Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:9]([C:10]#[N:11])=[C:8]([CH2:12][OH:13])[N:7]=[C:6]1[N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[C:2]#[C:3][CH3:4]>[O-2].[O-2].[Mn+4].ClCCl>[CH2:1]([N:5]1[C:9]([C:10]#[N:11])=[C:8]([CH:12]=[O:13])[N:7]=[C:6]1[N:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(CO)c1C#N
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C=O)c1C#N
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.7 %

Procedure:
3.28 g of manganese dioxide was added to a 5 ml dichloromethane solution of 1.35 g of t-butyl 4-[1-(2-butynyl)-5-cyano-4-hydroxymethyl-1H-imidazol-2-yl]piperazine-1-carboxylate. The reaction solution was stirred at room temperature for 15 hours, then stirred and heated under reflux for five hours. The solution was filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 1.11 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (2:3).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:16][C:17]1[CH:22]=[C:21]([NH:23][CH:24]([CH3:27])[CH2:25][NH2:26])[CH:20]=[C:19]([CH3:28])[N:18]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C)C=O>[CH3:16][C:17]1[CH:22]=[C:21]([NH:23][CH:24]([CH3:27])[CH2:25][NH:26][C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])[CH:20]=[C:19]([CH3:28])[N:18]=1
Reactant: O=C(O)/C=C/C(F)(F)F
Reactant: Cc1cc(NC(C)CN)cc(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(C)CNC(=O)/C=C/C(F)(F)F)cc(C)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (15.4 mg, 0.11 mmol) was dissolved in DCM (0.75 ml containing one drop of dimethyl formamide), oxalyl chloride was added (14 mg, 0.11 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of N2-(2,6-dimethyl-4-pyridyl)propane-1,2-diamine (21.6 mg, 0.1 mmol) and diisopropylethylamine (44 μl, 0.25 mmol) dissolved in dimethylformamide (1 ml) and the resulting mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 10.7 mg (0.035 mmol, 35%).
Reaction SMILES: CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([OH:31])=O)=[CH:24][C:23]=1[CH3:32].[CH3:33][C:34]1[CH:35]=[C:36]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=2)[S:37][CH:38]=1.C([O-])(O)=O.[Na+]>O>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([C:38]2[S:37][C:36]([C:39]3[CH:40]=[CH:41][C:42]([C:45]([F:46])([F:48])[F:47])=[CH:43][CH:44]=3)=[CH:35][C:34]=2[CH3:33])=[O:31])=[CH:24][C:23]=1[CH3:32]
Reactant: Cc1csc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: COc1ccc(CC(=O)O)cc1C
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: COc1ccc(CC(=O)c2sc(-c3ccc(C(F)(F)F)cc3)cc2C)cc1C
Temperature: 60 °C

