Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]([CH3:18])[C:6]1=O)=O.Cl.[CH:21]([NH2:23])=[NH:22].CC[O-].[Na+]>CCO>[CH2:11]([N:8]1[CH2:9][CH2:10][C:5]2[C:3](=[O:2])[NH:23][CH:21]=[N:22][C:6]=2[CH:7]1[CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N=CN
Reactant: COC(=O)C1CCN(Cc2ccccc2)C(C)C1=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC1c2nc[nH]c(=O)c2CCN1Cc1ccccc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 1-benzyl-2-methyl-3-oxo-piperidine-4-carboxylic acid methyl ester (1.0 g, 3.9 mmol), formamidine hydrochloride (930 mg, 11.6 mmol), and EtOH (6 mL) is treated with NaOEt solution (5.5 mL, 13.57 mmol, 21% w/w in EtOH) and the reaction is stirred at 90° C. for 2 h. Reaction is concentrated in vacuo after adjusting to pH 6. Residue is via semi-prep HPLC (C18; 10-100% I/H2O with 0.1% NH4OH) to give the title compound. MS (ESI) m/z 256.0 (M+1).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([Cl:26])[CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[C:24]([Cl:26])[CH:25]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1cc(-c2cc(Cl)cc(Cl)c2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, off-white solid (75 mg, 81%), MS (ISP) m/z=372.4 [(M+H)+], mp 244° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 3,5-dichloro-phenylboronic acid (62.0 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].C(OC([N:29]1[CH2:34][CH2:33][CH:32](O)[CH2:31][CH2:30]1)=O)(C)(C)C.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[ClH:67]>O1CCCC1.CO.O1CCOCC1.C(OCC)C>[ClH:1].[ClH:67].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([O:20][CH:32]3[CH2:33][CH2:34][NH:29][CH2:30][CH2:31]3)[CH:17]=[CH:16][C:15]=2[CH3:21])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1ccc(O)cc1NC(=O)CNc1ccc(F)c(Cl)c1
Agent: CCCCP(CCCC)CCCC
Agent: Cl
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(OC2CCNCC2)cc1NC(=O)CNc1ccc(F)c(Cl)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(3-chloro-4-fluoro-phenylamino)-N-(5-hydroxy-2-methyl-phenyl)acetamide (0.10 g) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (Synlett. 1998, 4, 379) (0.163 g) in tetrahydrofuran (3 ml) was added tributylphosphine (0.20 ml) and 1,1′-(azodicarbonyl)dipiperidine (0.204 g) and the mixture heated at 60° C. for 3 hours. Further 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.163 g), tributylphosphine (0.20 ml) and 1,1′-(azodicarbonyl)dipiperidine (0.204 g) were then added and the heating continued. After 3 hours, the reaction was cooled, poured into diethyl ether and filtered through Celite. After concentration, the residue was purified by NPHPLC (eluting with 0-5% ethanol in dichloromethane) to afford a white solid that was dissolved in methanol (3 ml) and HCl (2 ml of a 4M solution in dioxane) added. After 24 hours, the crystals were filtered off, washed with dichloromethane and dried in vacuo to give the title compound as a white powder (0.080 g).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([C@@H:18]([O:21]CC2C=CC=CC=2)[CH2:19][F:20])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:29]([CH3:31])[CH3:30])[S:14]2)[C@H:10]1[O:32]CC1C=CC=CC=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.[NH4+].[OH-]>ClCCl>[CH3:30][N:29]([CH3:31])[C:13]1[S:14][C@H:15]2[O:16][C@H:17]([C@H:18]([OH:21])[CH2:19][F:20])[C@@H:9]([OH:8])[C@H:10]([OH:32])[C@H:11]2[N:12]=1
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]([C@H](CF)OCc3ccccc3)O[C@@H]2S1
Agent: ClB(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H]([C@H](O)CF)O[C@@H]2S1
Yield: 23.6 %

