Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:12][C:13]1[C:22]2[C:17](=[C:18]([C:23]([NH2:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+]=[N-].C(Cl)(Cl)Cl>[Pd].C(O)C>[NH2:1][CH2:4][C@@H:5]([NH:12][C:13]1[C:22]2[C:17](=[C:18]([C:23]([NH2:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: [N-]=[N+]=NC[C@@H](Nc1ncnc2c(C(N)=O)cccc12)c1ccccc1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: NC[C@@H](Nc1ncnc2c(C(N)=O)cccc12)c1ccccc1

Procedure:
4-((S)-2-Azido-1-phenyl-ethylamino)-quinazoline-8-carboxylic acid amide ((0.28 g, 0.84 mmol) and palladium on carbon (5%, wet type, 56 mg) were combined in ethanol (5 mL) and chloroform (1 mL) and stirred under an atmosphere of hydrogen for 48 hours. The solution was filtered, rinsed with methanol and the solvent removed under reduced pressure. The sample was redissolved in THF/methanol and hydrogen chloride (4M solution in dioxane, 1 mL) was added. The solid formed was collected by filtration and purified by recrystallization from methanol/ethyl acetate (131 mg, 51%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.27-3.40 (m, 1 H) 3.84-3.98 (m, 1 H) 5.99 (br. s., 1 H) 7.29-7.36 (m, 1 H) 7.39 (t, J=7.39 Hz, 2 H) 7.60 (d, J=7.32 Hz, 2 H) 7.88 (s, 1 H) 8.16 (br. s., 1 H) 8.43 (br. s., 3 H) 8.59 (d, J=0.83 Hz, 1 H) 8.80 (s, 1 H) 9.29 (br. s., 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11](CC2N3C=C(C4C=CC=CC=4N)N=C3SC=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1[N:40]=[C:41]2[N:45]([CH:46]=1)[CH:44]=[C:43]([CH2:47]O)[S:42]2)([O-])=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:47][C:43]2[S:42][C:41]3=[N:40][C:39]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[NH2:30])=[CH:46][N:45]3[CH:44]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2csc3nc(-c4ccccc4N)cn23)CC1
Reactant: O=[N+]([O-])c1ccccc1-c1cn2cc(CO)sc2n1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cn3cc(-c4ccccc4N)nc3s2)CC1

Procedure:
Essentially the same procedure used during the preparation of 4-[6-(2-amino-phenyl)-imidazo[2,1-b]thiazol-3-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester was employed, except that [6-(2-nitro-phenyl)-imidazo[2,1-b]thiazol-2-yl]-methanol was used as the starting material.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][C:17](=[O:19])[N:16]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:15]2=[O:30])=[CH:10][CH:9]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:18][C:17](=[O:19])[N:16]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)(=[O:21])=[O:22])[C:15]2=[O:30])=[CH:12][CH:13]=1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(N2CC(=O)N(S(=O)(=O)c3ccc(Cl)cc3)C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(N2CC(=O)N(S(=O)(=O)c3ccc(Cl)cc3)C2=O)cc1
Yield: 84.4 %

Procedure:
In 1.5 ml of trifluoroacetic acid (TFA), were dissolved 120 mg (0.27 mmol) of 1-(4-t-butoxycarbonylphenyl)-3-(4-chlorobenzenesulfonyl)-imidazolidin-2,4-dione obtained in Example 53. The resultant solution was stirred at room temperature for 10 minutes. The liquid reaction mixture was concentrated under reduced pressure and added with diethyl ether. Crystals deposited were collected by filtration to obtain 90 mg (yield: 85.2%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH3:19])[C:9]([N:11]1[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13][CH2:12]1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O>>[NH2:7][CH:8]([CH3:19])[C:9]([N:11]1[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13][CH2:12]1)=[O:10]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)N1CCS(=O)(=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(N)C(=O)N1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 159.8 %

