Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:4]1[NH:16][C:15]2[C:14](=[O:17])[N:9]([CH2:10]C(O)=O)[C:8](=[O:18])[N:7]([CH3:19])[C:6]=2[N:5]=1)CC.ON1C(=O)CCC1=O.O>CN(C=O)C>[N:9]1([C:14](=[O:17])[C:15]2[NH:16][CH:4]=[N:5][C:6]=2[N:7]([CH3:19])[C:8]1=[O:18])[CH3:10]
Reactant: CCCc1nc2c([nH]1)c(=O)n(CC(=O)O)c(=O)n2C
Agent: O=C1CCC(=O)N1O
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 mg of 8-propylcarboxytheophylline was dissolved in 1 ml of DMF, and added with 3 mg of N-hydroxysuccinimide and 5 mg of water-soluble carbodiimide, followed by stirring at room temperature for 2 hours, to obtain activated theophylline. 10 mg of bovine serum albumin (BSA) was dissolved in 1 ml of a 0.1M aqueous solution of sodium hydrogencarbonate and added with 500 μl of the aforementioned activated theophylline solution. The mixed solution was allowed to stand at room teperature for an hour, and then unreacted substances were removed through a Sephadex-G25 column preliminarily equilibrated with PBS to obtain 9 mg of the objective large molecule antigen (theophylline-BSA conjugate)
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH2:8][CH2:9][CH3:10])[N:6]=[N:5][CH:4]=1.S(Cl)([Cl:13])=O>>[ClH:13].[Cl:13][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][CH3:10])[N:6]=[N:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CCCn1nncc1CO
Product: CCCn1nncc1CCl
Product: Cl
Temperature: 25 °C

Procedure:
To a solution of aluminum lithium hydride (0.72 g) in THF (64 ml) was added dropwise a solution of methyl 1-propyl-1,2,3-triazole-5-carbonate (3.2 g) in. THF (32 ml) at 0° C. The mixture was stirred for 1 hour at room temperature, and an aqueous solution of saturated sodium thiosulfate was added to the mixture at 0° C. The mixture was filtered with Celite, and washed with ethanol. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 5-hydroxymethyl-1-propyl-1,2,3-triazole (2.8 g). To 5-hydroxymethyl-1-propyl-1,2,3-triazole (2.8 g) was added thionyl chloride (16.8 ml) at 0° C., and the mixture was heated to reflux for 1 hour. After allowing the mixture to be cooled to room temperature, the solvent was removed under reduced pressure, and to the obtained residue was added ethyl acetate and the precipitates were filtered, to give 5-chloromethyl-1-propyl-1,2,3-triazole hydrochloride (2.1 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[C:22]([O:26][C:27]([C@H:29]1[CH2:36][C:33]2([CH2:35][CH2:34]2)[CH2:32][NH:31][C@@H:30]1[C:37](O)=[O:38])=[O:28])([CH3:25])([CH3:24])[CH3:23].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:37]([C@@H:30]3[C@@H:29]([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:36][C:33]4([CH2:34][CH2:35]4)[CH2:32][NH:31]3)=[O:38])=[CH:18][CH:19]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(COc2ccc(N)cc2)c2ccccc2n1
Reactant: CC(C)(C)OC(=O)[C@H]1CC2(CC2)CN[C@@H]1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(COc2ccc(NC(=O)[C@H]3NCC4(CC4)C[C@@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4-(2-Methylquinolin-4-ylmethoxy)phenylamine as an HCl salt (94.0 mg, 0.28 mmol) and (6S,7S)-7-(tert-butoxycarbonyl)-5-azaspiro[2.5]octane-6-carboxylic acid (70.0 mg, 0.27 mmol) were dissolved in DMF (2.0 mL). BOP (143.0 mg, 0.32 mmol) was added to the above solution and then cooled to 0° C. Diisopropylethylamine (0.175 mL, 1.0 mmol) was added to the above mixture at 0° C. and then the reaction was stirred at room temperature for 2 h. The mixture was diluted with water, extracted with ethyl acetate, the combined extract was washed with brine, dried and concentrated. The crude tert-butyl(6S,7S)-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}amino)carbonyl]-5-azaspiro[2.5]octane-7-carboxylate (140 mg) was used in the next step without purification. ESI (M+H)+502.4.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11]C(C)(C)C)=O)[CH:5]=[CH:4][N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>O>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:9](=[O:11])[CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:20]3[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]3)[CH:7]=2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)Cc1ccnc(Cl)c1
Reactant: CN1CCNCC1
Solvent: O
Product: CN1CCN(C(=O)Cc2ccnc(N3CCN(C)CC3)c2)CC1
Temperature: 140 °C
Yield: 71 %