Procedure:
A solution of 104 (400 mg, 0.7 mmol) in dichloromethane (15 mL) was treated with BCl3 (7 mL, 7 mmol, 1M in dichloromethane) for 30 min at −60° C., then quenched with methanol (20 mL). Volatiles were distilled out to give a residue, which was dissolved into methanol (5 mL) and neutralized with Con. NH4OH (2 ml, 26% aqueous solution). After concentration, the crude product was purified by a silica gel column, eluted with 10% methanol in dichloromethane to give a mixture of the two epimers; the two epimers were separated by Prep-HPLC with the following conditions: (Agilent Prep 1200 Detecl): Column, SunFire Prep C18; mobile phase, Water with 0.05% ammonia and CH3CN; 5% CH3CN up to 100% in 8 min Detector, 220 nm to afford (3aR,5S,6S,7R,7aR)-2-(dimethylamino)-5-((S)-2-fluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol as a white solid (46.3 mg, 23%), faster eluting isomer; (ES, m/z): [M+H]+ 281.0; III NMR (300 MHz, D2O) δ 6.17 (d, J=6.6 Hz, 1H), 4.29-4.69 (m, 2H), 3.95-4.15 (m, 3H), 3.68-3.72 (m, 1H), 3.54-3.58 (m, 1H), 2.88 (s, 3H), 2.87 (s, 3H); and (3aR,5S,6S,7R,7aR)-2-(dimethylamino)-5-((R)-2-fluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol as a white solid (64 mg, 31%), slower eluting isomer; (ES, m/z): [M+H]+ 281.0; 1H NMR (300 MHz, D2O) δ 6.17 (d, 6.3 Hz, 1H), 4.44-4.57 (m, 1H), 4.28-4.39 (m, 1H), 3.92-4.12 (m, 3H), 3.67-3.72 (m, 1H), 3.27-3.49 (m, 1H), 2.89 (s, 3H), 2.87 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[O:14][CH3:15])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O[NH:50][C:51]([C:53]1[C:54]2[CH:55]=[CH:56][N:57]=[CH:58][C:59]=2[CH:60]=[CH:61][CH:62]=1)=[NH:52]>CN(C)C=O>[CH3:3][CH:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]2[O:11][N:52]=[C:51]([C:53]3[CH:62]=[CH:61][CH:60]=[C:59]4[C:54]=3[CH:55]=[CH:56][N:57]=[CH:58]4)[N:50]=2)=[CH:7][C:6]=1[O:14][CH3:15])[CH3:1]
Reactant: N=C(NO)c1cccc2cnccc12
Reactant: COc1cc(C(=O)O)ccc1OC(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(-c2nc(-c3cccc4cnccc34)no2)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 4-[(1-methylethyl)oxy]-3-(methyloxy)benzoic acid (Journal of the American Chemical Society (1955), 77 757-8; 135 mg, 0.641 mmol), HATU (244 mg, 0.641 mmol), Hunig's base (0.3 ml, 1.718 mmol) in N,N-dimethylformamide (DMF) (1 ml) was stirred at room temperature for 1 hr before the addition of N-hydroxy-5-isoquinolinecarboximidamide (D1; 100 mg, 0.534 mmol) in N,N-dimethylformamide (DMF) (1 ml). The reaction mixture was stirred at room temperature for 2-3 hrs and then heated in a microwave at 140° C. for 1.5 hr. The reaction mixture was concentrated in vacuo, dissolved in 1-2 ml of N-methylpyrrolidinone and purified by Preparative HPLC (Waters Sunfire C18 column, eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN+0.1% Formic acid)). The solvent was evaporated in vacuo to give the title compound (5 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1.C(O)(=O)C>O1CCCC1.O>[CH3:3][CH:4]1[CH2:8][CH2:7][N:6]([C:19](=[O:20])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][CH:16]=2)[C:5]1=[O:9]
Reactant: COc1ccc(N=C=O)cc1
Reactant: CC1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(NC(=O)N2CCC(C)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
While 2 g of sodium hydride (60% oily) was being stirred in 50 ml of tetrahydrofuran, 5 g of 3-methyl-2-pyrrolidinone was added to the mixture, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to not higher than 0° C., and 7.5 g of 4-methoxyphenyl isocyanate was added dropwise to the mixture, followed by stirring at the same temperature for 5 hours. Acetic acid was then added to the reaction mixture for neutralization, water was thereafter added to the mixture, and the solvent was distilled off in a vacuum. Water was added to the residue, and the precipitate was filtered off, giving 8.2 g of 3-methyl-1-(4-methoxyphenylcarbamoyl)-2-pyrrolidinone (yield 66%) having a melting point of 71° to 72° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[OH:11][CH:12]([CH:22]1[CH2:27][CH:26]2[CH2:28][CH:23]1[CH:24]=[CH:25]2)[C:13]([F:21])([F:20])[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16].Cl>C1(C)C=CC=CC=1>[CH:23]12[CH2:28][CH:26]([CH:25]=[CH:24]1)[CH2:27][CH:22]2[CH:12]([OH:11])[C:13]([F:20])([F:21])[CH:14]([OH:19])[C:15]([F:18])([F:17])[F:16]
Reactant: O=C(C(F)(F)F)C(F)(F)C(O)C1CC2C=CC1C2
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: OC(C1CC2C=CC1C2)C(F)(F)C(O)C(F)(F)F
Temperature: 20 °C
Reaction time: 10 h
Yield: 95.2 %

