Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[C:19](=[O:20])[O:18][CH:17]3[OH:22])[N:4]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31].Cl>O1CCCC1>[C:30]([O:22][CH:17]1[C:16]2[C:21](=[C:12]([O:11][C:5]3[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=3)[CH:13]=[CH:14][CH:15]=2)[C:19](=[O:20])[O:18]1)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3O)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3OC(C)=O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.3 g of 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-hydroxy-phthalide (see Example 84) are dissolved in 30 ml of tetrahydrofuran, and 0.6 ml of triethylamine is added to the solution which is then treated dropwise at 25° C. (internal temperature) with 0.5 ml of acetyl chloride. After subsequently stirring for 2 hours at room temperature, the reaction mixture is treated with ice-water and dilute hydrochloric acid and extracted with ethyl acetate, and the organic phase is washed with sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. Column chromatography on silica gel [eluant: ethyl acetate/n-hexane (2:3)] yields 3-acetoxy-7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-phthalide in the form of white crystals, m.p. 119°-120° C.
Reaction SMILES: C[O-].[Na+].[NH:4]([CH2:11][CH2:12][C:13]#[N:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:15]([O:18][C:19]1[CH:28]=[C:27]([CH:29](O)CS(C)(=O)=O)[CH:26]=[C:25]([O:36][CH2:37][CH:38]=[CH2:39])[C:20]=1[NH:21][C:22](=[O:24])[CH3:23])[CH:16]=[CH2:17]>CS(C)=O>[CH2:15]([O:18][C:19]1[CH:28]=[C:27]([CH2:29][C:12]([C:13]#[N:14])=[CH:11][NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:26]=[C:25]([O:36][CH2:37][CH:38]=[CH2:39])[C:20]=1[NH:21][C:22](=[O:24])[CH3:23])[CH:16]=[CH2:17]
Reactant: N#CCCNc1ccccc1
Reactant: C=CCOc1cc(C(O)CS(C)(=O)=O)cc(OCC=C)c1NC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C=CCOc1cc(CC(C#N)=CNc2ccccc2)cc(OCC=C)c1NC(C)=O
Reaction time: 3 h

Procedure:
A mixture of 1.4 g. of sodium methylate, 3.75 g. of β-anilino-propionitrile and 6.3 g. of 2',6'-bis(allyloxy)-4'-[1-hydroxy-2-(methylsulfonyl)-ethyl]-acetanilide in 43 ml. of absolute dimethylsulfoxide was stirred at room temperature under an atmosphere of nitrogen and the exclusion of moisture for 3 hours, poured into 200 ml. of water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried and evaporated. After chromatography on aluminum oxide and recrystallization from ethanol, there was obtained 2',6'-bis-(allyloxy)-4'-(3-anilino-2-cyano-allyl)-acetanilide having a melting point of 176°-178° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]([NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[C:29]4[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=4)[N:23]([CH3:31])[N:22]=3)[N:19]=2)[N:14](COCC[Si](C)(C)C)[CH:13]=1)=[O:11])[CH3:8].C(O)(C(F)(F)F)=O.C(N)CN.[ClH:51].CO>C(Cl)Cl>[ClH:51].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]([NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[C:29]4[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=4)[N:23]([CH3:31])[N:22]=3)[N:19]=2)[NH:14][CH:13]=1)=[O:11])[CH3:8]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ccccn1
Agent: Cl
Solvent: NCCN
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ccccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)-amide (117 mg, 0.21 mmol) in CH2Cl2 (2 mL) was added TFA (1 mL, 13.0 mmol). The bright yellow-orange reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in CH2Cl2 (2 mL) and ethylene diamine (0.5 mL, 7.50 mmol) was added. The reaction mixture was stirred for 1 h then chromatographed directly with 50% to 100% EtOAc/hexanes to 5% MeOH/EtOAc. The white solid thus isolated was triturated with EtOAc then suspended in CH2Cl2 and MeOH (1:1, 6 mL). 1.0M HCl in MeOH (2 eq) was added which caused complete dissolution. The solution was concentrated and dried under high vacuum to afford 67 mg (69%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)-amide hydrochloride as a light yellow solid. MS (M+H)+=416; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.93 (d, J=2.6 Hz, 1H), 9.13 (s, 1H), 8.83 (d, J=7.6 Hz, 1H), 8.73 (dd, J=8.9, 5.5 Hz, 1H), 8.59 (d, J=4.9 Hz, 1H), 8.44 (d, J=3.0 Hz, 1H), 8.07 (br. s., 1H), 7.76 (d, J=7.9 Hz, 1H), 7.68 (dd, J=9.6, 2.1 Hz, 1H), 7.53 (br. s., 1H), 7.05 (td, J=9.1, 1.9 Hz, 1H), 5.44 (quin, J=7.0 Hz, 1H), 4.15 (s, 3H), 1.67 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([C:4]1[Se:5][CH:6]=[CH:7][CH:8]=1)[CH2:2][CH3:3].[Li]CCCC.[Br:14]Br.S([O-])(O)=O.[Na+]>C(OCC)C>[Br:14][C:6]1[Se:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:8][CH:7]=1
Reactant: BrBr
Reactant: CCCc1ccc[se]1
Agent: O=S([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: CCCc1ccc(Br)[se]1
Temperature: -70 °C
Reaction time: 3 h

