Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14](OC)=[O:15].[H-].C([Al+]CC(C)C)C(C)C.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][OH:15]
Reactant: COC(=O)Cc1nc(-c2ccccc2)oc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCO
Yield: 118.4 %

Procedure:
A 750-ml 4-necked flask equipped with a mechanical stirrer, a thermometer, a dropping funnel and an argon inlet, cooled with a CO2/acetone bath, was charged with a solution of 49.15 g of crude methyl 2-(5-methyl-2-phenyl-4-oxazolyl)acetate (ca. 0.16 mol) and 90 ml of toluene and stirred. 400 ml of diisobutyl aluminiumhydride 1.2 M in toluene were added under argon at ca. −20 to −25° C. during 60 min. After additional 15 min a solution of 191 g of citric acid monohydrate in 400 ml of deionized water was added with cooling during 30 min, so that the temperature did not exceed 5-10° C. The aqueous phase of the clear biphasic mixture was extracted with 200 ml of toluene. The combined organic phases were washed twice with 40 ml, a total of 80 ml of deionized water, twice with 40 ml, a total of 80 ml of brine and dried (Na2SO4). Rotary evaporation (50° C., 8 mbar, 1 h) afforded 38.5 g of crude 2-(5-Methyl-2-phenyl-4-oxazolyl)ethanol (theor. amount 32.4 g) which was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH:5]=[CH:6][CH:7]([N:19]([CH3:36])[C:20](=[O:35])[C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)C.[OH-].[Li+]>CO.O1CCCC1.O>[CH3:36][N:19]([CH:7]([CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[CH:6]=[CH:5][C:4]([OH:37])=[O:3])[C:20](=[O:35])[C:21]1[CH:22]=[C:23]([C:31]([F:33])([F:34])[F:32])[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1
Reactant: CCOC(=O)C=CC(Cc1ccc2ccccc2c1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C=CC(=O)O)Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 23.0 g of 4-[N-methyl-N-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(naphth-2-yl)-pent-2-enoic acid ethyl ester [see example 20d)] and 9.23 g of lithium hydroxide (monohydrate) in 240 ml of methanol, 175 ml of tetrahydrofuran and 72 ml of water is stirred at room temperature for 120 minutes and then concentrated by evaporation. The residue is dissolved in 200 ml of water, acidified to pH=2 with 0.1N hydrochloric acid and extracted three times using 200 ml of ethyl acetate each time. The combined organic phases are washed with water and saturated NaCl solution, dried (magnesium sulfate) and concentrated by evaporation. Filtration of the residue over silica gel with hexane/ethyl acetate 1:1 yields the title compound in the form of a yellow foam. Rf value=0.41 (methylene chloride/methanol 19:1). IR(CH2Cl2) cm-1 : 3050,1709, 1644, 1402, 1337,1277, 1183,1142, 905, 849, 821
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH:9](Br)[CH2:10][CH3:11])=[CH:4][CH:3]=1.FCCCC(C1C=CC=CC=1)=O.[CH3:26][NH:27][CH3:28]>C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH:9]([N:27]([CH3:28])[CH3:26])[CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CCC(Br)C(=O)c1ccc(F)cc1
Agent: O=C(CCCF)c1ccccc1
Solvent: CCOCC
Product: CCC(C(=O)c1ccc(F)cc1)N(C)C
Reaction time: 12 h

Procedure:
240 g (0.98 mol) of 1-(4-fluorophenyl)-2-bromobutan-1-one (prepared by bromination of 4-fluorobutyrophenone by the method described in EP-A-3,002) are dissolved in 250 ml of diethyl ether. This solution is slowly added dropwise to a mixture of 265 g (5.87 mol) of dimethylamine in 1250 ml of diethyl ether at 0°. After the mixture has been stirred at 0° for 12 hours, the excess dimethylamine is removed at room temperature by blowing through N2 and the suspension is poured onto water. The ether phase is washed with water and dried over MgSO4. After filtration and evaporation of the solution, 202.8 g of crude product remain as a colourless oil, which is used without further purification for the subsequent reaction.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]=[O:12])=[CH:5][NH:6]2.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([N:6]1[C:7]2[C:3](=[C:2]([Br:1])[CH:10]=[CH:9][CH:8]=2)[C:4]([CH:11]=[O:12])=[CH:5]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1c[nH]c2cccc(Br)c12
Product: CC(=O)n1cc(C=O)c2c(Br)cccc21
Yield: 74 %

