Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]2)=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[N:13][C:12]([C:15]#[N:16])=[CH:11][N:10]=2)=[N:6][CH:7]=1.C[O:33][CH:34]1[CH:38]([CH:39]=O)[CH2:37][CH:36](OC)O1>CN(C=O)C.C1(C)C=CC=CC=1>[C:15]([C:12]1[N:13]=[CH:14][C:9]([NH:8][C:5]2[CH:4]=[C:3]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]3)[C:2]([N:1]3[CH:36]=[CH:37][C:38]([CH:34]=[O:33])=[CH:39]3)=[CH:7][N:6]=2)=[N:10][CH:11]=1)#[N:16]
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2N)C1
Reactant: COC1CC(C=O)C(OC)O1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2-n2ccc(C=O)c2)C1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
tert-Butyl 3-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (60 mg, 0.141 mmol) (Synthesis 101-C) was dissolved in DCE/AcOH (1/1, 5 mL). 2,5-Dimethoxytetrahydrofuran-3-carboxaldehyde (28 uL, 0.211 mmol) was added and the solution was stirred at 80° C. for 1 h. The solution was evaporated to dryness and the product (143 mg, approximately 50% purity) was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:5][C:6](=[O:9])[C:7]=1[CH3:8])=O.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1>C(O)(=O)C>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:17]2[C:6](=[O:9])[C:7]([CH3:8])=[C:2]([CH3:1])[C:3]2=[O:5])=[CH:14][CH:13]=1
Reactant: COc1ccc(CN)cc1
Reactant: CC1=C(C)C(=O)OC1=O
Solvent: CC(=O)O
Product: COc1ccc(CN2C(=O)C(C)=C(C)C2=O)cc1

Procedure:
2,3-Dimethylmaleic anhydride (1 g, 7.9 mmol) and 4-methoxybenzylamine (1 mL, 7.9 mmol) were heated to reflux in 5 mL glacial acetic acid for 4.5 h. Solvent was evaporated. The residue was taken up in EtOAc and washed with sat'd aq NaHCO3, water, and brine. The organic phase was dried (MgSO4), filtered, and evaporated. The title compound was obtained as a solid and used without further purification (1.9 g, quant).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].CC(C)([O-])C.[K+].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br>CN(C)C=O.C(#N)C>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[C:24]([F:23])([F:33])[F:34])[N:8]=1)=[O:5]
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Reactant: FC(F)(F)c1ccccc1CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(Nc1ccn(Cc2ccccc2C(F)(F)F)n1)c1c(F)cccc1F
Reaction time: 0.17 h

Procedure:
A solution of 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide ((for a preparation see Intermediate 9)(31.9 mg, 0.1 mmol) in dimethylformamide (0.4 ml) was treated with potassium t-butoxide (11.3 mg, 0.1 mmol) and allowed to stand at room temperature for 10 min. A solution of 2-(trifluoromethyl)benzyl bromide (22.3 mg, 0.1 mmol, Aldrich) in acetonitrile (0.2 ml) was finally added and the solution left to stand for 16 h at room temperature. The solvent was removed using a Genevac and the crude mixture dissolved in a 1:1 mixture of dimethylsulphoxide:methanol (0.6 ml) and the solution purified by MDAP on SUNFIRE C18 (Method D). The appropriate fraction was concentrated in vacuo using a Genevac to give the title compound (2.3 mg);
Reaction SMILES: [OH:1][C@H:2](/[CH:15]=[CH:16]/[CH2:17][CH2:18][S:19][C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:3][C:4](N1[C@H](C(C)C)CSC1=S)=[O:5].[Li+].[OH-].Cl.CC[O:44]C(C)=O>C1COCC1.O>[OH:1][C@H:2](/[CH:15]=[CH:16]/[CH2:17][CH2:18][S:19][C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:3][C:4]([OH:44])=[O:5]
Reactant: CC(C)[C@@H]1CSC(=S)N1C(=O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 86 %

