Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH2:5]1)C=O.[Br:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21](O)=[O:22])[CH:16]=[CH:17][C:18]=1[OH:19]>O=P(Cl)(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[OH:10][C:8]1[CH:7]=[C:6]([OH:11])[CH:5]=[C:2]([OH:1])[C:9]=1[C:21](=[O:22])[CH2:20][C:15]1[CH:16]=[CH:17][C:18]([OH:19])=[C:13]([Br:12])[CH:14]=1
Reactant: O=CC1(O)C=C(O)C=C(O)C1
Reactant: O=C(O)Cc1ccc(O)c(Br)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Cc1ccc(O)c(Br)c1)c1c(O)cc(O)cc1O
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 18.4 %

Procedure:
1,3.5-Trihydroxybenzaldehyde (1.01 g, 6.95 mmol) and 3-bromo-4-hydroxyphenylacetic acid (1.44 g, 6.25 mmol) were suspended in POCl3 (4 mL). After 1 min, an exothermic reaction occurred. The mixture was allowed to cool to room temperature. Zinc chloride (1M ether solution, 4.7 mmol) was added and the mixture was heated at 75° C. for 1 h. After cooling, the mixture was partitioned in ethyl acetate and 1 M aqueous HCl. The organic layer was washed with brine and dried with MgSO4. Purification on silica gel (MeOH/dichloromethane, gradient) afforded 1-(2,4,6-trihydroxyphenyl)-2-(3-bromo-4-hydroxyphenyl)ethanone (390 mg) as a tan solid.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:12](N1C=CN=C1)(N1C=CN=C1)=[O:13].[CH2:24]([O:31][C:32](=[O:49])[C:33]([CH3:48])([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH:42]2[CH2:47][CH2:46][CH2:45][NH:44][CH2:43]2)[CH:37]=1)[CH3:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>C1(C)C=CC=CC=1.O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:12]([N:44]2[CH2:45][CH2:46][CH2:47][CH:42]([C:38]3[CH:39]=[CH:40][CH:41]=[C:36]([O:35][C:33]([C:32]([O:31][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:49])([CH3:34])[CH3:48])[CH:37]=3)[CH2:43]2)=[O:13])=[CH:10][CH:11]=1)([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(Oc1cccc(C2CCCNC2)c1)C(=O)OCc1ccccc1
Reactant: CC(C)c1ccc(CO)cc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1ccc(COC(=O)N2CCCC(c3cccc(OC(C)(C)C(=O)OCc4ccccc4)c3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.3 %

Procedure:
To a solution of 4-isopropylbenzyl alcohol (0.86 g, 5.75 mmol) in 10 mL toluene was added 1,1′-carbonyldiimidazole (0.87 g, 5.40 mmol). This solution was stirred 18 h at ambient temperature. 2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid benzyl ester (Preparation 2, Method C; 1.27 g, 3.59 mmol) was added in 5 mL toluene and the resultant solution was stirred 18 h at ambient temperature. The reaction was diluted with water (200 mL), acidified with 1N aqueous hydrochloric acid and extracted with diethyl ether (2×150 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 10% ethyl acetate/hexanes to yield 1.07 g (56%) of the desired 3-[3-(1-Benzyloxycarbonyl-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-isopropyl-benzyl ester as a clear oil.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6])#[CH:2].[CH2:11]([N:18]=[N+:19]=[N-:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O.O>[CH2:11]([N:18]1[CH:2]=[C:1]([C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[CH:5]=[O:6])[N:20]=[N:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:11]([N:18]1[C:1]([C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[CH:5]=[O:6])=[CH:2][N:20]=[N:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C#Cc1ccccc1C=O
Reactant: [N-]=[N+]=NCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccccc1-c1cn(Cc2ccccc2)nn1
Product: O=Cc1ccccc1-c1cnnn1Cc1ccccc1
Yield: 65 %
Yield: 30 %

