Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.[C:6]1([CH3:33])[CH:11]=[CH:10][C:9]([N:12]=[C:13]([OH:32])[C:14]2[C:15](=[CH:19][C:20]([N+]([O-])=O)=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]([OH:18])=[S:17])=[CH:8][CH:7]=1.Cl>CS(C)=O>[C:6]1([CH3:33])[CH:11]=[CH:10][C:9]([N:12]=[C:13]([OH:32])[C:14]2[C:15](=[CH:19][C:20]([O:2][CH3:1])=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]([OH:18])=[S:17])=[CH:8][CH:7]=1
Reactant: Cc1ccc(N=C(O)c2c(C(O)=S)cc([N+](=O)[O-])cc2-c2ccccc2)cc1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: COc1cc(C(O)=S)c(C(O)=Nc2ccc(C)cc2)c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
110 ml of 1.0 M sodium methylate solution in 110 mmols of absolute methanol are evaporated to dryness and the residue is suspended in 200 ml of dimethyl sulfoxide. 39.04 g (100 mmols) of 5-nitro-3-phenylthiophthalic acid N-p-toluylimide in 200 ml of dimethyl sulfoxide are added, the mixture is stirred for one day at 25° C. and then discharged into 1.5 liters of dilute hydrochloric acid and the resulting mixture is extracted with chloroform. The organic phase is washed three times with water, dried over sodium sulfate and evaporated. After recrystallisation from toluene/cyclohexane, 31.68 g (84% of theory) of the title imide, with a melting point of 166°-168° C., are obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[O:18][CH3:19])[N:7]([CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:6]=1[CH3:27])=[O:4].[OH-].[Na+].Cl>O1CCOCC1.O>[CH:21]1([CH2:20][N:7]2[C:8]([C:10]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=3[O:18][CH3:19])=[CH:9][C:5]([C:3]([OH:4])=[O:2])=[C:6]2[CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COC(=O)c1cc(-c2cc(OC)ccc2OC)n(CC2CCCCC2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(OC)c(-c2cc(C(=O)O)c(C)n2CC2CCCCC2)c1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
To a solution of 2.3 g of 1-cyclohexylmethyl-5-(2,5-dimethoxy-phenyl)-2-methyl-1H-pyrrole-3-carboxylic acid methyl ester in dioxane (50 ml) and water (50 ml) was added 18.8 ml of a 1N solution of sodium hydroxide. The reaction mixture was heated at reflux for 16 hours. After such time the reaction mixture was allowed to cool down to room temperature before being neutralized with 18.8 ml of a 1N solution of hydrochloride acid. Dioxane was distilled off and the precipitate was then filtered and washed with water to give 2.1 g of the title compound; MS (ISP) 356.3 (M-H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[F:12])=[O:3].[CH3:13][Mg]Cl.C(O)(=O)C.O>O1CCCC1>[F:12][C:5]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[C:2]([OH:3])([CH3:13])[CH3:1]
Reactant: C[Mg]Cl
Reactant: COc1ccc(C(C)=O)c(F)c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(C)(C)O)c(F)c1
Temperature: 30 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
A solution of 2-fluoro-4-methoxyacetophenone (78.1 g, 460 mmol) in tetrahydrofuran (58.6 ml) was added to 3M methylmagnesium chloride solution in THF (199 ml, 598 mmol) at 20 to 35° C. under a nitrogen atmosphere over 30 min without cooling. Additional THF (19.53 ml) was used to rinse all starting material into the vessel. After complete addition, the mixture was stirred at 30° C. for 10 min., then was quenched into acetic acid (52.6 ml, 920 mmol) and water (273 ml) at 5-25° C. THF (20 ml) was used to rinse the vessel. Heptane (156 ml) was then added. The biphasic mixture was stirred at 20-25° C. for 30 min, and then the organic layer was separated. The organic layer was assayed and was found to contain 83.0 g of the desired product, which corresponds to 98% yield. The organic layer was concentrated under vacuum to remove THF, then was flushed with IPAC (200 ml), and the volume was increased to 500 ml by addition of more IPAC. This was used directly in the next step.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:13]([NH:21][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCCCCCN
Product: CCCCCCCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
The process was carried out in essentially the same manner as in Example 1, but using 9 g of glucose and 13.2 g of octylamine.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:19])[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[N:12]3)=[C:6]([F:20])[CH:5]=[CH:4][C:3]=1[NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl.O=[Mn]=O>[F:1][C:2]1[C:7]([C:8]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[N:12]3)=[O:19])=[C:6]([F:20])[CH:5]=[CH:4][C:3]=1[NH:21][C:22](=[O:27])[C:23]([CH3:25])([CH3:24])[CH3:26]
Reactant: CC(C)(C)C(=O)Nc1ccc(F)c(C(O)c2ccc3nccnc3c2)c1F
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
To a solution of N-(2,4-difluoro-3-(hydroxy(quinoxalin-6-yl)methyl)phenyl)pivalamide (541 mg, 1.46 mmol, 1.0 eq.) in DCM (10 mL) was added MnO2 (640 mg, 73 mmol, 5.0 eq.). The resulting mixture was stirred at 50° C. overnight. The solid was removed by filtration and the filtrate was concentrated. The resulting residue was purified via flash column chromatography (PE/EA=2/1, v/v) to afford N-(2,4-difluoro-3-(quinoxaline-6-carbonyl)phenyl)pivalamide as a yellow foam (495 mg, 92%).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:8]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[OH-].[Na+]>O1CCCC1>[CH3:1][NH:2][CH2:3][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:8]1
Reactant: CNC(=O)CCn1nc(-c2ccccc2)c2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CNCCCn1nc(-c2ccccc2)c2ccccc21
Yield: 2.5 %

