Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)C(C)C)C>C(#N)C>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:6]2[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(Cl)n1

Procedure:
A solution of 2,4-dichloro-6-methyl-pyrimidine (1.25 g, 7.68 mmol, 1.0 equiv; commercially available), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 10.0 mmol, 1.3 equiv) and N-ethyl diisopropylamine (3.0 mL, 2.3 g, 17.7 mmol, 2.3 equiv) in acetonitrile (16 mL) was heated by microwave irradiation to 160° C. for 20 min. The reaction mixture was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 1.15 g (46%) of the title compound. 1H NMR (400 MHz, DMSO): δ 1.24-1.31 (m, 2H), 1.40 (s, 9H), 1.80-1.83 (br d, 2H), 2.18 (s, 3H), 2.90 (br s, 2H), 3.87 (br s, 2H), 3.96 (br s, 1H), 6.23 (br s, 1H), 7.68 (d, J=8.0 Hz, 1H). MS (ISP): 327.4 [M+H]+.
Reaction SMILES: CN(C)C=O.[CH2:6]([N:8]([CH2:22][CH3:23])[CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([NH2:21])=[N:13]1)[CH3:7].Br.Br[CH2:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[CH2:22]([N:8]([CH2:6][CH3:7])[CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([NH:21][CH2:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[N:13]1)[CH3:23]
Reactant: CCN(CC)CCCn1nc(N)c2ccccc21
Reactant: CCN(CC)CCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCCNc1nn(CCCN(CC)CC)c2ccccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 52.2 %

Procedure:
To 60 ml of anhydrous N,N-dimethylformamide were added 4.00 g of 1-(3-diethylaminopropyl)-3-aminoindazole prepared by the same method as Example 26, 8.98 g of 3-bromopropyldiethylamine hydrobromide and 7.89 g of anhydrous potassium carbonate, and the mixture was stirred for 12 hours at 80° C. After cooling the reaction mixture, the mixture was added with 80 ml of water and extracted with diethyl ether. Then the ether layer was extracted three times with 2N-hydrochloric acid. The hydrochloric acid layer was washed with diethyl ether and the pH of the layer was adjusted to 14 with potassium carbonate. The layer was extracted three times with chloroform. The chloroform layer was dried with anhydrous sodium sulfate and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography (alumina: 200 g) using chloroform as the solvent to give 3.05 g of 1-(3-diethylaminopropyl)-3-(3-diethylaminopropylamino)indazole in a yield of 52%.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][Br:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1-c1ccc2ccccc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccccc1-c1ccc2ccccc2c1

Procedure:
105 g (0.48 mol) of 13 and 90 g (0.5 mol) of N-bromosuccinimide were dissolved at room temperature in 2000 cm3 of carbon tetrachloride, admixed with 3 g of azobisisobutryronitrile and heated under reflux for 4 hours. The precipitated succinimide was filtered off, the solvent was removed under reduced pressure and the residue was purified by filtration through 1000 g of silica gel (hexane/methylene chloride 9:1). This gave 112 g (79%) of 14 as a colorless, lacrymatory oil.
Reaction SMILES: [BH4-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)=[O:8].Cl>O.CCO>[OH:3][C:4]1[CH:5]=[C:6]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[OH:8])[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(c1cccc(O)c1)c1cccc(O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Oc1cccc(C(O)c2cccc(O)c2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
A solution of sodium borohydride (NaBH4) (0.19 g, 5.14 mmol) in H2O (5 mL) was added to an orange solution of 3,3′-dihydroxybenzophenone (1.00 g, 4.67 mmol) in EtOH (15 mL) and the resulting mixture was stirred for 1 h. After this time, the reaction mixture was added to ice-water (40 mL) containing conc. HCl (2.5 mL) and the solution was extracted with EtOAc (2×60 mL). The combined organic layers were washed with NaOH (3M, 2×50 mL) and the combined basic washes were acidified with conc. HCl. The organic components that appeared were extracted with EtOAc (2×100 mL). The combined EtOAc extracts were dried (MgSO4) and the solvent was removed in vacuo to give the crude product as a brown oil which solidified on standing. Purification was achieved by recrystallisation from H2O to give the title compound as a brown crystalline solid (0.86 g, 85%, mp 141-142° C.); δH (270 MHz, d6-DMSO) 9.27 (2H, br s, ArOH), 7.05 (2H, t, J=8.2, ArH), 6.84-6.72 (4H, m, ArH), 6.63-6.54 (2H, m, ArH), 5.72 (1H, br s, CHOH), 5.50 (1H, s, CHOH); δC (68 MHz, d6-DMSO) 157.1 (2×C), 147.2 (2×C), 128.9 (2×CH), 117.0 (2×CH), 113.6 (2×CH), 113.1 (2×CH), 74.1 (CH); LCMS (ES−) 215.0 ([M−H]−, 30%), 196.9 (10), 168.8 (15), 120.7 (100); HRMS (FAB+) Found 216.0785, C13H12O3 requires 216.0786.
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([N:14]=[C:15]=[O:16])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](C(O)=O)=[CH:22]1>>[C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15]([C:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:21][CH:22]=2)=[O:16])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N=C=O
Product: CC(C)(C)c1ccccc1Oc1ncccc1NC(=O)c1c[nH]c2ccccc12

