Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]3[C@@H:16]([CH3:17])[CH2:15][N:14]([CH2:18][CH3:19])[C:13](=[O:20])[C:9]3=[C:10]([O:11][CH3:12])[C:6]=2[C:5](=[O:21])[NH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][C:39]=1[Cl:46]>CN(C=O)C>[NH2:1][C:2]1[C:7]2[N:8]3[C@@H:16]([CH3:17])[CH2:15][N:14]([CH2:18][CH3:19])[C:13](=[O:20])[C:9]3=[C:10]([O:11][CH3:12])[C:6]=2[C:5](=[O:21])[N:4]([CH2:42][C:41]2[CH:44]=[CH:45][C:38]([F:37])=[C:39]([Cl:46])[CH:40]=2)[N:3]=1
Reactant: Fc1ccc(CBr)cc1Cl
Reactant: CCN1C[C@H](C)n2c(c(OC)c3c(=O)[nH]nc(N)c32)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCN1C[C@H](C)n2c(c(OC)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(N)c32)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (6S)-4-amino-8-ethyl-10-methoxy-6-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.94 g, 3.23 mmol) in anhydrous DMF (32 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (3.87 mL, 1 M, 3.87 mmol) was added. The mixture was stirred at room temperature for 15 minutes and treated with 4-fluoro-3-chlorobenzyl bromide (0.72 g, 3.23 mmol). The reaction mixture was stirred at room temperature for 1 hour and concentrated under vacuum. The residue was partitioned between chloroform and dilute hydrochloric acid. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 0-20% methanol in ethyl acetate gradient. Collection and concentration of appropriate fractions provided the title material.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([N:37]=C=O)[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[ClH:44]>C1COCC1.O>[ClH:44].[ClH:44].[NH2:37][C@:21]12[CH2:33][CH2:32][C@@H:31]([C:34]([CH3:36])=[CH2:35])[C@@H:22]1[C@@H:23]1[C@@:18]([CH3:40])([CH2:19][CH2:20]2)[C@@:17]2([CH3:41])[C@@H:26]([C@:27]3([CH3:30])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:42])([CH3:43])[C:12]([C:10]2[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=2)=[CH:29][CH2:28]3)[CH2:25][CH2:24]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N=C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 24 h
Yield: 86.8 %

Procedure:
To a solution of crude methyl 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (2.93 g, 4.99 mmol) in THF (35 mL) was added 12N HCl (10 mL, 121 mmol). After stirring the mixture for 24 h, the mixture was diluted with water (100 mL) until solids precipitated. The solids were collected by filtration and were washed with water to afford the title compound (2.75 g, 4.33 mmol, 87% yield), as an off-white solid that was used in the next step with no additional purification. LCMS: m/e 562 (M+H)+, 1.96 min (method 2).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O-:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na+].Br[CH2:13][CH2:14][CH:15]=[CH2:16]>CN(C)C=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:16][CH2:15][CH:14]=[CH2:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc([O-])cc1
Reactant: C=CCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCOc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C

