Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1OC.[C:33]([O-])([O-])=[O:34].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[CH:24][C:25]([C:28](=[O:30])[CH3:29])=[C:26]([O:34][CH3:33])[CH:27]=4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc2c(C3CCNCC3)noc2c1
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OCCCN2CCC(c3noc4cc(Cl)ccc34)CC2)ccc1C(C)=O

Procedure:
A stirred mixture of 6-chloro-3-(4-piperidinyl)-1,2-benzisoxazole (4.7 g, 0.02 mol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone (4.8 g, 0.02 mol, K2CO3 (2.8), several crystals of KI and acetonitrile (120 ml) was refluxed for 16 hours. The reaction was filtered and the filtrate was concentrated to yield a solid-oil mixture. The residue was chromatographed on a Waters Prep 500 utilizing silica columns and eluting with methylene chloride/methanol (5%). Concentration of the desired fractions yielded 3.2 g of a beige solid, which upon recrystallization from ethanol afforded 2.7 (31%) of 1-[4-[3-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperdinyl]propoxy]-3-methoxyphenyl]ethanone as a beige solid, m.p.=116°-118° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][O:8][C:9]=1[C:10]([OH:12])=O)=[O:4].O/[N:20]=[C:21](/[C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)=[CH:25][CH:24]=1)\[NH2:22].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:1][NH:2][C:3]([C:5]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][O:8][C:9]=1[C:10]1[O:12][N:22]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([CH2:27][N:28]3[CH2:29][CH:30]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:31]3)=[CH:39][CH:40]=2)[N:20]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Reactant: CNC(=O)c1c(-c2ccccc2)noc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(CN3CC(C(=O)OC(C)(C)C)C3)cc2)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.3 %

Procedure:
A mixture of 4-(methylcarbamoyl)-3-phenylisoxazole-5-carboxylic acid (32 mg, 0.130 mmol), (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int.1, (39.7 mg, 0.130 mmol), HOBT (31.8 mg, 0.208 mmol), EDC (58.5 mg, 0.305 mmol) and diisopropylethylamine (0.091 mL, 0.520 mmol) in DMF (1 mL) was stirred at rt for 18 hr. After warming to 60° C. for 3 hr, the reaction mixture was partitioned between EtOAc (30 mL) and saturated sodium bicarbonate solution (30 mL). The organic layer was washed with water (2×30 mL) and brine (30 mL). After drying (MgSO4) and filtration, the organic layer was concentrated to a yellow oil that was chromatographed on a 4 gm Isco silica gel cartridge, eluting with a 0-90% EtOAc/Hex gradient. The essentially pure fractions containing product were concentrated to afford tert-butyl 1-(4-(5-(4-(methylcarbamoyl)-3-phenylisoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (29 mg, 0.056 mmol, 43.3% yield) as a colorless glassy solid. HPLC retention time=1.50 minutes (YMC Combi 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1 TFA a 2 minute gradient. MS: (M+H)=516.27.
