Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH2:6][C:7](=[O:8])[N:4]2[C:3]([C:9]([O-:11])=[O:10])=[CH:2]1.[SH:12][C@@H:13]1[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[C@H:15]([CH:31]2[N:34]([CH3:35])[C:33](=[O:36])[CH2:32]2)[CH2:14]1>>[OH:36][C@@H:33]([C@H:6]1[C:7](=[O:8])[N:4]2[C:3]([C:9]([O:11][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:10])=[C:2]([S:12][C@@H:13]3[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]4[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=4)=[O:19])[C@H:15]([CH:31]4[N:34]([CH3:35])[C:33](=[O:36])[CH2:32]4)[CH2:14]3)[CH2:1][C@H:5]12)[CH3:32]
Reactant: CN1C(=O)CC1[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C([O-])C1=CC[C@@H]2CC(=O)N12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CC(=O)N4C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@H]12
Yield: 185.8 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (5R,6S)-2-diphenoxyphosphoryloxy-6-8 (R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (235 mg, 0.40 mmol) and (2S,4S)-4-mercapto-2-(N-methyl-2-azetidinon-4-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine (149 mg, 0.41 mmol, compound of Reference Example 7) to obtain p-nitrobenzyl (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(2S,4S)-2-(N-methyl-2-azetidinon-4-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (265 mg, yield: 94.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:25]1[C@@H:33]2[C@@H:28]([CH2:29][CH:30]=[CH:31][CH2:32]2)[CH2:27][NH:26]1.C1(C)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:26]2[CH2:27][C@H:28]3[C@H:33]([CH2:32][CH:31]=[CH:30][CH2:29]3)[CH2:25]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: C1=CC[C@H]2CNC[C@H]2C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1C[C@H]2CC=CC[C@H]2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of 1.13 g of 3,4-dichlorophenylacetic acid in 6 mL of THF was added 0.90 g of 1,1'-carbonyldiimidazole. After 30 minutes a solution of 0.61 g of cis-3a,4,7,7a-tetrahydroisoindoline in 2 mL of THF was added and the mixture was stirred at room temperature overnight. Toluene (50 mL) was added, and the solution was washed successively with 5% hydrochloric acid, water, and 10% aqueous sodium carbonate solution, dried, and concentrated to give 1.50 g of cis-2-(3,4-dichlorophenylacetyl)-3a,4,7,7a-tetrahydroisoindole.
Reaction SMILES: [C:1]([OH:16])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>O1CCCC1>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:1](=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:32][CH2:31]1
Reactant: CN1CCNCC1
Reactant: CCCCCCCCCCCCCC(=O)O
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCC(=O)N1CCN(C)CC1

