Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:20]([CH3:22])([CH3:21])[O:19][C:18]([NH:23][C@H:24]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[N:17][S:16]2(=[O:42])=[O:41])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.C(N(CC)CC)C>CO.[Pd]>[Si:28]([O:27][CH2:26][CH2:25][C@H:24]([NH:23][C:18]1[O:19][C:20]([CH3:22])([CH3:21])[CH:15]([C:11]2[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=2)[S:16](=[O:42])(=[O:41])[N:17]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([C:31]([CH3:34])([CH3:32])[CH3:33])([CH3:30])[CH3:29]
Reactant: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2)=NS(=O)(=O)C1c1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2)=NS(=O)(=O)C1c1cccc(O)c1
Reaction time: 3.75 h
Yield: 87.1 %

Procedure:
Under inert gas, 1.03 g [5-(3-benzyloxyphenyl)-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-2-yl]-[(S)-3-(tert-butyldimethylsilanyloxy)-1-phenylpropyl]amine were initially charged in 20 ml of methanol and, with addition of 0.24 ml of triethylamine and 359 mg of 10% Pd/C, stirred under a hydrogen atmosphere for 3.75 hours. The completeness of the conversion was checked by LCMS, and the reaction was once again admixed with 359 mg of 10% Pd/C and stirred under a hydrogen atmosphere for a further 16 hours. According to LCMS, the detachment of the benzyl protecting group remained incomplete. After filtration to remove the solid residues, the filtrate was admixed again with 359 mg of 10% Pd/C. After stirring under a hydrogen atmosphere for 5 h, another 359 mg of 10% Pd/C were added and, after a further 2 hours, the reaction was found to be complete by checking with LCMS. After filtration to remove the catalyst residues, the filtrate was freed of the solvent under reduced pressure. This gave the product (764 mg) with a molecular weight of 518.8 g/mol (C26H38N2O5SSi); MS (ESI): m/e=519 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[NH3:11]>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:11])=[O:6]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: N
Solvent: c1ccccc1
Product: NC(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a stirred solution of m-fluorobenzoyl chloride (15.9 g, 0.10 mole) in benzene (200 ml) at 5° C. is bubbled anhydrous ammonia gas for 30 minutes. A white solid precipitates and the reaction mixture is allowed to stir at room temperature overnight. The white solid is removed by filtration and then triturated with water. The solid is dried to afford 10 g of m-fluoroenzamide, mp 130°-33° C. Elemental analysis calculated. for C7H6FNO: C, 60.40; H, 4.34; F, 13.66; N, 10.08. Found: C, 59.97; H, 4.43; F, 13.86; N, 10.39.
Reaction SMILES: [O:1]1[CH2:5]CC[CH2:2]1.[Br:6][C:7]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([Br:17])[NH:9][N:8]=1.C(N(CC)C(C)C)(C)C.COCCl>O>[Br:17][C:10]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([Br:6])[N:8]([CH2:2][O:1][CH3:5])[N:9]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)c1c(Br)n[nH]c1Br
Agent: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1c(Br)nn(COC)c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a tetrahydrofuran (262 mL) solution of ethyl 3,5-dibromo-1H-pyrazole-4-carboxylate (20.93 g, 703 mmol) was added N,N-diisopropylethylamine (24.5 mL, 141 mmol), and chloromethyl methyl ether (6.42 mL, 84.3 mmol) was added dropwise while cooling on ice, and stirred at room temperature for one hour. After the reaction was completed, water was added while cooling on ice, the reaction mixture was extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane/ethyl acetate=3/1) to obtain the title compound (23.4 g, 68.5 mmol).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1CC#N.[OH-:13].[Na+].[CH2:15]([OH:17])[CH3:16]>>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:16][C:15]([OH:13])=[O:17]
Reactant: CCO
Reactant: [OH-]
Reactant: N#CCc1nc2ccccc2[nH]1
Agent: [Na+]
Product: O=C(O)Cc1nc2ccccc2[nH]1
Yield: 95 %