Procedure:
24.3 g (about 0.97 mol) of crude 2-propylselenophene are initially introduced in 100 ml of diethyl ether, and 64.5 ml (0.10 mol, 15% soln. in hexane) of n-BuLi are rapidly metered. The mixture is heated under reflux for 1 h and subsequently cooled to −70° C. 16.5 g (0.10 mol) of bromine are added, and the batch is stirred for 1 h at 0° C. and for 3 h at RT. The mixture is added to semi-conc. sodium hydrogensulfite soln., and the organic phase is separated off. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by vacuum distillation.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].[Cl:9][C:10]([C:12]1[C:16]([CH3:17])=[CH:15][N:14]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)[CH:13]=1)=[O:11]>COCCOC.C(Cl)(Cl)Cl.CO>[ClH:9].[NH:7]([C:10]([C:12]1[C:16]([CH3:17])=[CH:15][N:14]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)[CH:13]=1)=[O:11])[C:6]([NH2:8])=[NH:5]
Reactant: Cc1cn(-c2nccc3ccccc23)cc1C(=O)Cl
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: Cc1cn(-c2nccc3ccccc23)cc1C(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
1.37 g (25.37 mmol) of sodium methoxide are added at a temperature in the region of 20° C. under an argon atmosphere to 25 mL of methanol. After complete dissolution, 2.5 g (26.2 mmol) of guanidine hydrochloride are added. After stirring at a temperature in the region of 20° C. for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is suspended in 25 mL of 1,2-dimethoxyethane and then again concentrated to dryness. The residue is suspended in a mixture of 50 mL of tetrahydrofuran, 25 mL of acetonitrile and 50 mL of dichloromethane at a temperature in the region of 20° C. under an argon atmosphere and then 1.18 g (4.36 mmol) of 3-chlorocarbonyl-1-(isoquinol-1-yl)-4-methyl-1H-pyrrole, dissolved in 20 mL of chloroform, are added thereto. After stirring at a temperature in the region of 20° C. for 18 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is triturated in 100 mL of water. After filtering, a gum is obtained, which gum is dissolved in 50 mL of methanol. The solution obtained is partially concentrated to a volume of 5 to 10 mL and is then purified by silica gel chromatography [eluent: chloroform/methanol (75/25 by volume)]. After concentrating the fractions under reduced pressure and triturating in ethyl ether, 0.62 g of 3-guanidinocarbonyl-1-(isoquinol-1-yl)-4-methyl-1H-pyrrole hydrochloride is obtained in the form of a white solid melting at 247° C. Mass spectrum (EI): EI: m/e 293 (M+.), m/e 234.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27]>CC(C)=O>[CH2:27]([O:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:4](=[O:18])[CH:3]=1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: O=c1cc(O)c2cccnc2n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(=O)n(-c2ccccc2)c2ncccc12

Procedure:
To a mixture of 62 g. of 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one, 39.6 g. of anhydrous potassium carbonate and 1,800 ml of acetone there is added dropwise, with stirring, 37.5 g. of allyl bromide. The reaction mixture is refluxed for 22 hours, concentrated in vacuo, and the residue extracted with 600 ml. of chloroform. The organic extract is washed with water, 1N sodium hydroxide solution and again with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude solid is triturated with 3×400 ml of boiling isopropyl ether, filtered, yielding the insoluble product, wt. 38.5 g. m.p. 171°-174°. Recrystallization from methanol produces the product as a colorless solid, m.p. 176°-177° C.
Reaction SMILES: C(C1OC(CC(C)(C)C)OC(CC(C)(C)C)O1)C(C)(C)C.Cl.[CH3:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH:26]=O.C(=O)(O)[O-].[Na+].[CH3:35][O:36][C:37]([C@@H:39]([NH:47][C:48]([C@@H:50]([NH2:55])[CH2:51][C:52]([OH:54])=[O:53])=[O:49])[CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:38]>C1(C)C=CC=CC=1.CO.[Pd].C1C=CC=CC=1>[CH3:23][C:24]([CH2:25][CH2:26][NH:55][C@H:50]([C:48]([NH:47][C@H:39]([C:37]([O:36][CH3:35])=[O:38])[CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:49])[CH2:51][C:52]([OH:54])=[O:53])([CH3:29])[CH3:28]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Reactant: CC(C)(C)CC=O
Agent: [Pd]
Agent: CC(C)(C)CC1OC(CC(C)(C)C)OC(CC(C)(C)C)O1
Agent: Cl
Solvent: c1ccccc1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NCCC(C)(C)C
Temperature: 68.5 °C
Reaction time: 14 h
Yield: 57 %

