Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[O:29]([C:31]#[N:32])[K]>CC#N.O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:31](=[O:29])[NH2:32])[CH2:21]3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCNC3)n2)c1
Reactant: N#CO[K]
Solvent: CC#N
Solvent: O
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCN(C(N)=O)C3)n2)c1
Reaction time: 4 h
Yield: 6.8 %

Procedure:
To a mixture of 2-(3-acetamidophenylamino)-4-(piperidin-3-ylmethylamino)pyrimidine-5-carboxamide (40 mg, 0.104 mmol) in CH3CN (2 mL), a solution of KOCN (50 mg, 0.617 mmol) in H2O (1 mL) was added. The mixture was stirred at 70 C for 4 h. It was then purified by HPLC to give the titled compound (3 mg). MS 427.4 (M+H); UV 202.2, 248.6 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([C:14](OCC)=[O:15])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:19].[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].[NH4+].[Li].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([CH2:14][OH:15])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:19]
Reactant: CCOC(=O)c1ccc2nc(C)n(Cc3ccccc3Cl)c2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1nc2ccc(CO)cc2n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
A solution of 2.66 g of 1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole in 20 ml of tetrahydrofuran was slowly added to a solution of 1.54 g of lithium aluminum hydride in 20 ml of tetrahydrofuran at a temperature of from 20 to 25° C. Further, the mixture was stirred at room temperature for 1 hour. Thirty milliliters of tetrahydrofuran were added thereto to dilute the reaction solution. Lithium ammonium hydride was decomposed and solidified with a saturated aqueous solution of sodium sulfate, and the tetrahydrofuran layer was separated. The solvent was distilled off, and the residue was purified through silica-gel column chromatography (eluent: a mixture of chloroform and methanol at a ratio of 9:1) to give 1.45 g of 1-(2-chlorobenzyl)-6-hydroxymethyl-2-methylbenzimidazole.
Reaction SMILES: [F:1][C:2]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][C:18]=1[CH3:25]>>[F:1][C:2]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[C:18]([CH3:25])[CH:19]=1)=[O:5]
Reactant: COc1ccc([Mg]Br)cc1C
Reactant: CON(C)C(=O)c1cccc(F)c1F
Product: COc1ccc(C(=O)c2cccc(F)c2F)cc1C

Procedure:
Prepared according to Method A step B from 2,3-difluoro-N-methoxy-N-methyl-benzamide (2.5 g, 12.4 mmol) and 4-methoxy-3-methyl-phenylmagnesium bromide (26 mL, 0.5 M in THF) to give 0.97 g of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O-:11])=[O:10])=[N:6][CH:7]=1.[Na+].BrBr.P(Br)(Br)[Br:16]>>[Br:16][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C([O-])Cc1ccc(F)cn1
Reactant: BrP(Br)Br
Agent: BrBr
Agent: [Na+]
Product: O=C(O)C(Br)c1ccc(F)cn1

Procedure:
Sodium 2-(5-fluoropyridin-2-yl)acetate is treated with 1-1.5 equiv of Br2 in the presence of phosphorus tribromide under standard Hell-Volhard-Zelinskii reaction conditions (J. March “Advanced Organic Chemistry” 3rd Edition, 1985, p. 531 and references therein) to afford 2-bromo-2-(5-fluoropyridin-2-yl)acetic acid.
Reaction SMILES: [CH3:1][C@@H:2]1[O:9][C:7](=[O:8])[C@H:6](C)[O:5][C:3]1=[O:4].[CH2:11]1[O:18][C:16](=[O:17])[CH2:15]O[C:12]1=O>>[CH2:2]1[O:9][C:7](=[O:8])[CH2:6][O:5][C:3]1=[O:4].[C:16]1(=[O:17])[O:18][CH2:11][CH2:12][CH2:2][CH2:1][CH2:15]1
Reactant: C[C@@H]1OC(=O)[C@H](C)OC1=O
Agent: O=C1COC(=O)CO1
Product: O=C1CCCCCO1