Procedure:
To methanesulfonic acid (8 ml) in a flask under N2 was added P2O5 (0.56 g), the resulting suspension was heated to 60° C. until a clear solution formed. The mixture was cooled to room temperature prior to addition of 4-methoxy-3-methyl-phenylacetic acid (0.3549) and 4-methyl-2-[4-(trifluoromethyl)phenyl]thiophene (intermediate 102, 0.4 g). The mixture was then heated to 60° C. for 90 minutes. The reaction mixture was cooled to room temperature and then poured into iced water. The suspension was made basic by cautious addition of NaHCO3 and the products extracted into ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and evaporated to yield a brown oil. Purification by flash column chromatography eluting with 5% EtOAc/cyclohexane yielded the title compound as a brown gum.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][C@@H:37]5[CH2:41][CH2:40][CH2:39][O:38]5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].O1CCC[C@H:47]1CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][C:37]5[O:38][C:39]([CH3:47])=[CH:40][CH:41]=5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)(=[O:12])=[O:11])[CH3:9]
Reactant: NC[C@@H]1CCCO1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC[C@@H]5CCCO5)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNCc5ccc(C)o5)c4)cc23)CC1
Yield: 48.8 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 1-(5-methyl-2-furanyl)methanamine (58 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 28.3 mg of the title compound (48.8%).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].[CH:6]1([NH:9][C:10](=[O:32])[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21](OC)=[O:22])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1>CO.C(Cl)Cl.O>[CH:6]1([NH:9][C:10](=[O:32])[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([NH:2][OH:3])=[O:22])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1
Reactant: NO
Reactant: COC(=O)/C=C/c1ccc(C=C(C(=O)NC2CC2)c2ccc(F)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: O=C(/C=C/c1ccc(C=C(C(=O)NC2CC2)c2ccc(F)cc2)cc1)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
Hydroxylamine hydrochloride (0.86 g, 12.3 mmol) in methanol (3 mL) was mixed with KOH (0.69 g, 12.3 mmol) in methanol (3 mL) at 0° C., and sonicated for 2 minutes, the white precipitate formed was filtered. The filtrate was added to methyl 3-(E)(4-(3-(cyclopropylamino)-2-(4-fluorophenyl)-3-oxoprop-1-en-1-yl)phenyl)acrylate (0.25 g, 0.68 mmol) in DCM (1.5 mL) and the mixture was stirred at room temperature, for 30 minutes. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2×150 mL). The ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated to obtain a sticky compound, which was triturated with DCM (15 mL). The pale brown solid obtained was filtered and washed with DCM (3×5 mL) to afford the title compound (0.07 g, 28% yield). 1H NMR (DMSO-d6) δ (ppm): 0.49-0.53 (2H, dd, —CH2), 0.61-0.66 (2H, m, —CH2), 2.72-2.77 (1H, m, —CH), 6.38-6.42 (1H, d, ═CH), 7.00-7.02 (2H, d, Ar—H), 7.16-7.27 (5H, m, Ar—H and ═CH), 7.33-7.43 (3H, m, Ar—H and ═CH), 7.81-7.82 (1H, d, —NH), 9.04 (1H, s, —OH), 10.73 (1H, s, —NH). MS m/z: 367.1 (M++1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(#N)C.[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=1.Cl.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CN(C)C=O>[N:24]1([CH2:23][CH2:22][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: ClCCN1CCOCC1
Reactant: NC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: NC(=O)c1ccc(OCCN2CCOCC2)cc1
Reaction time: 0.5 h
Yield: 23.8 %

Procedure:
Potassium carbonate (15.1 g, 109 mmol, 3 eq.), acetonitrile (73 mL) and then 4-hydroxybenzamide (5 g, 36.5 mmol, 1 eq.) are placed in a 250 mL round-bottomed flask. The suspension is stirred for 30 minutes, followed by addition of 4-(2-chloroethyl)morpholine hydrochloride (8.82 g, 47 mmol, 1.3 eq.). 10 mL of dimethylformamide are added to this suspension, and the mixture is then stirred at a temperature in the region of 40° C. for 16 hours. The solvent is then evaporated off and the residue is diluted with water and extracted with dichloromethane. The aqueous phase is acidified with 5 N hydrochloric acid and reextracted with dichloromethane. The organic phases are combined, dried over magnesium sulfate and then concentrated to dryness under vacuum. 4-(2-Morpholin-4-ylethoxy)benzamide 2.17 g (23%) is thus obtained in the form of a white solid, which is used directly in the following step.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[N:28]1([C:33]([C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[NH2:37])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([C:33]([C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[NH:37][C:2]2[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=3)[N:3]=2)=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1ccccc1C(=O)N1CCCC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)N3CCCC3)n2)cc1)OCC

Procedure:
The title product was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate and the commercially available 2-(pyrrolidin-1-ylcarbonyl)aniline. MS (ES+): m/z 578.34 (100) [MH+]; HPLC: tR=1.02 min (UPLC, purity).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Cl:8].[SH:9][CH2:10][CH2:11][CH2:12][Si:13]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].CC[O-].[Na+]>>[Si:13]([CH2:12][CH2:11][CH2:10][S:9][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Cl:8])([O:17][CH2:18][CH3:19])([O:20][CH2:21][CH3:22])[O:14][CH2:15][CH3:16]
Reactant: CCO[Si](CCCS)(OCC)OCC
Reactant: ClCCCCCCCl
Agent: CC[O-]
Agent: [Na+]
Product: CCO[Si](CCCSCCCCCCCl)(OCC)OCC
Temperature: 80 °C