Procedure:
Example 72 was prepared from 2-(2-tert-butylphenoxy)pyridin-3-amine (1a) and 1H-indole-3-carboxylic acid using the procedure described for Example 70. LC-MS m/z 386.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:28])([CH3:27])[CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=2)=[CH:6][CH:5]=1)[CH3:2].BrC1C=C(C(C)(C)COCC2C=CC=C(OC3C=CC=CC=3)C=2)C=CC=1OCC>C1C=CC=CC=1>[O:20]([C:16]1[CH:15]=[C:14]([CH3:13])[CH:19]=[CH:18][CH:17]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1.[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:27])([CH3:28])[CH2:11][OH:12])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C(C)(C)COCc2cccc(Oc3ccccc3)c2)cc1
Agent: CCOc1ccc(C(C)(C)COCc2cccc(Oc3ccccc3)c2)cc1Br
Solvent: c1ccccc1
Product: CCOc1ccc(C(C)(C)CO)cc1
Product: Cc1cccc(Oc2ccccc2)c1
Temperature: 50 °C

Procedure:
The reaction mixture was cooled to 50° C. and the residual pressure was released, and 70 ml of benzene was added into the autoclave to dissolve the oil layer. The catalyst was removed by filtration, and the filtrate was allowed to stand still to cause phase separation to give a benzene layer. Then, the benzene layer was washed with 100 ml of water three times, and benzene was removed by distillation under reduced pressure to give an oily product. From the results of the analysis of oil product by gas chromatography according to the internal standard method, it was found that the oily product comprised 98.6% of 3-phenoxybenzyl 2-(4-ethoxyphenyl)-2-methylpropyl ether and 0.4% of unreacted starting 3-phenoxybenzyl 2-(3-bromo-4-ethoxyphenyl)-2-methylpropyl ether, and that the content of each of 3-phenoxytoluene and 4-ethoxyneophyl alcohol formed by cleaving of the ether linkage was lower than 0.3%. The amount of the obtained oily product was 23.8 g and the yield was 94.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1I.C([Mg]Cl)(C)C.[Cl-].[Li+].[C:17]([N:20]1[CH2:28][CH2:27][CH:23]([C:24](Cl)=[O:25])[CH2:22][CH2:21]1)(=[O:19])[CH3:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:24]([CH:23]1[CH2:22][CH2:21][N:20]([C:17](=[O:19])[CH3:18])[CH2:28][CH2:27]1)=[O:25]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: Clc1ccc(Cl)c(I)c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Product: CC(=O)N1CCC(C(=O)c2cc(Cl)ccc2Cl)CC1

Procedure:
The title compound was prepared according as described on example 65A18 from 2,5 Dichloro 1-iodobenzol, isopropyl magnesium chloride-lithium chloride (2M in THF) and 1-acetyl-isonipecotoyl chloride. (m/e): 301.1 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:16]2[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])#[N:2].[OH-].[Na+].O.C(O)(=O)C>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])#[N:2]
Reactant: CCCCCCOc1ccc(-n2cc(C(=O)OCC)cn2)cc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCCCCCOc1ccc(-n2cc(C(=O)O)cn2)cc1C#N
Temperature: 50 °C
Yield: 72.6 %

