Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][C:3]=1[CH:18](Br)Br.C([O-])(=[O:23])C.[Na+]>C(O)(=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][C:3]=1[CH:18]=[O:23]
Reactant: CCCCCOc1cc(C(Br)Br)c(Br)c2ccccc12
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCCOc1cc(C=O)c(Br)c2ccccc12
Yield: 82.9 %

Procedure:
1-Bromo-2-dibromomethyl-4-pentyloxynaphthalene (1.13 g, 2.43 mmol), acetic acid (8 ml) and sodium acetate (0.8 g, 9.72 mmol) were mixed, and this solution was refluxed under heating for 4 hours. Acetic acid was evaporated under reduced pressure. Water (5 ml) was added, and the aqueous layer was extracted twice with ethyl acetate (20 ml). The organic layers were combined, washed with saturated brine (10 ml), a saturated aqueous sodium hydrogencarbonate solution (10 ml) and saturated brine (10 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=25/1) to give 1-bromo4-pentyloxynaphthalene-2-carbaldehyde (0.647 g, 83%) as colorless crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6](O)(=[O:10])[CH:7]([CH3:9])[CH3:8]>O>[CH3:8][CH:7]([CH3:9])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: CC(C)C(=O)O
Reactant: c1ccsc1
Solvent: O
Product: CC(C)C(=O)c1cccs1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A mixture containing thiophene (10.1 g, 120 mmol), isobutyric acid (8.8 g, 100 mmol) and 20 g of polyphosphoric acid was magnetically stirred at 75° C. for 2 hours. The reaction mixture was diluted with water (100 ml) and extracted with CH2Cl2 (2×). The combined organic extracts were washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure to yield a brown oil: 14 g (77%) GC-MS: M=154.0.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:24]1[S:28][N:27]=[CH:26][N:25]=1)[S:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=[CH:13]2)(=[O:9])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:28]1[C:24]([NH:6][S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])=[N:25][CH:26]=[N:27]1
Reactant: COC(=O)c1cccc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3ncns3)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 500-mL two-neck flask was charged with 5-bromo-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (Intermediate D; 10 g, 19.22 mmol), palladium (ii) acetate (0.216 g, 0.961 mmol), and Xantphos (1.112 g, 1.922 mmol). Triethylamine (77 ml, 19.22 mmol), toluene (48.0 ml), and methanol (15.55 ml, 384 mmol) were added, and the reaction was fitted with a reflux condensor. The reaction was evacuated and back-filled with carbon monoxide three times, then the reaction was heated to 70° C. and stirred for four hours under an atmosphere of carbon monoxide. The reaction was filtered through a pad of diatomaceous earth, which was thoroughly washed with ethyl acetate. The filtrate was concentrated, triturated in ethyl acetate and filtered. The solids were collected and the filtrate was concentrated. The trituration procedure was repeated twice, and the solids resulting from each trituration were combined with the previously isolated material. After the third trituration, the mother liquor was purified via column chromatography (80 g silica gel column, gradient elution 0 to 50% EtOAc:Heptane). The clean product fractions were combined with the previously isolated material and the resulting slurry was concentrated to afford methyl 6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-1-naphthoate as a light yellow solid. m/z (ESI) 500.3 (M+H)+. 60 mg of methyl 6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-1-naphthoate was dissolved in 1 mL of DCM and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature. The material was concentrated, dissolved in acetonitrile and loaded onto a Biotage Isolute® PEAX ion exchange column (Biotage AB, Uppsala, Sweden) (pre-wetted with acetonitrile). The column was flushed several times with acetonitrile, then the product was liberated by flushing the column several times with about 1M HCl solution in MeOH/EtOAc. The second filtrate was concentrated to afford methyl 6-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-1-naphthoate. 1H NMR (400 MHz, DMSO-d6) δ ppm=8.90 (d, J=9.2 Hz, 1H), 8.60 (d, J=2.0 Hz, 1H), 8.53-8.44 (m, 2H), 8.29 (dd, J=1.3, 7.3 Hz, 1H), 7.96 (dd, J=2.1, 9.2 Hz, 1H), 7.76 (dd, J=7.3, 8.2 Hz, 1H), 3.95 (s, 3H). m/z (ESI) 350.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[C:30]([NH:34][CH2:35][CH2:36]O)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([NH:34][CH2:35][CH2:36][N:19]1[C:18](=[O:23])/[C:17](=[CH:16]/[C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH2:6][C:5]2[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=2[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]3)/[S:21][C:20]1=[O:22])([CH3:33])([CH3:32])[CH3:31]
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)NCCO
Product: CC(C)(C)NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-3-[2-(tert-Butylamino)ethyl]-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 2-(N-tert-butylamino)ethanol following General Procedure J.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][P:7](=[O:18])([O:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][CH2:29][C:30]2[C:31]([N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])=[N:32][CH:33]=[CH:34][CH:35]=2)[C:25]([C:42]([F:45])([F:44])[F:43])=[CH:24][N:23]=1.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>>[F:49][C:48]([F:51])([F:50])[C:46]([OH:52])=[O:47].[CH3:41][N:36]([S:37]([CH3:40])(=[O:39])=[O:38])[C:31]1[C:30]([CH2:29][NH:28][C:26]2[C:25]([C:42]([F:45])([F:43])[F:44])=[CH:24][N:23]=[C:22]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:6][P:7](=[O:18])([O:8][CH2:9][CH2:10][CH2:11][CH3:12])[O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=3)[N:27]=2)=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: CN(c1ncccc1CNc1nc(Cl)ncc1C(F)(F)F)S(C)(=O)=O
Reactant: CCCCOP(=O)(Cc1ccc(N)cc1)OCCCC
Solvent: O=C(O)C(F)(F)F
Product: CCCCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(NCc3cccnc3N(C)S(C)(=O)=O)n2)cc1)OCCCC
Temperature: 105 °C
Yield: 73 %

