Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[K+].[CH3:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9].[CH2:10](Br)[C:11]#[CH:12]>C1COCC1.C1(C)C=CC=CC=1>[CH3:3][N:4]1[CH2:8][CH2:7][N:6]([CH2:12][C:11]#[CH:10])[C:5]1=[O:9]
Reactant: CN1CCNC1=O
Reactant: C#CCBr
Agent: [H-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C#CCN1CCN(C)C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of potassium hydride (10.44 g of a 35% by wt suspension in mineral oil, washed with ether to remove oil, 0.09 mol) in dry THF (50 mL) was added dropwise, with cooling, to a stirred solution of 1-methyl-2-imidazolidinone (7.6 g, 0.076 mol) in dry THF (150 mL). After warming to room temperature and stirring for 20 min, the reaction was cooled again and propargyl bromide (13.54 g of an 80% solution in toluene, 0.09 mol) was added dropwise. The reaction was then allowed to slowly warm to room temperature and was stirred for 0.5 hr. The reaction was quenched with methanol and water and the solvents were removed under reduced pressure. The residual oil was partitioned between ethyl acetate and water; evaporation of the organic phase gave 10.65 g crude product. The compound was purified by chromatography on silica gel in chloroform to get 4.51 g of crystalline product.
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([O:10]CC)=O.[NH2:22][C@H:23]([C:25]([OH:27])=[O:26])[CH3:24].[O-]CC.[Na+].Cl>CN(C=O)C.O>[OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([NH:22][C@H:23]([CH3:24])[C:25]([OH:27])=[O:26])=[O:10]
Reactant: CCOC(=O)c1ncc2c(-c3ccccc3)noc2c1O
Reactant: C[C@H](N)C(=O)O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](NC(=O)c1ncc2c(-c3ccccc3)noc2c1O)C(=O)O
Temperature: 25 °C
Yield: 48 %

Procedure:
Ethyl 7-hydroxy-3-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (0.1 g, 0.35 mmol) was dissolved in 10 mL of DMF. L-Alanine (0.627 g, 7.04 mmol) and sodium ethoxide (0.36 g, 5.28 mmol) were added and the mixture was refluxed for 3 h. The mixture was cooled to room temperature and diluted with 70 mL of water. Concentrated hydrochloric acid was added dropwise until pH was 2. The resulting suspension was filtered and the solid was dried under vacuum to give 55 mg of the title compound. MS: (+) m/z 328.00 (M+1).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[OH:15])=[O:6].[I:17]N1C(=O)CCC1=O.CO>C(Cl)(Cl)Cl>[I:17][C:4]1[C:5](=[O:6])[C:7]2[C:8](=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[O:15][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc(C(=O)C=CN(C)C)c(O)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2c(=O)c(I)coc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(dimethylamino)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (20.0 g, 90.37 mmol) in anhydrous chloroform (100 ml) at 0° C. was added N-iodosuccinimide (23.5 g, 99.22 mmol) and silica gel (40 g). The reaction mixture was stirred at 0° C. for 60 minutes, then the insoluble material filtered off. The filtrate was washed with aqueous sodium thiosulfate (0.5M, 2×50 ml), followed by brine (100 ml), then dried over sodium sulfate. The solvent was removed under reduced pressure, providing an orange solid. To this solid was added methanol (30 ml), and the mixture was sonicated, filtered, the solid washed with methanol (2×5 ml), and the solid dried under reduced pressure, to give 3-iodo-7-methoxychromen-4-one as a pale yellow solid.
Reaction SMILES: Br.[NH2:2][C:3]1[N:4]=[C:5]([Br:8])[S:6][CH:7]=1.N1C=CC=CC=1.[C:15]([O-])(=[O:17])[CH3:16].[Na+]>C(OC(=O)C)(=O)C>[C:15]([NH:2][C:3]1[N:4]=[C:5]([Br:8])[S:6][CH:7]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)[O-]
Reactant: Nc1csc(Br)n1
Agent: Br
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1csc(Br)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
4-Amino-2-bromothiazole hydrobromide (52 g, 0.2 m) was suspended in acetic anhydride (200 ml.) then treated dropwise with pyridine (100 ml.), maintaining the temperature at 0° C. by means of an ice bath. After the addition was complete, the reaction mixture was stirred for 2 hours at room temperature then poured onto 20% aqueous sodium acetate (2 1.) The solution was cooled, filtered and the precipitate washed with water (2 × 200 ml.). The product was air dried and recrystallised from acetone to give 4-acetamido-2-bromo-thiazole (35 g, 80%). m.p. 165° C.
Reaction SMILES: [C:1]([C:4]1[C:9]2[CH2:10][C:11](=O)[C:12]3[CH:18]=[CH:17][CH:16]=[C:15](F)[C:13]=3[S:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)([OH:3])=[O:2].[OH2:21].NN>C(O)C.O1CCOCC1>[C:1]([C:4]1[C:9]2[CH2:10][CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:21])[C:13]=3[S:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O
Reactant: O=C(O)c1cccc2c1CC(=O)c1cccc(F)c1S2
Agent: NN
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(O)c1cccc2c1CCc1cccc(O)c1S2
Reaction time: 2 h
Yield: 12.7 %

