Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:18]C(=O)OC(C)(C)C)[C@@H:9]([OH:17])[CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C(Cl)Cl>[NH2:18][C@@H:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C@@H:9]([OH:17])[CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CN1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CC1CCCCC1)[C@@H](O)CN1CCCC1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.4 %

Procedure:
0.41 g (1.16 mmol) of t-butyl [(1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-3-(2-oxo-1-pyrrolidinyl)propyl]carbamate was dissolved in 5 ml of methylene chloride, treated at 0° with 1.5 ml of 90% trifluoroacetic acid and subsequently stirred at room temperature for 5 hours. Thereafter, the reaction mixture was slowly added dropwise to 2N sodium carbonate solution, subsequently treated with 3N sodium hydroxide solution and finally extracted with methylene chloride. The methylene chloride extracts were dried over potassium carbonate and evaporated under reduced pressure, whereby there were obtained 249 mg of 1-[(2S,3S)-3-amino4-cyclohexyl-2-hydroxybutyl]-2-pyrrolidinone as an oil, MS: 255 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-])=O)[CH3:2].[BH4-].[Na+].CO>O1CCCC1.[Pd]>[CH2:1]([NH:3][C:4]1[C:5]([NH2:10])=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCNc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCNc1ccccc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
To a solution of ethyl-(2-nitro-phenyl)-amine (12.5 g, 75 mmol) in anhydrous tetrahydrofuran (150 mL) was added sodium borohydride (5.8 g, 153 mmol), and 5% palladium on carbon (150 mg). Methanol (25 mL) was then added at room temperature under nitrogen in a dropwise manner. After addition, the reaction mixture was stirred at room temperature for about 30 minutes until the reaction was complete. The reaction mixture was then filtered through a pad of Celite. The filtrate was diluted with ethyl acetate (200 mL), washed with a saturated aqueous solution of ammonium chloride (80 mL), dried over sodium sulfite, and concentrated in vacuo to afford crude N-ethyl-benzene-1,2-diamine (8.4 g, 62 mmol) which was used in next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:22][C:23]2[CH:24]=[C:25]([CH:26]=[CH:27][CH:28]=2)[C:29]#[N:30])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1cccc(C#N)c1
Yield: 75.4 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.414 g, 1.55 mmol), α-bromo-m-tolunitrile (0.466 g, 2.38 mmol), KI (53 mg, 0.32 mmol), and DIPEA (0.55 mL, 3.16 mmol) in DMF (8 mL) was heated at 60° C. for 18 hours. Purification of the crude material by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.447 g (75%) of 3-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzonitrile as a beige solid. 1H NMR (CDCl3) δ 1.56-1.72 (m, 3H), 2.05-2.10 (m, 1H), 2.18-2.34 (m, 2H), 2.41 (s, 6H), 3.53 (s, 2H), 4.10 (d, 2H, J=11.1 Hz), 6.71 (s, 1H), 6.83 (d, 1H, J=7.8 Hz), 6.93-7.00 (m, 3H), 7.13 (d, 1H, J=7.5 Hz), 7.25-7.27 (m, 2H), 8.39 (dd, 2H, J=4.8, 1.2 Hz); ES-MS m/z 383 (M+H).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C=O.F[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1[N+:24]([O-:26])=[O:25]>O>[N+:24]([C:15]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:14]=1[N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([O-:26])=[O:25]
Reactant: C1CCCNCC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
Hexahydro-1H-azepine (682 μl, 6.05 mmol, commercially available product) was added at 0° C. to an N,N-dimethylformamide (DMF; 2 ml) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (506 mg, 2.42 mmol, commercially available product). The resulting mixture was warmed to room temperature and stirred for one hour. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=7/1). Thus, hexahydro-1-[2-nitro-4-(trifluoromethyl)phenyl]-1H-azepine (680 mg, 97.5%) was yielded as an orange-colored solid.
Reaction SMILES: [OH-].[K+].NC1[S:5][C:6]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:7]=2[N:8]=1.Cl>C(O)(=O)C>[NH2:8][C:7]1[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:6]=1[SH:5]
Reactant: COc1ccc2nc(N)sc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc(N)c(S)c1