Procedure:
In this embodiment, LPLG-b-P(GA-co-CL) copolymer is formed by mixing the L-lactide and glycolide monomers with a solvent and catalyst to form a polymerization solution. Once LPLG is formed in the solution, glycolide monomers and caprolactone monomers are added into the solution containing the formed LPLG copolymer to form LPLG-b-P(GA-co-CL) copolymer. In one embodiment, the glycolide monomers and caprolactone monomers are added to the same solution of LPLG-formed copolymer to allow glycolide and caprolactone monomers to react with LPLG in the solution to form LPLG-b-P(GA-co-CL) copolymer. Alternatively, the glycolide monomers and caprolactone monomers are added in a solution of LPLG which includes different solvent(s).
Reaction SMILES: N#N.[CH2:3]1[CH2:7][O:6][CH2:5][CH2:4]1.[CH2:8]([Li])[CH2:9][CH2:10][CH2:11]CC.C1(O)CC1>CN1C(=O)N(C)CCC1>[CH2:5]([CH:4]1[CH2:3][CH:7]1[OH:6])[CH2:11][CH2:10][C:9]#[CH:8]
Reactant: C1CCOC1
Reactant: [Li]CCCCCC
Agent: N#N
Agent: OC1CC1
Solvent: CN1CCCN(C)C1=O
Product: C#CCCCC1CC1O
Temperature: 0 °C
Reaction time: 0.07 h
Yield: 98 %

Procedure:
To a 2-neck 15-mL round bottomed flask equipped with a temperature probe, N2 inlet, and septum was added 1 g of 4 (7.28 mmol, 1.0 equiv) and 3.0 mL THF. The solution was cooled to an internal temperature of 0° C. with an ice bath. To this solution was added 2.95 mL of 33 wt % n-Hexyllithium (7.28 mmol, 1.0 equiv) slowly via syringe pump over 1 hour. Internal temperature rose to 6.8° C. and solution became yellow. In a separate 3-neck 100-mL round bottomed flask equipped with a temperature probe, N2 inlet, and septum 0.82 g of lithium acetylide-ethylenediamine complex (8.01 mmol, 1.1 equiv) was slurried in 5.0 mL of DMPU at room temperature. To this room temperature slurry, the cold solution of the deprotonated cyclopropanol was transferred via cannula over 5 min. After the addition, the brown mixture was heated to an internal temperature of 52° C. with a heating mantle for 3 hours or until greater than 98% conversion was observed by GC. The brown mixture was cooled with an ice bath to 3° C. and then the ice bath was removed to prevent freezing. To this was slowly added 17.5 mL of 0.5 N HCl and an ice bath was applied to maintain an internal temperature below 21° C. The mixture was then diluted with 10 mL MTBE and 5 mL of water before transfer to a separatory funnel and removal of the aqueous layer. The aqueous layer was extracted once with 15 mL MTBE and then the combined organic layers were washed with 20 mL water followed by 20 mL brine. The organic layer was then concentrated in vacuo to afford 1.27 g of rac-5 as a yellow oil (72 wt %, 98% yield). 1H NMR (400 MHz, CDCl3) δ 3.24 (dt, 1H, J=2.6, 5.3 Hz), 2.25 (dt, 2H, J=2.6, 7.6 Hz), 1.96 (t, 1H, J=2.6 Hz), 1.92 (s, 1H, OH), 1.64 (pent, 2H, J=7.3 Hz), 1.38 (sext, 1H, J=6.9 Hz), 1.24 (sext, 1H, J=6.9 Hz), 0.93 (m, 1H), 0.72 (m, 1H), 0.35 (q, 1H, J=6.0 Hz); 13C NMR (100 MHz, CDCl3) δ 84.49, 68.37, 52.45, 30.50, 27.74, 20.17, 18.01, 14.25; GC: HP1 (30 m×0.32 mm; 0.25 μm), 25 psi, 200° C. front inlet. 5 min @ 50° C., ramp 25° C./min to 250° C. then hold for 4 min, tr(4)=7.15 min, tr(rac-5)=6.72 min.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([NH:16][C:17]2[N:22]=[C:21]([N:23]([CH:33]3[CH2:35][CH2:34]3)[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:20]3=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]3[N:18]=2)=[CH:11][C:10]=1[C:41]#[N:42])(=O)=O.CCN(CC)CC.[NH:50]1[CH2:53][CH:52]([OH:54])[CH2:51]1>C(#N)C.CN(C=O)C.CCOC(C)=O>[Cl:15][C:13]1[CH:14]=[C:9]([CH2:8][CH2:7][CH2:6][N:50]2[CH2:53][CH:52]([OH:54])[CH2:51]2)[C:10]([C:41]#[N:42])=[CH:11][C:12]=1[NH:16][C:17]1[N:22]=[C:21]([N:23]([CH:33]2[CH2:35][CH2:34]2)[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:20]2=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]2[N:18]=1
Reactant: OC1CNC1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)c(CCCOS(C)(=O)=O)cc3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)c(CCCN4CC(O)C4)cc3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 60 °C
Yield: 30.1 %

