Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:19]3[O:18][CH2:17][CH2:16][O:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.BrC[CH:22]=[O:23].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].O1[CH2:37][CH2:36][O:35][CH2:34]C1>C(OCC)(=O)C.CO.O>[O:15]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([N:7]3[CH2:6][CH2:5][N:4]([CH2:3][CH2:2][NH:1][CH2:37][CH:36]([O:35][CH3:34])[O:23][CH3:22])[CH2:9][CH2:8]3)[C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: NCCN1CCN(c2cccc3c2OCCO3)CC1
Reactant: O=CCBr
Reactant: C1COCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(CNCCN1CCN(c2cccc3c2OCCO3)CC1)OC

Procedure:
A mixture of 1-(2-amino-1-ethyl)-4-(1,4-benzodioxan-5-yl)piperazine (9.1 g), bromoacetaldehyde dimethylacetale (6.5 g), potassium iodide (0.5 g), and potassium carbonate (4.8 g) in 1,4-dioxan (200 ml) was refluxed for 16 h. Water was added followed by extraction with ethyl acetate. The organic phase was concentrated in vacuo leaving an oil which was applied to a silica gel column (eluent: ethyl acetate/methanol=1:3). The product, 1-(1,4-benzodioxan-5-yl)-4-[2-(2,2-dimethoxy-1-ethylamino)-1-ethyl]piperazine, was obtained as an oil (4.7 g).
Reaction SMILES: [Br-:1].[N+:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N+:9]([CH2:15][CH2:16][CH3:17])=[CH:10]2)([O-])=O>CO.[Pt]=O>[BrH:1].[NH2:2][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][N:9]([CH2:15][CH2:16][CH3:17])[CH2:10]2
Reactant: [Br-]
Reactant: CCC[n+]1ccc2c([N+](=O)[O-])cccc2c1
Agent: O=[Pt]
Solvent: CO
Product: Br
Product: CCCN1CCc2c(N)cccc2C1
Yield: 100.2 %

Procedure:
5-Nitro-2-n-propylisoquinolinium bromide (8.2 g) was dissolved in methanol (150 ml) and the solution hydrogenated over platinum oxide (0.6 g) at 45 psi. When the hydrogenation was complete, the catalyst was removed by filtration and the solvent removed in vacuo to leave a light orange solid residue of 5-amino-2-n-propyl-1,2,3,4-tetrahydroisoquinoline hydrobromide (7.5 g). This residue was recrystallized from ethanol and the product obtained as pale orange crystals, m.p. 238°-239.5° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:21])[CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C:15]1=[O:20].Br[C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:21])[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:32]=2[N:31]=[CH:30][CH:29]=[CH:28]3)[CH2:16][C:15]1=[O:20]
Reactant: O=C1CNCCN1CC(O)CN1CCc2ccccc2C1
Reactant: Brc1cccc2cccnc12
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1CN(c2cccc3cccnc23)CCN1CC(O)CN1CCc2ccccc2C1
Temperature: 110 °C
Yield: 15.8 %

