Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[C:20]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=1)(=[O:27])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(Cl)Cl>CN(C=O)C.CO>[CH2:1]([C:5]1[N:6]([CH2:40][C:37]2[CH:38]=[CH:39][C:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[S:25](=[O:27])(=[O:26])[NH:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[CH:35][CH:36]=2)[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nn(-c2ccccc2Cl)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CCCCc1nn(-c2ccccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To a solution of 78 mg (0.310 mmole) of 5-n-butyl-2-(2-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 5, Step A) in 620 μL of dry DMF was added 14.9 mg (0.372 mmole) of sodium hydride (60% in oil), and the mixture was stirred under N2 at 50° C. for 1 hour, until gas evolution was complete. The resulting solution was cooled to room temperature and treated dropwise with a solution of 178 mg (0.465 mmole) of [2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl bromide (from Example 12, Step D) in DMF. The mixture was stirred at 50° C. for 1.5 hours, by which time TLC (98:2 CH2Cl2 --MeOH) indicated complete reaction. The mixture was quenched by addition of approximately 6 ml of H2O followed by extraction with 3×10 ml of EtOAc. The combined EtOAc extracts were washed with 2×15ml of H2O followed by 15 ml of brine. The organic phase was dried over Na2SO4, filtered, and concentrated. Column chromatography of the residue on silica gel (elution with 0.5% MeOH in CH2Cl2) yielded 130 mg (76%) of the title compound as a white, stiff foam, homogeneous by TLC in 98:2 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 553 (M+1)+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>O1CCCC1>[CH3:4][C:3]1[CH2:11][C:10]2[C:1]([CH:2]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: [Li]CCCC
Reactant: CCCCCC
Solvent: C1CCOC1
Product: CC1=Cc2ccccc2C1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
The ligand (1.0 g) obtained from the previous procedure was dissolved in anhydrous tetrahydofuran (40 ml) and a solution of n-butyllithium in hexane (1.6M, 4.4 ml) was and stirred for 3 hours. The solvents were removed under vacuum to obtain a off-white solid which was washed with dry hexane under nitrogen atmosphere. The solid was cooled to −78° C. and methylene chloride prechilled to −78° C. was added followed by a slurry of zirconium tetrachloride in methylene chloride which was also prechilled to −78° C. The reaction mixture was allowed to gradually come to room temperature and stirred overnight. The solution was filtered and the solid was washed with hexane. The hexane washings were added to the filtrate at which time a off-white solid precipitated. Upon filtration the filtrate was concentrated and cooled to −78° C. for several hours to obtain a yellow solid. This yellow solid (0.30 g) was isolated by filtration and was found to be a mixture (65:35) of rac- and meso-isomers by NMR spectroscopy. 1HNMR (CD2Cl2) (in ppm), 7.67(2d), 7.45(d), 7.08(t), 6.99(t), 6.76(s), 6.74(s), 6.64(s), 2.44(s), 2.20(s), 1.42(s), 1.29(s), 1.22(s). The solid was used as such in polymerizations.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:27][C@H:26]([CH2:28][O:29]CC3C=CC=CC=3)[C@@H:17]([O:18]CC3C=CC=CC=3)[C@H:8]2[O:9]CC2C=CC=CC=2)[C:5]2[CH:37]=[C:38]([N+:44]([O-:46])=[O:45])[C:39]([N+:41]([O-:43])=[O:42])=[CH:40][C:4]=2[N:3]=1.B(Cl)(Cl)Cl.CO>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[N:6]([C@@H:7]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:17]([OH:18])[C@H:8]2[OH:9])[C:5]2[CH:37]=[C:38]([N+:44]([O-:46])=[O:45])[C:39]([N+:41]([O-:43])=[O:42])=[CH:40][C:4]=2[N:3]=1