Procedure:
To a solution of [2-(1,1-Dioxo-1lambda*6*-thiomorpholin-4-yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (5.6 g, 18.2 mmol) in CH2C12 (70 mL) was added trifluoroacetic acid (5 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 3 hours. After removal of CH2Cl2 and excess trifluoroacetic acid under reduced pressure, 2-Amino-1-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-propan-1-one (6.0 g, yield 100%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:20](Br)#[C:21][CH3:22].O>CC(C)=O>[CH2:22]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[C:2]([Cl:1])=[N:3]1)[C:21]#[CH:20]
Reactant: O=[N+]([O-])c1ccc2c(Cl)n[nH]c2c1
Reactant: CC#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C#CCn1nc(Cl)c2ccc([N+](=O)[O-])cc21

Procedure:
Compounds III-A, III-B and III-D were prepared by a modification of the procedure of Zaugg, Swett and Stone (5). In a stirred solution of sodium ethylate prepared from 0.23 g (0.01 mol) of sodium metal and 50 ml of absolute ethanol was dissolved 0.01 mole of the appropriate nitro- or chloroindazole. To such solution was added 2.38 g (0.02 mol) of propynyl bromide, and the reaction mixture was stirred for twenty-four hours at room temperature during which time sodium bromide precipitated. The reaction mixture was poured into 100 ml of water and the oily layer was extracted with ether. The ether layer was separated, washed with water, 10% potassium hydroxide solution, saturated sodium chloride solution, dried (Na2SO4) and concentrated in vacuo. The residue was recrystallized from 95% ethanol to give the desired N-(2-propynyl) indazoles. To prepare compound III-C, a mixture of 10 g (0.043 mol) of 3-chloro-6-nitroindazole, 6.9 g (0.043 mol) of anhydrous potassium carbonate and 0.10 g (0.086 mol) of propynyl bromide was placed in 100 ml of acetone. The reaction mixture was refluxed for twenty-four hours, and then poured into 100 ml of water. The oily layer was extracted with ether, and the ether layer was separated, washed with water, 10% sodium hydroxide solution, saturated sodium chloride solution, dried (Na2SO4) and concentrated in vacuo. The residue was recrystallized from 95% ethanol to give N-(2-propynyl)-3-chloro-6-nitroindazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:12][C:13]1(C)[O:20][C:18](=O)[CH2:17][C:15](=O)[O:14]1.C1CCC(N=C=NC2CCCCC2)CC1.C(O)C=C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](=[O:11])[CH2:12][C:13]([O:14][CH2:15][CH:17]=[CH2:18])=[O:20])=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C=CCO
Product: C=CCOC(=O)CC(=O)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a CH2Cl2 (210 mL) solution of 4-fluorophenyl acetic acid (32.28 g, 209.42 mmol) at 0° C. was added DMAP (25.58 g, 209.42 mmol), and Meldrum's Acid (30.18 g, 209.42 mmol) followed by DCC (43.21 g, 209.42 mmol). The reaction mixture was warmed to ambient temperature and stirred for 4 h. The reaction was filtered to remove the DCU and the filtrate washed with 1N HCl, H2O, and brine. The organics were dried (Na2SO4), filtered and concentrated to a yellow oil. The residue was redissolved in THF (200 mL) and allyl alcohol (14.38 mL, 211.51 mmol). The reaction mixture was refluxed for 3 h and then concentrated to deliver 47 g (95% yield) of the title compound as a pale yellow oil and used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([O:38]C)=[O:37])[CH:27]=3)[C:22]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:46][CH3:47])=[O:5])[CH3:2].[OH-].[Na+]>CO.CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[C:28]([C:36]([OH:38])=[O:37])[CH:27]=3)[C:22]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:46][CH3:47])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(=O)OC)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(=O)O)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29.7 %