Procedure:
At 0° C. to a solution of (S,E)-3-hydroxy-1-((R)-4-isopropyl-2-thioxothiazolidin-3-yl)-7-(tritylthio)hept-4-en-1-one (934 mg, 1.66 mmol, prepared according to the procedure in Yurek-George, A. et al, J. Am. Chem. Soc. 2004, 126, 1030) in THF (30 mL) was added a solution of LiOH (196.1 mg, 8.19 mmol) in H2O (10 mL). The reaction mixture was allowed to warm to rt over 1 h, whereupon 1M HCl was added until the pH reached 2. EtOAc (30 mL) was then added and the layers were separated. The aqueous layer was extracted with EtOAc (20 mL) the organic layers were combined, dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography (eluant 3:7-1:1-1:0 EtOAc/Hexane) gave the 6 as a white solid (600 mg, 1.43 mmol, 86%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[CH:4][N+:3]=1[O-].[OH-].[K+].O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:5]1[N:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[N:3][CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ncc[n+]([O-])c1C
Agent: [K+]
Agent: [OH-]
Product: Cc1ncc(Cl)nc1C
Reaction time: 2 h

Procedure:
2,3-Dimethyl-pyrazine 1-oxide (25 g, 0.2 mol) was dissolved in POCl3 (200 mL) under cooling. The mixture was gradually heated to reflux and stirred for 2 hours. After cooling, the reaction mixture was poured onto ice, basified to pH 8 with a saturated KOH solution under cooling and extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated. The residue was purified by column (P.E./EtOAc 100:1-60:1) to obtain 5-chloro-2,3-dimethylpyrazine. 1HNMR (CDCl3, 300 MHz) δ 8.31 (s, 1H), 2.53 (s, 6H). MS (ESI) m/e (M+H+) 143.2.
Reaction SMILES: C(OC(N[C@:7]([CH2:35][CH2:36]CC)([C:15]([N:17]1[CH2:34][CH2:33][CH2:32][C@H:18]1[C:19]([NH:21][C@H:22]([CH:30]=[O:31])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:29])[NH2:28])=[O:20])=O)CC1C=CC=CC=1)=O)C.Cl.[CH2:40]([O:42][C:43]([NH:45][C@:46](CCCC)([C:54](N1CCC[C@H]1C(OCC1C=CC=CC=1)=O)=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:44])[CH3:41]>>[CH2:40]([O:42][C:43]([NH:45][C@H:46]([C:54]([C@@:18]1([C:19]([NH:21][C@H:22]([CH:30]=[O:31])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:29])[NH2:28])=[O:20])[CH2:32][CH2:33][CH2:34][N:17]1[CH2:15][CH2:7][CH2:35][CH3:36])=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:44])[CH3:41]
Reactant: CCCC[C@@](Cc1ccccc1)(NC(=O)OCC)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: CCCC[C@@](Cc1ccccc1)(NC(=O)OCC)C(=O)N1CCC[C@H]1C(=O)N[C@H](C=O)CCCNC(=N)N
Agent: Cl
Product: CCCCN1CCC[C@]1(C(=O)N[C@H](C=O)CCCNC(=N)N)C(=O)[C@H](Cc1ccccc1)NC(=O)OCC

Procedure:
By methods substantially equivalent to those described in Example 17, 1.47 g of EtOCO-Phe(αn-Bu)-Pro-Arg-H·HCl was prepared from EtOCO-Phe(αn-Bu)-Pro-OBzl (TLC Rf =0.74, 50% ethyl acetate:hexanes). EtOCO-Phe(αn-Bu)-Pro-Arg-H·HCl was purified by RPHPLC (98/2 (A/B), 60 min; to 85/15 (A/B), 300 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][S:30]([CH:29]=[CH2:28])(=[O:32])=[O:31])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52.3 %