Procedure:
210 mL of diisobutylaluminum hydride (1.0M toluene solution) was added under nitrogen atmosphere at 0° C. to the mixture of 27.0 g of 1-hydroxy-1-(5-norbornene-2-yl)-2,2,4,4,4-pentafluorobutane-3-one (synthesized according to [Example 1]) and 50 g of toluene, then the solution was stirred for 10 hours at 20° C. Dilute hydrochloric acid was added to quench the reaction and to neutralize it, and then the standard aqueous work-up was performed. The product was purified by silica gel column chromatography to yield 25.9 g of 1-(5-norbornene-2-yl)-2,2,4,4,4-pentafluorobutane-1,3-diol (yield was 95%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[C:11]1[C:12]2[C:17]([C:18]([C:25]3[C:30]([O:31]C)=[CH:29][CH:28]=[CH:27][C:26]=3[O:33]C)=[C:19]3[C:24]=1[CH:23]=[CH:22][CH:21]=[CH:20]3)=[CH:16][CH:15]=[CH:14][CH:13]=2.[I-].[Li+].Cl>CN1C(=O)CCC1>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[C:4]=1[C:11]1[C:24]2[C:19]([C:18]([C:25]3[C:26]([OH:33])=[CH:27][CH:28]=[CH:29][C:30]=3[OH:31])=[C:17]3[C:12]=1[CH:13]=[CH:14][CH:15]=[CH:16]3)=[CH:20][CH:21]=[CH:22][CH:23]=2
Reactant: COc1cccc(OC)c1-c1c2ccccc2c(-c2c(OC)cccc2OC)c2ccccc12
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: Oc1cccc(O)c1-c1c2ccccc2c(-c2c(O)cccc2O)c2ccccc12
Temperature: 190 °C
Reaction time: 48 h

Procedure:
22.5 g (50 mmol) of 9,10-bis(2,6-dimethoxyphenyl)anthracene are dissolved in 500 ml of NMP, 107.1 g (800 mmol) of lithium iodide (anhydrous) are added, and the mixture is stirred at 190° C. for 48 h. After cooling, the reaction mixture is introduced into 2000 ml of 1N HCl with stirring. The precipitated solid is filtered off and washed three times with 200 ml of water each time and then three times with 100 ml of ethanol each time. Finally, the product is recrystallised from DMSO (15 ml/g) and dried under reduced pressure. Yield: 16.9 g, 85.7% of theory, purity: 99.0% according to HPLC.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I.CS[C:19]1[NH:20][CH2:21][CH2:22][CH2:23][N:24]=1.[ClH:25]>CO>[ClH:25].[C:10]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][NH:9][C:19]2[NH:24][CH2:23][CH2:22][CH2:21][N:20]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: CSC1=NCCCN1
Agent: Cl
Agent: I
Solvent: CO
Product: c1ccc(C(CNC2=NCCCN2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A flask containing a mixture of 2,2-diphenylethylamine (5.92 g; 3.00×10-2 mole) and 2-methylthio-1,4,5,6-tetrahydropyrimidine hydroiodide (7.74 g, 3.00×10-2 mole) was immersed in an oil bath which had been preheated to ca. 155° C. The reaction was stirred at between 150°-168° C. for 1.5 hours. The resulting yellow glass was dissolved in methanol. The methanol was evaporated and the resulting yellow oil was dissolved in dichloromethane. This solution was transferred to a separatory funnel where it was washed with 2N aqueous NaOH and saturated aqueous NaCl. After drying over anhydrous Na2SO4, the dichloromethane was evaporated giving a foam which was dissolved in methanol (125 ml). This solution was cooled to 0° C. at which time it was treated with a methanolic solution of HCl. After 10-15 minutes most of the methanol was evaporated and 2-butanone was added. After several days the crystals were collected by filtration. Recrystallization from isopropanol afforded 2-(2,2-diphenylethylamino)-1,4,5,6-tetrahydropyrimidine hydrochloride as off-white crystals: 3.80 g (40%), m.p. 180°-182° C.
Reaction SMILES: [Cr](O)(O)(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:17]2[NH:18][C:19](=[O:27])[C:20]([CH:22]3[CH2:25][CH:24]([OH:26])[CH2:23]3)=[CH:21][C:16]2=[N:15][N:14]=1.[CH:28](O)([CH3:30])C.O>CC(C)=O>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:17]2[N:18]=[C:19]([O:27][CH2:30][C:28]3[N:15]([CH3:16])[N:14]=[CH:13][N:17]=3)[C:20]([CH:22]3[CH2:23][C:24](=[O:26])[CH2:25]3)=[CH:21][C:16]2=[N:15][N:14]=1
Reactant: O=c1[nH]n2c(-c3ccccc3F)nnc2cc1C1CC(O)C1
Reactant: CC(C)O
Agent: O=[Cr](=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: Cn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1C1CC(=O)C1

