Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][N:8]([CH3:37])[C:9]1[CH:36]=[CH:35][C:12]([CH:13]([C:23]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][C:24]=2[C:25]([OH:27])=[O:26])[C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.OC1C=CC2C(=CC=CC=2)C=1N=NC1C=C(S(O)(=O)=O)C=CC=1O.O=O>>[CH3:22][N:20]([CH3:21])[C:17]1[CH:16]=[CH:15][C:14]([C:13]2([C:12]3[CH:11]=[CH:10][C:9]([N:8]([CH3:7])[CH3:37])=[CH:36][CH:35]=3)[C:23]3[C:24](=[CH:28][C:29]([N:32]([CH3:34])[CH3:33])=[CH:30][CH:31]=3)[C:25](=[O:27])[O:26]2)=[CH:19][CH:18]=1
Reactant: CN(C)c1ccc(C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: O=O
Agent: O=S(=O)(O)c1ccc(O)c(N=Nc2c(O)ccc3ccccc23)c1
Product: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3)OC(=O)c3cc(N(C)C)ccc32)cc1
Temperature: 90 °C

Procedure:
In accordance with the process of Example 1, the aqueous solution containing sodium carbonate and 2-[4,4'-bis-(dimethylamino)-benzhydryl]-5-dimethylaminobenzoic acid and cobalt complex of 1-[(2-hydroxynaphthyl)azo]-2-hydroxybenzene-5-sulfonic acid, was heated at 90° C. and 1.6 wt. parts of oxygen was fed into it under the atmospheric pressure during 5 hours, and the precipitate was separated by a filtration and washed with a dilute aqueous solution of sodium hydroxide and with water to obtain 40.7 wt. parts of 3,3-bis-(4-dimethylaminophenyl)-6-dimethylaminophthalide having a melting point of 181° to 183° C.
Reaction SMILES: [CH2:1]1[C@@H:5]([OH:6])[CH2:4][NH:3][CH2:2]1.Cl.[OH-].[Na+].[C:10](Cl)([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[Cl-].[Na+]>O>[OH:6][C@@H:5]1[CH2:1][CH2:2][N:3]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:4]1
Reactant: O[C@@H]1CCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(OCc1ccccc1)N1CC[C@@H](O)C1
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A solution of 10.2 g (82.6 mmol) of R-3-hydroxypyrrolidine hydrochloride (Chem. Letts., 1966, pp 893-6) in 50 m of water was cooled to 0° and treated with 22.5 ml (90 mmol) of 4.0 N sodium hydroxide. The neutral solution was treated dropwise with 15.6 g (87 mmol) of carbobenzyloxy chloride maintaining the pH at 11.0±0.5 by the dropwise addition of 87 ml of 1.0 N sodium hydroxide and the temperature below 5° with a salt-ice bath. When the addition was complete, the mixture was stirred at 5° for two hours and stored at 5° for 18 hours. The reaction mixture was saturated with sodium chloride and extracted with ethyl acetate (2 ×500 ml). The combined organic layers were washed with 1.0 N sodium hydroxide (4×50 ml), water, dried (MgSO4) and evaporated in vacuo to give 17.5 g of the title compound.