Procedure:
To a solution of 1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)piperazin-2-one (100 mg, 0.35 mmol) in 10 mL of dry toluene was added 8-bromoquinoline (108 mg, 0.52 mmol), Pd2(dba)3 (32 mg, 0.035 mmol), NINAP (44 mg, 0.07 mmol) and t-BuONa (101 mg, 1.05 mmol). The flask was degassed and charged with N2, then heated at 110° C. for 16 h. The reaction mixture was cooled, filtered, and concentrated. The residue was purified by preparative HPLC purification. (23 mg, yield 15.8%) MS (ESI+) e/z: 417.2 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 8.96-8.85 (m, 1H), 8.53-8.39 (m, 1H), 8.38-8.29 (m, 1H), 7.70-7.62 (m, 1H), 7.62-7.51 (m, 2H), 7.37-7.24 (m, 4H), 7.24-7.17 (m, 1H), 4.60-4.52 (m, 1H), 4.52-4.41 (m, 2H), 4.08-3.98 (m, 2H), 3.87-3.78 (m, 2H), 3.77-3.69 (m, 1H), 3.69-3.58 (m, 4H), 3.57-3.49 (m, 1H), 3.42-3.34 (m, 1H), 3.32-3.27 (m, 1H), 3.27-3.13 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([F:11])[C:6]=1[CH2:12][NH2:13])[CH3:2].[I:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[C:22]([C:27](OCC)=[O:28])[CH:21]=[N:20]2.C(N(CCNC(C1C=NC2C(=CC=C(I)C=2)N=1)=O)CCOC1C(F)=NC=CC=1)C>>[CH2:14]([N:3]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([F:11])[C:6]=1[CH2:12][NH:13][C:27]([C:22]1[CH:21]=[N:20][C:19]2[C:24](=[CH:25][CH:26]=[C:17]([I:16])[CH:18]=2)[N:23]=1)=[O:28])[CH2:1][CH3:2])[CH3:15]
Reactant: CCN(CC)Cc1ccnc(F)c1CN
Reactant: CCOC(=O)c1cnc2cc(I)ccc2n1
Agent: CCN(CCNC(=O)c1cnc2cc(I)ccc2n1)CCOc1cccnc1F
Product: CCN(CC)Cc1ccnc(F)c1CNC(=O)c1cnc2cc(I)ccc2n1
Yield: 56.8 %

Procedure:
This compound was prepared, starting from compounds 90 (0.70 g, 3.31 mmol) and 9 (1.09 g, 3.31 mmol), according to the procedure developed for compound 10. Reaction time under reflux: 12 h; the purification was performed using column chromatography (Al2O3, CH2Cl2/EtOH, 99/1, v/v) to give compound 91 (926 mg, 1.88 mmol) as a beige solid. Yield 57%; Rf (Al2O3, CH2Cl2/EtOH, 99/1, v/v) 0.38; mp 147-149° C.; IR (KBr) ν 1160, 1413, 1477, 1508, 1679, 2967 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.13 (t, 6H, J=7.1 Hz), 2.66 (m, 4H), 3.80 (se, 2H), 4.82 (d, 2H, J=6.0 Hz), 7.19 (m, 1H), 7.71 (d, 1H, J=8.8 Hz), 8.02 (dd, 1H, J=1.8, 8.8 Hz), 8.08 (d, 1H, J=4.8 Hz), 8.55 (d, 1H, J=1.8 Hz), 9.14 (m, 1H), 9.61 (s, 1H); ESI-MS m/z 493.9 [M+H]+.
Reaction SMILES: [C:1]([N:4]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[S:21][C:20]([C:22]([O:24]C)=[O:23])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:26])[CH2:6]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:1]([N:4]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[S:21][C:20]([C:22]([OH:24])=[O:23])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:26])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(C(=O)O)s2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.3 %

Procedure:
Methyl 5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}thiophene-2-carboxylate (80 mg, 0.17 mmol, 1 eq.) was dissolved in methanol (6 ml). A solution of potassium carbonate (200 mg, 1.4 mmol, 8 eq.) in water (2 ml) was added and reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated and the residue was acidified with a 1N HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydro-quinolin-1(2H)-yl]carbonyl}thiophene-2-carboxylic acid (76 mg, 99%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:17][C@H:18]([NH2:21])[CH2:19][CH3:20].CCN(C(C)C)C(C)C>CS(C)=O>[C@@H:18]([NH:21][C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)([CH2:19][CH3:20])[CH3:17]
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: CC[C@H](C)N
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)Nc1nc2cc(C(=O)OC)ccc2[nH]c1=O
Temperature: 70 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (200 mg, 0.84 mmol) in DMSO (2 mL) was added (S)-butan-2-amine (93 mg, 1.27 mmol) and DIEA (163 mg, 1.26 mmol). The resulting solution was stirred for 3 hours at 70° C. and then quenched by the addition of water (10 mL). The solids were collected by filtration to afford (S)-methyl 3-(sec-butylamino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as light yellow solid (150 mg, 65%).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][C:5](OC)=[N:4]1)[CH3:2].[Cl-:11].[NH4+:12]>CO>[ClH:11].[CH2:1]([CH:3]1[NH:4][C:5](=[NH:12])[CH2:6][CH2:7][CH2:8]1)[CH3:2]
Reactant: CCC1CCCC(OC)=N1
Reactant: [NH4+]
Reactant: [Cl-]
Solvent: CO
Product: CCC1CCCC(=N)N1
Product: Cl

