Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([NH:10][NH2:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:13]([O-])=O.[Na+]>O>[C:1]1([S:7]([N:10]=[N+:11]=[N-:13])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=N[O-]
Reactant: NNS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
26.3 g of benzenesulphonohydrazide, 100 ml of water, 21 ml of 10N hydrochloric acid and 1.3 g of Emulgator [emulsifier] FD (a fatty alcohol/ethylene oxide addition product) are stirred for 30 minutes, 60 g of ice are added, and a solution of 19.5 g of sodium nitrite in 50 ml of water is then added dropwise in the course of about 30 minutes. The batch is stirred for 30 minutes, excess nitrite is then destroyed with a small amount of sulphamic acid, and excess acid is neutralised with about 5 ml of 10N sodium hydroxide solution. An emulsion of benzenesulphonyl azide is obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][C@@H:4]([C:7]2[C:8]([N+:21]([O-:23])=[O:22])=[CH:9][C:10]([Cl:20])=[C:11]([NH:13]C(=O)C(F)(F)F)[CH:12]=2)[CH2:3]1.[OH-].[Na+]>C(O)C.C(OCC)(=O)C.O>[NH2:13][C:11]1[CH:12]=[C:7]([C@@H:4]2[CH2:5][NH:6][C:2](=[O:1])[CH2:3]2)[C:8]([N+:21]([O-:23])=[O:22])=[CH:9][C:10]=1[Cl:20]
Reactant: O=C1C[C@H](c2cc(NC(=O)C(F)(F)F)c(Cl)cc2[N+](=O)[O-])CN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Nc1cc([C@@H]2CNC(=O)C2)c([N+](=O)[O-])cc1Cl
Temperature: 50 °C
Yield: 55.4 %

Procedure:
To a solution of N-(5-((3R)-5-oxopyrrolidin-3-yl)-2-chloro-4-nitrophenyl)-2,2,2-trifluoroacetamide (8.7 g, 24.7 mmol) in 48 mL of ethanol was added 9 mL of 4N NaOH aqueous solution. The mixture was then heated to 50° C. for 3 h. The reaction mixture was diluted with ethyl acetate (100 mL) and water (50 mL). The layers were separated. The organic layer was dried over Na2SO4 and concentrated in vacuo to provide the title compound (3.5 g, 57% yield). MS (ESI) m/z 256.03 (M+H)+.
Reaction SMILES: C([O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]2)=[C:6]([F:19])[C:5]=1[F:20])C.Br.C(O)(=O)C.O>C1(C)C=CC=CC=1>[F:20][C:5]1[C:6]([F:19])=[C:7]([C@H:10]2[CH2:11][CH2:12][C@H:13]([CH2:16][CH2:17][CH3:18])[CH2:14][CH2:15]2)[CH:8]=[CH:9][C:4]=1[OH:3]
Reactant: CCC[C@H]1CC[C@H](c2ccc(OCC)c(F)c2F)CC1
Agent: Br
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCC[C@H]1CC[C@H](c2ccc(O)c(F)c2F)CC1
Temperature: 30 °C

Procedure:
1-Ethoxy-2,3-difluoro-4-(trans-4-propylcyclohexyl)benzene (5) (50.0 g), 48% hydrobromic acid (44.8 g), and glacial acetic acid (250 ml) were put in a reaction vessel, and stirred under reflux for 64 hours. After completion of the reaction had been confirmed by means of gas chromatographic analysis, the reaction mixture was cooled to 30° C. Water (500 ml) and toluene (500 ml) were added to the solution obtained, and mixed. Then, the mixture was allowed to stand until it had separated into an organic phase and an aqueous phase, and an extractive operation into an organic phase was carried out. The organic phase obtained was fractionated, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure, and the residue obtained was purified by recrystallization from heptane and dried, giving 41.8 g of 2,3-difluoro-4-(trans-4-propylcyclohexyl)phenol (6). The yield based on the compound (5) was 92.9%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31].[CH2:32]([C:36]1[N:37]([CH2:49][CH2:50][CH2:51][CH2:52]O)[C:38]2[C:47]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[N:41]=[CH:40][C:39]=2[N:48]=1)[CH2:33][CH2:34][CH3:35].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:32]([C:36]1[N:37]([CH2:49][CH2:50][CH2:51][CH2:52][O:20][N:21]2[C:22](=[O:31])[C:23]3[C:24](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:26])[C:38]2[C:47]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[N:41]=[CH:40][C:39]=2[N:48]=1)[CH2:33][CH2:34][CH3:35]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCc1nc2cnc3ccccc3c2n1CCCCON1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 36.5 %