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]([F:14])([F:13])[CH2:6][CH2:7][C:8]([O:10]CC)=[O:9]>O.CO.O1CCCC1>[F:4][C:5]([F:14])([F:13])[CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)CCC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCC(F)(F)F
Reaction time: 8 h
Yield: 95.3 %

Procedure:
A solution of lithium hydroxide monohydrate (324 g) in water (1.8 L) was added to a stirred solution of ethyl 4,4,4-trifluorobutyrate (436 g) in methanol (2.0 L) and dry tetrahydrofuran (2.0 L) and the suspension was stirred overnight. After the suspension was partially evaporated, the residue was diluted with water and washed with diethyl ether. The aqueous layer was acidified with 6M hydrochloric acid and extracted with diethyl ether. The combined extracts were washed (brine), dried (MgSO4), and filtered. The filtrate was evaporated and the residue distilled (bp 165°-168° C.) to give 4,4,4-trifluorobutyric acid (347 g, 95%); mp 27°-30° C.; partial NMR; (300 MHz, CDCl3): 2.33-2.57 (m, 2H, CF3CH2), 2.66 (t, 2H, CH2CO2H).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:18][C:19]1[CH:20]=[C:21](I)[CH:22]=[CH:23][CH:24]=1>>[Br:18][C:19]1[CH:24]=[C:23]([C:12]2[C:11]3[C:6]([C:5]4[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=4[CH:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:22]=[CH:21][CH:20]=1
Reactant: Brc1cccc(I)c1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Product: Brc1cccc(-c2cc3ccccc3c3ccccc23)c1

Procedure:
9-(3-Bromophenyl)phenanthrene was synthesized by the same method, except that in Synthetic Example 1, 9-phenanthreneboronic acid was used in place of 2-naphthaleneboronic acid and that 3-bromoiodobenzene was used in place of 4-bromoiodobenzene.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH3:11])=[CH:6][C:7]=1[C:8]([OH:10])=O)=[O:2].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH2:40]([N:42]([CH2:46][CH3:47])[CH2:43][CH2:44][NH2:45])[CH3:41]>CN(C)C=O.C(=O)(O)[O-].[Na+].[Cl-].[Na+].O>[CH2:40]([N:42]([CH2:46][CH3:47])[CH2:43][CH2:44][NH:45][C:8]([C:7]1[CH:6]=[C:5]([CH3:11])[NH:4][C:3]=1[CH:1]=[O:2])=[O:10])[CH3:41]
Reactant: Cc1cc(C(=O)O)c(C=O)[nH]1
Reactant: CCN(CC)CCN
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1cc(C)[nH]c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (320 mg, 2.1 mmol) in dimethylformamide (3 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (483 mg, 1.2 equiv.), 1-hydroxybenzotriazole (340 mg, 1.2 equiv.), triethylamine (0.59 mL, 2 equiv.) and N,N-diethylethylenediamine (0.32 mL, 1.1 equiv.). After stirring at room temperature overnight, the reaction was diluted with saturated sodium bicarbonate and brine (with extra salt) and extracted with 10% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide.
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26])([CH3:19])([CH3:18])[CH3:17].C1(O)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:18][C:16]([C:20]1[CH:25]=[C:24]([CH:23]=[CH:22][C:21]=1[OH:26])[CH:9]=[O:10])([CH3:19])[CH3:17]
Reactant: CC(C)(C)c1ccccc1O
Reactant: CN(C=O)c1ccccc1
Solvent: Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(C=O)ccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into 184.4 ml (1,494 mol) of N-methylformanilide were added dropwise, with cooling, 130.9 ml (1,404 mol) of phosphoryl chloride over a period of 20 minutes. The mixture was allowed to warm to room temperature and stirred for one hour. Ortho-tertbutylphenol (138.2 ml; 0.9 mol) was then added dropwise to the reaction solution over a period of 25 minutes. After phenol addition was complete, the resulting reaction mixture was stirred for an additional 30 minutes at room temperature and then heated to approximately 60° C. and stirred for five hours at that temperature. The reaction mixture was poured into a volume of crushed ice and extracted with chloroform. The aqueous layer was separated and washed again with chloroform. The chloroform layers were combined and extracted with 2000 ml of a 5% potassium hydroxide solution. The aqueous potassium hydroxide extract was then added to 