Procedure:
1-N-Monomethylcarbamoylethyl-3-phenylindazole (m.p. 111°-112° C) (50 g) was dissolved in anhydrous tetrahydrofuran (40 ml) and to the solution was added lithium aluminum hydride (1.5 g) under cooling with ice followed by heating under reflux for 20 min. while stirring. Aqueous ether and aqueous sodium hydroxide solution were added to the resulting reaction mixture to separate an organic layer. 10% Hydrochloric acid was added to the organic layer to separate water layer. The water layer was alkalized with the addition of an aqueous sodium hydroxide solution, extracted with benzene, and the extract was washed with water, dried over sodium sulfate and concentrated under reduced pressure to obtain 1.2 g of 1-N-monomethylaminopropyl-3-phenylindazole as an oily product. The product was converted to its oxalate by a conventional way and then recrystallized from methanol to obtain crystals having a melting point between 197°-198° C (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13]([OH:15])=[O:14].[CH2:22](O)[CH3:23]>Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13]([O:15][CH2:22][CH3:23])=[O:14]
Reactant: CCO
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Agent: Cl
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1

Procedure:
A solution of 3-(2,4-difluorophenylthio)-4-nitrobenzoic acid (1.2 g) in 20% hydrogen chloride in ethanol (3 ml) was refluxed for 2 hours. The mixture was concentrated. The residue was dissolved in ethyl acetate and washed with an aqueous solution of sodium bicarbonate and water successively. The extract was evaporated and the residual oil was crystallized from a mixture of hexane and ethanol to give crystals of ethyl 3-(2,4-difluorophenylthio)-4-nitrobenzoate (1.1 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:5]=1[N:11]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13]
Reactant: COC(=O)c1cccc(Br)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(Br)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.2 %