Procedure:
To a solution of N-(3-bromophenyl)-4,6-quinazolindiamine (315 mg, 1 mmol) and triethylamine (0.5 mL) in THF (50 mL) at 0° C. was dropwise added 2-chloroethylsulfonyl chloride (490 mg, 3 mmol). After the solution was stirred at 0° C. for 10 min, it was chromatographed on silica gel with 10% methanol in chloroform to give 212 mg of ethenesulfonic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide as an light yellow solid: HRMS (m/e): M+403.9937. Modified a method from A. A. Goldberg, J. Chem., Soc., 464 (1945).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:36])[CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])=[CH:23][CH:22]=2)=[O:19])[CH:15]=[CH:16][CH:17]=1.C(O)(C(F)(F)F)=O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:36])[CH2:28][C:29]([OH:31])=[O:30])=[CH:23][CH:22]=2)=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: CC(CC(=O)OC(C)(C)C)c1ccc(NC(=O)c2cccc(NC=NN)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(CC(=O)O)c1ccc(NC(=O)c2cccc(NC=NN)c2)cc1

Procedure:
The compound of Example 30 was hydrolyzed with TFA under conditions similar to those described in Example 33.
Reaction SMILES: COC1C=CC(C([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[OH:38])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.C(N=C=NC(C)C)(C)C>N1C=CC=CC=1>[C@@H:27]1([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[O:28][C@H:24]([CH2:23][OH:22])[C@@H:25]([OH:38])[CH2:26]1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: c1ccncc1
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O

Procedure:
In a nitrogen-replaced glove box, 5′-O-(4,4′-dimethoxytrityl)thymidine and N,N′-diisoproyl carbodiimide were dissolved in dehydrated pyridine with a concentration of 0.1 mol/L and 0.2 mol/L, respectively.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]3[C:35]([SH:36])=[N:34][C:33]4[C:28]3=[N:29][CH:30]=[N:31][CH:32]=4)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[CH3:37]N(C)C=O.[H-].[Na+].IC>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]3[C:35]([S:36][CH3:37])=[N:34][C:33]4[C:28]3=[N:29][CH:30]=[N:31][CH:32]=4)[CH2:21][CH2:20]2)=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(Cn2c(CC3CCN(CCn4c(S)nc5cncnc54)CC3)nc3ccccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CSc1nc2cncnc2n1CCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred mixture of 34.5 parts of 9-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-9H-purine-8-thiol and 180 parts of N,N-dimethylformamide were added portionwise 3.2 parts of a sodium hydride dispersion 50%. Upon completion, stirring was continued for 0.5 hours at room temperature. 11.5 Parts of iodomethane were added dropwise. After complete addition, the whole was stirred for 1 hour. The reaction mixture was poured into water. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 28.3 parts (80%) of 9-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-8-(methylthio)-9H-purine; mp. 133.1° C. (507).
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]=1.[I:26]I>O1CCCC1>[Br:16][C:17]1[CH:25]=[C:24]([I:26])[C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]=1
Reactant: II
Reactant: O=C(O)c1ccc(Br)nc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Br)cc1I
Temperature: -25 °C
Reaction time: 16 h
Yield: 64775.4 %

