(=O)Nc3nc4ccccc4[nH]3)c(C)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Acetaldehyde (0.088 g, 2.0 mmol) was weighed out into a dry 25 ml round bottom flask. N5-(1H-benzo[d]imidazol-2-yl)-N4-(2-methyl-4-(piperidin-4-yloxy)phenyl)-1H-imidazole-4,5-dicarboxamide (0.0465 g, 0.1 mmol) was added, followed by a DMF solution (3.0 ml) of sodium triacetoxyborohydride (0.106 g, 0.5 mmol). The reaction mixture was stir at room temperature over night (16 hours). The reaction mixture was then treated with 1 mL of 1N hydrochloric acid and concentrated under reduced pressure. The resulting crude material was purified by reverse phase HPLC (ammonium acetate/acetonitrile) to give N5-1H-benzimidazol-2-yl-N4-{4-[(1-ethylpiperidin-4-yl)oxy]-2-methylphenyl}-1H-imidazole-4,5-dicarboxamide. 1H-NMR (400 MHz, DMSO-d6): δ 9.49 (s, 1H), 8.22 (s, 1H), 7.52 (m, 1H), 7.41 (m, 2H), 7.23 (m, 2H), 6.97 (m, 2H), 4.75 (m, 1H), 3.54 (m, 2H), 3.37 (m, 3H), 3.12 (m, 4H), 2.24 (m, 4H), 1.22 (s, 3H); MS (EI): 488.7 (MH+).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[C:31]([OH:33])=[O:32])=[C:4]([F:36])[CH:3]=1.Cl.[F:38][C:39]1([F:43])[CH2:42][NH:41][CH2:40]1>>[F:38][C:39]1([F:43])[CH2:42][N:41]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[C:13]([O:16][CH2:17][C:18]5[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=5)[CH:14]=[CH:15][C:10]=4[N:9]=[C:8]3[C@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]3[C:31]([OH:33])=[O:32])=[C:4]([F:36])[CH:3]=2)[CH2:40]1
Reactant: Cc1ccc(COc2ccc3nc([C@@H]4CCCC[C@@H]4C(=O)O)n(Cc4ccc(Br)cc4F)c3c2)nc1
Reactant: FC1(F)CNC1
Agent: Cl
Product: Cc1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(N5CC(F)(F)C5)cc4F)c3c2)nc1

Procedure:
The title compound was prepared in a manner analogous to that in Example 152 substituting (1S,2R)-2-{1-(4-bromo-2-fluorobenzyl)-6-[(5-methylpyridin-2-yl)methoxy]-1H-benzimidazol-2-yl}cyclohexanecarboxylic acid and 3,3-difluoroazetidine hydrochloride. MS (ESI): mass calcd. for C31H31F3N4O3, 564.23; m/z found, 565.2 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.34 (5, 1H), 7.67-7.63 (m, 1H), 7.55 (d, J=8.6, 1H), 7.45 (d, J=8.0, 1H), 7.02-6.98 (m, 2H), 6.81 (t, J=8.5, 1H), 6.39 (dd, J=12.3, 2.3, 1H), 6.24 (dd, J=8.4, 2.3, 1H), 5.47 (d, J=16.6, 1H), 5.41 (d, J=16.6, 1H), 5.12 (5, 2H), 4.21 (t, J=12.0, 4H), 3.68-3.54 (m, 1H), 2.91-2.82 (m, 1H), 2.35 (s, 3H), 2.34-2.26 (m, 1H), 2.12-2.02 (m, 1H), 1.90-1.75 (m, 4H), 1.56-1.49 (m, 1H), 1.49-1.42 (m, 1H).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH:17]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH2:17][N:29]2[CH2:28][CH2:27][N:26]([C:23]3[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=3)[CH2:31][CH2:30]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(c3ccc(Cl)cc3)CC2)cc1-c1cccs1