Procedure:
A 1-liter separable flask equipped with a nitrogen gas inlet, thermometer, Dimroth condenser and dropping funnel was charged with 310.0 g (2.0 mol) of 1,6-dichlorohexane and heated at 80° C. With stirring, the reaction product of 3-mercaptopropyltriethoxysilane with sodium ethylate was slowly added dropwise. After the completion of dropwise addition, the solution was continuously stirred at 80° C. for 5 hours, and then cooled. From the solution, the salt was filtered off and the ethanol and excess 1,6-dichlorohexane were distilled off in vacuum. The residual solution was subjected to vacuum distillation, collecting 64.2 g of a colorless clear liquid at a boiling point of 148–150° C./0.005 Torr. On analysis by IR, 1H-NMR and MS, the liquid was identified to be a compound of the following formula: (CH3CH2O)3Si(CH2)3S(CH2)6Cl Analysis by gas chromatography gave a purity of 98.7%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=2)[CH:26]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=2)[CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=3)[CH:26]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)c(F)c2)CC1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN(c3ccc(F)c(F)c3)C3CCN(C(=O)OC(C)(C)C)CC3)ccn2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[(3,4-difluorophenyl)amino]piperidine (625 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])=[C:8]([CH:17]=1)[O:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([O-:3])=[O:2].[CH3:25][C:26]([CH3:28])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[CH:26]([N:14]1[CH2:15][CH2:16][CH:11]([CH2:10][O:9][C:8]2[CH:17]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[C:18]([F:24])([F:23])[C:19]([F:20])([F:21])[F:22])[CH2:12][CH2:13]1)([CH3:28])[CH3:25]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(OCC2CCNCC2)c1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)N1CCC(COc2cc([N+](=O)[O-])ccc2C(F)(F)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolved 4-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-piperidine (646 mg) in 1,2-dichloroethane (6.4 ml), then added acetone (136 ul), NaBH(OAc)3 (541 mg) and finally AcOH (105 ul). Stirred the cloudy yellow solution under N2 at RT overnight. Added another 130 uL acetone and stirred at RT over weekend. Quenched the reaction with 30 mL N NaOH/H2O and stirred 10 min. Extracted with Et2O and the organic layer was brine-washed, dried over Na2SO4, filtered and concentrated in vacuo. Dried under high vacuum for several h to obtain 1-isopropyl-4-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-piperidine as a yellow orange solid.
Reaction SMILES: C([O:5][C:6]([C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[C:18]([F:20])[C:17]([N:21]3[CH:26]=[CH:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)=O)CCC.[CH3:29][NH2:30]>CO>[CH3:29][NH:30][C:6]([C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]([F:28])[C:17]([N:21]3[CH:26]=[CH:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[C:18]([F:20])[CH:19]=2)[CH2:9]1)=[O:5]
Reactant: CN
Reactant: CCCCOC(=O)[C@H]1CN(c2cc(F)c(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2cc(F)c(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Temperature: 45 °C
Yield: 85 %

Procedure:
To a stirred solution of (5R)-3-[3,5-Difluoro-4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)phenyl]-2-oxo-5-oxazolidinecarboxylic acid butyl ester (EXAMPLE 76, Step 5, 132 mg) in MeOH (1 mL) is added MeNH2 (2 mL, 4.0 mmol, 2.0 M solution in MeOH). The reaction mixture is then heated at 40-50° C. until all of the solid disappears. Solvent is removed and the residue is dissolved in 20% MeOH/CH2Cl2 and purified by silica gel chromatography (10% MeOH/CH2Cl2) to give the title compound as a yellow solid (100 mg, 76%), 1H NMR (300 MHz, DMSO) δ 8.40 (m, 1H), 7.52-7.38 (m, 3H), 5.08 (dd, 1H), 5.00 (d, 1H), 4.26 (t, 1H), 4.01 (dd, 1H), 3.78 (t, 2H), 2.65 (d, 3H); MS for C16H15F2N3O4 m/z 352.5 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH:40]([CH3:42])[CH3:41])[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:24][CH2:23][N:22]([C@@H:25]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=4)[C:26]3=[O:38])[CH2:21][C@H:20]2[F:39])=[CH:15][CH:14]=1)=[O:11])=O)(C)(C)C.[ClH:43].C(OCC)C>C(Cl)Cl>[ClH:43].[NH2:8][C@@H:9]([CH:40]([CH3:42])[CH3:41])[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:24][CH2:23][N:22]([C@@H:25]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=4)[C:26]3=[O:38])[CH2:21][C@H:20]2[F:39])=[CH:15][CH:14]=1)=[O:11]
Reactant: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(OC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)cc4)[C@H](F)C3)C2=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(OC(=O)[C@@H](N)C(C)C)cc4)[C@H](F)C3)C2=O)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 44 %