Procedure:
680 mg (3 meq) of myristic acid and 486 mg (3 meq) of carbonyl diimidazole are reacted in a minimum volume of tetrahydrofuran at ambient temperature for 1.5 hours. 1-Methyl-piperazine (0.33 ml, 3 meq) is added and reacted overnight at ambient temperature. The reaction mixture is evaporated under reduced pressure, dried in vacuo and purified on a column of silica gel in the system CH2Cl2 :CH3OH (5:1). The fractions having Rf 0.80 on TLC silica gel CH2Cl2 :CH3OH (5:1)-iodine are combined, evaporated under reduced pressure (<30°) and dried in vacuo to yield 85 mg of title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]([OH:16])=O)=[CH:4]1)[CH3:2].C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[NH4+:26].[OH-]>CN(C=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]([NH2:26])=[O:16])=[CH:4]1)[CH3:2]
Reactant: [NH4+]
Reactant: CCn1cc(C(=O)O)c2ccc(OC)cc21
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCn1cc(C(N)=O)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
1-Ethyl-6-methoxy-1H-indole-3-carboxylic acid (250 mg, 1.14 mmol) is suspended in a solution of CH2Cl2 (12.5 mL) and DMF (10 μL). Oxalyl chloride (230 μL, 2.64 mmol) is added, and the reaction mixture is stirred for 1 hour at room temperature. This mixture is then slowly poured into a rapidly stirring solution of concentrated NH4OH (5 mL). This is then partitioned in H2O and EtOAc. The residue from the ethyl acetate layer is triturated with acetone to yield 1-ethyl-6-methoxy-1H-indole-3-carboxamide (134 mg, 54%) as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:30].[Mg+2]>C(Cl)Cl.CO.C([O-])(O)=O.[Na+]>[CH3:1][S:2]([C:3]1[N:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:23])([F:25])[F:24])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1)=[O:30]
Reactant: CSc1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: O=C([O-])O
Agent: [Mg+2]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CS(=O)c1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(methylthio)-6-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyridazine (1.62 g, 4.39 mmol) in CH2Cl2/MeOH (2:1, 22 mL) was added magnesium monoperoxyphthalate (1.3 g, 2.2 mmol). The mixture was stirred at room temperature for 18 h. Additional magnesium monoperoxyphthalate (300 mg) was added and after 1 h, the mixture was diluted with saturated aqueous NaHCO3 (50 mL), extracted with (3×20 mL) of EtOAc and dried over Na2SO4. Evaporation of the solvent followed by purification by Combiflash chromatography (SiO2, eluant 5% MeOH/EtOAc) afforded the desired product. 1H NMR (500 MHz, acetone-d6): δ 1.92-1.98 (m, 2H), 2.14-2.18 (m, 2H), 2.84 (s, 3H), 3.90-4.08 (m, 5H), 5.01-5.03 (m, 1H), 7.11 (t, 1H), 7.38 (d, 1H), 7.51 (d, 1H), 7.61-7.67 (m, 2H), 7.82 (d, 1H). MS (+ESI) m/z 386 (MH+).
Reaction SMILES: [CH:1]1([N:7]2[C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[CH:10]=[CH:9][C:8]2=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[Br:20][C:9]1[C:8](=[O:19])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:12]2[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1ncc2ccc(=O)n(C3CCCCC3)c2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ncc2cc(Br)c(=O)n(C3CCCCC3)c2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
8-Cyclohexyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (4 g, 14.5 mmol) was dissolved in dimethyl formamide (100 mL) and to this solution was added N-bromosuccinimide (3.9 g, 21.8 mmol) and benzoylperoxide (0.53 g, 2.2 mmol). The reaction mixture was stirred at room temperature for 3 days then diluted with ethyl acetate and washed with water then twice with saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, filtered and evaporated to give 6-bromo-8-cyclohexyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one a cream colored solid (8 g). This crude intermediate was redissolved in CH2Cl2 and treated with 2-benzenesulfonyl-3-phenyl-oxaziridine (3.78 g, 14.5 mmol). The resulting solution was stirred at room temperature overnight then concentrated under reduced pressure and chromotographed on silica gel eluting with ethyl acetate. 6-Bromo-8-cyclohexyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one was obtained as a colorless solid (3.72 g, 67%). 1H NMR: δ (400 MHz, CDCl3) 8.90 (s, 1H), 8.13 (s, 1H), 5.41 (br s, 1H), 2.96 (s, 3H), 2.58–1.70 (m, 2H), 1.87 (br d, J=13 Hz, 2H), 1.31–1.47 (m, 2H), 1.28 (t, J=3 Hz, 2H).
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][NH:19][CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36]>ClCCl.CN(C)C1C=CN=CC=1>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][N:19]([C:35](=[O:36])[C:34]5[CH:38]=[CH:39][CH:40]=[C:32]([C:31]([F:30])([F:41])[F:42])[CH:33]=5)[CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCNC[C@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccc(C(F)(F)F)c1)N1CCC(=O)N2C[C@@H](Oc3cnc(C4CC4)cn3)C[C@@H]2C1
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
(8S,9aR)-8-[(5-Cyclopropylpyrazin-2-yl)oxy]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride (40 mg, 0.123 mmol, 1.0 equivalent, prepared as described in Example 46, Part H) was suspended in dichloromethane (1.0 mL) in a 4-mL scintillation vial, and triethylamine (0.051 mL, 0.37 mmol, 3.0 equivalents) was added. 3-(Trifluoromethyl)benzoyl chloride (33.4 mg, 0.160 mmol, 1.3 equivalents) was added as a solution in 0.1 mL of dichloromethane followed by 4-(dimethylamino)pyridine (1.50 mg, 0.012 mmol, 0.1 equivalent). The reaction was stirred for 30 minutes. The reaction solution was loaded directly onto a 4 g silica column and eluted with 50:50 to 100:0 ethyl acetate:heptanes (flow rate=18 mL/minute) over 20 minutes to give the title compound as a white solid (31 mg, 54%). 1H NMR (400 MHz, pyridine-d5, 90° C.) δ ppm 8.07 (d, J=1.3 Hz, 1H), 7.98 (d, J=1.3 Hz, 1H), 7.91 (s, 1H), 7.72 (d, J=7.7 Hz, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 5.47 (t, J=4.4 Hz, 1H), 4.51 (s, 1H), 4.34 (dd, J=17.0, 9.1 Hz, 1H), 4.22 (d, J=13.6 Hz, 2H), 3.84-3.75 (m, 1H), 3.26 (dd, J=12.7, 11.1 Hz, 1H), 3.04 (dd, J=14.2, 9.5 Hz, 1H), 2.94-2.77 (m, 1H), 2.71 (dd, J=15.4, 4.9 Hz, 1H), 2.41 (dd, J=14.0, 6.7 Hz, 1H), 2.05-1.82 (m, 2H), 1.00 (dt, J=4.9, 2.9 Hz, 2H), 0.93-0.80 (m, 2H); MS (ESI+) m/z 461.1 (M+H)+; [α]D23.6=−0.09 (c=0.13, CH3OH).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[N:40][CH:39]=1.C(N(CC)CC)C>CN(C)C=O>[C:37]([NH:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[N:40][CH:39]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)c4cccnc4)cc3)cc21
Yield: 70.1 %