Procedure:
n-Butyllithium (2.5M in hexanes, 297 mL, 0.743 mol) was added over 1 h to a cooled (−25° C.) solution of 2,2,6,6,-tetramethylpiperidine (131 mL, 0.77 mol) in tetrahydrofuran (1 L). The mixture was left to stir for 16 h at −25° C. then cooled to −55° C. before addition of solid 6-bromonicotinic acid (50.0 g, 0.25 mmol). The mixture was allowed to warm to −20° C. and stirred for 2 h. The reaction mixture was cooled to −70° C. then poured onto a pre-cooled (−70° C.) solution of iodine (188.5 g, 0.74 mol) in tetrahydrofuran (500 mL). The mixture was then poured into the original reaction vessel and the contents allowed to warm to ambient temperature and stirred for 1 h. The solvent was evaporated and the resultant residue dissolved in water (500 mL) and washed with dichloromethane (3×300 mL). The aqueous phase was separated and the pH adjusted to 2 by the addition of concentrated hydrochloric acid. Aqueous sodium metabisulfite solution (20% w/w, 30 mL) was added and the solid which deposited was collected by filtration. The resultant solid was washed with water (75 mL) and pentane (75 mL) and dried at 75° C. under vacuum to furnish the title compound as a tan solid (53.1 g, 65%). 1H NMR (DMSO-D6, 300 MHz): 8.62 (s, 1H), 8.35 (s, 1H). LCMS (Method B): RT=2.16 min, M+H+=328/330.
Reaction SMILES: [CH:1]12[O:10][CH:7]([CH2:8][CH2:9]1)[CH:6]1[CH:2]2[C:3](=[O:12])[O:4][C:5]1=[O:11].[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCOCC1>[CH2:13]([O:20][C:5]([CH:6]1[CH:2]([C:3]([OH:12])=[O:4])[CH:1]2[O:10][CH:7]1[CH2:8][CH2:9]2)=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: O=C1OC(=O)C2C3CCC(O3)C12
Solvent: C1COCCO1
Product: O=C(O)C1C2CCC(O2)C1C(=O)OCc1ccccc1
Temperature: 80 °C

Procedure:
A mixture of 4,10-dioxa-tricyclo[5.2.1.02,6]decane-3,5-dione (8, 3.7 g, 22.0 mmol) and benzyl alcohol (9) (4.5 mL, 44.0 mmol) in dioxane was heated at 80° C. for 16 h. Cooled to room temperature and evaporated to remove solvent. Residue obtained was triturated with diisopropyl ether (20 mL) to give white solid of 10 which was filtered, washed with diisopropyl ether (10 mL) and dried. Yield: 3.6 g (59%). 1H NMR (300 MHz, CDCl3) δ 1.45-1.55 (m, 2H); 1.78-1.81 (m, 2H); 3.05 (s, 2H); 4.91 (d, J=9.4 Hz, 2H); 5.02 (d, J=6.3 Hz, 1H); 5.13 (d, J=6.3 Hz, 1H); 7.28-7.40 (m, 5H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][S:9]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10].Cl[C:23]1[N:32]=[C:31]([NH2:33])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>C(O)CC(C)C>[NH2:33][C:31]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[C:23]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][S:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[N:32]=1
Reactant: NCCCCCCNS(=O)(=O)c1cccc2ccccc12
Reactant: Nc1nc(Cl)nc2ccccc12
Solvent: CC(C)CCO
Product: Nc1nc(NCCCCCCNS(=O)(=O)c2cccc3ccccc23)nc2ccccc12

Procedure:
A solution of naphthalene-1-sulfonic acid (6-amino-hexyl)-amide (0.450 g) and 2-chloro-quinazolin-4-ylamine (see: U.S. Pat. No. 3,956,495) (0.264 g) in 20 ml of isopentylalcohol is heated up to 120° C. for 15 h. Concentration of the reaction mixture followed by chromatography on silica gel (B1) yields naphthalene-1-sulfonic acid [6-(4-amino-quinazolin-2-ylamino)-hexyl]-amide as a white powder, melting at 98-101° C. Rf(B1) 0.28, FAB-MS: (M+H)+=450. Analytical C26H29N5O2S+HCl+H2O+0.6 1,4 dioxane. m.p. 98-101° C.
Reaction SMILES: I.I.[N:3]1([C:10]2[N:14]([CH:15]=[CH2:16])[C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[N:11]=2)[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:21][O:22][C:23]1[CH:48]=[CH:47][C:46]([N:49]2[CH:53]=[N:52][N:51]=[N:50]2)=[CH:45][C:24]=1[C:25]([N:27]1[CH2:31][CH2:30][C:29]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([CH2:32][CH2:33]OS(C)(=O)=O)[CH2:28]1)=[O:26].C(N(CC)CC)C>C(#N)C>[CH3:21][O:22][C:23]1[CH:48]=[CH:47][C:46]([N:49]2[CH:53]=[N:52][N:51]=[N:50]2)=[CH:45][C:24]=1[C:25]([N:27]1[CH2:31][CH2:30][C@@:29]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([CH2:32][CH2:33][N:6]2[CH2:7][CH2:8][CH2:9][N:3]([C:10]3[N:14]([CH:15]=[CH2:16])[C:13]4[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=4[N:11]=3)[CH2:4][CH2:5]2)[CH2:28]1)=[O:26]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: C=Cn1c(N2CCCNCC2)nc2ccccc21
Agent: I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=Cn1c(N2CCCN(CC[C@]3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4OC)C3)CC2)nc2ccccc21
Reaction time: 0.08 h
Yield: 21.2 %