Procedure:
8N Chromic acid was added to a solution of 3-(2-fluorophenyl)-7-(3-hydroxycyclobutyl)-1,2,4-triazolo[4,3-b]pyridazin-6-one (0.36 g, 1.2 mmol) in acetone (50 ml) dropwise, until excess was present (red colour remained). The reaction was then stirred for 2 hours before isopropanol was added until the blue colour remained and no excess chromic acid was present. Water (50 ml) was added and the aqueous layer extracted with ethyl acetate (4×50 ml), organic layers were combined, washed with brine (50 ml), dried (MgSO4), filtered and concentrated to give the desired product as a white solid. Data for the title compound: 1H NMR (360 MHz, DMSO) δ3.41 (2H, s), 3.43 (2H, s), 3.73-3.78 (1H, m), 7.42-7.50 (2H, m), 7.64-7.72 (1H, m), 7.83-7.88 (1H, m), 8.38 (1H, s); MS (ES+) m/e 299 [MH]+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[C:11]1[C:12]2[NH:16][C:15]([C:17]([C:55]3[C:60]([O:61]C)=[CH:59][CH:58]=[CH:57][C:56]=3[O:63]C)=[C:18]3[N:54]=[C:21]([C:22]([C:44]4[C:49]([O:50]C)=[CH:48][CH:47]=[CH:46][C:45]=4[O:52]C)=[C:23]4[NH:43][C:26](=[C:27]([C:33]5[C:38]([O:39]C)=[CH:37][CH:36]=[CH:35][C:34]=5[O:41]C)[C:28]5[CH:29]=[CH:30][C:31]=1[N:32]=5)[CH:25]=[CH:24]4)[CH:20]=[CH:19]3)=[CH:14][CH:13]=2.B(Br)(Br)Br>ClCCl.C(Cl)(Cl)Cl.O1CCCC1>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[C:4]=1[C:11]1[C:12]2[NH:16][C:15]([C:17]([C:55]3[C:56]([OH:63])=[CH:57][CH:58]=[CH:59][C:60]=3[OH:61])=[C:18]3[N:54]=[C:21]([C:22]([C:44]4[C:49]([OH:50])=[CH:48][CH:47]=[CH:46][C:45]=4[OH:52])=[C:23]4[NH:43][C:26](=[C:27]([C:33]5[C:34]([OH:41])=[CH:35][CH:36]=[CH:37][C:38]=5[OH:39])[C:28]5[CH:29]=[CH:30][C:31]=1[N:32]=5)[CH:25]=[CH:24]4)[CH:20]=[CH:19]3)=[CH:14][CH:13]=2
Reactant: COc1cccc(OC)c1-c1c2nc(c(-c3c(OC)cccc3OC)c3ccc([nH]3)c(-c3c(OC)cccc3OC)c3nc(c(-c4c(OC)cccc4OC)c4ccc1[nH]4)C=C3)C=C2
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: Oc1cccc(O)c1-c1c2nc(c(-c3c(O)cccc3O)c3ccc([nH]3)c(-c3c(O)cccc3O)c3nc(c(-c4c(O)cccc4O)c4ccc1[nH]4)C=C3)C=C2
Temperature: 25 °C
Reaction time: 17 h