Procedure:
Triphenylphosphine (21.2 g, 80.7 mmol) and N-hydroxyphthalimide (13.2 g, 80.7 mmol) were added to a solution of 4-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (16.0 g, 53.8 mmol) in tetrahydrofuran (200 mL). The mixture was stirred for five minutes and then was cooled to approximately 0° C. Diisopropyl azodicarboxylate (19.6 g, 96.8 mmol) was added dropwise, and the reaction was allowed to warm to room temperature and stirred for three hours. An analysis by LC/MS indicated the presence of starting material, and the reaction was stirred at 60° C. overnight. An analysis by LC/MS indicated the presence of starting material, and additional triphenylphosphine, N-hydroxyphthalimide, and diisopropyl azodicarboxylate (26.9 mmol of each) were added to the reaction mixture. The reaction was stirred at room temperature for two hours and heated at reflux for three hours. The reaction was concentrated under reduced pressure, and the residue was dissolved in chloroform (200 mL). The resulting solution was washed with brine (3×150 mL), dried over magnesium sulfate, filtered through a layer of CELITE filter aid, and concentrated under reduced pressure. An analysis of the crude product mixture by LC/MS indicated that starting material was still present. The mixture was dissolved in tetrahydrofuran (200 mL) and treated with triphenylphosphine (21.2 g, 80.7 mmol), N-hydroxyphthalimide (13.2 g, 80.7 mmol), and diisopropyl azodicarboxylate (19.6 g, 96.8 mmol) as described above. The reaction was stirred overnight at room temperature. The product was present as a white precipitate, which was isolated by filtration and washed with tetrahydrofuran to provide 8.68 g of 2-[4-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]-1H-isoindole-1,3(2H)-dione as a white solid.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Br:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[N:59]([CH3:66])[CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1>CN(C=O)C.O>[Br:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[N:59]([CH3:66])[CH:60]1[CH2:65][CH2:64][N:63]([C:11](=[O:13])[CH2:10][NH:9][C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:62][CH2:61]1
Reactant: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cc1
Reactant: CN(c1ccccc1Br)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(c1ccccc1Br)C1CCN(C(=O)CNC(=O)c2ccc(-c3ccccc3)cc2)CC1
Reaction time: 8 h
Yield: 36.5 %