Procedure:
4-Bromo-1H-indole-3-carbaldehyde (4.0 g, 17.8 mmol) was stirred in acetic anhydride (20 mL) at reflux for 4 h. The reaction was cooled and concentrated in vacuo. Cold MeOH was added to precipitate a white solid, which was collected by filtration to give 3.5 g (74%) of 1-acetyl-4-bromo-1H-indole-3-carbaldehyde. MS (ES) [m+H] calc'd for C11H8BrNO2, 266, 268; found 266, 268.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH:22]([F:24])[F:23])[CH2:9]1)C1C=CC=CC=1.C(N1CCO[C@H](CC2C=CC=C(C=CC3C=NC=CC=3)C=2)C1)(OC(C)(C)C)=O.ClC(OC(Cl)C)=O>>[F:24][CH:22]([F:23])[O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][CH:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: FC(F)Oc1ccccc1CC1CN(Cc2ccccc2)CCO1
Agent: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3cccnc3)c2)C1
Agent: CC(Cl)OC(=O)Cl
Product: FC(F)Oc1ccccc1CC1CNCCO1

Procedure:
Example 75 was prepared as described for example 27, but using N-benzyl-2-(2-difluoromethoxy-benzyl)-morpholine, intermediate (a) and 1-chloroethyl chloroformate and example 75 was isolated as a colorless oil (7.9 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[CH3:11][N:12]([CH3:26])[C:13]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[NH:1][CH:16]1[CH2:15][CH2:14][C:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([N:12]([CH3:26])[CH3:11])[CH2:18][CH2:17]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: NC1Cc2ccccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)C1(c2ccccc2)CCC(NC2Cc3ccccc3C2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.2 %

Procedure:
2-Aminoindane (266 mg, 2 mmol) and 4-dimethylamino-4-phenylcyclohexanone (434 mg, 2 mmol) were dissolved in dry 1,2-dichloroethane (10 ml) under argon. Glacial acetic acid (2 mmol) and sodium triacetoxyborohydride (600 mg) were added to this mixture and the mixture was stirred for 24 hours at RT. For working up, the mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (4×20 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product was chromatographed over silica gel with ethyl acetate/ethanol (1:1). 490 mg N′-Indan-2-yl-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained as a white solid which, for preparation of the hydrochloride, was dissolved in 2-butanone (10 ml), and 1.85 M ethanolic HCl (2 ml) was added. The mixture of cis- and trans-N′-indan-2-yl-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride obtained was filtered off with suction and dried (540 mg, m.p. 224-226° C.).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][SH:18])=[CH:15][CH:14]=1.[H-].[Na+]>CN(C)C=O>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][S:18][C:2]2[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: O=C(O)c1cnccc1Cl
Reactant: COc1ccc(CS)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CSc2ccncc2C(=O)O)cc1
Temperature: 0 °C

Procedure:
A stirred and ice-cooled mixture of 788 mg (0.005 mole) 4-chloronicotinic acid [prepared by the process set forth in W. C. J. Ross, J. Chem. Soc.(C), 1816 (1966)] and 771 mg (0.005 mole) of 4-methoxybenzylmercaptan in 6 mL of dry N,N-dimethylformamide was treated with 480 mg (0.012 mole) of 60% sodium hydride dispersion. The reaction was stirred at room temperature for 4 hours during which a thick solid formed, which was taken up in 75 mL of ice water. After extraction with 25 mL of hexane, the aqueous layer was acidified with 2.5N hydrochloric acid to precipitate 4-(4-methoxybenzylthio)-nicotinic acid; yield 1.2 g (89% of theory), m.p. 230° C.
Reaction SMILES: [ClH:1].[CH3:2][C:3]([CH3:29])([CH3:28])[C:4]([C:6]1[N:10]2[CH2:11][CH2:12][N:13]([CH3:27])[C:14]3([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[C:9]2=[CH:8][CH:7]=1)=[O:5]>C(Cl)Cl>[ClH:1].[ClH:1].[CH3:2][C:3]([CH3:29])([CH3:28])[C:4]([C:6]1[N:10]2[CH2:11][CH2:12][N:13]([CH3:27])[C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:9]2=[CH:8][CH:7]=1)=[O:5]
Reactant: CN1CCn2c(C(=O)C(C)(C)C)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: ClCCl
Product: CN1CCn2c(C(=O)C(C)(C)C)ccc2C12CCNCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 110.6 %

