Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7](/[CH:10]=[C:11](/[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])\[CH3:12])=[CH:8][CH:9]=1)=[O:4].[OH-].[Li+].Cl>O1CCCC1>[C:16]([O:15][C:13](/[C:11](/[CH3:12])=[CH:10]/[C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)c1ccc(/C=C(\C)C(=O)OC(C)(C)C)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C/C(=C\c1ccc(C(=O)O)s1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
5-[(1E)-2-(tert-Butoxycarbonyl)-prop-1-en-1-yl]thiophene-2-carboxylic acid methyl ester (1.18 g, 4.19 mmol) obtained in step 1 was dissolved in tetrahydrofuran (5 mL), 1N aqueous lithium hydroxide solution (4.6 ml) was added, and the mixture was stirred overnight. The mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated to give the title compound (1.06 g).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.[N:17]1([CH2:21][C@H:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:25]=2)[NH2:23])[CH2:20][CH2:19][CH2:18]1>>[N:17]1([CH2:21][C@@H:22]([NH:23][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([C:31]([F:32])([F:33])[F:34])[CH:25]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: N[C@H](CN1CCC1)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: NC(=O)c1ccnc2c(N[C@H](CN3CCC3)c3ccc(Cl)c(C(F)(F)F)c3)ncnc12

Procedure:
Compound 41 was prepared following general synthesis scheme 8 wherein 4-hydroxy-pyrido[3,2-d]pyrimidine-8-carboxylamide (G) was reacted with (S)-2-(azetidin-1-yl)-1-(4-chloro-3-(trifluoromethyl)phenyl)ethanamine dihydrochloride to give the title compound as a off-white solid. LC/MS [451 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.20 (s, 1H), 9.01 (d, 1H), 8.56 (d, 1H), 8.39 (dd, 1H), 8.20 (d, 1H), 8.05 (s, 1H), 7.80 (d, 1H), 7.68 (d, 1H), 5.38 (t, 1H), 3.11 (ddd, 5H), 2.84 (dd, 1H), 1.93 (p, 2H). IC50 p70S6K: 1.6 nM, Akt: 11 nM
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[F:15][C:16]1[CH:48]=[CH:47][C:19]2[N:20]=[C:21]([NH:23][C:24]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH:27]3[CH2:39][O:40][C:41]3[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=3)=[O:25])[S:22][C:18]=2[CH:17]=1>CO>[ClH:1].[ClH:1].[F:15][C:16]1[CH:48]=[CH:47][C:19]2[N:20]=[C:21]([NH:23][C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH:27]3[CH2:39][O:40][C:41]3[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=3)=[O:25])[S:22][C:18]=2[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2nc3ccc(F)cc3s2)C(COc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(Nc1nc2ccc(F)cc2s1)N1CCNCC1COc1cccnc1
Reaction time: 1 h
Yield: 90 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(6-fluorobenzo[d]thiazol-2-ylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (122 mg, 0.203 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure, yielding 83.9 mg (90%) of the title compound as a white solid. LC-MS: RT=4.61 min, [M+H]+=388.1.
Reaction SMILES: C(OC(=O)[CH:5]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[O:27])[N:24]([CH3:26])[CH3:25])[CH:18]=2)=[O:15])=[N:10][CH:9]=1)[CH3:6])C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(C[C:50]([OH:52])=[O:51])N=2)CCCC1.C1(CNC2C=C(C=CC=2)C(N(C)C)=O)CCCC1.C(OC(=O)C(SC1SC(N)=NC=1)C)C>>[CH:29]1([CH2:28][N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[O:27])[N:24]([CH3:26])[CH3:25])[CH:18]=2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:5][CH2:6][C:50]([OH:52])=[O:51])=[CH:9][N:10]=2)[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CCOC(=O)C(C)Sc1cnc(NC(=O)N(CC2CCCC2)c2cccc(C(=O)N(C)C)c2)s1
Reactant: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: CCOC(=O)C(C)Sc1cnc(N)s1
Agent: CN(C)C(=O)c1cccc(NCC2CCCC2)c1
Product: CN(C)C(=O)c1cccc(N(CC2CCCC2)C(=O)Nc2ncc(SCCC(=O)O)s2)c1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-dimethylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3-(cyclopentylmethyl-amino)-N,N-dimethyl-benzamide and (2-amino-thiazol-5-ylsulfanyl) propionic acid ethyl ester
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:12][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:11]=2)[C:6](=[O:19])[C:7]([C:13]2[N:17]([CH3:18])[N:16]=[N:15][N:14]=2)=[CH:8]1
Reactant: C1COCCN1
Reactant: Cn1nnnc1-c1cn(C)c2cc(F)ccc2c1=O
Product: Cn1nnnc1-c1cn(C)c2cc(N3CCOCC3)ccc2c1=O