Procedure:
To a stirred solution of [(biphenyl-4-carbonyl)-amino]-acetic acid (0.1 g, 0.00039 mol) in DMF (2 mL), was added DIPEA (0.2025 g, 0.00156 mol), HOBt (0.053 g, 0.00039 mol) and EDCI.HCl (0.0901 g, 0.00047 mol) at ambient temperature. After 2 minutes (2-bromo-phenyl)-methyl-piperidin-4-yl-amine hydrochloride (0.119 g, 0.00039 mol) was added and the resulting mixture was stirred at the same temperature overnight. The reaction mixture was diluted with cold water, and the resulting precipitate was isolated by filtration. Purification by preparative TLC using 30% ethyl acetate in hexane afforded 0.072 g (36%) of biphenyl-4-carboxylic acid (2-{4-[(2-bromo-phenyl)-methyl-amino]-piperidin-1-yl}-2-oxo-ethyl)-amide. LCMS: 506.1 (M+1)+, 97.07%, 1H NMR (DMSO-d6): δ 8.6 (t, 1H), 8.0 (d, 2H), 7.8 (d, 2H), 7.75 (m, 4H), 7.6-7.25 (m, 6H), 7.0 (t, 1H), 4.4 (m, 1H), 4.2 (m, 1H), 3.9 (m, 1H), 3.05 (m, 1H), 2.7 (m, 1H), 2.6 (s, 3H), 1.8-1.5 (m, 4H).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([Cl:18])[CH:10]=2)=[N:5]1.[N:20]1[C:24]2[CH:25]=[CH:26][C:27]([C:29](O)=[O:30])=[N:28][C:23]=2[NH:22][CH:21]=1.CCN(C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C>>[Cl:18][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:29]([C:27]3[N:28]=[C:23]4[NH:22][CH:21]=[N:20][C:24]4=[CH:25][CH:26]=3)=[O:30])[CH3:19])[N:5]=2)[CH:16]=[C:15]([F:17])[C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1ccc2nc[nH]c2n1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1ccc2nc[nH]c2n1
Yield: 54.9 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.060 g, 0.215 mmol), 3H-imidazo[4,5]pyridine-5-carboxylic acid (0.035 g, 0.215 mmol), DIPEA (0.112 ml, 0.646 mmol), HOBt hydrate (0.050 g, 0.323 mmol) and EDCI (0.062 g, 0.323 mmol) using the method of Example 274 affording 0.050 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.22 (d, 3H), 4.46 (m, 3H), 6.99 (d, 1H), 7.81 (d, 1H), 7.89 (m, 3H), 8.09 (d, 1H), 8.63 (s, 1H), 8.80 (d, 1H), 13.00 (bs, 1H).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[F:27][C:28]([F:38])([F:37])[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH2:33].O>CS(C)=O>[F:27][C:28]([F:37])([F:38])[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH:33][CH2:11][CH:12]1[O:25][C:16]2=[C:17]3[C:21](=[CH:22][CH:23]=[C:15]2[O:14][CH2:13]1)[NH:20][C:19](=[O:24])[CH2:18]3
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Reactant: NCc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CS(C)=O
Product: O=C1Cc2c(ccc3c2OC(CNCc2cccc(C(F)(F)F)c2)CO3)N1
Temperature: 85 °C
Yield: 19.6 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.01 g, 2.70 mmole) and 3-trifluoromethylbenzylamine (1.75 ml, 12.0 mmole) were combined in 15 ml of dry DMSO and heated to 85° C. for 4 hours under a nitrogen atmosphere. After cooling to room temperature, 200 ml of water was added and the mixture was extracted twice with 250 ml portions of 50% ethyl acetate in hexane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuum to yield an oil, which was column chromatographed on silica gel using 2% methanol/CH2Cl2 as eluant. The free base of the title compound (0.20 g, 20%) thus obtained was crystallized from isopropanol with the addition of one equivalent of fumaric acid to give 0.17 g of the (S) enantiomer of the title compound as a light yellow solid fumarate, one-half hydrate, m.p. 158°-160° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:6][C:7]2[CH:12]=[CH:11]N=C[CH:8]=2)[CH2:3][CH2:2]1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=2)=[CH:25][CH:24]=1)=[O:21].[CH:40]([NH:43]C(C)C)(C)C>CN(C)C=O>[F:37][C:36]([F:39])([F:38])[C:33]1[CH:34]=[CH:35][C:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][C:20]([N:16]3[CH2:15][CH2:14][CH:13]([N:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH2:6][C:7]4[CH:8]=[N:43][CH:40]=[CH:11][CH:12]=4)[CH2:18][CH2:17]3)=[O:21])=[CH:24][CH:25]=2)=[N:31][CH:32]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CC(C)NC(C)C
Reactant: c1cc(CN(CC2CC2)C2CCNCC2)ccn1
Solvent: CN(C)C=O
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(N(Cc2cccnc2)CC2CC2)CC1

