Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:4][C:3]=1[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(O)ccc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(OS(C)(=O)=O)ccc1Br
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-bromo-3-methylphenol (9.87 g, 52.8 mmol) and triethylamine (10.70 g, 106 mmol) in CH2Cl2 (50 mL) at 0° C. was added methanesulfonyl chloride (7.25 g, 63.3 mmol), dropwise. After 30 min at 0° C., the reaction mixture was concentrated in vacuo. The residue was partitioned between saturated aqueous NaHCO3 and EtOAc. The layers were separated and the organic extract was washed with aqueous NaHCO3, then 3 N aqueous HCl, then brine, then dried over Na2SO4, filtered, and concentrated in vacuo to provide the titled product.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26](O)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:30][C@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]1[C:37]([O:39][CH2:40][CH3:41])=[O:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3([C:26]([NH:30][C@@H:31]4[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]4[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)[C@H]1CCCC[C@@H]1N
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)O)CCCC3)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CCCC[C@H]1NC(=O)C1(c2ccc(-c3ccc(CCN4CCC[C@H]4C)cc3)cc2)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-1-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)cyclopentanecarboxylic acid (15 mg, 0.040 mmol), (1S,2S)-ethyl 2-aminocyclohexanecarboxylate hydrochloride (9.08 mg, 0.044 mmol), HATU (16.62 mg, 0.044 mmol), and TEA (0.017 mL, 0.119 mmol) in DMF (0.4 mL) was stirred at room temperature overnight. The mixture was acidified with 1M HCl and purified by HPLC to give the title compound. LCMS m/z=531.6 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20]Cl>>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH3:1]
Reactant: Cc1nc2ccccc2[nH]1
Reactant: COCCOCCOCCCl
Product: COCCOCCOCCn1c(C)nc2ccccc21
Yield: 82 %

Procedure:
1-[2-[2-(2-Methoxyethoxy)ethoxy]ethyl]-2-methyl-1H-benzimidazole was synthesized as in Synthesis Example 1 except that an equimolar amount of 2-methylbenzimidazole was used instead of benzimidazole and an equimolar amount of 2-chloroethyl 2-(2-methoxyethoxy)ethyl ether was used instead of 2-chloroethyl methyl ether. Yield 82%.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][N:8]=[C:9]2[OH:12])=[CH:4][CH:3]=1.[C:13]([O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:13]([O:17][C:18](=[O:27])[C:19]1[CH:20]=[CH:21][C:22]([CH2:25][N:8]2[N:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=3)[C:9]2=[O:12])=[CH:23][CH:24]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Oc1nncc2ccc(Br)cc12
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(Cn2ncc3ccc(Br)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 7-bromo-1-hydroxy-3-azaisoquinoline (7.02 g, 28.2 mmol) in dimethylformamide (75 mL) is treated with 4-bromomethylbenzoic acid tert-butyl ester (12.5 g, 36.7 mmol) and cesium carbonate (11.94 g, 36.7 mmol), then stirred overnight at room temperature. The dimethylformamide is evaporated in vacuo, the residue is diluted with ethyl acetate, washed with 1N HCl, the organic portion washed with brine, dried over MgSO4 and evaporated to dryness. The residue is triturated with hot hexanes/ethyl acetate, cooled to room temperature, and the solid is collected by filtration and dried to give the desired product. Step (2): 4-[1-oxo-7-(3-phenyl-prop-1-ynyl)-1H-3-azaisoquinolin-2-ylmethyl]benzoic acid tert-butyl ester
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[C:5]1([SH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCOCC.[OH-].[K+]>[C:5]1([S:11][C:2](=[CH2:3])[CH2:1][OH:4])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Sc1ccccc1
Reactant: C#CCO
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: C=C(CO)Sc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.7 %