Procedure:
Reflux a stirred solution of 2-[1,4]diazepan-1-yl-1-vinyl-1H-benzoimidazole dihydroiodide (0.70 g, 1.40 mmol), 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl-3-phenyl-3-(2-methanesulfonyloxyethyl)-pyrrolidine (0.61 g, 1.3 mmol, example 47.2), triethylamine (4.48 mmol) and acetonitrile (18 mL) under argon for 48 hours. Cool and concentrate in vacuo. Thin layer analysis (silica gel, 10% methanol/0.1% ammonium hydroxide solution in acetonitrile) indicates a mixture with a major component Rf=0.40. Dilute with dichloromethane (150 mL), wash the organic phase with NaHCO3 solution (50 mL), dry (Na2SO4) the organic phase, filter and evaporate in vacuo. Purify the residue by flash chromatography (silica gel, 7×15 cm) eluting with 10% methanol/0.1% ammonium hydroxide solution in dichloromethane, concentrate the appropriate fractions to afford a tan solid. Purify the solid (in three separate injections of 110 mg, 250 mg and 250 mg) by reverse phase chromatography (PrepPak 40×100 mm μBondapak C18, 10 μm, 125 A°, Waters 037684, flow rate 35 mL/minute using the following gradients: 5 minutes with 10% acetonitrile/90% water with 0.1% trifluoroacetic acid, increase over 30 minutes to 50/50 water/acetonitrile, hold 5 minutes at 50/50 water/acetonitrile, increase over 5 minutes to 100% acetonitrile, hold 15 minutes at 100% acetonitrile). Combine the desired fractions to afford 0.17 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@H:14]2[CH2:18][OH:19])(=[O:12])=[O:11])=[C:5]([CH3:20])[CH:4]=1.[OH-].[Na+].Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>ClCCl.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:20])[C:6]([S:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@H:14]2[CH2:18][O:19][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1cc(C)c(S(=O)(=O)N2CCC[C@H]2CO)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCC[C@H]2COCC(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
To a solution of (S)-(1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methanol (2.7 g, 9.0303 mmol) in dichloromethane (45 ml) was added 35% aq NaOH solution (45 ml) followed by addition of tetra-n-butylammonium chloride (290 mg, 0.09308 mmol). The reaction mixture was stirred for 15 min at room temperature. Then it was cooled to 0° C. and tert-butyl 2-bromoacetate (1.7 ml, 10.83 mmol) was added and the mixture stirred for 2 h at room temperature. After completion of the reaction the organic layer was separated and washed with water and brine. The organic layer was dried over sodium sulfate and purified by column chromatography. Yield: 81%.
Reaction SMILES: [Br-].[Li+].[Br-].[CH2:4]([O:6][C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Zn+])[CH3:5].Cl[C:16]1[N:25]=[C:24]2[C:19]([CH:20]=[C:21]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:23]2)=[CH:18][CH:17]=1.CN1C(=O)N(C)CC1>C1COCC1>[C:32]1([C:21]2[CH:20]=[C:19]3[C:24](=[N:23][C:22]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:25]=[C:16]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]([O:6][CH2:4][CH3:5])=[O:14])[CH:17]=[CH:18]3)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Clc1ccc2cc(-c3ccccc3)c(-c3ccccc3)nc2n1
Reactant: CCOC(=O)CCCCC[Zn+]
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCN(C)C1=O
Product: CCOC(=O)CCCCCc1ccc2cc(-c3ccccc3)c(-c3ccccc3)nc2n1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture comprising lithium bromide (307 mg, 3.54 mmol) and PEPPSi-iPr catalyst (75 mg, 0.110 mmol) in THF (2 ml) was stirred at room temperature for 15 minutes until a solution formed. (6-Ethoxy-6-oxohexyl)zinc(II) bromide (13.26 ml of a 0.5M solution in THF, 6.62 mmol) was added and the mixture was cooled to 0° C. A solution of 7-chloro-2,3-diphenyl-1,8-naphthyridine (step 1) (350 mg, 1.105 mmol) in THF (3 ml)/DMI (1 ml) was added and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was partitioned between EtOAc and water and the organic portion was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-50% EtOAc in iso-hexane afforded the title product as a yellow oil; LC-MS Rt=1.54 mins; [M+H]+425.3, Method 2minLC_v002
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][O:33][C:32]([CH3:37])([CH3:36])[CH2:31]1>>[CH3:36][C:32]1([CH3:37])[CH2:31][CH:30]([CH2:29][CH2:28][CH2:27][N:20]2[C:19]([O:23][CH3:24])=[N:18][C:17]3[C:21]2=[N:22][C:14]([O:13][C@H:9]([CH3:8])[CH2:10][CH2:11][CH3:12])=[N:15][C:16]=3[NH2:25])[CH2:35][CH2:34][O:33]1
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: CC1(C)CC(CCCBr)CCO1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCOC(C)(C)C3)c2n1

