Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21]3[C:12](=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=[N:14]4)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:28](Br)[CH:29]=[CH2:30]>COCCOC.C1(C)C=CC=CC=1>[CH2:30]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:21]3[C:12](=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=[N:14]4)[N:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH:29]=[CH2:28]
Reactant: Oc1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Reactant: C=CCBr
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: C=CCOc1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Temperature: 35 °C
Reaction time: 24 h

Procedure:
4-p-hydroxyphenyl-7-phenyl-1,10-phenanthroline (0. 348 g) is reacted with Na metal (0.023 g) in ethylene glycol dimethyl ether (100 mL). To this mixture is added a solution of allylbromide (0.125 g) in ethylene glycol dimethyl ether (10 mL). The resulting mixture is stirred at 35° C. for 24 hours, or until the reaction is judged complete by TLC. The reaction mixture is diluted with toluene, washed with 10% NaOH, washed with water and dried over MgSO4. Roto-evaporation of the solvent gives a residue that is purified by column chromatography on silica gel.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH2:12])[CH2:4][CH2:3]1.C([NH:15][C:16](=O)[O-:17])C>C(O)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:16]([NH2:15])=[O:17])[CH2:4][CH2:3]1
Reactant: CCNC(=O)[O-]
Reactant: NC1CCC(=O)c2ccccc21
Solvent: CCO
Product: NC(=O)NC1CCC(=O)c2ccccc21

Procedure:
Equimolar quantities of 1,2,3,4-tetrahydro-4-oxo-1-naphthylamine and ethylcarbamate are mixed and heated until ethanol is no longer released. The crude product, 1,2,3,4-tetrahydro-4-oxo-1-naphthylurea is washed with water then with cold ethanol and dried.
Reaction SMILES: [C:1]([O:20][CH:21]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:22][C:23]([OH:25])=O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:43][C@H:44]([C:48]([OH:50])=[O:49])[CH:45]([CH3:47])[CH3:46].[OH-].[Na+].Cl>CN(C)C=O>[C:1]([O:20][CH:21]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:22][C:23]([NH:43][C@H:44]([C:48]([OH:50])=[O:49])[CH:45]([CH3:47])[CH3:46])=[O:25])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CCCCCCCCC=CCCCCCCCC(=O)OC(CCCCCCCC=CCCCCCCCC)CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCCCCCCC=CCCCCCCCC(=O)OC(CCCCCCCC=CCCCCCCCC)CC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
To a solution of N-hydroxysuccinimide ester of 3-(9-octadecenoyloxy)-11-eicosenoic acid (3 g) in N,N-dimethylformamide (30 ml) was added a solution of L-valine (4.42 g) and a 1N sodium hydroxide solution (37 ml) at 0° C. The resulting mixture was stirred at ambient temperature overnight. The reaction mixture was acidified with 1N hydrochloric acid solution, extracted with ethyl acetate, washed with water and dried over magnesium sulfate. Ethyl acetate was distilled off to give powder of N-[3-(9-octadecenoyloxy)-11-eicosenoyl]-L-valine (2.7 g).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[C:5]2[CH2:9][O:10][CH2:11][CH:12]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[C:4]=2O1.[OH-].[NH4+:22]>>[O:1]=[C:2]1[NH:22][C:4]2[CH:12]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[CH2:11][O:10][CH2:9][C:5]=2[C:6](=[O:8])[NH:7]1
Reactant: [NH4+]
Reactant: N#Cc1ccc(C2COCc3c2oc(=O)[nH]c3=O)cc1
Agent: [OH-]
Product: N#Cc1ccc(C2COCc3c2[nH]c(=O)[nH]c3=O)cc1

Procedure:
4-(2,4-dioxo-2,3,4,5,7,8-hexahydropyrano[3,4-e][1,3]oxazin-8-yl)benzonitrile (Intermediate AA(3)) was reacted as described in Intermediate X(4) with ammonium hydroxide to give 4-(2,4-dioxo-2,3,4,5,7,8-hexahydro-1H-pyrano[4,3-d]pyrimidin-8-yl)benzonitrile (Intermediate AA(4)). LC-MS (M−H)+=270.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@@H:11]1/[CH:16]=[CH:17]/[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=1)[OH:19].[C:28]1([CH3:37])[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@@H:11]1/[CH:16]=[CH:17]/[CH:18]([OH:19])[C:20]1[CH:21]=[C:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH3:37])[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)CCCCCCN1C(=O)CC[C@@H]1/C=C/C(O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)CCCCCCN1C(=O)CC[C@@H]1/C=C/C(O)c1cccc(-c2ccccc2C)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42.1 %

