Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].CS(O[CH2:21][CH:22]1[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24][CH2:23]1)(=O)=O>CN(C=O)C>[NH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:21][CH:22]2[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24][CH2:23]2)[C:6]1=[O:15]
Reactant: NC1Cc2ccccc2NC1=O
Reactant: CC1(C)OCC(COS(C)(=O)=O)CO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(CN2C(=O)C(N)Cc3ccccc32)CO1
Temperature: 60 °C
Yield: 57.1 %

Procedure:
Sodium hydride (60% in oil, 1.60 g, 39.80 mmol) was added to 3-amino-3,4-dihydroquinolin-2(1H)-one hydrochloride (3.59 g, 18.09 mmol), in anhydrous DMF (50 mL) at 0° C. over a period of 10 min. The reaction was stirred for a further 30 min before addition of (2,2-dimethyl-1,3-dioxan-5-yl)methyl methanesulfonate [CAS registary number 131372-64-0] (4.05 g, 18.09 mmol) and the reaction has then heated to 60° C. for a period of 16 h. The reaction was then cooled and evaporated before addition of sat. aqueous NaHCO3 (200 mL) and EtOAc (500 mL). The organic layer was then dried (MgSO4), filtered and evaporated and the residue was purified by column chromatography (MeOH:DCM, 3:37) to afford the title compound (3.00 g, 57%) as a colourless oil.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]3[NH:21]N=[CH:19][C:14]=3[CH:15]=2)[C:10]1=[O:22]>CO.[Pd]>[NH2:21][C:13]1[CH:12]=[C:11]2[C:16]([CH2:17][CH2:18][N:9]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][C:3]=3[C:2]([F:24])([F:23])[F:1])[C:10]2=[O:22])=[CH:15][C:14]=1[CH3:19]
Reactant: O=C1c2cc3[nH]ncc3cc2CCN1c1cnccc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: Cc1cc2c(cc1N)C(=O)N(c1cnccc1C(F)(F)F)CC2
Yield: 0.1 %

Procedure:
6-Methyl-7-nitro-2-(4-(trifluoromethyl)pyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (72A: 350 mg, 1 mol) in methanol (10 mL) was reduced with 10% Pd/C (100 mg) to afford 300 mg of the product (93.7% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C:31]([OH:33])=O)[CH2:25]2)=[O:22])=[CH:17][CH:16]=1.[NH2:34][CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C:31](=[O:33])[NH:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:25]2)=[O:22])=[CH:19][N:20]=1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCN(CC(=O)O)C2)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCN(CC(=O)NC3CCOCC3)C2)cn1
Yield: 74 %

Procedure:
As described for example 42, (3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-acetic acid (70 mg, 0.16 mmol) was converted, using 4-aminotetrahydropyran instead of methylamine, to the title compound (61 mg, 74%) which was obtained as an off white solid. MS: m/e=534.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1.Cl([O-])=[O:22].[Na+].P([O-])(O)(O)=O.[K+]>O1CCOCC1.O>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:22])=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Reactant: [O-][Cl+][O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Temperature: 25 °C
Yield: 114 %