Procedure:
5.0 g of 9-carboxy-4-fluoro-10,11-dihydrodibenzo[b,f]thiepin-11-one and 5.0 g of 100% hydrazine hydrate were dissolved in the mixed solvent of 50 ml of ethanol and 50 ml of dioxane. The resulting mixture was heated under reflux for 5 hours. The solvent was evaporated under reduced pressure to obtain the residue, which was washed with ethanol. To this was added 5.0 g of sodium hydroxide in 100 ml of diethylene glycol and the resulting mixture was heated with stirring at 180°-200° C. for 2 hours. After cooling, water was added to the mixture, which was extracted with benzene. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain a glutinous residue which was chromatographed over silica gel, and eluted with benzene-ethyl acetate (1:1). Recrystallization of the thus obtained crude product from methanol-water afforded 600 mg of 9-carboxy-4-hydroxy-10,11-dihydrodibenzo-[b,f] thiepin having a melting point of 171°-173° C.
Reaction SMILES: N=[C:2]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[N:5]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:4](=[S:17])[N:3]1[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=1.C[OH:31].O>Cl>[O:31]=[C:2]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[N:5]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:4](=[S:17])[N:3]1[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=1
Reactant: CO
Reactant: Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=N)C23CCC3)cc1
Agent: Cl
Solvent: O
Product: Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: 25 °C

Procedure:
A mixture of 7b (0.041 g, 0.1 mmol) in HCl aq., 2N (3 ml) and methanol (1 ml) was heated to reflux for 2 h. After being cooled to room temperature, the reaction mixture was poured into cold water (5 ml) and extracted with ethyl acetate (6 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane) to yield 4-(8-oxo-6-thioxo-5-(4-methylphenyl)-5,7-diazaspiro[3.4]oct-7-yl)-2-trifluoromethylbenzonitrile, 4-(8-oxo-6-thioxo-5-(4-methylphenyl)-5,7-diazaspiro[3.4]oct-7-yl)-2-trifluoromethylbenzonitrile, 7c (0.04 g, 0.096 mmol, 96%) as a white powder.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[C:8]([Br:13])[CH:9]=[CH:10][C:11]=1[F:12]>OS(O)(=O)=O>[Br:13][C:8]1[CH:7]=[C:6]([F:5])[C:11]([F:12])=[CH:10][C:9]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Fc1ccc(Br)cc1F
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(F)c(F)cc1Br
Temperature: 0 °C

Procedure:
Dissolve fuming nitric acid (24 mL) in concentrated H2SO4 in a round bottom flask. Add 3,4-difluorobromobenzene (20 g, 104 mmol) dropwise via pipette with vigorous stirring. After addition, stir the reaction at room temperature for 2 hours, pour the reaction into ice water and extract with Et2O (2×250 mL). Collect and combine the organic layers, dry over MgSO4, filter, and remove the solvent to give 1-bromo-4,5-difluoro-2-nitrobenzene as a light yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>N1C=CC=CC=1>[NH:11]([C:2]1[C:7]([I:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1)[NH2:12]
Reactant: NN
Reactant: Cc1ccnc(Cl)c1I
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccnc(NN)c1I
Reaction time: 24 h
Yield: 86.9 %