Procedure:
(2R,4S)-2-Ethyl-6-methoxy-4-{(3-methoxycarbonyl-5-trifluoromethylbenzyl)-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (86 mg) is dissolved in methanol (9 ml) and N,N-dimethylformamide (1 ml), and thereto is added 1N aqueous NaOH solution (3 ml). The mixture is stirred at room temperature for 1.5 hours, and partitioned by adding 1N HCl and ethyl acetate. The organic layer is washed with saturated brine, then dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by thin layer silica gel chromatography (chloroform:methanol=9:1) to give (2R,4S)-4-{(3-carboxy-5-trifluoromethylbenzyl)-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (25 mg). MS (m/z): 645 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[C:15]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([O:7][CH3:15])=[O:6]
Reactant: COc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc([N+](=O)[O-])ccc1OC
Temperature: 80 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of 2-methoxy-5-nitrobenzoic acid (25.0 g, 0.12 mol) in DMF (100 mL) was added K2CO3 (26.3 g, 0.19 mol). The reaction mass was stirred at 80° C. for 1 h followed by addition of methyl iodide (12.3 mL, 0.19 mol). The reaction mass was further stirred at 80° C. for 5-6 h. The reaction mass was filtered and the obtained filtrate was concentrated. The residue was further diluted with water and obtained solid was filtered off to afford 20.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.83 (s, 3H), 3.97 (s, 3H), 7.38 (d, 0.1=9.3 Hz, 1H), 8.41 (dd, J=2.4 Hz & 2.4 Hz, 1H), 8.47 (s, 1H); MS (m/z): 212.44 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[CH2:13][CH2:12][CH:11](O)[CH2:10]2)=[C:4]([F:15])[CH:3]=1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[CH2:13][CH2:12][CH:11]([N:20]3[C:16](=[O:26])[C:17]4[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:19]3=[O:21])[CH2:10]2)=[C:4]([F:15])[CH:3]=1
Reactant: OC1CCC(c2cc(F)c(Br)cc2F)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C1CCC(c2cc(F)c(Br)cc2F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.8 %

Procedure:
To a solution of 13.9 g (50 mmol)oof 3-(4-bromo-2,5-difluorophenyl)cyclopentanol, 7.4 g (50 mmol) of phthalimide and 13.1 g (50 mmol) of triphenylphosphine in 50 ml of dry tetrahydrofuran was added dropwise at room temperature a solution of 8.7 g (50 mmol) of diethyl azodicarboxylate in 20 ml of dry tetrahydrofuran. The reaction was stirred at room temperature for 18 hours and the solvent was removed in vacuo. The residue was triturated with ether and the solid removed by filtration. The filtrate was evaporated in vacuo and the residue was chromatographed on silica gel (E. Merck - 230-400 Mesh) eluting with chloroform-ethyl acetate (4:1) to give 15.6 g of the title compound; mp 47°-48°.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:47][CH:48]1[CH2:52][CH2:51][C:50](=[CH:53][N:54]([CH3:61])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]1=[O:62].[C:63]([C:67]1[CH:72]=[CH:71][C:70](Br)=[CH:69][CH:68]=1)([CH3:66])([CH3:65])[CH3:64].CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:63]([C:67]1[CH:72]=[CH:71][C:70]([C:48]2([CH3:47])[CH2:52][CH2:51][C:50](=[CH:53][N:54]([CH3:61])[C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:49]2=[O:62])=[CH:69][CH:68]=1)([CH3:66])([CH3:65])[CH3:64]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: CC1CCC(=CN(C)c2ccccc2)C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CN(C=C1CCC(C)(c2ccc(C(C)(C)C)cc2)C1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 70.2 %

Procedure:
An oven dried Schlenk tube equipped with a rubber septum was cooled under an argon purge. The septum was removed and the tube was charged with palladium acetate (5.6 mg, 0.025 mmol, 5 mol % Pd), (S)-BINAP (23.3 mg, 0.0375 mmol, 7.5 mol %) and 2-methyl-5-(N-methyl-anilinomethylene)-cyclopentanone (108 mg, 0.5 mmol). Toluene (2 mL) was added and the mixture was stirred for 1 min at room temperature. 4-t-Butylbromobenzene (0.17 mL, 1.0 mmol) and sodium t-butoxide (96 mg, 1.0 mmol) were added to the tube, the tube was capped with the septum, purged with argon, and additional toluene (4 mL) was added through the septum. The mixture was heated to 100° C. with stirring until the starting ketone had been completely consumed as judged by GC analysis. The mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (10 mL) and diluted with ether (20 mL). The mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was extracted with ether (20 mL), and the combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 122 mg (70%) of the title compound. The ee was determined to be 89% by chiral HPLC analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[NH:14][C:15](=[O:26])[NH:16][C:17]1[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=O)[N:21]=1)=[O:6].[CH3:31][NH2:32].C1COCC1>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[NH:14][C:15](=[O:26])[NH:16][C:17]1[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:32][CH3:31])=[O:25])[N:21]=1)=[O:6]
Reactant: COc1ccccc1C(=O)c1ccc(C)cc1NC(=O)Nc1nc(CC(=O)O)cs1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)Cc1csc(NC(=O)Nc2cc(C)ccc2C(=O)c2ccccc2OC)n1
Yield: 75 %