Procedure:
In a flask 2-bromo-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (3.11 g, 8.74 mmol) was dissolved in dioxane (120 mL) and H2O (30 mL) and the mixture cooled at 0° C. Sufamic acid (5.09 g, 52.4 mmol) was added, followed by a solution of sodium chlorite (1.28 g, 11.4 mmol) and potassium dihydrogen phosphate (14.3 g, 104.9 mmol) in H2O (75 mL) via an addition funnel over 15 min. The mixture was allowed to warm to room temperature over 2 h. The resulting yellow solid was filtered off, washed with H2O and hexane and dried. The filtrate was then extracted with EtOAc, and the combined organics washed with brine, dried over MgSO4 and concentrated to give additional product. In total 3.71 g of 2-bromo-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid was obtained as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[N:8][CH:7]=1.[N+:20]([O-])([OH:22])=[O:21].C(=O)([O-])O.[Na+]>C(Cl)Cl>[O:1]([CH2:2][CH2:3][NH:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)=[N:8][CH:7]=1)[N+:20]([O-:22])=[O:21]
Reactant: O=[N+]([O-])O
Reactant: CN1CCN(c2ccc(C(=O)NCCO)cn2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)NCCO[N+](=O)[O-])cn2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of 11.00 g of the compound (obtained in Example 1) in 20 ml of methylene chloride was added dropwise 5 ml of fuming nitric acid while stirring below 0° C. The stirring was continued for 2 hours. The reaction mixture was poured into an aqueous sodium hydrogen carbonate solution and extracted with methylene chloride. The extract was washed twice with water and once with a saturated aqueous saline solution, dried over anhydrous magnesium sulfate and concentrated to afford N-(2-nitroxyethyl)-6-(4-methyl-1-piperazinyl)nicotinamide. The product was dissolved in ethanol and to the solution was added under ice-cooling hydrogen chloride-saturated ethanol. The hydrochloride thus formed was recrystallized from ethanol to give 0.54 g of N-(2-nitroxyethyl)-6-(4-methyl-1piperazinyl)nicotinamide dihydrochloride (yield 34%).
Reaction SMILES: Cl[P:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[O:3]1.[OH2:16].Cl>>[CH:12]1[C:5]2[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[PH:2](=[O:16])[O:3][C:4]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O
Reactant: ClP1Oc2ccccc2-c2ccccc21
Agent: Cl
Product: O=[PH]1Oc2ccccc2-c2ccccc21
Temperature: 180 °C
Yield: 99.9 %

Procedure:
77.6 g (0.331 mol) of 6-chloro-(6H)-dibenzo[c,e][1,2]oxaphosphorin are heated to 110° C. 5.96 g (0.331 mol) of water are subsequently added over the course of 30 minutes with vigorous stirring, during which some of the hydrogen chloride gas produced departs. The temperature is subsequently raised in steps to 180° C. and is maintained until no further hydrogen chloride is evolved (a period of approximately 2 hours). The reaction product is subsequently cooled, solidifies, and is comminuted. 71.5 g of 6H-dibenzo[c,e][1,2]-oxaphosphorin-6-one (melting point: 117° C.) are obtained, corresponding to a yield of 100 % of theory. In accordance with 31P NMR spectroscopy the purity is 99%, and the content of hydrogen chloride is 0.08%.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[Br:7][C:8]1[NH:9][C:10]([Br:16])=[C:11]([Br:15])[C:12]=1[C:13]#[N:14].C(I)C>O1CCCC1.O>[Br:7][C:8]1[N:9]([CH2:1][CH3:2])[C:10]([Br:16])=[C:11]([Br:15])[C:12]=1[C:13]#[N:14]
Reactant: N#Cc1c(Br)[nH]c(Br)c1Br
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCI
Product: CCn1c(Br)c(Br)c(C#N)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium t-butoxide (0.75 g, 6.7 mmol) is added in portions at room temperature to a solution of 2,4,5-tribromopyrrole-3-carbonitrile (2.0 g, 6.1 mmol) in anhydrous tetrahydrofuran (20 mL). After 30 minutes, ethyl iodide (1.04 g, 6.7 mmol) is added dropwise. The reaction solution is stirred at room temperature for 30 minutes and then refluxed for 90 minutes. The mixture is cooled, diluted with water and extracted with ethyl acetate. The organic layer is washed with water and saturated sodium chloride and dried (Na2SO). Evaporation of the solvent and crystallization from ether-hexanes gives a solid which is further purified by flash column chromatography on silica gel, packed with methylene chloride and eluted with 3% ethyl acetate in methylene chloride. The analytically pure sample is finally crystallized from methylene chloride-hexanes as a white solid (1.55 g); mp 108.5°-109.5° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].O=[C:12]([CH3:24])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>O.CO>[OH:23][CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH:12]([NH:1][CH2:2][C@H:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[OH:4])[CH3:24])=[CH:16][CH:17]=1
Reactant: CC(=O)COc1ccc(CCO)cc1
Reactant: NC[C@@H](O)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Solvent: O
Product: CC(COc1ccc(CCO)cc1)NC[C@@H](O)c1ccccc1
Yield: 16.5 %