Procedure:
77 mg (73%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propanal (50 mg, 0.191 mmol), 1-(4-chlorophenyl)piperazine (34 mg, 0.191 mmol), DIPEA (0.050 mL, 0.287 mmol) and NaBH(OAc)3 (121 mg, 0.573 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:24]([CH2:25][CH3:26])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([C@@H:18]4[CH2:20][C@H:19]4[N:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=3)[N:9]=[CH:10][C:5]=2[C:4](=[O:27])[C:3]=1[C:28]([NH2:30])=[O:29].CC[Cl:33]>CO>[ClH:33].[NH2:1][C:2]1[N:24]([CH2:25][CH3:26])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([C@@H:18]4[CH2:20][C@H:19]4[N:21]([CH3:23])[CH3:22])=[CH:16][CH:17]=3)[N:9]=[CH:10][C:5]=2[C:4](=[O:27])[C:3]=1[C:28]([NH2:30])=[O:29]
Reactant: CCCl
Agent: CCn1c(N)c(C(N)=O)c(=O)c2cnc(Nc3ccc([C@@H]4C[C@H]4N(C)C)cc3)nc21
Solvent: CO
Product: Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 0.05 g (0.13 mmol) of the product prepared in step 15.6 in 2.5 mL of methanol is added 0.20 mL (0.4 mmol) of 2.0 M hydrochloric ether. The mixture is stirred for 5 minutes at room temperature and then evaporated to dryness. The residue is purified by preparative HPLC. The fraction corresponding to the expected pure product is evaporated to dryness under then taken up in methanol. Ether is added and the solid is drained by suction and dried in an oven under vacuum. 0.031 g of the expected product is obtained. Yield (dihydrochloride)=49%. m.p.=208-210°C. (decomposition). M+H+=408.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([OH:9])=O.[N+:10]([C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16])([O-:12])=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCOC(C)=O>CN(C=O)C>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([NH:16][C:15]1[CH:17]=[CH:18][CH:19]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=1)=[O:9]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CN1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCC[C@H]1C(=O)Nc1cccc([N+](=O)[O-])c1
Reaction time: 20 h

Procedure:
To a solution of (S)-1-methylpyrrolidine-2-carboxylic acid (258 mg, 2 mmol) in DMF (4 mL) was added 3-nitroaniline (276 mg, 2 mmol) and HATU (760 mg). After stirring for 20 h, it was added with EtOAc, washed with Sat. NaHCO3, brine, dried and concentrated to give (S)-1-methyl-N-(3-nitrophenyl)pyrrolidine-2-carboxamide.
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=[CH:38][CH:37]=2)[C:13]([NH:15][C@H:16]([C:32](O)=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:47][CH:48]([CH2:57][CH:58]([CH3:60])[CH3:59])[CH:49]([OH:56])[C:50]([O:52][CH:53]([CH3:55])[CH3:54])=[O:51].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:56][CH:49]([CH:48]([NH:47][C:32](=[O:33])[CH:16]([NH:15][C:13](=[O:14])[CH:12]([CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[CH2:57][CH:58]([CH3:60])[CH3:59])[C:50]([O:52][CH:53]([CH3:54])[CH3:55])=[O:51]
Reactant: CC(C)CC(N)C(O)C(=O)OC(C)C
Reactant: O=C(NCCCC[C@H](NC(=O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CC(NC(=O)C(CCCCNC(=O)OCc1ccccc1)NC(=O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12)C(O)C(=O)OC(C)C
Temperature: -10 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
N-[3-(1-naphthalenyl)-2-(1-naphthalenylmethyl)-1-oxopropyl]-N6 -[(phenylmethoxy)carbonyl]-L-lysine, 4 g (6.6 mmol), 1.58 g (6.6 mmol) of [2R-(2R*,3S*)]-3-amino-2-hydroxy-5-methylhexanoic acid, 1-methylethyl ester, monohydrochloride, and 1.79 g (13.2 mmol) of 1-hydroxybenzotriazole are combined in 80 ml of dimethylformamide. The [2R-(2R*,3S*)]-3-amino-2-hydroxy-5-methylhexanoic acid, 1-methylethyl ester, monohydrochloride is neutralized with 1.4 ml (10.1 mmol) of triethylamine. The solution is cooled to -10° C. and 1.36 g (6.6 mmol) of dicyclohexylcarbodiimide is added with stirring. The reaction mixture is kept cold for 8 hours while stirring under nitrogen, allowed to warm to room temperature overnight, filtered, the filtrate concentrated and the residue partitioned between ethyl acetate and water. The organic layer is separated and extracted with saturated solution of sodium bicarbonate, dried (sodium sulfate), filtered and concentrated. The residue is flash chromatographed over silica gel 60 (230-400 mesh), eluted with hexane-ethyl acetate (2:3), the eluates collected, dissolved in diethyl ether, filtered and the filtrate concentrated to afford 4.01 g (77%) of the title compound as a white amorphous solid.
Reaction SMILES: [C:1](OCC)(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Mg].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.OS(O)(=O)=O>CCOCC.C(Cl)(Cl)(Cl)Cl.CCO>[Cl:13][C:14]1[CH:19]=[C:18]2[C:17](=[CH:16][CH:15]=1)[C:20]1([CH2:24][CH2:23][CH2:22][CH2:21]1)[C:25](=[O:26])[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:1]2[OH:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)C1(c2ccc(Cl)cc2)CCCC1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCCC2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67.5 %