Procedure:
2,4,6-Trineopentyl-1,3,5-trioxane (3.3 g, about 10.7 mmol) was dissolved in toluene (3 mL) and 0.5 mL of 20% aqueous hydrochloric acid was added. The mixture was refluxed under nitrogen atmosphere for 1 hour (68-69° C.). The NMR analysis showed the only signals corresponding to 3,3-dimethylbutyraldehyde and benzene. The mixture was neutralized with sodium bicarbonate to pH=7 and the organic layer was transferred to the stirred suspension of aspartame (9.4 g, 31.9 mmol) and Pd/C (0.4 g) in methanol (150 mL) under nitrogen. Nitrogen was removed by hydrogen and the reaction mixture was vigorously stirred for 14 hours under light hydrogen pressure (<1 psi). Then, the mixture was filtered through Celite. The Celite layer was washed with methanol (25 mL) and evaporated under vacuum to half (about 80-90 mL), filtered and water (about 100 mL) was added to the residue. The mixture was gently evaporated under vacuum to remove methanol (without heating to keep low temperature of about 0-5° C.), and then kept at room temperature for 24 hours. The precipitate was filtered off, washed with water (30 mL) and dried under vacuum for 14 hours to give neotame (6.88 g, 57%).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([N:6]2[CH:10]=[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=4)[N:13]([S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH:12]=3)[CH:8]=[N:7]2)[CH2:3]1.CCN(CC)CC.[Si]([N:41]=[C:42]=[O:43])(C)(C)C>>[F:20][C:16]1[CH:15]=[C:14]2[C:19]([C:11]([C:9]3[CH:8]=[N:7][N:6]([CH:4]4[CH2:3][N:2]([C:42]([NH2:41])=[O:43])[CH2:5]4)[CH:10]=3)=[CH:12][N:13]2[S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:22])=[O:23])=[CH:18][CH:17]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CNC3)c2)c2ccc(F)cc21
Reactant: C[Si](C)(C)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Product: NC(=O)N1CC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)C1
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
A mixture of 3-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-6-fluoro-1-(phenylsulfonyl)-1H-indole hydrochloride (Intermediate 24; 350 mg; 0.81 mmol), Et3N (0.34 ml; 2.44 mmol) and TMSNCO (121 mg; 1.05 mmol) was stirred for 1.5 hours. The reaction mixture was concentrated to afford 355 mg (100%) of the title compound as a brown solid, which was used directly without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].Cl.N1C=CC=CC=1.[NH2:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[N:29][NH:30]2)=[CH:26][CH:25]=1>C(OCCO)C>[NH:30]1[C:31]2[C:27](=[CH:26][CH:25]=[C:24]([NH:23][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=4)[N:5]=[CH:4][C:3]=3[C:14]#[N:15])[CH:32]=2)[CH:28]=[N:29]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: COc1ccc2c(Cl)c(C#N)cnc2c1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1ccc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2c1
Yield: 97.2 %

Procedure:
Using an analogous procedure to that described in Example 141, 200.0 mg (0.914 mmol) of 4-chloro-7-methoxy-3-quinolinecarbonitrile in 10 mL of 2-ethoxyethanol and in the presence of 105.6 mg (0.914 mmol) of pyridine hydrochloride was reacted with 147.8 mg (1.1 mmol) of 6-aminoindazole to give 280.0 mg (97.3%) of the product as a deep yellow solid, m.p.>250° C., mass (electrospray, m/e): M+H 315.9. HRCIMS: calcd 315.112 for C18H13N5O (M+), obsd 315.1124.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[C:12]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:13][CH2:14][C:15]([CH3:17])=O.N1CCCC1.Cl>CCOCC.O.C1(C)C=CC=CC=1>[CH2:20]([O:19][C:12](=[O:18])[CH2:13][CH2:14][C:15]1([CH3:17])[CH2:10][C:9](=[O:11])[C:3]2[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[O:1]1)[CH3:21]
Reactant: CCOC(=O)CCC(C)=O
Reactant: CC(=O)c1ccc(O)cc1O
Agent: Cl
Solvent: CCOCC
Solvent: C1CCNC1
Solvent: O
Product: CCOC(=O)CCC1(C)CC(=O)c2ccc(O)cc2O1
Yield: 58.1 %