Procedure:
The title product was prepared from cyclopropylmethyl-piperidin-4-yl-pyridin-4-ylmethyl-amine and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, 3 equivalent of diisopropylamine was added, solvent: dimethylformamide. The crude reaction mixture was evaporated without addition of acetic acid, preparative HPLC (method C) (22%, off-white solid. HPLC-MS m/z=(M+1) 513.3, Rt: 2.70 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.CC(C)=O.C(=O)=O.C([Li])CCC.[Cl:27]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.Cl.CCOC(C)=O>[Cl:27][C:10]1[CH:11]=[C:12]2[C:7]([CH:6]=[CH:5][CH:4]=[C:3]2[O:2][CH3:1])=[CH:8][C:9]=1[O:13][CH3:14]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: COc1ccc2c(OC)cccc2c1
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1cc2cccc(OC)c2cc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A 0.5 L round bottom flask equipped with magnetic stirring bar and thermometer was charged with 1,6-dimethoxynaphtalene (14.56 g, 77.36 mmol), THF (50 ml) and resultant solution was cooled to −78° C. (acetone/dry ice bath). Solution of butyl lithium (1.6 M in hexane, 53.18 ml, 85.09 mmol) was added through a syringe during 10 min. Mixture was allowed to warm to room temperature and stirred for 20 h. Then reaction mixture was cooled again to −78° C. and solution of hexachloroethane (20.144 g, 85.09 mmol) in THF (50 ml) was added through a syringe during 10 min. Reaction mixture was allowed to warm to room temperature, diluted with 1N HCl (150 ml), EtOAc (200 ml) and transferred into separation funnel. Organic phase was washed with saturated NaCl solution (2×30 ml), dried over MgSO4 and concentrated in vacuum. Residue was purified by vacuum flash chromatography (SiO2, 150 g, 35-65 m, eluent 10% EtOAc in hexane) to give a mixture (˜3:2) of 47 and 46. Pure desired product (47) was obtained by multiple crystallizations from ether (5.0 g, 22.5 mmol, yield=29%) as white solid. 1H NMR (CDCl3): δ 8.38 (s, 1H), 7.49-7.37 (m, 3H), 6.82 (dd, J=7.2, 1.0 Hz; 1H), 4.11 (s, 3H), 4.08 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1(C)[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.N1C=CC=C[CH:20]=1>>[C:10]1([CH3:20])[C:11]([S:14]([O:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:15])=[O:16])=[CH:12][CH:13]=[CH:8][CH:9]=1
Reactant: c1ccncc1
Reactant: OCC1CCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccccc1S(=O)(=O)OCC1CCCC1
Reaction time: 2 h
Yield: 74.7 %

Procedure:
To cyclopentanemethanol (2.0 g, 20 mmol) in pyridine (30 ml) was added para-toluenesulfonyl chloride (3.81 g, 20 mmol) with stirring. After 2 hrs at room temperature, the reaction mixture was concentrated for removement of pyridine, extracted with dichloromethane, dried, filtered, concentrated and separated by a column chromatography to give a desirable product (3.80 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH3:10])[CH3:9])[N:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>C1C=CC=CC=1>[CH3:9][N:8]([CH3:10])[C:4]1[N:3]=[C:2]([NH:1][C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)c1cccc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: CC(=O)Nc1cccc(N(C)C)n1

Procedure:
Acetylation of 2-amino-6-dimethylaminopyridine from Part A with acetic anhydride in benzene for 2 hours at reflux gives a quantative yield of the title compound. Melting point is 118°-119°.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH3:13])=[CH:7][N:6]=1)(=[O:3])[CH3:2].[OH-].[K+]>CO>[OH:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH3:13])=[CH:7][N:6]=1.[C:1]([O:4][CH2:5][CH3:10])(=[O:3])[CH3:2]
Reactant: COc1cnc(OC(C)=O)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCOC(C)=O
Product: COc1cnc(O)c(C)c1
Yield: 197.9 %