Procedure:
To a solution of (S)-4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (0.025 g, 0.043 mmol) in DCM (1.5 mL) at −20° C. was added HCl in diethyl ether (2.5 ml, 2.50 mmol, 1.0 M). The reaction mixture was slowly warmed to rt over 10 min and then allowed to stir at rt for 19 h. The solvent was then removed in vacuo to provide a pale yellow semisolid. The crude product was then purified by RP-HPLC on a Sunfire C18 (250×20 mm) 5 μm column using a gradient of 10% solvent B to 75% solvent B over 12 minutes at 15 mL/min where solvent A=0.05% HCl in water and solvent B=acetonitrile. Active fractions were concentrated by lyophilization to provide 10.2 mg (44%) of (S)-4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl 2-amino-3-methylbutanoate hydrochloride, the titled compound of example 2 as an off-white solid. LC-MS (Method A) RT=2.20 min, (M+H)+=482.2. 1H NMR: (400 MHz, DMSO-d6) δ ppm 8.64-8.78 (m, 3H) 7.38-7.46 (m, 2H) 7.23 (d, J=8.53 Hz, 2H) 7.18 (s, 4H) 5.04-5.26 (m, 1H) 4.42 (d, J=9.54 Hz, 3H) 4.17-4.23 (m, 2H) 3.29-3.40 (m, 4H) 3.19-3.28 (m, 2H) 2.30 (s, 6H) 2.04-2.19 (m, 2H) 1.11 (dd, J=12.55, 7.03 Hz, 6H). 19F NMR (376 MHz, DMSO-d6) δ −183.904.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:13]3[CH2:14][CH2:15][CH:9]2[CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12]3)=[N:4][CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([N:8]2[CH:9]3[CH2:15][CH2:14][CH:13]2[CH2:12][NH:11][CH2:10]3)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2c1ncccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cccnc1N1C2CCC1CNC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 8-(3-chloro-2-pyridinyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (285 mg, 880 μmol) in dry dichloromethane (2 mL) was treated with trifluoroacetic acid (2 mL). After stirring at ambient temperature for 30 minutes, the mixture was concentrated under reduced pressure and the residue was treated with 1N sodium hydroxide solution. The mixture was extracted with ethyl acetate and the organic phase was concentrated under reduced pressure to provide the title compound. MS (DCI/NH3) m/z: 224 (M+H)+; 1H NMR (CDCl3) δ 1.87 (m, 2H), 1.97 (m, 2H), 2.75 (dd, 2H), 3.24 (dd, 2H), 4.44 (dd, 2H), 6.73 (dd, 1H), 7.54 (dd, 1H), 8.08 (dd, 1H).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[N:16]([CH2:17][CH2:18][CH:19]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:15](=[O:32])[NH:14][C:13]1=[O:33])=[O:5])C>[OH-].[Na+]>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[N:16]([CH2:17][CH2:18][CH:19]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:15](=[O:32])[NH:14][C:13]1=[O:33])([OH:5])=[O:3]
Reactant: CCCCCC(CCN1C(=O)NC(=O)C1CCCCCCC(=O)OCC)OC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCC(CCN1C(=O)NC(=O)C1CCCCCCC(=O)O)OC1CCCCO1