Procedure:
A mixture of 2-benzimidazolylacetonitrile (5.58 g, 35.5 mmol) and 4M sodium hydroxide solution (25 ml) in ethanol (100 ml) was heated at reflux for 8 h. The reaction mixture was concentrated in vacuo, the residue dissolved in water (100 ml), and extracted with ethyl acetate (2×100 ml). The aqueous phase was acidified with dilute hydrochloric acid to pH 4-5, the precipitated solid was filtered, washed with water, and dried to give the title compound (5.97 g, 95%) as a buff solid; δH (DMSO-d6) 2.47 (2H, s, CH2CO2H), 7.09 (2H, m, ArH), 7.39 (1H, brs, ArH), 7.48 (1H, brs, ArH), and 12.13 (1H, brs, NH).
Reaction SMILES: [Cl:1][C:2]1[C:28]([Cl:29])=[CH:27][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:19][N:18]([C:20](OC(C)(C)C)=[O:21])[CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([O:30][CH3:31])[CH:3]=1.[CH2:32](N(CC)CC)[CH3:33].C(Cl)(=O)C=C>Cl.CO.C(Cl)Cl>[C:20]([N:18]1[CH2:17][CH:16]([N:13]2[CH2:14][CH2:15][CH:10]([C:8]([NH:7][CH2:6][C:5]3[CH:27]=[C:28]([Cl:29])[C:2]([Cl:1])=[CH:3][C:4]=3[O:30][CH3:31])=[O:9])[CH2:11][CH2:12]2)[CH2:19]1)(=[O:21])[CH:32]=[CH2:33]
Reactant: CCN(CC)CC
Reactant: COc1cc(Cl)c(Cl)cc1CNC(=O)C1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Agent: C=CC(=O)Cl
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: C=CC(=O)N1CC(N2CCC(C(=O)NCc3cc(Cl)c(Cl)cc3OC)CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A mixture of tert-butyl 3-(4-(4,5-dichloro-2-methoxybenzylcarbamoyl)piperidin-1-yl)azetidine-1-carboxylate (210 mg, 0.44 mmol) in HCl/MeOH (10 mL, 2.86 M) was stirred at room temperature for 1 h. The mixture was concentrated in vacuo to yield the crude residue. The residue was dissolved in DCM (5 mL), triethylamine (0.5 mL) and acryloyl chloride (40 mg, 0.43 mmol) were added. The reaction mixture was stirred at room temperature for 30 min and then partitioned between DCM and water. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (150 mg, 82% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10]C)=[CH:6][C:4]=1[NH2:5].[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22]C)C(O)=O>>[Cl:12][C:13]1[CH:14]=[C:15]([C:1]2[O:2][C:3]3[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:4]=3[N:5]=2)[CH:19]=[CH:20][C:21]=1[OH:22]
Reactant: COc1ccc(C(=O)O)cc1Cl
Reactant: COc1ccc(OC)c(N)c1
Product: Oc1ccc2oc(-c3ccc(O)c(Cl)c3)nc2c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,5-dimethoxyaniline, and 3-chloro-4-methoxybenzoic acid and was obtained as a white solid, m.p. 254–256° C.; MS m/e 260 (M−H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8]O)[CH:2]=[CH2:3].S(Cl)([Cl:15])=O.CN(C=O)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][Cl:15])[CH:2]=[CH2:3]
Reactant: O=S(Cl)Cl
Reactant: C=CCOc1cccc(CO)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCOc1cccc(CCl)c1

Procedure:
To a solution of 3-allyloxybenzyl alcohol (7.2 g) in dichloromethane (100 ml) at 0° C. was added thionyl chloride (4.8 ml) in dichloromethane dropwise and a drop of DMF and the mixture stirred at ambient temperature for 1.5 hours, and poured into cold sodium bicarbonate solution. The organic layer was washed with sodium bicarbonate (2×100 ml), dried (magnesium sulphate), filtered and evaporated to give 3-allyloxybenzyl chloride (8.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Cl[C:16]1[N:17]=[CH:18][C:19]2[C:25](=[O:26])[C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][N:22]([CH2:32][CH3:33])[C:20]=2[N:21]=1>>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:16]3[N:17]=[CH:18][C:19]4[C:25](=[O:26])[C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][N:22]([CH2:32][CH3:33])[C:20]=4[N:21]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(CC)c2nc(Cl)ncc2c1=O
Reactant: Clc1ccc(CN2CCNCC2)cc1
Product: CCOC(=O)c1cn(CC)c2nc(N3CCN(Cc4ccc(Cl)cc4)CC3)ncc2c1=O
Yield: 74 %

