Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1(Cl)[CH2:8][C:7]([Cl:9])=[C:6]([Cl:10])[NH:5][C:4]1=[O:11]>>[Cl:2][C:3]1[C:4]([OH:11])=[N:5][C:6]([Cl:10])=[C:7]([Cl:9])[CH:8]=1
Reactant: O=C1NC(Cl)=C(Cl)CC1(Cl)Cl
Agent: Cl
Product: Oc1nc(Cl)c(Cl)cc1Cl

Procedure:
U.S. Pat. No. 4,996,323 (Pews) discloses a process for preparing 3,5,6-trichloropyridin-2-ol by conducting the following three separate reactions: trichloroacetyl chloride is added to acrylonitrile in the presence of a catalytic amount of copper or a cuprous salt to produce 2,2,4-trichloro-4-cyanobutanoyl chloride; the 2,2,4-trichloro-4-cyanobutanoyl chloride is cyclized by contacting it with acidic reagents, preferably in an anhydrous state, to form 3,3,5,6-tetrachloro-3,4-dihydropyridin-2-one; and hydrogen chloride can be eliminated from this dihydropyridinone compound to yield 3,5,6-trichloropyridin-2-ol in an aromatization reaction. However, the dihydropyridinone compound can alternatively split off water to yield 2,3,5,6-tetrachloropyridine. The water produced as a by-product during formation of the 2,3,5,6-tetrachloropyridine is a major contributor to yield loss via numerous side reactions.
Reaction SMILES: CC(OC(=O)[NH:7][CH:8]([CH3:18])[CH2:9][CH:10]=[CH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)(C)C>Cl>[CH3:18][CH:8]([NH2:7])[CH2:9][CH:10]=[CH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(CC=Cc1cccnc1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(N)CC=Cc1cccnc1

Procedure:
As in Example 133, hydrolysis of 3.88 g of (R,S)-Z]-[1-methyl-4-(3-Pyridinyl)-3-butenyl]carbamic acid 1,1-dimethylethyl ester in 50 mL of 1N HCl yielded, after the usual work-up and evaporative distillation of the product (100-120° C./0.1 mm), 1.7 g of [(R,S)-Z]-1-methyl-4-(3-pyridinyl)-3-butenamine as an oil.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10](O)=[O:11])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.Cl>CCOCC>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CCC[C@H]1CC[C@H](CO)CC1

Procedure:
Trans-4-n-propylcyclohexane carboxylic acid (23.8 g, 0.14 mole), was dissolved in 150 ml of dry ether and added dropwise with stirring into a suspension of 11.4 g (0.3 mole) of LiAlH4 in 300 ml of ether. After the addition the mixture was heated for 2 hours at reflux, and then the supernatant LiAlH4 was decomposed with water while being cooled. The reaction mixture was then poured onto 20% hydrochloric acid and stirred until the inorganic salts dissolved. The product of formula (31) was extracted with diethyl ether; the combined organic phases were washed with water, dried with MgSO4 and concentrated.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:35])=[C:12]([CH2:17][NH:18][C:19]([C:21]3[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[N:23][C:22]=3[Cl:34])=[O:20])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:36][CH:37](C[AlH]CC(C)C)C.C([Zn]CC)C>C1COCC1.CCOC(C)=O>[Cl:34][C:22]1[N:23]=[CH:24][N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:21]=1[C:19]([NH:18][CH2:17][C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([O:9][C:4]2[CH:3]=[C:2]([CH2:36][CH3:37])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:11]=1[F:35])=[O:20]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Reactant: CC(C)C[AlH]CC(C)C
Agent: CC[Zn]CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of N-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (112 mg, 0.180 mmol) and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (7.33 mg, 8.98 μmol) in THF (10 ml) was added DIBAL-H (1.0 M solution in DCM) (2.55 mg, 0.018 mmol), followed by diethylzinc (1.0 M solution in heptane) (22.18 mg, 0.180 mmol). The reaction mixture was stirred for one hour at 60° C., cooled to room temperature, diluted with EtOAc and washed with water. The solvent was removed and the crude material (64 mg) was used directly in the next step without purification. LC-MS (ES+) m/z 572 [M+H].
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:26](Cl)(=[O:37])[O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1>N1C=CC=CC=1>[C:26](=[O:37])([O:27][C:28]1[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=1)[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](=[O:13])[NH2:14])=[CH:10][N:9]=2)[CH2:6][CH2:7]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccc(N2CCC(O)CC2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: NC(=O)c1ccc(N2CCC(OC(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)nc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
To the solution of 6-(4-hydroxypiperidin-1-yl)nicotinamide (3.32 g, 15 mmol) in pyridine (10 mL) was added DIPEA (3.87 g, 30.0 mmol) and 4-nitrophenyl carbonochloridate (6.03 g, 30 mmol). The resulting mixture was stirred at 30° C. for 2 h before it was concentrated under reduced pressure to afford the crude product. The residue was further purified by silica gel chromatography (DCM: MeOH=100:0 to 20:1) to afford the title compound (3 g, 50%) as a white solid. [LCMS RtB=1.79 min, [M+H]+=387.0].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=2)[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[N:6][CH:7]=1.C([O:34][C:35](=[O:38])[CH2:36]Br)(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:27])[F:28])[CH:20]=2)[CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:36][C:35]([OH:38])=[O:34])=[CH:15][CH:16]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccc(N(CCc2ccc(O)cc2)Cc2cccc(OC(F)(F)F)c2)nc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(N(CCc2ccc(OCC(=O)O)cc2)Cc2cccc(OC(F)(F)F)c2)nc1