Procedure:
The product of EXAMPLE 153 in MeOH is reacted with ammonium chloride by the method of EXAMPLE 27 to generate the title material.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:15][C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18]>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:17](=[O:18])[C:16]([CH3:21])([CH3:20])[CH3:15])[CH:3]=1
Reactant: Nc1cccnc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-aminopyridine (9.41 g, 100 mmol) and triethylamine (16.7 mL, 120 mmol) in CH2Cl2 (300 mL) at 0° C. was added trimethylacetyl chloride (14.8 mL, 120 mmol) dropwise over 15 min. The reaction was warmed to rt and stirred overnight. The mixture was concentrated in vacuo, the residue partitioned between EtOAc and H2O, and the layers separated. The aqueous layer was made basic with saturated NaHCO3 and extracted with EtOAc. The combined organic layers were washed with saturated NaHCO3 and brine, dried over MgSO4, filtered, and concentrated in vacuo to give N-(pyridin-3-yl)-2,2-dimethylpropanamide as a tan solid. 1H NMR (CDCl3, 300 MHz) δ 8.57 (d, 1H), 8.33 (dd, 1H), 8.17 (ddd, 1H), 7.69 (br s, 1H), 7.27 (dd, 1H), 1.33 (s, 9H).
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:19])[C@:12]([OH:18])([CH3:17])[C:13]([F:16])([F:15])[F:14])=[C:6]([Cl:20])[C:5]=1[F:21])=O.F[C:23](F)(F)C(OC(=O)C(F)(F)F)=O>>[CH2:1]([S:2][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:19])[C@:12]([OH:18])([CH3:17])[C:13]([F:16])([F:15])[F:14])=[C:6]([Cl:20])[C:5]=1[F:21])[CH3:23]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CS(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1F
Product: CCSc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1F
Temperature: 25 °C

Procedure:
A suspension of (R)-N-[4-methylsulphinyl-3-fluoro-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 2) (5.41 g) in trifluoroacetic anhydride (65 ml) was heated under reflux for 30 minutes. The reaction mixture was evaporated and the residue was redissolved in MeOH (32 ml) and triethylamine (32 ml) and ethyl iodide (2.2 ml) was added. The reaction mixture was heated under reflux for 3 hours, allowed to cool to room temperature and volatile material was removed by evaporation. The residue was partitioned between EtOAc (150 ml) and brine (100 ml); the organic phase was separated, dried and volatile material was removed by evaporation. The residue was purified by flash column chromatography eluting with 10-20% EtOAc/isohexane to give the title compound (2.16 g) as a yellow solid. NMR (CDCl3) 1.27 (s, 3H), 1.76 (s, 3H), 2.88-2.95 (q, 2H), 3.55 (s, 1H), 7.32 (t, 1H), 8.15 (d, 1H), 8.92 (s, 1H); m/z: 344.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[N:15]3)[O:10][C:9]2=[O:19])[CH:5]=[CH:4][C:3]=1[C:20]1[O:24][N:23]=[C:22]([C:25](OCC)=[O:26])[CH:21]=1.[BH4-].[Li+].Cl>CO.ClCCl.CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[N:15]3)[O:10][C:9]2=[O:19])[CH:5]=[CH:4][C:3]=1[C:20]1[O:24][N:23]=[C:22]([CH2:25][OH:26])[CH:21]=1
Reactant: CCOC(=O)c1cc(-c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)on1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CO
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2cc(CO)no2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
Ethyl 5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yl]phenyl}isoxazole-3-carboxylate (Example 2, 0.4 g, 1.1 mmol) was suspended in methanol/dichloromethane/dimethylsulfoxide (9 ml:3 ml:1 ml). Lithium borohydride (0.12 g, 5.5 mmol) was added portionwise. The reaction mixture was stirred under nitrogen at room temperature for 1 hour. The pH was adjusted to pH 3–4 using 1N hydrogen chloride, the mixture was cooled to 0° C., and the resulting white precipitate was collected by suction filtration. The white solid was dried in vacuo, giving 0.28 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][CH2:13]S(C1C=CC=CC=1)(=O)=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.[ClH:23].[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]2[O:33][N:32]=[C:31]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:30]=2[CH:40]=1.C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[ClH:23].[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]2[O:33][N:32]=[C:31]([CH:34]3[CH2:39][CH2:38][N:37]([CH2:13][CH2:12][CH2:11][C:10]4[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[NH:3][C:2]=4[CH3:1])[CH2:36][CH2:35]3)[C:30]=2[CH:40]=1
Reactant: COc1ccc2onc(C3CCNCC3)c2c1
Reactant: Cc1[nH]c2ccccc2c1CCCS(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: COc1ccc2onc(C3CCN(CCCc4c(C)[nH]c5ccccc45)CC3)c2c1