Procedure:
A procedure similar to that described in Example 3 was repeated, except that 1.4 g of 2-amino-1(S)-phenylethanol (prepared as described in Preparation 16), 2.4 g of 2-[4-(2-oxopropoxy)phenyl]ethanol (prepared as described in Preparation 7), 100 ml of benzene, 100 ml of absolute methanol and 0.95 g of sodium cyanoborohydride were used and that, after the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was then concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 30:1 by volume mixture of ethyl acetate and ethanol as the eluent. 0.53 g of the title compound was obtained as crystals, melting at 93°-96° C. (after recrystallization from ethyl acetate).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])=[CH:8]2)=[O:4]>[Li+].[OH-].C1COCC1>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C:9]1[NH:10][C:11]2[C:7]([CH:8]=1)=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:13][CH:12]=2
Reactant: COC(=O)c1ccc2[nH]c(-c3c(Cl)cccc3Cl)cc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2[nH]c(-c3c(Cl)cccc3Cl)cc2c1

Procedure:
A solution of 2-(2,6-dichloro-phenyl)-1H-indole-5-carboxylic acid methyl ester in 2N LiOH aqueous solution (1 mL) and THF (1 mL) was stirred at room temperature for 16 h. The mixture was washed with Et2O. The aqueous layer was acidified with 1N HCl aqueous solution, extracted with Et2O. The organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-(2,6-dichloro-phenyl)-1H-indole-5-carboxylic acid as a white solid: MS (m/z) 306.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: Nc1ccc(NC(=O)c2ccc(N)cc2)cc1
Temperature: 25 °C
Reaction time: 20.7 h

Procedure:
A portion (22.0 grams, 0.1532 nitro equivalents) of 4,4'-dinitrobenzanilide from A above and ethanol (300 milliliters) are added to a 400 milliliter heavy walled glass bottle and then sparged with nitrogen. After removal of air by nitrogen sparging, Raney nickel catalyst (6.0 grams of a 75 % wt. slurry in water at pH 10) is added to the slurry in the glass bottle which is then stoppered and multiply purged with hydrogen to replace the nitrogen atmosphere. The bottle is then placed on a shaking type agitator, and pressurized to 46.5 psig hydrogen. Shaking of the pressurized slurry at room temperature (25° C.) commences until 20.7 hours later, the hydrogen pressure reading indicated that 42 psig of hydrogen has been consumed. The product slurry is recovered, diluted into dimethylsulfoxide (250 milliliters) to provide a solution of product containing precipitated Raney nickel, then filtered through a medium porosity fritted glass funnel. The recovered dimethylsulfoxide product solution is rotary evaporated at 130° C. under vacuum to provide a solid product. The solid product is further dried in a vacuum oven at 120° C. and 3 mm Hg to a constant weight of 16.98 grams. The product thus recovered is light golden orange in color. Fourier transform infrared spectrophotometric analysis of a nujol mull of the product on a sodium chloride plate confirms the product structure (disappearance of the absorbances observed for the conjugated nitro group, secondary amide N-H stretching (solid state) and primary amine N-H group stretching absorbances observed at 3393, 3318 and 3207 cm-1 and secondary amide carbonyl stretching (solid state) absorbance observed at 1630 cm-1). Proton magnetic resonance spectroscopy further confirms the product structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([O:15]CC)=[O:14])=[C:11]([C:18]([O:20]CC)=[O:19])[S:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]([OH:15])=[O:14])=[C:11]([C:18]([OH:20])=[O:19])[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1snc(-c2ccc(Cl)cc2)c1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1snc(-c2ccc(Cl)cc2)c1C(=O)O
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 4,5-diethyl 3-(4-chlorophenyl)-1,2-thiazole-4,5-dicarboxylate (3.28 g, 9.84 mmol, 1.00 equiv) in ethanol (20 mL) and a solution of sodium hydroxide (2.36 g, 59.00 mmol, 6.00 equiv) in water (20 mL). The resulting solution was stirred for 2.5 h at 90° C. in an oil bath. The pH value of the solution was adjusted to 3 with hydrogen chloride (1 mol/L). The resulting solution was extracted with 3×150 mL of dichloromethane. The organic layers were combined, washed with 1×10 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.86 g (69%) of 3-(4-chlororphenyl)-1,2-thiazole-4,5-dicarboxylic acid as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.COC1C=C(C2C=CC=C(B3OCC(C)(C)CO3)C=2)C=CC=1.Cl[C:39]1[CH:48]=[CH:47][N:46]=[C:45]2[C:40]=1[CH:41]=[CH:42][C:43]([C:49]([F:52])([F:51])[F:50])=[N:44]2>>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:39]3[CH:48]=[CH:47][N:46]=[C:45]4[C:40]=3[CH:41]=[CH:42][C:43]([C:49]([F:52])([F:50])[F:51])=[N:44]4)[CH:3]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: COc1cccc(-c2cccc(Br)c2)c1
Agent: COc1cccc(-c2cccc(B3OCC(C)(C)CO3)c2)c1
Product: COc1cccc(-c2cccc(-c3ccnc4nc(C(F)(F)F)ccc34)c2)c1
Yield: 13 %