Procedure:
A suspension of tert-butyl 2-(2-chloropyridin-4-yl)acetate (600 mg, 2.64 mmol) and N-methyl piperazine (2 ml) was heated in a sealed tube for 24 h at 140° C. The reaction mixture was cooled to room temperature, water was added and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to get the crude product. Purification by column chromatography over neutral alumina using 5% MeOH in CHCl3 as eluent afforded 600 mg (71%) of 1-(4-methylpiperazin-1-yl)-2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)ethanone as colorless liquid.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.CN(C=O)C.[H-].[Na+].I[CH2:25][CH3:26].[CH3:27][CH2:28]OC(C)=O>>[CH2:27]([N:15]([CH2:25][CH3:26])[C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)[CH3:28]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CCI
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (500 mg, 2.28 mmol, 1 eq.) is dissolved in anhyd. DMF (5 mL) and cooled to 0° C. NaH (60% dispersion, 201 mg, 5.02 mmol, 2.2 eq.) is added and the resulting mixture is stirred at 0° C. for 30 min after which iodoethane (0.38 mL, 2.1 eq) is added dropwise to the reaction mixture. Once this addition is complete, the reaction mixture is allowed to warm to room temperature and stir for 3 days. The reaction is diluted with EtOAc and sequentially washed with H2O (5×) and saturated aqueous NaCl. The organic solution is dried over Na2SO4 and concentrated to give Diethyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amine as a sticky tan solid: ESMS m/z 276.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:17]([O:16][C:14]([C:12]1[N:11]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][N:24]=2)[N:10]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:13]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: COC(=O)c1ccc(CBr)nc1
Reactant: CC(C)(C)OC(=O)c1cc(-c2ccc(Cl)c(Cl)c2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)c(Cl)c3)cc2C(=O)OC(C)(C)C)nc1

Procedure:
To a solution of the intermediate from step C (522 mg, 1.66 mmol) in DMF (10 mL) was added the intermediate from step D (460 mg, 2.0 mmol), followed by cesium carbonate (815 mg, 2.5 mmol). After stirring the reaction at room temperature for 3 hours, it was quenched by adding water and extracting with ethyl acetate (3×). The organic layer was washed with brine and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 30% ethyl acetate-hexanes. 1H NMR (CDCl3, 500 MHz): 9.21 (d, J=2.1 Hz, 1H), 8.25 (dd, J=2.2, 8.2 Hz, 1H), 7.97 (d, J=1.8 Hz, 1H), 7.69 (dd, J=2.1, 8.3 Hz, 1H), 7.5 (d, J=8.2 Hz, 1H), 7.18 (s, 1H), 6.95 (d, J=8.2 Hz, 1H), 6.01 (s, 2H), 3.97 (s, 3H), 1.53 (s, 9H). LC-MS: 2.87 min; (M+H−56)=406.0.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:7]=[C:8]([S:17][C:18]2([CH2:24][CH2:25][O:26][C:27](=[O:29])[CH3:28])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:37][O:38][C:39]([C:41]1[N:42]([CH3:50])[C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:44][CH:45]=1)=[O:40]>ClCCl.C(OCC)(=O)C>[CH3:37][O:38][C:39]([C:41]1[N:42]([CH3:50])[C:43]([S:46]([N:21]2[CH2:20][CH2:19][C:18]([CH2:24][CH2:25][O:26][C:27](=[O:29])[CH3:28])([S:17][C:8]3[CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]([OH:12])=[C:6]([C:2]([CH3:3])([CH3:4])[CH3:5])[CH:7]=3)[CH2:23][CH2:22]2)(=[O:48])=[O:47])=[CH:44][CH:45]=1)=[O:40]
Reactant: CC(=O)OCCC1(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CCNCC1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)n1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(S(=O)(=O)N2CCC(CCOC(C)=O)(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)n1C
Reaction time: 0.08 h
Yield: 83.1 %

