Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.O[NH:61][C:62](=[NH:64])[CH3:63]>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([N:10]2[CH2:17][CH2:16][CH2:15][CH:11]2[C:12]2[O:14][N:64]=[C:62]([CH3:63])[N:61]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N2CCC[C@H]2C(=O)O)ccc(C#N)c1Cl
Reactant: CC(=N)NO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(C2CCCN2c2ccc(C#N)c(Cl)c2C)n1
Temperature: 21 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(3-chloro-4-cyano-2-methylphenyl)proline (0.200 g, 0.756 mmol), TBTU (0.364 g, 1.136 mmol), diisopropylethylamine (0.458 g, 3.78 mmol) and N-hydroxybenzotriazole (0.023 g, 0.150 mmol) in DMF add N-hydroxyacetamidine (0.084 g, 1.136 mmol). Stir the solution at 21° C. for 18 h. then heat the reaction at 100° C. in a microwave for 1 h. Partition the reaction between ethyl acetate and 2N aqueous hydrochloric acid. Extract the organic phase with 2N aqueous sodium hydroxide and brine, dry over magnesium sulphate, filter and remove the solvent under reduced pressure. Purify the resulting residue by reverse phase HPLC (Princeton SPHER C-18 column, gradient of 80:20 to 5:95 [water:acetonitrile], with 0.1% acetic acid modifier)) to yield the title compound. (0.81 g, 35%) mass spectrum (m/e): 303.1 (M+Na)); 1H NMR (400 MHz, CDCl3): δ 7.35 (d, 1H), 6.99 (d, 1H), 5.11 (t, 1H), 3.88 (m, 1H), 3.16 (m, 1H), 2.56 (m, 1H), 2.39 (s, 3H), 2.31 (s, 3H), 2.30-2.15 (m. 3H), 2.06 (m, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[OH-].[Na+].[CH2:18]=O.Cl>O>[CH2:18]1[C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH2:3][C@H:2]([C:13]([OH:15])=[O:14])[NH:1]1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: C=O
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@H]1Cc2c([nH]c3ccccc23)CN1
Yield: 87.4 %

Procedure:
20.0 g D-tryptophan is suspended in 40 ml of water and 7.83 g 50%(w/w) sodium hydroxide solution is added and this mixture is stirred to give a clear solution. 7.95 g 37% formaldehyde is added and this mixture is stirred for 2 hours at room temperature, then refluxed for 3 hours. The hot solution is poured into 200 ml water and, with vigorous stirring, the pH is adjust to 5 with 6N hydrochloric acid, giving a precipitate. The slurry is stirred for 18 hours, filtered, and the solid dried at 70° C./0.1 mm Hg overnight to give 18.5 g (3R)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]([C:11]#[C:12][Si](C)(C)C)=[CH:9][CH:10]=1)=[O:5])[CH3:2].C1(S([NH:26][C:27]2[C:32](I)=[CH:31][C:30]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:29][CH:28]=2)(=O)=O)C=CC=CC=1.C([O-])(=O)C.[K+].O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]([C:11]2[NH:26][C:27]3[C:28]([CH:12]=2)=[CH:29][C:30]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:31][CH:32]=3)=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(C#C[Si](C)(C)C)o1
Reactant: CS(=O)(=O)c1ccc(NS(=O)(=O)c2ccccc2)c(I)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cc3cc(S(C)(=O)=O)ccc3[nH]2)o1
Temperature: 100 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To a solution of the compound obtained in Example 29 (2) (0.1 g) in N,N-dimethylformamide (1 ml), 2-benzenesulfonylamino-3-iodo-5-methanesulfonylbenzene (0.0925 g), bistriphenylphosphine palladium dichloride (0.015 g), cuprous iodide (0.004 g) and potassium acetate (0.04 g) were added successively and the mixture was stirred in a sealed tube at 100° C. for 2 hours. After cooling, the reaction solution was poured into water, extracted with ethyl acetate, washed with a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 0.0462 g of the desired product as a brown solid.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=2[O:2]1.O[C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1>>[CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][O:7][C:13]3[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=3)=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: OCc1ccc2c(c1)OCO2
Product: CCOC(=O)c1ccc(OCc2ccc3c(c2)OCO3)cc1