Procedure:
Prepared similarly to Intermediate 223 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(3-bromopropyl)-2,2-dimethyltetrahydro-2H-pyran but conducting the alkylation over 1 hour at 60° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[Br:8][C:9]1[N:14]=[CH:13][C:12](O)=[CH:11][CH:10]=1>>[Br:8][C:9]1[N:14]=[CH:13][C:12]([O:1][C@@H:2]2[CH2:6][CH2:5][NH:4][C:3]2=[O:7])=[CH:11][CH:10]=1
Reactant: O=C1NCC[C@@H]1O
Reactant: Oc1ccc(Br)nc1
Product: O=C1NCC[C@H]1Oc1ccc(Br)nc1

Procedure:
Typical Procedure 3 was followed. Reaction of (S)-3-hydroxy-pyrrolidin-2-one with 6-bromo-pyridin-3-ol provided the subtitle compound. MS ESI+: m/z=257 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][N:8]=[C:7]2O.P(Cl)(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][N:8]=[C:7]2[Cl:15]
Reactant: Oc1ncnc2c(Br)cccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2c(Br)cccc12
Reaction time: 0.08 h
Yield: 99.6 %

Procedure:
A suspension of 8-bromoquinazolin-4-ol (410 mg, 1.822 mmol) in phosphorous oxychloride (15.000 mL, 161 mmol) was heated to reflux. After refluxing 45 min, a clear, amber solution was observed. Refluxed an additional 30 min, concentrated in-vacuo, and concentrated 2× from methylene chloride to remove residual phosphorous oxychloride. The residue was taken up in ethyl acetate (50 mL), treated with the careful addition of saturated sodium bicarbonate, and this mixture was stirred for 5 minutes, until gas evolution had ceased. The layers were separated, the and the aqueous phase was extracted with ethyl acetate (20 mL). The combined organic phases were washed with saturated sodium bicarbonate, water, and saturated sodium chloride, dried over sodium sulfate, and concentrated in-vacuo to yield the title compound (442 mg, 1.815 mmol, 100% yield) as a tan powder which was used as-is in the next step.