1000 ml of chloroform. The pH of the resulting two-phase mixture was adjusted to approximately pH 2.0 with concentrated hydrochloric acid. The mixture's layers were separated and the aqueous layer was again extracted with chloroform. The organic layer from the two-phase mixture and the chloroform extract were combined, washed with water and then dried over sodium sulfate. The volatile components of the solution were removed under reduced pressure to provide a residue. This residue was dissolved in 100 ml of hot toluene and the resulting solution was diluted with 100 ml of hexanes. The solution was slowly cooled to room temperature while a precipitate formed. This precipitate was recovered by filtration, washed with hexanes and then dried under vacuum to provide 20.0 g of the desired substituted intermediate.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=1>O.CC(C)=O>[Cl:13][C:14]1[CH:19]=[C:18]([O:12][C:9]2[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=2)[N:17]=[CH:16][N:15]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Clc1cc(Cl)ncn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Yield: 99.5 %

Procedure:
Dissolve NaOH (2.8 g, 71.9 mmol) in water (90 mL) at 0° C. Add para-nitrophenol (10 g, 71.9 mmol), and then a solution of 4,6-dichloropyrimidine (10.7 g, 71.9 mmol) in acetone (90 mL). Stir the reaction at 70° C. for 24 hrs. Cool the reaction, collect the solid, rinse the solid with the mixture of acetone-water (1:1, 20 mL), and dry the solid to afford the title compound (18 g, 77.8%). MS: (M+Na): 274.0.
Reaction SMILES: C1C=C2C=CC(O)=C(C3C4C(=CC=CC=4)C=CC=3O)C2=CC=1.[H-].C([Al+]CC(C)C)C(C)C.CC(O)C.[CH2:37]([Cl:46])[C:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:39].Cl>C1(C)C=CC=CC=1.O>[Cl:46][CH2:37][C@H:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[OH:39]
Reactant: O=C(CCl)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: O[C@H](CCl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a slurry solution of 143 mg (0.5 mmol) of (R)-1,1′-bi-2-naphthol in 10 ml of toluene was added 0.5 ml (0.5 mmol) of toluene solution of diisobutylaluminum hydride (1.0 M) at room temperature, and the mixture was stirred at room temperature for 1 hour. Thereto 1.52 ml (20 mmol) of 2-propanol was added and the mixture was stirred further at room temperature for 30 minutes. Thereto 1.55 g (10 mmol) of phenacyl chloride was added and the mixture was stirred at 50° C. for 4 hours. To the mixture were added 6 ml of 1N hydrochloric acid and 20 ml of water to conduct hydrolysis. The mixture was extracted with ethyl acetate and concentrated to obtain an oily product. The after-treatment and the analysis of the product were then carried out in the same manner as described in Example 2.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)O.C(=O)=O.[CH3:15][CH:16]([CH2:18][CH2:19][CH2:20][CH:21]([CH2:23][CH2:24][CH2:25][CH:26]([CH2:28][CH2:29][CH2:30][C:31]([OH:35])([CH:33]=[CH2:34])[CH3:32])[CH3:27])[CH3:22])[CH3:17]>>[CH3:10][C:4]1[C:3]([OH:11])=[C:2]([CH3:1])[C:8]2[CH2:34][CH2:33][C@:31]([CH2:30][CH2:29][CH2:28][C@@H:26]([CH2:25][CH2:24][CH2:23][C@@H:21]([CH2:20][CH2:19][CH2:18][CH:16]([CH3:15])[CH3:17])[CH3:22])[CH3:27])([CH3:32])[O:35][C:6]=2[C:5]=1[CH3:9]
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: O=C=O
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
15.02 g (98.8 mmol) of trimethylhydroquinone and 10.59 g of the strongly acid ion exchanger Amberlyst A15 were placed in a 300 ml autoclave, and 116 g of CO2 were condensed in. Heating to 100° C. resulted in a pressure of 185 bar. 37.80 ml (29.48 g; 99.6 mmol) of isophytol were injected by means of an HPLC pump over the course of 1.5 hours (h) at 108° C. After stirring at 108° C. for a further 30 minutes (min), the autoclave was cooled to room temperature (RT), and the pressure was released. The ion exchanger was removed from the product by centrifuging the mixture. The 48.9 g of isolated pale yellow oil contained 83% tocopherol, which corresponds to an 84% yield of pure α-tocopherol.