Procedure:
To acetic acid 2-[4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidin-4-yl]-ethyl ester hydrochloride (Ex. 1c, 370 mg, 0.83 mmol) in 8 mL of dichloromethane was added triethylamine (293 mg, 2.9 mmol). After stirring for 5 min, 5-chlorosulfonyl-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (296 mg, 1.25 mmol) was added in 3 portions. The reaction mixture was stirred for 3 h at room temperature, and then diluted with Ethyl acetate (40 mL), washed with water (50 mL), 0.5 N HCl (2×30 mL) and water (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was chromatographed with 5-30% Ethyl acetate/hexanes to afford 5-[4-(2-acetoxy-ethyl)-4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-sulfonyl]-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester as a clear oil (420 mg, 83%). ESI/CI-MS m/z 609 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C.Cl.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:34]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][CH:13]=1)[S:39]([C:35]1[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=1)(=[O:41])=[O:40]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CCCCc1ccc(CNCCCCCCC(=O)OC)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1ccc(CN(CCCCCCC(=O)OC)S(=O)(=O)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7-(4-butyl-benzylamino)-heptanoic acid methyl ester prepared of Example 1, Step A (0.10 g, 0.33 mmol), N,N-diisopropylethylamine (0.85 g 0.66 mmol) and pyridine-3-sulfonyl chloride hydrochloride, prepared of Preparation 2, (0.070 g, 0.33 mmol) in 3 mL CH2Cl2 was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and the organic solution was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (10% EtOAc/hexanes to 30% EtOAc/hexanes) to afford the title compound of Step B. 1H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 8.75 (d, 1H), 8.04 (d, 1H), 7.41 (dd, 1H), 7.23 (m, 4H), 4.30 (s, 2H), 3.62 (s, 3H), 3.08 (t, 2H), 2.55 (t, 2H), 2.19 (t, 2H), 1.10-1.58 (m, 12H), 0.87 (t, 3H); MS 447 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]1[CH2:15]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>ClCCl>[ClH:19].[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]1[CH2:15][Cl:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(CO)n(Cc2ccccc2)c1C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1nc(CCl)n(Cc2ccccc2)c1C
Product: Cl
Reaction time: 8 h

Procedure:
A suspension of 15 g (69 mmol) of 1-benzyl-4,5-dimethyl-2-hydroxymethylimidazole in 50 ml of dichloromethane was added portionwise over a period of 30 minutes to a stirred solution of 25 ml of thionyl chloride in 25 ml of dichloromethane. The solution obtained was boiled under reflux for 1.5 hours and then left to stand at room temperature overnight. Evaporation of the solution gave 23.5 g of crude 1-benzyl-2-chloromethyl-4,5-dimethylimidazole hydrochloride in the form of an oil which was used in the next step without further purification.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][C:8](C)([O-])[CH3:9].[K+].C(Br)C=C.C1(=O)CCCCC1>>[CH2:9]([CH:2]1[CH2:3][CH2:4][CH2:5][C:1]1=[O:6])[CH:8]=[CH2:7]
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCCC1
Agent: [K+]
Solvent: O=C1CCCCC1
Solvent: C=CCBr
Product: C=CCC1CCCC1=O

Procedure:
Ex-30a) Cyclopentanone is treated with potassium-t-butoxide and then with allyl bromide in the same manner and in the same proportions as described for cyclohexanone in Example 6a, yielding 2-allylcyclopentanone.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]([CH3:30])[S:8]([N:11]1[C:15](SC2C=CC=CC=2)=[CH:14][N:13]=[C:12]1[Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])(=[O:10])=[O:9].[CH2:31]([O:33]CC)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:30][N:7]([CH3:6])[S:8]([N:11]1[C:15]([CH:31]=[O:33])=[CH:14][N:13]=[C:12]1[Si:23]([C:26]([CH3:28])([CH3:29])[CH3:27])([CH3:24])[CH3:25])(=[O:10])=[O:9]
Reactant: CN(C)S(=O)(=O)n1c(Sc2ccccc2)cnc1[Si](C)(C)C(C)(C)C
Reactant: CCOCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Product: CN(C)S(=O)(=O)n1c(C=O)cnc1[Si](C)(C)C(C)(C)C
Temperature: -70 °C
Yield: 83 %

Procedure:
Methyl triphenylphosphonium bromide (2.75 g, 7.70 mmol) was suspended in 50 mL of diethyl ether. At −10° C., nBuLi (3.08 mL, 7.70 mmol, 2.5M soln in hexanes) was added. This mixture was stirred for 35 m before cooling to −70° C. A solution of (R)-(+)-4,4a,5,6,7,8-hexahydro-4a-methyl-2(3H)-naphthalenone (1) (1.0 g, 6.09 mmol) in 15 mL of ether was added via syringe. This mixture was warmed to 0° C. over 30 m and the stirred at rt for another 30 m. The solution was washed with brine (2×20 mL) dried over MgSO4, filtered and the solvent was removed. Chromatography on SiO2 with hexanes gave 0.82 g (83%) of the diene 2 as a clear colorless oil.
Reaction SMILES: [C:1]1([CH:9]=O)[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.S(=O)(=O)(O)O.O.[CH3:17][C:18]1[N:23]=[C:22]([NH2:24])[N:21]=[C:20]([NH2:25])[N:19]=1>CO>[NH2:25][C:20]1[N:21]=[C:22]([NH2:24])[N:23]=[C:18]([CH:17]=[CH:9][C:1]2[CH:2]=[CH:3][C:4]([CH:7]=[O:8])=[CH:5][CH:6]=2)[N:19]=1
Reactant: Cc1nc(N)nc(N)n1
Reactant: O=Cc1ccc(C=O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: Nc1nc(N)nc(C=Cc2ccc(C=O)cc2)n1
Temperature: 80 °C
Yield: 41 %