Procedure:
In a similar way to that described in Example 30, 7-fluoro-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone (1 g) was heated with morpholine (25 ml) at 100° for 103 hours to give 1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-7-morpholino-4-quinolone, m.p. 235°-238°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([C:21]([N:23]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:24][CH2:25][C:26](O)=[O:27])=[O:22])=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[C:64]([O:68][C:69](=[O:74])[NH:70][CH2:71][CH2:72][NH2:73])([CH3:67])([CH3:66])[CH3:65]>O1CCCC1.O.C(OCC)(=O)C>[C:64]([O:68][C:69](=[O:74])[NH:70][CH2:71][CH2:72][NH:73][C:26](=[O:27])[CH2:25][CH2:24][N:23]([C:21]([C:19]1[CH:18]=[CH:17][C:14]2[N:15]([CH3:16])[C:11]([CH2:10][NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)=[N:12][C:13]=2[CH:20]=1)=[O:22])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)([CH3:67])([CH3:65])[CH3:66]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccn3)ccc21
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCC(=O)NCCNC(=O)OC(C)(C)C)c3ccccn3)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of the product of 2a (2.20 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU, 2.20 mmol) and N-methyl-morpholin (2.20 mmol) in dry tetrahydrofuran (100 mL) was stirred at room temperature for 15 minutes. Then (2-amino-ethyl)-carbamic acid tert-butyl ester (2.20 mmol) was added and the mixture stirred at room temperature for another 24 hours. The mixture was then diluted with 40 mL water, the product was isolated through extraction with ethyl acetate and purified by chromatography (silica gel; dichloromethane/methanol 15:1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][CH:9]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][CH:9]=1
Reactant: [H][H]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(N)cn1

Procedure:
Ethyl 2-(5-nitropyridin-2-yl)acetate (1.75 g, 8.33 mmol) was dissolved in ethyl acetate (20 ml) the added Pd/C (1.0 g, 9.4 mmol) and stirred under a balloon of hydrogen for 3 hrs. Filtered off the catalysts and concentrated to yield ethyl 2-(5-aminopyridin-2-yl)acetate: LC-MS: M+1=181
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:8][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][N:11]=2)[N:3]=1.CN(C=O)C.[Na+].[I-].[Cl:25][C:26]1[CH:31]=[C:30]([CH2:32]Cl)[CH:29]=[CH:28][N:27]=1>O>[Cl:25][C:26]1[CH:31]=[C:30]([CH2:32][N:6]2[C:2]([CH3:1])=[N:3][C:4]([C:7]3[O:8][C:9]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:10][N:11]=3)=[N:5]2)[CH:29]=[CH:28][N:27]=1
Reactant: Cc1nc(-c2nnc(-c3ccccc3)o2)n[nH]1
Reactant: ClCc1ccnc(Cl)c1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2nnc(-c3ccccc3)o2)nn1Cc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a solution of 2-(5-methyl-1H-1,2,4-triazol-3-yl)-5-phenyl-1,3,4-oxadiazole (1.00 mg, 0.44 mmol) in DMF (3 mL) Cs2CO3 (430 mg, 1.32 mmol), NaI (78 mg, 0.52 mmol) and 2-chloro-4-(chloromethyl)pyridine (78 mg, 0.48 mmol) were added. The reaction was allowed to stir overnight at RT and then diluted with H2O (10 mL), extracted with EtOAc (3×10 mL), 4:1 CHCl3:i-PrOH (5×10 mL), dried with MgSO4 and concentrated. The crude product was purified on a Biotage pre-packed silica gel column (EtOAc:Hexane 12% to 100% EtOAc) to afford 2-(1-((2-chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazol-3-yl)-5-phenyl-1,3,4-oxadiazole (88 mg, 57%) as an off-white powder. MS (ES+) C17H13ClN6O requires: 352 found: 353 [M+H]+.
Reaction SMILES: [CH2:1]([CH:6]([CH2:9][OH:10])[CH2:7][OH:8])[CH2:2][CH2:3][CH2:4][CH3:5].[OH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([CH:19]=O)[CH2:15][CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([CH:6]1[CH2:9][O:10][CH:19]([C@H:16]2[CH2:17][CH2:18][C@H:13]([CH2:12][OH:11])[CH2:14][CH2:15]2)[O:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C[C@H]1CC[C@H](CO)CC1
Reactant: CCCCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC1COC([C@H]2CC[C@H](CO)CC2)OC1

