Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]([NH2:7])C.[OH-].[Na+].[C:10](Cl)([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>CN(C=O)C.O>[NH2:7][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:10](=[O:11])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(N)CCCN
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: NCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.2 %

Procedure:
To a solution of 1,4-diaminopentane (25 g, 155 mmol) in 100 mL DMF/H2O (1:1) was added 5N NaOH to adjust the pH to 9. CBZ-Cl (3.7 mL, 26 mmol) was added as one portion and stirred at room temperature for 16 hrs. The reaction was acidified to pH 1.25 and washed with diethyl ether. The pH of the reaction was then adjusted to 9.5 and the reaction extracted with EtOAc. The organic layer was washed with H2O, brine, dried over Na2SO4 and evaporated to give title compound (1.57 g, 30%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:13]2[CH:12]=[N:11][N:10]([CH3:9])[CH:14]=2)[CH:7]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cncc(Br)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cncc(Br)c2)cn1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
3,5-Dibromopyridine (500 mg, 2.11 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (400 mg, 1.9 mmol), 1,1′bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (172 mg, 0.211 mmol), and potassium phosphate tribasic (1.34 g, 6.33 mmol) were combined in a 20 mL microwave vial and dissolved in dioxane (9 mL) and water (1 mL). The vial was sealed and flushed with argon. The reaction mixture was stirred at 90° C. for 2 hours. The vial was then cooled to ambient temperature and diluted with ethyl acetate. The organic layer was washed with water, brine, and then dried over anhydrous magnesium sulfate. The solution was then filtered and concentrated in vacuo. The crude material was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM) to afford the title compound. 1H NMR (500 MHz, CDCl3) δ 8.58 (s, 1H), 8.44 (s, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.63 (s, 1H), 3.91 (s, 3H). LRMS (ESI) calc'd for C9H8BrN3 [M+H]+: 238. Found: 238.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si](C)(C)N[Si](C)(C)C.[Na].[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:28](=O)[O:27][CH2:26]2>C(COC)OC.CN(C=O)C>[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:28](=[C:5]1[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][C:6]1=[O:11])[O:27][CH2:26]2
Reactant: Nc1ccc2c(c1)COC2=O
Reactant: O=C1Cc2cc(Cl)ccc2N1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: Nc1ccc2c(c1)COC2=C1C(=O)Nc2ccc(Cl)cc21
Reaction time: 0.13 h
Yield: 31.3 %

Procedure:
To a solution of 5-chlorooxindole (0.629 g, 3.78 mmol) in 10.0 mL monoglyme was added 7.51 mL sodium hexamethyldisilazane (1.0 M in THF) over 3 min. After stirring a troom temperature for 8 min, a solution of 5-aminophthalide (0.561 g, 3.78 mmol) in 3.0 mL of DMF was added over 1 min. The mixture was stirred for 40 min and then quenched into 4% aqueous HCl solution. The aqueous solution was neutralized to pH 7 with 1 M NaOH and then made basic with saturated NaHCO3. The solid was filtered and washed with H2O and then partitioned between EtOAc and saturated NaHCO3 (heated to dissolve the solid). The organic phase was washed with H2O, brine and then dried with Na2SO4. The solvent was removed in vacuo and the residue triturated with MeOH to give the title compound (353 mg, 31%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[CH2:9]([Li])[CH2:10][CH2:11][CH3:12].CN(C)CCN(C)C.C=CCC>>[CH3:9][CH:10]([CH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)[CH2:11][CH3:12]
Reactant: [Li]CCCC
Reactant: Cc1ccc(C)cc1
Agent: C=CCC
Agent: CN(C)CCN(C)C
Product: CCC(C)Cc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 162 mmols of p-xylene were added 7 mmols of n-butyl lithium and 9 mmols of N,N,N',N'-tetramethylethylenediamine, and the mixture was stirred at room temperature for 2 hours, whereupon it turned brilliant orange. The resulting product was placed in an autoclave, and at the same time, 143 mmols of 1-butene was introduced into it. When they were reacted at 80° to 100°C. at an initial pressure of 15 Kg/cm2, the pressure of the inside of the autoclave decreased gradually. After reacting for 5 hours, 3-methyl-4-(p-tolyl) butane was obtained in a selectivity of about 90%. This compound was distilled under reduced pressure to purity it. The resulting product was used in the following Examples.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:16]=1[C:10]1([CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:9](=[O:17])[C:8]([C:18](OCC)=[O:19])=[C:7]2[OH:23].Cl.[NH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:16]=1[C:10]1([CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:9](=[O:17])[C:8]([C:18]([NH:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:19])=[C:7]2[OH:23]
Reactant: CCOC(=O)C1=C(O)c2cccc(F)c2C2(CCOCC2)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cccc(F)c2C2(CCOCC2)C1=O
Temperature: 90 °C
Yield: 83.7 %