Procedure:
To a solution of sodium 4-nitrophenolate (11 grams; 56 mmole) in dimethylformamide (50 ml.) is added 4-bromo-1-butene (5 g; 37 mmole). After 2.5 hours of heating at 100° C., the reaction mixture is diluted with 400 ml. of water and extracted with light petroleum ether. The ether extracts are re-extracted with cold 5% sodium hydroxide and then washed with water and dried over magnesium sulfate. This solution is evaporated under reduced pressure and the residual oil crystallized from petroleum ether at 0° to yield 4-(4-nitrophenoxy)-1-butene.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:29][CH:28]=1)[C:5](=[O:26])[N:6]2[C:11]1[CH:12]=[C:13]([N:17](C)[C:18](=O)OC(C)(C)C)[CH:14]=[CH:15][CH:16]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:29][CH:28]=1)[C:5](=[O:26])[N:6]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH3:18])[CH:12]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(-n2c(=O)n(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1cccc(-n2c(=O)n(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of tert-butyl 3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (31) (450 mg, 0.86 mmol) in DCM (8 mL) was added TFA (2 mL) dropwise. The reaction mixture was stirred at rt for 1 h and then concentrated. The residue was purified by column chromatography (silica gel, 0 to 10% methanol in methylene chloride (0.3% Et3N)) to give 6-amino-9-(3-(methylamino)phenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one (32) (364 mg, 100%). LC-MS (ESI): m/z (M+1) 425.
Reaction SMILES: [C:1]1([CH3:50])[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH2:11][CH2:12][N:13]([S:40]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)(=[O:42])=[O:41])[CH2:14][CH2:15][N:16]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH2:17][CH2:18][NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:54][CH2:55][O:56][CH2:57][CH2:58]Cl.O>CN(C=O)C>[C:26]1([CH3:29])[CH:27]=[CH:28][C:23]([S:20]([N:19]2[CH2:18][CH2:17][N:16]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:31])=[O:32])[CH2:15][CH2:14][N:13]([S:40]([C:43]3[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=3)(=[O:41])=[O:42])[CH2:12][CH2:11][N:10]([S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:50])=[CH:2][CH:3]=3)(=[O:8])=[O:9])[CH2:58][CH2:57][O:56][CH2:55][CH2:54]2)(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: ClCCOCCCl
Reactant: Cc1ccc(S(=O)(=O)NCCN(CCN(CCNS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCOCCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To a stirred solution of 1,4,7,10-tetra(p-toluenesulfonyl)-1,4,7,10-tetraazadecane prepared as in Example 15B (35.3 g, 0.0463 mole) in anhydrous DMF (460 ml) was added sodium hydride (2.77 g-80% in mineral oil, 0.0925 mole) in portions and the resulting mixture was stirred for 30 minutes under a dry argon atmosphere. The solution was then heated to 100° C. and a solution of 2-chloroethyl ether (6.61 g, 0.0463 mole) in anhydrous DMF (90 ml) was added dropwise over a 1.5 h period, maintaining the temperature at 100° C. After stirring the solution an additional 1.5 h at 100° C., H2O (3 l) was added while cooling (ice bath) to crystallize the product. The resulting tan solid was filtered and dried in vacuo. The crude product was purified by crystallization from CH2Cl2 -hexane to give 13.2 g (34% yield) of the product as an off-white solid: mp 197.5°-201° C.; 1H NMR (CDCl3) δ 2.44 (s, 12 H), 3.28 (m, 16 H), 3.57 (m, 4 H), 7.35 (m, 8 H), 7.69 (m, 8 H).
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][C:24]=1[CH3:25])=[O:19])=O)C1C=CC=CC=1.[N:26]1[C:35]2[C:30](=[N:31][C:32]([CH:36]=O)=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1.N1CCCCC1>CC(O)C>[N:31]1[C:30]2[C:35](=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:34]=[CH:33][C:32]=1[CH:36]=[C:15]1[NH:11][C:12]([NH:17][C:18]([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[CH3:25])=[O:19])=[N:13][C:14]1=[O:16]
Reactant: O=Cc1ccc2ncccc2n1
Reactant: Cc1ccsc1C(=O)NC1=NC(=O)CN1C(=O)OCc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: Cc1ccsc1C(=O)NC1=NC(=O)C(=Cc2ccc3ncccc3n2)N1
Temperature: 25 °C
Yield: 30.5 %

Procedure:
To a mixture of 2-[(3-methyl-thiophene-2-carbonyl)-amino]-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (42.0 mg, 0.12 mmol), 1,5-naphthyridine-6-carboxaldehyde (18.6 mg, 0.12 mmol) and iPrOH (5.0 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 4 hrs to give a suspension. The reaction mixture was cooled to r.t. and the solid was collected by filtration, washed with MeOH, and ether to give 3-methyl-thiophene-2-carboxylic acid (5-[1,5]naphthyridin-2-ylmethylene-4-oxo-4,5-dihydro-1H-imidazol-2-yl)-amide as a light yellow solid (13.3 mg, 30.5%). HR-ES (+) m/e calcd. for C18H13N5O2S: (M+H)+ 364.0863. Found: 364.0862.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:11]([F:14])([F:13])[F:12])=[N:8][O:9][CH:10]=1)=[O:5])C.Cl.O>C(O)(=O)C>[F:14][C:11]([F:12])([F:13])[C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:10][O:9][N:8]=1
Reactant: CCOC(=O)c1conc1C(F)(F)F
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1conc1C(F)(F)F
Temperature: 70 °C
Reaction time: 2 h
Yield: 8.1 %