Procedure:
To a stirred solution of 8N potassium hydroxide (1.3 l) was added 2-amino-6-methoxybenzothiazole (750 g) and the mixture was refluxed overnight. The resulting solution was neutralized by the addition of conc. HCl to pH 8.0, then acetic acid to pH 6.0. The precipitate which formed was filtered and washed with water to afford the title compound which was used immediately in Step 3.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:19]=[C:20]([C:23]([OH:25])=[O:24])[S:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H-].[Na+].[CH2:28](I)[CH3:29]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([NH:17][C:18]1[CH:19]=[C:20]([C:23]([O:25][CH2:28][CH3:29])=[O:24])[S:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1csc(C(=O)O)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1csc(C(=O)OCC)c1
Reaction time: 1 h

Procedure:
A solution of 7.20 g. of 4-(hexadecylamino)-2-thiophenecarboxylic acid in 25 ml. of hexamethylphosphoramide is added to a stirred mixture of 0.800 g. of sodium hydride (57% in mineral oil) and 25 ml. of hexamethylphosphoramide. The solution which forms after one hour is treated with 11.0 g. of ethyl iodide and is then stirred at 25° C. for 18 hours. Dilution with water followed by filtration affords a white solid which is crystallized from ethanol to yield ethyl 4-(hexadecylamino)-2-thiophenecarboxylate as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[N:7].[ClH:8].[CH2:9]([OH:11])[CH3:10]>>[ClH:8].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[NH:7])[O:11][CH2:9][CH3:10]
Reactant: N#Cc1cccs1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1cccs1

Procedure:
Ethyl 2-thiophenecarboximidate hydrochloride was synthesized in the same manner as in Reference Example 2. That is, 2-thiophenecarbonitrile (25.2 g, 0.231 mol) was treated with hydrogen chloride in ethanol (250 mL) to give 16.3 g (37%) of the target compound as colorless crystals.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH3:13])=[C:5]1[CH:14]=O.[BH4-].[Na+].O>CO>[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH3:13])=[C:5]1[CH2:14][NH:2][CH3:1]
Reactant: CN
Reactant: Cc1c(C=O)n(C)c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1c(C)c2ccccc2n1C
Temperature: 0 °C
Reaction time: 5 h
Yield: 85.2 %

Procedure:
Methylamine (0.53 mL, 13.1 mmol) was added to a solution of 1,3-dimethyl-1H indole-2-carbaldehyde (760 mg, 4.3 mmol) in methanol (15 mL) and stirred for 5 h. The mixture was cooled to 0° C. and sodium borohydride (159 mg, 4.3 mmol) added slowly. The mixture was warmed to rt and stirred overnight. Water (3 mL) was added slowly at 0° C. and evaporated to a paste. Water was added and the mixture extracted with dichloromethane. The organic phase was washed with water, dried and evaporated to afford the title compound (690 mg, 85%). 1H NMR (400 MHz, DMSO-d6) δ 7.44 (d, J=7.8 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.10 (t, J=7.6 Hz, 1H), 6.98 (t, J=8.0 Hz, 1H), 3.77 (s, 2H), 3.71 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH2:8][O:9]S(C(F)(F)F)(=O)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[O:22].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1([CH2:8][O:9][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[CH:21]=[O:22])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(O)c1
Reactant: CC1(COS(=O)(=O)C(F)(F)F)CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(COc2cccc(C=O)c2)CCCCC1
Temperature: 80 °C
Yield: 44 %

Procedure:
A mixture of compound iii (0.5 mmol), 3-hydroxy-benzaldehyde (iv, 0.6 mmol) and K2CO3 (0.7 mmol) were dissolved in DMF (3 mL). The solution was heated to 80° C. for 4 hr. The solution was poured into water, extracted with ethyl acetate (10 mL) three times, and concentrated. The residue was purified by chromatography and resulted in 0.22 mmol of 3-(1-methyl-cyclohexylmethoxy)-benzaldehyde (v) with a 44% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[N+:25]([O-])=O)[N:9]=2)=[CH:4][CH:3]=1>O1CCOCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[NH2:25])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2nc3cccc([N+](=O)[O-])c3nc2-c2ccc(C)cc2)cc1
Solvent: C1COCCO1
Product: Cc1ccc(-c2nc3cccc(N)c3nc2-c2ccc(C)cc2)cc1