Procedure:
A mixture of 4.0 g of 2-methyl-3-(3-phenylsulfonylpropyl)indole, 3.0 g of 5-methoxy-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride, 8.0 g of potassium carbonate and 70 ml of 2-butanone was heated under reflux, with stirring, and refluxed under nitrogen for 16 hours. The reaction mixture was poured into water and the aqueous suspension was extracted with ethyl acetate. The insoluble material was collected and washed with diluted sodium hydroxide to give a solid. The ethylacetate extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to give an additional solid. Treatment of the combined solids with a saturated hydrogen chloride-toluene solution gave the salt. The salt was triturated with acetone and recrystallized from ethanol-ether to give an ethanolate, mp 163°-165° (foaming). Recrystallization of the alcoholate from acetonitrile and subsequent drying of the sample at 100° and ca 1 mm gave 1.60 g (33%) of product, mp 130°-132°.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]1[C:10]([N+:11]([O-])=O)=[CH:9][N:8]=[C:7]([NH:14][C:15](=[O:17])[CH3:16])[CH:6]=1.[H][H]>C(O)C.[Pt]=O>[C:15]([NH:14][C:7]1[CH:6]=[C:5]2[CH:4]=[CH:3][NH:11][C:10]2=[CH:9][N:8]=1)(=[O:17])[CH3:16]
Reactant: [H][H]
Reactant: CC(=O)Nc1cc(C=CN(C)C)c([N+](=O)[O-])cn1
Agent: O=[Pt]
Solvent: CCO
Product: CC(=O)Nc1cc2cc[nH]c2cn1
Yield: 33.3 %

Procedure:
N,N-Dimethyl-2-(2-acetylamino-5-nitropyridin-4-yl)ethenamine (6 g, 24 mmol) was hydrogenated over platinum oxide (0.5 g) in ethanol (120 mL) at 35 psi of hydrogen for 15 min. The catalyst was removed by filtration and the solvent evaporated in vacuo. The residue was chromatographed on silica eluting with a gradient of 5 to 10% MeOH in DCM to afford a purple solid. This was triturated with ether and the precipitate collected by filtration to give the title compound (1.4 g, 33%) as a beige solid. mp 220° C. (dec.). 1H NMR (360 MHz, d6 -DMSO) δ 2.07 (3H, s), 6.45 (1H, s), 7.55-7.57 (1H, m), 8.21 (1H, s), 8.46 (1H, s), 10.16 (1H, br s) and 11.42 (1H, br s).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH:15]=[CH:16][CH:17]=1>O1CCCC1>[CH:1]([NH:11][C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=2)[CH:15]=[CH:16][CH:17]=1)=[O:2]
Reactant: Nc1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Reactant: O=CO
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: O=CNc1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 50 °C