Procedure:
Hydrogen chloride (5.1 mL of 4 M, 20.22 mmol) was added to a solution of tert-butyl 6-(2,2-dimethylpropanoyl)-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (1.75 g, 4.49 mmol) in CH2Cl2 (12.3 mL) at room temperature. The mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure to give 2,2-dimethyl-1-(2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl)propan-1-one dihydrochloride (1.8 g, 99%) as a tan solid. ESI-MS m/z calc. 289.2, found 290.5 (M+1)+; Retention time: 0.97 minutes.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[C:21]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:28])=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(Cl)(Cl)(Cl)Cl>[C:21]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][Br:1])=[CH:37][CH:36]=1)(=[O:28])=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Temperature: 25 °C

Procedure:
N-Bromosuccinimide (387 mg, 2.17 mmol), α,α'-azobis(isobutyronitrile) (catalytic), 2'-(N-t-butylsulfamoyl)-4-methylbiphenyl (from Step C) (550 mg, 1.81 mmol) and carbon tetrachloride (50 ml) were heated with stirring at reflux for 3 hours. After cooling to room temperature the mixture was filtered and the filtrate evaporated to dryness. Flash chromatography (silica gel, initially 10 and then 20% ethyl acetate-hexane) afforded the title compound [699 mg, 77% pure (the remainder of the material was the corresponding dibromo derivative)] as a white solid; 1H NMR (300 MHz, CDCl3) δ8.17 (dd, J=7.5, 1.6 Hz, 1H), 7.68-7.45 (m, 6H), 7.31 (dd, J=7.5, 1.6 Hz, 1H), 4.55 (s, 2H), 3.52 (s, 1H), 1.00 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.Cl>CO.O.C(O)(=O)C.[Pt](=O)=O>[NH:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:5][CH2:6]1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: O=C1Cc2c(cccc2C2CCNCC2)N1
Reaction time: 72 h
Yield: 95.2 %

Procedure:
A suspension of 4-pyridin-4-yl-1,3-dihydro-indol-2-one (4.28 g, 20.4 mmol, prepared according to WO2002055517) in methanol (160 ml), water (70 mL) and acetic acid (30 mL) was added 37% hydrochloric acid (2 mL) and platinum(IV) oxide (360 mg). The system was hydrogenated for three days. The reaction mixture was filtered through Celite, washed with methanol. The filtrate was evaporated and dried under reduced pressure. The residue was dissolved in methanol (500 mL) and neutralized with hydroxide from resin to pH=9-10. The resin was filtered and washed with methanol, the filtrate was evaporated and concentrated under reduced pressure to give 4-piperidin-4-yl-1,3-dihydro-indol-2-one (4.2 g, 96%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]2[C:6]([CH3:11])([CH3:10])[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.BrCCBr.[Mg].[C:19](=[O:21])=[O:20].Cl>O1CCCC1>[CH3:10][C:6]1([CH3:11])[C:5]2[CH:12]=[CH:13][C:2]([C:19]([OH:21])=[O:20])=[CH:3][C:4]=2[O:9][CH2:8][CH2:7]1
Reactant: O=C=O
Reactant: CC1(C)CCOc2cc(Br)ccc21
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC1(C)CCOc2cc(C(=O)O)ccc21
Temperature: 0 °C

