Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:17][CH2:18][CH2:19][O:20][CH3:21])[C:10]=2[O:12][CH2:13][CH2:14][O:15][CH3:16])[N:5]=[CH:4][C:3]=1[C:22]#[N:23].[CH3:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH2:33])[CH:28]=1)=[O:26]>>[C:25]([C:27]1[CH:28]=[C:29]([NH:33][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:17][CH2:18][CH2:19][O:20][CH3:21])[C:10]=3[O:12][CH2:13][CH2:14][O:15][CH3:16])[N:5]=[CH:4][C:3]=2[C:22]#[N:23])[CH:30]=[CH:31][CH:32]=1)(=[O:26])[CH3:24]
Reactant: COCCOc1ccc2ncc(C#N)c(Cl)c2c1OCCOC
Reactant: CC(=O)c1cccc(N)c1
Product: COCCOc1ccc2ncc(C#N)c(Nc3cccc(C(C)=O)c3)c2c1OCCOC

Procedure:
In the manner of Example 116, 4-Chloro-5,6-bis(2-methoxyethoxy)-3-quinolinecarbonitrile was reacted with 3-aminoacetophenone to give the title compound; recrystallized from ethanol to give off-white solid, mp 250-253 (dec).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=[C:2]=[O:3].[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:37]([NH2:39])=[S:38])([CH3:29])[CH3:28]>>[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:37]([NH:39][C:2]([NH:1][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[CH:18][CH:17]=3)[N:12]=2)[CH:6]=1)=[O:3])=[S:38])([CH3:29])[CH3:28]
Reactant: O=C=NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Reactant: CC(C)c1ccccc1NC(N)=S
Product: CC(C)c1ccccc1NC(=S)NC(=O)NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CB34) and 1-(2-isopropylphenyl)thiourea and isolated as an off-white solid (0.213 g, 47%).
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[C:21]([NH:23][C@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)=[O:22]>C(OCC)C.O>[NH3:5].[NH2:5][C:1]([CH2:2][CH2:3][N:26]1[CH2:27][CH2:28][C@H:24]([NH:23][C:21]([C@@H:16]2[CH2:17][CH2:18][CH2:19][CH2:20][N:15]2[C:7]2[O:6][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=2)=[O:22])[CH2:25]1)=[O:4]
Reactant: O=C(N[C@H]1CCNC1)[C@@H]1CCCCN1c1nc2ccccc2o1
Reactant: C=CC(N)=O
Solvent: O
Solvent: CCOCC
Product: N
Product: NC(=O)CCN1CC[C@H](NC(=O)[C@@H]2CCCCN2c2nc3ccccc3o2)C1
Yield: 83.9 %

Procedure:
Acrylamide (11.6 mg) was added to a solution of (2S)-1-(1,3-benzoxazol-2-yl)-N2-[(3S)-pyrrolidin-3-yl]-2-piperidinecarboxamide (51.6 mg) [see Example 4] in diethyl ether (3 ml). The reaction mixture was refluxed for 18 hours, after which time the ethereal layer was diluted with water. The aqueous layer was separated and then extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 93:7:1, changing to 90:10:1, dichloromethane:methanol:0.88 aqueous ammonia solution to afford (2S)-N2-[(3S)-1-(aminocarbonylethyl)pyrrolidin-3-yl]-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxamide (26.4 mg) as an off-white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH2:35][NH:36][CH2:37]2>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:36]5[CH2:37][CH:38]6[N:33]([CH3:32])[CH:34]([CH2:40][CH2:39]6)[CH2:35]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:30])[F:31])[CH:3]=1
Reactant: CN1C2CCC1CNC2
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN1C2CCC1CN(C1=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S1)C2