Procedure:
Condensation of 1-p-chlorobenzyl-piperazine with 2-chloro-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido-(2,3-d)pyrimidine, as described in Example VII, gives, in a yield of 74%, 2-(4'-p-chlorobenzyl-piperazino)-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine; melting point 150°C, after recrystallisation from ethyl acetate.
Reaction SMILES: [I-:1].[Na+].[C:3]([O:6][C:7]1([CH2:16]Cl)[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH2:8]1)(=[O:5])[OH:4]>CC(C)=O>[C:3]([O:6][C:7]1([CH2:16][I:1])[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH2:8]1)(=[O:5])[OH:4]
Reactant: O=C(O)OC1(CCl)C=CC([N+](=O)[O-])=CC1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O)OC1(CI)C=CC([N+](=O)[O-])=CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
5 g of sodium iodide (Aldrich) is added to a solution of 1-chloromethyl carbonate (3) in 50 ml of acetone (Aldrich), and the reaction mixture is stirred at 50° C. for 24 h. After stirring overnight, the solvent is evaporated and the residue is redissolved in diethyl ether (Fisher). The ether layer is washed successively with 10% aqueous sodium sulfite and then water, and dried over anhydrous Na2SO4. The ether layer is separated and evaporated to give 1-iodomethyl p-nitrophenol carbonate (4) as a yellow oil which is confirmed by NMR. 1H-NMR (CDCl3): 6.03 (2H, s), 7.39 (2H, d, J=9 Hz), 8.24 (2H, d, J=9 Hz).
Reaction SMILES: [OH-].[Na+].[CH:3]([C:5]1[CH:20]=[C:19]([CH3:21])[C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[C:7]([CH3:22])[CH:6]=1)=[O:4].C(Cl)(Cl)Cl.CO>CO>[CH:3]([C:5]1[CH:20]=[C:19]([CH3:21])[C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[C:7]([CH3:22])[CH:6]=1)=[O:4]
Reactant: CCOC(=O)CCCCOc1c(C)cc(C=O)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1cc(C=O)cc(C)c1OCCCCC(=O)O
Yield: 101.9 %

Procedure:
2 N aqueous NaOH (30 mL) was added to ethyl 5-(4-formyl-2,6-dimethylphenoxy)valerate (4.0 g, mw 278.4, 14 mmol; prepared as in Example 18) dissolved in methanol (40 mL) and that the solution stirred at 25° C. for 1 hour, at which point TLC (CHCl3-methanol, 99:1) indicated the reaction was complete. Methanol was removed under reduced pressure and the reaction diluted with water (150 mL), washed with ethyl acetate (2×25 mL, discarded), acidified to pH 4 with 6 N aqueous HCl, and extracted with ethyl acetate (3×30 mL). The organic extract was washed with brine (2×75 mL), dried over Na2SO4, filtered and concentrated to yield 3.57 g (99%) of an amber oil. A portion of the oil was purified by flash chromatography on silica (CHCl3-methanol, 45:1) to provide NMR and TLC (Rf origin) pure title product:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.CN(C=O)C.[H-].[Na+].[CH3:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][O:26][CH2:27]Cl>>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:30])([CH3:29])[CH3:22])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.0 g, 0.010 mol) and DMF (30.0 mL, 0.387 mol) was cooled to 0° C. Sodium hydride (320 mg, 0.013 mol) (60% in oil) was added and the mixture was stirred for 10 min. [β-(Trimethylsilyl)ethoxy]methyl chloride (2.4 mL, 0.013 mol) was added and the resulting mixture was stirred for 20 min at 0° C. and 2 h at room temperature. The reaction was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrazole as a crude material. LC/MS (M+H)+: 325, 1H NMR (CDCl3) δ 7.85 (s, 1H), 7.80 (s, 1H), 5.45 (s, 2H), 3.55 (t, 2H), 1.35 (s, 12H), 0.95 (t, 2H), 0.0 (s, 9H).
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:54]([OH:56])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].[N:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[N-:63][CH3:64].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:54]([OH:56])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:37])[CH3:38])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[N-:63][CH3:64]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)C(C)C)C(=O)O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[N-]c1ccccn1
Agent: On1nnc2ccccc21
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(C)C)C(=O)O