Procedure:
As the solvent, acetic acid, propionic acid, butyric acid or the like is usable. The reaction temperature can be controlled by considering the kind of the solvent and the other conditions, usually a temperature of 80°-120° C. is selected. The reaction time is 5-12 hours, preferably 5-8 hours. After such condensation of these compounds, the tarry reaction mixture obtained by filtrating the reaction solution is purified by, for example, silica gel chromatography or the like to obtain 5,10,15,20-tetra(2',6'-dimethoxyphenyl)porphyrin. Then, 5,10,15,20-tetra(2',6'-dimethoxyphenyl)porphyrin is dissolved in a suitable dry solvent (dichloromethane, chloroform, tetrahydrofuran or the like), cooled in an ice-water bath 40 times or more of the molar quantity of boron tribromide is added and the mixture is stirred at room temperature for 10-24 hours. The reaction solution is poured dropwise into ice water, the solution is extracted by an organic solvent such as ethyl acetate, the organic layer is evaporated to dryness, and the solid is purified by silica gel chromatography to obtain 5,10,15,20-tetra(2',6'-dihydroxyphenyl)porphyrin (in the above process, the compound represented by H2T2,6-OH PP).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)([O-])=O.C1COCC1.Cl>[Fe].O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(OCc2cc(Cl)ccc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2cc(Cl)ccc2N)cc1
Reaction time: 13 h
Yield: 100.4 %

Procedure:
A mixture of methyl 4-(2-nitro-5-chlorophenylmethoxy)benzoate (460 mg; prepared in Reference Example 9.), THF (10 ml), water (3 ml), 1N HCl (0.4 ml) and iron powder (500 mg) was stirred for 13 hours. The reaction mixture was filtered. The filtrate was washed, dried over and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (hexane-AcOEt) to give the title compound (419 mg) having the following physical data.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:11]2[CH:12]=[C:13]([CH:14]([CH3:16])[CH3:15])[CH:8]([CH:9]([CH3:17])[NH:10]2)[CH2:7]1)=[O:5])[CH3:2].[H][H]>[Pt]=O.C(O)(=O)C>[CH3:17][CH:9]1[CH:8]2[CH:13]([CH:14]([CH3:15])[CH3:16])[CH2:12][CH:11]([CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7]2)[NH:10]1
Reactant: [H][H]
Reactant: CCOC(=O)C1CC2C(C(C)C)=CC1NC2C
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCOC(=O)C1CC2C(C)NC1CC2C(C)C
Yield: 96.9 %

Procedure:
A mixture of ethyl-3-methyl-8-isopropyl-2-azabicyclo[2.2.2]oct-7-ene-6-carboxylate (21.4 g, 78 mmol), acetic acid (200 mL) and platinum oxide (2.1 g) was placed on a Parr hydrogenator at 44 psi of hydrogen pressure for 41/4 hours. The catalyst was removed by filtration and the solvent was removed in vacuo. The residue was dissolved in water, neutralized with NH4OH to a pH of 10 and the mixture was extracted with CH2Cl2 (3×50 mL). The organic layers were combined, washed with brine and dried over MgSO4. The solvent was removed in vacuo to afford 18.1 g (97%) of ethyl 3-methyl-8-isopropyl-2-azabicyclo-[2.2.2]octane-6-carboxylate. The product was dissolved in ethanol and treated with 6.9N ethanolic HCl to afford 10.2 g of the hydrochloride salt as a white solid, m.p. 157.5°-158.5° C.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[OH-].[K+].Br[CH2:8][C:9]1([CH3:13])[CH2:12][O:11][CH2:10]1>>[CH3:8][C:9]1([CH2:13][O:3][CH2:2][CH2:1][OH:4])[CH2:12][O:11][CH2:10]1
Reactant: OCCO
Reactant: CC1(CBr)COC1
Agent: [K+]
Agent: [OH-]
Product: CC1(COCCO)COC1
Temperature: 70 °C
Yield: 29.3 %

