Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[CH:14]([CH2:15]2)[CH2:13][NH:12]4)[CH2:5][C@H:4]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:3]1.[N+:26]([O-])([OH:28])=[O:27].N>S(=O)(=O)(O)O>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[C:9]([N+:26]([O-:28])=[O:27])[CH:10]=[C:11]4[C:17]=3[CH:14]([CH2:15]2)[CH2:13][NH:12]4)[CH2:5][C@H:4]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:3]1
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4c3C(CN4)C[C@H]2N(C)C1
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc([N+](=O)[O-])cc4c3C(CN4)C[C@H]2N(C)C1
Reaction time: 0.25 h
Yield: 71 %

Procedure:
Under ice cooling, 10 mmol of 3-(2,3-dihydro-6-methyl-8α-ergolinyl)-1,1-diethylurea is dissolved in 100 ml of concentrated sulfuric acid; 7 ml of a solution of 10 ml of 65% nitric acid in 90 ml of concentrated sulfuric acid is added thereto, and the mixture is stirred for 15 minutes in an ice bath. The reaction solution is then slowly introduced dropwise into ice, made alkaline under ice cooling with 32% ammonia solution, and extracted by shaking with methylene chloride. After washing the organic phase with water and drying with magnesium sulfate, the nitrated compound is obtained in a 90% crude yield. After chromatographic separation and purification, respectively, 3-(2,3-dihydro-6-methyl-13-nitro-8α-ergolinyl)-1,1-diethylurea is obtained in a 71% yield.
Reaction SMILES: [C:1]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:20]3[NH:24][C:23]4[CH:25]=[CH:26][C:27]([CH:29]=O)=[CH:28][C:22]=4[N:21]=3)[CH2:14][CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:32]O.Cl.O1CCOCC1>CN(C)C=O.Cl.[OH-].[Na+]>[C:1]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:20]3[NH:24][C:23]4[CH:25]=[CH:26][C:27]([C:29]#[N:32])=[CH:28][C:22]=4[N:21]=3)[CH2:14][CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc2[nH]c(NCC3CCN(Cc4cccc5ccccc45)CC3)nc2c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: N#Cc1ccc2[nH]c(NCC3CCN(Cc4cccc5ccccc45)CC3)nc2c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
After dissolving 2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboaldehyde (2.7 mg, 0.0570 mmol) in anhydrous dimethylformamide (1 ml) under a nitrogen stream, hydroxylamine hydrochloride (8 mg, 0.115 mmol) and one drop of 6N hydrochloric acid were added and the mixture was stirred at 80° C. for 2 hours and 30 minutes. Two drops of 5N aqueous sodium hydroxide were then added, and after extraction with ethyl acetate, extraction was repeated with dichloromethane. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. Anhydrous dimethylformamide (1 ml) and nine drops of a 4N hydrogen chloride/1,4-dioxane solution were added to the residue, and the mixture was stirred at 100° C. for 12 hours. After neutralization with 5N aqueous sodium hydroxide, the same extraction procedure was carried out and the obtained residue was purified by thin-layer silica gel chromatography (dichloromethane/methanol/triethylamine=85/10/5) to obtain 2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carbonitrile.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][CH:17]4[CH2:22][CH2:21][CH2:20][N:19]([C:23]5[N:28]=[CH:27][C:26]([C:29]6[CH:33]=[CH:32][N:31]([CH:34]7[CH2:39][CH2:38][N:37](C([O-])=O)[CH2:36][CH2:35]7)[N:30]=6)=[CH:25][N:24]=5)[CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.[ClH:43]>C(Cl)Cl.O1CCOCC1>[ClH:43].[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][CH:17]4[CH2:22][CH2:21][CH2:20][N:19]([C:23]5[N:28]=[CH:27][C:26]([C:29]6[CH:33]=[CH:32][N:31]([CH:34]7[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]7)[N:30]=6)=[CH:25][N:24]=5)[CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cnc3nnn(CC4CCCN(c5ncc(-c6ccn(C7CCN(C(=O)[O-])CC7)n6)cn5)C4)c3n2)cn1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1cc(-c2cnc3nnn(CC4CCCN(c5ncc(-c6ccn(C7CCNCC7)n6)cn5)C4)c3n2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
4-(3-(2-(3-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (25 mg, 0.04 mmol) was dissolved in CH2Cl2(5 ml), and then 4 N HCl in dioxane (1 ml) was added, followed by stirring at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and then purified with ether, to give 6-(1-methyl-1H-pyrazol-4-yl)-1-((1-(5-(1-(piperidin-4-yl)-1H-pyrazol-3-yl)pyrimidin-2-yl)piperidin-3-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine hydrochloride (18 mg, 75%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]1([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][CH2:2][C:3]([N:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(CCl)N(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 75.5 %