Procedure:
To a stirred solution of 2-acetoxy-methyl-5-methoxy-pyridine (1.41 g, 7.8 mmol) in methanol (30 mL) was added excess potassium hydroxide (1.6 g), and the mixture was refluxed for 2 hours. The solvent was removed in vacuo, and the residue was purified by column chromatography eluting with a heptane to ethyl acetate gradient. The extremely volatile 2-hydroxy-methyl-5-methoxy-pyridine was obtained as a solution in ethyl acetate (0.68 g, 63% yield).
Reaction SMILES: [C:1]12[CH:24]=[C:22]3[N:23]=[C:19]([CH:20]=[CH:21]3)[CH:18]=[C:16]3[NH:17][C:13]([CH:14]=[CH:15]3)=[CH:12][C:10]3=[N:11][C:7]([CH:8]=[CH:9]3)=[CH:6][C:4]([NH:5]1)=[CH:3][CH:2]=2.[Zn:25](OC(C)=O)OC(C)=O.O.O>C(Cl)(Cl)Cl.CO>[C:1]12[CH:24]=[C:22]3[N:23]=[C:19]([CH:20]=[CH:21]3)[CH:18]=[C:16]3[NH:17][C:13]([CH:14]=[CH:15]3)=[CH:12][C:10]3=[N:11][C:7]([CH:8]=[CH:9]3)=[CH:6][C:4]([NH:5]1)=[CH:3][CH:2]=2.[Zn:25]
Reactant: CC(=O)O[Zn]OC(C)=O
Agent: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: [Zn]

Procedure:
Synthesis. A sample of 4-bromobenzaldehyde dimethylacetal46 was coupled with di-tert-butylphosphite to give 4-(di-tert-butyloxyphosphoryl)benzaldehyde dimethylacetal. The latter was used in a mixed-aldehyde condensation47 with pyrrole under standard conditions of BF3.O(Et)2-ethanol cocatalysis48 followed by oxidation with DDQ to give porphyrin 1. Porphyrin 1 was metalated with Zn(OAc)2.2H2O in CHCl3/methanol to afford zinc porphyrin Zn1 in 73% yield (Scheme 1). Cleavage of the tert-butyl groups was achieved by following the known procedure45 with TMS-Cl/TEA in refluxing CHCl3 (stabilized with amylenes). In this manner, the porphyrin Zn2 was obtained without demetalation in 89% yield. Note that CHCl3 stabilized with amylenes rather than ethanol was used to avoid the possible reaction of ethanol with TMS-Cl.
Reaction SMILES: [CH:1]([CH:3]([NH:8][C:9](=[O:19])[C@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:11][C:12](=[O:14])[CH3:13])[CH2:4][CH2:5][CH2:6][CH3:7])=O.[CH2:20]([SH:23])[CH2:21][SH:22].B(F)(F)F.CCOCC>C(Cl)Cl>[S:22]1[CH2:21][CH2:20][S:23][CH:1]1[CH:3]([NH:8][C:9](=[O:19])[C@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:11][C:12](=[O:14])[CH3:13])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC(C=O)NC(=O)[C@H](CC(C)C)NC(C)=O
Reactant: SCCS
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCC(NC(=O)[C@H](CC(C)C)NC(C)=O)C1SCCS1
Yield: 73.7 %

Procedure:
In 20 ml of methylene chloride was dissolved 1.8 g of N-acetyl-L-leucine-(1-formyl)pentylamide obtained in the same manner as in Example 16-(c), and 700 mg of 1,2-ethanedithiol and 1.5 ml of boron trifluoride ethyl etherate were added thereto. The mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by medium-pressure column chromatography on silica gel to obtain 1.7 g of the titled compound as a colorless crystal.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH2:14])[CH:5]=[CH:4][C:3]1=2.[CH2:16]([Li])[CH2:17][CH2:18][CH3:19].ICCCC.[Cl-].[Na+]>O1CCCC1>[CH2:16]([NH:14][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:15])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1)[CH2:17][CH2:18][CH3:19]
Reactant: [Li]CCCC
Reactant: CC1(C)CCC(C)(C)c2cc(N)ccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCI
Solvent: C1CCOC1
Product: CCCCNc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 15 h
Yield: 37 %