Procedure:
In a similar manner to that described in Example 47, a reaction was carried out using 5-{4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylmethoxy]benzyl}thiazolidine-2,4-dione dihydrochloride (400 mg), nicotinoylchloride (195 mg), triethylamine (354 mg) and anhydrous N,N-dimethylformamide (8 ml) and the reaction mixture was purified to give the title compound (297 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)=[CH:4][CH:3]=1.[N:25]([Sn](CCCC)(CCCC)CCCC)=[N+:26]=[N-:27].O1CCOCC1.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[N:18]=[N:25][NH:26][N:27]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)c(-c1ccc(Cl)cc1)nn2C1CCCCO1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Clc1ccc(-c2n[nH]c3ccc(-c4nn[nH]n4)cc23)cc1
Yield: 35 %

Procedure:
The title compound was prepared from 3-(4-chlorophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.351 g, 1.04 mmol), azidotributyl tin (0.351 g, 0.627 mL, 2.29 mmol) in toluene (10 mL) as described for the preparation of compound 167. Deprotection was effected by treating a dioxane solution (5 mL) with 5 mL of 6.0N aqueous solution of hydrogen chloride. Half of the solid obtained upon completion of the reaction was purified by preparatory HPLC (0.054 g, 0.18 mmol, 35% yield over 2 steps) 1H NMR (DMSO-d6) 13.7 (s, 1H), 8.8 (s, 1H), 8.1 (t, 3H), 7.8 (d, 1H), 7.6 (t, 2H); ES-MS (m/z) 297 [M+1]+.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[C:25]([O:28][C:29]1[CH:30]=[C:31]([CH:37]=[CH:38][CH:39]=1)[CH:32]=[CH:33][C:34](O)=[O:35])(=[O:27])[CH3:26].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:25]([O:28][C:29]1[CH:30]=[C:31]([CH:32]=[CH:33][C:34]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:35])[CH:37]=[CH:38][CH:39]=1)(=[O:27])[CH3:26]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CC(=O)Oc1cccc(C=CC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1cccc(OC(C)=O)c1
Yield: 98.2 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 3-acetoxycinnamic acid (2.9 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (4.7 g, 98%) as an amorphous solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>>[CH3:13][S:14]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCCO)c1ccccc1
Product: CS(=O)(=O)OCCNC(=O)c1ccccc1

Procedure:
2-Benzamidoethyl methanesulfonate was prepared by following the general procedure of Example 43 for mesylation as a colorless oil (291 mg, 84%) from N-(2-hydroxyethyl) benzamide (245 mg, 1.30 mmol) and methanesulfonyl chloride (223 mg, 1.94 mmol). 1H NMR (CDCl3, 300 MHz) δ2.85 (s, 3H), 4.48 (t, 2H, J=9.5 Hz), 5.10 (t, 2H, J=10.2 Hz), 7.58-7.63 (m, 2H), 7.74-7.80 (m, 1H), 8.20-8.23 (m, 2H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:15][N:14]4[CH2:23][CH2:24][CH:25](Cl)[C:13]=34)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CN1C(=[O:33])CCC1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:15][N:14]4[CH2:23][CH2:24][CH:25]([OH:33])[C:13]=34)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN1CCCC1=O
Reactant: ClC1CCn2nc(-c3ccccn3)c(-c3ccnc4cc(Br)ccc34)c21
Product: OC1CCn2nc(-c3ccccn3)c(-c3ccnc4cc(Br)ccc34)c21