Procedure:
A mixture of dibutyl (4-aminobenzyl)phosphonate (18 mg, 0.06 mmol), N-[3-({[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2-yl]-N-methylmethanesulfonamide XLIa (20 mg, 0.05 mmol), TFA (12 uL, 0.15 mmol) and TFE (0.5 mL) was heated at 105° C. under nitrogen in a microwave reactor for 40 minutes. The resulting mixture was concentrated in vacuo and the residue purified by preparative HPLC (MDP) to afford 24 mg of dibutyl [4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate trifluoroacetate (Example 26, yield 73%).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]1[CH:40]=[CH:39][C:25]2/[C:26](=[C:35](/[CH3:38])\[C:36]#[N:37])/[C:27]3[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=3[O:29][CH2:30][C:24]=2[CH:23]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:1]([C:3]1[N:4]([CH2:21][C:22]2[CH:40]=[CH:39][C:25]3/[C:26](=[C:35](/[CH3:38])\[C:36]#[N:37])/[C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[O:29][CH2:30][C:24]=3[CH:23]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH3:2]
Reactant: CCc1nc(-c2ccccc2)c[nH]1
Reactant: C/C(C#N)=C1/c2ccc(CCl)cc2COc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1nc(-c2ccccc2)cn1Cc1ccc2c(c1)COc1ccccc1/C2=C(\C)C#N
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
[step 1] 2-Ethyl-4-phenylimidazole (Tetrahedron Lett. 2001, p 7079; 192 mg, 1.12 mmol) was dissolved in DMF (4.8 mL), potassium carbonate (0.700 g, 5.07 mmol) was added, and the mixture was stirred for 15 min. To this mixture was added (E)-2-(8-chloromethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)propiononitrile (300 mg, 1.01 mmol) obtained in Reference Example B5, and the mixture was stirred at 60° C. for 3 hr. Ethyl acetate was added to the mixture, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1 to 6/4) to give (E)-2-[8-(2-ethyl-4-phenylimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (434 mg, 99%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:4][C:3]=1[OH:18].[H][H]>[OH-].[K+].[Pd]>[O:15]1[CH2:14][CH2:13][N:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:2]=[C:3]([OH:18])[CH:4]=2)[CH2:17][CH2:16]1
Reactant: Oc1cc(N2CCOCC2)c2ccccc2c1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Product: Oc1cc(N2CCOCC2)c2ccccc2c1