Procedure:
Formic acid (2.5 mL, 66.3 mmol) and acetic anhydride (5 mL, 52.9 mmol) were mixed, and the mixture was stirred with heating at 50° C. for 3 hr. The reaction mixture was cooled to room temperature, diluted with tetrahydrofuran (50 mL), and cooled to 0° C. To the reaction mixture was added a solution of N-(3-aminophenyl)-3-(trifluoromethyl)benzamide (5.65 g, 20.2 mmol) in tetrahydrofuran (50 mL) and the mixture was stirred at the same temperature for 16 hr, during which the reaction temperature was allowed to gradually warm to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (50 mL) and ethyl acetate (250 mL). The solution was washed with saturated aqueous sodium hydrogen carbonate solution (150 mL×2) and saturated aqueous ammonium chloride solution (150 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give N-[3-(formylamino)phenyl]-3-(trifluoromethyl)benzamide as a yellow amorphous substance. To a solution of N-[3-(formylamino)phenyl]-3-(trifluoromethyl)benzamide produced above in tetrahydrofuran (100 mL) was added a 1.9M solution (21 mL, 39.9 mmol) of borane-dimethylsulfide complex in tetrahydrofuran, and the mixture was stirred at room temperature for 1.5 hr. Since the starting materials were not completely consumed, a 1.9M solution (2 mL, 3.8 mmol) of borane-dimethylsulfide complex in tetrahydrofuran was added, and the mixture was further stirred at room temperature for 1 hr. Methanol (30 mL) and acetic acid (10 mL) were added to the reaction solution and the mixture was stirred at room temperature for 14 hr, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (250 mL), washed with saturated aqueous sodium hydrogen carbonate solution (100 mL×2) and saturated brine (100 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate and hexane to give the title compound (5.54 g, total yield of 2 steps 93%) as yellow crystals.
Reaction SMILES: I[C:2]1[CH:7]=CC(C)=[CH:4][CH:3]=1.C(N(CC)CC)C.O1[CH2:21][CH2:20][O:19][CH2:18]C1.[CH:22]1([N:28]([BH2:35])[CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>[Pd].CCOCC>[CH3:18][O:19][C:20]1[CH:21]=[CH:4][C:3]([BH:35][N:28]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)=[CH:2][CH:7]=1
Reactant: C1COCCO1
Reactant: BN(C1CCCCC1)C1CCCCC1
Reactant: Cc1ccc(I)cc1
Agent: [Pd]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1ccc(BN(C2CCCCC2)C2CCCCC2)cc1
Temperature: 70 °C

Procedure:
1.130 g (0.19 mmol) of palladium catalyst (Ph3P)2PdCl2, 0.868 g (3.7 mmol) of p-iodotoluene, 2.5 ml (18.5 mmol) of triethylamine, 15 ml of dioxane and 0.708 g (3.7 mmol) of dicyclohexylaminoborane were introduced into a 100 ml Schlenk vessel dried beforehand under argon. The Schlenk vessel was subsequently equipped with a reflux condenser connected via the top to a bubbler. The reaction mixture was stirred magnetically and heated at 70° C. for 15 h. The reaction mixture was subsequently allowed to return, under argon, to ambient temperature. The solvent and the excess reactants were evaporated under the vacuum of a vane pump. The residue obtained was taken up in anhydrous ether and then filtered under argon through dry Celite® 545. The filtrate was again evaporated and the residue was distilled in a Kügelrohr distillation apparatus (T=40° C.) under a vacuum of 0.01 mmHg. 0.884 g (Yd=81%) of a white solid was isolated. The spectroscopic characteristics are as follows:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[C:5]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:4]=1.ClC(Cl)(O[C:23](=[O:29])[O:24][C:25](Cl)(Cl)Cl)Cl.[N-:31]=[C:32]=[O:33]>CCOC(C)=O.CN(C=O)C>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:32]([NH:31][C:3]2[C:25]3[O:24][C:23](=[O:29])[NH:10][C:9]=3[CH:6]=[CH:5][CH:4]=2)=[O:33])=[C:5]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:4]=1
Reactant: [N-]=C=O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCc1ccc(C(F)(F)F)cc1N1CCCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(C(F)(F)F)cc1N1CCCCC1)Nc1cccc2[nH]c(=O)oc12
Temperature: 80 °C
Yield: 14 %