Procedure:
A solution of 2-ethynylbenzaldehyde (200 mg, 1.54 mmol) and benzyl azide (0.38 mL, 3.0 mmol) in 2.0 mL of N,N-dimethylformamide was stirred at 80° C. overnight. The reaction mixture was diluted with water, and the solution was extracted with a 5:1 solution (12 mL) of ethyl acetate and hexane. The extract was washed with water, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=80/20 to 60/40) to obtain 2-(1-benzyl-1H-1,2,3-triazol-4-yl)benzaldehyde (259 mg, 65%) and 2-(1-benzyl-1H-1,2,3-triazol-5-yl)benzaldehyde (118 mg, 30%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[N:16][CH:17]=2)[N:14]([C:18]([NH2:20])=[O:19])[CH2:13][CH2:12][CH2:11]3)[CH:5]=[N:6][CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O1CCOCC1.O>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:3]=[C:4]([C:8]3[CH:9]=[C:10]4[C:15](=[N:16][CH:17]=3)[N:14]([C:18]([NH2:20])=[O:19])[CH2:13][CH2:12][CH2:11]4)[CH:5]=[N:6][CH:7]=2)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: NC(=O)N1CCCc2cc(-c3cncc(Br)c3)cnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: NC(=O)N1CCCc2cc(-c3cncc(-c4ccc(F)cc4)c3)cnc21
Temperature: 100 °C
Yield: 67 %

Procedure:
6-(5-Bromo-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (50 mg, 0.15 mmol), 4-fluorophenylboronic acid (42 mg, 0.30 mmol) and 2.0 M Na2CO3 aqueous solution (0.15 mL, 0.30 mmol) are dissolved in 2.0 mL of 1,4-dioxane. The Argon gas is bubbled through the solution for 5 min. Then PdCl2dppf (7.7 mg, 0.011 mmol) is added. The mixture is heated at 100° C. for 2 hrs before it is cooled down to room temperature. Then 30 mL of DCM and 20 mL of water are added. The organic layer is separated and the aqueous layer is extracted with DCM (2×20 mL). All the organic layers are combined, dried and concentrated to give crude product. Purification by flash column chromatography followed by washing with EtOAc (2×1 mL) affords 35 mg of the titled product.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][CH2:8][OH:9])[C:4]([CH3:11])([CH3:10])[O:3]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].O>ClCCl>[CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][CH2:8][O:9][S:21]([CH3:20])(=[O:23])=[O:22])[C:4]([CH3:11])([CH3:10])[O:3]1
Reactant: CC1(C)O[C@@H](CCO)C(C)(C)O1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)O[C@@H](CCOS(C)(=O)=O)C(C)(C)O1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 41.3 %