Procedure:
1-Chloro-4-morpholino-2-naphthol (15.0 g;0.057 mol), prepared as described in 2(a) above, was dissolved in 10% aqueous potassium hydroxide (100 ml) and was treated in the presence of palladium on charcoal (1.75 g;5%) at room temperature under 3 atmospheres of hydrogen until a stoichiometric amount of hydrogen was absorbed (approximately 24h). The palladium catalyst was removed by filtration and the filtrate neutralised with glacial acetic acid to afford 4-morpholino-2-naphthol as a white solid (8.5 g;65%), m.pt. 231°-232° C. ##STR19##
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:14])[CH2:12]Br.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[NH:23][C:24]([CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:25].CCCCCC>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:14])[CH2:12][N:30]1[CH2:31][CH2:32][N:27]([CH2:26][C:24]([NH:23][C:17]2[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:16]=2[CH3:15])=[O:25])[CH2:28][CH2:29]1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCNCC1
Reactant: OC(CBr)C1COc2ccccc2O1
Solvent: CCO
Solvent: CCCCCC
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)C2COc3ccccc3O2)CC1
Yield: 106.6 %

Procedure:
1-(1,4-Benzodioxan-2-yl)-2-bromoethanol (formula H) (12 g) prepared according to J. Med. Chem. 13, 169, (1970), is treated with 1-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine (14 g) in 500 ml of ethanol. The remainder of the procedure is described in Example 1 above and 21 g of the 1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine is obtained from hexane. The dihydrochloride salt has a melting point of 175°-176° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:3]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:1][CH:2]1[CH2:3][N:4]([CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[CH2:5]1)(=[O:22])=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC(O)C2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CC(OS(C)(=O)=O)C2)CC1

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of tert-butyl 4-(3-hydroxyazetidin-1-yl)piperidine-1-carboxylate (300 mg, 1.15 mmol, 1.00 equiv, 98%) in dichloromethane (20 mL), TEA (240 mg, 2.33 mmol, 2.00 equiv, 98%). To the resulting mixture was added MsCl (0.6 mg, 0.01 mmol, 4.50 equiv, 98%) dropwise with stirring. The resulting solution was stirred for 2 h at room temperature in an ice/salt bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with dichloromethane (2×50 mL) and the organic layers combined. The resulting mixture was washed with sodium chloride/H2O (1×100 mL). The resulting mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield tert-butyl 4-(3-(methylsulfonyloxy)azetidin-1-yl)piperidine-1-carboxylate as a white solid. MS: 335 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([OH:12])([CH3:11])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[Li]CCCC.C(O[B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1)(C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]([OH:12])([CH3:10])[CH3:11])[CH:5]=[C:6]([F:8])[C:7]=1[B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1
Reactant: CC(C)(O)c1cc(F)cc(F)c1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-(3,5-difluorophenyl)propan-2-ol (2.00 g, 11.6 mmol) in THF (46 mL) at −78° C., n-BuLi in hexanes (1.6 M; 18.2 mL, 29.0 mmol) was slowly added through a dripping funnel. When the addition was complete, the mixture was kept at −78° C. for 1 h. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.11 mL, 34.8 mmol) was then added in one portion. The mixture was allowed to warm up room temperature and stirred for 1 h, then the reaction was quenched with water and the solution was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the sub-title compound as a colorless oil. LCMS calc. for C15H21BF2O3Na (M+Na)+ m/z=321.2. found: 321.0.
Reaction SMILES: [OH-].[K+].[C:3]([C:7]1[CH:8]=[C:9]([CH3:12])[CH2:10][CH:11]=1)([CH3:6])([CH3:5])[CH3:4].[C:13]([C:17]1[CH:34]=[CH:33][C:20]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=2)=O)=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].Cl>C(OCC)C.C(COC)OC>[C:3]([C:7]1[CH:8]=[C:9]([CH3:12])[C:10](=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:25][CH:24]=2)[C:20]2[CH:33]=[CH:34][C:17]([C:13]([CH3:15])([CH3:14])[CH3:16])=[CH:18][CH:19]=2)[CH:11]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC1=CC(C(C)(C)C)=CC1
Reactant: CC(C)(C)c1ccc(C(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CCOCC
Product: CC1=CC(C(C)(C)C)=CC1=C(c1ccc(C(C)(C)C)cc1)c1ccc(C(C)(C)C)cc1