Procedure:
To a solution of 7-{(R)-2-[(E)-3-(3-bromo-phenyl)-3-hydroxy-propenyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid methyl ester, (0.2 g, 0.46 mmol) in 10 mL of DME stirred at room temperature was added Pd(Ph3P)4 (0.03 g, 0.05 eq). After stirring for 5 minutes, o-tolylboronic acid (0.12 g, 2 eq) an 2M Na2CO3 (0.6 mL, 2.5eq) were added and the mixture was refluxed overnight under N2 atmosphere. The reaction mixture was cooled to room temperature, diluted with 25% NH4Oac (10 mL), stirred for 5 minutes and then was extracted with ethyl acetate, the organic layer was dried over MgSO4 (anhydrous), concentrated under the reduced pressure and purified to yield 87 mg of 7-{(R)-2-[(E)-3-hydroxy-3-(2′-methyl-biphenyl-3-yl)-propenyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid methyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22](I)[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(SC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 95.2 %

Procedure:
A mixture of 1-tert-Butoxycarbonyl-4-[(4-hydroxyphenyl)sulfanyl]piperidine (3.09 g, 10.0 mmol), ethyl iodide (1.04 mL, 13.0 mmol), and potassium carbonate (1.80 g, 13.0 mmol) in DMF (15 mL) was stirred at 60° C. for 20 hours. The reaction mixture was evaporated under reduced pressure. The residue was diluted with ethyl acetate (40 mL), washed with water (10 mL), 0.5 N sodium hydroxide solution (10 mL×3), brine (10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using ethyl acetate/hexane (1/19 to 1/9) as eluent to afford the title compound (3.21 g, 9.52 mmol, 95%) as a colorless oil.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[CH2:10]([NH2:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>CC(C)=O>[Cl:6][C:5]1[N:7]=[C:8]([Cl:9])[N:1]=[C:2]([N:22]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:2]2[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=2)[N:4]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCCCCCCCCCCCN
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCCCCN(c1nc(Cl)nc(Cl)n1)c1nc(Cl)nc(Cl)n1
Reaction time: 4 h

Procedure:
To a solution of cyanuric chloride (38.0 g) in acetone (350 ml) was added dropwise a suspension of dodecylamine (18.5 g) in acetone (40 ml) at 10° C. After addition, the mixture was stirred for 4 hours at that temperature. The reaction mixture was poured into water (2 l) and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and ethyl acetate was distilled off. The resulting oil was purified with silica gel column chromatography (eluent=benzene:n-hexane=4:1) to afford N,N-bis-(2,4-dichloro-1,3,5-triazine-6-yl)-n-dodecylamine as white crystals melting at 50°-53° C.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N+:14]([O-])=O)=[CH:7][C:5]=2[N:6]=1>CC(O)=O.CCOC(C)=O.[Fe]>[CH:7]1[C:8]([NH2:14])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=[C:4]2[N:3]=[C:2]([Cl:1])[NH:6][C:5]=12
Reactant: O=[N+]([O-])c1cc2nc(Cl)[nH]c2cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1cc2[nH]c(Cl)nc2cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
15 A mixture of 1.213 g (5.0 mmol) of 2-chloro-5,6-dinitrobenzimidazole (22) and 1.398 g (25 mmol) of iron powder in 50 mL of AcOH was stirred at room temperature for 4 h. The reaction mixture was diluted with 100 mL of EtOAc, filtered, and the solid was washed with portions of EtOAc (total EtOAc used ~ 100 mL). The filtrate and washings were combined and washed with H2O (100 mL×3). The H2O layer was extracted with 100 mL of EtOAc. The EtOAc solutions were combined, evaporated, coevaporated with toluene (10 mL×3), MeOH (10 mL×2) to give a brown solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])=[CH:5][CH:4]=1.[NH:20]([C:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([N+:34]([O-:36])=[O:35])[CH:25]=1)=[O:23])[NH2:21].O.S(C1C=CC(C)=CC=1)(O)(=O)=O>>[N+:34]([C:26]1[CH:25]=[C:24]([C:22]([NH:20][N:21]=[C:15]([C:12]2[C:13]([OH:14])=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][CH:5]=3)[S:10][CH:11]=2)[CH3:17])=[O:23])[CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29])([O-:36])=[O:35]
Reactant: CC(=O)c1csc(-c2ccc(C(F)(F)F)cc2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2csc(-c3ccc(C(F)(F)F)cc3)c2O)cc1[N+](=O)[O-]
Yield: 80.5 %