Procedure:
A solution of 14.2 g of 7-bromo-3,4-dihydro-4,4-dimethyl-2H-1-benzopyran and 1.1 g of 1,2-dibromoethane in 80 ml of tetrahydrofuran was added dropwise using a heatable ultrasonics bath, to a suspension, boiling under reflux, of 1.6 g of magnesium shavings in 20 ml of tetrahydrofuran. After heating under reflux for an additional 2 hours, the reaction mixture was cooled to 0° C. and a strong stream of carbon dioxide gas was conducted in (about 1 hour). Thereafter, the mixture was poured on to ice, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic extracts were washed with water, dried and evaporated. After recrystallization from ethyl acetate/hexane, there were obtained 5.3 g of 3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-7-carboxylic acid, melting point 173°-174° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].[Li]CCCC.[CH2:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH:16]1C(Cl)=O.Cl>C1COCC1.CCOCC>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](=[O:8])[CH:21]1[CH2:22][CH2:23][C:24]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20]1)[CH3:2]
Reactant: O=C(Cl)C1CCc2ccccc2C1
Reactant: CCOC(=O)CC(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CC(=O)C1CCc2ccccc2C1
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 93.5 %

Procedure:
A solution of malonic acid monoethyl ester (3.8 g, 29 mmol) in THF (80 ml) was cooled to −78° C. n-BuLi (36 ml, 58 mmol, 1.6 M in hexane) was added dropwise so that the temperature of the reaction mixture at the end the addition was −5° C. After 5 min. stirring at −5° C., reaction mixture was cooled to −65° C. and treated with a solution of (RS)-1,2,3,4-tetrahydro-naphthalene-2-carbonyl chloride (3.2 g, 16.5 mmol) in THF. Mixture was stirred for 10 min. at −65° C. and then added to a stirring mixture containing Et2O (200 ml) and 1N HCl (100 ml). Aqueous phase was extracted with Et2O (2×150 ml). Combined organic phases were washed successively with a saturated solution of NaHCO3 (100 ml) and NaCl (100 ml), dried over Na2SO4 and concentrated to provide (RS)-3-oxo-3-(1,2,3,4-tetrahydro-naphthalen-2-yl)-propionic acid ethyl ester (3.8 g, 93%) as a light brown oil, MS: m/e=246 (M+).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[F:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[C:13]([F:15])[CH:14]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[F:8][C:9]1[CH:10]=[C:11]([N:6]2[CH2:5][CH2:4][NH:3][C@@H:2]([CH3:1])[CH2:7]2)[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: C[C@H]1CNCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@H]1CN(c2cc(F)cc(F)c2)CCN1
Temperature: 100 °C
Reaction time: 24 h
Yield: 43.3 %

Procedure:
A mixture composed of 2.48 g of (S)-2-methylpiperazine, 3.97 g of 3,5-difluorobromobenzene, 2.76 g of sodium tert-butoxide, 326 mg of dichlorobis[(tri-ortho-tolyl)phosphine]palladium (II) (PdCl2[P(o-tolyl)3]2) and 100 ml of toluene was stirred at 100° C. for 24 hours in an atmosphere of nitrogen. After removal of the insoluble matter by filtration, the filtrate was washed with water and then with saturated brine. The organic layer was dried with anhydrous sodium sulfate and then concentrated under a reduced pressure, the residue was applied to a silica gel column chromatography (270 to 400 mesh, 100 g) and developed with a methanol-chloroform (6:94) mixed solvent, and then the fractions containing the compound of interest were concentrated to obtain 1.89 g of the title compound.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]1COCC1.[O:16]=[C:17]1[CH2:22][O:21][CH2:20][C@@H:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].IC>COCCOC>[CH3:11][C@@H:22]1[O:21][CH2:20][C@@H:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:17]1=[O:16]
Reactant: CC(C)(C)OC(=O)N1C(=O)COC[C@H]1c1ccccc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: COCCOC
Product: C[C@@H]1OC[C@@H](c2ccccc2)N(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a 1 M solution of sodium bis(trimethylsilyl)amide in THF (0.79 mL, 0.79 mmol) at −78° C. was added dropwise a solution of tert-butyl (5R)-3-oxo-5-phenylmorpholine-4-carboxylate from Step C (200 mg, 0.72 mmol) in DME (5 mL) at −78° C. The resulting mixture was stirred at −78° C. for 10 min then iodomethane (0.049 mL, 0.79 mmol) was added. After stirring at −78° C. for a further 1 h, the reaction mixture was quenched with saturated aqueous NH4Cl (5 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was partially purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—90:10 to 60:40. Further purification was achieved by HPLC, using a ChiralPak AS column and eluting with hexane:i-PrOH—90:10, to give the title compound. MS: m/z=236 (M−C4H7).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH3:13][O:14][C:15]1[C:29]([O:30][CH3:31])=[CH:28][C:18]2[CH2:19][CH:20]([C:25]([OH:27])=[O:26])[S:21][CH2:22][C:23](=[O:24])[C:17]=2[CH:16]=1.C(OC)(=O)[C@@H](C)O>ClCCl.CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:13][O:14][C:15]1[C:29]([O:30][CH3:31])=[CH:28][C:18]2[CH2:19][C@H:20]([C:25]([OH:27])=[O:26])[S:21][CH2:22][C:23](=[O:24])[C:17]=2[CH:16]=1
Reactant: COc1cc2c(cc1OC)C(=O)CSC(C(=O)O)C2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: COC(=O)[C@@H](C)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C(=O)CS[C@@H](C(=O)O)C2
Temperature: 0 °C
Reaction time: 15 h
Yield: 36.7 %