Procedure:
3-Trifluoromethyl-isoxazole-4-carboxylic acid ethyl ester (Preparation 47, 1.00 g, 4.78 mmol), glacial acetic acid (4 ml), concentrated hydrochloric acid (2 ml, 20 mmol) and water (2 ml, 200 mmol) were heated together with stirring at 70° C. for 2 hours. Solvents were removed by evaporation in vacuo and the residue was left to stand at room temperature for 16 hours. Water (40 ml) and t-butylmethyl ether (80 ml) was added and the layers separated. The organic layer was washed with dilute hydrochloric acid (20 ml), then dried over anhydrous Na2SO4 (s), filtered and evaporated in vacuo to afford the title compound as a brown gum (70 mg, 8%). Material was taken on with no further purification.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([OH:14])=O)[N:3]=1.[NH:15]1[CH:19]=[CH:18][N:17]=[C:16]1[NH:20][C:21]([C:23]1[C:31]2[NH:30][C:29]([NH2:32])=[N:28][C:27]=2[CH:26]=[CH:25][CH:24]=1)=[O:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:17]1[CH:18]=[CH:19][N:15]=[C:16]1[NH:20][C:21]([C:23]1[C:31]2[N:30]=[C:29]([NH:32][C:12]([C:4]3[N:3]=[C:2]([CH3:1])[C:11]4[C:6]([CH:5]=3)=[CH:7][CH:8]=[CH:9][CH:10]=4)=[O:14])[NH:28][C:27]=2[CH:26]=[CH:25][CH:24]=1)=[O:22]
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Reactant: Cc1nc(C(=O)O)cc2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)Nc2nc3c(C(=O)Nc4ncc[nH]4)cccc3[nH]2)cc2ccccc12
Yield: 14.8 %

Procedure:
17.6 mg (15%) of 1-methyl-isoquinoline-3-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide was synthesized according to General Procedure A using 55 mg (0.29 mmol) of 1-methyl-isoquinoline-3-carboxylic acid, 70 mg (0.29 mmol) of intermediate B (2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide), 144 mg (0.38 mmol) of HBTU, 0.264 mL (1.5 mmol) of DIEA in 0.8 mL of DMF stirring at 85° C. for 2 h. 1H-NMR (400 MHz, DMSO): 8.66 (s, 1H), 8.38 (d, 1H), 8.28 (d, 1H), 7.89 (m 4H), 7.34 (m, 1H), 6.85 (b, 2H), 3.07 (s, 3H) ppm. LCMS: 412 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][C:9]([C:11]3[N:12]=[CH:13][N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=3)=[CH:8][C:4]=2[CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:30][C:31]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:32]=1[OH:40]>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[F:30][C:31]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:32]=1[O:40][C:4]1[CH:5]=[CH:6][N:7]=[C:2]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:22])[CH3:23])[CH:15]=3)[S:10][C:3]=12
Reactant: C[Si](C)(C)CCOCn1cnc(-c2cc3ccnc(Cl)c3s2)c1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
A suspension of 91 (4.2 g, 11.5 mmol), potassium carbonate (7.95 g, 57.5 mmol) and 2-fluoro-4-nitrophenol (4.97 g, 31.6 mmol) was heated at 190° C. in diphenyl ether (15 ml) for 4.5 hrs, cooled to room temperature, diluted with DCM and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (eluents hexane and acetone/hexane, 45:55) to afford title compound 92 (3.4 mg, 61% yield) as a yellow solid MS (m/z) 487.0 (M+H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[C:3]1=[O:10].[C:11]([O-])(C)(C)C.[K+].CI>C(O)(C)(C)C>[CH3:1][C:2]1([CH3:11])[CH2:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[C:3]1=[O:10]
Reactant: CC(C)(C)[O-]
Reactant: CC1Cc2sccc2C1=O
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CI
Product: CC1(C)Cc2sccc2C1=O
Reaction time: 1.5 h
Yield: 83.2 %

Procedure:
A solution of 28.6 g of 5,6-dihydro-5-methyl-4H-cyclopenta[b]thiophen-4-one in 210 ml of tert.-butanol is added dropwise at from +25° to +30° C. to a solution of 23.1 g of potassium tert.-butanolate in 250 ml of tert.-butanol. The dark reddish-brown solution is stirred for 1.5 hours, and then 12.9 ml of methyl iodide are added. After stirring for 1 hour, the reddish-brown suspension is filtered and the filtrate is concentrated by evaporation. After distillation of the residue there are obtained 26.0 g of 5,6-dihydro-5,5-dimethyl-4H-cyclopenta[b]thiophen-4-one in the form of a colourless oil having a boiling point of 43° C. at 0.03 mbar.
Reaction SMILES: [C:1](SC1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1)(=[O:18])[S:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([OH:13])=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=1.O.[NH2:36][NH2:37]>ClCCl>[NH:36]([C:1](=[O:18])[S:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([OH:13])=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=1)[NH2:37]
Reactant: NN
Reactant: CC(C)(C)c1cc(SC(=O)Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cc(SC(=O)NN)cc(C(C)(C)C)c1O
Reaction time: 48 h
Yield: 92.7 %