Procedure:
3,4-Methylenedioxybenzyl alcohol 18-1 (6.2 g, 40.0 mmol) and ethyl 4-hydroxybenzoate 18-2 (6.65 g, 40.0 mmol) were reacted as in Example 14. The desired ester 18-3 was obtained as a white solid.
Reaction SMILES: [CH:1]([C:3]1[O:8][CH2:7][CH2:6][CH2:5][C:4]=1[C:9]([O:11]CC)=O)=O.O.[NH2:15][NH2:16]>CO>[O:8]1[C:3]2[CH:1]=[N:15][NH:16][C:9](=[O:11])[C:4]=2[CH2:5][CH2:6][CH2:7]1
Reactant: CCOC(=O)C1=C(C=O)OCCC1
Reactant: NN
Solvent: CO
Solvent: O
Product: O=c1[nH]ncc2c1CCCO2
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 98.2 %

Procedure:
To a stirred 0° C. mixture of ethyl 6-formyl-3,4-dihydro-2H-pyran-5-carboxylate (1.705 g, 9.26 mmol) in methanol (80 mL) was added very quickly 35% hydrazine hydrate (0.311 g, 9.72 mmol). After 20 minutes, the solvent was removed under reduced pressure, and the residue was treated with acetic acid (70 mL) and water (7 mL) and stirred at 110° C. for 20 minutes. The solvents were removed in vacuo. The crude residue was eluted by silica gel chromatography with a 0 to 25% gradient of methanol/dichloromethane to afford the title compound (1.384 g) as a light yellow solid in better than 90% purity. MS (ESI) [m/e, (M+H)+]=153.2. 1H NMR (400 MHz, chloroform-d) δ ppm 10.56 (br s, 1H), 7.53 (s, 1H), 4.17-4.35 (m, 2H), 2.57 (t, J=6.57 Hz, 2H), 1.99-2.08 (m, 2H).
Reaction SMILES: [C:1]([C@@:4]1([OH:17])[C@H:12]([O:13][CH3:14])[C@H:11]([O:15][CH3:16])[CH2:10][O:9][C@:5]1([OH:8])[CH2:6][OH:7])([CH3:3])=[CH2:2].[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1.C(OCC)C.CCCCC>[C:24]1([CH3:25])[CH:26]=[CH:27][C:21]([S:18]([CH:6]([C@:5]2([O:9][CH2:10][C@@H:11]([O:15][CH3:16])[C@@H:12]([O:13][CH3:14])[C@@:4]2([C:1]([CH3:3])=[CH2:2])[OH:17])[OH:8])[OH:7])(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=C(C)[C@@]1(O)[C@H](OC)[C@H](OC)CO[C@]1(O)CO
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: CCCCC
Product: C=C(C)[C@@]1(O)[C@H](OC)[C@H](OC)CO[C@]1(O)C(O)S(=O)(=O)c1ccc(C)cc1
Yield: 70.8 %

Procedure:
Following the procedure described for the preparation of Example 10, starting from 0.80 g (3.22 mmol) of the compound obtained in Example 29 and 1.53 g of tosyl chloride in 15 ml of anhydrous pyridine, then purification by chromatography on silica gel (eluant: diethyl ether/pentane, 2:1), 0.92 g (2.28 mmol) of the desired product in the form of a white-coloured foam is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][NH:8][C:9](=[O:16])[O:10][C@H:11]1[CH2:15][CH2:14][O:13][CH2:12]1)([O-])=O.N#N>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][NH:8][C:9](=[O:16])[O:10][C@H:11]1[CH2:15][CH2:14][O:13][CH2:12]1
Reactant: O=C(NCc1cccc([N+](=O)[O-])c1)O[C@H]1CCOC1
Agent: [Pd]
Agent: N#N
Solvent: CCOC(C)=O
Product: Nc1cccc(CNC(=O)O[C@H]2CCOC2)c1