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:30](=[O:31])[N:7]2[C:8]([C:14]([O:16][CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:9]([CH2:12][OH:13])[CH2:10][S:11][C@H:6]12)(=[O:3])[CH3:2].C(Cl)Cl.ClC1C=CC=C(C(OO)=[O:43])C=1>C(O)(C)C>[C:1]([NH:4][CH:5]1[C:30](=[O:31])[N:7]2[C:8]([C:14]([O:16][CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])=[C:9]([CH2:12][OH:13])[CH2:10][S:11](=[O:43])[C@H:6]12)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS(=O)[C@H]12

Procedure:
To a stirred, cooled (0°-5° C.) solution of 876 mg. of benzhydryl 7-acetamido-3-hydroxymethyl-3-cephem-4-carboxylate in a mixture of 40 ml. of methylene chloride and 20 ml. of isopropanol there was added dropwise 407 mg. (equivalent, about 85% pure) of m-chloroperbenzoic acid in 20 ml. of isopropanol, During the addition a precipitate was formed which was collected and washed with ethyl acetate yielding 800 mg. of the titled compound, m.p. 178°-179° C. The NMR, IR, and UV spectra were consistent with the assigned structure.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:37][CH2:38][NH:39][C:40]([O:42][C:43]1[CH:48]=[CH:47][C:46]([CH2:49][C@H:50]([NH:60]C(OC(C)(C)C)=O)[C:51]([NH:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:52])=[CH:45][CH:44]=1)=[O:41])[C:9]([NH:11][C@@H:12]([CH2:16][S:17]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:13]([NH2:15])=[O:14])=[O:10])(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH2:83]([N:90]1[C:94](=[O:95])[CH:93]=[CH:92][C:91]1=[O:96])[C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1>ClC(Cl)C.O>[NH2:7][C@H:8]([C:9]([NH:11][C@@H:12]([CH2:16][S:17][CH:92]1[CH2:93][C:94](=[O:95])[N:90]([CH2:83][C:84]2[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=2)[C:91]1=[O:96])[C:13]([NH2:15])=[O:14])=[O:10])[CH2:37][CH2:38][NH:39][C:40]([O:42][C:43]1[CH:48]=[CH:47][C:46]([CH2:49][C@@H:50]([C:51]([NH:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:52])[NH2:60])=[CH:45][CH:44]=1)=[O:41]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)C(=O)Nc1ccccc1
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NC(=O)[C@H](CSC1CC(=O)N(Cc2ccccc2)C1=O)NC(=O)[C@@H](N)CCNC(=O)Oc1ccc(C[C@H](N)C(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
238 mg (0.25 mmol) of the compound of example 1B was dissolved in 10 ml dichloroethane. 0.12 ml Triethylsilane, approx. 10 ml trifluoroacetic acid and approx. 0.5 ml water was added. The reaction mixture was stirred for approx. 30 min at room temperature. 100 ml dichloroethane were added and the reaction mixture was evaporated under reduced pressure to approx. 1 ml of solvent volume. Approx. 100 ml water was added and the reaction mixture was extracted three times with approx. 50 ml dichloromethane. To the aqueous phase 15 ml of acetic acid was added. The aqueous phase was frozen and lyophilized. The lyophylistae was dissolved in approx. 50 ml methanol and 0.183 mg (0.98 mmol) N-benzylmaleimide was added. The reaction mixture was stirred over night at room temperature. The reaction mixture was evaporated to dryness and redissolved in approx. 5 ml methanol and purified by preparative RP-HPLC on a C18 with a water/methanol gradient. The fractions were collected in test tubes of 20 ml on an automated fraction collector. To ensure sufficient acidity each vial was filled with 0.5 ml acedic acid prior to collection. All fractions containing the compound of example 1C were combined. Acetonitrile was partially removed on a rotary evaporator at 30° C. water bath temperature and approx. 50 mbar for approx. 30 min. After addition of 0.5 ml acedic acid, the remaining solution was lyophilized. The total yield was 168 mg (0.24 mmol, 98% of theory) of the desired product.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[C:15]([C:19]([OH:21])=[O:20])=[CH:16][S:17][CH:18]=1.CN(P(N(C)C)(N(C)C)=[O:26])C.C1[CH2:37][O:36]CC1>>[Br:13][C:14]1[C:15]([C:19]([OH:21])=[O:20])=[C:16]([C:37]([OH:36])=[O:26])[S:17][CH:18]=1
Reactant: C1CCOC1
Reactant: O=C(O)c1cscc1Br