Procedure:
Step G To a solution of 2-((S)-2,2,5,5-tetramethyl-[1,3]dioxolan-4-yl)-ethanol (2.7 g, 15.8 mol) and triethylamine (4.6 g, 45 mmol) in dichloromethane (100 mL) at 0° C. was added methanesulfonyl chloride (2.7 g, 24 mmol) dropwise. The reaction mixture was stirred at 0° C. for 1.5 h, then water was added. The organic layer was separated, washed with water, brine, dried over MgSO4, concentrated to give methanesulfonic acid 2-((S)-2,2,5,5-tetramethyl-[1,3]dioxolan-4-yl)-ethyl ester as a yellow oil (2.5 g, 62%).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[Li][CH2:9]CCC.[C:13]12([C:23]3[CH:24]=[C:25]([C:31]4[CH:32]=[C:33]5[C:38](=[CH:39][CH:40]=4)[CH:37]=[C:36](CI)[CH:35]=[CH:34]5)[CH:26]=[CH:27][C:28]=3[O:29][CH3:30])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>C1COCC1.O>[C:13]12([C:23]3[CH:24]=[C:25]([C:31]4[CH:32]=[C:33]5[C:38](=[CH:39][CH:40]=4)[CH:37]=[C:36]([CH:5]4[S:1][C:2](=[O:7])[N:3]([CH3:9])[C:4]4=[O:6])[CH:35]=[CH:34]5)[CH:26]=[CH:27][C:28]=3[O:29][CH3:30])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2
Reactant: COc1ccc(-c2ccc3cc(CI)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=C1CSC(=O)N1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccc3cc(C4SC(=O)N(C)C4=O)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
To a stirred solution of 2,4-thiazolidinedione (0.094 g, 0.80 mmol) in 4.0 mL of anhydrous THF at −78° C. under argon was added n-BuLi (0.58 mL of 2.5 M in hexanes). After 20 minutes, the reaction mixture was allowed to warm to 0° C. for 30 minutes then cooled to −78° C. To this mixture was added 6-[3-(1-adamantyl)-4-methoxyphenyl]-naphthalen-2-yl-methyliodide (0.177 g, 0.35 mmol) in 3 mL anhydrous THF and stirred at −78° C. for 30 minutes. The reaction mixture was warmed to room temperature. After 14 hours, the reaction mixture was diluted with water and extracted with EtOAc (2×50 mL). The combined organics were washed with water (100 mL), sat. NH4Cl (100 mL), brine (100 mL), dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (eluent: hexane:EtOAc 4:1) to give 0.097 g of 6-[3-(1-adamantyl)-4-methoxyphenyl]-naphthalen-2-yl-methyl-2,4-thiazolidinedione (56%), mp 251–253° C. 1H NMR (300 MHz; DMSO-d6): δ 1.80 (brs, 6H), 2.10–2.18 (m, 9H), 3.32 (dd, J=9.6 Hz, J=14.1 Hz, 1H), 3.72 (dd, J=3.6 Hz, J=14.1 Hz, 1H), 3.90 (s, 3H), 4.65 (dd, J=3.6 Hz, J=9.9 Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 7.36 (dd, J=1.5 Hz, J=8.4 Hz, 1H), 7.52 (dd, J=1.8 Hz, J=8.7 Hz, 1H), 7.57 (d, J=2.1 Hz, 1H), 7.70–7.76 (m, 2H), 7.84 (d, J=3.3 Hz, 1H), 7.87 (d, J=3.6 Hz, 1H), 7.96 (d, J=0.3 Hz, 1H), 8.13 (brs, 1H). 13C NMR (75 MHz; DMSO-d6): 38.4, 46.6, 47.4, 62.7, 65.3, 122.6, 134.0, 134.7, 135.3, 137.3, 137.6, 137.9, 138.1, 141.5, 141.8, 142.3, 144.1, 147.7, 147.8, 168.1, 181.4, 185.5.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[CH2:23]1OC(O)C[O:25][CH:24]1O.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[OH:25][CH2:24][CH2:23][NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:20])[F:21])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: OC1COC(O)CO1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(NCCO)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
350 mg (1.15 mmol) of the 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Example 38 was dissolved in 11.5 ml of methanol, and thereafter, 1.15 ml of acetic acid and 552.5 mg (4.60 mmol) of glycolaldehyde dimer were added thereto. Thereafter, 722 mg (11.5 mmol) of sodium cyanoborohydride was added to the mixture under cooling on ice. The temperature of the mixture was increased to a room temperature, and the mixture was then stirred for 8 hours. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and was then concentrated. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=20:1 to 12:1), so as to obtain 61.8 mg (15%) of 7-(2-hydroxyethylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one in the form of a yellow amorphous substance, as well as 369.3 mg (82%) of 7-[bis(2-hydroxyethyl)amino]-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one in the form of a yellow foaming substance.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:2].[CH2:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].Cl>O1CCOCC1.[Pd](Cl)Cl>[CH3:8][CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:1]([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:2].[C:1]([O:3][CH2:4][CH2:5][CH2:6][CH3:7])(=[O:2])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: C=CCCCCCCCC
Reactant: CCCCOC=O
Agent: Cl[Pd]Cl
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCCCCC(C)C(=O)OCCCC
Product: CCCCCCCCCCC(=O)OCCCC
Reaction time: 0.08 h