Procedure:
A solution of 100 mmol of 2-pentylpropane-1,3-diol, 100 mmol of trans-4-hydroxymethylcyclohexanecarbaldehyde and 10 mmol of p-toluenesulfonic acid in 500 ml of toluene is heated at the boil on a water separator until the water separation is complete. Conventional work-up gives trans/trans-[4-(5-pentyl-1,3-dioxan-2-yl)cyclohexyl]methanol.
Reaction SMILES: [CH2:1]([CH:3]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][C:5]([NH2:7])=[O:6])[CH3:2].[Cl:12]O>C(OCC)(=O)C>[Cl:12][NH:7][C:5]([CH2:4][CH:3]([CH2:1][CH3:2])[CH2:8][CH2:9][CH2:10][CH3:11])=[O:6]
Reactant: CCCCC(CC)CC(N)=O
Reactant: OCl
Solvent: CCOC(C)=O
Product: CCCCC(CC)CC(=O)NCl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.8 %

Procedure:
2-ethylhexyl carboxamide (35.75 g, 250 mmol) was suspended in 300 ml of ethyl acetate and cooled to 1°. Hypochlorous acid (43.3 g of 30.6% solution, 252 m mol) was added dropwise over 13 minutes with stirring. After 10 minutes, the cooling bath was removed and stirring continued for 1 hour while the mixture warmed to room temperature. The ethyl acetate layer was then separated and dried (MgSO4) and the solvent was removed on the rotary evaporator and, finally, on the vacuum pump to give 44 g (98%) of colorless liquid N-chloro-2-ethylhexyl carboxamide.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6].[CH3:9][C:10]([CH2:26][CH2:27][CH2:28][CH:29]([CH3:36])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[CH:11][CH2:12][CH2:13][CH2:14]OS(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O>[CH3:9][C:10]([CH2:26][CH2:27][CH2:28][CH:29]([CH3:36])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[CH:11][CH2:12][CH2:13][CH2:14][O:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6]
Reactant: OCC(O)CO
Reactant: CC(=CCCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=CCCCOCC(O)CO)CCCC(C)CCCC(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 6 %

Procedure:
0.26 g (55%, 5.9 mmol) of sodium hydride was added to a solution of 0.54 g (5.9 mmol) of glycerol in dry N,N-dimethylformamide (6 mL) with cooling on ice. After the mixture was stirred for 30 min at 50° C., the above (5,9,13-trimethyltetradec-4-enyl)tosylate was added dropwise, with additional stirring for 18 hours at the same temperature. After addition of water at 0° C., the reaction mixture was extracted with ethyl acetate. The extract was washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane mixture) to obtain 73 mg of the title compound (6% yield in 2 steps). The results of NMR analysis of the obtained compound are as shown below.
Reaction SMILES: [N+:1]([C:4]1[C:13]([Br:14])=[C:12]([Br:15])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:17])[C:8](=[O:16])[NH:9]2)([O-])=O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[C:13]([Br:14])=[C:12]([Br:15])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:17])[C:8](=[O:16])[NH:9]2
Reactant: O=c1[nH]c2cc(Br)c(Br)c([N+](=O)[O-])c2[nH]c1=O
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1c(Br)c(Br)cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 90 °C
Reaction time: 4 h
Yield: 64.7 %