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: O=C(O)c1scc(Br)c1C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Diisopropylamine (17.92 mL, 128 mmol) was dissolved in THF (300 mL) and stirred at −30° C. while BuLi (8.91 g, 139 mmol) was added dropwise. The mixture was stirred at the same temperature for 0.5 h. Then the mixture was cooled to −78° C. and 4-bromothiophene-3-carboxylic acid (12 g, 58.0 mmol) and HMPA (2.02 mL, 11.6 mmol) dissolved in anhydrous THF (200 mL) were added slowly. The mixture was stirred at the same temperature for 1 h. Then the reaction mixture was purged with an excess of gaseous CO2 at −40° C. The resulting solution was stirred at RT for about 15 min and then quenched with H2O. 10% aq. NaOH was added. The aqueous layer was separated and washed with EtOAc. The aqueous layer was acidified with 10% aq. HCl to pH 1˜2 and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (11 g, 43.8 mmol, 76% yield) as white solid, which was used in the next step (example 1.2.3) without further purification. LC-MS (Method A): m/z 273 (M+Na)+, Rt: 0.58 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14](OC(C)(C)C)=O)=[CH:8][CH:7]=2.[Cl:21][C:22]1[N:27]=[N:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=1.Cl.[OH-].[Na+]>C(Cl)Cl.O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([C:14]([CH2:13][C:9]3[CH:10]=[C:11]4[C:6](=[CH:7][CH:8]=3)[N:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12]4)=[N:29][N:28]=2)[N:27]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: COc1cnc2ccc(CC(=O)OC(C)(C)C)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cnc2ccc(Cc3nnc4ccc(Cl)nn34)cc2c1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To a 5 ml CEM microwave tube was added tert-butyl 2-(3-methoxyquinolin-6-yl)acetate (0.05 g, 0.2 mmol), 1-(6-chloropyridazin-3-yl)hydrazine (0.04 g, 0.3 mmol), water (0.5 mL) and hydrochloric acid (0.05 ml, 0.5 mmol). The vial was sealed and first heated at 90° C. for 30 min then placed into CEM microwave for 10 min. at 100° C., with 100 Watts of power via Powermax. The reaction mixture was adjusted the pH to 7 by adding 5 N NaOH—brown ppt. was generated. The brown ppt. was dissolved in DCM. The organic was washed with water, dried over MgSO4, and removed solvent in vacuo. The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-026, 12 g SiO2, DCM:EtOAc:MeOH=75%:20%:5%, Flow=30 mL/min). A peak at 25 min was collected. The solvent was removed in vacuo to afford the desired product as light yellowish solid. Wt: 20.0 mg. MS (ESI pos. ion) m/z: 326.53. Calc'd exact mass for C16H12ClN5O: 325.75.
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:16]O>>[CH3:16][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[N:15][C:7]=1[Br:6]
Reactant: CO
Reactant: O=C(O)c1cccnc1Br
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccnc1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
H2SO4 (0.6 mL) was added to a solution of 2-bromonicotinic acid (1.5 g, 7.43 mmol, 1.00 eq.) in MeOH (20 mL). The resulting solution was stirred for 5 hours while the temperature was maintained at reflux in an oil bath. The mixture was cooled to room temperature and concentrated under vacuum. The resulting solution was diluted with EtOAc (50 mL) and the pH of the solution was adjusted to 10 with Na2CO3 (20%). The resulting organic layer was washed with water (1×50 mL) and saturated aqueous NaCl (2×100 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to yield 2-bromonicotinic acid methyl ester (1.1 g) as a yellow liquid.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]([OH:27])=O)=[CH:24][C:19]=4[N:18]=[CH:17]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C1N=CN([C:37]([N:39]2[CH:43]=[N:42][CH:41]=[CH:40]2)=O)C=1.C1[CH2:48][O:47][CH2:46]C1>>[N:39]1([CH2:40][CH2:41][NH:42][C:25]([C:23]2[CH:22]=[CH:21][C:20]3[N:16]([C:13]4[CH:12]=[CH:11][C:10]([O:9][CH2:8][C:7]5[CH:6]=[CH:5][C:4]([O:3][C:2]([F:31])([F:1])[F:30])=[CH:29][CH:28]=5)=[CH:15][CH:14]=4)[CH:17]=[N:18][C:19]=3[CH:24]=2)=[O:27])[CH2:37][CH2:48][O:47][CH2:46][CH2:43]1
Reactant: C1CCOC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc2c(c1)ncn2-c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Product: O=C(NCCN1CCOCC1)c1ccc2c(c1)ncn2-c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 16 h

Procedure:
A 0.3 M THF solution of 1-(4-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)-1H-benzimidazole-5-carboxylic acid (100 mg, 0.23 mmol) and CDI (76 mg, 0.46 mmol) was stirred at 60° C. for 4 h, after which the mixture was treated with a primary or secondary amine (0.35 mmol) and heating continued for a further 16 h. After this time, the mixture was concentrated in vacuo and the resulting residue purified by chromatography over silica gel. Recrystallization of the eluted product afforded
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:23])[CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:23])[CH:20]=[C:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[Cl:24])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(Br)c3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4ccccc4Cl)c3O2)cc1
Yield: 66.8 %

Procedure:
Treatment of (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.00 g, 4.98 mmol) with 2-chlorophenyl boronic acid (1.17 g, 7.48 mmol), dichlorobis(tri-o-tolylphosphine)palladium(II) (0.196 g, 0.249 mmol), and potassium carbonate (1.72 g, 12.46 mmol) generally according to the procedure described for Intermediate 37 afforded 1.44 g (67%) of (±)-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.26 (silica, ethyl acetate:hexanes 3:17); Anal. calcd. for C22H18ClFO4S: C, 61.04; H, 4.19. Found: C, 61.02; H, 3.95.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][OH:5].[H-].[Na+].Cl[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([F:19])=[CH:12][N:11]=1.O>O1CCCC1>[CH3:1][O:2][C:3](=[O:6])[CH2:4][O:5][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([F:19])=[CH:12][N:11]=1
Reactant: COC(=O)CO
Reactant: O=[N+]([O-])c1cc(F)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)COc1ncc(F)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Hydroxy-acetic acid methyl ester (0.96 g, 10.7 mmol) was dissolved in 2 ml of anhydrous tetrahydrofuran under nitrogen atmosphere, and sodium hydride (0.42 g, 10.7 mmol) was added thereto at room temperature. After stirring for 30 minutes, 2-chloro-5-fluoro-3-nitro-pyridine (1.57 g, 8.89 mmol) dissolved in 15 ml of anhydrous tetrahydrofuran was added dropwise at room temperature, and the reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction by adding water, the mixture was extracted with dichloromethane, and the combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of n-hexane:ethyl acetate=9:1. The fractions containing the product were collected and evaporated to obtain (5-fluoro-3-nitro-pyridin-2-yloxy)-acetic acid methyl ester as yellow liquid (1.35 g, 66%).
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.[CH3:27][N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:37]=O)=[CH:29]1>>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:37][C:30]3[C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:28]([CH3:27])[CH:29]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: Cn1cc(C=O)c2ccccc21
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2cn(C)c3ccccc23)CC1
Yield: 48.5 %

Procedure:
4-Amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (1.5 g) as starting compound and 1-methyl-1 H-indol-3-carboxaldehyde (0.81 g) were reacted and treated in the same manner as in Example 121 to give 1.0 g of 4-amino-5-chloro-N-((1-(5-((1-methyl-1 H-indol-3-ylmethyl)amino)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[C:25]([C:29]1[CH:30]=[C:31]([CH3:55])[C:32](=[C:34]([C:45]2[CH:50]=[CH:49][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:47][CH:46]=2)[C:35]2[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=2)[CH:33]=1)([CH3:28])([CH3:27])[CH3:26].O>C(OCC)C>[C:25]([C:29]1[CH:30]=[C:31]([CH3:55])[CH:32]([C:34]([C:1]2[C:13]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH:4]=[CH:3][CH:2]=2)([C:45]2[CH:50]=[CH:49][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:47][CH:46]=2)[C:35]2[CH:36]=[CH:37][C:38]([C:41]([CH3:44])([CH3:42])[CH3:43])=[CH:39][CH:40]=2)[CH:33]=1)([CH3:26])([CH3:27])[CH3:28]
Reactant: CC1=CC(C(C)(C)C)=CC1=C(c1ccc(C(C)(C)C)cc1)c1ccc(C(C)(C)C)cc1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: CC1=CC(C(C)(C)C)=CC1C(c1ccc(C(C)(C)C)cc1)(c1ccc(C(C)(C)C)cc1)c1cccc2c1Cc1ccccc1-2
Temperature: 25 °C

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 0.653 g of fluorene (3.93 mmol) was dissolved in 50 ml of dehydrated diethylether in a nitrogen atmosphere. To the solution, 2.7 ml of n-butyl lithium/hexane solution (1.58M: 4.27 mmol) was gradually added dropwise in an ice bath and stirred at room temperature over night. To the solution, a solution prepared by dissolving 2.09 g of 3-tert-butyl-1-methyl-6,6-di(4-tert-butyl-phenyl)fulvene (5.06 mmol) in 100 ml of dehydrated diethyl ether was added and stirred under reflux for 10 days and then stirred at room temperature for 11 days. To the reaction mixture, 30 ml of distilled water was gradually added dropwise in an ice bath, and then diethyl ether was added to separate an organic phase. The organic phase was washed with distilled water and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give a reddish-brown solid. The solid was purified with a column chromatography using 150 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure. The remaining product was re-crystallized using hexane and dried under reduced pressure, and thereby the aimed compound was obtained in an amount of 0.439 g (0.758 mmol) as a pale yellow solid (yield: 19%).