Procedure:
Charged 15 g of (S)-tetrahydrofuran-3-yl 3-nitrobenzylcarbamate 2c in 120 ml EtOAc to a 1 L Parr bomb at room temperature under a blanket of N2. The agitator was started and the vessel pressurized with N2 to 0.75 bar, then the pressure was released. This procedure was repeated 3 times, then the agitator was stopped before adding 0.225 g of 5% Pd/C. The agitator was started, the vessel pressurized with N2 to 0.75 bar, then the pressure was released. This procedure was repeated 3 times, then the agitator was stopped. The vessel was pressurized with H2 to 2 bar, then the pressure was released. This procedure was repeated 3 times, then the vessel was pressurized with H2 to 6.75 bar. The agitator was started and the suspension stirred until complete conversion was evident by HPLC. The H2 pressure was released, the vessel re-pressurized with N2 to 0.75 bar, then the pressure was released. This procedure was repeated 3 times then the agitator was stopped, the reaction mixture filtered through celite and the filter cake rinsed with 30 ml EtOAc to give crude (S)-tetrahydrofuran-3-yl 3-aminobenzylcarbamate 2d as a solution in EtOAc that was used as is immediately in the next step.
Reaction SMILES: C(=O)([O-])O.[Na+].Br.[S:7]1[CH:11]=[CH:10][C:9]2[C:12]([C:16]3[N:17]4[CH2:24][CH2:23][N:22]=[C:18]4[S:19][C:20]=3[CH3:21])=[CH:13][CH:14]=[CH:15][C:8]1=2.[Cl:25]CCl>O>[ClH:25].[S:7]1[CH:11]=[CH:10][C:9]2[C:12]([C:16]3[N:17]4[CH2:24][CH2:23][N:22]=[C:18]4[S:19][C:20]=3[CH3:21])=[CH:13][CH:14]=[CH:15][C:8]1=2
Reactant: ClCCl
Agent: Br
Agent: CC1=C(c2cccc3sccc23)N2CCN=C2S1
Agent: O=C([O-])O
Solvent: O
Product: Cl
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
A solution of sodium hydrogencarbonate (17.84 g) in water (300 ml) was added at 0° C. to a suspension of 3-(benzo[b]thiophen-4-yl)-2-methyl-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide (15.0 g) in dichloromethane (300 ml), the mixture was stirred vigorously for 25 minutes, then the organic phase was separated, dried (Na2SO4), and the solvent was removed in vacuo. The residue was dissolved in ethanol (100 ml), the solution was cooled to 0° C., and 2M ethereal hydrogen chloride solution (28 ml) was added. The mixture was stirred for 20 minutes then the solvent was removed in vacuo. The residue was triturated with a 1:1 mixture of ethanol and ether (50 ml), then the resulting solid was collected by filtration and recrystallised from propan-2-ol to give 3-(benzo[b]thiophen-4-yl)-2-methyl-5,6-dihydroimidazo[2,1-b]thiazole hydrochloride (6.3 g) as a colourless solid, m.p. 235-238° C. Concentration of the liquor yielded a second crop of 3-(benzo[b]thiophen-4-yl)-2-methyl-5,6-dihydroimidazo[2,1-b]thiazole hydrochloride (2.7 g) as a colourless solid, m.p. 234-237° C.
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:9]=[CH:8][NH:7][N:6]=1)[CH2:2][CH3:3].[CH2:10]([N:13]([CH2:17][CH:18]=[CH2:19])[C:14](Cl)=[O:15])[CH:11]=[CH2:12].O1CCCC1>C(N(CC)CC)C>[CH2:10]([N:13]([CH2:17][CH:18]=[CH2:19])[C:14]([N:7]1[CH:8]=[N:9][C:5]([S:4][CH2:1][CH2:2][CH3:3])=[N:6]1)=[O:15])[CH:11]=[CH2:12]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CCCSc1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)C(=O)n1cnc(SCCC)n1