Procedure:
3-(5-chloro-2-cyano-4-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)propyl methanesulfonate (45 mg, 0.074 mmol) was taken up in acetonitrile (1 mL) and Et3N (0.015 mL, 0.111 mmol) and azetidin-3-ol (6.50 mg, 0.089 mmol) were added. The reaction was heated at 60° C. overnight. A mixture of product and SM detected by LCMS. An additional 1.2 eq of amine in 0.2 ml of DMF was added, and the reaction was heated at 60° C. overnight. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed 2× with water and once with brine, then dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-10% MeOH/DCM; 24 g column). 2-((2-chloro-5-cyano-4-(3-(3-hydroxyazetidin-1-yl)propyl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (13 mg) was obtained as a purple glass.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:69]([NH:72][CH2:73][CH2:74][C:75]1[O:79][N:78]=[C:77]([NH2:80])[N:76]=1)([CH3:71])[CH3:70]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:14]([C:15](=[O:17])[N:72]([CH2:73][CH2:74][C:75]2[O:79][N:78]=[C:77]([NH2:80])[N:76]=2)[CH:69]([CH3:71])[CH3:70])[CH:13]=1)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: CC(C)NCCc1nc(N)no1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(CCc1nc(N)no1)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Temperature: 25 °C
Reaction time: 240 h
Yield: 47.8 %

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.104 g), TBTU (0.128 g), and HOBt (0.061 g) in DMF (1 ml) was added DIPEA (0.139 ml) and 5-(2-isopropylamino-ethyl)-[1,2,4]oxadiazol-3-ylamine (0.05 g). The reaction mixture was stirred at room temperature for 10 days, then silica was added and the solvent removed by evaporation at reduced pressure. The resulting silica was loaded onto the top of a column of silica which was then eluted with a gradient [cyclohexane:ethyl acetate (1:1 v/v) to neat ethyl acetate to ethyl acetate:methanol (9:1 v/v)]. Concentration of the required fraction at reduced pressure furnished the title compound as a yellow glass (0.069 g).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[C:18]([CH3:24])=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2.[CH3:29][N:30]([CH3:36])[CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1>CN1CCCC1=O>[CH:26]1([CH2:25][N:3]2[C:2]([N:33]3[CH2:34][CH2:35][CH:31]([N:30]([CH3:36])[CH3:29])[CH2:32]3)=[N:10][C:9]3[C:4]2=[N:5][C:6]([C:17]2[C:18]([CH3:24])=[N:19][C:20]([NH2:23])=[N:21][CH:22]=2)=[N:7][C:8]=3[N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH2:28][CH2:27]1
Reactant: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(Cl)n(CC3CC3)c2n1
Reactant: CN(C)C1CCNC1
Solvent: CN1CCCC1=O
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(N3CCC(N(C)C)C3)n(CC3CC3)c2n1
Temperature: 120 °C
Reaction time: 3.5 h
Yield: 46 %