Procedure:
Similarly prepared by alkylation of 4-(2-{(5-methylpyridin-2-yl)[3-(trifluoromethoxy)benzyl]amino}ethyl)phenol with tert-butyl-bromo-acetate, followed by standard TFA hydrolysis (general procedure I).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([O:13]CC)=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:16]([Mg]Br)[CH:17]=[CH2:18]>C1COCC1>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([CH:11]([OH:13])[CH2:18][CH:17]=[CH2:16])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCC(O)C1CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (1.12 g, 5.24 mmol, prepared as described in Pearson, et al. in J. Org. Chem. 1997, 62(16), 5284-5292) in THF (10 mL) cooled to −78° C. under argon was added a allylmagnesium bromide (18 mL, 18 mmol, 1 M in THF) dropwise. After the complete addition, the reaction mixture was allowed to reach room temperature overnight. It was then re-cooled to −78° C. and quenched with saturated NaHCO3 solution and warmed to room temperature. After extraction with ether, the organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 0-100% ether/hexanes) to afford the product.
Reaction SMILES: C1O[C:4]([CH2:6][CH2:7][CH2:8]Cl)([CH3:5])[O:3]C1.[N-:11]=[N+:12]=[N-:13].[Li+]>CN(C=O)C>[N:11]([CH2:8][CH2:7][CH2:6][C:4](=[O:3])[CH3:5])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(CCCCl)OCCO1
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(=O)CCCN=[N+]=[N-]
Reaction time: 24 h

Procedure:
5-Chloro-2-pentanone ethylene ketal (5.0 g, 30.4 mmol) was stirred in DMF with lithium azide (5.95 g, 120 mmol) at 60° C. for 48 hrs. The mixture was evaporated to dryness. The product was then dissolved in toluene (50 ml) and washed with water (3×15 ml). The organic phase was evaporated and the resulting 5-azido-2-pentanone ethylene ketal was stirred in 50 ml of 70% trifluoroacetic acid for 24 hrs. The reaction mixture was neutralized with sodium bicarbonate and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and evaporated to yield the desired ketone as an oil.
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]([CH3:15])=[C:11]([CH2:13][OH:14])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([C:8]1[NH:9][C:10]([CH3:15])=[C:11]([CH:13]=[O:14])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]c(Cc2ccccc2)nc1CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Product: Cc1[nH]c(Cc2ccccc2)nc1C=O