Procedure:
To 107.2 g (800 mmol) of benzene-1,4-dicarboxaldehyde suspended in 450 mL methanol was added with stirring 294.0 g of 31% aqueous sulfuric acid (50 mL of concentrated sulfuric acid was added slowly to 200 mL of water while stirring). The solid dissolved and a yellow solution was obtained. The solution was heated to 80° C. with an oil bath, and 25.0 g (200 mmol) 6-methyl-[1,3,5]triazine-2,4-diamine powder was added. The solution was stirred at 80° C. for 8 h then cooled to room temperature. Next, 1.2 g of yellow byproduct (1,4-bis[4-[2-(4,6-diamino-[1,3,5]triazin-2-yl)-vinyl]]-benzene) was removed by filtration, and the filtrate was treated with 2000 mL water. The resulting solid was collected by filtration and washed with saturated aqueous NaHCO3 and water until neutral. The excess benzene-1,4-dicarboxaldehyde was removed by sonicating and washing with acetone three times. Yield: 20.0 g of light yellow product. Yield=41%. 1HNMR (500 MHz, DMSO): δ9.992 (s, 1H), 7.894 (d, J=8.0 Hz, 2H), 7.847 (d, J=7.5 Hz, 2H), 7.806 (d, J=15.5 Hz, 1H), 6.928 (d, J=15.5 Hz, 1H), 6.806 (br, 4H). 13CNMR (500 MHz, DMSO): δ 193.914, 193.417, 170.671, 167.847, 141.836, 136.833, 131.461, 130.688, 128.883.
Reaction SMILES: [C:1]1([CH:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[OH:16])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:30](Br)[CH:31]=[CH2:32].[OH-].[K+]>C(O)C>[CH2:32]([O:23][C:20]1[CH:19]=[CH:18][C:17]([CH:15]([OH:16])[CH2:14][N:11]2[CH2:10][CH2:9][N:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:13][CH2:12]2)=[CH:22][CH:21]=1)[CH:31]=[CH2:30]
Reactant: C=CCBr
Reactant: Oc1ccc(C(O)CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CCOc1ccc(C(O)CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1
Yield: 63.7 %

Procedure:
In 1.2 liters of ethanol were dissolved 120 g (0.31 mol) of 2-(4-diphenylmethylpiperazinyl)-1-(4-hydroxyphenyl)-ethanol, 74.8 g (0.62 mol) of allyl bromide and 41 g of potassium hydroxide. The resultant solution was heated with refluxing for one hour. After cooling the solution and then removing the solvent, the residue was added with 1.0 liter of ethyl acetate. The resultant mixture was washed successively with an aqueous 1N solution of sodium hydroxide, water and saturated saline, followed by drying over anhydrous sodium sulfate. The solvent was removed, and the residue was crystallized from a mixed solvent of ethanol and n-hexane to give 84.6 g of 1-(4-allyloxyphenyl)-2-(4-diphenylmethylpiperazinyl)ethanol (yield: 64%).
Reaction SMILES: CC(C)(C)C([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[N:17]=[CH:16][CH:15]=[N:14]2)=[CH:8][C:7]=1[Cl:18])=O.[OH-].[Na+]>C(O)C>[Cl:18][C:7]1[CH:8]=[C:9]([CH2:12][N:13]2[N:17]=[CH:16][CH:15]=[N:14]2)[CH:10]=[CH:11][C:6]=1[OH:5]
Reactant: CC(C)(C)C(=O)Oc1ccc(Cn2nccn2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1ccc(Cn2nccn2)cc1Cl