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 1.58 g of powdery potassium hydroxide (28.2 mmol) and 100 ml of dehydrated dimethoxy ethane were added in a nitrogen atmosphere. To the suspension, 2.31 g of 3-tert-butyl-1-methyl-cyclopentadiene (17.0 mmol) was gradually added dropwise at room temperature and stirred under reflux for 1 hr. Thereafter, a solution prepared by dissolving 5.25 g of 4,4′-di-tert-butyl-benzophenone (17.8 mmol) to 40 ml of dehydrated dimethoxyethane was gradually added dropwise and stirred under reflux for 2 days. To the resulting reaction mixture, 50 ml of a hydrochloric acid aqueous solution (1N) was gradually added dropwise in an ice bath and stirred at room temperature for some time. Diethyl ether was added to the mixed solution to separate an organic phase. The organic phase was washed with a saturated sodium bicarbonate aqueous solution, 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 240 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure, and thereby the aimed compound was obtained in an amount of 2.10 g (5.09 mmol) as a reddish-orange solid (yield: 30%).
Reaction SMILES: [CH:1](OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:22][C:23]1[CH:33]=[CH:32][C:26]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:25][C:24]=1[NH:34][CH3:35]>O1CCCC1>[CH2:30]([NH:29][C:27]([C:26]1[CH:32]=[CH:33][C:23]2[N:22]=[CH:35][N:34]([CH3:1])[C:24]=2[CH:25]=1)=[O:28])[CH3:31]
Reactant: CCNC(=O)c1ccc(N)c(NC)c1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc2ncn(C)c2c1

Procedure:
Triethyl orthoformate (4 ml) and p-toluenesulfonic acid (200 mg) were added to a solution of 4-amino-N-ethyl-3-(methylamino)benzamide (1.92 g) in tetrahydrofuran (40 ml), followed by heating to reflux for one hour. The solvent was evaporated under reduced pressure and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The resulting residue was washed with diisopropylether to obtain N-ethyl-1-methyl-1H-benzimidazole-6-carboxamide (1.16 g), as a colorless solid.
Reaction SMILES: [Br-].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[O:14])[CH2:12][NH3+:13])=[CH:3]1.C(N(C(C)C)C(C)C)C.[C:24]1([N:34]=[C:35]=[O:36])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>C1COCC1>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[O:14])[CH2:12][NH:13][C:35]([NH:34][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[O:36])=[CH:3]1
Reactant: [NH3+]CC(=O)c1c[nH]c2ccccc12
Reactant: O=C=Nc1cccc2ccccc12
Agent: [Br-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCC(=O)c1c[nH]c2ccccc12)Nc1cccc2ccccc12
Reaction time: 1 h
Yield: 87 %

Procedure:
[2-(3-indolyl)-2-oxoethyl]ammonium bromide (2.00 g, 7.84) was suspended in dry THF (20 ml). Ethyldiisopropylamine (1.40 ml, 7.84 mmol) was added followed by 1-naphthyl-isocyanate (1.13 ml, 7.84 ml). After stirring for 1 hour the formed precipitate was removed by filtration and washed with THF followed by water to give the sub-title product (2.33 g, 87%) as a white solid after drying.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH:13]2[CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[CH2:23][N:24]=[C:25]=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH:13]2[CH:9]1[CH2:10][N:11]([C:25](=[O:26])[NH:24][CH2:23][C:17]1[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=1[Cl:15])[CH2:12]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC21
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Product: CC(C)(C)OC(=O)N1CC2CN(C(=O)NCc3ccc(Cl)cc3Cl)CC21
Yield: 88 %

Procedure:
In analogy to the experimental procedure of example 1a) rac-3,6-diaza-bicyclo[3.2.0]heptane-6-carboxylic acid tert-butyl ester instead of 6-(tert-butoxycarbonyl)-2,6-diaza-spiro[3.3]heptane oxalate was converted using 2,4-dichloro-1-(isocyanatomethyl)benzene into the title compound (691 mg, 88%) which was obtained as a colorless solid. MS (EI) m/e: 400.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7][OH:8].O.[F-].C([N+](CC)(CC)CC)C.Cl[CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1.O>CN(C=O)C>[N+:10]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[CH:9][C:6]=1[CH2:7][OH:8])([O-:12])=[O:11]
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=[N+]([O-])c1ccc(O)cc1CO
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2ccc3ccccc3n2)cc1CO
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.3 %