Procedure:
N-Methylpyrrolidone (1 ml) was added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-4-methylpyrimidin-2-amine (100 mg, 0.25 mmol) and 3-(dimethylamino)pyrolidine (285 mg, 2.49 mmol) and the resulting mixture was stirred at 120° C. for 3.5 hours. The reaction mixture was partitioned with chloroform and saturated brine and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was concentrated under reduced pressure, then methylene chloride-ether was added to the residue, and the precipitate was collected by filtration, washed with ether, and dried under reduced pressure to give the title compound (55 mg, 46%) as a pale orange solid.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(C(F)(F)F)=O.O=[Pt]=O>[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccc3ccccc3n2)cc1
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2ccc3c(n2)CCCC3)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 79.9 %

Procedure:
To a vigorously stirred solution of 2-phenylquinoline (6.0 g, 29 mmol) in TFA (30 mL) in a 250 mL round-bottomed flask under nitrogen was added PtO2 (332 mg, 1.5 mmol) in one portion. The resulting mixture was then placed under a hydrogen atmosphere (H2 flush for 5 min, then H2 balloon with a wide-bore needle) and heated to 60° C. Stirring was continued for 5 h, at which time GLC analysis indicated all of the starting material was consumed. The reaction was cooled to room temperature and the TFA was evaporated in vacuo. The residue was rendered basic with a minimum amount of 4 N NaOH and extracted with CHCl3 (3×50 mL), dried (MgSO4) and concentrated in vacuo. Purification of the residue by flash chromatography (silica gel, hexane/EtOAc 10:1) afforded 4.85 g of 2-phenyl-5,6,7,8-tetrahydroquinoline (80% yield).
Reaction SMILES: Br[CH:2]([CH2:7][C:8]([Br:11])([F:10])[F:9])[CH2:3][CH2:4][CH2:5][OH:6]>[Pd].C(O)C>[Br:11][C:8]([F:10])([F:9])[CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][OH:6]
Reactant: OCCCC(Br)CC(F)(F)Br
Agent: [Pd]
Solvent: CCO
Product: OCCCCCC(F)(F)Br
Yield: 24.9 %

Procedure:
Under a nitrogen atmosphere, 2.0 grams of 10% palladium on charcoal was weighed into a 500 ml Parr hydrogenation bottle. To the bottle was then added a solution of 11.0 grams (0.037 mole) of 4,6-dibromo-6,6-difluorohexan-1-ol in 75 ml of absolute ethanol. An additional 75 ml of absolute ethanol was used to wash any remaining hexan-1-ol from its container into the hydrogenation bottle. Sodium acetate, 3.1 grams (0.037 mole), was then added to the bottle, and the bottle was placed in the Parr hydrogenator. Upon completion of the uptake of the theoretical amount of hydrogen, the bottle was removed from the hydrogenator, and the contents were filtered. The filtrate was concentrated under reduced pressure to a residual solid. The solid was stirred in 100 ml of pentane, and the mixture was filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was purified by column chromatography on silica gel. Elution was accomplished using methylene chloride followed by ethyl acetate. The appropriate fractions were combined and concentrated under reduced pressure yielding 2.0 grams of 6-bromo-6,6-difluorohexan-1-ol. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:3]=12.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:11][C:10]1[C:3]2[C:4](=[N:5][CH:6]=[N:7][C:2]=2[Cl:1])[N:8]([CH3:12])[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nn(C)c2ncnc(Cl)c12
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nc(CBr)c2c(Cl)ncnc21

Procedure:
To a solution of 4-chloro-1,3-dimethyl-1H-pyrazolo[3,4-d]pyrimidine (752 mg, 4.12 mmol, Example 4) in carbon tetrachloride (45 mL) were added N-bromosuccinimide (964.4 mg, 5.36 mmol, Aldrich) and AlBN (209.6 mg, 1.25 mmol, Aldrich). The mixture was heated at reflux for 7 hours. The resulting reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (silica gel, hexanes-ethyl acetate, 95/5 to 70/30) to give 3-bromomethyl-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine as a white solid. (Yield 941.3 mg).
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:12]=[C:13]([O:18][CH2:19][C@@H:20]3[CH2:24][CH2:23][CH2:22][NH:21]3)[CH:14]=[N:15][C:16]=2[Cl:17])=[CH:5][CH:4]=1.[CH2:25]=O.Cl>C(O)=O>[N:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:12]=[C:13]([O:18][CH2:19][C@@H:20]3[CH2:24][CH2:23][CH2:22][N:21]3[CH3:25])[CH:14]=[N:15][C:16]=2[Cl:17])=[CH:5][CH:4]=1
Reactant: C=O
Reactant: Clc1ncc(OC[C@@H]2CCCN2)cc1C=Cc1ccncc1
Agent: Cl
Solvent: O=CO
Product: CN1CCC[C@H]1COc1cnc(Cl)c(C=Cc2ccncc2)c1
Temperature: 25 °C
Yield: 83 %