Procedure:
In a sealed flask was combined ethyl 8-fluoro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (1.8 g, 5.6 mmol), dioxane (75 mL), tert-butyl 2-aminoacetate hydrochloride (3.8 g, 22 mmol), and N-ethyl-N-isopropylpropan-2-amine (3.9 mL, 22 mmol). The flask was sealed and heated at 90° C. for 10 hours. After cooling to room temperature, the reaction was concentrated to give a solid that was purified by flash chromatography (20% EtOAc/hexane) to afford a white solid (1.9 g). MS m/e=406.1 (M+H)+.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[Cl:26][CH:27]1[CH2:30][CH:29]([C:31](O)=[O:32])[CH2:28]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:31]([CH:29]5[CH2:30][CH:27]([Cl:26])[CH2:28]5)=[O:32])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)C1CC(Cl)C1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)C1CC(Cl)C1

Procedure:
The title compound, white solid (15 mg, 51.4%), MS (ISP) m/z=447.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) ((25 mg, 0.062 mmol) and 3-chlorocyclobutanecarboxylic acid
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:13]=1)[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26][NH:27][O:28][CH3:29].CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:13]=1)[C:8]([N:27]([O:28][CH3:29])[CH3:26])=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)c1cc(OCCCOC2CCCCO2)cc(C(=O)O)c1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cc(OCCCOC2CCCCO2)cc(C(C)(C)C)c1
Reaction time: 2 h
Yield: 99.4 %

Procedure:
3-tert-Butyl-5-[3-(tetrahydropyran-2-yloxy)propoxy]benzoic acid (O4.059; 4.90 g) and N,O-dimethylhydroxylamine hydrochloride (1.42 g) were dissolved in DMF (80 ml) and admixed with Hünig's base (4.81 ml) and TOTU (4.78 g). After stirring for 2 h, the mixture was left to stand overnight. Then the DMF was drawn off, the mixture was partitioned between EA and saturated sodium hydrogencarbonate solution, and the EA phase was removed, dried over magnesium sulfate, filtered and concentrated. 5.49 g of the title compound were obtained.
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[C:25]12([N:35]=[C:36]=[O:37])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2>>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:36]([NH:35][C:25]23[CH2:34][CH:29]4[CH2:28][CH:27]([CH2:33][CH:31]([CH2:30]4)[CH2:32]2)[CH2:26]3)=[O:37])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1
Reactant: Cc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Agent: Cl
Product: Cc1ccc(C(OC2CN(C(=O)NC34CC5CC(CC(C5)C3)C4)C2)c2ccccc2C(F)(F)F)cc1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)-4′-methylbenzhydryloxy]azetidine hydrochloride (151) (0.56 mmol) and 1-adamantyl isocyanate (0.56 mmol) using the procedure described for compound (10). The desired product was obtained as a white foam (264 mg, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[S:32]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1)(=[O:35])(=[O:34])[NH2:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:41][CH2:40][C:39]4[CH:38]=[CH:37][C:36]([S:32](=[O:35])(=[O:34])[NH2:33])=[CH:43][CH:42]=4)=[O:24])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(CNC(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)cc2)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-sulfamoylbenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=615.91 (M+H+); retention time=0.75 minutes.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:62])(=O)=O)=CC=1>C(O)(=O)C>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@:9]([F:62])([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Solvent: CC(=O)O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@](C)(F)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reaction time: 18 h
Yield: 96.8 %