Procedure:
To a solution of 0.413 g (1.03 mmol) of the product of Example 198 in 10 mL of DMF was added 0.062 g (1.55 mmol) of 60% sodium hydride. Stirring was continued for 15 min at 25° C. and 0.125 mL (1.442 mmol) of benzyl bromide was then added and the mixture was stird for 18 h at 55° C. The reaction was cooled to room temperature and the reaction mixture was poured into 200 mL water and 50 mL 1N HCl. The aqueous layer was then extracted with dichlromethane (100 mL) and ethyl acetate (100 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica eluting with 10%-20% ethyl acetate/hexane to provide 0.390 g (77%) of the desired product. Electrospray Mass Spec 490.0 (M+H)
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl[C:15]1[C:24]([N:25]([CH:27]([CH3:29])[CH3:28])[CH3:26])=[N:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:30]([O:32][CH3:33])=[O:31])[CH:21]=2)[N:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:27]([N:25]([CH3:26])[C:24]1[C:15]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[N:16][C:17]2[C:22]([N:23]=1)=[CH:21][C:20]([C:30]([O:32][CH3:33])=[O:31])=[CH:19][CH:18]=2)([CH3:29])[CH3:28]
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc(C(F)(F)F)cc3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
To a solution of 4-(trifluoromethyl)phenylboronic acid (273 mg, 1.44 mmol) in dioxane (6 mL) was added methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (140 mg, 0.48 mmol), K3PO4 (303 mg, 1.44 mmol), Pd(PPh3)4 (27.6 mg, 0.02 mmol) and water (3 drops), and the reaction mixture was stirred for 4 hours at 90° C. in an oil bath under an inert atmosphere of nitrogen. The reaction mixture was concentrated in vacuo and then purified via silica gel column chromatography (2%-10% ethyl acetate in petroleum ether) to afford methyl 3-(isopropyl(methyl)amino)-2-(4-(trifluoromethyl)phenyl)quinoxaline-6-carboxylate as a light yellow solid (158 mg, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1.Br[CH:23]=[C:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:23]=[C:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=CBr)CC1
Reactant: OB(O)c1ccc(Cl)c(Oc2ccc(C(F)(F)F)cn2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccc(Cl)c(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 50 °C
Yield: 8.2 %

Procedure:
To a solution of 4-chloro-3-(5-(trifluoromethyl)pyridin-2-yloxy)phenylboronic acid (2.8 g, 8.82 mmol) and tert-butyl 4-(bromomethylene)piperidine-1-carboxylate (2.02 g, 7.32 mmol) in THF (10 mL) was added K3PO4 (4.7 g, 26.63 mmol). The air inside the flask was removed under vacuum and flushed with N2 three times. Water (0.56 mL) was added and the system was flushed with N2 again. PdCl2(dppf) (720.3 mg, 0.882 mmol) was added and the system was flushed with N2 two to three times again. The reaction mixture was refluxed at 50° C. for 1 h. The reaction mixture was concentrated, diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (2.5% EtOAc-97.5% Hexane) to give the pure title compound (280 mg). 1H NMR (500 MHz, CDCl3): δ 8.43 (s, 1H), 7.97 (d, J=8.65 Hz, 1H), 7.70 (d, J=1.9 Hz, 1H), 7.55 (d, J=8.35 Hz, 1H), 7.32 (d, J=8.35 Hz, 1H), 7.16 (d, J=8.7 Hz, 1H), 5.99 (s, 1H), 3.44 (m, 4H), 2.39 (m, 2H), 2.24 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=4[F:35])=[O:23])=[C:17]([F:36])[CH:16]=3)[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13]Br)[N:6]2[N:5]=[CH:4][N:3]=1.[CH3:37][O:38][CH2:39][C@@H:40]1[CH2:44][CH2:43][CH2:42][NH:41]1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=4[F:35])=[O:23])=[C:17]([F:36])[CH:16]=3)[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][N:41]3[CH2:42][CH2:43][CH2:44][C@H:40]3[CH2:39][O:38][CH3:37])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: COC[C@@H]1CCCN1
Reactant: Nc1ncnn2c(CCCBr)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC[C@@H]1CCCN1CCCc1cc(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn12
Temperature: 55 °C
Yield: 65.9 %