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 130 mg of Z-Phe-His-OH, 100 mg of H-Leu-Val-Ile-2-pyridyl-methyl amide, 46 mg of HOBt and 62 mg of DCCI, the title compound is obtained after flash chromatography (65 g of silica gel 60, 40-63 μm, eluant system B7). Rf (B7)=0.32.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][NH:7][C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.S(O)(O)(=O)=O.Cl[C:26]1[NH:27][CH2:28][CH2:29][N:30]=1>CC(O)C>[NH:30]1[CH2:29][CH2:28][N:27]=[C:26]1[NH:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][NH:7][C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: ClC1=NCCN1
Reactant: COc1ccc(C(=O)NCc2ccc(N)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: COc1ccc(C(=O)NCc2ccc(NC3=NCCN3)cc2)cc1
Temperature: 0 °C
Yield: 61.4 %

Procedure:
A mixture of N-(4-Aminobenzyl)-4-methoxybenzamide (15 g, 58.4 mmol), 2-chloroimidazoline sulfate (15.2 g, 74 mmol) and 2-propanol (380 mL) was heated at reflux for 2.5 h under N2. The mixture was cooled to 0° C. and filtered, and the filtrate was concentrated to dryness. To the resulting residue 10% aqueous sodium hydroxide was added to reach pH 13–14. The resulting suspension was filtered, and the solid N-[4-(4,5-dihydro-1H-imidazol-2-ylamino)-benzyl]-4-methoxybenzamide was crystallized from dichloromethane. Weight 11.9 g (61.4% yield). mp 160.3–160.6° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][C:24]([OH:26])=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:11]([N+:20]([O-:22])=[O:21])=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:19])=[CH:13]2.[C:27](OCC)(=O)[CH3:28]>C(O)C.S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:11]([N+:20]([O-:22])=[O:21])=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:19])=[CH:13]2
Reactant: CCOC(C)=O
Reactant: COc1cc(CC(=O)O)ccc1Oc1ccc2[nH]c(C)cc2c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)Cc1ccc(Oc2ccc3[nH]c(C)cc3c2[N+](=O)[O-])c(OC)c1
Reaction time: 16 h

Procedure:
A solution of 1.2 (1.65 g, 4.63 mmol) in ethanol (20 mL) with several drops of concentrated sulfuric acid was heated to reflux overnight. After 16 h, HPLC indicated that no 1.2 remained and the ethanol was removed in vacuo on a rotary evaporator. The concentrate was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The separated organic layer was washed with water then brine, stirred over magnesium sulfate, filtered and the filtrate concentrated in vacuo on a rotary evaporator to afford a dark oil. The desired product was isolated by trituration of the residue with ethyl acetate to yield the desired product as an orange solid. The filtrate from trituration was chromatographed on silica gel, eluting with an ethyl acetate/hexane gradient, to afford additional product. LC-MS ESI (pos.) m/z: 385.0 (M+H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[CH3:22][O:23][C:24]1[CH:30]=[C:29]([N:31]2[CH2:36][CH2:35][P:34]([CH3:38])(=[O:37])[CH2:33][CH2:32]2)[CH:28]=[CH:27][C:25]=1[NH2:26].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:26][C:25]2[CH:27]=[CH:28][C:29]([N:31]3[CH2:32][CH2:33][P:34]([CH3:38])(=[O:37])[CH2:35][CH2:36]3)=[CH:30][C:24]=2[O:23][CH3:22])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: COc1cc(N2CCP(C)(=O)CC2)ccc1N
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(N2CCP(C)(=O)CC2)ccc1Nc1nnc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:9][C:10]([NH:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[S:11])=[CH:4][C:3]=1[N+:25]([O-:27])=[O:26].IC.[C:30](=O)([O-])[O-].[K+].[K+]>CC(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:9][C:10]([S:11][CH3:30])=[N:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[CH:4][C:3]=1[N+:25]([O-:27])=[O:26]
Reactant: COC(CNC(=S)NC(c1ccccc1)c1ccc(N)c([N+](=O)[O-])c1)OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(CN=C(NC(c1ccccc1)c1ccc(N)c([N+](=O)[O-])c1)SC)OC
Temperature: 25 °C
Yield: 100 %