Procedure:
To a stirred solution of 36.0 g (0.64 mol) of propargyl alcohol and 0.12 g (1.8 mmol) of powdered potassium hydroxide, was added dropwise at 125° C. over 30 minutes, 60.0 g (0.54 mol) of thiophenol. The mixture was stirred for an additional 90 minutes, and allowed to cool to room temperature. The brown solution was diluted with 200 mL of ether, and extracted with three 100-mL portions of 2N sodium hydroxide, and two 100-mL portions of water. The organic phase was dried over MgSO4, filtered, and the solvent removed in vacuo from a water bath at 45° C. to give 90.4 g of a brown liquid, which, according to NMR analysis, contained 34% of the desired isomer. The mixture was fractionally distilled through a 0.8×20-cm column packed with glass helices to give 29.5 g of a colorless liquid, which by NMR analysis contained 67% of the desired isomer, bp 109°-116° C./1.2 Torr. This liquid was chromatographed on silica gel (100-200 mesh, 50 g/gram of compound) with 20% EtOAc/Skelly B as eluant, to give 16.4 g (18%) of the sulfide as a colorless liquid; IR (neat) cm-1 3360, 1610, 1580, 1470, 1430, 1040, 740, 690; 1H NMR (CDCl3) δ3.70 (t, 1H, OH), 4.10 (d, 2H, CH2), 5.2 (t, J=1 Hz, 1H, vinyl), 5.55 (t, J=1 Hz, 1H, vinyl), 7.15-7.55 (m, 5H, phenyl).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:12]N1C(=O)CCC1=O.OS(O)(=O)=O>C(O)(=O)C>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([I:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccccc1I
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)ccc1I
Temperature: 25 °C
Reaction time: 88 h

Procedure:
To a stirred slurry of methyl 2-iodo-benzoate (5.0 g, 0.019 mol) and N-bromosuccinimide (3.74 g, 0.021 mol) in acetic acid (10 mL) was added concentrated H2SO4 (10 mL) dropwise, keeping the temperature at 20–40° C. The mixture was stirred at room temperature for 88 hours and then heated at 50° C. for 4 hours. The mixture was cooled to 10° C., treated with 40 g of ice water, and extracted with 50 mL of CH2Cl2. The organic phase was washed in succession with 2×50 mL 5% NaHCO3, 50 mL 10% Na2S2O3, 50 mL water, and concentrated to colorless oil. The residue was purified by column chromatography (silica gel, 10:90 EtOAc:hexane) to provide the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.92 (d, J=4 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 7.27 (dd, J=8, 4 Hz, 1H), 3.92 (s, 3H); MS (DCl/NH3) [M+NH4]+ at 358, [M+NH3NH4]+ at 375.
Reaction SMILES: Cl.[CH:2]1([NH:7][C:8]([NH2:10])=[NH:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[O-]CC.[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([C:22]2[C:30]([C:31](=O)[C:32]#[CH:33])=[C:29]3[N:24]([CH:25]=[N:26][CH:27]=[CH:28]3)[N:23]=2)[CH:19]=[CH:20][CH:21]=1>C(O)C.O>[Cl:15][C:16]1[CH:17]=[C:18]([C:22]2[C:30]([C:31]3[CH:32]=[CH:33][N:10]=[C:8]([NH:7][CH:2]4[CH2:6][CH2:5][CH2:4][CH2:3]4)[N:9]=3)=[C:29]3[N:24]([CH:25]=[N:26][CH:27]=[CH:28]3)[N:23]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: N=C(N)NC1CCCC1
Reactant: C#CC(=O)c1c(-c2cccc(Cl)c2)nn2cnccc12
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Clc1cccc(-c2nn3cnccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
To a mixture of cyclopentyl guanidine hydrochloride (1.05g, 6.43 mmol) in ethanol (60 mL) was added sodium ethoxide (2.15 mL, 3 M in ethanol, 6.43 mmol). The mixture was stirred at room temperature for 30 minutes then cooled to 0° C. A solution of 1-[2-(3-chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-2-propyn-1-one (1.4 g, 4.97 mmol) in ethanol (100 mL) was added and the reaction mixture was stirred at room temperature 16 hours. The reaction mixture was diluted with water (200 mL) then concentrated to about two thirds the original volume. The precipitated solids were collected on a filter to provide 4-[2-(3-Chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentylpyrimidin-2-amine (1.25 g, 64%) as a white solid. Rf 0.19 (4:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ9.32 (s,1H), 8.22 (d,1H), 8.13 (d, 1H), 8.01 (d, 1H), 7.72 (s,1H), 7.55–7.39 (m, 3H), 6.38 (d,1H), 5.19 (d, 1H), 4.33 (m, 1H), 2.08 (m, 2H), 1.80–1.52 (m, 6H); MS m/z 391 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[O:2].[CH2:11](O)[CH2:12][OH:13].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:2]1[CH2:11][CH2:12][O:13][CH:1]1[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: OCCO
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C2OCCO2)cc1
Yield: 94.3 %