Procedure:
Chloroacetyl chloride (0.32 ml, 4.02 mmol) was dissolved in a mixed solvent of toluene (6 ml) and tetrahydrofuran (2 ml). The solution was added with diphenylamine (690 mg, 4.08 mmol) at room temperature, and the heated at 100° C. for 80 minutes. The solvent was evaporated under reduced pressure, and the solid precipitated was suspended and washed in ethyl ether. The solid was collected by filtration and dried under reduced pressure to obtain the title compound as colorless solid (746 mg, yield: 75%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([OH:21])=[O:20])[C:3]=1[Cl:22].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:33])([F:34])[F:35])=[CH:27][CH:26]=2)=[O:20])[C:3]=1[Cl:22]
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)O)c(Cl)c(N)c2F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccc(OC(F)(F)F)cc3)c(Cl)c(N)c2F)c1F
Temperature: 50 °C
Yield: 51.4 %

Procedure:
A suspension of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinic acid (200 mg, 0.573 mmol), 1-(bromomethyl)-4-(trifluoromethoxy)benzene (161 mg, 0.630 mmol) and K2CO3 (119 mg, 0.859 mmol) in DMF (2 mL) was heated at 50° C. overnight. The reaction mixture was then concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 0-80% EtOAc/hexane gradient) to yield a white solid (154 mg, 51.4%): mp 155-156° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.60 (d, J=8.7 Hz, 2H), 7.47 (dd, J=8.5, 1.5 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.29 (dd, J=8.5, 7.1 Hz, 1H), 7.14 (s, 2H), 5.41 (s, 2H), 3.95-3.90 (m, 3H); ESIMS m/z 523 ([M+H]+), 521 ([M−H]−).
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)=[C:2]=[O:3].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.CCCCCC>C1COCC1>[NH:8]1[C:9]2[C:5](=[C:4]([NH:1][C:2]([NH:20][CH2:19][C:18]3[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:23])[F:24])=[CH:22][CH:21]=3)=[O:3])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: O=C=Nc1cccc2[nH]ccc12
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2[nH]ccc12
Reaction time: 3 h

Procedure:
The product of Example 80A (0.16 g, 1 mmol) in THF (3 mL) was treated with 4-(trifluoromethyl)benzylamine (0.19 g, 1.1 mmol) at ambient temperature. After stirring for 3 hours, hexane was added to the reaction mixture to precipitate the title compound as a solid. mp 178° C. 1H NMR (300 MHz, DMSO-d6) δ 4.43 (d, 2H), 6.53 (t, 1H), (6.98 m, 3H), 7.26 (t, 1H), 7.57 (d, 2H), 7.62 (d, 1H), 7.71 (d, 2H), 8.37 (s, 1H), 11.04 (s, 1H); MS (DCI+) m/z 334 (M+H); Anal. Calcd. For C17H14N3F3O: C, 61.26; H, 4.23; N, 12.61. Found: C, 61.28, H, 3.83; N, 12.31.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH:5]([CH3:8])[CH2:4][NH:3]1.[C:9](Cl)(=[O:13])[CH2:10][CH2:11][CH3:12]>>[C:9]([N:3]1[CH2:4][CH:5]([CH3:8])[N:6]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH2:7][CH:2]1[CH3:1])(=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCCC(=O)Cl
Reactant: CC1CNC(C)CN1
Product: CCCC(=O)N1CC(C)N(C(=O)CCC)CC1C
Yield: 446.2 %