Reactant: O=[N+]([O-])c1cc2nc(Cl)n([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c2cc1[N+](=O)[O-]
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: O=[N+]([O-])c1cc2nc(Cl)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2cc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a solution of 0.464 g (0.719 mmol) of 60 in 12 mL of CH2Cl2, was added dropwise 8.4 mL of 1M BCl3 at -78° C. The reaction mixture was stirred at -78° C. for 2 h and then at -40° C. for 2 h. MeOH (5 mL) was added and stirring was continued at -40° C. for 10 min. The reaction mixture was diluted with EtOAc (75 mL). The EtOAc solution was washed with cold H2O (50 mL), sat. NaHCO3 solution (50 mL), sat. NaCl solution (50 mL), dried (Na2SO4), and evaporated. The residue was coevaporated with MeOH (3 x) and then suspended in a small amount of CHCl3 for a few hours. The solid product was filtered to give 0.209 g of 61. This sample was contaminated by a small amount of 2-chloro- 5,6-dinitrobenzimidazole. A part of the sample (0.18 g) was purified on a silica column (2.4×10 cm, eluted with pure EtOAc). Evaporation of the appropriate fractions and crystallization by addition of CHCl3 gave 0.084 g of 61 as a white solid. MP: 132°-135° C. MS: (El) m/e 374.0276 (1%, M+ =374.0265). 1H NMR (DMSO-d6): δ9.18 (s, 1, 7-H), 8.60 (s, 1, 4-H), 6.00 (d, 1, 1'-H, J1'-2' =7.5 Hz), 5.59 (d, 1, 2'-OH, J2'-2'OH =6.0 Hz), 5.52 (t, 1, 5'-OH, J5'-5'OH =4.5 Hz), 5.38 (d, 1, 3'-OH, J3'-3'OH =4.5 Hz), 4.01 (m, 1, 2'-H, J2'-3' =5.5 Hz), 4.16 (m, 1, 3'-H, J3'-4' =2.0 Hz), 4.07 (m, 1, 4'-H, J4'-5" =J4'-5" =2.5 Hz), 3.73 (m, 2, 5'-H and 5"-H, J5'-5" =12.0 Hz). 13C NMR (DMSO-d6): δ146.55 (C2), 142.63 (C3a), 138.90, 138.60 (C5 and C6), 134.12 (C7a), 116.67 (C4), 111.62 (C7), 89.98 (C1'), 86.91 (C4'), 72.86 (C2'). 69.84 (C3'), 60.85 (C5'). Anal. Calcd. for C12H11ClN4O8 : C, 38.47; H, 2.96; N, 14.95. Found: C, 38.46; H, 2.98; N, 14.62.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:12][N:13]([CH3:23])[C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[CH2:10][OH:11])=O)(C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC.C(O)C>[NH2:8][C@@H:9]([CH2:10][OH:11])[CH2:12][N:13]([CH3:23])[C:14](=[O:15])[O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CN(C[C@H](CO)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: CCO
Product: CN(C[C@@H](N)CO)C(=O)OCC[Si](C)(C)C
Temperature: 62.5 °C
Yield: 89.2 %

Procedure:
To a solution of (2R)-2-(t-butoxycarbonylamino)-3-(N-methyl-N-(2-(trimethylsilyl)-ethoxycarbonyl)amino)propan-1-ol (0.55 g, 1.58 mmol) in ether (5 mL) was added a solution of p-toluenesulfonic acid (0.31 g, 1.60 mmol) in ethanol (2 mL). Transfer of the p-toluenesulfonic acid was completed with the aid of ether (1 mL). The solution was placed on a rotary evaporator and the ether removed under vacuum at rt. Then, with continuing evacuation, the bath temperature was raised to 60-65° C. for 30 min, during which gas evolution was evident. The solid residue was dissolved in 1 N aq NaOH solution (5 mL) and extracted with CH2Cl2 (4×5 mL). The combined organic layers were washed with brine and dried over Na2SO4. Solvent was removed in vacuo to give (2-(trimethylsilyl)ethyl) (R)-2-amino-3-hydroxypropyl-methylcarbamate (0.35 g, 90%) as a free amine, which was without purification. MS m/z 249 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[CH:13][C:14](=[O:16])[N:15]=[C:10]3[CH:9]([OH:17])[N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:6]=2[CH:25]=1.