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 8-methyl-3,8-diaza-bicyclo[3.2.1]octane following General Procedure C.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5]1([O:11][CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:23])=[C:18]([CH:22]=1)[C:19](Cl)=[O:20].Cl>C(Cl)Cl.C(O)C>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:23])=[C:18]([C:19]([C:8]2[CH:9]=[CH:10][C:5]([O:11][CH3:12])=[CH:6][CH:7]=2)=[O:20])[CH:22]=1
Reactant: O=C(Cl)c1cc(Br)ccc1Cl
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Reaction time: 0.33 h
Yield: 71 %

Procedure:
Anhydrous aluminum trichloride (155 g, 1.16 mol) was suspended in methylene chloride (2050 mL) under a nitrogen protection. To the resulting mixture was added anisole (125 mL, 1.15 mol) in one batch at −5° C. After stirring for 20 mins, to the mixture was added dropwise a solution of 5-bromo-2-chlorobenzoyl chloride in methylene chloride (300 mL). The resulting mixture was reacted at −5° C. for 3 h. TLC indicated the completion of reaction. To the reaction mixture was poured 2N hydrochloric acid. The resulting mixture was separated into an organic phase and an aqueous phase. The organic phase was washed with a saturated sodium bicarbonate solution for two times and with a saturated sodium chloride solution, dried over anhydrous sodium sulphate, and evaporated by rotation to produce a solid. To the solid was added ethanol (150 mL), and the resulting mixture was washed and starched for 30 mins and filtered. The filter cake was oven dried to produce 265 g of a product in a yield of 71%.
Reaction SMILES: [Br-].[Li+].[CH2:3]([Mg]Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:12]([O:19][C:20]([NH:22][C@@H:23]([CH2:28][C:29](Cl)=[O:30])[C:24]([O:26][CH3:27])=[O:25])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH2:12]([O:19][C:20]([NH:22][C@@H:23]([CH2:28][C:29](=[O:30])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:24]([O:26][CH3:27])=[O:25])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)[C@H](CC(=O)Cl)NC(=O)OCc1ccccc1
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(=O)Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.1 %

Procedure:
To a suspension of copper(I) bromide-dimethyl sulfide complex (2.6 g, 12.72 mmol, 1.2 eq.) in dry THF was added a solution of lithium bromide (2.2 g, 25.44 mmol, 2.4 eq.) in dry THF. The mixture was stirred at room temperature (RT) for 20 min, and then was cooled to −78° C. A solution of benzyl magnesium chloride (13 mL, 12.72 mmol, 1.2 eq.) followed by a solution of (S)-methyl 2-(benzyloxycarbonylamino)-4-chloro-4-oxobutanoate (3.16 g, 10.6 mmol, 1 eq.) in dry THF were added. The mixture was stirred at −78° C. for 30 min and then was quenched with sat. ammonium chloride. The mixture was extracted with ethyl acetate. The organic layers were dried over magnesium sulfate and then concentrated in vacuo. The residue was purifed by flash column (1:1 ethyl acetate:hexane) to give 2 g of (S)-methyl 2-(benzyloxycarbonylamino)-4-oxo-5-phenylpentanoate.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:21]=[C:22]([F:26])[CH:23]=[CH:24][CH:25]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:26][C:22]1[CH:21]=[C:20]([N:13]2[C:14]3[C:10](=[CH:9][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12]2)[CH:25]=[CH:24][CH:23]=1
Reactant: Fc1cccc(Br)c1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1cccc(-n2ccc3ccccc32)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 89 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) 1H-indole (3, 2.43 g, 10 mmol), and 3-bromofluorobenzene (1.09 mL, 10 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes-EtOAc (9:1) to provide 1.88 g (88%) of the product 4-(3-fluoro-phenyl)-1H-indole as a colorless syrup.
Reaction SMILES: Cl.C(C1ON=C(N[C:12]([C@@H:14]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15]2)=[O:13])C=1)(C)(C)C.Br[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-:30].[K+].[K+]>CC(N(C)C)=O.CCOC(C)=O.[Cu]I>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([N:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C@H:14]2[C:12]([OH:13])=[O:30])=[CH:23][CH:24]=1
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCCN2)no1
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc(Br)cc1
Agent: [Cu]I
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=C(O)[C@@H]1CCCCCN1c1ccc(Cl)cc1