Procedure:
A mixture of 30.4 g of 2',4'-dihydroxyacetophenone, 28.8 g of ethyl levulinate, 21.3 g of pyrrolidine, and 400 ml of toluene was stirred and refluxed for 3 hours with removal of water by means of a Dean-Stark trap. The resulting mixture was cooled in an ice bath and treated with 300 ml of 1.2N aqueous hydrochloric acid. After being stirred at room temperature for 45 minutes, the mixture was treated with ether and the aqueous layer was separated. The organic solution was washed with 1.2N hydrochloric acid. The aqueous acidic solutions were combined and extracted twice with ether. The organic solutions were combined, washed with water, saturated aqueous sodium bicarbonate and brine, then dried (magnesium sulfate), filtered and concentrated under reduced pressure. The residual red oil (42 g) was chromatographed on 400 g of silica gel. Elution with 9:1 toluene-ethyl acetate gave 32.3 g (58.1%) of racemic-3,4-dihydro-7-hydroxy-2-methyl-4-oxo-2H-1-benzopyran-2-propanoic acid ethyl ester as an orange, viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:25](I)=[N:24][N:23]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][O:28]4)[C:18]=3[N:19]=[C:20]([Cl:22])[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:33]([Sn](CCCC)(CCCC)C=C)[CH2:34]CC>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.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:25]([CH:33]=[CH2:34])=[N:24][N:23]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][O:28]4)[C:18]=3[N:19]=[C:20]([Cl:22])[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cl)nc3c2c(I)nn3C2CCCCO2)CC1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C=Cc1nn(C2CCCCO2)c2nc(Cl)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 80 °C
Yield: 69.8 %

Procedure:
In a 1 L single necked flask were charged 4-[6-chloro-3-iodo-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (21.3 g, 37 mmol), anhydrous tetrahydrofuran (370 ml), and tributyl(vinyl)stannane (11.9 ml, 40.7 mmol). The mixture was degassed for 15 minutes using argon, dichlorobis(triphenylphosphine)palladium (1.3 g, 1.8 mmol) was then added. The resulting solution was heated at 80° C. overnight under argon, then evaporated under reduced pressure. Ethyl acetate and a 5% aqueous potassium fluoride solution were added to the residue, the resulting precipitate was filtered. The filtrate was recovered and the two layers separated, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified on a silica gel column chromatography using a gradient of ethyl acetate (0-40%) in cyclohexane to afford the title compound as a brown foam (12.3 g, 70%).
Reaction SMILES: Br[C:2]1[C:3]2[NH:7][C:6]([C:8]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:9]3[N:31]=[C:12]([CH:13]=[C:14]4[NH:30][C:17](=[C:18]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:19]5[CH:20]=[CH:21][C:22]=1[N:23]=5)[CH:16]=[CH:15]4)[CH:11]=[CH:10]3)=[CH:5][CH:4]=2.[CH:38]1[CH:43]=[C:42]2[CH:44]=[CH:45][C:46]([OH:59])=[C:47]([C:48]3[C:57]4[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=4)[CH:51]=[CH:50][C:49]=3[OH:58])[C:41]2=[CH:40][CH:39]=1.C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)Cl>[C:24]1([C:18]2[C:19]3[CH:20]=[CH:21][C:22]([N:23]=3)=[C:2]([O:59][C:46]3[CH:45]=[CH:44][C:42]4[C:41](=[CH:40][CH:39]=[CH:38][CH:43]=4)[C:47]=3[C:48]3[C:49]([OH:58])=[CH:50][CH:51]=[C:52]4[C:57]=3[CH:56]=[CH:55][CH:54]=[CH:53]4)[C:3]3[NH:7][C:6]([C:8]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[C:9]4[N:31]=[C:12]([CH:13]=[C:14]5[NH:30][C:17]=2[CH:16]=[CH:15]5)[CH:11]=[CH:10]4)=[CH:5][CH:4]=3)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Brc1c2nc(c(-c3ccccc3)c3ccc(cc4nc(c(-c5ccccc5)c5ccc1[nH]5)C=C4)[nH]3)C=C2
Reactant: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Oc1ccc2ccccc2c1-c1c(Oc2c3nc(c(-c4ccccc4)c4ccc(cc5nc(c(-c6ccccc6)c6ccc2[nH]6)C=C5)[nH]4)C=C3)ccc2ccccc12