Procedure:
A solution of S,S-bis[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] carbonodithioate (5.0 g, 9.9 mmol) in dichloromethane (50 mL) is added dropwise to a 0° C. solution of hydrazine monohydrate (1.1 g, 22.0 mmol) in dichloromethane (60 mL). The ice bath is removed and the reaction is stirred vigorously for 48 hours. The reaction mixture is diluted with ethyl acetate and washed four times with water and once with brine. The organic phase is dried over magnesium sulfate and the solvents are evaporated in vacuo. The residue is chromatographed on a 100 g silica column with ethyl acetate/hexane (1/9 then 1/1). The hydrazide is crystallized from isopropyl ether to give 2.72 g (92%) of S-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] hydrazinecarbothioate, mp 130.0-131.0° C.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C(OC([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]([C:33]([OH:35])=O)[N:30]([CH3:32])[CH:31]=2)=[CH:23][CH:22]=1)=O)(C)(C)C.[NH2:36][C:37]1[CH:38]=[C:39]([C:43]([O:45][CH3:46])=[O:44])[N:40]([CH3:42])[CH:41]=1>CN(C1C=CN=CC=1)C.CN(C=O)C>[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:28]=[C:29]([C:33]([NH:36][C:37]3[CH:38]=[C:39]([C:43]([O:45][CH3:46])=[O:44])[N:40]([CH3:42])[CH:41]=3)=[O:35])[N:30]([CH3:32])[CH:31]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)c1cc(N)cn1C
Reactant: Cn1cc(-c2ccc(NC(=O)OC(C)(C)C)cc2)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(NC(=O)c2cc(-c3ccc(N)cc3)cn2C)cn1C
Reaction time: 6 h

Procedure:
Two eq of EDCl and 2.5 eq of DMAP were added to a stirred solution of 6 (0.45 gm, 1.2 eq) in DMF (8 mL) and the mixture was allowed to stir for 30 minutes after which methyl 4-amino-1-methyl-1H-pyrrole-2-carboxylate (0.18 g, 1.18 mmol, 1.0 eq) was added. The reaction mixture was allowed to stir for a further 6 hours at which point TLC showed completion of reaction. The reaction was quenched by pouring it onto a mixture of ice/water mixture and the resulting mixture was extracted with ethyl acetate (3×150 mL). The combined extracts were sequentially washed with citric acid (100 mL), saturated aqueous NaHCO3 (100 mL), water (100 mL), brine (100 mL) and finally dried over MgSO4. Excess ethyl acetate was evaporated by rotary evaporator under reduced pressure and the crude product 9a (0.58 gm, yield 90.6%) was used for the boc deprotection step to afford 9 without further purification. For boc deprotection, 0.29 gm of 9a was dissolved in a small volume of MeOH and 4M HCl in dioxane (15 mL) was added slowly to the stirring solution. The reaction mixture was stirred for 6 hours at which point TLC showed completion of reaction. Excess solvent was evaporated under vacuum to obtain a brown coloured solid (9). The solid product was subjected to flash chromatography (n-hexane/EtOAc 9:1) to give pure 9. Yield 0.21 gm, 95%.
Reaction SMILES: CCCC[Sn]([O:14][Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])(CCCC)CCCC.[CH:28]([N:31]([CH:35]([CH3:37])[CH3:36])[CH2:32][CH2:33]O)([CH3:30])[CH3:29].O>C1C=CC=CC=1>[CH2:24]([Sn:15]([O:14][CH2:33][CH2:32][N:31]([CH:35]([CH3:37])[CH3:36])[CH:28]([CH3:30])[CH3:29])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH3:27]
Reactant: CC(C)N(CCO)C(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Solvent: c1ccccc1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)OCCN(C(C)C)C(C)C