Procedure:
A solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.89 g) in dichloromethane (80 ml) was added to a solution of (±)-1,2,4,5-tetrahydro-7,8-dimethoxy-5-oxo-3-benzothiepin-2-carboxylic acid (6.0 g) and methyl (R)-(+)-lactate (4.43 g) in N,N-dimethylformamide (DMF) (80 ml) at 0° C., followed by the addition of 4-dimethylaminopyridine (DMAP) (1.3 g). This mixture was stirred at 0° C. for 1 hour and at room temperature for 15 hours, and concentrated under reduced pressure. Ethyl acetate (500 ml) and water (500 ml) were added to the residue and then the organic layer was collected. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off; the residual solid was collected by filtration and washed with ether, followed by recrystallization twice from ethyl acetate-hexane to yield (R)-1-methoxycarbonylethyl ester of (2R)-(−)-1,2,4,5-tetrahydro-7,8-dimethoxy-5-oxo-3-benzothiepin-2-carboxylic acid (2.2 g, 28%). Colorless needles. Melting point 161-162° C. Optical rotation [α]D (16° C.) −194.1° (c=0.50, CHCl3). A filtrate of the above-mentioned solid was concentrated and the resulting crystals were collected by filtration with ether-hexane, followed by recrystallization twice from ethyl acetate-hexane to yield (R)-1-methoxycarbonylethyl ester of (2S)-(+)-1,2,4,5-tetrahydro-7,8-dimethoxy-5-oxo-3-benzothiepin-2-carboxylic acid (1.6 g, 20%). Colorless Plates. Melting point 121-122° C. Optical rotation [α]D (16° C.) +234.3° (c=0.50, CHCl3).
Reaction SMILES: C(=O)([O-])O.[K+].C([O:14][CH2:15][C:16](=[O:37])[C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:36])[CH2:27][CH2:28]2)[CH2:23][CH2:22]3)[CH2:19][CH2:18]1)(=O)C1C=CC=CC=1>O.CO.C(O)C>[CH2:15]([OH:14])[C:16](=[O:37])[C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:36])[CH2:27][CH2:28]2)[CH2:23][CH2:22]3)[CH2:19][CH2:18]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)COC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCO
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CO
Yield: 100.3 %