Procedure:
A solution of 7-bromo-4-(4-chloro-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline (765.0 mg, 1.80 mmol) in 15% (v/v) aqueous N-methyl pyrrolidinone (15 mL) is heated at 120° C. for 18 h. The mixture is concentrated in vacuo and the residue chromatographed on SiO2 (dichloromethane to 20% methanol in dichloromethane) to yield a yellow solid, 408.0 mg (60%).
Reaction SMILES: C([O-])(=[O:3])C.[Na+].C(O)(=O)C.[CH3:10][C:11]1[O:15][C:14]([CH:16]=[CH:17][CH2:18][CH2:19]O)=[CH:13][CH:12]=1.[Cl-].[Na+]>O>[CH2:17]([C:16]1[C:14](=[O:15])[CH2:13][CH:12]([OH:3])[C:11]=1[CH3:10])[CH:18]=[CH2:19]
Reactant: Cc1ccc(C=CCCO)o1
Reactant: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C=CCC1=C(C)C(O)CC1=O
Reaction time: 0.58 h
Yield: 219.8 %

Procedure:
A buffer solution was prepared by dissolving sodium acetate (1.03 g) and Paion D-408 (polyoxyethylene alkyl phenyl ether; manufactured by Takemoto Yushi Inc.) (0.44 g) in water (200 ml) and adjusting the pH value to 6.0 with acetic acid. In a reaction vessel, 5-methyl-2-furylallylcarbinol (5 g) and the entire amount of the buffer solution as prepared above were charged, and the temperature was elevated up to 150° C. in 35 minutes while stirring. The mixture was stirred at the same temperature for 3.5 hours. After ice-cooling, sodium chloride (50 g) was added, and the mixture was extracted with methyl isobutyl ketone (100 ml) four times. The extract was concentrated at 60° C. under reduced pressure to remove methyl isobutyl ketone, whereby an oily substance (4.6 g) was obtained. The crude product was purified by column chromatography with silica gel (60 g) (developing solvent, ethyl acetate-n-hexane (1:2 by volume)) to obtain 2-allyl-3-methyl-4-hydroxy-2-cyclopentenone (4.2 g). Yield, 84%.
Reaction SMILES: Cl.[C:2]1([C@H:8]2[C@@H:13]([O:14][CH2:15][C:16]3[C:24]4[O:23][CH:22]=[CH:21][C:20]=4[CH:19]=[C:18]([C:25]4[N:29]([CH3:30])[N:28]=[N:27][CH:26]=4)[CH:17]=3)[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:31][CH2:32][C:33]#[C:34][CH2:35]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:31][CH2:32][C:33]#[C:34][CH2:35][N:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([O:14][CH2:15][C:16]2[C:24]3[O:23][CH:22]=[CH:21][C:20]=3[CH:19]=[C:18]([C:25]3[N:29]([CH3:30])[N:28]=[N:27][CH:26]=3)[CH:17]=2)[C@@H:8]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC#CCCl
Reactant: Cn1nncc1-c1cc(CO[C@H]2CCCN[C@H]2c2ccccc2)c2occc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nncc1-c1cc(CO[C@H]2CCCN(CC#CCCl)[C@H]2c2ccccc2)c2occc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of [2S,3S]-2-phenyl-3-[(5-(1-methyl-1H-[1,2,3]triazol-5-yl)benzofuran-7-yl)methyloxy]piperidine hydrochloride (230 mg) in N,N-dimethylformamiide (2 ml) was slowly added to a solution of 1,4-dichlorobut-2-yne (106 ml) and potassium carbonate (224 mg) in N,N-dimethylformamide (2.0 ml). The solution was stirred for 18 hours at room temperature and the solvent removed under reduced pressure. To the residue was added water (40 ml) and the product was extracted with ethyl acetate (3×10 ml). The combined organic fractions were washed with water, saturated brine, dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue was purified by MPLC (10% ethyl acetate/hexane) to give [2S,3S]-1-(4-chlorobut-2-yn-1-yl)-2-phenyl-3-[(5-(1-methyl-1H-[1,2,3]triazol-5-yl)benzofuran-7-yl)methyloxy]piperidine as a yellow oil (205 mg). 1H NMR (360 MHz,CDCl3) δ1.57 (2H, m), 2.22 (2H, m), 2.98 (1H, m), 3.27 (2H, d, J=3.0 Hz), 3.43 (1H, br s), 3.62 (1H, br s), 3.95 (3H, s), 4.13 (2H, s), 4.46 (1H, d, J=11.0 Hz), 4.82 (2H, d, J=11.0 Hz), 6.77 (1H, d, J=1.0 Hz), 6.87 (1H, s), 7.15 (3H, m), 7.38 (2H, m), 7.43 (1H, s), 7.62 (2H, br s); MS m/z (CI+) 475 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)[CH3:2].[CH3:14][CH:15]([CH3:21])[CH2:16][CH:17]([NH:19][OH:20])[CH3:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[N+:19]([CH:17]([CH2:16][CH:15]([CH3:21])[CH3:14])[CH3:18])[O-:20])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH3:2]
Reactant: CC(C)CC(C)NO
Reactant: CCOc1cc(C=O)ccc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOc1cc(C=[N+]([O-])C(C)CC(C)C)ccc1OC