Procedure:
To a stirred mixture of 5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (327 mg, 0.89 mMol) in ethanol (10 mL) was added SnCl2 ·2H2O (1.0 g, 4.45 mMol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) with stirring for 4 h. The mixture was then cooled to room temperature and the yellow precipitate was collected by filtration, followed by washing with cold ethanol (2×1 mL), to get 227 mg (76%) of crude title product (contains minor impurities by NMR). Crystallization from DMSO/H2O gave 193 mg of pure title product as bright yellow needles; mp: 324°-6° C. (dec.), changed color from 270° C. IR (KBr, cm-1): 3456; 3281; 1700; 1643. NMR (1H, DMSO-d6): δ5.844 (s, 2H); 6.732 (s, 1H); 11.257 (s, 1H); 11.810 (s, 1H). Purity:>96.96% by HPLC. HRMS: calcd for C8H5N3O2Br2 (M+) m/z 332.8747; found: 332.8754. Potency relative to DCK: 341%.
Reaction SMILES: [C:1]([OH:15])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(Cl)(=O)C([Cl:19])=O>C1C=CC=CC=1>[C:1]([Cl:19])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99.9 %

Procedure:
To a stirred solution of 13.2 grams (61.5 mmol) of tridecanoic acid in 80 mL of benzene was added 26.2 grams (206 mmol) of oxalyl chloride. After stirring for 20 minutes, the mixture was heated to reflux and maintained at reflux overnight. The mixture was cooled to room temperature and the solvent was removed at reduced pressure to provide 14.3 grams (100%) of tridecanoyl chloride as an orange oil which was used without any further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[CH:3]=1.[O:16]1[CH2:21][CH2:20][N:19]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2B(O)O)(=[O:24])=[O:23])[CH2:18][CH2:17]1>>[F:15][C:4]1[CH:3]=[C:2]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[S:22]([N:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)(=[O:23])=[O:24])[CH:7]=[CH:6][C:5]=1[C:8]1[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Reactant: O=S(=O)(c1ccccc1B(O)O)N1CCOCC1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCOCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 42 using 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine and (2-(morpholinosulfonyl)phenyl)boronic acid. MS (ESI): mass calcd. for C20H19FN4O3S, 414.12; m/z found, 415.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.38 (s, 1H), 8.31 (s, 1H), 8.13-8.09 (m, 1H), 7.99 (m, 1H), 7.75-7.69 (m, 1H), 7.65-7.60 (m, 1H), 7.46-7.43 (m, 1H), 7.37-7.31 (m, 2H), 3.54-3.46 (m, 4H), 2.91-2.84 (m, 4H).
Reaction SMILES: [C:1]1([CH:7]([O:16][C:17]2[CH:24]=[CH:23][C:20]([CH2:21]O)=[CH:19][CH:18]=2)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Br-:31].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[C:1]1([CH:7]([O:16][C:17]2[CH:24]=[CH:23][C:20]([CH2:21][Br:31])=[CH:19][CH:18]=2)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Br-]
Reactant: OCc1ccc(OC(CCc2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: BrCc1ccc(OC(CCc2ccccc2)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
To an ice cold solution of 6-5 (1.19 g, 6.0 mmol) in acetonitrile (15 ml) was added pyridine (0.76 g, 9.6 mmol) and then triphenylphosphine dibromide (3.29 g, 7.8 mmol). The mixture was stirred at ice bath temperature for 1/4 hr under N2 and at ambient temperature for 1 &3/4 hrs and then was filtered. Concentration of the filtrate in vacuo gave a crude oil. The pure product 6-6 was obtained after three silica gel chromatographic separations.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19](Cl)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:29][CH2:30][CH2:31][OH:32]>>[NH2:29][CH2:30][CH2:31][O:32][C:19]1[N:18]=[CH:17][N:16]=[C:15]([NH:14][S:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][CH:7]=2)(=[O:13])=[O:12])[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1
Reactant: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: NCCO
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCN)cc1