Procedure:
A mixture of palladium chloride [27 mg, 0.15 mmol] and CuCl2 [41 mg, 0.30 mmol] in dioxane (10 ml) was stirred under carbon monoxide for 5 minutes. Then n-butyl formate (4 ml), 1-decene [0.75 g, 5.35 mmol] and aqueous hydrochloric acid (0.1 ml) were added and CO/O2 (1:1) was bubbled through the solution at room temperature and atmospheric pressure for a period of 24 hours. Analysis of the product gave n-butyl 2-methyldecanoate and n-butyl undecanoate with respectively 87% and 13% selectivity with a 64% conversion of the formic acid ester.
Reaction SMILES: N[C:2]1[C:3]([F:20])=[CH:4][C:5]([F:19])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:9]=2[CH3:18])[CH:7]=1.N(OCCC(C)C)=O.[I:29]I>C(Cl)(Cl)Cl>[F:19][C:5]1[CH:4]=[C:3]([F:20])[C:2]([I:29])=[CH:7][C:6]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:9]=1[CH3:18]
Reactant: II
Reactant: COC(=O)c1ccc(-c2cc(N)c(F)cc2F)c(C)c1
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(-c2cc(I)c(F)cc2F)c(C)c1

Procedure:
Methyl 5′-amino-2′,4′-difluoro-2-methylbiphenyl-4-carboxylate (STEP A, 500 mg, 1.80 mmol), 3-methylbutyl nitrite (317 mg, 2.71 mmol), iodine (549 mg, 2.16 mmol) and chloroform (15 ml) were refluxed in an oil bath for 5 hours then allowed to cooled to ambient overnight. Reaction crude was purified by flash chromatography (SiO2, Biotage 40+M cartridge) eluted with a EtOAc/hexanes gradient mixture. Related fractions were pooled and concentrated in vacuo to afford the title compound. LCMS (ESI) calc.=387.98; found=388.92 (M+1)+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:20][CH2:21][CH3:22])(=[O:19])[C:10]1[CH:18]=[CH:17][C:15]([OH:16])=[C:12]([O:13][CH3:14])[CH:11]=1>>[CH2:1]([O:16][C:15]1[CH:17]=[CH:18][C:10]([C:9]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][C:12]=1[O:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Reactant: BrCc1ccccc1
Product: CCOC(=O)c1ccc(OCc2ccccc2)c(OC)c1
Yield: 97 %

Procedure:
Benzyl bromide was reacted with ethyl vanillate using the conditions described in Example 1 to give ethyl 4-benzyloxy-3-methoxybenzoate in 97% yield m.p. 72°-74° C. Following the procedures described in the portion of Example 6 which is concerned with the preparation of starting materials the product so obtained was reacted with thiazol-2-yl-lithium and the resultant product was reacted with ethylmagnesium iodide to give the required starting material as an oil in 20% yield.
Reaction SMILES: [S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-])(=[O:3])=[O:2].FC(F)(F)C(O)=O.CC[N:21](C(C)C)C(C)C>>[CH3:9][C:8]1[CH:7]=[CH:6][C:5]([S:1]([NH2:21])(=[O:3])=[O:2])=[CH:11][CH:10]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(N)(=O)=O)cc1