[C:26]([O:30]C(=O)CC)(=[O:29])[CH2:27][CH3:28]>N1C=CC=CC=1>[C:26]([OH:30])(=[O:29])[CH2:27][CH3:28].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[CH:13][C:14](=[O:16])[N:15]=[C:10]3[CH:9]([OH:17])[N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:6]=2[CH:25]=1
Reactant: CCC(=O)OC(=O)CC
Agent: O=c1ccn2c(n1)C(O)N=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Solvent: c1ccncc1
Product: CCC(=O)O
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a solution of 9-chloro-5-hydroxy-7-(o-chlorophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one in pyridine was added propionic anhydride. The mixture was allowed to stand at room temperature for 6 hours and was then poured into ice water. The solids thus produced were recovered by filtration and recrystallized from methanol to give 9-chloro-5-hydroxy-7-(o-chlorophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one propionate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([C:23]2[C:28](Cl)=[N:27][CH:26]=[CH:25][N:24]=2)[NH:16][C:17](=O)[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C(C(N)C2C(Cl)=NC=C[N:46]=2)C=CC=1)C1C=CC=CC=1.CCN(CC)CC.C(Cl)(=O)C(C)(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:24]3[CH:25]=[CH:26][N:27]=[C:28]([NH2:46])[C:23]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl
Reactant: NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl
Agent: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nc(-c2cccc(OCc3ccccc3)c2)c2c(N)nccn12
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
N-[(3-Benzyloxyphenyl)-(3-chloropyrazin-2-yl)-methyl]-2,2-dimethylpropionamide: To a solution of the crude C-(3-benzyloxyphenyl)-C-(3-chloropyrazin-2-yl)-methylamine (444 mg, max. 1.36 mmol) in CH2Cl2 (5 mL), cooled by ice/water, are added NEt3 (210 μL, 152 mg, 1.51 mmol), DMAP (8 mg, 0.07 mmol), and pivaloyl chloride (185 μL, 181 mg, 1.50 mmol), then the cooling bath is removed, and the reaction solution is stirred at ambient temperature for 4.5 h. More pivaloyl chloride (90 μL, 88 mg, 0.73 mmol) and NEt3 (100 μL, 73 mg, 0.72 mmol) are added and also after further 2.5 h, and the solution is stirred overnight at ambient temperature. The reaction mixture is taken up in EtOAc (35 mL), washed with diluted HCl, water, NaHCO3 sol., and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude material is chromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with hexanes:EtOAc 10:1 (1-17)→3:1 (18-41)→2:1 (42-56)], yielding the title compound as orange oil; 1H NMR (CDCl3, 400 MHz) δ 1.21 (s, 9H), 5.03 (s, 2H), 6.50 (d, J=8.0 Hz, 1H), 6.86-6.90 (m, 1H), 6.93-6.97 (m, 2H), 7.23 (t, J=7.8 Hz, 1H), 7.29-7.43 (m, 6H), 8.32 (d, J=2.4 Hz, 2H), 8.50 (d, J=2.4 Hz, 1H). MS (ES+): m/z 410.1/412.1 (100/36) [MH+], 309.1/311.1 (32/12) [MH+-tBuCONH2].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7]/[CH:8]=[CH:9]/[CH2:10][OH:11])[CH2:3][CH2:2]1.O[C:13]1[CH:22]=[C:21]2[C:16]([C:17]([S:23][CH3:24])=[N:18][CH:19]=[N:20]2)=[CH:15][CH:14]=1>>[CH3:24][S:23][C:17]1[C:16]2[C:21](=[CH:22][C:13]([O:11][CH2:10]/[CH:9]=[CH:8]/[CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:14][CH:15]=2)[N:20]=[CH:19][N:18]=1