Procedure:
To a solution (20 ml) of ethyl 1-(3-cyano-4-hexyloxyphenyl)pyrazole-4-carboxylate (1.8 g) in ethanol was added 1 N aqueous sodium hydroxide solution (6 ml) with stirring, and the mixture was heated at 50° C. for 1 hour. After the completion of the reaction, the reaction mixture was poured into water and the mixture was neutralized with acetic acid. The precipitated crystals were recrystallized from a mixed solution of dioxane and water to give 1.2 g of 1-(3-cyano-4-hexyloxyphenyl)pyrazole-4-carboxylic acid, melting point 164-165° C.
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([O:28]C)[C:5]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[C:14]3[C:9](=[N:10][C:11]([OH:27])=[N:12][C:13]=3[O:25]C)[O:8][C:6]=2[N:7]=1.C(O)(=O)C.C(OC(=O)C)(=O)C>S(=O)(=O)(O)O.O>[OH:1][C:2]1[N:3]=[C:4]([OH:28])[C:5]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[C:14]3[C:9](=[N:10][C:11]([OH:27])=[N:12][C:13]=3[OH:25])[O:8][C:6]=2[N:7]=1
Reactant: COc1nc(O)nc2c1C(c1ccc([N+](=O)[O-])cc1)c1c(OC)nc(O)nc1O2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(C2c3c(O)nc(O)nc3Oc3nc(O)nc(O)c32)cc1
Reaction time: 9 h
Yield: 25 %

Procedure:
To a mixture of 3.4 mmol of 2,8-dihydroxy4,6-dimethoxy-5-(p-nitrophenyl)-5H-pyrano[2,3-d:6,5-d′]dipyrimidine, 10 ml of acetic acid, and 10 ml of acetic anhydride there are added 8-12 drops of concentrated sulfuric acid. The mixture is stirred while being boiled for 8-10 hours, and then poured into 150 ml of cold water and left over night. Separation and purification of the resulting substances is as described above. Yield 25-30%
Reaction SMILES: [CH2:1]([SnH:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH3:14][Sn:15]([Cl:18])([CH3:17])[CH3:16]>>[CH2:10]([SnH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:11][CH2:12][CH3:13].[CH3:14][SnH:15]([CH3:17])[CH3:16].[CH2:10]([Sn:5]([Cl:18])([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:11][CH2:12][CH3:13]
Reactant: C[Sn](C)(C)Cl
Agent: CCCC[SnH](CCCC)CCCC
Product: CCCC[Sn](Cl)(CCCC)CCCC
Product: C[SnH](C)C

Procedure:
A one liter apparatus similar to that of Example 2 was charged with 162 g tributyltin chloride. During 20 minutes 87.3 ml Reagent T was added while keeping the temperature at 28°-30° C. by using an ice-water bath. The mixture was then heated at 45°-50° C. for 30 minutes and filtered. The filtrate was stripped of toluene under reduced pressure and distilled to give 137.6 g (95% of theoretical yield) tributyltin hydride, boiling 118°-124° C. at 5 to 6 mm. A 15 g portion of the tributyltin hydride was mixed with 26.6 g trimethyltin chloride solution (38.6% in toluene) and distilled immediately. The distillate boiling up to 110° C. weighed 17.9 g and consisted, according to NMR analysis, of 46.8% trimethyltin hydride and 53.2% toluene. Thus the contained trimethyltin hydride (8.5 g) represents a 98.8% of theoretical yield based on trimethyltin chloride and a 93.9% of theoretical yield for the two stages of tributyltin chloride reduction to tributyltin hydride according to this invention and transposition to trimethyltin hydride and tributyltin chloride for recycle to the process. Inclusion of the hydride exchange reaction enables the relatively small losses of organotin species during the reduction step to be borne by the commercially available and less toxic tributyltin, thus economizing and minimizing exposure to the less available trimethyltin.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][C:13](=[O:15])[O:12][C:10](=[O:11])[CH2:9]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([OH:24])=[C:21]([CH:23]=1)[NH2:22]>ClCCl>[OH:24][C:20]1[CH:19]=[CH:18][C:17]([Cl:16])=[CH:23][C:21]=1[NH:22][C:13](=[O:15])[CH2:14][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][C:10]([OH:12])=[O:11]
Reactant: Nc1cc(Cl)ccc1O
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Solvent: ClCCl
Product: O=C(O)CC(CC(=O)Nc1cc(Cl)ccc1O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 87 %