Procedure:
From 2-(4-trifluoromethylphenyl)-3-hydroxy-4-methylcarbonylthiophene (57.3 mg, 0.2 mmol), methyl 4-hydrazinocarbonyl-2-nitrobenzoate (47.8 mg, 0.2 mmol) and tosylic acid monohydrate (11.4 mg, 0.06 mmol), 81.7 mg of the desired product was obtained in the same manner as in Synthetic Example 65 as a pale yellow solid (yield 81%).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:43])[C@H:7]([CH3:42])[CH2:8][C@H:9]([OH:41])[C@@H:10]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:11][C@@H:12]([CH:30]([CH3:32])[CH3:31])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22]CC2C=CC=CC=2)[CH:15]=1)[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[CH2:1]([NH:5][C:6](=[O:43])[C@H:7]([CH3:42])[CH2:8][C@H:9]([OH:41])[C@@H:10]([NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:11][C@@H:12]([CH:30]([CH3:31])[CH3:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([OH:22])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(OC)c(OCc2ccccc2)c1)C(C)C)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(OC)c(O)c1)C(C)C)NC(=O)OC(C)(C)C

Procedure:
4.7 g of N-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-benzyloxy-4-methoxy-phenyl)-octanoic acid (N-butyl)amide are hydrogenated in 60 ml of methanol in the presence of 2.35 g of 10% Pd/C at room temperature and under normal pressure for 1 hour. Filtration of the reaction mixture and concentration of the filtrate by evaporation under a high vacuum yield the title compound: Rf (hexane/ethyl acetate =1:1)=0.15; FAB-MS (M+H)+ =509.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]O>>[CH3:12][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([I:11])[CH:9]=[CH:10][C:2]=1[Cl:1]
Reactant: CO
Reactant: O=C(O)c1cc(I)ccc1Cl
Product: COC(=O)c1cc(I)ccc1Cl

Procedure:
A solution of 2-chloro-5-iodo-benzoic acid (25.63 g, 90 mmol) in methanol (500 mL) saturated with HCL gas was stirred at room temperature for 48 h. The reaction mixture was concentrated in vacuo, diluted with 1:1 ethyl acetate/Diethyl ether and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (25.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].[C:36]([O:42][CH:43](Cl)[CH3:44])(=[O:41])[CH2:37][CH2:38][CH2:39][CH3:40]>CN(C=O)C.CCOC(C)=O>[C:36]([O:42][CH:43]([N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1)[CH3:44])(=[O:41])[CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: CCCCC(=O)OC(C)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC(=O)OC(C)n1cc(C(=O)c2c(F)ccc(NS(=O)(=O)CCC)c2F)c2cc(-c3ccc(Cl)cc3)cnc21
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
To a suspension of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.3 g, 0.61 mmol) in anhydrous DMF (2.5 mL) was added KOH (69 mg, 1.23 mmol). The reaction was stirred at 10° C. for 30 min, followed by adding a solution of 1-chloroethyl pentanoate (0.1 g, 0.61 mmol) in anhydrous DMF (0.5 mL) dropwise over 30 min. The mixture was stirred at 10° C. for another 16 h, then diluted with EtOAc (40 mL) and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=7/1) to give the crude product. The crude product was recrystallized in PE/EtOAc (10/1) to give the title compound as a white solid (0.14 g, 37.8%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [CH3:1][C:2]#[N:3].[Li]CCCC.[F:9][C:10]([F:19])([F:18])[C:11]([CH3:17])([CH3:16])[C:12](OC)=[O:13]>C1COCC1>[F:9][C:10]([F:19])([F:18])[C:11]([CH3:17])([CH3:16])[C:12](=[O:13])[CH2:1][C:2]#[N:3]
Reactant: CC#N
Reactant: COC(=O)C(C)(C)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C(=O)CC#N)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
To a mixture of MeCN (13.9 mL, 264 mmol) in THF (500 mL) cooled to −78° C. was added n-BuLi (106 mL, 264 mmol). The mixture was stirred at −30° C. for 0.5 h. Then to the mixture was added methyl 3,3,3-trifluoro-2,2-dimethylpropanoate (30 g, 176 mmol) dropwise. The mixture was stirred at 25° C. for 10 h. The mixture was quenched with aqueous NH4Cl (50 mL), extracted with EA (300 mL×3). The organic layer was dried over Na2SO4, filtered and concentrated to yield a crude product of a yellow oil of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (22 g, 122.9 mmol, 70% yield): 1H NMR (400 MHz, CDCl3) δ 3.75 (s, 2H), 1.41 (s, 6H).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:36]([O-])=O)=[C:4]([NH:8][C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH2:19][N:20]4[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]4)[N:15]3[CH3:18])=[C:11]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1>[Pd]>[NH2:36][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[C:14]([CH2:19][N:20]3[CH2:21][CH2:22][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:24][CH2:25]3)[N:15]2[CH3:18])=[C:11]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:10]=1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Nc3cccc(F)c3[N+](=O)[O-])nc21
Agent: [Pd]
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Nc3cccc(F)c3N)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.4 %