Reaction SMILES: [C:1]1([CH3:42])[C:2]([S:7]([O:10][CH2:11][C@H:12]([CH2:21][O:22][C:23](=[O:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:13][CH:14](OCC)[O:15]CC)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.OS(C(F)(F)F)(=O)=O.CCCCCCC>C(#N)C.O>[C:23]([O:22][CH2:21][C@@H:12]([CH2:11][O:10][S:7]([C:2]1[C:1]([CH3:42])=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:9])=[O:8])[CH2:13][CH:14]=[O:15])(=[O:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](COS(=O)(=O)c1ccccc1C)CC(OCC)OCC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCCCCCC
Solvent: O
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CC=O)COS(=O)(=O)c1ccccc1C
Temperature: 37 °C
Reaction time: 1 h

Procedure:
A suspension of the product of Example 61 c) (4573 g, 7.47 mol) in acetonitrile (4 L) was added to a 50 L reactor equipped with a thermocouple and nitrogen inlet. An additional 13 L of acetonitrile was added and the suspension was heated to 37° C. with steam. A solution of triflic acid (1253 mL, 14.16 mol) in water (7.6 L) was added over 20 minutes. Then the mixture was stirred at 39–42° C. for 1 hour. The reaction mixture was quenched by adding it to 20 L of 23% aqueous sodium bicarbonate solution and 35 L of methyl t-butyl ether. The reaction flask was rinsed with 5 L of methyl t-butyl ether and an additional 20 L of 23% aqueous sodium bicarbonate was addded. This mixture was stirred for 10 minutes and the layers were separated. The organic layer was washed with a mixture of 25 L of 23% aqueous sodium bicarbonate solution and 15 L of 7% NaCl solution. Then the organic layer was washed with 25 L of 7% NaCl solution. The solvents were removed on a batch concentrator to provide a thick slurry. Heptane (32 L) was added to the slurry and then evaporated. Additional heptane (12 L) was added and evaporated. A further amount of heptane (40 L) was added and the suspensin was heated to 44° C. in 60 minutes, causing complete dissolution. The reaction flask was cooled to 40° C. in 10 minutes by running cold water over the surface of the flask. The solution was then allowed to slowly cool to 35° C., where cyrstallization occurs. The resulting thick mixture was stirred for 14 hours. The precipitate was filtered and rinsed twice with 4 L of heptane and then dried on the filter funnel for 2 hours and then in a vacuum oven with nitrogen purge for 60 hours at room temperature. The resulting solid (3200 g), heptane (30 L) and methyl t-butyl ether (1.6 L) were combined and heated with stirring to dissolution. The resulting solution was cooled over 1 hour to 42° C. and the resulting suspension was stirred for 20 hours while cooling to room temperature. The precipitate was filtered and dried in a vacuum oven with nitrogen purge for 20 hours at room temperature to give the desired product (2860 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([S:12]([NH2:15])(=[O:14])=[O:13])[C:5]=2[O:4][S:3]1(=[O:17])=[O:16].[CH3:18][N:19]=[C:20]=[O:21].N12CCCN=C1CCCCC2>C(#N)C.O>[CH3:1][CH:2]1[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([S:12]([NH:15][C:20]([NH:19][CH3:18])=[O:21])(=[O:14])=[O:13])[C:5]=2[O:4][S:3]1(=[O:17])=[O:16]
