Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]([NH:18][C:19]1[O:20][C:21]([CH3:35])([CH3:34])[CH:22]([C:27]2[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=2)[S:23](=[O:26])(=[O:25])[N:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.CI.[CH3:38][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>[CH3:38][O:33][C:29]1[CH:28]=[C:27]([CH:22]2[C:21]([CH3:34])([CH3:35])[O:20][C:19]([NH:18][C@H:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:10][CH2:9][OH:8])=[N:24][S:23]2(=[O:26])=[O:25])[CH:32]=[CH:31][CH:30]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2)=NS(=O)(=O)C1c1cccc(O)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C2C(C)(C)OC(N[C@@H](CCO)c3ccccc3)=NS2(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 452 mg of 3-{2-[(S)-3-(tert-butyldimethylsilanyloxy)-1-phenylpropylamino]-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-5-yl}phenol and 148 mg of methyl iodide in THF at 0° C. was added dropwise 0.44 ml of a 2 N solution of sodium bis(trimethylsilyl)amide in THF. After stirring at constant temperature for 45 minutes and then warming up to room temperature, the reaction solution was stirred for a further 4 hours and then the conversion was checked by LCMS. A further 0.20 ml of the 2 N solution of sodium bis(trimethylsilyl)amide in THF and 114 mg of methyl iodide were added. After stirring at room temperature for 16 hours, the reaction solution was diluted with 60 ml of water, 5 ml of 5% aqueous sodium thiosulfate solution were added and the mixture was extracted twice with 30 ml of ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by rotary evaporation. To detach the protecting group, the residue was dissolved in 5 ml of methanol and, after addition of 0.5 ml of concentrated hydrochloric acid, stirred at room temperature for 1 hour. The reaction solution was diluted with 50 ml of water and extracted twice with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by rotary evaporation, and the residue was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined and lyophilized. This gave the product (41.1 mg) with a molecular weight of 418.5 g/mol (C21H26N2O5S); MS (ESI): m/e=419 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[CH2:10]O)[CH:7]=[CH:6][S:5]2.BrCC1N2C(SC=C2)=NC=1Cl.[CH3:23][C:24]1[N:29]=[C:28]([SH:30])[N:27]=[C:26]([OH:31])[CH:25]=1>>[Cl:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[CH2:10][S:30][C:28]1[N:27]=[C:26]([OH:31])[CH:25]=[C:24]([CH3:23])[N:29]=1)[CH:7]=[CH:6][S:5]2
Reactant: Cc1cc(O)nc(S)n1
Reactant: OCc1c(Cl)nc2sccn12
Agent: Clc1nc2sccn2c1CBr
Product: Cc1cc(O)nc(SCc2c(Cl)nc3sccn23)n1
Yield: 22 %

Procedure:
{6-chloroimidazo[2,1-b][1,3]thiazol-5-yl}methanol was converted to 5-(bromomethyl)-6-chloroimidazo[2,1-b][1,3]thiazole, which was then reacted with 6-methyl-2-sulfanylpyrimidin-4-ol to give the title compound as a white solid (0.27 g, 22% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 4.67 (s, 2H), 6.04 (bs, 1H), 7.42 (d, J=4.7 Hz, 1H), 8.02 (d, J=4.7 Hz, 1H); M+312.8.
Reaction SMILES: Cl.Cl.[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([OH:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:11]=2)[C:8]2[CH:33]=[CH:34][CH:35]=[CH:36][C:7]=2[N:6]=1)[CH3:4].CCN(C(C)C)C(C)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C1COCC1>[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([OH:26])[CH2:25][CH2:24][CH2:23][N:22]([S:47]([CH3:46])(=[O:49])=[O:48])[CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[N:11]=2)[C:8]2[CH:33]=[CH:34][CH:35]=[CH:36][C:7]=2[N:6]=1)[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCCNC3)n(C)c2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCCN(S(C)(=O)=O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.3 %