Reactant: CSc1ncnc2cc(O)ccc12
Reactant: OC/C=C/CN1CCOCC1
Product: CSc1ncnc2cc(OC/C=C/CN3CCOCC3)ccc12
Yield: 55.6 %

Procedure:
Using an analogous procedure to that described in the second last paragraph of Note [12] above, (E)-4-morpholinobut-2-en-1-ol (J. Med. Chem., 1972, 15 110-112; 1.27 g), was reacted with 7-hydroxy-4-methylthioquinazoline (1.2 g) to give 4-methylthio -7-[(E)-4-morpholinobut-2-en-1-yloxy]quinazoline (1.15 g); NMR Spectrum: (CDCl3) 2.45 (br s, 4H), 2.7 (s, 3H), 3.05 (d, 2H), 3.7 (t, 4H), 4.7 (d, 2H), 5.9 (m, 2H), 7.15-7.25 (m, 2H), 7.95 (d, 1H), 8.9 (d, 1H); Mass Spectrum: M+H+ 332.
Reaction SMILES: [CH:1]1([N:7]2[C:15]3[CH:14]=[CH:13][N:12]=[C:11]([O:16]C)[C:10]=3[C:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([N:7]2[C:15]3[CH:14]=[CH:13][NH:12][C:11](=[O:16])[C:10]=3[C:9]([C:18]3[CH:19]=[CH:20][C:21]([S:24]([NH2:27])(=[O:25])=[O:26])=[CH:22][CH:23]=3)=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NS(=O)(=O)c1ccc(-c2nn(C3CCCCC3)c3cc[nH]c(=O)c23)cc1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 58.7 %

Procedure:
To a solution of 4-(1-cyclohexyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (53 mg) in acetonitrile (10 mL) were added sodium iodide (41 mg) and chloro(trimethyl)silane (119 mg), and the mixture was stirred at 60° C. for 20 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (30 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH2:30]([O:37][C:38]1[CH:47]=[C:46]2[C:41]([C:42]([NH:49][CH2:50][CH2:51][O:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[C:43]([NH2:48])[CH:44]=[N:45]2)=[CH:40][CH:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClC(Cl)C.CN(C)C1C=CN=CC=1.C(OCC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:49]([CH2:50][CH2:51][O:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:42]2[C:41]3[CH:40]=[CH:39][C:38]([O:37][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:47][C:46]=3[N:45]=[CH:44][C:43]=2[N:48]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Reactant: Nc1cnc2cc(OCc3ccccc3)ccc2c1NCCOc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCOc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
Under a nitrogen atmosphere, a solution of 5-(tert-butoxycarbonylamino)valeric acid (1.50 g, 6.91 mmol) in dichloroethane (30 mL) was cooled to −25° C. Triethylamine (2.40 mL, 17.2 mmol) and pivaloyl chloride (0.85 mL, 6.91 mmol) were added, and the reaction was stirred for three hours, during which time the temperature rose to −10° C. 7-Benzyloxy-N4-(2-phenoxyethyl)quinoline-3,4-diamine (0.850 g, 2.20 mmol), prepared as described in Parts A-B of Example 46, was added in one portion followed by a small scoop of 4-dimethylaminopyridine. The reaction was allowed to warm to room temperature and stirred overnight and then heated at reflux for three hours. The reaction solution was washed with saturated sodium bicarbonate, water (2×), and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with sequentially with 98:2 and 95:5 chloroform:methanol) to yield a solid. The solid was treated with diethyl ether and concentrated under reduced pressure to provide 1.03 g of tert-butyl{4-[7-benzyloxy-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-2-yl]butyl}carbamate as a white powder.