Procedure:
Prepared by dissolving an equimolar mixture of 3-(4-chlorophenyl)glutaric anhydride and commercial 5-chloro-2-hydroxyaniline in boiling dichloromethane. Upon cooling to rt product precipitates and yields after isolation 87% of N-(2-hydroxy-5-chlorophenyl)-3-(4-chlorophenyl)glutaramic acid as colourless crystals.
Reaction SMILES: Br[C:2]1[C:3]2[CH:4]=[CH:5][C:6]([N:43]=2)=[C:7]([C:34]2[C:39]([CH3:40])=[CH:38][C:37]([CH3:41])=[CH:36][C:35]=2[CH3:42])[C:8]2[NH:12][C:11]([CH:13]=[C:14]3[N:33]=[C:17]([C:18]([C:24]4[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=4[CH3:32])=[C:19]4[NH:23][C:22]=1[CH:21]=[CH:20]4)[CH:16]=[CH:15]3)=[CH:10][CH:9]=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:52]([NH:55][C:56]1[CH:61]=[CH:60][C:59](B(O)O)=[CH:58][CH:57]=1)(=[O:54])[CH3:53]>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.C1COCC1>[C:52]([NH:55][C:56]1[CH:61]=[CH:60][C:59]([C:2]2[C:3]3[CH:4]=[CH:5][C:6]([N:43]=3)=[C:7]([C:34]3[C:35]([CH3:42])=[CH:36][C:37]([CH3:41])=[CH:38][C:39]=3[CH3:40])[C:8]3[NH:12][C:11]([CH:13]=[C:14]4[N:33]=[C:17]([C:18]([C:24]5[C:25]([CH3:32])=[CH:26][C:27]([CH3:31])=[CH:28][C:29]=5[CH3:30])=[C:19]5[NH:23][C:22]=2[CH:21]=[CH:20]5)[CH:16]=[CH:15]4)=[CH:10][CH:9]=3)=[CH:58][CH:57]=1)(=[O:54])[CH3:53]
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Reactant: Cc1cc(C)c(-c2c3nc(c(Br)c4ccc([nH]4)c(-c4c(C)cc(C)cc4C)c4nc(cc5ccc2[nH]5)C=C4)C=C3)c(C)c1
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: C1CCOC1
Product: CC(=O)Nc1ccc(-c2c3nc(c(-c4c(C)cc(C)cc4C)c4ccc(cc5nc(c(-c6c(C)cc(C)cc6C)c6ccc2[nH]6)C=C5)[nH]4)C=C3)cc1
Reaction time: 0.17 h
Yield: 73 %