Procedure:
A mixture of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidin-3-ol dihydrochloride from Example 746 (150 mg, 0.28 mmol) and DIPEA (192 μL, 1.12 mmol) in THF (3 mL) was stirred for 5 min before the addition of methanesulfonyl chloride (22 μL, 0.28 mmol). The resulting mixture was stirred at r.t. for 4 h then partitioned between H2O and DCM. The organic phase was washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) affording 765 (67 mg, 44%). LCMS (method I): RT 3.30 min, [M+H]+ 541.2. 1H NMR (DMSO, 400 MHz): δ 8.02-8.01 (1 H, m), 7.64-7.64 (1 H, m), 7.25-7.24 (2 H, m), 6.05 (1 H, s), 4.26 (4 H, brd s), 3.96 (3 H, s), 3.78 (4 H, t, J=4.60 Hz), 3.61 (2 H, s), 3.44-3.41 (1 H, m), 3.28-3.26 (2 H, m), 3.06-3.03 (1 H, m), 2.95 (3 H, s), 2.17-2.14 (1 H, m), 2.09-1.92 (2 H, m), 1.80-1.70 (1 H, m), 1.33 (3 H, t, J=7.43 Hz)
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([N:16]=[CH:17][C:18]=2[C:19]#[N:20])[CH:12]=[C:13]([Cl:15])[N:14]=1)C1C=CC=CC=1.B(Br)(Br)Br.CCN(CC)CC.N(CC)CC>C(Cl)Cl.CO>[Cl:15][C:13]1[N:14]=[C:9]([OH:8])[C:10]2[N:11]([N:16]=[CH:17][C:18]=2[C:19]#[N:20])[CH:12]=1
Reactant: N#Cc1cnn2cc(Cl)nc(OCc3ccccc3)c12
Agent: BrB(Br)Br
Solvent: CCNCC
Solvent: CO
Solvent: ClCCl
Product: N#Cc1cnn2cc(Cl)nc(O)c12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
4-(benzyloxy)-6-chloropyrazolo[1,5-a]pyrazine-3-carbonitrile (295 mg, 1.04 mmol) was dissolved in DCM (10 mL) under Ar and the resulting mixture was cooled to −78° C. under Ar. A 1.0 M BBr3 in DCM solution (5.2 mL, 5.2 mmol) was then added, and the resulting mixture was stirred 15 min and was then removed from the cold bath. After stirring an additional 1.25 h, the reaction was quenched with a mixture of Et3N (4.3 mL, 31 mmol), Et2NH (0.21 mL, 2.1 mmol) and MeOH (5 mL). After stirring an additional 10 min, the reaction mixture was concentrated and taken up in MeOH. The mixture was concentrated, and the concentrate was purified by silica gel chromatography (50-100% acetone in hexanes) to provide 6-chloro-4-hydroxypyrazolo[1,5-a]pyrazine-3-carbonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C7H4ClN4O: 195.0; found: 194.7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.C(N(CC)CC)C.C1COCC1.[C:23](#[N:26])[CH:24]=[CH2:25]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH2:25][CH2:24][C:23]#[N:26])[CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: OCc1cc(Cl)nc(Cl)c1
Reactant: C=CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CCCOCc1cc(Cl)nc(Cl)c1
Reaction time: 2 h
Yield: 49.2 %