Procedure:
4-Formyl-benzonitrile (3.00 g, 22.9 mmol), ethane-1,2-diol (6.38 mL, 115 mmol) and toluene-4-sulfonic acid monohydrate (197 mg, 1.15 mmol) were dissolved in toluene (60 mL), and the solution was stirred under reflux for 10 hours. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=10:1), and the title compound (3.78 g, 21.6 mmol, 94%) was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:8]2)[C:5]2[CH:26]=[CH:27][CH:28]=[CH:29][C:4]=2[N:3]=1.[C:30]([O:34][C:35]([N:37]1[CH:42]2[CH2:43][CH2:44][CH:38]1[CH2:39][NH:40][CH2:41]2)=[O:36])([CH3:33])([CH3:32])[CH3:31]>CO>[C:20]1([C:13]2([N:10]3[CH2:11][CH2:12][CH:7]([N:6]4[C:5]5[CH:26]=[CH:27][CH:28]=[CH:29][C:4]=5[N:3]=[C:2]4[N:40]4[CH2:41][CH:42]5[N:37]([C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:36])[CH:38]([CH2:44][CH2:43]5)[CH2:39]4)[CH2:8][CH2:9]3)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: Clc1nc2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1nc3ccccc3n1C1CCN(C3(c4ccccc4)CCCCCC3)CC1)C2
Temperature: 120 °C
Reaction time: 96 h
Yield: 73.9 %

Procedure:
A mixture of 2-chloro-1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazole (0.12 g, 0.294 mmol), 8-t-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octane (0.12 g, 0.565 mmol,: D.Barlocco et al, J. Med. Chem. 1998, 41, 674), and methanol (1.5 ml) was stirred in a sealed tube at 120° C. for 4 days. After cooling down to room temperature, the reaction mixture was concentrated and purified by preparative TLC (1 mm plate×2, developed by CH2Cl2/MeOH: 10/1) to give 0.1269 g (74%) of an oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]4[C:21]5[CH:35]=[CH:34][S:33][C:22]=5[C:23](=[O:32])[NH:24][C:25]=4[C:26]([Cl:31])=[CH:27][C:28]=3[O:29][CH3:30])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)(C)(C)C.C(O)(C(F)(F)F)=O>>[ClH:31].[NH2:7][CH2:8][C:9]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:20]4[C:21]5[CH:35]=[CH:34][S:33][C:22]=5[C:23](=[O:32])[NH:24][C:25]=4[C:26]([Cl:31])=[CH:27][C:28]=3[O:29][CH3:30])=[CH:17][CH:18]=2)[CH2:10][CH2:11][CH2:12]1
Reactant: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C2(CNC(=O)OC(C)(C)C)CCC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C2(CN)CCC2)cc1
Product: Cl
Yield: 138.7 %

Procedure:
Following General Procedure C, tert-butyl(1-(4-(6-chloro-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)cyclobutyl)methylcarbamate (25 mg, 0.05 mmol) was reacted with TFA (2.5 mL) to afford the desired product (16 mg, 80%) as a white solid: 1H NMR (500 MHz, MeOD) δ 7.66 (s, 1H), 7.55 (s, 1H), 7.47 (s, 2H), 7.34 (s, 2H), 6.04 (s, 1H), 3.77 (s, 3H), 3.47 (s, 2H), 2.68-2.54 (m, 2H), 2.47-2.35 (m, 2H), 2.31-2.20 (m, 1H), 2.12-2.02 (m, 1H); ESI MS m/z 426 [C23H21ClN2O2S+H]+; HPLC >99% (AUC), tR=9.87 min.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH:19]([CH3:23])[C:20]([OH:22])=[O:21])[CH:13]=[CH:12]2>>[CH3:23][CH:19]([C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:10]=2)[CH:15]=1)[C:20]([OH:22])=[O:21]
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Reactant: CCCCCCI
Product: CCCCCCOc1ccc2cc(C(C)C(=O)O)ccc2c1

Procedure:
The title compound is prepared according to the method of Example 7 using 1-iodohexane and racemic 6-hydroxy-α-methyl-2-naphthaleneacetic acid. White crystals are obtained having a melting point of 88°-91° C.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:17][NH2:18]>CO>[CH3:17][NH:18][C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(F)cc1N1CCCCC1
Solvent: CO
Product: CNc1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Yield: 100 %