Procedure:
The reaction of 5 g (0.044 mole) of 2,5-dimethylpiperazine with 12.15 g (0.0114 mole) of butyryl chloride is conducted as described in Example III, and the crude product obtained is an oily solid. The solid is washed with hexane, recrystallized from hexane/acetone, and dried in vacuo for 16 hours at 55° C. over phosphorus pentoxide to yield 6.47 g of 1,4-dibutryl-2,5-dimethylpiperazine: mp, 92°-94° C., as confirmed by IR and NMR spectroscopic analysis.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.C([Li])CCC.Cl[C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:22]=1>O1CCCC1.CCCCCC.[Cl-].[Cl-].[Zn+2]>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:22]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCS2
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCS3)nc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Reaction vessels used in this procedure were flame dried under vacuum and all operations carried out in an oxygen-free, argon or nitrogen atmosphere. To a solution of 465.7 mg (2.3019 mmol) of 4,4-dimethyl-6-ethynyl-thiochroman in 4 ml of dry tetrahydrofuran at 0° C. was added dropwise 1.5 ml of 1.6M (2.4 mmol) n-butyllithium in hexane. This was stirred at 0° C. for 10 minutes and at room temperature for 10 minutes, cooled again to 0° C. and then treated with a solution of 330 mg (2.4215 mmol) of fused ZnCl2 in 4 ml dry tetrahydrofuran using a double ended needle. Thereafter the solution was stirred at 0° C. for 30 minutes, then at room temperature for 10 minutes. A solution of 426.3 mg (2.2967 mmol) of ethyl 6-chloronicotinoate (from Example 5) in 4 ml dry tetrahydrofuran was transferred by double ended needle into a suspension of 430 mg (0.37 mmol) of tetrakistriphenylphosphine palladium in 4 ml dry tetrahydrofuran and stirred at room temperature for 10 minutes, then treated by double ended needle with the solution of the alkynylzinc prepared above. This mixture was stirred at room temperature for 18 hours, then quenched with 100 ml water. Product was recovered by extraction with 3×75 ml ether. Ether fractions were combined and washed with saturated NaCl solutions and dried (mgSO4). Solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexane) followed by HPLC (Whatman Partisil M-9 10/50; 4% ethyl acetate in hexane) to give the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10].C([O-])([O-])=O.[K+].[K+].[F:17][CH:18]([F:25])[CH2:19]OS(C)(=O)=O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[O:10][CH2:19][CH:18]([F:25])[F:17]
Reactant: Oc1c(Cl)cc(Cl)cc1Br
Reactant: CS(=O)(=O)OCC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)COc1c(Cl)cc(Cl)cc1Br

Procedure:
To a solution of 2-bromo-4,6-dichloro-phenol (14.6 g, 60.3 mmol, Step A compound) in DMF (10 ml) were added K2CO3 (16.53 g, 120.6 mmol) and methanesulfonic acid 2,2-difluoro-ethyl ester (10.7 g, 66.4 mmol, Step B compound) and the mixture was heated to reflux for 16 h. The DMF was then evaporated in vacuo and the resulting residue was dissolved in EtOAc (300 ml). This solution was washed two times with water, with brine, dried with Na2SO4 and evaporated. The remaining crude product was purified by chromatography (silica gel; hexane) and the title compound was obtained as white solid (14.5 g, 79%). MS: m/z=304 [M]+.
Reaction SMILES: [Br:1]CCCC1CCCCN1C(OCC1C=CC=CC=1)=O.O[CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:25]1>>[Br:1][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:25]1
Reactant: O=C(OCc1ccccc1)N1CCCC(CCO)C1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCCBr
Product: O=C(OCc1ccccc1)N1CCCC(CCBr)C1

Procedure:
Prepared similarly to Intermediate 10 from phenylmethyl 3-(2-hydroxyethyl)-1-piperidinecarboxylate (for example, as prepared for Intermediate 15).
Reaction SMILES: [H-].[Na+].CS([O:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)(=O)=O.S([O-])(=O)(=O)C.C1(C)C=CC=CC=1.[CH3:32][O:33][C:34]1[CH:42]=[CH:41][C:40]2[CH2:39][CH2:38][CH2:37][C:36]=2[C:35]=1O>CN(C)C=O>[CH3:32][O:33][C:34]1[C:35]([O:7][C@H:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9]2)=[C:36]2[C:40](=[CH:41][CH:42]=1)[CH2:39][CH2:38][CH2:37]2
Reactant: COc1ccc2c(c1O)CCC2
Reactant: CS(=O)(=O)O[C@@H]1CCN(Cc2ccccc2)C1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1O[C@H]1CCN(Cc3ccccc3)C1)CCC2
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
In 540 ml of anhydrous dimethylformamide 5 g of 2,3-dihydro-5-methoxy-1H-inden-4-ol were dissolved. The solution was stirred, placed under a steam of nitrogen and 1.5 g of a 60% dispersion of sodium hydride in oil was added. The reaction mixture was stirred at room temperature for half an hour. The temperature was raised to 100° C. and a solution of 7.78 g of (R)-3-methanesulfonyloxy-1-(phenylmethyl)-pyrrolidine in 78 ml of anhydrous dimethylformamide was added dropwise over 1 hour. Another 3,0 g of mesylate in 30 ml of anhydrous dimethylformamide were added dropwise over 0.5 hours and the reaction continued for another 1.5 hours at 100° C. Evaporation in vacuo gave a semi solid that was partitioned between water and ethyl acetate. The ethyl acetate extract was dried and evaporated in vacuo. The derived product was isolated by chromatography over silica using toluene/-ethanol as the eluent giving 9.45 g of (S)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy]-1-(phenylmethyl)-pyrrolidine as an oil. M.S. (C.I.) (M/Z): 324 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([CH2:10][OH:11])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[C:12]([C:14]1[CH:19]=[CH:18][N:17]=[N:16][C:15]=1[Cl:20])#[N:13]>O1CCOCC1.Cl.C(O)(C)C>[ClH:20].[ClH:20].[C:12]([C:14]1[CH:19]=[CH:18][N:17]=[N:16][C:15]=1[N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][OH:11])[CH2:5][CH2:6]1)#[N:13]
Reactant: OCC(O)CN1CCNCC1
Reactant: N#Cc1ccnnc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: N#Cc1ccnnc1N1CCN(CC(O)CO)CC1