Procedure:
A solution of the ester (6.2 g) in 0.5N-sodium hydroxide solution (80 ml) was allowed to stand at room temperature for 21/2 hours after which the solution was washed with ether, the aqueous layer was acidified with 2N-hydrochloric acid, and the precipitated oil was extracted with ether. The washed and dried ether extract was evaporated to give 5-(6-carboxyhexyl)-1-(3-(tetrahydropyran-2-yloxy)octyl)hydantoin as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5])[CH3:2].[CH3:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([CH3:37])[C:35]=1[F:36])[CH:31]=O>C1COCC1>[F:36][C:35]1[C:28]([CH3:27])=[CH:29][C:30]([CH:31]=[C:6]([CH3:7])[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:33][C:34]=1[CH3:37]
Reactant: CCOC(=O)CC[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C=O)cc(C)c1F
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=Cc1cc(C)c(F)c(C)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Ethoxy-carbonylethylene triphenyl phosphorane (0.476 g, 1.314 mmol) and 3,5-dimethyl-4-fluorobenzaldehyde (0.200 g, 1.314 mmol) were weighed into a microwave tube followed by the addition of 3 mL of THF. After stirred under microwave irradiation at 100° C. for 1 h, the reaction mixture was concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-30% ethyl acetate/hexanes to give the title compound as a white solid (0.267 g, 86% yield). LC-MS: tR=10.6 & 11.3 min; m/z 237 (M+H)+.
Reaction SMILES: Cl[C:2]1(Cl)[CH2:4][C:3]1([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[F:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+].CO>C1COCC1.C(OCC)(=O)C>[F:5][C:3]1([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)[CH2:2][CH2:4]1
Reactant: Cc1ccc(C2(F)CC2(Cl)Cl)cc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C2(F)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.7 %

Procedure:
A solution of 1-(2,2-dichloro-1-fluoro-cyclopropyl)-4-methyl-benzene (1.18 g, 5.39 mmol) in THF (10 mL) was added at 0° C. to a suspension of lithium aluminum hydride (1.64 g, 43.1 mmol) in THF. The reaction mixture was stirred for 16 h at RT, then another portion of lithium aluminum hydride (613 mg, 16.1 mmol) was added, then after 3 h, 1 M aq. potassium sodium tartrate solution, methanol and ethyl acetate were added. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane) afforded the title compound (702 mg, 87%). Colourless liquid, MS (EI) 150.1 (M+).
Reaction SMILES: CO[C:3]1[C:16]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9](=[O:17])[N:8]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:27](OCC)(=[O:29])C.ClCCl.CO>[Pd]>[CH3:27][O:29][C:5]1[CH:4]=[CH:3][C:16]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:17])[N:8]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:7]=2[CH:6]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc(Cn2c(=O)c3cccnc3c3c(OC)cccc32)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(Cn2c(=O)c3c(c4ccc(OC)cc42)NCCC3)cc1
Reaction time: 18 h
Yield: 99 %

Procedure:
To a stirred solution of the compound of 8-methoxy-6-(4-methoxybenzyl)benzo[h][1,6]naphthyridine-5(6H)-one (192.4 mg, 0.555 mmol) prepared in step 3 in ethyl acetate/dichloromethane/methanol, was added 10%-palladium (Pd) (20 mg) and the mixture was stirred for 18 hours under hydrogen gas. Once the reaction was completed, 10%-palladium (Pd) was filtered out, and the filtrate was concentrated under reduced pressure to obtain the title compound (192.7 mg, yield: 99%, ivory solid).
Reaction SMILES: C(N1CCCC(C(OCC)=O)C1)(=O)C1C=CC=CC=1.Cl.[O:21]=[C:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH:23]1[C:28]([O:30][CH3:31])=[O:29].Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>>[CH2:36]([O:35][C:33]([N:25]1[CH2:26][CH2:27][C:22](=[O:21])[CH:23]([C:28]([O:30][CH3:31])=[O:29])[CH2:24]1)=[O:34])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)C1CNCCC1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Agent: Cl
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CCC1=O

Procedure:
This compound may be prepared in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with commercially available methyl 4-oxo-3-piperidinecarboxylate hydrochloride, diisopropylethylaamine and commercially available benzyl chloroformate.