Procedure:
2-(2-{3-[2-(2-Methoxy-benzoyl)-5-methyl-phenyl]-ureido}-thiazol-4-yl)-N-methyl-acetamide (164 mg, 75%) was prepared from (2-{3-[2-(2-methoxy-benzoyl)-5-methyl-phenyl]-ureido}-thiazol-4-yl)-acetic acid (213 mg, 0.5 mmol) and 1 N solution of methylamine in THF (0.5 mL, 0.5 mmol) following the general procedure K.
Reaction SMILES: [OH:1][CH:2]1[CH:6]([CH2:7][OH:8])[O:5][CH:4]([N:9]2[CH:17]=[N:16][C:15]3[C:14](=[O:18])[NH:13][C:12]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[N:11][C:10]2=3)[CH:3]1[O:25][CH3:26].[C:27](Cl)(C1C=CC=CC=1)([C:36]1[CH:43]=[CH:42][C:39]([O:40][CH3:41])=[CH:38][CH:37]=1)[C:28]1[CH:35]=[CH:34][C:31]([O:32][CH3:33])=[CH:30][CH:29]=1>N1C=CC=CC=1>[CH3:41][O:40][C:39]1[CH:38]=[CH:37][C:36]([CH:27]([C:28]2[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[CH:34][CH:35]=2)[O:8][CH:7]([C:28]2[CH:35]=[CH:34][CH:31]=[CH:30][CH:29]=2)[CH:6]2[O:5][CH:4]([N:9]3[CH:17]=[N:16][C:15]4[C:14](=[O:18])[NH:13][C:12]([NH:19][C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])=[N:11][C:10]3=4)[CH:3]([O:25][CH3:26])[CH:2]2[OH:1])=[CH:43][CH:42]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: COC1C(O)C(CO)OC1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Solvent: c1ccncc1
Product: COc1ccc(C(OC(c2ccccc2)C2OC(n3cnc4c(=O)[nH]c(NC(=O)C(C)C)nc43)C(OC)C2O)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 41.1 %

Procedure:
Compound 16.2 (6.18 g, 17.19 mmol) was dissolved in 15 mL anhydrous pyridine, and treated with DMTCl (6.4 g, 18.91 mmol). The mixture was stirred for 12 h and poured on to 200 mL ice-water, filtered, and the solid was washed with 2×100 mL water. The solid was redissolved in 200 mL ethyl acetate. The organic layer was washed with 3×100 mL water, dried over MgSO4, filtered, and concentrated down under reduced pressure. The residue was subjected to a silica gel column chromatography to yield product 16.3 (2.6 g, 23% yield).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:15]([OH:17])=O.[NH2:18][C@H:19]([C:24]([NH:26][C@H:27]([C:32]([NH:34][C@H:35]([C:40]([NH:42][C@H:43]1[CH2:47][CH2:46][O:45][CH:44]1[O:48][CH3:49])=[O:41])[CH2:36][CH:37]([CH3:39])[CH3:38])=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22]>>[CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:15]([NH:18][C@H:19]([C:24]([NH:26][C@H:27]([C:32]([NH:34][C@H:35]([C:40]([NH:42][C@H:43]1[CH2:47][CH2:46][O:45][CH:44]1[O:48][CH3:49])=[O:41])[CH2:36][CH:37]([CH3:38])[CH3:39])=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17]
Reactant: COC1OCC[C@@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C
Reactant: O=C(O)c1ccc2c(c1)Nc1ccccc1S2
Product: COC1OCC[C@@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)c1ccc2c(c1)Nc1ccccc1S2
Yield: 21 %