Procedure:
A mixture of diethyl malonate (5.3 g, 33 mmol) and magnesium (0.80 g, 33 mmol) was treated with anhydrous EtOH 10 mL and 0.1 mL CCl4. The mixture was stirred at room temperature for 20 minutes and was then diluted with 50 mL anhydrous ether and refluxed for 1 hour under nitrogen. 1-(4-Chlorophenyl)cyclopentanecarbonyl chloride (7.3 g, 30 mmol) in 20 mL ether was then added dropwise to the above refluxed mixture, and the resulting mixture was refluxed for 20 minutes, M+1=341. The mixture was cooled to room temperature, diluted with 100 mL ether, washed with H2O (2×50 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give 11 g of the crude product as a pale yellow solid. The crude product was treated with concentrated H2SO4 (48 mL, 900 mmol) and stirred for 4 hours, M+1=321. The mixture was poured into 500 g ice and extracted with ether (3×100 mL). The organic layers were combined and washed with H2O (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with 10-20% ether/hexane to give the title compound (6.5 g) as a pale yellow solid. MS (m/z)=321 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](F)([O:10]CC)[C:6]([F:9])([F:8])[F:7])[CH3:2].[Sb](F)(F)(F)(F)F>>[F:7][C:6]([F:8])([F:9])[C:5](=[O:10])[C:4]([O:3][CH2:1][CH3:2])=[O:14]
Reactant: CCOC(=O)C(F)(OCC)C(F)(F)F
Agent: F[Sb](F)(F)(F)F
Product: CCOC(=O)C(=O)C(F)(F)F
Yield: 82.9 %

Procedure:
A nitrogen-flushed, 500 ml 3-neck pot, equipped as described in Example 17, was charged with 340.3 g (1.56 mol) of ethyl-2-ethoxytetrafluoropropionate and 19.5 g (0.09 mol) of SbF5. Gas was evolved. The mixture was heated and distilled to give 220 g (83.0% yield) of ethyl trifluoropyruvate, b.p. 88° to 89°. The gaseous product was collected and identified by IR as largely ethyl fluoride.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)/[CH:10]=[N:11]/[S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:25]([Mg]Cl)=[CH2:26]>C1COCC1>[Si:1]([O:8][CH:9]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[CH:10]([NH:11][S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[CH:25]=[CH2:26])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C=C[Mg]Cl
Reactant: CC(C)(C)S(=O)/N=C/C(O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: C=CC(NS(=O)C(C)(C)C)C(O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Reaction time: 1 h

Procedure:
To a solution of 2.4 g (6.20 mmol) of N-[(1E)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-chlorophenyl)ethylidene]-2-methylpropane-2-sulfinamide in 20 mL anhydrous THF cooled to 0° C. under nitrogen atmosphere (from Step D) was added a 1.6 M solution of vinyl magnesium chloride in THF (3.90 mL, 6.2 mmol) via syringe and the resulting mixture stirred for 1 h. The mixture was allowed to warm to room temperate and stirred for an additional hour. The reaction was quenched with saturated solution of ammonium chloride and extract with ethyl acetate. Combine organics, dry over magnesium sulfate, filter and concentrate under vacuum. The residue was purified by Horizon MPLC, with a 40M+ silica gel column, eluting with a gradient eluent system of 0-35% ethyl acetate in hexane to afford all four diastereomers as single isomers.