Procedure:
According to Example 4b), 500 mg 4-tert.-butyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-benzene sulfonamide was reacted with 2-amino-ethanol to give 450 mg N-[6-(2-amino-ethoxy)-5-p-tolyl-pyrimidin-4-yl]4-tert.-butyl-benzenesulfonamide. LC-MS: tR=3.90 min, [M−1]−=439.44.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)=[N:7][C:6]=2[CH:16]=1.C(=O)([O-])[O-].[Ca+2].C(COC)OC.[C:29](Cl)(Cl)=[S:30]>O>[N:1]([C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)=[N:7][C:6]=2[CH:16]=1)=[C:29]=[S:30]
Reactant: S=C(Cl)Cl
Reactant: Cc1cc2oc(-c3ccccn3)nc2cc1N
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: COCCOC
Solvent: O
Product: Cc1cc2oc(-c3ccccn3)nc2cc1N=C=S
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
A mixture of 5-amino-6-methyl-2-(2-pyridinyl)benzoxazole (8.7 g, 0.044 mole), calcium carbonate (4.44 g, 0.044 mole), glyme (150 ml) and water (50 ml) is cooled to 5° C in an ice-bath, and thiophosgene (5.11 g, 0.044 mole) is added. The mixture is stirred for 0.5 hour at 5° C and then allowed to warm to room temperature and stirred for about 16 hours. The precipitated material is collected, washed with water and crystallized from glyme/water (3:1) yielding 8.1 g of the title compound, melting point 192°-194° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:23])[CH2:14][O:15]CC2C=CC=CC=2)=[CH:8][CH:7]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:24])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:23])[CH2:14][OH:15])=[CH:8][CH:7]=1
Reactant: COC(=O)COc1ccc(NC(=O)COCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)COc1ccc(NC(=O)CO)cc1
Reaction time: 5 h
Yield: 77 %

Procedure:
[4-(2-Benzyloxyacetylamino)phenoxy]acetic acid methyl ester 49 (25 g, 76 mmol) was dissolved in methanol (450 ml) in a pressure vessel. Palladium on carbon (5%, 10 g) was added and the mixture stirred under a hydrogen atmosphere (2 kg) for 5 hrs. Catalyst was removed by filtration and methanol distilled off. Crude 50 was recrystallised in chloroform:hexane (1:6) to give pure 50 (14 g) as a white powder with an m.p. between 147.5-150° C.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@@H:14]([OH:15])[CH2:13][C@H:12]([O:16][C@H:17]3[C@@H:22]([OH:23])[CH2:21][C@H:20]([O:24][C@@H:25]4[CH2:30][C@H:29]5[CH2:31][CH2:32][C@H:33]6[C@@:38]7([OH:48])[CH2:39][CH2:40][C@H:41]([C:42]8[CH2:47][O:46][C:44](=[O:45])[CH:43]=8)[C@@:37]7([CH3:49])[C@H:36]([OH:50])[CH2:35][C@@H:34]6[C@@:28]5([CH3:51])[CH2:27][CH2:26]4)[O:19][C@@H:18]3[CH3:52])[O:11][C@@H:10]2[CH3:53])[CH2:5][C@H:4]([OH:54])[C@@H:3]1[OH:55].O.O.O.O.O.O.O.O.[OH-].[Sr+2].[OH-].S([O:72][CH3:73])(OC)(=O)=O>>[CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@@H:14]([OH:15])[CH2:13][C@H:12]([O:16][C@H:17]3[C@@H:22]([OH:23])[CH2:21][C@H:20]([O:24][C@@H:25]4[CH2:30][C@H:29]5[CH2:31][CH2:32][C@H:33]6[C@@:38]7([OH:48])[CH2:39][CH2:40][C@H:41]([C:42]8[CH2:47][O:46][C:44](=[O:45])[CH:43]=8)[C@@:37]7([CH3:49])[C@H:36]([OH:50])[CH2:35][C@@H:34]6[C@@:28]5([CH3:51])[CH2:27][CH2:26]4)[O:19][C@@H:18]3[CH3:52])[O:11][C@@H:10]2[CH3:53])[CH2:5][C@H:4]([OH:54])[C@@H:3]1[OH:55].[CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@@H:14]([OH:15])[CH2:13][C@H:12]([O:16][C@H:17]3[C@@H:22]([OH:23])[CH2:21][C@H:20]([O:24][C@@H:25]4[CH2:30][C@H:29]5[CH2:31][CH2:32][C@H:33]6[C@@:38]7([OH:48])[CH2:39][CH2:40][C@H:41]([C:42]8[CH2:47][O:46][C:44](=[O:45])[CH:43]=8)[C@@:37]7([CH3:49])[C@H:36]([OH:50])[CH2:35][C@@H:34]6[C@@:28]5([CH3:51])[CH2:27][CH2:26]4)[O:19][C@@H:18]3[CH3:52])[O:11][C@@H:10]2[CH3:53])[CH2:5][C@H:4]([OH:54])[C@@H:3]1[O:72][CH3:73]
Reactant: COS(=O)(=O)OC
Agent: C[C@H]1O[C@@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3[C@@H](O)C[C@H](O[C@H]4CC[C@@]5(C)[C@H](CC[C@@H]6[C@@H]5C[C@@H](O)[C@]5(C)[C@@H](C7=CC(=O)OC7)CC[C@]65O)C4)O[C@@H]3C)O[C@@H]2C)C[C@H](O)[C@@H]1O
Agent: [OH-]
Agent: [Sr+2]
Solvent: O
Product: CO[C@H]1[C@@H](O)C[C@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3[C@@H](O)C[C@H](O[C@H]4CC[C@@]5(C)[C@H](CC[C@@H]6[C@@H]5C[C@@H](O)[C@]5(C)[C@@H](C7=CC(=O)OC7)CC[C@]65O)C4)O[C@@H]3C)O[C@@H]2C)O[C@@H]1C
Yield: 72.62 %