Procedure:
To 5-(2-(4-pyridinyl)ethenyl)-6-chloro-3-(2-(S)-pyrrolidinyl-methoxy)pyridine from Example 33 (110 mg, 0.27 mmol) was added formalin (38%, 3.0 mL) and formic acid (88%, 1.5 mL). The mixture was refluxed for five hours then cooled to room temperature. Hydrochloric acid (36%, 0.3 mL) was added, and the mixture was extracted with Et2O (3×8 mL). The aqueous layer was heated under vacuum to dryness. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with CHCl3 /MeOH 10:1 to afford an oil (72 mg, 83%). MS (CI/NH3) m/z 330 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.70-2.10 (m, 4H), 2.38-2.40 (m, 1H), 2.51 (s, 3H), 2.65-2.76 (m, 1H), 3.10-3.19 (m, 1H), 3.96-4.10 (m, 2H), 6.96-7.04 (m, 1H), 7.39-7.44 (m, 2H), 7.53 (s, 1H), 7.52-7.60 (m, 1H), 8.05-8.08 (m, 1H), 8.63-8.67 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][S:21]([O-:24])(=[O:23])=[O:22].[Na+]>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][S:21]([OH:24])(=[O:23])=[O:22])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)([O-])CCCCCCBr
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(O)CCCCCCN1CCN(Cc2ccccc2)CC1
Temperature: 180 °C
Reaction time: 16 h
Yield: 64.5 %

Procedure:
1-Benzylpiperazine (3.5 g), sodium 6-bromohexylsulfonate (16.2 g) and dry dimethylformamide (150 ml) are added to a flask and the mixture is heated and stirred at 180° C. for 16 hours. Precipitated crystals are collected by filtration and recrystallized from ethanol-diethyl ether to give 6-(4-benzyl-1-piperazinyl)hexylsulfonic acid (4.36 g, 63.5%) as colorless prisms. mp. 228°-230° C.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH2:7][CH2:8]Cl)[CH3:6].[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[C:24]([NH2:25])=[CH:23][NH:22][N:21]=2)=[O:19])=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[F:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]([C:20]2[C:24]([N:25]3[CH2:8][CH2:7][N:5]([CH3:6])[CH2:4][CH2:3]3)=[CH:23][NH:22][N:21]=2)=[O:19])=[CH:15][CH:16]=1
Reactant: Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Reactant: CN(CCCl)CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(c2c[nH]nc2C(=O)Nc2ccc(F)cc2)CC1
Temperature: 200 °C
Yield: 19.8 %

Procedure:
Bis(2-chloroethyl)methylamine hydrochloride (97 mg; 0.5 mmol) was added to a stirred solution of 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)-amide (100 mg; 0.45 mmol), tetrabutylammonium iodide (20 mg; 0.045 mmol) and diisopropyethylamine (200 ul) 1.13 mmol) in DMF (5 ml), and the resulting mixture was heated at 200° C. (100 W) for 30 minutes in a CEM Discover™ microwave synthesiser. The DMF was removed under vacuum, then purified by flash column chromatography, eluting with dichloromethane/methanol/acetic acid/water (90:18:3:2). Product containing fractions were combined and evaporated, treated with HCl in ethyl acetate and then re-evaporated with toluene (2×20 ml) to give an off white solid (27 mg). (LC/MS: Rt 1.64, [M+H]+ 378).
Reaction SMILES: [Br:1]Br.[CH:3]1[C:20]2[C:7](=[C:8]3[C:17](=[CH:18][CH:19]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[S:10](=[O:22])(=[O:21])[NH:9]3)[N:6]=[CH:5][CH:4]=1.C(Cl)(Cl)Cl>O1CCOCC1.C(Cl)(Cl)Cl>[Br:1][C:19]1[CH:18]=[C:17]2[C:8](=[C:7]3[C:20]=1[CH:3]=[CH:4][CH:5]=[N:6]3)[NH:9][S:10](=[O:21])(=[O:22])[C:11]1[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S1(=O)Nc2c(ccc3cccnc23)-c2ccccc21
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: O=S1(=O)Nc2c(cc(Br)c3cccnc23)-c2ccccc21
Reaction time: 2 h
Yield: 64.6 %