Procedure:
A mixture of 8.79 gm. of 2-benzyl-5-methyl-4-imidazolemethanol and 55.7 ml. of concentrated HNO3 is left at room temperature overnight. The solution is heated for 45 minutes on a steam bath, cooled, the basified with aqueous sodium carbonate. After heating the resulting mixture on a steam bath, it is cooled and the solid collected. Two recrystallizations from ethanol give the desired product, m.p. 171°-173° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:29])[NH:21]2)[CH2:17][CH2:16]1.[CH:30]12[CH2:36][CH:33]([CH:34]=[CH:35]1)[CH2:32][CH:31]2[CH:37]=O.C(O)(C(F)(F)F)=O>ClCCCl.CC#N.O>[CH:30]12[CH2:36][CH:33]([CH:34]=[CH:35]1)[CH2:32][CH:31]2[CH2:37][N:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:29])[NH:21]2)[CH2:17][CH2:16]1
Reactant: O=C1NC2(CCNCC2)c2ccccc21
Reactant: O=CC1CC2C=CC1C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=C1NC2(CCN(CC3CC4C=CC3C4)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Sodium triacetoxyborohydride (31 mg, 0.15 mmol) was added to a stirred solution of spiro[isoindoline-1,4′-piperidin]-3-one 3a (20 mg, 0.10 mmol) and bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (18 mg, 0.15 mmol) in 1,2-dichloroethane (1 mL) and the mixture was stirred at room temperature for 6 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC (5-70% CH3CN—H2O gradient with 0.05% TFA, 15 min) to give compound no. 267. LC/MS m/z [M+H]+ 309.0 retention time 1.7 min (10-90% CH3CN—H2O gradient, with 0.05% TFA, 5 min).
Reaction SMILES: Br[C:2]1[C:9]([C:10]#[N:11])=[CH:8][C:7]([C:12]#[N:13])=[CH:6][C:3]=1[C:4]#[N:5].C[S-:15].[Na+]>>[C:4]([C:3]1[C:2]([SH:15])=[C:9]([CH:8]=[C:7]([C:12]#[N:13])[CH:6]=1)[C:10]#[N:11])#[N:5]
Reactant: N#Cc1cc(C#N)c(Br)c(C#N)c1
Reactant: C[S-]
Agent: [Na+]
Product: N#Cc1cc(C#N)c(S)c(C#N)c1

Procedure:
If the procedure described in Preparation LV is followed starting from 6 g (26.10-3 mol) of 2-bromo-3,5-dicyanobenzonitrile and 6 g (86.10-3 mol) of sodium thiomethylate, 6 g (quantitative yield) of the expected product are obtained in the form of an oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:35]#[N:36])[C:32]=1[O:33][CH3:34])[C:27](Cl)=[O:28])([CH3:23])([CH3:22])[CH3:21]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:20]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:35]#[N:36])[C:32]=1[O:33][CH3:34])[C:27]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:28])([CH3:23])([CH3:21])[CH3:22]
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1c(C#N)cc(C(=O)Cl)cc1C(C)(C)C
Agent: C=O
Agent: Nc1ccccc1S
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1c(C#N)cc(C(=O)N2CSc3ccccc32)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (943 mg) and 37% formalin (0.57 mL) in the same manner as in Example 1 was dissolved in chloroform (15 mL), and triethylamine (1.04 mL) and 3-t-butyl-5-cyano-4-methoxybenzoyl chloride (630 mg) was added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to obtain the title compound (904 mg) as a yellow oily substance.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:19][CH2:20][NH:21][C:22]2[C:23]([CH3:29])=[N:24][C:25]([Br:28])=[CH:26][CH:27]=2)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=O)C.CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:3])[N:21]([C:22]3[C:23]([CH3:29])=[N:24][C:25]([Br:28])=[CH:26][CH:27]=3)[CH2:20][CH2:19]2)[CH2:7][CH2:8]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)C1(CCNc2ccc(Br)nc2C)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(Br)ccc1N1CCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[2-(6-bromo-2-methyl-pyridin-3-ylamino)-ethyl]-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.44 g, 0.94 mmols) in THF (20 mL) was added a solution of potassium t-butoxide (1 M in THF) (2 mL), and allowed to stir at room temperature for 4 hours. The reaction mixture was then diluted with ethyl acetate (20 mL), quenched with water (5 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The combined organics were washed with brine, and concentrated under vacuum to afford crude product. Purification on silica gel eluting with ethyl acetate in heptanes (0-75%) afforded 0.238 (60%) of title compound.
Reaction SMILES: F[B-](F)(F)F.[OH-].[K+].O=C1CC[C@H]2[C@H:15]3[C@H:25](CC[C@]12C)[C@:23]1([CH3:24])[CH:18]([CH2:19][CH2:20][CH2:21][CH2:22]1)[CH2:17][CH2:16]3.F[B-](F)(F)F.C1([S+](C2C=CC=CC=2)C2C=CC=CC=2)CC1.CC(O[CH2:53][C:54]1[C:67]2[C:62](=C[CH:64]=[CH:65][CH:66]=2)[C:61]([CH2:68][O:69]C(C)=O)=[C:60]2[C:55]=1C=CC=C2)=O.F[B-](F)(F)F.[H+]>CS(C)=O>[C@@:67]12([CH2:66][CH2:65][C@H:64]3[C@H:15]4[C@H:25]([CH2:60][CH2:55][C@:54]13[CH3:53])[C@:23]1([CH3:24])[CH:22]([CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:17][CH2:16]4)[CH2:62][CH2:61][C:68]2=[O:69]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: C[C@]12CCCCC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@]12CCCCC1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@@]21CCC1=O
Temperature: 25 °C