Procedure:
A solution of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine (1) (0.3 g, 1.5 mmole) in 30 mL tetrahydrofuran (THF) was cooled to −78° C. and 2.5 M n-butyllithium solution (0.6 mL) was added dropwise. The reaction mixture was allowed to warm to 0° C. over a one hour period. Iodobutane (0.171 mL) was added at 0° C. and the reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was then poured into 50 mL of a saturated aqueous sodium chloride solution and extracted with three portions of 50 mL of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to provide a brown oil. The product was purified by flash chromatography (SiO2, 5% ethyl acetate/hexanes) to provide 143 mg (37%) of butyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amine (7) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12](O)=[O:13])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.CN1CCOCC1.[BH4-].[Na+]>O1CCCC1.O>[OH:13][CH2:12][C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NC1(CO)CC1
Reaction time: 0.33 h
Yield: 91.1 %

Procedure:
A solution of 1-(N-tert-butoxycarbonylamino)cyclopropanecarboxylic acid (5 g) in tetrahydrofuran was cooled to −20° C. Isobutyl chloroformate (3.24 ml) and N-methylmorpholine (2.74 ml) were added thereto, and the mixture was stirred at the same temperature as above for 20 minutes. Then, sodium borohydride (1.12 g) and water (1 ml) were added thereto, and the mixture was further stirred at room temperature for 40 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain the title compound (4.24 g).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:25][C:26]1[O:30][C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:28][C:27]=1[CH2:37][CH2:38]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:38][CH2:37][C:27]2[N:28]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:30][C:26]=2[CH3:25])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1OC
Product: COc1ccccc1OC(C)(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared using the representative Standard Procedure (E) from 3-(4-Hydroxyphenyl)-2-(2-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3): • 7.99-7.97 (m, 2H), 7.47 (dd, 3H, J=5.08 Hz, 1.96 Hz), 7.18 (d, 2H, J=8.60), 7.07 (td, 1H, J=6.65 Hz, 1.56 Hz), 6.89-6.80 (m, 4H), 6.63 (dd, 1H, J=7.82 Hz, 1.56 Hz), 4.21 (t, 2H, J=6.26 Hz), 3.82 (s, 3H), 3.30 (d, 1H, J=14.1 Hz), 3.10-3.04 (m, 3H), 2.41 (s, 3H), 1.30 (s, 3H). MS [ES+] m/z exact mass calcd for C29H30NO6 488.2073, found 488.2086.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:28](OCC)=[O:29])=[N:6][C:7]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[CH:21]=2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])([O-])=O.ClC1N=C([C:40](OCC)=[O:41])C([N+]([O-])=O)=C(NC2C=CC=CC=2OC)N=1.[NH2:57]C1C=C(C=CC=1)CO.C(N(C(C)C)CC)(C)C>CN(C)C=O>[OH:27][CH2:26][C:22]1[CH:21]=[C:20]([NH:19][C:7]2[N:8]=[C:9]3[C:4]([NH:1][C:40](=[O:41])[N:10]3[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[C:5]([C:28]([NH2:57])=[O:29])[N:6]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1nc(Nc2cccc(CO)c2)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Reactant: CCOC(=O)c1nc(Cl)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Reactant: Nc1cccc(CO)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(Nc3cccc(CO)c3)nc21
Yield: 93 %

Procedure:
Ethyl 5-nitro-2-(3-(hydroxymethyl)phenylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate. Ethyl 2-chloro-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate (See Example 30.A) (0.300 g, 0.852 mmol), 3-aminobenzyl alcohol (0.125 g, 1.2 mmol) and diisopropylethylamine (0.219 g) were reacted according to General Procedure C, except at room temperature and in dimethylformamide (5 ml). The crude reaction mixture was condensed and purified using Biotage chromatography (60 to 100% EtOAc in hexanes) to afford the title compound (0.350 g., 93%). MS (ESI) m/z 440.5 [M+1]+.