Reaction SMILES: C(C1C=CC(S([N:13]=[N+:14]=[N-])(=O)=O)=CC=1)(O)=O.[CH2:16]([O:23][C:24]([CH2:26][C:27](=[O:34])[CH2:28][CH:29]1[NH:32][C:31](=[O:33])[CH2:30]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(CC)CC>C(#N)C.CCOC(C)=O>[CH2:16]([O:23][C:24]([C:26](=[N+:13]=[N-:14])[C:27](=[O:34])[CH2:28][CH:29]1[NH:32][C:31](=[O:33])[CH2:30]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: O=C(CC(=O)OCc1ccccc1)CC1CC(=O)N1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: [N-]=[N+]=C(C(=O)CC1CC(=O)N1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.5 %

Procedure:
Freshly recrystallized p-carboxy benzene sulfonylazide (241 mg, 1.06 mmol) is added to a solution of 4-(3-benzyloxycarbonyl-2-oxopropyl)-azetidin-2-one (276 mg, 1.06 mmol) in anhydrous acetonitrile (6.6 ml). The resulting suspension is cooled in an ice-bath and stirred while Et3N (443 μl, 3.18 mmol) is added. The resulting yellow solution is stirred at room temperature. A precipitate forms quickly. After 90 mins, the mixture is diluted with EtOAc (50 ml) and filtered. The filtrate is washed with H2O (2×10 ml), 0.5 N NaOH (2×10 ml), H2O (4×10 ml) and brine, dried with MgSO4, filtered, and evaporated i.v. to an off-white solid (273 mg). This is triturated with Et2O to provide 4-(3-benzyloxycarbonyl-3-diazo-2-oxopropyl)-azetidin-2-one (227 mg) as a cream colored powder: ir (film from CHCl3) 3.0, 4.65, 5.66, 5.82, 6.05, 7.21, 7.70 and 8.23 cm- 1 ; nmr (CDCl3) δ2.63 (ddd, 1), 2.97 (dd, 1), 3.15 (ddd, 1), 3.40 (dd, 1), 3.98 (m, 1), 5.27 (s, 2), 6.13 (m, 1), and 7.38 (s, 5); mass spectrum m/e 259, 245, 231, and 218.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][B:9]([OH:11])[OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(#N)C>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][S:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][B:9]([OH:11])[OH:10])=[CH:6][CH:7]=1)[CH3:26]
Reactant: OB(O)Oc1ccc(S)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CSc1ccc(OB(O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
4-Mercaptophenylboric acid 5.55 g (32.5 mmol) was dissolved in 80 mL of acetonitrile, followed by addition of potassium carbonate 6.73 g (48.7 mmol), sodium iodide 0.73 g (4.87 mmol) and ethyl bromoacetate 5.40 mL (8.13 g, 48.7 mmol), and the mixture was stirred for 18 hours at room temperature. The reaction solution was concentrated, followed by addition of water to the residue, and the residue was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was concentrated to give the title compound 7.80 g (yield 100%).