Procedure:
A mixture of 2-chloro-3-iodo-4-methylpyridine (preparation 28a, 2.0 g, 7.9 mmol) and hydrazine hydrate (1.2 mL, 24.2 mmol) in pyridine (12 mL) under an argon atmosphere was stirred and heated to reflux. After 24 hours, the mixture was cooled and evaporated to dryness. The crude mixture was triturated with water and the solid was filtered and washed with water to give the title compound (1.71 g, 87%) which was used without further purification in the next reaction.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[N:11][C:12]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=4[CH3:30])[CH2:19][CH2:18]3)=[O:16])=[CH:13][CH:14]=2)[C:5]1=[O:31])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[CH3:30][C:24]1[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=1[N:20]1[CH2:19][CH2:18][N:17]([C:15]([C:12]2[N:11]=[CH:10][C:9]([N:6]3[CH2:7][CH2:8][NH:4][C:5]3=[O:31])=[CH:14][CH:13]=2)=[O:16])[CH2:22][CH2:21]1
Reactant: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ccc(C)cc4C)CC3)nc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCNC4=O)cn3)CC2)c(C)c1
Yield: 36.5 %

Procedure:
To a mixture of 1-acetyl-3-{6-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]pyridin-3-yl}imidazolidin-2-one (70 mg) described in Example 388 and potassium carbonate (35 mg) was added methanol (5 mL), and the mixture was stirred with heating under reflux for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (23 mg).
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH2:20][NH:21][C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=S)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]>C1COCC1.CCOC(C)=O.C(O[Hg]OC(=O)C)(=O)C>[CH:24]1([C:22]2[N:19]3[C:14]4[CH:13]=[CH:12][N:11]([S:1]([C:4]5[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=5)(=[O:3])=[O:2])[C:15]=4[N:16]=[CH:17][C:18]3=[CH:20][N:21]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=S)C4CCCCC4)cnc32)cc1
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc(C4CCCCC4)n23)cc1
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a solution of N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)cyclohexanecarboxamide (0.081 g, 0.196 mmol) in THF (1 mL) at ambient temperature was added 2,4-bis(4-phenoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (0.104 g, 0.196 mmol, TCI). After about 15 h, the reaction mixture was concentrated under reduced pressure. The residue was suspended in EtOAc/DCM (1:1) and filtered through a plug of silica gel (5 g) eluting with EtOAc/DCM (1:1, approximately 100 mL). Concentration of the filtrate provided the crude N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)cyclohexanecarbothioamide. The crude thioamide was dissolved in THF (1 mL) and diacetoxymercury (0.0626 g, 0.196 mmol) was added. After about 30 min at ambient temperature, additional diacetoxymercury (0.0626 g, 0.196 mmol) was added. After about 4 h, the reaction mixture was diluted with EtOAc, filtered, concentrated under reduced pressure, and purified by silica gel chromatography eluting with a gradient of 50-95% EtOAc in heptane to provide 1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine as a yellow oil (0.020 g, 25%): LC/MS (Table 2, Method a) Rt=2.77 min; MS m/z: 395 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[C:33]([O:37][C:38]([NH:40][C@@H:41]1[CH2:46][CH2:45][C@H:44]([NH2:47])[CH2:43][CH2:42]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:33]([O:37][C:38]([NH:40][C@H:41]1[CH2:42][CH2:43][C@@H:44]([NH:47][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]=[CH:7]3)[CH2:45][CH2:46]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: Brc1cccc2cnccc12
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Nc2cccc3cnccc23)CC1
Temperature: 70 °C
Yield: 77.1 %

Procedure:
Under nitrogen atmosphere, a suspension of 5-bromoisoquinoline (253 mg), tris(dibenzylideneacetone)palladium(0) (58 mg), 2-(di-tert-butylphosphino)biphenyl (74 mg), Intermediate 38 (311 mg) and sodium tert-butoxide (165 mg) in toluene was stirred with heating at 70° C. for 3 hours. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (320 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8](S)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:13]>>[Cl:13][C:8]1[O:9][C:10]2[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Sc1nc2cccc(Cl)c2o1
Product: Clc1nc2cccc(Cl)c2o1