Procedure:
0.36 g of 2,6-dichloro-4-pyridinemethanol and 0.1 g of triethylamine were dissolved into 2 ml of THF, 0.12 g of acrylonitrile were added to the solution at room temperature, and stirring was conducted for 2 hours. After the reacted solution was left overnight at room temperature, ethyl acetate was added. The organic phase was washed with water, and was dried by adding sodium sulfate. The solvent was removed by evaporation, and the residue was purified by silica gel column chromatography to obtain 0.23 g of 2,6-dichloro-4-(2-cyanoethoxymethyl)pyridine (Compound No. 6).
Reaction SMILES: [CH2:1]([NH:11][C:12]([O:14][C@H:15]([CH2:41][O:42][C:43](=[O:55])[NH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:16][S:17][CH2:18][C@H:19]([NH:23][C:24](=[O:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:20]([OH:22])=O)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].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.[NH2:89][CH2:90][CH2:91][O:92][CH2:93][CH2:94][O:95][CH2:96][CH2:97][O:98][CH2:99][CH2:100][P:101](=[O:108])([O:105][CH2:106][CH3:107])[O:102][CH2:103][CH3:104]>C(Cl)Cl>[CH2:106]([O:105][P:101]([CH2:100][CH2:99][O:98][CH2:97][CH2:96][O:95][CH2:94][CH2:93][O:92][CH2:91][CH2:90][NH:89][C:20](=[O:22])[C@@H:19]([NH:23][C:24](=[O:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:18][S:17][CH2:16][C@H:15]([O:14][C:12](=[O:13])[NH:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:41][O:42][C:43](=[O:55])[NH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])(=[O:108])[O:102][CH2:103][CH3:104])[CH3:107]
Reactant: CCOP(=O)(CCOCCOCCOCCN)OCC
Reactant: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC[C@@H](COC(=O)NCCCCCCCCCC)OC(=O)NCCCCCCCCCC)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC[C@@H](COC(=O)NCCCCCCCCCC)OC(=O)NCCCCCCCCCC)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-3-((R)-2,3-bis(decylcarbamoyloxy)propylthio)-2-palmitamidopropanoic acid and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (2.4 eq), followed by diethyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethylphosphonate (1.2 eq, from example 18, step 4). The reaction was stirred at room temperature for 4 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-10% MeOH/DCM to afford the title compound as an off-white oil.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:13]2[S:12](=[O:15])(=[O:14])[N:11]=[C:10]([C:16]3[C:17](=[O:32])[N:18]([NH:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:19]4[C:24]([C:25]=3[OH:26])=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:9][C:8]=2[S:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>N1C=CC=CC=1.[OH-].[NH4+]>[NH2:1][CH2:4][C:5]1[C:13]2[S:12](=[O:14])(=[O:15])[N:11]=[C:10]([C:16]3[C:17](=[O:32])[N:18]([NH:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:19]4[C:24]([C:25]=3[OH:26])=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:9][C:8]=2[S:7][CH:6]=1
Reactant: [N-]=[N+]=NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Agent: [NH4+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To the solution of 3-[7-(azidomethyl)-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-1-[(cyclopropylmethyl)amino]-4-hydroxyquinolin-2(1H)-one (357 mg, 0.62 mmol) in pyridine (4.6 mL) and concentrated ammonium hydroxide (3 mL) was added triphenylphosphine (397 mg, 1.51 mmol) at room temperature. The solution was stirred at room temperature overnight and concentrated under reduced pressure. The residue was diluted with 30% hexane/toluene and the solid was filtered to give 3-[7-(aminomethyl)-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-1-[(cyclopropylmethyl)amino]-4-hydroxyquinolin-2(1H)-one (250 mg, 90%). MS (ESI−) m/z 446 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 0.21 (m, 2 H) 0.46 (br d, J=8.09 Hz, 2 H) 1.00 (m, 1 H) 4.12 (s, 2 H) 5.98 (t, J=6.43 Hz, 1 H) 7.12 (m, 1 H) 7.22 (s, 1 H) 7.58 (m, 1 H) 7.72 (d, J=7.72 Hz, 1 H) 8.04 (m, 1 H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:42])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[N:12]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)c1ccccc1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with benzoyl chloride (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C36H37N2O2Cl2 [(M+H)+] 599.2227, observed 599.2223.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12]C)=[O:11])=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(N(CC)CC)C.O1CCOCC1>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3]2[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH2:24][CH2:23]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(Cc2ccc(CC(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.5 %

Procedure:
In triethylamine (3 ml)-dioxane (80 ml) were dissolved 2.4 g of methyl 4-bromomethylphenylacetate and 1.9 g of 1-(2-methoxyphenyl)piperazine and the solution was stirred at room temperature for 4 hours. The solvent was then distilled off and the residue was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by column chromatography [silica gel, hexane-ethyl acetate=2:1] and the resulting oil was refluxed in a mixture of 30 ml 2N-sodium hydroxide and 10 ml methanol for 3 hours. The solvent was then distilled off and the residue was dissolved in water and filtered. The filtrate was neutralized with acetic acid and extracted with chloroform. The solvent was then distilled off and the residue was recrystallized from methanol-ethylether to provide 2.0 g of the title compound melting at 87° C.-90° C. The IR absorption spectrum of this product is presented in FIG. 2.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][N:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.Br.[NH+]1C=CC=CC=1.[OH-].[NH4+]>O>[CH2:15]([N:11]1[CH2:12][CH2:13][CH:14]=[C:9]([C:5]2[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=2)[CH2:10]1)[CH2:16][CH3:17]
Reactant: CCCN1CCC=C(c2cccc(OC)c2)C1
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCCN1CCC=C(c2cccc(O)c2)C1
Temperature: 200 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
A mixture of 3.9 g of the product of Step A and 7.8 g of pyridinium hydrobromide was stirred under an inert atmosphere for 2 hours at 200° C. and was then cooled and taken up in water. The mixture was stirred until dissolution and was made alkaline by addition of ammonium hydroxide. The mixture was extracted with methylene chloride and the organic phase was washed with aqueous saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 95-5 chloroform-methanol mixture. The solution was distilled to dryness under reduced pressure and the residue was taken up in methylene chloride. The solution was filtered and evaporated to dryness under reduced pressure to obtain 3.13 g of 3-(1-propyl-1,2,5,6-tetrahydropyridin-3-yl)-phenol.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([OH:10])[N:7]([C:11](=[O:14])[NH:12][CH3:13])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CC(CC)=O.[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O>[CH2:26]([O:10][C:8]1[N:7]([C:11](=[O:14])[NH:12][CH3:13])[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[N:9]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: ClCc1ccccc1
Reactant: CNC(=O)n1nc(C(C)(C)C)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CNC(=O)n1nc(C(C)(C)C)nc1OCc1ccccc1
Yield: 3.5 %