Reaction SMILES: [C:1]1([CH2:7][C:8]2([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:12]3[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH2:16][N:11]3[C:10](=[O:24])[O:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:26]1([CH2:25][C:8]2([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:12]3[CH2:13][NH:14][CH2:15][CH2:16][N:11]3[C:10](=[O:24])[O:9]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)OC(Cc3ccccc3)(Cc3ccccc3)C2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1OC(Cc2ccccc2)(Cc2ccccc2)C2CNCCN12
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.4 %

Procedure:
To a solution of 1,1-dimethylethyl 1,1-bis(phenylmethyl)-tetrahydro-3-oxo-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxylate (1.3 g, 3.2 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (4 mL), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated and extracted with ethyl acetate. The extract was washed with a 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added diethyl ether, the resulting crystals were collected by filtration and washed with diethyl ether to obtain the title compound (0.86 g, yield 85%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1N=CN([C:19]([N:21]2C=N[CH:23]=[CH:22]2)=O)C=1.C(N(CC)CC)C.Cl.N1CCC1>C1COCC1>[N:21]1([C:11](=[O:13])[CH2:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:19][CH2:23][CH2:22]1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: C1CNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cc1cccc([N+](=O)[O-])c1)N1CCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
THF (30 mL) was added to a mixture of 2-(3-Nitrophenyl)acetic acid (1 g, 5.52 mmol) and CDI (1.34 g, 8.28 mmol), the mixture was stirred for 2 hrs at 0° C. followed by addition of triethylamine (2.308 ml, 16.56 mmol) and azetidine hydrochloride (1.033 g, 11.04 mmol). The reaction mixture was stirred for 12 hrs at room temperature and then concentrated under vacuum. The crude residue was purified by column chromatography using 0-50% ethyl acetate in hexanes as eluent to afford the title product (0.53 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([O:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=3)[N:3]=2)=[C:23]([O:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:22]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: OB(O)c1ccc(Cl)cc1OC1CCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(Cl)cc3OC3CCCC3)n2)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A batch with crude crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (175 mg), [4-chloro-2-(cyclopentyloxy)phenyl]boronic acid (141 mg; 0.59 mmol; Combi-Blocks Inc.) and [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (72 mg; 0.09 mmol) in 1,2-dimethoxyethane (2.0 mL) and 2M solution of potassium carbonate (0.6 mL) was degassed using argon. The batch was stirred under argon for 60 minutes at 100° C. After cooling the batch was diluted with ethyl acetate. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:7])[CH2:4][CH2:5][CH3:6].[CH2:8]([O:10][CH2:11][CH2:12]Br)[CH3:9]>>[CH2:8]([O:10][CH2:11][CH2:12][O:7][CH:3]([CH2:4][CH2:5][CH3:6])[C:2]#[CH:1])[CH3:9]
Reactant: CCOCCBr
Reactant: C#CC(O)CCC
Product: C#CC(CCC)OCCOCC
Yield: 44.7 %

Procedure:
In accordance with the procedure of the step 1 of Example 10, 21.8 g of 1-hexyn-3-ol was allowed to react with 37.2 g of 2-bromoethyl ethyl ether to obtain 16.9 g of 3-(2-ethoxyethoxy)-1-hexyne.
Reaction SMILES: [C:1](=O)(OC)OC.N1C2C(=CC=CC=2)C=C1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2>>[CH3:1][N:23]1[C:24]2[C:20](=[CH:19][C:18]([O:17][CH3:16])=[CH:26][CH:25]=2)[CH:21]=[CH:22]1
Reactant: COC(=O)OC
Reactant: COc1ccc2[nH]ccc2c1
Agent: c1ccc2[nH]ccc2c1
Product: COc1ccc2c(ccn2C)c1

Procedure:
With dimethyl carbonate as a methylating agent, the N-methylation of indole system containing electron-donating groups was also studied. For an example, N-methylation of 5-methoxyindole with dimethyl carbonate at reflux temperature for 5 hours gave 1-methyl-5-methoxyindole in 97% isolated yield. However, other indole substrates, such as gramine, indole-3-methanol, indole3-ethanol and tryptamine gave a complex mixture of unidentified products. These results indicated that N-methylation with dimethyl carbonate is not applicable to such indole systems.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:17])[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[OH:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][C:30]=1[O:38][CH3:39]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:17][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([O:28][CH2:27][CH2:26][CH2:25][OH:24])=[C:30]([O:38][CH3:39])[CH:31]=2)[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)CC)c2c1N
Reactant: COc1cc(C(=O)O)ccc1OCCCO
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](CC)NC(=O)c3ccc(OCCCO)c(OC)c3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate (Example 97b) and 4-(3-hydroxypropoxy)-3-methoxybenzoic acid (Baraldi, P. G. et al. J. Med. Chem. 1999, 42, 5131.) as brown solid (41%). MS 526 (MH+).