Procedure:
(a-3) A mixture of 22.3 parts of (+)-N-[(4-amino-3-nitrophenyl)phenylmethyl]-N'-(2,2-dimethoxyethyl)thiourea, 10.2 parts of iodomethane, 11.8 parts of potassium carbonate and 240 parts of 2-propanone was stirred over weekend at room temperature. The reaction mixture was filtered over diatomaceous earth and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the elunet was evaporated, yielding 23 parts (100%) of (+)-methyl N-[(4-amino-3-nitrophenyl)phenylmethyl]-N'-(2,2-dimethoxyethyl)carbamimidothioate as a residue (141).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:71])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:60]=[CH:59][C:58]4[C:53](=[CH:54][CH:55]=[C:56]([O:61][Si](C(C)(C)C)(C)C)[CH:57]=4)[CH:52]=3)[CH:46]([O:69][CH3:70])[CH2:45]2)[CH:7]([CH3:72])[CH:6]([OH:73])[CH2:5][C:4]1=[O:74])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:71])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:60]=[CH:59][C:58]4[C:53](=[CH:54][CH:55]=[C:56]([OH:61])[CH:57]=4)[CH:52]=3)[CH:46]([O:69][CH3:70])[CH2:45]2)[CH:7]([CH3:72])[CH:6]([OH:73])[CH2:5][C:4]1=[O:74])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5cc(O[Si](C)(C)C(C)(C)C)ccc5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5cc(O)ccc5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 4 h
Yield: 67.6 %

Procedure:
To a stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(6"'-tert-butyldimethylsilyloxynaphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (73 mg, 0.07 mmol) in CH2Cl2 (2 mL) was added a solution of p-toluenesulfonic acid in methanol (2 mL, 10% solution). The flask was capped and the mixture stirred 4 hours. The reaction was quenched with saturated aqueous NaHCO3 and extracted 4× with CH2Cl2. The organic extracts were combined and dried over anhydrous Na2SO4. The mixture was filtered and concentrated in vacuo. The product was isolated by preparative TLC on silica gel (eluted with 2:1 hexanes/acetone) to afford 44.2 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(6"'-hydroxynaphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (Rf =0.23). (1H NMR and mass spectral analysis were consistent with the desired structure).
Reaction SMILES: NCCC(NC1C=C2C(=CC=1)N=CN=C2NC1C=CC(OCC2C=CC=C(F)C=2)=C(Cl)C=1)=O.C(OC(=O)[NH:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45](=[O:74])[NH:46][C:47]1[CH:48]=[C:49]2[C:54](=[CH:55][CH:56]=1)[N:53]=[CH:52][N:51]=[C:50]2[NH:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([F:72])[CH:67]=2)=[C:60]([Cl:73])[CH:59]=1)(C)(C)C>>[Cl:73][C:60]1[CH:59]=[C:58]([NH:57][C:50]2[C:49]3[C:54](=[CH:55][CH:56]=[C:47]([NH:46][C:45](=[O:74])[CH2:44][CH2:43][CH2:42][CH2:41][NH2:40])[CH:48]=3)[N:53]=[CH:52][N:51]=2)[CH:63]=[CH:62][C:61]=1[O:64][CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[C:68]([F:72])[CH:67]=1
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Agent: NCCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Product: NCCCCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Yield: 97.4 %

Procedure:
The procedure of (20-1) of Example 20 was repeated except for using 0.42 g of the compound obtained in Example 114 instead of the compound obtained in Example 19 to obtain the title compound (0.34 g, 98%).