Procedure:
A mixture of 5-hydroxy-2-nitrobenzyl alcohol (5.1 g, 30 mmol), tetraethylammonium fluoride hydrate (8.94 g, 60 mmol) and 2-chloromethylquinoline (5.31 g, 30 mmol) in DMF (90 ml) was stirred at room temperature for 72 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The extract was dried over MgSO4 and concentrated in vacuo. To the residue was added methylene chloride (25 ml) and the solid was filtered to provide 3.1 g of 2-nitro-5-(2-quinolylmethoxy)benzyl alcohol.
Reaction SMILES: O=[C:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:3]([NH:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.C(O)(=O)C.[NH2:29][CH2:30][CH2:31][C@H:32]1[O:37]B(C2C=CC=CC=2)[O:35][C@@H:34]([CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:33]1>C(O)C>[C:12]1([C:11]2[N:29]([CH2:30][CH2:31][C@@H:32]([OH:37])[CH2:33][C@@H:34]([OH:35])[CH2:44][C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])[C:2]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:3]([C:4]3[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=3)[N:10]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(NC(C(=O)c1ccccc1)c1ccncc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OB(c2ccccc2)O1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C[C@H](O)C[C@H](O)CCn1c(-c2ccccc2)nc(-c2ccncc2)c1-c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of N-(2-oxo-2-phenyl-1-(pyridin-4-yl)ethyl)benzamide, 67 (1.6 g) and acetic acid (1.5 mL) in ethanol (50 mL) is added tert-butyl 2-((4R,6R)-6-(2-aminoethyl)-2-phenyl-1,3,2-dioxaborinan-4-yl)acetate (7.9 g). Upon heating under reflux for 16 h, the solution is cooled to room temperature and the solvent is evaporated. The residue is partitioned between saturated aqueous sodium hydrogen carbonate and dichloromethane, the layers separated and the organic phase washed with brine, dried (magnesium sulfate), filtered and concentrated. Purification of the residue via chromatography affords the title compound, 68 (0.35 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[CH2:20][C:19]2[C:10](=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[C:9]1=[O:21].C([O:25][CH2:26][CH3:27])(=O)C>C(O)C.[Pd]>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH2:15][CH2:16][N:17]=3)[C:12]([CH2:11][CH:10]3[CH2:19][CH2:27][C:26](=[O:25])[NH:8][CH2:9]3)=[CH:11][C:10]=2[C:9]1=[O:21]
Reactant: O=C1c2ccc3cccnc3c2CN1[C@H]1CCCC[C@@H]1O
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: CCO
Product: O=C1CCC(Cc2cc3c(c4c2=CCCN=4)CN([C@H]2CCCC[C@@H]2O)C3=O)CN1
Reaction time: 15 h

Procedure:
To a solution of 5-{[6-benzyloxy)pyridine-3-yl]methyl}-8-[(1S,2S)-2-hydroxycyclohexyl]-8,9-dihydro-7H-pyrrolo[3,4-h]quinolin-7-one (Example 19, 0.070 g, 0.15 mmol) in a mixture of 1 mL of ethyl acetate and 1 mL of ethanol under an atmosphere of nitrogen was added palladium on carbon (1.6 mg, 0.015 mmol). The mixture was placed under an atmosphere of hydrogen (1 atm) for 15 hr, filtered through a pad of Celite and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 394.2134 for [M+H]+ [Calc'd for C23H28N3O3, [M+H]+=394.2134]: 1H NMR (400 MHz, CD3OD) δ 7.54-7.51 (m, 1H), 7.21 (d, J=1.8 Hz, 1H), 6.90 (s, 1H), 6.59 (d, J=9.4 Hz, 1H), 4.33-4.22 (m, 2H), 4.00-3.82 (m, 1H), 3.82 (s, 2H), 3.75-3.69 (m, 1H), 3.37-3.32 (m, 1H), 2.84-2.69 (m, 3H), 2.11-2.09 (m, 1H), 1.97-1.92 (m, 2H), 1.92-1.67 (m, 3H), 1.64-1.57 (m, 1H), 1.44-1.29 (m, 4H) ppm.