Procedure:
2-Diisopropylaminoethyl Tributylstannyl Ether is prepared from 89.4 gm (0.15 mole) bis(tributyltin) oxide and 43.5 gm (0.30 mole) 2-diisopropylaminoethanol in 200 ml benzene. This is stirred and heated to reflux in a system that contains a Dean-Starke tube. After refluxing for 23 hours a total of 2.6 ml of water (theory 2.7 ml) had collected in the Dean-Starke tube. Solvent is stripped off on a rotating evaporator to provide 134.3 gm of orange liquid. This is fractionated at reduced pressure with collection at 147°-155° C. at 0.4 mm of 87.6 gm of straw liquid (Percent theory - 73). Infrared spectral analysis shows this liquid to be the desired ether.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([CH2:21][CH2:22][CH2:23][CH2:24][B:25]2[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:34]1[CH2:38]OC[CH2:35]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(Br)C=C>C(OCC)(=O)C>[CH2:38]([C:15]([N:14]=[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:21][CH2:22][CH2:23][CH2:24][B:25]1[O:26][C:27]([CH3:32])([CH3:33])[C:28]([CH3:31])([CH3:30])[O:29]1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:34]=[CH2:35]
Reactant: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)N=C(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C=CCBr
Product: C=CCC(CCCCB1OC(C)(C)C(C)(C)O1)(N=C(c1ccccc1)c1ccccc1)C(=O)OCC
Temperature: -78 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
A solution of ethyl 2-(diphenylmethyleneamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (2.79 g, 6.21 mmol) in freshly distilled (THF 15 mL, 0.4 M) was cooled to −78° C. and treated with lithium bis(trimethylsilyl)amide (6.8 mL, 1.0 M in THF). After stirring for 10 min allyl bromide (2.25 g, 18.6 mmol) was added the reaction was warmed to room temperature and stirred for 16 h. After being complete by TLC, the reaction mixture was cooled to 0° C., diluted with ethyl acetate and washed successively with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-20% ethyl acetate in heptane with 0.5% triethylamine over 6 CV) gave ethyl 2-allyl-2-(diphenylmethyleneamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate as a colorless oil (1.81 g, 59%). Rf 0.52 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 7.58-7.53 (m, 2H), 7.39-7.22 (m, 6H), 7.16-7.12 (m, 2H), 5.89-5.74 (m, 1H), 5.07 (dd, J1=15.3 Hz, J2=2.1 Hz, 1H), 5.05 (dd, J1=8.7 Hz, J2=2.1 Hz, 1H), 3.70 (q, J=7.5 Hz, 1Hdiasterotopic), 3.69 (q, J=7.2 Hz, 1Hdiasterotopic), 2.70 (dd, J1=7.2 Hz, J2=1.2 Hz, 2H), 1.92-1.83 (m, 2H), 1.44-1.35 (m, 2H), 1.35-1.23 (m, 2H), 1.19 (s, 12H), 1.10 (t, J=7.2 Hz, 3H), 0.78 (t, J=6.6 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[CH3:16][CH2:17]O>>[CH2:16]([O:13][C:12]([C:10]1[O:11][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][C:8]=2[CH:9]=1)=[O:14])[CH3:17]
Reactant: CCO
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2o1
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2o1

Procedure:
5-Nitro-benzofuran-2-carboxylic acid (500 mg, 2.41 mmol) was esterified with EtOH using Method A to give the title compound.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[CH2:8][C:9]1[N:10]([CH3:35])[C:11]2[C:16]([N:17]=1)=[C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:14]=[C:13]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH2:33][CH3:34])[N:12]=2.[O:36]1[CH2:39][C:38](=O)[CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:33]([C:25]1[N:24]([C:13]2[N:12]=[C:11]3[C:16]([N:17]=[C:9]([CH2:8][N:2]4[CH2:3][C@@H:4]5[CH2:7][C@H:1]4[CH2:6][N:5]5[CH:38]4[CH2:39][O:36][CH2:37]4)[N:10]3[CH3:35])=[C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:14]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=1)[CH3:34]
Reactant: O=C1COC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3C[C@@H]4C[C@H]3CN4)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3C[C@@H]4C[C@H]3CN4C3COC3)n(C)c2n1
Reaction time: 16 h
Yield: 76.1 %

Procedure:
A solution of of 8-[(1S,4S)-1-(2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]-2-(2-ethyl-benzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (250 mg, 0.53 mmol), oxetan-3-one (40 mg, 0.31 mmol) and molecular sieves (4 Å, powdered, 200 mg) in DCE (7 mL) was stirred at ambient temperature for 4 h. Sodium triacetoxyborohydride (148 mg, 0.70 mmol) was added and the mixture stirred for 16 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH, gradient from 100:0 to 90:0) to afford 598 as a white solid (125 mg, 45%). LCMS (method I): RT=2.39 min, M+H+=530. 1H NMR (CDCl3, 400 MHz) δ 8.02 (m, 1 H), 7.76 (m, 1 H), 7.26 (m, 2 H), 4.72-4.65 (m, 4 H), 4.34 (m, 4 H), 4.01-3.86 (m, 10 H), 3.35 (m, 4 H), 2.99 (m, 1 H), 2.82 (m, 1 H), 2.76 (m, 2 H), 1.79 (m, 2 H) and 1.45 (t, J=7.5 Hz, 3 H)