Procedure:
1-{4-[4-amino-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea (Example 193 step 1) (50 mg, 0.088 mmol) and (2S)-2-(methoxymethyl)pyrrolidine (36 uL, 0.263 mmol) were added to a vial. DMF was added (1 mL) followed by triethylamine (15 uL, 0.109 mmol) and KI (spatula tip). The vial was capped and the reaction heated at 55° C. for two hours. Upon cooling the product precipitated out of solution. The solids were collected by filtration and rinsed with ether to yield 35 mg (65%) of clean product. 1H-NMR (DMSO-d6) δ 9.41 (s, 1H), 9.25 (s, 1H), 8.65 (d, J=7.2 Hz, 1H), 8.26 (t, J=8.4 Hz, 1H), 7.89 (s, 1H), 7.55 to 7.21 (m, 4H), 6.57 (s, 1H), 3.32 (s, 3H), 3.18 to 2.83 (m, 7H), 2.37 to 1.45 (m, 5H); MS [M+H]+=604.2; LCMS RT=2.59
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][C:14]=1[N+:22]([O-])=O)([O-])=O.[OH-].[Na+]>O.[Pd].[Pt]=O>[CH:6]1[C:5]2[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][C:14]=3[N:22]=[N:1][C:4]=2[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=1
Reactant: O=C(O)c1ccc(-c2ccc(C(=O)O)cc2[N+](=O)[O-])c([N+](=O)[O-])c1
Agent: O=[Pt]
Agent: [Pd]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc2c(c1)nnc1cc(C(=O)O)ccc12
Yield: 63.4 %

Procedure:
16.8 g (0.05 mol) of 2,2'-dinitro-biphenyl-4,4'-dicarboxylic acid are dissolved in 150 ml of water and 13.5 g (0.1 mol) of 30% sodium hydroxide solution. 100 mg of palladium-on-active charcoal (10%) and 50 mg of platinum oxide are added and the mixture is hydrogenated under normal pressure. 4.7 l of hydrogen are absorbed. The catalyst is filtered off with suction and the filtrate is rendered slightly acid. The precipitate is filtered off with suction and recrystallised from dimethylsulfoxide. 8.5 g (63.4%) of benzo-[c]-cinnoline-3,8-dicarboxylic acid are obtained.
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:22]3[CH:30]=[CH:31][C:32]([C:34](=[N:36][OH:37])[NH2:35])=[CH:33][C:21]=3[N:20]=2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C=CC=CC=1>O1CCCC1>[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:23]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)[C:22]3[CH:30]=[CH:31][C:32]([C:34]4[NH:35][S:1](=[O:2])[O:37][N:36]=4)=[CH:33][C:21]=3[N:20]=2)=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: NC(=NO)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=S1NC(c2ccc3c(c2)nc(-c2ccc(OCc4ccccc4)cc2)n3C2CCCCC2)=NO1
Reaction time: 3 h
Yield: 39.7 %

Procedure:
Thionyl chloride (0.010 mL, 0.14 mmol) was added dropwise to a suspension of 2-[4-(Benzyloxy)phenyl]-1-cyclohexyl-N′-hydroxy-1H-benzimidazole-5-carboximidamide (0.025 g, 0.057 mmol, see above for preparation) and pyridine (0.020 mL, 0.25 mmol) in tetrahydrofuran (2 mL) at 0° C. The resulting solution was stirred for 3 h, and then concentrated on a rotary evaporator. As starting material remained, the residue was resubjected to the reaction conditions (0.020 mL thionyl chloride and 0.040 mL pyridine). The residue was purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.05% trifluoroacetic acid) to afford the product as a yellow solid (0.011 g, 32%). 1H NMR (CD3OD) δ 8.32 (d, 1H, J=8.8 Hz), 8.25 (s, 1H), 8.04 (d, 1H, J=8.8 Hz), 7.77 (d, 2H, J=9.1 Hz), 7.49 (d, 2H, J=6.6 Hz) 7.43-7.35 (m, 5H), 5.27 (s, 2H), 4.55 (m, 1H), 2.45 (m, 2H), 2.15 (m, 2H), 2.00 (m, 2H), 1.80 (m, 1H), 1.44 (m, 3H); ESI-MS m/e 487.3 (M+1); HPLC purity (ELSD)>95%.
Reaction SMILES: [CH:1]1([C:6]#[CH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.C1(O[C:20]#[N:21])C=CC=CC=1.[OH-].[Na+]>C1COCC1.CCCCCC>[CH:1]1([C:6]#[C:7][C:20]#[N:21])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#COc1ccccc1
Reactant: C#CC1CCCC1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#CC#CC1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
To a solution of cyclopentylacetylene (0.50 g, 5.3 mmol) in THF (5 mL) at −78° C. was added 2.5 M n-butyllithium in hexane (2.23 mL). The mixture was stirred for 15 min followed by the dropwise addition of phenyl cyanate (0.70 g, 5.8 mmol) in THF (3 mL). The reaction was warmed to room temperature. Into the reaction mixture was poured 6 N NaOH, and the mixture was stirred for 5 minutes. The product was extracted with diethyl ether. The extracts were washed with 6 N NaOH and with brine, then dried over sodium sulfate, decanted and the solvent was removed in vacuo to afford product (600 mg, 95%). 1H NMR (300 MHz, CDCl3): 2.81-2.68 (m, 1H), 2.07-1.54 (m, 8H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([CH2:22][CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)C(OCC)=O)[CH3:2].O.[Cl-].[Li+]>CS(C)=O>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[CH2:22][CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:2]
Reactant: CCOC(=O)C(CC=Cc1ccccc1)(Cc1cccc2ccccc12)C(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(CC=Cc1ccccc1)Cc1cccc2ccccc12
Yield: 68.5 %