Procedure:
To a mixture of 2-{1-[2-(3-fluoro-2-nitrophenylamino)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]piperidin-4-yl}propan-2-ol (95 mg, 0.18 mmol) in IMS (5 mL) was added 10% Pd on charcoal (20 mg) under an argon atmosphere. The vessel was evacuated and backfilled with hydrogen (the process was repeated three times). The reaction mixture was stirred at room temperature for 18 hours then filtered through celite. The filtrate was concentrated under reduced pressure and the residue was subjected to flash chromatography (Si—PCC, 0-10% MeOH in EtOAc) to give 2-{1-[2-(2-Amino-3-fluoro-phenylamino)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]piperidin-4-yl}propan-2-ol as a red oil (65 mg, 72%). LCMS (Method H): RT=0.28 min and 2.82 min, [M+H]− 499
Reaction SMILES: C1(SC[Cl:9])C=CC=CC=1.C1(S[CH2:17][N:18]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[S:19]2(=[O:21])=[O:20])C=CC=CC=1.S(Cl)(Cl)(=O)=O>C1(C)C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[Br-]>[Cl:9][CH2:17][N:18]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[S:19]1(=[O:21])=[O:20]
Reactant: ClCSc1ccccc1
Reactant: O=C1c2c(-c3ccccc3)cccc2S(=O)(=O)N1CSc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O=S(=O)(Cl)Cl
Product: O=C1c2c(-c3ccccc3)cccc2S(=O)(=O)N1CCl
Yield: 93 %