Procedure:
A mixture of 5.75 g. 3-propylthio-1,2,4-triazole, 6.8 g. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 8 ml. dry triethylamine was refluxed under anhydrous conditions for 3 hours. The reaction mixture was worked up as described in Example 1 to produce an oil which was distilled under reduced pressure to give 1-diallylcarbamoyl-3-propylthio-1,2,4-triazole, b.p. 134° - 135°C./0.1 mm. Gas-liquid chromatographic (GLC) assay indicated a content of 1-isomer of 94.2%. Elemental analysis satisfactory.
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14](F)=[C:13](C#N)[CH:12]=2)=[CH:7][CH:6]=1.C[CH2:39][N+:40](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClCCl>[C:2]([C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:33])[CH3:34])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:39]#[N:40])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)#[N:1]
Reactant: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3ccc(F)c(C#N)c3)cc2)C(N)=O)CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc(C#N)cc3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(3′-cyano-4′-fluorobiphenyl-4-yl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 22, step (i), 366 mg) in dichloromethane (5 mL) was treated with Burgess' reagent (205 mg) and the mixture was stirred at room temperature for 18 h. The reaction mixture was evaporated to afford the sub-titled compound as a crude mixture (336 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]2[CH:9]([C:10]([O:12]CC)=[O:11])[C:8]2([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[OH-].[K+]>O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH:9]([C:10]([OH:12])=[O:11])[C:8]2([CH3:15])[CH3:16])=[CH:17][CH:18]=1
Reactant: CCOC(=O)C1C(Oc2ccc(Cl)cc2)C1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)C(Oc2ccc(Cl)cc2)C1C(=O)O

Procedure:
The ethyl 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylate (l.5 g) is hydrolyzed by heating under reflux with 10% potassium hydroxide in a mixture of 20% water and 80% ethyl alcohol for 1 hr and letting stand at 25° overnight. The solution is cooled and solvent is removed in vacuo. The residue is diluted with water and extracted with ether. The aqueous phase is then acidified with aqueous HCl and extracted with ether. The organic phase is washed with water and brine, dried over sodium sulfate and the solvent removed in vacuo to give 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[CH2:11]([NH2:15])[CH2:12][CH2:13][CH3:14]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:11](/[N:15]=[CH:4]/[C:3]1[C:2]([F:1])=[CH:9][CH:8]=[CH:7][C:6]=1[F:10])[CH2:12][CH2:13][CH3:14]
Reactant: O=Cc1c(F)cccc1F
Reactant: CCCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCC/N=C/c1c(F)cccc1F
Temperature: 25 °C
Yield: 86.1 %

Procedure:
A mixture of 25.4 g (179 mmol) 2,6-difluorobenzaldehyde, 19.5 ml (197 mmol) N-butylamine and 0.68 g (3.57 mmol) p-toluenesulfonic acid in 120 ml toluene was heated in a Dean-Stark apparatus at reflux for 3 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed sequentially with water (twice) and with saturated brine. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound 30.4 g (86%) as a brown oil which was used in the next step without further purification. MS (ISP): 198.3 ([M+H]+, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[C:14](/[CH:17]=[C:18](/[N+:21]([O-:23])=[O:22])\[CH2:19][CH3:20])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6]1.O.C(=O)(O)[O-].[Na+:29]>>[Cl:1][C:2]1[C:15]([Cl:16])=[C:14](/[CH:17]=[C:18](/[N+:21]([O-:23])=[O:22])\[CH2:19][CH3:20])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1([C:9]([O-:11])=[O:10])[CH2:8][CH2:7][CH2:6]1.[Na+:29]
Reactant: CC/C(=C\c1ccc(OC2(C(=O)O)CCC2)c(Cl)c1Cl)[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC/C(=C\c1ccc(OC2(C(=O)[O-])CCC2)c(Cl)c1Cl)[N+](=O)[O-]