Procedure:
To a solution of 1.5 g of the malonic acid diethyl ester obtained in 10 ml of dimethyl sulfoxide and 0.3 ml of water was added 0.92 g of lithium chloride, and the mixture was heated for 4.5 hours at from 180° to 190° C. After cooling, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The ethereal layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.85 g of 2-(1-naphthylmethyl)-5-phenyl-4-pentenoic acid ethyl ester as a yellow oil.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][N:2]1[C:14]1[N:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][N:15]=1.CC(C)([O-])C.[K+].[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1.CCOC(C)=O.O.C1OCCOCCOCCOCCOCCOC1>[C:30]1([S:36]([N:12]2[C:13]3[CH2:1][N:2]([C:14]4[N:15]=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:19]=4)[CH2:3][CH2:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)c1cnc(N2CCc3c([nH]c4ccccc34)C2)nc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cnc(N2CCc3c(n(S(=O)(=O)c4ccccc4)c4ccccc34)C2)nc1
Temperature: 0 °C
Reaction time: 0.21 h
Yield: 27.5 %

Procedure:
To a stirred solution of Example 8 (150 mg, 0.487 mmol) in THF (15 mL) was added potassium t-butoxide (81 mg, 0.720 mmol) and 18-crown-6 (2 mg) at 0° C. The suspension was stirred for 10-15 min at 0° C. and then benzenesulfonyl chlorde (0.86 mg, 0.486 mmol) was added. The reaction mixture was further stirred at 0° C. for 30 min. and then stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc and water. The organic layer was washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography using EtOAc in hexanes (50%) to obtain methyl 2-[9-(phenylsulfonyl)-1,3,4,9-tetrahydro-2H-b-carbolin-2-yl]pyrimidine-5-carboxylate (60 mg). 1HNMR (200 MHz, DMSO-d6) ppm: 8.8 (s, 2H), 8.14-7.25 (m, 9H), 5.42 (s, 2H), 4.26 (t, 2H, J=5.4 Hz), 3.91 (s, 3H), 2.81 (2H, t, J=5.4 Hz); m/e=449 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH2:5][CH2:6][N:7](CC2C=CC=CC=2)[CH2:8][CH:9]=1)(=[O:3])[CH3:2].[CH2:17]([O:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[C:1]([C:4]1[CH2:9][CH2:8][N:7]([C:25]([O:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:26])[CH2:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)C1=CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)C1=CCN(C(=O)OCc2ccccc2)CC1

Procedure:
To a solution of 4-acetyl-1-benzyl-1,2,3,6-tetrahydropyridine (9.63 g) and benzyloxycarbonyl chloride (9.06 ml) in toluene was heated at 85° C. for 8 hours. After the solvent was removed in vacuo, the residual solution was dissolved in ethyl acetate (100 ml), washed with saturated aqueous sodium hydrogen carbonate (100 ml×3) and brine (100 ml) successively. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo to give an oil, which was chromatographed on silica gel (500 ml) eluting with a mixture of hexane and ethyl acetate (1:1, V/V) to give 4-acetyl-1-benzyloxycarbonyl-1,2,3,6-tetrahydropyridine (10.2 g).