Procedure:
3-Bromo-3′-methoxybiphenyl (prepared as described in patent WO 0130764) was converted to 2-(3′-methoxybiphenyl-3-yl)-5,5-dimethyl[1,3,2]-dioxaborinane using the procedure described in Example 7 part f). The crude product of this transformation (83 mg, 0.28 mmol) was coupled to 5-chloro-2-trifluoromethyl[1,8]-naphthyridine (50 mg, 0.22 mmol) as described in Example 7 part g), affording 5-(3′-methoxybiphenyl-3-yl)-2-trifluoromethyl[1,8]naphthyridine (11 mg, 13%). δH (360 MHz, CDCl3) 3.87 (3H, s), 6.95 (1H, m), 7.14-7.25 (2H, m), 7.40 (1H, t, J 7.9), 7.47 (1H, d, J 7.7), 7.56-7.69 (3H, m), 7.77-7.83 (2H, m), 8.59 (1H, d, J 8.8), 9.29 (1H, d, J 4.2). m/z (ES+) 381 [MH]
Reaction SMILES: C(OC1C2=C3C(CC4C=C(OCC)C(OCC)=CC=42)N(CCCCC)CC(O)C3=CC=1OCC)C.COC1C2=C3C(CC4C=CC(OC)=CC=42)N(C(C)C)CC(O)C3=C(OC)C=1OC.[CH3:65][O:66][C:67]1[C:78]2=[C:79]3[CH:74]([CH2:75][C:76]4[CH:83]=[C:82]([O:84][CH3:85])[C:81]([O:86][CH3:87])=[CH:80][C:77]=42)[N:73]([CH2:88][CH:89]2[CH2:91][CH2:90]2)[CH2:72][CH:71]([OH:92])[C:70]3=[CH:69][C:68]=1[O:93][CH3:94].C(OC1C2=C3C(CC4C=C(OC)C(OC)=CC=42)N(CC2CCC2)CC(O)C3=CC=1OCC)C>>[CH3:65][O:66][C:67]1[C:78]2=[C:79]3[CH:74]([CH2:75][C:76]4[CH:83]=[C:82]([O:84][CH3:85])[C:81]([O:86][CH3:87])=[CH:80][C:77]=42)[N:73]([CH2:88][CH:89]([CH3:91])[CH3:90])[CH2:72][CH:71]([OH:92])[C:70]3=[CH:69][C:68]=1[O:93][CH3:94]
Reactant: COc1cc2c(cc1OC)-c1c(OC)c(OC)cc3c1C(C2)N(CC1CC1)CC3O
Agent: CCCCCN1CC(O)c2cc(OCC)c(OCC)c3c2C1Cc1cc(OCC)c(OCC)cc1-3
Agent: CCOc1cc2c3c(c1OCC)-c1cc(OC)c(OC)cc1CC3N(CC1CCC1)CC2O
Agent: COc1ccc2c(c1)-c1c(OC)c(OC)c(OC)c3c1C(C2)N(C(C)C)CC3O
Product: COc1cc2c(cc1OC)-c1c(OC)c(OC)cc3c1C(C2)N(CC(C)C)CC3O