Reactant: CC1Cc2cccc(S(N)(=O)=O)c2OS1(=O)=O
Reactant: CN=C=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CNC(=O)NS(=O)(=O)c1cccc2c1OS(=O)(=O)C(C)C2
Temperature: 25 °C

Procedure:
A solution of 24.96 g of 3,4-dihydro-3-methyl-2,2-dioxo-1,2-benzoxathiin-8-ylsulfonamide in 120 ml of absolute acetonitrile is cooled to +8° C. After the addition of 6 ml of methyl isocyanate, a solution of 13.4 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene in 15 ml of acetonitrile is added dropwise over 15 minutes at 10° C. The reaction mixture is stirred for a further hour at room temperature. The mixture is subsequently diluted with 180 ml of water. The product is precipitated by the dropwise addition of 48 ml of 2N hydrochloric acid. The precipitate is isolated and dried, affording 26.4 g of N-(3,4-dihydro-3-methyl-2,2-dioxo-1,2-benzoxathiin-8-ylsulfonyl)-N'-methylurea with a melting point of 235°-238° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl.C(=O)([O-])O.[Na+]>[CH3:15][S:16]([O:1][CH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC1(CO)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(C#N)CC1
Reaction time: 1 h
Yield: 88.5 %

Procedure:
A stirred mixture of 1-(hydroxymethyl)cyclopropanecarbonitrile (24.30 mmol, 2.36 g) in dichloromethane (30 mL) was treated with triethylamine (48.6 mmol, 6.83 mL, 4.92 g) and portionwise with methanesulfonyl chloride (31.6 mmol, 2.445 mL, 3.62 g) keeping the reaction mixture at 0° C. The solution was allowed to stir for 1 hour then diluted with saturated sodium hydrogencarbonate and extracted with 10% methanol/dichloromethane (×3). The organic layers were combined and concentrated under reduced pressure to give the intermediate (1-cyanocyclopropyl)methyl methanesulfonate (3.77 g).
Reaction SMILES: Br[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C1(C)C=CC=CC=1.C(O)C.[OH-].[Na+].O>[OH:8][C:7]1[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cccnc1Br
Reactant: OB(O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Oc1cccnc1-c1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
A mixture of 2-bromo-3-hydroxypyridine (2.20 g, 12.6 mmol), phenylboronic acid (2.00 g, 16.3 mmol) and palladium (tetrakis)triphenylphosphine (250 mg) in toluene (30 mL), ethanol (15 mL) and 5% aqueous sodium hydroxide (15 mL) was degassed with a stream of nitrogen and stirred vigorously at 100° C. overnight. The mixture was diluted with water (50 mL) and ethyl acetate (100 mL), and the organic layer was dried over sodium sulfate and concentrated, affording a yellow solid. This material was suspended in water (100 mL), a few mL of 1N HCl was added, and the resulting solution was extracted with ethyl acetate. The aqeuous layer was neutralized with saturated aqueous sodium bicarbonate, and again was extracted with ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated to an oily solid, which was triturated with 2:1 hexane/ethylacetate, affording 0.98 g of 3-hydroxy-2-phenylpyridine.