Procedure:
Following a procedure similar to that described in Preparation 1, the latter (0.33 g, 0.0012 mol) was reacted with 0.3 g (0.0019 mol) of chloromethyl phenyl sulfide in 15 ml of toluene in the presence of 0.08 g (0.0025 mol) of TBAB and the product, 2-phenylthiomethyl-4-phenylsaccharin (0.48 g, 100%), treated with sulfuryl chloride in MDC to give 0.36 g (95%) of 2-chloromethyl-4-phenylsaccharin.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[K+].[K+].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[N+:40]([CH2:42][C:43]([O:45][CH3:46])=[O:44])#[C-:41]>CN(C)C=O>[CH3:46][O:45][C:43]([C:42]1[N:40]=[CH:41][O:16][C:14]=1[CH:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:13][CH2:12]1)=[O:44]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1ncoc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
To an ice-cold mixture of 1-Boc-4-piperidinecarboxylic acid (9.65 g, 42.1 mmol) and K2CO3 (23.3 g, 168.4 mmol) in N,N-dimethylformamide (60 mL) were added diphenylphosphoryl azide (16.1 g, 58.5 mmol) and methyl isocyanoacetate (5.0 g, 50.5 mmol). After being stirred at room temperature for 16 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, saturated NaHCO3 solution, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate 80:20 to 20:80) to give the title compound (9.07 g, 69%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.[N+:19]([O-])([O-:21])=[O:20].[Na+]>>[NH2:1][C:2]1[C:11]([N+:19]([O-:21])=[O:20])=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Reactant: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc2oc(=O)[nH]c2cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 2.0 g (13.3 mmol) of 6-amino-3H-benzoxazol-2-one [J. Chem. Soc., 321 (1938)] in 20 ml of trifluoroacetic acid 1.2 g (14.1 mmol) of sodium nitrate is added below 20° C. The reaction mixture is stirred at room temperature overnight, then concentrated. The residue is purified by column chromatography using Kieselgel 60 as adsorbent (Merck) and toluene:methanol=4:1 as eluent to yield. 2.50 g (96%) of the title compound. Mp.: 198° C. (toluene-methanol).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH:10]=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=O)[O:12]2)[CH:5]=1)([O-])=O.O.[NH2:22][NH2:23].[Cl-].[NH4+]>[Fe].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:12])[NH:23][N:22]=2)[CH:5]=1
Reactant: NN
Reactant: O=C1OC(=Cc2cc([N+](=O)[O-])ccn2)c2ccccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccnc(Cc2n[nH]c(=O)c3ccccc23)c1
Temperature: 90 °C
Yield: 31 %

Procedure:
A suspension of 3-(4-nitro-pyridin-2-ylmethylene)-3H-isobenzofuran-1-one (0.67 g, 2.5 mmol) in hydrazine monohydrate (0.25 g, 5.0 mmol) was heated to 90° C. for 1 hour and then cooled to room temperature. Ethanol (5 mL) added, followed by ammonium chloride (0.16 g, 3.0 mmol) and iron powder (0.28 g, 5.0 mmol), the mixture was then heated to 90° C. for 3 hours. The reaction mixture was filtered hot through celite which was washed with ethyl acetate (20 mL). The filtered was concentrated in vacuo and then diluted with ethyl acetate (10 mL) washed with brine (10 mL), dried over magnesium, sulphate and dried in vacuo to afford the title cpd as a pale yellow powder. Single peak in LC-MS analysis, (0.20 g, 31% yield) requiring no further purification, m/z (LC-MS, ESP), RT=1.58 (M+H) 253;
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH3:15])[C:5]1[CH:14]=[CH:13][C:8]([CH2:9][CH:10]([NH2:12])[CH3:11])=[CH:7][CH:6]=1.C([O-])(=O)C.[Na+].[Br:21]Br>C(O)(=O)C>[ClH:1].[ClH:1].[Br:21][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:5]=1[N:4]([CH3:3])[CH3:15])[CH2:9][CH:10]([NH2:12])[CH3:11]
Reactant: CC(N)Cc1ccc(N(C)C)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(N)Cc1ccc(N(C)C)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2.51 g of 4-dimethylamino-α-methylphenethylamine dihydrochloride and 5.0 g of anhydrous sodium acetate in 50 ml of acetic acid is added dropwise with stirring a solution of 0.51 ml of bromine in 50 ml of acetic acid. The mixture is stirred at room temperature for 2 hours. The solvent is evaporated and the residue dissolved in 200 ml of water. The solution is alkalized with sodium hydroxide and extracted with ether. The ether extract is dried over anhydrous sodium sulphate and acidified with hydrogen chloride in ether. The precipitate is filtered off and recrystallized from ethanol-ethyl acetate. Yield: 2.3 g, m.p. 190°-191°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[Br:12][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2nccnc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: BrCc1ccc2nccnc2c1

Procedure:
A mixture of 6-methylquinoxaline (1.5 g, 10.4 mmol), N-bromosuccinimide (2.2 g, 12.5 mmol) and benzoylperoxide (0.30 g, 1.25 mmol) in benzene (35 mL) was stirred rapidly and heated to reflux for 5 h. Upon cooling, the mixture was diluted with ethyl acetate (25 mL), washed with IN sodium hydroxide solution (50 mL) and saturated sodium chloride solution (50 mL). The organic layer was dried (MgSO4) and evaporated to a crystalline solid (2.5 g, 77% desired product, 23% α,α-dibrominated product as determined by 1H NMR). The mixture was used in subsequent reactions.