Procedure:
A solution of 2.34 g (3 millimoles) of digoxin is treated with 797 mg (3 millimoles) of strontium hydroxide octahydrate and the mixture is methylated with 757 g (6 millimoles) of dimethyl sulfate at 0° C., the procedure being the same as in Example 6. Evaporation of the fractions collected gives 119 mg (4.90% of theory of dimethyldigoxin, 403 mg (17.16%) of digoxin and 1.732 g (72.62% of theory) of β-methyldigoxin, from which 1.59 g of pure β-methyldigoxin are obtained after recrystallization from acetone. The yield is 66.67% and the selectivity of the reaction is 80.48%.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.ClC(Cl)(Cl)[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[CH:26]=[N:25][CH:24]=[CH:23]2)=[O:16].C1CCN2C(=NCCC2)CC1>>[CH:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][C:18]=2[NH:17][C:15]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=2)=[O:16])[CH:23]=[CH:24][N:25]=1
Reactant: O=C(Nc1cccc2ccncc12)C(Cl)(Cl)Cl
Reactant: NCc1ccc(C(F)(F)F)cc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2ccncc12

Procedure:
The title compound was prepared using 4-(trifluoromethyl)benzylamine, the product from Example 57D, DBU and the procedure described in Example 1B. MS (ESI+) m/z 346 (M+H)+; 1H NMR (DMSO-d6) δ 9.58 (s, 1H), 9.10 (s, 1H), 8.49 (d, 1H), 8.12 (d, 1H), 7.81-7.54 (m, 7H), 7.20 (t, 1H), 4.47 (d, 2H); Anal. Calcd for C18H14F3N3O*0.2 H2O: C, 61.96, H 4.16, N 12.04. Found: C 62.06, H 4.23, N 11.91.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[NH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:16][O:17][CH2:18]Cl.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH3:16][O:17][CH2:18][N:1]1[C:5]2[C:4](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:3]=[CH:2]1
Reactant: COCCl
Reactant: c1cnc2[nH]cnc2c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCn1cnc2ncccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Azabenzimidazole (7.5 g) was dissolved in DMF (125 mL), and cesium carbonate (68 g) was added thereto. Subsequently, chloromethyl methyl ether (7.0 mL) was added dropwise thereto under ice cooling, and the mixture was stirred for one hour at room temperature. Chloromethyl methyl ether (1.9 mL) was added to the reaction mixture, and the mixture was stirred for 12 hours at room temperature. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (0% to 15% methanol/chloroform), and the title compound (5.7 g) was obtained.