Procedure:
The experimental protocol of this peptide condensation is the same as that described for the synthesis of intermediate 1.1, this time using 10H-phenothiazine-2-carboxylic acid (intermediate 1.10) and L-leucyl-L-leucyl-N1-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide (intermediate 1.8). The reaction product is purified by chromatography on silica (eluent: ethyl acetate/heptane in proportions of 7/3 to 1/1). 228 mg of a yellow solid is obtained with a yield of 21%. Melting point: 164-165° C.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29][CH2:30][CH2:31][CH2:32][C:33]([O:36][Si](CC)(CC)CC)([CH3:35])[CH3:34])[CH2:12][C@@H:11]([O:44][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29][CH2:30][CH2:31][CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[CH2:12][C@@H:11]([OH:44])[CH2:10]1
Reactant: CC[Si](CC)(CC)OC(C)(C)CCCOCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(O)CCCOCC1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 36.8 %

Procedure:
To a solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-17-(4-triethylsilyloxy-4-methylpentyloxymethyl)androsta-5,7,16-triene (278.7 mg, 0.367 mmol) in tetrahydrofuran (2 ml), was added a 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (3.3 ml, 3.3 mmol), followed by reflux under heating for 14 hours. The reaction solution was diluted with ethyl acetate, washed with 5% hydrochloric acid, a saturated aqueous sodium bicarbonate solution and saturated brine in that order, the organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove the solvent. The thus obtained residue was purified by column chromatography (dichloromethane:ethanol=10:1) and preparative thin layer chromatography (4 sheets (each 0.5 mm thickness), dichloromethane:ethanol=20:1, developed twice, and then dichloromethane:ethanol=10:1, developed twice) to give the titled compound (56.3 mg, 37%) as a colorless foam.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH:11]1[N:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14](=[O:24])[CH2:13]C1>>[CH3:11][N:15]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14]([CH2:13][N:1]1[CH2:9][CH2:8][N:7]([CH2:13][C:14](=[O:24])[N:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:11])[CH2:6][CH2:5][N:4]([CH2:13][C:14](=[O:24])[N:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:11])[CH2:3][CH2:2]1)=[O:24]
Reactant: C1CNCCNCCN1
Reactant: O=C1CCC(Br)N1OCc1ccccc1
Product: CN(OCc1ccccc1)C(=O)CN1CCN(CC(=O)N(C)OCc2ccccc2)CCN(CC(=O)N(C)OCc2ccccc2)CC1

Procedure:
From 1,4,7-triazacyclononane (1.1.3), 5-bromo-1-benzyloxy-2-pyrrolidone (1.2.6.11) and base. 1.3.5.15 N,N′,N″-Tris(1-oxy-2-pyrrolidone-5-yl)-1,4,7-triazacyclononane.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH2:22][CH2:23][CH3:24])[N:15]=2)[CH:3]=1.[NH3:25]>CO>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:25])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH2:22][CH2:23][CH3:24])[N:15]=2)[CH:3]=1
Reactant: CCCc1nc(Nc2cc(Cl)nnc2C(=O)OCC)ccc1OC
Reactant: N
Solvent: CO
Product: CCCc1nc(Nc2cc(Cl)nnc2C(N)=O)ccc1OC
Temperature: 50 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a mixture of ethyl 6-chloro-4-(5-methoxy-6-propylpyridin-2-ylamino)pyridazine-3-carboxylate (1.22 g, 3.48 mmol) in methanol (10 mL) was added 7 N ammonia in methanol (23.6 g, 30 mL, 210 mmol) and the mixture stirred at 50° C. in a sealed tube for 16 h. The mixture was concentrated in vacuo to give 6-chloro-4-(5-methoxy-6-propylpyridin-2-ylamino)pyridazine-3-carboxamide (1.113 g, 3.46 mmol, 100%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.72 (s, 1H), 8.89 (s, 1H), 8.77 (s, 1H), 8.13 (s, 1H), 7.47 (d, J=8.6 Hz, 1H), 7.01 (d, J=8.6 Hz, 1H), 3.81 (s, 3H), 2.74 (t, J=7.3 Hz, 2H), 1.75 (m, 2H), 0.97 (t, J=7.3 Hz, 3H); MS (EI/CI) m/z: 321.9 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N+]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)([O-])=O.[H-].[Na+]>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:17]1[CH:18]=[CH:19][C:14]([O:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
Following the general procedure of J. Polym. Sci., Polym. Chem. Ed. (1980), 18(10), 3069-80, 4-hydroxybenzoic acid, 4-nitro-1-(trifluoromethyl)benzene, and sodium hydride in DMF were heated at 130° C. to afford the title compound.