Procedure:
3-Ethoxy-4-methoxybenzaldehyde (12.0 g, 0.0666 mol) and N-(4-methylpent-2-yl)hydroxylamine (9.36 g, 0.0799 mol) were mixed into benzene (200 mL) with p-toluenesulfonic acid monohydrate (1.0 g, 5.26 mol.). The mixture was refluxed for 16 hours under an argon atmosphere with a Dean-Stark trap to remove the generated water. The solution was rotary evaporated, dissolved in ethyl acetate, washed with 5% aqueous sodium hydroxide solution, dried over magnesium sulfate, filtered and concentrated. The title compound was obtained as a white solid (17.07 g, 91.8% yield). m.p. 87.2° C. (Rf=0.31 on a silica gel plate using hexanes;EtOAc,, 1:1, v/v, as an eluant). The N-(4-methyl-2-pentyl)hydroxylamine precursor was obtained by sodium cyanoborohydride reduction of 4-methyl-2-pentanone oxime in methanol, with hydrochloric acid catalysis.
Reaction SMILES: I.[C@H:2]1([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:23](=[NH:26])SC)[CH:18]=3)[N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(O)C>[C@H:2]1([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:23]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[NH:26])[CH:18]=3)[N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CSC(=N)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: C1COCCN1
Agent: I
Solvent: CCO
Product: N=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)N1CCOCC1
Yield: 51.6 %

Procedure:
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-2-methyl-isothiourea hydroiodide (345 mg, 0.72 mmol) was dissolved in 10 mL ethanol. Morpholine (350 mg, 4 mmol) was added and the reaction mixture was refluxed overnight. The solvent was evaporated and the residue was purified by column chromatography (silica gel, dichloromethane/methanol 40:1). The title compound (144 mg, 51%) was obtained as a light yellow foam; MS: m/e=388.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:29])[N:22]=[C:23]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2].CN(C1C=CC=CN=1)C.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:43]2[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:29])[N:22]=[C:23]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C(CC)CC)nc(C)c2c(=O)[nH]1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nn2c(C(CC)CC)nc(C)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.114 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-(1-ethylpropyl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride are initially charged in 5 ml of dichloromethane and a spatula tip of 4 dimethylaminopyridine is added, followed by 30 mg (0.342 mmol) of N-methylpiperazine. The mixture is stirred at room temperature overnight, diluted with dichloromethane, washed twice with saturated ammonium chloride solution, dried over sodium sulphate, concentrated and filtered through silica gel (methanol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1/[CH:20]=[CH:21]/[C:22](Cl)=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=[C:22]1/[CH:21]=[CH:20]/[C:16]1[S:15][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1Nc1ccccn1
Reactant: O=C(Cl)/C=C/c1cccs1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1cccs1

Procedure:
The titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-3-(2-thienyl)acryloyl chloride (Aitken, R. A.; Boeters, C.; Morrison, J. J. J. Chem. Soc. Perkin. Trans. I, 1994, 17, 2473) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A).