Procedure:
Erythromycin A (5 g, 6.813 mmole) and N-fluorobenzenesulfonimide (2.2 g 6,813 mmole) were dissolved in glacial acetic acid (20 mL) at room temperature and stirred for 18 hours. The reaction was worked-up in the same manner as Example 1 to afford 4.96 g of crude flurithromycin. This material was recrystallized as described in Example 1 to yield 2.25 g (44% yield) of fluorithromycin. This example shows that reasonably good yields of flurithromycin may be obtained in the process of the invention without buffering.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH:20]=O)[CH:14]=1)[CH2:8][CH:9]([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2].[CH:23]1([NH2:26])[CH2:25][CH2:24]1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH2:20][NH:26][CH:23]2[CH2:25][CH2:24]2)[CH:14]=1)[CH2:8][CH:9]([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(C=O)c1)CC(F)F
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(CNC2CC2)c1)CC(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
A mixture of (4-chloro-3-formyl-benzyl)-(2,2-difluoro-ethyl)-carbamic acid tert-butyl ester (563 mg, 1.69 mmol) and cyclopropylamine (0.180 mL, 2.52 mmol) in MeOH (18 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt. NaBH4 (96 mg, 2.53 mmol) was added by portions, and the reaction was stirred for 1 h. The solvents were removed under reduced pressure, and the resulting oil was diluted with EtOAc. The mixture was washed with aq. sat. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2Cl2/MeOH 95:5) yielded the title compound (558 mg, 88%). LC-MS: tR=0.76 min; ES+: 375.17.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1.[F:21][C:22]1[CH:28]=[C:27]([CH3:29])[C:26]([OH:30])=[CH:25][C:23]=1[NH2:24]>C(O)(C)C>[ClH:2].[F:21][C:22]1[CH:28]=[C:27]([CH3:29])[C:26]([OH:30])=[CH:25][C:23]=1[NH:24][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: Cc1cc(F)c(N)cc1O
Reactant: Clc1ncnc2cc(OCc3ccncc3)ccc12
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(F)c(Nc2ncnc3cc(OCc4ccncc4)ccc23)cc1O
Yield: 33.9 %

Procedure:
A mixture of 4-chloro-7-(4-pyridylmethoxy)quinazoline hydrochloride (350 mg, 1 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (155 mg, 1.1 mmol), (prepared as described for the starting material in Example 13), in isopropanol (15 ml) was heated at reflux for 1 hour. The resulting precipitate was collected by filtration and purified by reverse phase HPLC using a gradient (0-75%) of methanol in water. Concentrated hydrochloric acid (0.5 ml) was added to the combined fractions of pure product and the solvent was removed by evaporation to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(4-pyridylmethoxy)quinazoline hydrochloride (140 mg, 28%).
Reaction SMILES: C(O)C.Cl[C:5]1[N:13]=[C:12]([NH2:14])[N:11]=[C:10]2[C:6]=1[N:7]=[C:8]([CH3:21])[N:9]2[CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CO.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>[CH3:21][C:8]1[N:9]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:10]2[C:6]([N:7]=1)=[C:5]([C:25]1[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=1)[N:13]=[C:12]([NH2:14])[N:11]=2
Reactant: OB(O)c1ccncc1
Reactant: Cc1nc2c(Cl)nc(N)nc2n1C1CCOCC1
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: [K+]
Solvent: CO
Solvent: CCO
Product: Cc1nc2c(-c3ccncc3)nc(N)nc2n1C1CCOCC1
Temperature: 150 °C
Yield: 99.1 %

Procedure:
Anhydrous ethanol (4 mL) was added to an argon-purged vial containing 6-chloro-8-methyl-9-(tetrahydro-2H-pyran-4-yl)-9H-purin-2-amine (140 mg, 0.52 mmol), pyridine-4-yl-boronic acid (97 mg, 0.79 mmol, 1.5 equiv.), K2CO3 (109 mg, 0.79 mmol, 1.5 equiv.), and Pd(PPh3)4 (30 mg, 0.026 mmol, 0.05 equiv.) and the mixture was heated for 30 min in the microwave oven at 150° C. After cooling to ambient temperature, the reaction mixture was diluted with methanol (8 mL), filtered through a Nylon 0.45 μm filter and the filtrate concentrated in vacuo. Preparative HPLC purification of the residue afforded, after evaporation and drying, the desired compound as an orange solid (160 mg, 99% yield). TFA salt. 1H NMR (300 MHz, CD3OD) δ, ppm: 9.09 (d, J=6.6 Hz, 2H), 8.95 (d, J=6.2 Hz, 2H), 4.61-4.52 (m, 1H), 4.11 (dd, J=11.5, 4.5 Hz, 2H), 3.61 (app t, J=11.3 Hz, 2H), 2.96-2.82 (m, 2H), 2.68 (s, 3H), 1.84 (dd, J=12.7, 2.3 Hz, 2H); MS (EI) m/z 311.3 (MH)+.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:25][C:11]3[CH:12]=[N:13][C:14]([NH:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[O:18])=[CH:15][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[C:26]12([C:36](Cl)=[O:37])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2.C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[C:26]12([C:36]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[NH:25][C:11]5[CH:12]=[N:13][C:14]([NH:16][C:17]([C:19]6[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=6)=[O:18])=[CH:15][C:10]=5[N:9]=4)=[CH:6][CH:7]=3)=[O:37])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccc(-c2nc3cc(NC(=O)c4ccccn4)ncc3[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(Nc1cc2nc(-c3ccc(C(=O)C45CC6CC(CC(C6)C4)C5)cc3)[nH]c2cn1)c1ccccn1
Yield: 41.5 %