Procedure:
(±)-5,6,6a,7-tetrahydro-1,2,9,10-tetraethoxy-6-n-pentyl-4H-dibenzo[de,g]quinolin-4-ol; (±)-5,6,6a,7-tetrahydro-1,2,3,10-tetramethoxy-6-isopropyl-4H-dibenzo[de,g]quinolin-4ol; (±)-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-6-cyclopropylmethyl-4H-dibenzo[de,g]quinolin-4-ol; (±)-5,6,6a,7-tetrahydro-1,2-diethoxy-9,10-dimethoxy-6-cyclobutylmethyl-4H-dibenzo[de,g]quinolin-4-ol.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][OH:15].N1C=CN=C1.S(=O)(=O)(O)O>CN(C)C=O.CCOCC>[Si:1]([O:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][OH:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: OCc1cccc(CO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=S(=O)(O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CO)c1
Yield: 42.7 %

Procedure:
33.3 g of tert-butyldimethylsilyl chloride is added to a solution of 30 g of 3-hydroxymethylbenzyl alcohol and 30 g of imidazole in 250 ml of dimethylformamide at 0° C. under argon and stirred for. 20 hours at 25° C. It is diluted with 1.5 1 of ether, shaken twice with 100 ml of 10% sulfuric acid each, washed neutral with brine, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/0-80% ether, 23.4 g of 3-tert-butyldimethylsilyloxymethyl-benzyl alcohol is obtained as colorless oil.
Reaction SMILES: C(C1N=C(C2C=C(OC3CC4N(C(=O)CCCCCC=CC5C(C(O)=O)(NC4=O)C5)C3)C3C(=C(C)C(OC)=CC=3)N=2)SC=1)(C)C.[CH:46]([C:49]1[N:50]=[C:51]([C:54]2[CH:63]=[C:62]([O:64][CH:65]3[CH2:83][CH:82]4[N:67]([C:68](=[O:94])[CH2:69]C[CH2:71][CH2:72][CH2:73][CH2:74][CH:75]=[CH:76][CH:77]5[C:79]([C:85]([NH:87][S:88]([CH:91]6[CH2:93][CH2:92]6)(=[O:90])=[O:89])=[O:86])([NH:80][C:81]4=[O:84])[CH2:78]5)[CH2:66]3)[C:61]3[C:56](=[CH:57][C:58]([O:95][CH3:96])=[CH:59][CH:60]=3)[N:55]=2)[S:52][CH:53]=1)([CH3:48])[CH3:47]>>[CH:46]([C:49]1[N:50]=[C:51]([C:54]2[CH:63]=[C:62]([O:64][CH:65]3[CH2:83][CH:82]4[N:67]([C:68](=[O:94])[CH2:69][CH2:71][CH2:72][CH2:73][CH2:74][CH:75]=[CH:76][CH:77]5[C:79]([C:85]([NH:87][S:88]([CH:91]6[CH2:92][CH2:93]6)(=[O:90])=[O:89])=[O:86])([NH:80][C:81]4=[O:84])[CH2:78]5)[CH2:66]3)[C:61]3[C:56](=[CH:57][C:58]([O:95][CH3:96])=[CH:59][CH:60]=3)[N:55]=2)[S:52][CH:53]=1)([CH3:48])[CH3:47]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Agent: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1