Procedure:
A solution of 1-(5-fluoro-2-nitro-phenyl)-piperidine (200 mg, 0.89 mmol) in 4 mL of 2M methylamine in MeOH was heated in a sealed tube for 12 h at 80° C. Removal of the solvent under vacuum afforded methyl-(4-nitro-3-piperidin-1-yl-phenyl)-amine (209 mg, 100%). Mass spectrum (ESI, m/z): Calcd. for C12H17N3O2, 236.1 (M+H), found 236.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24](N5CCCCC5)=[CH:23][C:22]=4C)=[O:19])=[CH:13][C:12]=3[CH:34]=2)=[CH:4][CH:3]=1.C[I:36].[CH3:37][N:38]([CH3:41])[CH:39]=O>>[I-:36].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([CH2:37][N+:38]5([CH3:41])[CH2:4][CH2:3][CH2:2][CH2:1][CH2:39]5)=[CH:25][CH:26]=4)=[O:19])=[CH:13][C:12]=3[CH:34]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(N4CCCCC4)cc2C)CCC3)cc1
Reactant: CN(C)C=O
Reactant: CI
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C[N+]4(C)CCCCC4)cc2)CCC3)cc1
Product: [I-]

Procedure:
A solution of 2-(4-methylphenyl)-N-(4-piperidino-methylphenyl)-6,7-dihydro-5H-benzocycloheptene-8-carboxamide (0.26 g) and methyl iodide (0.15 ml) in dimethylformamide (15 ml) was stirred at room temperature over night. The solvent was evaporated, and to the residue was added ethyl acetate. Precipitated crude crystal was filtered, which were recrystallized from ethanol-ethyl acetate to give 1-(N-(2-(4-methylphenyl)-6,7-dihydro-5H-benzocycloheptene-8-carbonyl)-4-aminobenzyl)-1-methylpiperidinium iodide (Compound 92) (0.3 g) as colorless crystals.
Reaction SMILES: [CH:1]1([NH:4][C:5]2([C:12]#N)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH2:14]([O:16][C:17](=[O:27])[C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1)[CH3:15].C(N(CC)CC)C.C1C[O:38]CC1>>[CH2:14]([O:16][C:17](=[O:27])[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:12](=[O:38])[C:5]3([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[N:4]([CH:1]3[CH2:3][CH2:2]3)[C:25]2=[O:26])=[CH:20][CH:19]=1)[CH3:15]
Reactant: N#CC1(NC2CC2)CCCCCC1
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(N2C(=O)N(C3CC3)C3(CCCCCC3)C2=O)cc1
Reaction time: 24 h

Procedure:
1.62 g (9.08 mmol) of 1-Cyclopropylamino-cycloheptanecarbonitrile and the crude 4-Isocyanato-benzoic acid ethyl ester in 15 ml THF were stirred for 3 h at RT and then 3.8 ml (27.3 mmol) of triethylamin was added. The stirring was continued for 24 h and then the reaction mixture was concentrated under reduced pressure to dryness. To the dry residue was added 17 ml of 2N HCl and 33 ml of Ethanol and the whole was refluxed for 1 h. The reaction mixture was taken up in EtOAc and washed with water. The organic layers were concentrated under reduced pressure and the crude product was purified by chromatography over silica gel with EtOAc/Heptan 1:2 to give 265 mg of pure 4-(1-Cyclopropyl-2,4-dioxo-1,3-diaza-spiro[4.6]undec-3-yl)-benzoic acid ethyl ester. MS (ESI): 357.3 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[CH:40][N:39]=[N:38]2)[CH:32]=1)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:23][C:28](=[O:27])[CH2:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[CH:40][N:39]=[N:38]2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Yield: 39.7 %