Procedure:
2.02 g of 2,3-di(4-methylphenyl)-5-nitroquinoxaline was dissolved in 30 g of dioxane, followed by purging with argon and adding 0.6 g of 5% Pd/C (hydrous). After purging with argon again, the system was purged with hydrogen for reaction at room temperature for 18 hours. After completion of the reaction, the system was filtered. The filtration residue was washed with acetone and then with dioxane and filtered again. The solvent was removed from the resulting filtrate, followed by extracting a reaction product by use of a silica gel column.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([S:16][CH:17]1[N:20]([CH2:21][C:22](=[O:31])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19](=[O:32])[CH2:18]1)[CH2:13][CH2:14][CH3:15].C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>ClCCl.CCOCC>[CH2:12]([S:16]([CH:17]1[N:20]([CH2:21][C:22](=[O:31])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19](=[O:32])[CH2:18]1)=[O:9])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCSC1CC(=O)N1CC(=O)CCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCS(=O)C1CC(=O)N1CC(=O)CCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of m-chloroperbenzoic acid (0.81 g, 0.0047 moles) in dichloromethane (50 ml) was added dropwise to a stirred solution of 4-butylthio-N-(4-phenyl-2-oxobutyl)azetidin-2-one (1.2 g, 0.0039 moles) in dichloromethane (50 ml) at -60° C. Stirring continued at -60° C. for 30 minutes then the mixture was poured into an aqueous solution of sodium hydrogen carbonate and sodium sulphite. The layers were separated and the aqueous was extracted with dichloromethane. The combined extracts were dried and evaporated to give a solid which was slurried in ether, filtered, washed with ether and petrol. The solid was recrystallised from ether to give the title compound as white crystals, 280 mg (22%), mp 145-6° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]([NH:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1)=[O:21])[C:6]([CH2:8]P(=O)(OC)OC)=[O:7].[N:32]1[CH:37]=[CH:36][C:35]([CH:38]=O)=[CH:34][CH:33]=1.[OH-].[Na+].C(O)(=O)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6](=[O:7])[CH:8]=[CH:38][C:35]2[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]([NH:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1)=[O:21]
Reactant: COc1cc(C(=O)CP(=O)(OC)OC)ccc1OCC(=O)Nc1nc2ccccc2s1
Reactant: O=Cc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc(C(=O)C=Cc2ccncc2)ccc1OCC(=O)Nc1nc2ccccc2s1
Reaction time: 5 h
Yield: 79.7 %

Procedure:
To a solution of dimethyl {[3-methoxy-4-(2-benzothiazolylaminocarbonylmethoxy)benzoyl]methyl}phosphonate (1.7 g) and pyridine-4-aldehyde (0.5 g) in tetrahydrofuran (30 ml) is added a 5% aqueous sodium hydroxide solution (6 ml) under ice-cooling, and the mixture is stirred for 5 hours. The mixture is neutralized with acetic acid, and the precipitated crystals are collected by filtration, and then recrystallized from dichloromethane-ethanol-diethyl ether to give 2-{2-methoxy-4-[3-(4-pyridyl)acryloyl]phenoxymethylcarbonylamino}benzothiazole (1.3 g).
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]1[CH2:19][C:17](=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1>[C].[Pd]>[CH:13]1[CH:12]=[C:11]2[CH:10]=[CH:9][C:19]3[C:6]4[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=4)[NH:7][C:17]=3[C:16]2=[CH:15][CH:14]=1
Reactant: NNc1ccccc1
Reactant: O=C1CCCc2ccccc21
Agent: [Pd]
Product: c1ccc2c(c1)ccc1c3ccccc3[nH]c21