Procedure:
Amine 2c (1 g, 3.8 mmol) (Scheme 7) was dissolved in 20 ml of AcOEt and at 0° C. triphosgene (1.13 g, 3.8 mmol) was added to the solution. The mixture was warmed at 80° C. for 4 hours then evaporated and the residue was dissolved in 5 ml of DMF. The solution of the isocyanate was added dropwise to a solution in DMF (10 ml) of compound 1c (390 mg, 2.6 mmol) and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt1/petroleum ether 1). The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column gave 160 mg of a white solid. Yield=14% 1HNMR (DMSO, 200 MHz) δ 1.56 (2H, bs), 1.69 (4H, bs), 2.85 (4H, m), 4.42 (2H, d, J=5.6 Hz), 6.66 (1H, dd, J=8 Hz, J′=0.8 Hz), 7.01 (2H, m), 7.32 (1H, s), 7.44 (2H, dd, J=7.6 Hz), 7.72 (1H, dd, J=8.6 Hz, J′=1 Hz), 8.73 (1H, bs), 11.68 (1H, bs); [M+1] 435.2 (C21H21F3N4O3 requires 434.4).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])/[CH:5]=[C:6](\[NH:14][C:15](=[O:17])[CH3:16])/[C@H:7]([CH3:13])[C@H:8]([CH3:12])[CH2:9][CH2:10][CH3:11])[CH3:2]>CO>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C@@H:6]([NH:14][C:15](=[O:17])[CH3:16])[C@H:7]([CH3:13])[C@H:8]([CH3:12])[CH2:9][CH2:10][CH3:11])[CH3:2].[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C@H:6]([NH:14][C:15](=[O:17])[CH3:16])[C@H:7]([CH3:13])[C@H:8]([CH3:12])[CH2:9][CH2:10][CH3:11])[CH3:2]
Reactant: CCC[C@@H](C)[C@@H](C)/C(=C/C(=O)OCC)NC(C)=O
Solvent: CO
Product: CCC[C@@H](C)[C@@H](C)[C@@H](CC(=O)OCC)NC(C)=O
Product: CCC[C@@H](C)[C@@H](C)[C@H](CC(=O)OCC)NC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ten mL ampoules were each charged with 20 mg of (4R,5R)-3-acetylamino-4,5-dimethyl-(Z)-oct-2-enoic acid ethyl ester (substrate), 2 mL of MeOH, and approximately 10 mg of catalyst. The ampoules were placed in a multi-reactor, purged with hydrogen, then pressurized to 20 psig with hydrogen and shaken at room temperature for 18 hours. For each ampoule following reaction, the solids were removed by filtration and the filtrate was analyzed by chiral GC (CHIRASIL-DEX CB, 140° C. isothermal). The table below provides conversion and ratio of (3R,4R,5R)-3-acetylamino-4,5-dimethyl-octanoic acid ethyl ester (desired diastereoisomer) to (3S,4R,5R)-3-acetylamino-4,5-dimethyl-octanoic acid ethyl ester (undesired diastereoisomer) for various hydrogenation catalysts.
Reaction SMILES: [Cl-].[C:2]([C:5]1[CH:10]=[CH:9][N+:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])[NH2:3].[H][H]>CO.[Pd]>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([N:8]2[CH2:9][CH2:10][CH:5]([C:2]([NH2:3])=[O:4])[CH2:6][CH2:7]2)=[CH:16][CH:15]=1
Reactant: COc1ccc(-[n+]2ccc(C(N)=O)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Cl-]
Solvent: CO
Product: COc1ccc(N2CCC(C(N)=O)CC2)cc1
Yield: 51.4 %

Procedure:
A suspension of 4-carbamoyl-1-(4-methoxyphenyl)-pyridinium chloride (22.0 g) in methanol (250 ml) was hydrogenated at ambient temperature and pressure in the presence of 10% palladium-on-carbon catalyst (1.0 g) for 2 days. Further catalyst (0.75 g) was added, and when no more hydrogen was taken up, the catalyst was removed by filtration. The filtrate was basified by the addition of an excess of triethylamine and the solvent removed in vacua. The residue was partitioned between water and a 19:1 mixture of chloroform and methanol. The solvent was removed in vacuo from the organic layer and the residue dried in vacuo over phosphorus pentoxide to give 1-(4-methoxyphenyl)piperidine-4-carboxamide as a white solid (10 g), m.p. 178°-181° C.