Procedure:
Prepared from [2-amino-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example G33) (163 mg, 0.5 mmol) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example H2) (181 mg, 0.7 mmol) according to the general procedure K. Obtained as a yellow oil (107 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:15])=[C:4]([O:13][CH3:14])[C:5]([N+:10]([O-])=O)=[C:6]([CH:9]=1)[CH:7]=[O:8]>CCO.O.[Fe]>[NH2:10][C:5]1[C:4]([O:13][CH3:14])=[C:3]([OH:15])[C:2]([Br:1])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: COc1c(O)c(Br)cc(C=O)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: O
Product: COc1c(N)c(C=O)cc(Br)c1O
Temperature: 100 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To the mixture of phenol 154 (25.4 g, 92 mmol) in EtOH/H2O (350 mL/100 mL) were added FeSO47H2O (4.7 g) and Fe powder (47 g). The mixture was stirred at 100° C. for 1 hr. The mixture was cooled down to 50° C. and filtered to remove inorganic materials through celite. The filtrate was concentrated in vacuo to provide the title compound 155 (19.0 g, 84%).
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.Cl[CH2:19][C:20](Cl)=O.[NH:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30](=[O:37])[O:29]2)[CH2:25][CH2:24]1>>[ClH:13].[Cl:13][C:10]1[CH:11]=[CH:12][C:7]2[CH2:6][CH2:5][C:4]3[CH:14]=[CH:15][CH:16]=[CH:17][C:3]=3[CH:2]([NH:1][CH2:19][CH2:20][N:23]3[CH2:28][CH2:27][C:26]4([C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[C:30](=[O:37])[O:29]4)[CH2:25][CH2:24]3)[C:8]=2[CH:9]=1
Reactant: O=C(Cl)CCl
Reactant: NC1c2ccccc2CCc2ccc(Cl)cc21
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Product: Cl
Product: O=C1OC2(CCN(CCNC3c4ccccc4CCc4ccc(Cl)cc43)CC2)c2ccccc21

Procedure:
The title compound, m.p. 228° C. and MS: m/e=473 (M+H+), was prepared in accordance with the general method of example 1 from 5-amino-3-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene, chloroacetyl chloride, spiro[isobenzofuran-1(3H),4'-piperidin]-3-one and Hcl.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[CH2:24]([N:31]1[CH:35]=[C:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:33]([OH:41])=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:24]([N:31]1[CH:35]=[C:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:33]([O:41][CH2:2][C:3]2[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[O:16][CH:17]=[CH:18][CH:19]=4)[O:12][C:13]=3[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=2)=[N:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 85.8 %

Procedure:
A mixture of 4-(4-chloromethyl-2-methoxyphenoxy)methyl-5-methyl-2-(2-furyl)-1,3-oxazole (1.94 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (1.31 g), potassium carbonate (0.73 g) and N,N-dimethylformamide (50 mL) was stirred at 80° C. for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to give ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carboxylate (2.48 g, yield 86%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 117-118° C.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.Cl[CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][O:28][C:27]1=[O:31]>>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:12][CH2:13][N:14]([CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][O:28][C:27]4=[O:31])[CH2:15][CH2:16]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)CC(N1CCNCC1)c1ccccc1O2
Reactant: O=C1OCCN1CCCl
Product: O=C1OCCN1CCN1CCN(C2Cc3cc(Br)ccc3Oc3ccccc32)CC1

Procedure:
In an analogous manner to that described in Example 6, from 1-[2-bromo-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazine and 3-(2-chloro-ethyl)-2-oxazolidinone, there is obtained 3-[2-{4-[2-bromo-10,11-dihydro-dibenz[b,f]-oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinone having a melting point of 150°-152° C. The dihydrochloride, prepared in ethanol, melts at 175°-176° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[O:11]=[CH:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CC=O)CC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Oxalyl chloride (3.6 mL, 0.0425 mol) was dissolved in DCM (87 mL) at −78° C. Dimethyl sulfoxide (6.58 mL, 0.0927 mol) was added and the solution was held at −78° C. for 10 min. To the resultant mixture was added a solution of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (from Oakwood, 8.90 g, 0.0386 mol) in DCM (44 mL) over 15 min. The reaction was stirred at −78° C. for 1 h, then triethylamine (26.9 mL, 0.193 mol) was added. The mixture was warmed to RT over 30 minutes and then stirred at RT for another 30 min. The mixture was diluted with DCM, washed with water (2×), brine (1×), dried over sodium sulfate, and concentrated. The crude product (8.10 g, 91.8%) was used directly in next step without further purification. 1H NMR (400 MHz, CDCl3): δ 9.70 (1H, s), 3.48 (4H, m), 3.19 (2H, s), 2.47 (4H, m), 1.45 (9H, s) ppm.