Procedure:
1,2-benzo-3,4-dihydrocarbazole synthesized from phenylhydrazine and α-tetralone according to the method of J. Am. Chem. Soc., 69, 2910 (1947) was dehydrogenized with palladiumcarbon to obtain 1,2-benzocarbazole.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[Br:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[NH:10][CH:9]=1>C1COCC1>[Br:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]([CH3:3])[CH:9]=1
Reactant: COc1ccc2[nH]cc(CCBr)c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CCBr)cn2C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A flask was charged with NaH (145 mg, 3.62 mmol), MeI (0.45 mL, 7.24 mmol) and THF (1.7 mL). The resulting grey suspension was stirred at rt for 5 min, then a solution of 3-(2-bromo-ethyl)-5-methoxy-1H-indole (230 mg, 0.90 mmol) in THF (4.1 mL) was added dropwise. After stirring for 18 h at rt, the reaction mixture was concentrated and purification by FC (hex/EtOAc 2:1, Rf=0.5) yielded the title compound as an yellow solid. LC-MS conditions 08Z acidic tR=0.93 min, [M+H]+=no ionization.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([N:43]([CH3:45])[CH3:44])[N:38]=1>>[CH3:44][N:43]([CH3:45])[C:39]1[N:38]=[C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)[CH:42]=[CH:41][CH:40]=1
Reactant: CN(C)c1cccc(Br)n1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cccc(N(C)C)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromo-6-(dimethylamino)pyridine following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=1.39 min, m/z=474; 1H NMR (CD3OD) 0.96 (s, 3H), 1.26 (s, 3H), 1.58 (d, 3H), 2.18 (s, 2H), 2.28 (m, 1H), 2.50 (2H), 3.12 (m, 1H), 3.34 (s, 6H), 5.59 (q, 1H), 6.99 (d, 1H), 7.18 (3H), 7.25-7.40 (5H), 7.57 (d, 2H), 7.98 (m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.C1CCC(N=C=NC2CCCCC2)CC1.[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[O:40][C:39]([CH2:41][CH2:42][NH2:43])=[CH:38][CH:37]=2)[CH:32]=[CH:33][C:34]=1[Cl:35].C(Cl)Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[O:40][C:39]([CH2:41][CH2:42][NH:43][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[O:12])=[CH:38][CH:37]=2)[CH:32]=[CH:33][C:34]=1[Cl:35]
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
Indazole-3-carboxylic acid (30 mg; 0.182 mmol), DCC (56 mg, 0.273 mmol) and DMAP (2 mg) were dissolved in DCM:DMF (1:1, 4 ml). 2-(5-(3,4-dichlorophenyl)furan-2-yl)ethanamine (46 mg, 0.182 mmol) was added and the reaction mixture was stirred for overnight at RT. DCM (30 ml) was added and organic layer washed with water (3×15 ml). Combined organic phases were dried over Na2SO4, evaporated and purified by chromatography (silica column, eluent: 1% MeOH/DCM) to give 25 mg (34%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 3.00 (t, 2H), 3.63 (q, 2H), 6.37 (d, 1H), 7.02 (d, 1H), 7.23 (t, 1H), 7.41 (t, 1H), 7.60 (d, 1H), 7.61 (d, 2H), 7.85 (d, 1H), 8.16 (d, 1H), 8.54 (d, 1H), 13.56 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)[N:12]=[C:11]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:36]([F:47])[CH:35]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[F:47][C:36]1[CH:35]=[C:34]([NH:33][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([CH2:14][N:13]3[C:9]([CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:10][C:11]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=4)=[N:12]3)=[CH:16][CH:17]=2)[CH:39]=[CH:38][C:37]=1[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]
Reactant: O=Cc1ccc(Cn2nc(-c3ccc(C(F)(F)F)cc3)cc2CCc2ccccc2)cc1
Reactant: CCOC(=O)CCc1ccc(N)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)CCc1ccc(NCc2ccc(Cn3nc(-c4ccc(C(F)(F)F)cc4)cc3CCc3ccccc3)cc2)cc1F
Reaction time: 1 h