Procedure:
The azatetracyclic compounds that are the subject of the invention herein can be prepared in the following reaction Schemes I and II. In reaction Scheme I a method of producing azatetracyclic benzamides is shown and in reaction Scheme II a method for producing azatetracyclic amines is shown. ##STR10## Referring to reaction Scheme I, trans-1,2-di-carbomethoxy-4-methylene-cyclopentane is reacted with sodium hydroxide followed with acid to produce trans-4-methylene-1,2-cyclopentanedicarboxylic acid. The dicarboxylic acid is reacted with acetic anhydride to produce cis-tetrahydro-5-methylene-1H-cyclopenta[c]furan-1,3(3aH)-dione. The ammonium salt 4 is prepared by reacting the anhydride 3 in dry methylene chloride with ammonia gas. The imide 5 is prepared from the ammonium salt by reacting the ammonium salt with acetyl chloride. The imide is reacted with lithium aluminum hydride and ditertiarybutyl dicarbonate to produce cis-1,1-dimethylethylhexahydro-5-methylenecyclopenta[c]pyrrole-2(1H)carboxylate 6. The term BOC is used herein to refer to t-butyloxy carbonyl. The BOC-amine 6 is reacted with bis(P-toluenesulfonyl) sulfodiimide to produce the p-toluenesulfonamide 7. The term Tos is used herein to represent P-toluenesulfonyl. The p-toluenesulfonamide is reacted with thexyl borane to produce the endo alcohol 8. The endo alcohol is reacted with p-toluenesulfonyl chloride to produce the tosylate 9. The tosylate 9 is reacted with trifluoroacetic acid and treated with Hunig's base to provide the p-toluenesulfonamide tetracycle 10. The sulfonamide tetracycle 10 was reductively cleaved to produce the aminoazatetracycle 11 Coupling of the aminoazatetracycle 11 with benzoic acid derivative 12 under mixed anhydride conditions gave the protected benzamide tetracycle 13. Basic hydrolysis of the acetamide 13 gives the benzamide tetracycle 14 which upon treatment with HCl produces the hydrochloride salt of the benzamide tetracycle 15.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][N:22]1[C:34]2[CH2:33][CH2:32][CH:31]([CH2:35][C:36]3[N:37]=[CH:38][NH:39][C:40]=3[CH3:41])[C:30](=[O:42])[C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2.C(N(CC)CC)C.O>CN(C=O)C>[CH3:21][N:22]1[C:34]2[CH2:33][CH2:32][CH:31]([CH2:35][C:36]3[N:37]=[CH:38][N:39]([C:7]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:40]=3[CH3:41])[C:30](=[O:42])[C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2
Reactant: Cc1[nH]cnc1CC1CCc2c(c3ccccc3n2C)C1=O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(CC2CCc3c(c4ccccc4n3C)C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 57 %

Procedure:
A solution of triphenylchloromethane (286 mg) in dry DMF (10 ml) was added dropwise to a stirred solution of 1,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4-yl)methyl]-4H-carbazol-4-one (292 mg) and triethylamine (101 mg) in dry DMF (20 ml) and the resulting solution was stirred at room temperature under nitrogen for 3.5 h. The reaction mixture was then poured into water (100 ml) and the resultant suspension was extracted with dichloromethane (3×50 ml). The combined, dried organic extracts were adsorbed onto FCC silica which was then applied to a column and FCC eluting with System A (150:8:1) gave a solid which was further purified by crystallisation from dichloromethane:hexane (2:1) to give the title compound (304 mg), m.p. 193°-195°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]([O:28]CC)=O)[C:5]2[C:6](=O)[CH:7]([C:19]3[N:23]([CH3:24])[N:22]=[CH:21][N:20]=3)[CH:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[NH:9][C:10]=2[CH:11]=1.O.[NH2:32][NH2:33]>CO>[F:1][C:2]1[CH:11]=[C:10]2[NH:9][CH:8]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)[CH:7]([C:19]3[N:23]([CH3:24])[N:22]=[CH:21][N:20]=3)[C:6]3=[N:32][NH:33][C:26](=[O:28])[C:4]([CH:3]=1)=[C:5]23
Reactant: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ncnn1C)C(c1ccc(F)cc1)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: Cn1ncnc1C1c2n[nH]c(=O)c3cc(F)cc(c23)NC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 84 %