Procedure:
Ethylene glycol (26.25 g, 0.42 mol) and KOH (19.45 g, 0.35 mol) were added to a round-bottom flask equipped with a magnetic stirrer and a reflux condenser. When all KOH had dissolved the 3-bromomethyl-3-methyloxetane (4) (46.30 g, 0.28 mol) was added. The system was heated to 70° C. for 3 hours. The reaction material was then distilled under vacuum (10 Torr) and collected as a single fraction. The distilled material was then extracted with diethyl ether and water. The water fraction was then extracted with CHCl3 multiple times to obtain 11.98 g (29.2% yield) of the final product, though analysis of the water phase indicated a significant amount of HE 1Ox was unextracted. H1 NMR (CDCl3): δ 1.31 ppm (—CH3, 3H, s), δ 2.63 ppm (—OH, 1H, t), δ 3.54 ppm (—CH2—, 2H, s), δ 3.60 ppm (—OCH2—, 2H, t), δ 3.76 ppm (HOCH2—, 2H, q), δ 4.38 ppm (oxetane CH2, 2H, d), δ 4.55 ppm (oxetane CH2, 2H, d).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:20]([N:22]1[CH2:51][CH2:50][CH2:49][CH2:48][C@H:23]1[C:24]([NH:26][C@H:27]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:37])[NH:33][N+:34]([O-:36])=[O:35])=[O:25])=[O:21])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].Cl.CCOC(C)=O.CN1CCOCC1.[N:73]1([C:88]([O:90][CH2:91][C:92]2[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=2)=[O:89])[CH2:87][CH2:86][CH2:85][C@H:74]1[C:75]([O:77]N1C(=O)CCC1=O)=O>>[N:73]1([C:88]([O:90][CH2:91][C:92]2[CH:93]=[CH:94][CH:95]=[CH:96][CH:97]=2)=[O:89])[CH2:87][CH2:86][CH2:85][C@H:74]1[C:75]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:20]([N:22]1[CH2:51][CH2:50][CH2:49][CH2:48][C@H:23]1[C:24]([NH:26][C@H:27]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:37])[NH:33][N+:34]([O-:36])=[O:35])=[O:25])=[O:21])[CH2:11][O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:77]
Reactant: O=C(ON1C(=O)CCC1=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](COCc1ccccc1)C(=O)N1CCCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: N=C(NCCC[C@H](NC(=O)[C@@H]1CCCCN1C(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)OCc1ccccc1)N[N+](=O)[O-]

Procedure:
The desired compound was prepared from 0.68 g of Boc-Asn-Ser(Bzl)-Pip-Arg(NO2)-OBzl, 3 ml of 4N HCl-AcOEt, 0.14 ml of NMM and 0.32 g of Z-Pro-OSu in the same manner as in Example 12-(2).
Reaction SMILES: [C:1]([C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])=[C:7]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][C:11]([OH:13])=[O:12])=[C:7]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1ccc(C(C)(C)C)cc1CN1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1ccc(OCC(=O)O)c(CN2CCCCC2)c1
Reaction time: 15 h
Yield: 173.1 %

Procedure:
To a methylene dichloride (2.0 ml) solution of tert-butyl [4-tert-butyl-2-(piperidin-1-ylmethyl)phenoxy]acetate (75 mg, 0.21 mmol), trifluoroacetic acid (0.2 ml, 2.7 mmol) was added at ambient temperature under nitrogen atmosphere. After being stirred for 15 hours, additional trifluoroacetic acid (1.0 ml, 13.5 mmol) was added. After being stirred additionally for 10 hours, the resulting mixture was concentrated under reduced pressure and azeotrope with toluene to furnish 111 mg of the title compound as slightly yellow oil, which was used for the next reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1>C(N)(C)C>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([NH:9][CH:5]([CH3:6])[CH3:4])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)N1CCc2cc(Oc3cc(Cl)ncn3)ccc21
Solvent: CC(C)N
Product: CC(C)Nc1cc(Oc2ccc3c(c2)CCN3C(=O)Nc2cccc(C(F)(F)F)c2)ncn1

Procedure:
A solution of 261 mg (0.60 mMol) 5-(6-chloro-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (WO 03/099771; ex. 163) in 15 ml isopropylamin is stirred for 18 h at rt and then concentrated in vacuo. The residue is dissolved in EtOAc and water and the aqueous layer extracted twice with EtOAc. -The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; EtOAc/hexane 1:1) gives the title compound: m.p.: 189° C.; MS: [M+1]+=458; TLC(EtOAc): Rf=0.45.