Procedure:
To a flask was added 157 mg (0.250 mmol) of 10-bromo-5,15-bis(2,4,6-trimethylphenyl)porphyrin, (6), 1.06 g (5.00 mmol) of potassium phosphate tribasic, 314 mg (1.76 mmol) of 4-acetamidophenylboronic acid (supplied by Acros), and 70 mL of THF. The suspension was flushed with argon for 10 min, and then 39 mg (0.025 mmol) of tetrakis(triphenylphosphine)palladium(0) was added and the argon flushing procedure continued for an additional 10 min. The reaction mixture was then warmed to reflux under an argon atmosphere for 48 h. The solvent was evaporated at reduced pressure, the residue was redissolved in dichloromethane and washed with water, the organic phase was dried over sodium sulfate, and the solvent was once again evaporated at reduced pressure. The crude product was chromatographed on silica gel (dichloromethane/1% acetone) to give 124 mg (73% yield) of the desired porphyrin. 1H NMR (300 MHz) δ−2.89 (2H, s, N—H), 1.84 (12H, s, Ar—CH3), 2.33 (3H, s, acetyl-CH3), 2.67 (6H, s, Ar—CH3), 7.29 (4H, s, Ar—H), 7.47 (1H, s, N—H), 7.85 (2H, d, J=8 Hz, Ar—H), 8.15 (2H, d, J=8 Hz, Ar—H), 8.72 (2H, d, J=5 Hz, β-H), 8.82 (4H, d, J=5 Hz, β-H), 9.26 (2H, d, J=5 Hz, β-H), 10.11 (1H, s, meso-H); MALDI-TOF-MS m/z calcd for C46H41N5O1 679.33, obsd 679.33.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.[Cl:17][C:18]1[CH:19]=[C:20]([N:25]2[C:33]3[CH2:32][CH2:31][CH2:30][CH:29]([CH2:34][C:35](OCC)=[O:36])[C:28]=3[CH:27]=[N:26]2)[CH:21]=[CH:22][C:23]=1[Cl:24].O>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[C:20]([N:25]2[C:33]3[CH2:32][CH2:31][CH2:30][CH:29]([CH2:34][CH2:35][OH:36])[C:28]=3[CH:27]=[N:26]2)[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: CCOC(=O)CC1CCCc2c1cnn2-c1ccc(Cl)c(Cl)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: OCCC1CCCc2c1cnn2-c1ccc(Cl)c(Cl)c1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A solution of DIBALH (1 M) in toluene (13 mL, 13.0 mmol) is slowly added, maintaining the reaction temperature under −65° C., to a solution of ethyl 2-(1-(3,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-indazol-4-yl)acetate (1.83 g, 5.2 mmol) in 20 mL of dried Cl2CH2 cooled at −75° C. under N2 atmosphere. The resulting mixture is maintained under stirring at −70° C. during 30 minutes, effecting a follow-up of the reaction by TLC. Next, the temperature is raised to 0° C., and 10 mL of cold water are added, while the temperature is maintained at 0° C. A precipitate is formed, which is filtered and washed with Cl2CH2. The organic phase is washed twice with water, dried, and evaporated under reduced pressure. The resulting crude is purified by silica-gel chromatography, giving 2-(1-(3,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-indazol-4-yl)ethanol (1.06 g, 3.41 mmol, 66%, oil).
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[Cl:13][C:14]1[CH:15]=[C:16]([N:21]2[CH:25]=[C:24]([C:26]([OH:28])=O)[N:23]=[CH:22]2)[CH:17]=[CH:18][C:19]=1[Cl:20].N.O>CN(C=O)C>[Cl:13][C:14]1[CH:15]=[C:16]([N:21]2[CH:25]=[C:24]([C:26]([NH2:3])=[O:28])[N:23]=[CH:22]2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=C(O)c1cn(-c2ccc(Cl)c(Cl)c2)cn1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cn(-c2ccc(Cl)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Carbonyldiimidazole (0.49 g, 3 mmol) was added to a stirred suspension of 1-(3,4-dichloro-phenyl)-1H-imidazole-4-carboxylic acid (0.64 g, 2.5 mmol) in DMF (10 ml). After 1 h at 60° C., the reaction mixture was cooled to rt, aqueous ammonia (25%, 20 ml) was added and stirring was continued for 12 h. Then H2O (100 ml) was added and the precipitated product was filtered. Recrystallisation from EtOH afforded the title compound as off-white crystals. Mp. 244-245° C. (EtOH), MS: m/e=255 (M+).
Reaction SMILES: [O:1]1CCCC1.[Cl:6][C:7]1[C:8]([C:21]([NH2:23])=O)=[N:9][CH:10]=[C:11]([Cl:20])[C:12]=1[O:13][CH:14]([CH3:19])[C:15]([F:18])([F:17])[F:16].[C:24]([N:31]1C=CN=C1)(N1C=CN=C1)=[O:25].N12CCCN=C1CCCCC2>O>[Cl:6][C:7]1[C:8]([C:21]2[NH:23][O:1][C:24](=[O:25])[N:31]=2)=[N:9][CH:10]=[C:11]([Cl:20])[C:12]=1[O:13][CH:14]([CH3:19])[C:15]([F:18])([F:17])[F:16]
Reactant: C1CCOC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(Oc1c(Cl)cnc(C(N)=O)c1Cl)C(F)(F)F
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(Oc1c(Cl)cnc(-c2nc(=O)o[nH]2)c1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4 ml of tetrahydrofuran were added 0.55 g of 3,5-dichloro-4-(2,2,2-trifluoro-1-methylethoxy)pyridine-2-carboxamide=oxime and 0.36 g of 1,1′-carbonyldiimidazole, and the mixture was stirred at room temperature for 2 hours. Thereafter, 0.34 g of 1,8-diazabicyclo[5,4,0]undec-7-ene was added, and the mixture was stirred for 16 hours. To the reaction solution were added water and a 10% aqueous HCl solution, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.5 g of 3-[3,5-dichloro-4-(2,2,2-trifluoro-1-methylethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-one (present compound (48)).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[NH:4][C:5](=[O:10])[CH2:6][C:7]([CH3:9])=[O:8].[CH2:15](N)[CH2:16][CH2:17][CH3:18].C1(C)C=CC=CC=1.[OH2:27]>C(O)(=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[NH:4][C:5]([C:6]1[C:15](=[O:27])[CH:16]=[C:17]([CH3:18])[O:8][C:7]=1[CH3:9])=[O:10]
Reactant: O
Reactant: CCCCN
Reactant: CC(=O)CC(=O)Nc1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1cc(=O)c(C(=O)Nc2ccccc2Cl)c(C)o1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 29 %