Procedure:
The title compound was prepared from 17-[2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-2,14-dioxo-3,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (62) following the procedure reported for synthesis of N-[[18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]nonadec-7-en-4-yl]carbonyl](cyclopropyl)sulfonamide 11: m/z=722 (M+H)+. 1H NMR (CDCl3): 0.99-1.77 (m, 17H), 1.94 (dd, J=6.0 Hz, J=9.7 Hz, 1H), 2.12-2.26 (m, 2H), 2.37 (dd, J=7.3 Hz, 16.4 Hz, 1H), 2.57-2.71 (m, 3H), 2.96 (m, 1H), 3.04 (m, 1H), 3.22 (m, 1H), 3.92 (m, 1H), 3.96 (s, 3H), 4.14 (dd, J=3.7 Hz, 11.3 Hz, 1H), 4.58 (t, J=7.9 Hz, 1H), 5.05 (t, J=10.6 Hz, 1H), 5.53 (m, 1H), 5.66 (m, 1H), 6.58 (s, 1H), 7.06 (s, 1H), 7.12 (dd, J=2.5 Hz, J=9.1 Hz, 1H), 7.37 (d, J=2.5 Hz, 1H), 7.56 (s, 1H), 7.93 (d, J=9.1 Hz, 1H), 10.8 (br s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)=O)[CH:8]=[C:9]([F:11])[CH:10]=1)=O)C.C([O-])(=O)C.[NH4+:26].O>C(O)(=O)C>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[NH:26][C:4](=[O:3])[C:6]3[N:7]([CH:8]=[C:9]([F:11])[CH:10]=3)[CH:12]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cc(F)cn1CC(=O)c1ccc(Br)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(-c2ccc(Br)cc2)cn2cc(F)cc12
Temperature: 110 °C
Reaction time: 18 h

Procedure:
A suspension of 27.4 g (77.3 mmol) 1-[2-(4-bromo-phenyl)-2-oxo-ethyl]-4-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester and 140 g (1.82 mol) ammonium acetate in 150 ml acetic acid is heated to 110° C. and the resulting solution is stirred for 18 hours at 110° C. The reaction mixture is allowed to cool to room temperature and added to 1.5 I water under stirring. The resulting precipitate is filtered off, washed with water and dried under vacuum. It is taken up in isopropyl acetate, heated to reflux and filtered while hot. The residue is washed with isopropyl acetate and dried under vacuum to afford 3-(4-bromo-phenyl)-7-fluoro-2H-pyrrolo[1,2-a]pyrazin-1-one as grey crystals; HPLC/MS 1.83 min (A), [M+H] 307/309;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:16]=2[C:25](O)=[O:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.C([N:38](CC)CC)C.N>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:16]=2[C:25](=[O:26])[NH2:38])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cc([N+](=O)[O-])cc(C(=O)O)c1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cc(C(N)=O)c1OC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3-carboxy-5-methylnitrobenzene (3.6 g) in dichloromethane (60 ml) were added isobutyl chloroformate (1.4 ml) and triethylamine (1.6 ml) in an ice bath and the mixture was stirred at the same temperature for 0.5 hours. To the reaction mixture was added 28% aqueous ammonia (0.7 ml) and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane/methanol=19/1 as an eluant to give the desired compound (3.9 g, yield quantitative) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[C:5](=[CH:6][C:7]([C:11]#[CH:12])=[CH:8][CH:9]=2)[C:4]([CH3:14])([CH3:13])[CH:3]1[CH3:15].Br[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1>>[CH3:1][C:2]1([CH3:16])[C:10]2[C:5](=[CH:6][C:7]([C:11]#[C:12][C:18]3[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=3)=[CH:8][CH:9]=2)[C:4]([CH3:14])([CH3:13])[CH:3]1[CH3:15]
Reactant: C#Cc1ccc2c(c1)C(C)(C)C(C)C2(C)C
Reactant: O=Cc1ccc(Br)cc1
Product: CC1C(C)(C)c2ccc(C#Cc3ccc(C=O)cc3)cc2C1(C)C
Yield: 29.1 %

Procedure:
Using a procedure similar to that described in Example 1c, 8 g (40 millimoles) of (2,3-dihydro-1,1,2,3,3-pentamethyl-5(1H)-indenyl)-ethyne and 4.6 g (25 millimoles) of 4-bromobenzaldehyde were reacted, the solution was filtered and the filtrate was evaporated down to give a residue, which was extracted with sodium bicarbonate solution-methylene chloride. Stirring the residue with methylene chloride and a little cyclohexane gave 2.3 g (29%) of the title compound of melting point 106°-107° C.