Procedure:
When carrying out the process of this invention, we prefer to utilize cyclopropylidiphenylsulfonium fluoroborate as reagent in dimethylsulfoxide as inert organic solvent and with powdered potassium hydroxide as the strong base. Usually, to a 17-oxo androstane devoid of other oxo functions (e.g. 3β-hydroxy-5-androstane-17-one) in an inert organic solvent (e.g. dimethylsulfoxide) there is added from about 1 to about 5 equivalents of the reagent containing an arylsulfurcyclopropane grouping (e.g. cyclopropyldiphenylsulfonium fluoroborate) and the reaction mixture is stirred under an inert atmosphere (e.g. under nitrogen) at room temperature for a few minutes. About 3 to 25 equivalents of powdered potassium hydroxide is then added, the reaction mixture stirred under an inert atmosphere for a few hours, then is poured into a large volume of ice water, and acetic or fluoroboric acid is added until the pH of the reaction mixture is at about pH 7 (i.e. treatment of the intermediate in situ with aqueous acid). The resulting (17R)-spiro-[androstane-17,1'-cyclobutan]-2'-one product (e.g. (17R)-spiro-[3β-hydroxy-5-androstene-17,1'-cyclobutan] -2'-one) is then isolated and purified utilizing techniques well known in the art; for example, by extraction with ethyl acetate, washing the combined organic solution with water, evaporation of the organic solution in vacuo to a residue followed by chromatography thereof.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:17])[C:10](=[O:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20]([C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[N:24]=[C:25]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:26]([CH3:32])=[N:27]2)=[O:21].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH3:17])[C:10](=[O:16])[CH:11]([CH2:19][C:20]([C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[N:24]=[C:25]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:26]([CH3:32])=[N:27]2)=[O:21])[C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1nc2cccc(C(=O)CBr)c2nc1NC(C)(C)C
Reactant: COC(=O)CC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)C(CC(=O)c1cccc2nc(C)c(NC(C)(C)C)nc12)C(=O)C(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
At RT, a solution of (R)-methyl 4-((tert-butoxycarbonyl)amino)-3-oxopentanoate (603) (5.38 g, 21.95 mmol) in 20 mL of THF and 20 mL of DMF was treated with 2-bromo-1-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)ethanone (606) (5.44 g, 16.18 mmol) and K2CO3 (5.59 g, 40.4 mmol) and stirred at RT for 6 h. It was diluted with 250 mL of EtOAc, filtered through a flitted funnel, rinsed with 2×15 mL of EtOAc. The filtrate was washed with sat NH4Cl (2×25 mL) followed by brine (15 mL). The organic solution was dried over Na2SO4 and concentrated. The residue was passed through a short column (35-75% EtOAc in hexanes) to get rid of the solvent front peaks and the base line peaks. Fractions with m/z (ESI, +ve) 501.2 (M+H)1 were collected and concentrated to give methyl 4-((tert-butoxycarbonyl)amino)-2-(2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxopentanoate (326a) as a brown residue. To the brown residue in a glass tube in 25 mL of EtOH and 10 mL of HOAc was added NH4OAc (8.46 g, 110 mmol). The tube was sealed and heated in an oil bath at 50° C. for 8 h. The mixture was concentrated to half of its volume, diluted with 250 mL of EtOAc, washed sequentially with 15 mL of water, 15 mL of 1 N NaOH and 5 mL of brine. The organic solution was concentrated and the residue was purified on a silica gel column (eluted with a gradient of 35-65% EtOAc in hexanes) to give methyl 2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (326b) (6.3 g, 71% yield) as a yellow amorphous. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.42 (1H, br.), 7.76 (1H, dd, J=7.4, 1.2 Hz), 7.63 (1H, dd, J=8.0, 1.2 Hz), 7.38 (2H, m), 7.03 (1H, d, J=7.8 Hz), 5.94 (1H, s), 5.44 (1H, m), 3.77 (3H, s), 2.56 (3H, s), 1.58 (9H, s), 1.40 (12H, m). m/z (ESI, +ve) 482.1 (M+H)+.
Reaction SMILES: ClCCl.[C:4]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([CH3:7])([CH3:6])[CH3:5].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:15]([NH:22][CH:11]1[CH2:12][CH2:13][N:8]([C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:9][CH2:10]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)N1CCC(NCc2ccccc2)CC1