Procedure:
A solution of (S)-perhydro-azepine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide hydrochloride (prepared according to Method T, step 6) (0.60 g, 4.20 mmol), 1-Bromo-4-chloro-benzene (0.80 g, 4.20 mmol), potassium carbonate (0.87 g, 6.29 mmol) and copper (I) iodide (0.08 g, 0.42 mmol) in DMA (10.0 mL), is heated at 100° C. in a sealed tube for 48 hours. The reaction mixture is diluted with EtOAc and washed with water. The water phase is acidified with 1N HCl and then extracted with EtOAc. The organic layers are combined, and after drying over anhydrous Na2SO4, removal of the solvent affords the title product that is used in the next step without any further purification. m/z 254 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[C:21]1([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH2:30][NH2:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:27]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:34]=[CH:33][CH:32]=[C:29]([CH2:30][NH:31][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:6]([Cl:20])=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:16])[CH:28]=1
Reactant: NCc1cccc(-c2ccccc2)c1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCc1cccc(-c2ccccc2)c1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (100 mg, 0.28 mmol) and 3-phenyl benzylamine (55 mg, 0.32 mmol). The title compound was obtained as a solid (24 mg, 17% yield). 1H NMR (400 MHz, CDCl3) δ: 8.74 (2H, m), 7.86 (1H, s), 7.55 (3H, m), 7.53 (1H, m), 7.46 (3H, m), 7.38 (1H, m), 7.26 (1H, m), 6.27 (1H, m), 4.63 (2H, m). MS m/z: 514.07, 516.04 [M+H]+.
Reaction SMILES: [CH:1]1([N:6]([C:16]2[N:24]=[CH:23][N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][N:20]3[CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30])[CH2:7][C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-:35].[NH4+]>CN(C)C=O>[ClH:35].[CH:1]1([N:6]([C:16]2[N:24]=[CH:23][N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][N:20]3[CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[NH:33][N:32]=[N:31][N:30]=2)[CH2:7][C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [Cl-]
Reactant: Cc1ccc(C)c(CN(c2ncnc3c2ncn3CCCCC#N)C2CCCC2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C)c(CN(c2ncnc3c2ncn3CCCCc2nnn[nH]2)C2CCCC2)c1
Product: Cl
Reaction time: 6 h
Yield: 38 %

Procedure:
A mixture of 3.8 g. (9.4 mmole) of the compound of Example 18, 1.9 g. sodium azide, 1.5 g. ammonium chloride and 30 ml. dimethylformamide is heated to 125° C. for 3 days. A further 1.2 g. sodium azide and 1.0 g. ammonium chloride are added thereto, stirring is continued for 6 hours at 125° C., the reaction mixture is cooled and evaporated and the residue is taken up in ethyl acetate, washed with water, extracted with 1N aqueous sodium hydroxide solution and the aqueous phase is acidified with hydrochloric acid. After extraction with dichloromethane, evaporation and trituration of the residue with diethyl ether, there is obtained 1.7 g. of the title compound (38% of theory); m.p. 140°-142° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:12]=[CH:13][C:14]([OH:16])=O.[NH2:22][C:23]1[CH:35]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]=[CH:32][C:24]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:13]/[C:14]([NH:22][C:23]2[CH:35]=[C:34]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:33]=[CH:32][C:24]=2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:16])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(/C=C/C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)cc1OC
Reaction time: 1 h