Procedure:
Grams 6.9 of 1-(2,3-dihydroxypropyl)piperazine and 3.0 g of 4-cyano-3-chloropyridazine in 60 ml dioxane were refluxed for 2 hours. The reaction mixture was settled, the supernatant liquor evaporated to dryness and the residue, which formed, was dissolved in 10 ml concentrated hydrochloric acid and diluted with 10 volumes of isopropanol. A precipitate was obtained formed by a gummy oil, which solidified afterwards giving 5.9 g of 3-[4-(4-cyanopyridazin-3-yl)piperazin-1yl]propane-1,2-diol dihydrochloride which melted at 128°-130° C.
Reaction SMILES: N[C@H:2]([CH:7]=O)[CH2:3]CSC.[C:9]1([C:15]2[CH2:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:26]([OH:28])=[O:27])[CH:21]=3)[N:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(=O)C>C(O)(C)C>[C:9]1([C:15]2[CH2:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:26]([O:28][CH:2]([CH3:7])[CH3:3])=[O:27])[CH:21]=3)[N:16]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)CC(c1ccccc1)=N2
Reactant: CSCC[C@H](N)C=O
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(C)OC(=O)c1ccc2c(c1)C(=O)CC(c1ccccc1)=N2
Temperature: 0 °C
Yield: 78.8 %

Procedure:
Metal sodium (0.33 gram) is dissolved in 40 ml of anhydrous isopropyl alcohol and the solution is heated to reflux for one hour with 2 grams of the 2-phenyl-4-quinolone-6-carboxylic acid obtained in Example 2. After cooling, the solution is mixed with ice water, acidified with acetic acid, the crystals which separate out therefrom are collected by filtration. The crystals are washed with water, washed with methanol, and dried to give 0.6 gram of isopropyl 2-phenyl-4-quinolone-6-carboxylate, colorless powder, melting at above 300° C.
Reaction SMILES: C(O)(=O)C(O)=O.[C:7]([O:11][C:12]([N:14]1[CH2:20][C:16]2([NH:19][CH2:18][CH2:17]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClCCl>[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([N:19]2[C:16]3([CH2:15][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[CH2:20]3)[CH2:17][CH2:18]2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CCN2)C1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2(CCN2S(=O)(=O)c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 177.9 %

Procedure:
To a stirred solution of 6-(tert-butoxycarbonyl)-1,6-diaza-spiro[3.3]heptane oxalate (350 mg, 719 μmol) in dichloromethane (6 mL) was added at 0° C. triethylamine (221 μl, 1.58 mmol) followed by 4-fluorobenzene-1-sulfonyl chloride (294 mg, 1.51 mmol). The reaction mixture was stirred at ambient temperature for 15 h. Further 4-fluorobenzene-1-sulfonyl chloride (100 mg, 0.51 mmol) and triethylamine (200 μl, 1.4 mmol) were added, the reaction mixture was stirred at ambient temperature for another 3 h. The reaction mixture was then diluted with dichloromethane 10 mL) and quenched with water (10 mL). The aqueous phase was extracted with CH2Cl2, and the combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (SiO2; heptane:ethyl acetate 2:1) to give the title compound (456 mg, 89%) as a colorless oil. MS (EI) m/e: 357.1 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH3:13]O>>[C:3]([CH:2]1[CH2:6][CH2:7][CH2:8][NH:1]1)([O:5][CH3:13])=[O:4]
Reactant: CO
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCCN1