Procedure:
To a solution of ethyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (840 mg, 2.04 mmol) in methanol (2 mL) was added hydrazine monohydrate (1 mL), and the mixture was stirred under 25° C. for 10 hr. Then the mixture was filtered to obtain a white solid (650 mg, yield 84%). LC-MS (ESI) m/z: 381 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.66 (s, 3H), 4.97-5.04 (m, 2H), 6.91-6.94 (dd, J1=11.2 Hz, J2=2.4 Hz, 1H), 7.06-7.09 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.14-7.18 (m, 3H), 7.47-7.51 (m, 2H), 7.72 (s, 1H), 7.80 (s, 1H), 12.35 (s, 1H)
Reaction SMILES: O.[OH-].[Na+].[C:4]([C:6]1([CH2:12][C:13]([O:15]CC)=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)#[N:5]>CO>[C:4]([C:6]1([CH2:12][C:13]([OH:15])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)#[N:5]
Reactant: CCOC(=O)CC1(C#N)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#CC1(CC(=O)O)CCCCC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a suitable reactor is charged 120 L of water, 32 kg of 50% aqueous sodium hydroxide solution, 21 L of methanol, and 70 kg of ethyl 1-cyanocyclohexaneacetate. This mixture is stirred at 50° C. for 1 hour, after which 40 to 60 L of solvent is removed by vacuum distillation while maintaining a temperature of below 50° C. After cooling to 20° to 25° C., the reaction mixture is filtered through a 0.45 micron Pall filter. The filtered solution is then diluted with 70 L of water and extracted with 20 L of methylene chloride, followed by a second extraction with 15 L of methylene chloride. The aqueous solution is charged to a pH of 8 with 37% hydrochloric acid solution. About 6 to 8 kg of 37% hydrochloric acid solution is required. The solution is then extracted two times with 20 L each of methylene chloride. After the final extraction, the aqueous solution is stirred under full vacuum at 20° to 30° C. for 30 minutes minimum, then cooled to 3° to 10° C. While maintaining this temperature, 37% hydrochloric acid solution is charged to a pH of 3. About 32 to 36 kg of 37% hydrochloric acid solution is required. After the addition is complete, the product slurry is stirred at 3° to 10° C. for 30 minutes. The product is then collected on a centrifuge and washed with 300 to 400 L of water which is prechilled to 5° C. or less. The product is spun a dry as possible on the centrifuge and is then removed from the centrifuge and stored as a wet cake in a cold room at 5° C. or less. After vacuum drying at 40° C. for 24 hours 1-cyanocyclohexaneacetic acid is obtained; mp 103°-105° C.
Reaction SMILES: [O:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=[CH:2]1.[Cl:11][C:12]1[CH:13]=[C:14](F)[CH:15]=[CH:16][C:17]=1[Cl:18]>>[ClH:11].[Cl:11][C:12]1[CH:13]=[C:14]([O:10][CH:9]2[CH2:8][NH:7][CH2:6][C:5]3[O:1][CH:2]=[CH:3][C:4]2=3)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: OC1CNCc2occc21
Product: Cl
Product: Clc1ccc(OC2CNCc3occc32)cc1Cl

Procedure:
The same method as in Example 3 was conducted using 4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 4) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[C:19](Cl)(=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].Cl>CN(C)C=O.O>[C:19]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])(=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: Cc1ccc(C(=O)O)cc1N
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(=O)Nc1cc(C(=O)O)ccc1C
Yield: 56.5 %

Procedure:
A stirred solution of 3-amino-4-methylbenzoic acid (15.1 g) in dry dimethylformamide (150 ml), containing triethylamine (20.2 g) was treated with n-hexadecanoyl chloride (27.5 g) during 30 minutes. The temperature of the reaction mixture was maintained at 25°-45° C. during the addition by water cooling. The mixture was then stirred for a further hour and was poured into water (1000 ml). The mixture was adjusted to pH 1 by the addition of concentrated hydrochloric acid (strength 0.6% w.v). The solid was collected, was washed with water and was recrystallised from ethanol (1500 ml) to give 3-(n-hexadecanamido)-4-methylbenzoic acid (22.0 g), in the form of a white solid, m.p. 238°-240° C.