Procedure:
A dichloromethane solution (3 mL) containing 1-tert-butylpiperidin-4-one (COMPOUND PPA-1) (120 mg, 0.77 mmol), benzyl amine (0.17 mL, 1.56 mmol), acetic acid (0.05 mL) and sodium triacetoxy borohydride (246 mg, 1.16 mmol) was stirred for several days. The solution was concentrated and the residue partitioned between aqueous potassium carbonate and ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using CHCl3/MeOH/NH4OH (87/12/1) as eluent to give N-benzyl-1-tert-butylpiperidin-4-amine. Mass spectrum (ESI) 247 (M+1). 1H NMR (500 MHz, CD3OD): δ 1.09(s, 9H); 1.38-1.48(m, 2H); 1.91-1.97(m, 2H); 2.11-2.18(m, 2H); 2.40-2.48(m, 1H); 3.02-3.08(m, 2H); 3.76(s, 2H); 4.87(s, 1H); 7.21-7.26(m, 1H); 7.29-7.36(m, 4H).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:19][C:20]([N:22]1[CH2:31][CH2:30][C:29]2[CH:28]=[N:27][C:26]([NH:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:25][C:24]=2[CH2:23]1)=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=1)(C(C)(C)C)(C)C.C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[Cl:18][C:13]1[CH:12]=[C:11]([C@H:10]([NH:19][C:20]([N:22]2[CH2:31][CH2:30][C:29]3[CH:28]=[N:27][C:26]([NH:32][CH:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[N:25][C:24]=3[CH2:23]2)=[O:21])[CH2:9][OH:8])[CH:16]=[CH:15][C:14]=1[F:17]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](NC(=O)N1CCc2cnc(NC3CCOCC3)nc2C1)c1ccc(F)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@H](CO)c1ccc(F)c(Cl)c1)N1CCc2cnc(NC3CCOCC3)nc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)—N-(2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethyl)-2-(tetrahydro-2H-pyran-4-ylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxamide (0.250 g, 0.443 mmol) and THF (5 mL) at RT was added TBAF (0.532 mL, 0.532 mmol) and the reaction was stirred for 1 h at RT, poured into water and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (500:20 to 500:30) to afford 0.100 g (50.2%) of I-46: 1H NMR (400 MHz, d6-DMSO) δ 8.08 (s, 1H), 7.52 (d, 1H), 7.32 (d, 2H), 6.91-6.86 (m, 2H), 4.85 (br s, 1H), 4.74 (m, 1H), 4.40-4.30 (m, 2H), 3.87-3.84 (m, 3H), 3.58-3.54 (m, 4H), 3.38-3.31 (m, 2H), 2.56-2.54 (m, 2H), 1.81-1.78 (m, 2H), 1.53-1.46 (m, 2H); MS m/z (APCI-pos) M+1=450.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[CH:7][C:8]([O:10][CH3:11])=[O:9].[BH4-].[Na+].[ClH:20]>C1COCC1.CO>[ClH:20].[ClH:20].[NH2:5][CH:6]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C=C(N)c1cccnc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CC(N)c1cccnc1
Temperature: -2.5 °C
Reaction time: 5 h
Yield: 89.2 %

Procedure:
Glacial acetic acid (526.9 g, 8.78 mol) was added dropwise at <−5° C. to a suspension of methyl 3-amino-3-(3-pyridyl)-2-propenoate (0.45 mol) and sodium borohydride (44.3 g, 1.17 mol) in THF (500 g) and the resulting reaction mixture was stirred at −5-0° C. After 5 h, methanol (600 g) was added dropwise to the solution at −5-0° C. After 0.5 hours, HCl (163 g, 4.47 mol) was bubbled through the solution and stirred at 0° C. After 8 h, the white precipitate was filtered off and dried at 40° C. to yield 101.6 g (89%) of methyl 3-Amino-3-(3-pyridyl)propanoate dihydrochloride.