Procedure:
A solution containing 7.5 g of potassium hydrogen carbonate in 14 ml of water is added to the suspension containing 2.5 g (5.7 mmoles) of 4-pregnene-3,20-dione-21-ol benzoate in 100 ml of methanol and the mixture is refluxed for 3 hours. Subsequently, the solvent is evaporated and the residue is taken up in 150 ml of water. The product is extracted 3 times with 80 ml of ethyl acetate each, the organic phase is washed with water, dried and evaporated. The residue is recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 1.89 g 99% yield of the aimed product, m.p.: 132°-135° C., [α]D =+175.2° (c=0.5 in ethanol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([N+:20]([O-])=O)[C:14]=3[N:13]([CH2:23][C:24](OC)=[O:25])[C:12]2=[O:28])(=[O:10])=[O:9])=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]3[C:14]4[N:13]([CH2:23][C:24](=[O:25])[NH:20][C:19]=4[CH:18]=[CH:17][CH:16]=3)[C:12]2=[O:28])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)Cn1c(=O)n(S(=O)(=O)c2ccc(C)cc2)c2cccc([N+](=O)[O-])c21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2c(=O)n3c4c(cccc42)NC(=O)C3)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of methyl {3-[(4-methylphenyl)sulfonyl]-7-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetate from Step C (1.00 g, 2.47 mmol) and 10% Pd/C (100 mg) was stirred vigorously in EtOAc (100 mL) under an atmosphere of hydrogen (ca. 1 atm). After 4 h, the mixture was filtered through a pad of Celite, washing with EtOAc (300 mL). To the filtrate was added AcOH (2 mL) and this solution was heated at 80° C. for 1 h, then concentrated in vacuo to give the title compound. MS: m/z=344 (M+1).
Reaction SMILES: [B]1[B]C([B]B(C(OCC(OC(B(C2[B][B][B][B]2)[B]C2[B][B][B][B]2)=O)[C:18]2[C:40]3[NH:41][C:20](=[CH:21][C:22]4[NH:26][C:25]([CH:27]=[C:28]5[N:32]=[C:31]([CH:33]=[C:34]6[N:38]=[C:37]([CH:39]=3)[C:36](C)=[C:35]6CCC(O)=O)[C:30](CCC(O)=O)=[C:29]5C)=[C:24](C)[C:23]=4C(OC(B(C3[B][B][B][B]3)[B]C3[B][B][B][B]3)=O)COC(B(C3[B][B][B][B]3)[B]C3[B][B][B][B]3)=O)[C:19]=2C)=O)C2[B][B][B][B]2)[B][B]1.COC(=O)CC1C(CC(OC)=O)=CNC=1>C(Cl)Cl>[CH2:21]1[C:22]2[NH:26][C:25](=[CH:24][CH:23]=2)[CH2:27][C:28]2[NH:32][C:31](=[CH:30][CH:29]=2)[CH2:33][C:34]2[NH:38][C:37](=[CH:36][CH:35]=2)[CH2:39][C:40]2[NH:41][C:20]1=[CH:19][CH:18]=2
Reactant: CC1=C(CCC(=O)O)c2cc3nc(cc4[nH]c(cc5[nH]c(cc1n2)c(C)c5C(COC(=O)B([B]C1[B][B][B][B]1)C1[B][B][B][B]1)OC(=O)B([B]C1[B][B][B][B]1)C1[B][B][B][B]1)c(C)c4C(COC(=O)B([B]C1[B][B][B][B]1)C1[B][B][B][B]1)OC(=O)B([B]C1[B][B][B][B]1)C1[B][B][B][B]1)C(C)=C3CCC(=O)O
Agent: COC(=O)Cc1c[nH]cc1CC(=O)OC
Solvent: ClCCl
Product: c1cc2[nH]c1Cc1ccc([nH]1)Cc1ccc([nH]1)Cc1ccc([nH]1)C2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A boronated porphyrin of the present invention, NiTCP, was synthesized using Lindsey's cyclization method as shown in Reaction Scheme 1. Pyrrole-3,4-diacetic acid dimethyl ester (prepared according to Chiusoli et al., 1989) in the amount of 79 mg and 3-o-carboranylmethyloxybenzaldehyde (prepared according to Miura et al., 1990) in the amount of 91 mg were dissolved in 20 ml of CH2Cl2 and then deoxygenated with nitrogen (N2) for 20 minutes. 15 μl of BF3.Et2O was added and then allowed to stir at 25° C. under N2 for approximately 1.5 hours to form an intermediate porphyrinogen.