Procedure:
250 mg of (E)-1-[2,3-dichloro-4-(2-nitro-1-butenyl)phenoxy]cyclobutane-1-carboxylic acid is dissolved in 31 ml of 0.1 N sodium bicarbonate and sufficient isotonic buffer to make a final volume of 100 ml. The water from all sources was pyrogen-free. The solution is sterilized by filtration.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[C:12]([O:14]CC)=O.C([O-])C.[Na+]>C(O)C>[CH3:9][C:4]1[N:5]=[CH:6][C:7]([CH3:8])=[C:2]2[C:3]=1[CH:10]=[CH:11][C:12](=[O:14])[NH:1]2
Reactant: CCOC(=O)/C=C/c1c(C)ncc(C)c1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ncc(C)c2[nH]c(=O)ccc12
Temperature: 80 °C
Yield: 58.2 %

Procedure:
A mixture of (E)-ethyl 3-(4-amino-2,5-dimethylpyridin-3-yl)acrylate (5 g, 22.7 mmol) and sodium ethanolate (6.2 g, 91 mmol) in ethanol (100 mL) was heated to 80° C. for 2 h. The reaction mixture was concentrated and diluted with water (50 mL). The aqueous phase was extracted with EtOAc (100 mL×3), and the combined organic layers were washed with saturated sodium chloride solution, dried with sodium sulfate, and concentrated to give 2.3 g of the product as a yellow solid. MS (ESI): m/z 175.1 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:19])[CH:11]=[C:12]([CH:16]([F:18])[F:17])[N:13]([CH3:15])[CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[F:18][CH:16]([F:17])[C:12]1[N:13]([CH3:15])[CH:14]=[C:9]([OH:8])[C:10](=[O:19])[CH:11]=1
Reactant: Cn1cc(OCc2ccccc2)c(=O)cc1C(F)F
Agent: [Pd]
Solvent: CO
Product: Cn1cc(O)c(=O)cc1C(F)F
Reaction time: 0.42 h
Yield: 79.7 %

Procedure:
A mixture of 5-benzyloxy-2-difluoromethyl-1-methyl-1H-pyridin-4-one (1.90 g, 7.16 mmol) and 10% Pd/C (190 mg) in methanol (60 mL) was hydrogenated under a hydrogen atmosphere at 15 psi of pressure in a Parr apparatus for 25 min. The mixture was diluted with methanol (180 mL), sonicated for 15 min, and then filtered through a pad of CELITE™ (pre-treated with dilute HCl and washed to neutral with deionized water). The volume of the filtrate was reduced using a rotary evaporator until a solid precipitated out. The mixture was diluted with 2 mL of methanol and the solid was collected by suction filtration. The solid was thoroughly washed with ether, and then dried in a vacuum oven to afford the title product (1.00 g, 79% yield). HPLC purity (peak area percent) of the product is 99.2% at λ=288 nm using HPLC Method 1 as described above. 1H NMR (400 MHz, DMSO-D6) δ (ppm): 7.56 (s, 1H), 7.12 (t, J=52.7 Hz, 1H, CF2H), 6.47 (s, 1H), 3.70 (s, 3H, N—CH3); MS-ESI (m/z): 176.5 [M+1]+, 126.2; Anal. Calcd. for C7H7F2NO2: C, 48.01; H, 4.03; N, 8.00%. Found: C, 48.15; H, 4.14; N, 7.88%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>C(O)C>[CH2:13]([O:12][C:10]([N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH2:2]1)=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccncc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(OCc1ccccc1)N1C=CC=CC1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 74.3 %

Procedure:
A solution of pyridine (4.0 g., 0.050 mol) and NaBH4 (2.0 g, 0.026 mol) in 20 ml of absolute ethanol is treated with benzyl chloroformate (8.5 g, 0.05 mol) over about 1 hour followed by stirring for 1.5 hour at -78° C. The mixture is added to ice-water and extracted with ether, and the extract is washed with 3% HCl solution and 3% NaOH solution. After the extract is dried and evaporated, 8.0 g of N-benzyloxycarbonyl1,2-dihydropyridine is obtained in 74% yield. A 5% solution of N-benzyloxycarbonyl-1,2-dihydropyridine is then irradiated using a Rayonet photochemical reactor (RP-300 lamps) until NMR spectrum shows consumption of the starting materials. The solvent is evaporated to give the crude product, N-(benzyloxycarbonyl)-2-azabicyclo[2.2.0]hex-5-ene (VIII). Pure (VIII) is obtained by passing the crude product through basic alumina with ether. (VIII) is then reacted with ozone in methanol at -78° C. followed by reaction with peroxyacetic acid to form cis-N-(benzyloxycarbonyl)-azetidine-2,3- dicarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9](Cl)[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:12][O-:13].[Na+].Cl>CN(P(N(C)C)(N(C)C)=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:13][CH3:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc(Cl)cc(C(=O)O)c1
Temperature: 170 °C
Yield: 75 %