Procedure:
A solution of 22 (0.065 g, 0.197 mmol), adamantane carbonyl chloride (0.060 g, 0.30 mmol) in dry Pyridine (5 ml) was stirred at 80° C. for 2 h. After usual work-up the solid was treated with 10% K2CO3 for 1 h. The solid was filtered and passed through SiO2 gel, eluting with EtOAc affording diamide 24 (0.039 g, 40%). M.p. 305° C.; 1H NMR (DMSO-d6, 500 MHz): δ 13.19 (1H, brs, NH), 10.47 (1H, brs, NH), 9.39 (1H, brs), 8.765 (1H, d, J=4.5 Hz), 8.73 (1H, brs), 8.45 (1H, brs), 8.24 (1H, d, J=8.0 Hz), 8.14-8.09 (2H, m), 7.89 (2H, d, J=8.5 Hz), 7.72 (1H, dt, J=5.0 and 7.5 Hz), 2.0 (3H, brs), 1.92 (6H, brs), 1.72 (6H, brs); EIMS m/z: 493.5 (M+1); Anal (C29H28N6O2×1.23 H2O) C, H, N.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](F)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC([O:24]C(Cl)=O)C.CO>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([OH:24])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: OC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reaction time: 1 h
Yield: 55 %

Procedure:
To 1-benzyl-4-fluoro-4-phenyl-piperidine (0.22 g) in dry DCM (5 mL) was added 1-chloroethylchloroformate (1 mmol). The mixture was stirred for 1 hour and then methanol (5 mL) was added and the mixture stirred overnight. The solvent was removed under vacuum, and the resulting solid triturated from diethyl ether to give the title compound as a white solid (0.12 g). LCMS m/z 180.1 [M+H]+. R.T.=2.27 min (Analytical Method 4).
Reaction SMILES: [NH:1]=[C:2]([C:7]#[N:8])[C:3](=[NH:6])[C:4]#[N:5].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](N)=[C:12](N)[CH:11]=1.FC(F)(F)C(O)=O>O>[Cl:9][C:10]1[CH:11]=[C:12]2[C:13](=[CH:14][CH:15]=1)[N:6]=[C:3]([C:4]#[N:5])[C:2]([C:7]#[N:8])=[N:1]2
Reactant: Nc1ccc(Cl)cc1N
Reactant: N#CC(=N)C(=N)C#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N#Cc1nc2ccc(Cl)cc2nc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
A mixture of 0.5 g (4.7 mmols) of the diiminosuccinonitrile and 0.67 g (4.7 mmols) of 4-chloro-1,2-phenylenediamine was slowly added to 10 ml of trifluoroacetic acid at about 20° C. over a period of 30 minutes, and the resulting mixture was stirred at room temperature for 8 hours and then allowed to stand overnight. To the reaction mixture was added 50 ml of water, and the solid precipitated was filtered and sufficiently washed with water. The solid thus obtained was dried under reduced pressure, followed by a silica gel column chromatography (eluent: hexane/ethyl acetate (75/25)) and then recrystallization from chloroform/ethanol, wherein 0.6 g (59%) of 6-chloro-2,3-dicyanoquinoxaline was obtained as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[NH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Br[CH2:12][C:13]([NH2:15])=[O:14].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH2:12][C:13]([NH2:15])=[O:14])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: NC(=O)CBr
Reactant: Cn1cc(Br)c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1cc(Br)c(=O)n(CC(N)=O)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-bromo-1-methylpyrimidine-2,4(1H,3H)-dione (200 mg, 0.976 mmol), 2-bromoacetamide (162 mg, 1.171 mmol) and K2CO3 (162 mg, 1.171 mmol) in DMSO (4 mL) was stirred at room temperature for 4 hours. The reaction mixture was subsequently filtered and purified via preparative HPLC, eluting with a gradient of 1-40% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA) to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]3[CH:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:29]1([C:19]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:27]3[CH:23]([CH2:24][N:25]([C:9](=[O:11])[CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[OH:1])[CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)Cc1ccccc1O
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3O)CC12
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
N,N'-Carbonyldiimidazole (1.14 g) is added to a solution of 2-hydroxyphenylacetic acid (1.06 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 30 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.23 g) and triethylamine (1.96 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 4 cm, height 40 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting 125 cc fractions. Fractions 4 to 11 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from a mixture of acetonitrile (15 cc) and isopropyl ether (30 cc). The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(2-hydroxyphenyl)acetyl]-4-perhydroisoindolone (0.8 g) is obtained in the form of white crystals melting at 232° C.