Procedure:
To a mixture of 3-tert-butyl-1-N-methylcarbamoyl-5-hydroxy-1,2,4-triazole 5.94 g (0.03 mole) and potassium carbonate 6.21 g (0.045 mole) was added 100 ml of methyl-ethyl ketone. Then to the mixture was added, while stirring, 4.17 g (0.033 mole) of benzyl chloride, and the mixture was heated under reflux for 2 hours. After the reaction mixture was concentrated under a reduced pressure, the residue obtained was diluted with water and extracted with methylene chloride. The organic phase was dried over anhydrous sodium sulfate, and then concentrated under a reduced pressure, and the pale yellow oily substance obtained was subjected to silica gel column chromatography and eluted with a solvent mixture of 1:2 of ethyl acetate and n-hexane, to give 0.3 g of 5-benzyloxy-3-tert-butyl-1-N-methylcarbamoyl- 1,2,4-triazole as a white solid (yield 3.5%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[N:10]([O-])=O.[Na+].S(=O)(O)[O-].[Na+].[OH-].[Na+]>Cl.O>[ClH:9].[Br:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:10])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)c(Br)c1
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Cl)c(Br)c1
Temperature: -10 °C

Procedure:
3-Bromo-4-chloroaniline (41.3 g., 0.2 mole) in 90 ml of 6 N hydrochloric acid, cooled to -10° is treated with 14 g. of sodium nitrite in 30 ml. of water. Add this solution, with stirring, to a cold (-10° C.) solution of 55 g. of sodium bisulfite and 20 g. of sodium hydroxide in 200 ml. of water. After the red precipitate appears, allow the mixture to warm to room temperature. Add 200 ml. of concentrated hydrochloric acid and heat at 90°-100° C. for 4 hours. Allow the mixture to cool overnight, collect the material washing with 50 ml of cold 3 N hydrochloric acid. The product is dried. Recrystallization from ether-methanol yields the desired material, m.p. 208°-210° C.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH:15]=[N:16][CH:17]2[C:21]([O:23]CC1C=CC=CC=1)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+:35].[K+]>O1CCCC1.O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH:15]=[N:16][CH:17]2[C:21]([O-:23])=[O:22])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[K+:35]
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccccc3)N=CSC12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)[O-])N=CSC12
Temperature: 25 °C
Reaction time: 1.8 h
Yield: 110.5 %

Procedure:
To a solution of benzyl 7-phenoxyacetamido-8-oxo-5-thia-1,3-diazabicyclo[4,2,0]oct-3-ene-2-carboxylate (400 mg.) in tetrahydrofuran (12 ml.) was added a solution of potassium carbonate (195 mg.) in water (12 ml.) at 0° C. After the mixture was stirred at the same temperature for an hour and at room temperature for 1.8 hours, the reaction mixture was neutralized to pH 7 with cation-exchange resin Amberlite IRC-50 (™; manufactured by Rohm & Haas Co., Ltd.) and then filtered. The filtrate was concentrated and lyophilized to give a powder (388 mg.) of potassium 7-phenoxyacetamido-8-oxo-5-thia-1,3-diazabicyclo[4,2,0]oct-3-ene-2-carboxylate.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:48]1[CH:49]=[C:50]([CH:53]=[CH:54][C:55]=1[N+:56]([O-:58])=[O:57])[C:51]#[N:52].[NH2:59][C:60]1[N:68]=[C:67]2[C:63]([NH:64][C:65](=[O:75])[N:66]2[CH:69]2[CH2:74][CH2:73][O:72][CH2:71][CH2:70]2)=[C:62]([Cl:76])[N:61]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:76][C:62]1[N:61]=[C:60]([NH:59][C:48]2[CH:49]=[C:50]([CH:53]=[CH:54][C:55]=2[N+:56]([O-:58])=[O:57])[C:51]#[N:52])[N:68]=[C:67]2[C:63]=1[NH:64][C:65](=[O:75])[N:66]2[CH:69]1[CH2:70][CH2:71][O:72][CH2:73][CH2:74]1
Reactant: Nc1nc(Cl)c2[nH]c(=O)n(C3CCOCC3)c2n1
Reactant: N#Cc1ccc([N+](=O)[O-])c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: N#Cc1ccc([N+](=O)[O-])c(Nc2nc(Cl)c3[nH]c(=O)n(C4CCOCC4)c3n2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30.1 %