Procedure:
The general procedure was used to couple 5-bromo-10,20-diphenylporphin (54.2 mg, 0.1 mmol) with R-(+)-1,1′-Bi-2-naphthol (14.3 mg, 0.05 mmol), using Pd2(dba)3 (4.6 mg, 0.005 mmol) and DPEphos (10.8 mg, 0.02 mmol) in the presence of Cs2CO3 (37.6 mg, 0.1 mmol). The reaction was conducted in toluene at 100° C. for 24 h. The title compound was isolated by flash chromatography (silica gel, methylene chloride: hexanes (v/v)=8:2) as a purple-red solid (10 mg, 17%). 1H NMR (300 MHz, CDCl3) δ 10.12 (s, 1H), 9.27 (d, J=4.8 Hz, 4H), 8.97 (d, J=4.8 Hz, 4H), 8.78 (d, J=4.8 Hz, 4H), 8.17 (m, 4H), 7.99 (d, J=9.0 Hz, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.86 (d, J=8.7 Hz, 1H), 7.74 (m, 6H), 7.40-7.66 (m, 8H), 6.42 (d, J=9.6 Hz, 1H), −2.83 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 141.2, 134.7, 131.6, 131.0, 130.8, 130.4, 129.5, 128.6, 128.3, 127.9, 127.8, 127.6, 126.9, 125.2, 124.9, 124.6, 123.7, 119.8, 117.8, 117.2, 104.7, 88.5. UV-vis (CH2Cl2, λmax, nm): 414, 511, 545, 586, 641. HRMS-EI ([M]+): calcd for C52H34N4O2, 746.2682, found 746.2680.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:22]C)[C:10](=[O:21])[N:11]([CH3:20])[C:12]=2[C:16]([O:18]C)=O)[C:7]1=[O:24].[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:22])[C:10](=[O:21])[N:11]([CH3:20])[C:12]=2[C:16]([N:31]([CH2:32][CH3:33])[CH2:29][CH3:30])=[O:18])[C:7]1=[O:24]
Reactant: COC(=O)c1c2c(c(OC)c(=O)n1C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Reactant: CCNCC
Product: CCN(CC)C(=O)c1c2c(c(O)c(=O)n1C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2

Procedure:
The title compound was prepared from methyl 6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate in a manner similar to that described in Example 12, Steps 12, 13 and 14, using diethyl amine in place of dimethylamine in the step corresponding to Step 13 of Example 12.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
(S)-1-Benzyl-3-hydroxypyrrolidine (20.2 g, 114 mmol) was dissolved in toluene (200 mL). To this stirred solution, triethylamine (20 mL, 142 mmol) was added followed by methanesulfonyl chloride (10.5 mL, 136 mmol) during a period of 40 min at 0° C. The resultant slurry was allowed to stir for two hours at 0° C. and 7% sodium bicarbonate (200 mL) was added to the reaction mixture. Organic layer was separated, and the aqueous layer was extracted with toluene (3×100 mL). The combined organic layers were washed with saturated sodium bicarbonate (3×200 mL), dried over Na2SO4 and concentrated under reduced pressure to give (S)-methanesulfonic acid 1-benzyl-pyrrolidin-3-yl ester as a yellow oil (28 g, 96%). The material was used directly for next step without purification. 1H NMR (400 MHz, CDCl3) δ 7.34-7.17 (m, 5H), 5.24-5.18 (m, 1H), 3.71 (d, JAB=13.0 Hz, 1H), 3.64 (d, JAB=13.0 Hz, 1H), 3.01 (s, 3H), 2.89-2.80 (m, 3H), 2.56-2.50 (m, 1H), 2.38-2.31 (m, 1H), 2.14-2.07 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][NH2:17])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.[Cl:25][CH2:26][C:27](Cl)=[O:28]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][NH:17][C:27](=[O:28])[CH2:26][Cl:25])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NNC(=O)CCl)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (see reference WO 9703986 A1 19970206)(25 g, 103 mmol) was dissolved in dichloromethane (300 ml) and 4-methylmorpholine (12.5 ml, 113 mmol) was added. The mixture was cooled using an ice bath and chloroacetyl chloride (8.2 ml, 103 mmol) was added drop wise. The reaction was warmed to room temperature and was stirred for 4 hours. The reaction mixture was partitioned with aqueous sodium hydrogen carbonate solution, dried over magnesium sulphate, filtered and the filtrate evaporated to give the title compound as an off white solid (29.6 g).