Procedure:
1.3 mL of methylene chloride, 1.3 μL of N,N-dimethylformamide and 0.031 mL of oxalyl chloride were added to 69 mg of 3,4-dimethoxycinnamic acid at room temperature sequentially and stirred at the same temperature for 1 hour. Tine reaction mixture was added to a mixed solution of 54 mg of tert-butyl 2-amino-4-phenylbenzoate, 3.7 mL of methylene chloride and 0.22 mL of triethylamine and stirred at room temperature for 2 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane; ethyl acetate=4:1] to obtain (E)-tert-butyl 2-(3-(3,4-dimethoxyphenyl)acrylamido)-4-phenylbenzoate.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C[O:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C)[C:8]=1[CH:9]=[O:10]>ClCCl>[OH:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:8]=1[CH:9]=[O:10]
Reactant: COc1cccc(OC)c1C=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=Cc1c(O)cccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
Into a 3000-mL three neck round-bottom flask, was placed a solution of AlCl3 (240 g, 1.80 mol, 3.00 equiv) in dichloromethane (1200 mL). A solution of 2,6-dimethoxybenzaldehyde (100 g, 601.78 mmol, 1.00 equiv) in dichloromethane (800 ml) was added to the reaction mixture dropwise at 0° C. The resulting solution was stirred overnight at room temperature, and then it was quenched with 200 mL of diluted HCl (2M). The resulting solution was extracted with 2×200 mL of dichloromethane. The combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:200-1:50) as eluent to furnish 40 g (48%) of 2,6-dihydroxybenzaldehyde as a yellow solid.
Reaction SMILES: C[O:2][C:3]([P:5]([O:11][O:12][CH2:13][CH3:14])([O:7][O:8][CH2:9][CH3:10])=[O:6])=O.O.[NH2:16][NH2:17]>C(O)C>[CH2:9]([O:8][O:7][P:5]([C:3]([NH:16][NH2:17])=[O:2])([O:11][O:12][CH2:13][CH3:14])=[O:6])[CH3:10]
Reactant: NN
Reactant: CCOOP(=O)(OOCC)C(=O)OC
Solvent: O
Solvent: CCO
Product: CCOOP(=O)(OOCC)C(=O)NN
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
19.6 parts by weight of diethoxyphosphonoformic acid methyl ester are diluted with 10 parts by volume of ethanol, and a solution of 5.0 parts by weight of hydrazine hydrate in 10 parts by volume of ethanol is added at +10 to +20° C. The mixture is stirred at room temperature for 8 hours, the solvent is moved in vacuo and 19.4 parts by weight (yield 99%) of crude diethoxyphosphonoformic acid hydrazide, which is further processed without purification, are obtained.
Reaction SMILES: C(C1C=C(C2O[N:12]=[C:11]([C:14]3[CH:29]=[C:28]([CH3:30])[C:17]([O:18][CH2:19][CH:20]([OH:27])[CH2:21][NH:22][C:23](=[O:26])[CH2:24][OH:25])=[C:16]([CH3:31])[CH:15]=3)[N:10]=2)C=CC=1)=O.[CH:32]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=O)=[CH:36][C:35]=1[CH3:43])=[O:33].OCC(NCC(O)COC1C(C)=CC(C(=N)NO)=CC=1C)=O>>[CH:32]([C:34]1[CH:42]=[CH:41][C:37]([C:38]2[O:40][N:12]=[C:11]([C:14]3[CH:15]=[C:16]([CH3:31])[C:17]([O:18][CH2:19][CH:20]([OH:27])[CH2:21][NH:22][C:23](=[O:26])[CH2:24][OH:25])=[C:28]([CH3:30])[CH:29]=3)[N:10]=2)=[CH:36][C:35]=1[CH3:43])=[O:33]
Reactant: Cc1cc(C(=O)O)ccc1C=O
Reactant: Cc1cc(-c2noc(-c3cccc(C=O)c3)n2)cc(C)c1OCC(O)CNC(=O)CO
Agent: Cc1cc(C(=N)NO)cc(C)c1OCC(O)CNC(=O)CO
Product: Cc1cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)ccc1C=O

Procedure:
The title compound was prepared in analogy to rac-N-(3-{4-[5-(3-formyl-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide, starting from 4-formyl-3-methyl benzoic acid and rac-2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[C:10]([C:13]([OH:15])=[O:14])[CH:9]=[CH:8]2.C(N(CC)CC)C.[C:23]([O:27][C:28](ON=C(C1C=CC=CC=1)C#N)=[O:29])([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[C:28]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[C:10]([C:13]([OH:15])=[O:14])[CH:9]=[CH:8]2)([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29]
Reactant: NCc1cccc2ccc(C(=O)O)cc12
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1cccc2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 61.8 %