Procedure:
To a mixture of 4-({5-(2-phenylethyl)-3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)benzaldehyde (868 mg, 2.0 mmol), ethyl 3-(4-amino-2-fluorophenyl)propanoate (420 mg, 2.0 mmol), acetic acid (300 mg, 5.0 mmol) and 1,2-dichloroethane (15 mL) was added sodium triacetoxyborohydride (1.20 g, 6.0 mmol) by small portions at room temperature and the mixture was stirred for 1 hr. The reaction mixture was poured into 10% aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-60% ethyl acetate/hexane) to give the title compound as a yellow oil.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C@@H:10]([O:38][Si](C(C)(C)C)(C)C)[CH2:11][C@@H:12]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[CH:16][CH:15]=1)=O)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[NH2:8][C@@H:9]([CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C@@H:10]([OH:38])[CH2:11][C@@H:12]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2nccs2)cc1)C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2nccs2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 116 %

Procedure:
To the product from Example 146B (0.042 g, 0.056 mmol) was added tetrabutyl ammonium fluoride solution in tetrahydrofuran (0.28 mL, 1N) and the mixture was stirred at room temperature for 18 hours. The tetrahydrofuran was evaporated and the mixture was partitioned between ethyl acetate and water. The organic was washed with brine, dried over MgSO4, filtered and evaporated. The residue was dissolved in dichloromethane (0.40 mL) and trifluoroacetic acid (0.20 mL) was added and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated and the residue was partitioned between chloroform and dilute NaHCO3, and brine, dried over MgSO4, filtered and concentrated to give the title compound (0.035 g), which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:22][CH2:21][C:8]2([CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][CH:15]([C:18](O)=[O:19])[CH2:14][CH2:13]3)[CH2:9]2)[CH2:7]1)=[O:5])[CH3:2].Cl.[CH3:24][C:25]1([NH2:29])[CH2:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:24][C:25]1([NH:29][C:18]([CH:15]2[CH2:16][CH2:17][N:12]([CH:10]3[CH2:11][C:8]4([CH2:21][CH2:22][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7]4)[CH2:9]3)[CH2:13][CH2:14]2)=[O:19])[CH2:28][CH2:27][CH2:26]1
Reactant: CC1(N)CCC1
Reactant: CCOC(=O)N1CCC2(CC(N3CCC(C(=O)O)CC3)C2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC2(CC(N3CCC(C(=O)NC4(C)CCC4)CC3)C2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
1-[6-(Ethoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]piperidine-4-carboxylic acid (0.368 g, 1.10 mmol) was dissolved in DMF (8 mL) and (1-methylcyclobutyl)amine hydrochloride (0.200 g, 1.64 mmol), HATU (0.458 g, 1.21 mmol) and DIPEA (0.708 g, 5.45 mmol) were added. The reaction mixture was stirred at rt overnight under nitrogen. The solvents were removed in vacuo, and the residue was partitioned between DCM and sat. NaHCO3 sol., organic layer washed with sat. NaCl sol. and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 A, 12 mL per min, gradient 1% to 8% MeOH in DCM]) to give ethyl 2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate isomer 2 (0.147 g, 35.5%) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=[O:5].[Si](C=[N+]=[N-])(C)(C)[CH3:15]>CO.C(#N)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: O=C(O)c1c(F)cccc1[N+](=O)[O-]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC#N
Product: COC(=O)c1c(F)cccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To 2-fluoro-6-nitrobenzoic acid (712 mg, 3.85 mmol) in methanol/acetonitrile (10 mL/10 mL) was dropwise added TMSCHN2 at 0° C. under N2 until yellow color persistent, and stirred additional 30 min. Then the reaction was quenched with HOAcat 0° C. until the yellow color disappears. Partial of the solvent was removed o rotary vacuum, the residue was dissolved in small amount of EtOAc, purified on flash chromatography eluting with 30˜50% EtOAc/hexanes (600 mL) to afford the expected product, methyl 2-fluoro-6-nitrobenzoate, (716 mg, 94% yield) which was used in step-2; 1H NMR (400 MHz, CDCl3) δ ppm 3.96 (s, 3 H), 7.40-7.48 (m, 1 H), 7.58 (td, J=8.31, 5.54 Hz, 1 H), 7.94 (d, J=8.31 Hz, 1 H); Mass spec. 200.05 (MH+), Calc. for C8H6FNO4 199.03.