Procedure:
To a solution of 3,5-dichlorobenzoic acid (1.91 g, 10 mmol, 1.0 equiv.) in 10 mL of HMPA was added NaOMe (1.62 g, 30 mmol, 3.0 equiv.). The mixture was heated in a 170° C. oil bath for 72 h. After cooling to room temperature, the mixture was poured into 50 mL of 1 M aqueous HCl. The precipitates were collected by filtration, and washed twice with 20 mL of water. The white solid was dried under vacuum to give 1.4 g of 38a. 1H-NMR (DMSO-d6): δ 14.0 (s, 1H), 7.47 (s, 1H), 7.38 (s, 1H), 7.29 (s, 1H), 3.82 (s, 3H).
Reaction SMILES: Cl.C([O:4][C:5](=[NH:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])C>CC(C)=O>[C:7]([CH2:6][C:5]([NH2:12])=[O:4])([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=N)CC(=O)OCC
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)CC(N)=O
Temperature: 110 °C
Yield: 80.6 %

Procedure:
200 g of ethyl β-ethoxy-β-iminopropionate hydrochloride were placed into a 1,000 ml flask and heated at 110° C. on an oil bath for 2 hours. The reaction mixture was redissolved with 500 ml of acetone, filtered by washing on the filter with other solvent. The filtrate was dried under vacuum and the obtained oily residue was grinded in 1,500 ml of ethyl ether. 108 g of a crystalline product were obtained. Upon TLC analysis, the product proved to be pure.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])[N:14]3[CH3:17])=[C:10]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[CH:35][C:5]=2[N:4]=1)[CH3:2].CCN(CC)CC.[C:43](Cl)(=[O:47])[CH:44]([CH3:46])[CH3:45]>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]([CH:20]4[CH2:21][CH2:22][N:23]([C:43](=[O:47])[CH:44]([CH3:46])[CH3:45])[CH2:24][CH2:25]4)=[O:19])[N:14]3[CH3:17])=[C:10]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[CH:35][C:5]=2[N:4]=1)[CH3:2]
Reactant: CC(C)C(=O)Cl
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)C3CCNCC3)n(C)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)C3CCN(C(=O)C(C)C)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 13 %

Procedure:
To a solution of [2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidin-4-ylmethanone and NEt3 (27 μL, 0.20 mmol) in DCM (5 mL) was added isobutyryl chloride (10 μL, 0.12 mmol) and the resulting mixture stirred at r.t. for 3 h. The reaction mixture was quenched with H2O and extracted with DCM. The combined organic phases were dried (MgSO4) and concentrated in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% NH4OH in water on a gradient acetonitrile 40-70%) affording 863 (7 mg, 13%). LCMS (method I): RT 4.19 min, [M+H]+ 545.3. 1H NMR (CDCl3, 400 MHz): δ 8.06-8.05 (1 H, m), 7.88-7.81 (1 H, m), 7.39-7.31 (2 H, m), 4.75-4.63 (2 H, m), 4.14-4.02 (5 H, m), 3.93-3.91 (5 H, m), 3.51-3.40 (2 H, m), 3.31-3.40 (1 H, m), 2.84-2.82 (2 H, m), 2.08-1.96 (2 H, m), 1.89-1.62 (4 H, m), 1.49 (3 H, t, J=7.43 Hz), 1.20-1.12 (6 H, m)