Procedure:
Bromine (170 μl, 3.30 mmol) was added dropwise to a solution of 5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 184 (467 mg, 1.65 mmol) in 1,4-dioxane/chloroform (1:1, 124 ml) at 0° C. After 2 h, chloroform (30 ml) was added and the resulting precipitate was collected by filtration. The solid was triturated from MeOH to give the title compound (385 mg, 64%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[C:7]([OH:9])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[CH:37]1([CH2:40][N:41]2[C:49]3[N:48]=[C:47]([CH2:50][C:51]4[CH:56]=[CH:55][C:54]([NH:57][CH3:58])=[CH:53][CH:52]=4)[NH:46][C:45]=3[C:44](=[O:59])[N:43]([CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=3[F:67])[C:42]2=[O:68])[CH2:39][CH2:38]1>ClCCl>[CH:37]1([CH2:40][N:41]2[C:49]3[N:48]=[C:47]([CH2:50][C:51]4[CH:52]=[CH:53][C:54]([N:57]([CH3:58])[C:7]([C:6]5[S:5][N:4]=[N:3][C:2]=5[CH3:1])=[O:9])=[CH:55][CH:56]=4)[NH:46][C:45]=3[C:44](=[O:59])[N:43]([CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=3[F:67])[C:42]2=[O:68])[CH2:39][CH2:38]1
Reactant: Cc1nnsc1C(=O)O
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnsc1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 15.6 %

Procedure:
A mixture of 4-methyl-[l,2,3]thiadiazole-5-carboxylic acid (12 mg, 0.08 mmol) in dichloromethane (2.0 mL) cooled to 0° C. was treated with triphenylphosphine (27 mg , 0.10 mmol), and N-chlorosuccinimide (14 mg, 0.10 mmol). This mixture was stirred at 0° C. for 30 min and at 25° C. for 10 min. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione ( 75 mg, 0.17 mmol). The reaction was then stirred at 25° C. for 18 h. At this time, the reaction was diluted with dichloromethane. The organics were washed with a saturated aqueous sodium bicarbonate solution. This solution was extracted with a 90/10 dichloromethane/methanol solution. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (25 mL). The aqueous layer was re-extracted with dichloromethane (1×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dried in vacuo for 24 h to afford 4-methyl-[1,2,3]thiadiazole-5-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (7.0 mg, 14.5%) as a white solid: 1H NMR (DMSO-d6, 300 MHz) δ13.14 (broad s, 1H), 6.92–6.67 (m, 8H), 4.75 (s, 2H), 3.70 (s, 2H), 3.47 (d, J=7.32 Hz, 2H), 2.99 (s, 3H), 2.26 (s, 3H), 0.82 (m, 1H), 0.03 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1.O[C:12]([C:15](O)([CH3:17])[CH3:16])([CH3:14])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([B:8]2[O:10][C:15]([CH3:17])([CH3:16])[C:12]([CH3:14])([CH3:13])[O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(O)C(C)(C)O
Reactant: OB(O)c1cccc(Cl)c1
Product: CC1(C)OB(c2cccc(Cl)c2)OC1(C)C
Yield: 75 %

Procedure:
The title compound (75%, oil) was prepared from 3-chlorophenylboronic acid and pinacol.