Procedure:
To an oven-dried 2-neck flask under Ar was added racemic BINAP (2.59 g, 4.17 mmol, 0.35 equiv.) followed by anhydrous toluene (20 mL) and Pd(OAc)2 (1.20 g, 1.79 mmol, 0.15 equiv.) and the mixture was stirred under Ar, at room temperature for 15 min. A deep yellow paste is formed. Then, 3-bromo-4-nitro-benzonitrile (3.51 g, 15.47 mmol, 1.3 equiv.), 2-amino-6-chloro-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one (3.2 g, 11.9 mmol, 1.0 equiv.) and cesium carbonate (5.81 g, 17.8 mmol, 1.5 equiv.) were added as solids, under Ar, followed by anhydrous toluene (27 mL), and the reaction mixture was stirred at room temperature for 10 min, then stirred at 100° C. for 22 h (LC-MS shows reaction to be complete). The reaction mixture was cooled to room temperature, diluted with toluene (450 mL) and passed through Celite. The filtrate was concentrated in vacuo to give a dark brown residue. The desired product was recrystallized as a bright orange solid from the residue using mixtures of 100 mL acetonitrile/100 mL water. Repeated recrystallizations resulted in isolation of 1.49 g of desired product (30% yield) in high purity. 1H NMR (300 MHz, CDCl3) δ, ppm: 10.40 (s, 1H), 9.33 (s, 1H), 8.35 (d, 1H), 7.85 (br s, 1H), 7.31 (d, 1H), 4.65-4.50 (m, 1H), 4.19 (dd, 2H), 3.55 (app t, 2H), 2.70 (tdd, 2H), 1.90 (br d, 2H); MS (EI) m/z 416.2 (MH)+.
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[CH3:27][NH:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[CH3:36].[CH3:38][C:39]1[CH:49]=[CH:48][CH:47]=[CH:46][C:40]=1[C:41]([O:43]CC)=O>O1CCCC1>[OH:43][C:41]1([C:40]2[CH:46]=[CH:47][CH:48]=[CH:49][C:39]=2[CH3:38])[CH2:36][C:31]2[N:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29](=[O:37])[N:28]1[CH3:27]
Reactant: CCOC(=O)c1ccccc1C
Reactant: CNC(=O)c1cccnc1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: Cc1ccccc1C1(O)Cc2ncccc2C(=O)N1C
Reaction time: 2 h

Procedure:
109 ml. of 1.6 M. n-butyl lithium in hexane (174.4 mmol.) were added to a solution of 24.4 ml. of diisopropylamine in 200 ml. of dry tetrahydrofuran stirred at -10°--30° C. under nitrogen. To the resulting solution of lithium diisopropylamide, 13.1 g. (87.3 mmol.) of 2-methylnicotinic acid N-methylamide (Compound XII), dissolved in 110 ml. of dry tetrahydrofuran, were added slowly at -30°--20° C. with stirring under nitrogen. Stirring under nitrogen was continued for 2 hours at -30°--20° C. Then 14.3 g. (87.2 mmol.) of freshly distilled ethyl 2-methylbenzoate dissolved in 60 ml. of dry tetrahydrofuran were slowly added at the same temperature and stirring under nitrogen was continued for a further 2 hours at the same temperature. The reaction mixture was then quenched with 150 ml. of concentrated sodium chloride solution and the reaction mixture was extracted three times with ethyl acetate. The ethyl acetate extracts were combined, washed six times with water, once with concentrated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to obtain a crude material (20.4 g.). The crude material was dissolved in ethyl acetate and filtered through silica gel. Evaporation at reduced pressure yielded 16.3 g. of material which was separated into neutral and basic components by dissolving in toluene and cold 2 N. hydrochloric acid and extracting the toluene phase twice with cold 2 N. hydrochloric acid. The three aqueous phases were combined, made basic with sodium hydroxide solution and extracted twice with methylene chloride. The methylene chloride extracts were combined, dried over anhydrous sodium sulfate and evaporated at reduced pressure to obtain the basic component (8.7 g.), i.e., the crude hydroxylactam of Formula XV.