Procedure:
A mixture of 7-chloro-2-mercaptobenzoxazole (14.8 g.) and phosphorus pentachloride (29.2 g.) was heated at 160°-170° under reflux for 3 hours. The flask was fitted with a distilling head and the product was distilled in vacuo. The first two fractions were unreacted phosphorus chloride. Afterwards, the product distilled to give 2,7-dichlorobenzoxazole. This compound was reacted with hydrazine using the method described in procedure (a) of Example 1 and then reacted with acrylonitrile using procedure (c) of Example 1 to give 3-[1-(7-chloro-2-benzoxazolyl)hydrazino]propanenitrile, m.p. 114°-115° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C:12]([CH3:19])([CH2:17][NH2:18])[CH2:13][N:14]([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>CS(C)=O>[CH3:15][N:14]([CH3:16])[CH2:13][C:12]([CH3:19])([CH3:11])[CH2:17][NH:18][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CN(C)CC(C)(C)CN
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CN(C)CC(C)(C)CNc1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 101.1 %

Procedure:
To a solution of 1-fluoro-2-nitrobenzene (353 mg, 2.5 mmol) in DMSO (5 mL) is added 2,2,N*1*,N*1*-Tetramethyl-propane-1,3-diamine (391 mg, 3 mmol), followed by Hunig's base (0.65 mL, 3.8 mmol). The reaction flask is sealed and heated to 80° C. for 16 h. The reaction is cooled to room temperature, is poured over ice water and is extracted with CH2Cl2. The organic layer is washed with water, brine, is dried (Na2SO4) and concentrated to afford the title crude compound (635 mg, crude) as an orange oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].Br[CH2:18][CH:19]=[CH2:20].[In]>CO.O>[CH2:20]([C:2]1([OH:1])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH:19]=[CH2:18]
Reactant: O=C1CCCC1C(=O)OCc1ccccc1
Reactant: C=CCBr
Agent: [In]
Solvent: O
Solvent: CO
Product: C=CCC1(O)CCCC1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of benzyl 2-oxocyclopentanecarboxylate (from step A, 5 g, 22.91 mmol) in a mixture of methanol (20 ml) and water (60.00 ml) was added 3-bromoprop-1-ene (8.31 g, 68.7 mmol) and indium (1.081 ml, 68.7 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and to the residue was added 1N hydrogen chloride (15 mL) and stirred at room temperature for 5 min. The reaction mixture was partitioned between ethyl acetate (30 mL) and water (4 mL). The ethyl acetate layer is washed with brine (4 mL), dried over anhydrous Na2SO4 and concentrated under the reduced pressure. The residue was subjected to preparative HPLC (Shimadzu VP-ODS 20×100 mm, 8 min. gradient, Solvent A: 10% MeOH, 90% H2O, 0.1% TFA; Solvent B: 90% MeOH, 10% H2O, 0.1% TFA; wavelength: 220 nM). The desired fractions were collected, concentrated under reduced pressure to yield the desired product as a diastereomer mixture. The diastereomer mixture was subjected to chiral preparative HPLC to yield four individual isomers. The fractions corresponding to the second isomer was concentrated and freeze dried to yield a solid (800 mg, 3.08 mmol, 13.4% yield). Chiral HPLC method: Column. ChiralPak AD-H, 250×3 cm, 5 μm; Flow rate: 130 mL/min; Mobile Phase: CO2/MeOH=70/30; Inj. Vol.=0.7 mL, Wavelength=220 nM,: Retention time=3.18 min. MS (ESI+)=283 (M+Na)+
Reaction SMILES: [Br:1][C:2]1[C:3]([F:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CCN(C(C)C)C(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:9])=[C:4]([N:5]([S:20]([CH3:19])(=[O:22])=[O:21])[S:20]([CH3:19])(=[O:22])=[O:21])[CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(Br)c1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N(c1cccc(Br)c1F)S(C)(=O)=O
Reaction time: 2 h