Procedure:
To a solution of L-proline (2.23 g) in dry methanol (15 ml) cooled to −5° C., thionyl chloride (4.52 g) was added drop wise, while stirring and maintaining the temperature of the reactants below 0° C. The reaction mixture was allowed to attain room temperature (25° C.) and further stirred for 2 h. The solvent was distilled off from it and the residue stored in ice-chest for 12 h. The solid mass that separated was added to an aqueous potassium carbonate solution (50%, 20 ml) at 0° C. and the separated oily layer extracted into ether (15 ml×3). The combined ethereal layers were dried over anhydrous sodium sulfate and distilled to afford 2.3 g of 2-(carbomethoxy)-pyrrolidine [85%, MS (m/z) M+129 (1%), 114 (0.5), 70(100), 68(50), 43(80), 41(90)]. To an ice-cooled solution of the compound in dry diethyl ether (15 ml), t-butylhypochlorite (2.16 g) was added drop-wise. The reaction was monitored on thin layer of silica gel using chloroform as the eluant. After 15 min. anhydrous potassium acetate (2.76 g) was added gradually added to it over 10 min., and the mixture stirred at 25° C., while monitoring the reaction by TLC. At the end of the reaction (3 h), the solution was filtered and the solvent distilled under reduced pressure to afford 2-carbomethoxy)-1-pyrrroline [Yield: 1.9 g, MS (m/z) M+ 127(1%), 112(0.5), 97 (15), 69,(100), 54 (50), 41 (75)]. To a suspension of magnesium turnings (0.43 g) in dry diethylether, iodine (0.01 g) was added followed by a solution of methyl iodide (3.08 g) in ether (5 ml) dropwise at 35° C. The mixture was stirred until the disappearance of magnesium (15 min) and then after cooling to 0° C., a solution of 2-(carbomethoxy)-1-pyrrroline (1.9 g) in dry diethylether (5 ml) was added over 5 min. On completion of the reaction (2 h) as found by GC, the product was worked up by addition of dilute hydrochloric acid (5%, 10 ml) and separation of the organic layer. The aqueous layer was further extracted with diethylether (10 ml×2) and the combined organic layers dried over anhydrous sodium sulphate. Removal of the solvent afforded pure 2-acetyl-1-pyrroline [1.2 g, 95% purity, MS (m/z) M+ 111 (5%), 96 (0.1), 83 (15), 69(8), 68 (10), 55(2), 52 (0.2), 43 (100), 42 (25), 41 (50)].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)C(C)C)(C)C.[C:37]1([S:43](Cl)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[F:26][C:23]1[CH:22]=[CH:21][C:20]([N:19]2[C:10]3=[C:11]4[C:15](=[C:6]5[N:5]([CH3:27])[CH:4]=[CH:3][C:2]([NH:1][S:43]([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=6)(=[O:45])=[O:44])=[C:7]5[CH:8]=[CH:9]3)[C:14](=[O:16])[NH:13][C:12]4=[CH:17][CH2:18]2)=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1C=CC(N)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1C=CC(NS(=O)(=O)c2ccccc2)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stock solution of Example 23e and N,N-diisopropylethylamine (0.08 M and 0.16 M in dichloromethane, respectively, 500 μL, 0.042 mmol Example 23e and 0.083 mmol N,N-diisopropylethylamine), and benzenesulfonyl chloride (0.40 M in dichloromethane, 239 μL, 0.096 mmol) were mixed and stirred at ambient temperature overnight. The reaction mixture was concentrated, dissolved in methanol (1 mL) and injected on the reverse phase HPLC(C8, acetonitrile/water (0.1% TFA), 5-100%) to yield the title compound as an impure mixture.
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26].C(N(C(C)C)CC)(C)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:7]1[C:2]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[N:3][C:4]([CH3:23])=[CH:5][CH:6]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(C)nc3C#C[Si](C)(C)C)c2cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.6 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), trimethylsilylacetylene (39 mg), and bis(triphenylphosphine)palladium(II) chloride (14 mg) were dissolved in tetrahydrofuran (1 ml) to prepare a solution. Diisopropylethylamine (0.2 ml) and copper iodide (3.8 mg) were added to the solution, and the mixture was stirred at room temperature for 18 hr. The reaction solution was filtered, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform to give the title compound (45 mg, yield 58%).