Procedure:
A mixture of 2-chloro-4-(2-2H-1,2,3-triazolyl)methylphenyl 2,2-dimethylpropanoate (3 g), 20% aqueous sodium hydroxide solution (10 ml)and ethanol (60 ml) was heated at reflux for 5 hours. The reaction mixture was then concentrated under reduced pressure, to which water was added, and the mixture was adjusted to pH 6.0 with concentrated hydrochloric acid. This mixture was extracted with ethyl acetate. The organic layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, which afforded 2-chloro-4-(2-2H-1,2,3-triazolylmethyl)phenol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:24][CH2:23][CH2:22][N:12]2[C:13]=1[C:14]1[N:15]=[N:16][C:17]([NH:20][NH2:21])=[CH:18][CH:19]=1.[CH:25]1([CH:28]=O)[CH2:27][CH2:26]1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[CH:25]1([C:28]2[N:16]3[N:15]=[C:14]([C:13]4[N:12]5[CH2:22][CH2:23][CH2:24][C:11]5=[N:10][C:9]=4[C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])[CH:19]=[CH:18][C:17]3=[N:20][N:21]=2)[CH2:27][CH2:26]1
Reactant: NNc1ccc(-c2c(-c3ccc(F)cc3F)nc3n2CCC3)nn1
Reactant: O=CC1CC1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: Fc1ccc(-c2nc3n(c2-c2ccc4nnc(C5CC5)n4n2)CCC3)c(F)c1
Temperature: 2 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
The 2-(2,4-difluorophenyl)-3-(6-hydrazinylpyridazin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (5.00 g, 15.2 mmol, Example #35, Step E) was reacted with cyclopropanecarbaldehyde (1.60 g, 22.8 mmol) overnight at ambient temperature in DCM (300 mL). The reaction mixture was cooled to about 0-4° C. Iodobenzene diacetate (5.4 g, 16.75 mmol) was added and the reaction mixture stirred at about 0-4° C. for about 30 min and then at ambient temperature for about 3 h. The reaction mixture was partitioned between DCM and a saturated aqueous Na2CO3 solution. The aqueous phase was back-extracted with of DCM (2×50 mL). The combined organics were dried over MgSO4, filtered, concentrated and purified by chromatography on silica gel using DCM/MeOH (gradient, 100:0 to 95:5) and subsequently triturated with a 90:10 mixture of DCM/Et2O to give the title compound (3.7 g, 64%): LC/MS (Table 1, Method a) Rt=2.22 min; MS m/z: 379.3 (M+H)+; 1H NMR (CDCl3) δ 7.84 (d, 1H), 7.66 (m, 1H), 7.08-7.00 (m, 1H), 6.95-6.85 (m, 2H), 4.55-4.45 (m, 2H), 3.12-3.01 (m, 2H), 2.78 (m, 2H), 2.53-2.42 (m, 1H), 1.45-1.38 (m, 2H), 1.28-1.19 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]([NH:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:34][CH2:35][CH:36]=[CH2:37].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:37]([O:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]([NH:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1)[CH2:36][CH:35]=[CH2:34]
Reactant: C=CCCBr
Reactant: COC(=O)c1ccc(Nc2nc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCCOc1ccc(CNc2nc(Nc3ccc(C(=O)OC)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 65 °C
Yield: 40.1 %

Procedure:
To a solution of methyl 4-(4-(4-hydroxybenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (100 mg, 0.223 mmol) in DMF (2 mL) was added 4-bromobut-1-ene (90 mg, 0.668 mmol) and Potassium Carbonate (154 mg, 1.113 mmol). The mixture was heated to 65° C. for 16 h. After cooling to rt, the mixture was diluted with EtOAc, washed with water, and brine. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography using 20-40% EtOAc/Hexanes to give methyl 4-(4-(4-(but-3-enyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (45 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]1[C@H:9]([CH2:10]OS(C2C=CC(C)=CC=2)(=O)=O)[C@H:8]([NH:22][C:23](=[O:31])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]1=[O:32].[I-:39].[Na+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]1[C@H:9]([CH2:10][I:39])[C@H:8]([NH:22][C:23](=[O:31])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]1=[O:32]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2COS(=O)(=O)c2ccc(C)cc2)c(OC)c1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2CI)c(OC)c1

Procedure:
To 70 ml of acetone was added 2.27 g of cis-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-4-(p-toluenesulfonyloxymethyl)-2-oxoazetidine and 4.95 g of sodium iodide, and the mixture is heated under reflux for 6 hours with stirring, and then concentrated in vacuo. To the residue are added methylene chloride and water to dissolve it, and the methylene chloride layer is separated and washed successively with an aqueous sodium thiosulfate solution and an aqueous sodium chloride solution. The methylene chloride layer is then dried over magnesium sulfate and the solvent is distilled off in vacuo. Ethyl acetate is added to the residue and the precipitated crystals are collected by filtration to give cis-1-(2,4-dimethoxybenzyl)-4-iodomethyl-3-phenylacetamido-2-oxoazetidine, m.p. 181°-182° C.