Procedure:
A solution of 3-bromo-2-fluoroaniline (Intermediate 34-1, 160 mg, 0.842 mmol) and DIEA (0.368 mL, 2.105 mmol) in DCM (3 mL) was stirred at ca. −5° C. and treated with methanesulfonyl chloride (0.098 mL, 1.263 mmol) and stirred at that temperature for 2 h. The mixture was partitioned between DCM and NaHCO3 (aq). The organic phase was washed with brine, dried and concentrated to provide N-(3-bromo-2-fluorophenyl)-N-(methylsulfonyl)methanesulfonamide as a yellow solid (308 mg, quantitative), used without further purification. 1H NMR (400 MHz, chloroform-d) δ 7.70 (1H, ddd, J=8.1, 6.4, 1.5 Hz), 7.33 (1H, ddd, J=8.1, 6.5, 1.6 Hz), 7.15 (1H, td, J=8.1, 1.4 Hz), 3.46 (6H, s). Mass spectrum m/z 363, 365 (M+NH4)+.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])[CH2:3][CH2:4][OH:5].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:31]1[CH:36]=[CH:35][CH2:34][CH2:33][CH2:32]1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][N:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])[CH2:3][CH2:4][O:5][CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][O:31]1
Reactant: CN(CCO)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(CCOC1CCCCO1)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A mixture of 4-[N-methyl--N-(2-hydroxyethyl)-amino]-3-nitrobenzotrifluoride (29.0 g, 110 mmol), p-toluenesulfonic acid monohydrate (2.09 g, 11.0 mmol), 3,4-dihydro-2H-pyran (18.5 g, 220 mmol) and tetrahydrofuran (600 ml) was stirred at room temperature for 4.5 hours. Sodium hydrogencarbonate (10 g) was added to the reaction mixture and the resulting mixture was stirred at room temperature for 30 minutes, after which the insoluble materials were filtered off. The filtrate was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane= 5/95) to obtain an oil of 4-[N-methyl-N-[2-(2-tetrahydro-2H-pyranyl) oxyethyl]amino]-3-nitrobenzotrifluoride.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:3]1.[ClH:24]>O1CCCC1.O1CCOCC1>[ClH:24].[O:1]=[C:2]1[CH2:6][NH:5][C@H:4]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C1CN[C@H](C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of (S)-2-benzyl 1-tert-butyl 4-oxopyrrolidine-1,2-dicarboxylate (2.82 g, 8.8 mmol) in anhydrous tetrahydrofuran (44 mL) was added 4N HCl in 1,4-dioxane (9.3 mL) at room temperature. The mixture was stirred for 18 hours at room temperature. The product was then three times with toluene on rotovap to dryness to remove all the excess acid and further dried on a high vacuum overnight and used as is in the next step. Quantitative yield.
Reaction SMILES: [OH:1][CH:2]([C:4](=[CH2:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:3].N1C=CC=CC=1.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[C:17]([O:1][CH:2]([C:4](=[CH2:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:3])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: C=C(C(=O)OCC)C(C)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C(C(=O)OCC)C(C)OC(C)=O
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(1-hydroxyethyl)acrylate (40 g) and pyridine (26.9 ml) in dichloromethane (277 ml) was added dropwise acetyl chloride (23.7 ml) at 0° C. The reaction mixture was stirred for 1 hour and quenched with water (200 ml). The aqueous layer was separated and extracted twice with dichloromethane. The combined organic layers were washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate water and an aqueous sodium chloride in turn, and then, dried over magnesium sulfate. After the resultant solution was evaporated, the residue was distilled in vacuo to give ethyl 2-(1-acetoxyethyl)acrylate (41.44 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1.C(N(CC)CC)C>C(O)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:5]1[N:6]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[C:7]2[C:3]([N:4]=1)=[C:2]([NH:25][CH:26]1[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]1)[N:10]=[CH:9][N:8]=2
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 80 °C
Yield: 93.4 %

Procedure:
To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purine (151 mg, 0.403 mmol, 1 eq.) in 4 mL of ethanol was added tert-butyl 4-aminopiperidine-1-carboxylate (96 mg, 0.483 mmol, 1.2 eq.) and triethylamine (0.08 mL, 0.6 mmol, 1.5 eq.). The reaction was heated to 80° C. for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 203 mg (94%) of tert-butyl 4-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}piperidine-1-carboxylate. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.38-1.55 (m, 11 H) 2.14 (d, J=12.34 Hz, 2 H) 2.98 (t, J=12.10 Hz, 2 H) 4.00-4.21 (m, 2 H) 4.28-4.52 (m, 1 H) 5.83 (d, J=7.63 Hz, 1 H) 7.17-7.27 (m, 2 H) 7.31-7.44 (m, 5 H) 7.50 (d, J=6.88 Hz, 1 H) 8.44 (s, 1 H), [M+H]+ 539.4.