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:15][C:16]([F:19])([F:18])[O-:17].CN([S+](N(C)C)N(C)C)C.O>C(#N)C>[C:3]1([CH:2]([O:17][C:16]([F:19])([F:18])[F:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: [O-]C(F)(F)F
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: O
Solvent: CC#N
Product: FC(F)(F)OC(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
Bromodiphenylmethane, 20.7 g (0.084 mol), was added portionwise at 25° to a stirred solution of 0.093 mole of tris(dimethylamino)sulfonium trifluoromethoxide (prepared as in Example 1) in 75 mL of acetonitrile. The reaction mixture was stirred for 18 h and then poured into water. The aqueous mixture was extracted with ether, and the ether extracts were washed with water, dried (MgSO4), and then distilled to give 8.34 g of trifluoromethyl diphenylmethyl ether as a colorless oil: bp 83.3° (0.7 mm); 1H NMR (CDCl3) δ6.17 ppm (s, 1H), 7.27 ppm (m, 10H); 19F NMR (CDCl3) δ-58.4 ppm (s). Anal. Calcd. for C14H11F3O: C, 66.66; H, 4.40; F, 22.60. Found: C, 66.82; H, 4.57; F, 22.39.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:14]3[O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:13]3=[N:12][C:4]=1[CH:5]=[N+:6]2[O-].[NH4+:20].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:14]3[O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:13]3=[N:12][C:4]=1[C:5]([NH2:20])=[N:6]2
Reactant: [NH4+]
Reactant: [O-][n+]1cc2nc3n(c2c2ccccc21)OCCCC3
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1nc1n2OCCCC1
Reaction time: 0.67 h

Procedure:
A solution of 8,9,10,11-tetrahydro[1,2]oxazepino[2′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide (0.1384 g, 0.5421 mmol) in 6 mL of dichloromethane was treated with 3 mL of concentrated aqueous NH4OH solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (0.12 g, 0.65 mmol) was carefully added. Rapid stirring was continued for 40 minutes. The reaction mixture was then diluted with more dichloromethane, washed successively with dilute aqueous K2CO3, H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. The solid was triturated with ether and filtered. Crystallization from acetonitrile gave 0.0369 g of 8,9,10,11-tetrahydro[1,2]oxazepino[2′,3′:1,2]imidazo[4,5-c]quinolin-6-amine as a white powder, dec. 247-255° C. MS (APCI) m/z 255 (M+H)+; Anal. calcd for C14H14N4O: C, 66.13; H, 5.55; N, 22.03. Found: C, 65.82; H, 5.27; N, 22.11.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:15][CH3:16])[NH:12]2)=[C:8]([NH2:17])[N:7]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38]>CN(C=O)C>[NH2:17][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[N:10]=[C:11]([O:15][CH3:16])[N:12]2[CH2:25][CH2:26][CH2:27][N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CCCN3C(=O)c4ccccc4C3=O)c2n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(Butyloxy)-8-(methyloxy)-9H-purin-6-amine (7.5 g, 31.6 mmol) was dissolved in DMF (100 ml) and potassium carbonate (4.37 g, 31.6 mmol) was added. After the suspension had been stirred at room temperature for 15 min., 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione (8.00 g, 29.8 mmol) was added and the suspension was vigorously stirred at room temperature for 10 hours. The reaction mixture was extracted with ethyl acetate, washed with water, brine and dried. The crude material was recrystallized from EtOAc/diethyl ether to give the title compound in three different batches (2.02 g), (2.44 g) and (1.60 g).