Reaction SMILES: [CH:1](O)=[O:2].CC(OC(C)=O)=O.[NH2:11][CH:12]([C:18]#[N:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1COCC1>[C:18]([CH:12]([NH:11][CH:1]=[O:2])[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:19]
Reactant: CCOC(=O)C(N)C#N
Reactant: O=CO
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(C#N)NC=O
Temperature: 25 °C
Yield: 70.4 %

Procedure:
Under N2, HCOOH (2.44 g, 53 mmol) was added to Ac2O (6.48 g, 63.6 mmol) at 0° C. After it was allowed to warm to ambient temperature the reaction was heated at 50° C. for 15 hr. It was allowed to cool to ambient temperature. This mixed acid anhydride was then added dropwise to a solution of ethyl 2-amino-2-cyanoacetate (128 mg, 1 mmol) in dry THF (5 mL) at 0° C. After the cooling bath was removed, the reaction was maintained at ambient temperature for additional 1 hr. The reaction mixture was concentrated and purified by silica gel column chromatography (5:1 PE/EtOAc) to afford ethyl 2-cyano-2-formamidoacetate (110 mg, 70%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:14])[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][NH2:16]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH3:14])[C:10]([NH:15][NH2:16])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: COC(=O)[C@H](C)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NN
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)propanoate (1.00 g, 4.92 mmol) and hydrazine (0.23 mL, 1.5 equiv) in THF (8 mL) was heated in a sealed tube at 72° C. for 15 hours. Additional hydrazine (0.23 mL, 1.5 equiv) was added and heating was continued for another 21 hours. The reaction was then cooled to room temperature and concentrated in vacuo to give crude (S)-tert-butyl(1-hydrazinyl-1-oxopropan-2-yl)carbamate (1 g, white solid), which was used without purification. 1H NMR (400 MHz, CDCl3) δ 4.20 (m, 1H), 1.44 (s, 9H), 1.36 (d, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[ClH:11].[N:12]([O-])=O.[Na+].C([O-])(=O)C.[NH4+]>C(#N)C.O.[Zn]>[ClH:11].[NH2:12][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[CH3:1]
Reactant: O=N[O-]
Reactant: CC1Cc2ccccc2N1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CC1Cc2ccccc2N1N
Temperature: 45 °C
Reaction time: 2 h

Procedure:
140 g of 2-methylindoline was dissolved in 750 ml of acetonitrile. 110 ml of concentrated hydrochloric acid was added and the solution was cooled. A solution of 75 g of sodium nitrite in 300 ml of water was added dropwise. The pH of the solution was adjusted to about 7 with ammonium acetate followed by portionwise addition of 160 g of zinc dust and 385 g of ammonium acetate. Next, 100 ml of water was added and the mixture was stirred for about 2 hours at 45° C. The solids were filtered off and washed with toluene (3×250 ml). The tolune washes were then used to extract the filtrate. The toluen washes were then combined, acidified with 120 ml of concentrated hydrochloric acid and 120 g of ice was added to obtain the crystals of the title compound. The crystals were separated by filtration, washed with toluene and dried. The dried material was checked by TLC and was of good quality.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CC[O:9]CC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH:27]=2)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].OO>C1COCC1.C(O)C.O>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][C@H:27]2[OH:9])=[CH:22][CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(OCc3ccccc3)cc2)CC1
Reactant: CCOCC
Agent: FB(F)F
Agent: OO
Agent: [BH4-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(OCc3ccccc3)cc2)[C@H](O)C1
Temperature: 0 °C
Yield: 85.9 %

Procedure:
To a stirring mixture of NaBH4 (0.93 g, 24.6 mmol) in THF (25 mL) cooled to 0° C. was added boron trifluoride etherate (3.2 mL, 25 mmol) and the mixture was allowed to warm up to rt over 1 h. It was then re-cooled to 0° C. and to it was added a solution of tert-butyl 4-(4-(benzyloxy)-phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (3 g, 8.2 mmol) in THF (10 mL). The resulting mixture was allowed to warm up to rt over 2 h. The reaction mixture was cooled again to 0° C. and H2O (10 mL), ethanol (10 mL), 10 M NaOH (10 mL) and H2O2 (8 mL, 26 mmol) were sequentially added. The final mixture was heated to 65° C. overnight. After cooling, the reaction was quenched with water and the mixture was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo yielding 2.7 g of (±)-rel-(3S,4S)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (82% yield) as off-white solid. LCMS (method O) RT 2.41 min, m/z 382 (M−H). 1H NMR (400 MHz, DMSO-d6) δ 1.41 (s, 9H), 1.63 (m, 1H), 1.67 (m, 1H), 2.67 (m, 1H), 3.37-3.41 (m, 1H), 3.92 (m, 1H), 4.10 (m, 1H), 4.73 (d, J=2.4, 1H), 5.07 (s, 2H), 6.91 (d, J=9, 2H), 7.14 (d, J=9, 2H), 7.31-7.44 (m, 4H).