Procedure:
Part D--A solution of 8-aminomethyl-2-naphthoic acid (0.50 g, 0.03025 mol) and triethylamine (0.038 mL, 0.028 30 g, 0.000275 mol) in aqueous tetrahydrofuran (50%, 5 mL) was added, portionwise as a solid, 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (0.068 g, 0.000275 mol). All was stirred at ambient temperature over 5 hours. The solution was concentrated to half volume and extracted with diethylether. The aqueous layer was then acidified to a pH of 1.0 using hydrochloric acid (1N) and then extraced with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give the title compound, N-(BOC)-8-aminomethyl-2-naphthoic acid (0.050 g, 0.00017 mol) as a white solid. mp=190-191° C.; 1H NMR (DMSO) d 13.1 (bs, 1H), 8.8 (s, 1H), 8.0 (q, 2H, J=7.9 Hz), 7.9 (d, 1H, J=8.1 Hz), 7.6 (t, 1H, J=7.5 Hz), 7.65-7.55 (m, 2H), 4.6 (d, 2H, J=5.5 Hz), 1.4 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.CCCP(=O)=O>O1CCCC1.C(OCC)(=O)C>[C:18]1([C:16]2[N:17]=[C:11]3[CH:10]=[C:9]([NH:8][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][C:5]=4[C:25]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:26])=[O:24])[CH:14]=[CH:13][N:12]3[N:15]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C1CCNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: CCCP(=O)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCCC2)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 20.9 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), pyrrolidine (228 μl, 2.76 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7 ml) is stirred for 3 hours at 70° C. The mixture is diluted with ethyl acetate and washed with sat. aqueous sodium hydrogencarbonate solution and brine. The organic layer is separated, dried with magnesium sulfate and the solvent is evaporated. The residue (65 mg white solid) is triturated with diethylether affording 2-methyl-4-(pyrrolidine-1-carbonyl)-2H-pyrazole-3-carboxylic acid (2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (24 mg, 20.9%) as a white solid. mp.: 210-215° C. MS: m/z=416.2 (M+H+).
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]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([CH:58]([CH3:60])[CH3:59])([CH:55]([CH3:57])[CH3:56])[CH:52]([CH3:54])[CH3:53])[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6](O)[CH2:5][C:4]1=[O:66])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[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]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([CH:55]([CH3:57])[CH3:56])([CH:52]([CH3:54])[CH3:53])[CH:58]([CH3:60])[CH3:59])[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]=[CH:5][C:4]1=[O:66])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C(C)C)(C(C)C)C(C)C)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C(C)C)(C(C)C)C(C)C)C(OC)C3)C(C)C=CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 58.2 %

Procedure:
A solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-triisopropylsilyloxy-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 (150 mg, 0.16 mmol) in MeCl2 (5.0 ml) containing triethylamine (92.2 mg, 0.91 mmol) and 4-dimethylaminopyridine (61 mg, 0.49 mmol) at 0° C., was treated with methanesulfonyl chloride (69.6 mg, 0.61 mmol). After stirring at RT for 2.5 hr, the reaction mixture was diluted with MeCl2 (10 ml) and water. The aqueous layer was separated and extracted with additional MeCl2. After drying over magnesium sulfate, the solvent was removed in vacuo. The residue was chromatographed over SiO2 (10 g). Elution with n-hexane/ethyl acetate (3:1) yielded 17-ethyl-1-hydroxy-12-[2'-(4"-triisopropylsilyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos- 14,18-diene-2,3,10,16-tetraone (86.6 mg, 58%). Mass Spec: C52H89NO11Si (930.36) FAB+Li:1090 (M+ +Li+MATRIX) 936 (M+Li).