Procedure:
A solution of 4.23 g (20 m mol) of o-chloroacetoacetanilide, 1.46 g (20 m mol) of n-butylamine and 20 ml of toluene, after one drop of acetic acid was added, was stirred for 1.5 hours at 60° C. and was refluxed for 30 minutes while resulted water was distilled off from the reaction mixture together with about 10 ml of toluene. After 8.10 g (80 m mol) of triethylamine was added, a solution of 4.20 g (50 m mol) of diketene in 20 ml of toluene was dropwise added over a period of 40 minutes and the reaction mixture was further refluxed for 2 hours. The reaction mixture was heated to distill off about 12 ml of solvent from the reaction mixture and was cooled to room temperature. The resulting crystals were filtered off, washed and dried under reduced pressure to obtain 1.59 g of the title compound. (Yield: 29%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][C:17]#[N:18]>CC#N>[F:1][C:2]1[CH:3]=[C:4]([O:8][CH2:16][C:17]#[N:18])[CH:5]=[N:6][CH:7]=1
Reactant: N#CCBr
Reactant: Oc1cncc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCOc1cncc(F)c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 43 %

Procedure:
To a mixture of 5-fluoropyridin-3-ol (0.95 g, 8.40 mmol) and K2CO3 (1.16 g, 8.40 mmol) in CH3CN (6 mL) was added dropwise 2-bromoacetonitrile (1.01 g, 8.42 mmol) at rt and upon the end of addition the mixture was stirred at rt for 40 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=3:1) to give the title compound as a yellow solid (0.55 g, 43%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:12][C:11]3=[N:21][N:22]([CH3:24])[CH:23]=[C:10]3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:33])=[O:34])=[CH:28][CH:27]=4)[CH:7]=3)=[CH:9][C:10]3[C:11](=[N:21][N:22]([CH3:24])[CH:23]=3)[N:12]=2)=[CH:15][CH:16]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: Cn1cc2cc(-c3ccnc(Cl)c3)c(-c3ccc(F)cc3)nc2n1
Product: Cn1cc2cc(-c3ccnc(Nc4ccc(S(N)(=O)=O)cc4)c3)c(-c3ccc(F)cc3)nc2n1

Procedure:
Following a similar procedure to that described in example 214, but starting from 5-(2-chloropyridin-4-yl)-6-(4-fluorophenyl)-2-methylpyrazolo[3,4-b]pyridine (obtained in example 263) and 4-aminobenzenesulfonamide, the title compound was obtained.