Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[B:6](OC(C)C)([O:11]C(C)C)[O:7]C(C)C.C(=O)=O.CC(C)=O.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]=[CH2:34])=[CH:29][N:28]=1.Cl>C1COCC1.FC1C=CC(C=C)=CN=1>[F:26][C:27]1[C:32]([B:6]([OH:11])[OH:7])=[CH:31][C:30]([CH:33]=[CH2:34])=[CH:29][N:28]=1
Reactant: C=Cc1ccc(F)nc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: C=Cc1cnc(F)c(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 639.6 %

Procedure:
2-Fluoro-5-vinylpyridine (64.8 mg, 0.526 mmol) was dissolved in THF (2.0 mL) and the reaction flask was cooled in a dry ice/acetone bath. Then, n-butyllithium (1.6 M solution in hexanes, 0.40 mL, 0.64 mmol) was added via syringe dropwise, turning the solution red. The reaction was stirred at −78° C. for 45 minutes, and then triisopropyl borate (Aldrich, St. Louis, Mo. 98+%, 0.190 mL, 0.826 mmol) was added, and the reaction was allowed to slowly warm up to room temperature (the dry ice/acetone bath was removed after 80 minutes). The reaction was stirred at room temperature for 45 minutes, and then quenched with water. The layers were separated, and the organic phase was discarded. The aqueous phase was treated with 5 N HCl to lower the pH from 9 to 4. Then, the aqueous phase was extracted with 10:1 DCM/MeOH, and the organic extracts were combined and set aside. In a separate flask, 2-fluoro-5-vinylpyridine (4.15 g, 33.7 mmol) was decanted from a solid precipitate, which was washed with THF. The 2-fluoro-5-vinylpyridine was dissolved in THF (120 mL), and the reaction flask was cooled in a dry ice/acetone bath under nitrogen. Then, n-butyllithium solution (1.6 M in hexanes, 25.5 mL, 40.8 mmol) was added via syringe, turning the yellow solution into a deep red color. The reaction was stirred at −78° C. for 50 minutes, and then triisopropyl borate (Aldrich, St. Louis, Mo. 98+%, 11.5 mL, 50.0 mmol) was added via syringe, and the reaction was allowed to warm to room temperature (after 90 minutes, the dry ice/acetone bath was removed). Almost 5 hours after the addition of triisopropyl borate, the reaction was quenched with water (125 ml), slowly at first. The biphasic solution was stirred for 15 minutes, and then the layers were separated. The organic phase extracted one time with saturated sodium bicarbonate. This sodium bicarbonate washing was discarded. The organic phase was extracted two times with 1 N NaOH (60 mL and then 50 mL). These aqueous extractions were combined, treated with concentrated HCl to lower the pH to 4, and extracted with 10:1 DCM/MeOH. These organic extracts did not contain product, so they were discarded, along with these second aqueous extractions. The original aqueous phase (from the initial phase separation after quenching the reaction with water) was treated with 5 N HCl to lower the pH to around 3-4. This aqueous phase was extracted with 10:1 DCM/MeOH. These organic extracts were combined with the organic extracts from the first reaction, concentrated, and dried under high vacuum at room temperature to afford 2-fluoro-5-vinylpyridin-3-ylboronic acid (882 mg, 61% purity, 11% yield over 2 steps). MS (ESI pos. ion) m/z 168 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH3:10]>>[F:9][C:5]1[C:6]([NH2:10])=[N:7][C:2](=[O:1])[NH:3][CH:4]=1
Reactant: Oc1ncc(F)c(Cl)n1
Reactant: N
Product: Nc1nc(=O)[nH]cc1F

Procedure:
A process for the preparation of 5-fluorocytosine comprising reacting 2,5-difluoro-4-chloropyrimidine with a proton acid in the presence of water to yield 2-hydroxy-4-chloro-5-fluoropyrimidine, and reacting the 2-hydroxy-4-chloro-5-fluoropyrimidine with ammonia to yield 5-fluorocytosine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:27][CH2:26][C:25]4[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)[N:7]=3)=[CH:12][NH:11][N:10]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(-c2n[nH]cc2-c2ccnc(Cl)n2)cc1
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNc2nccc(-c3c[nH]nc3-c3ccc(F)cc3)n2)cc1
Yield: 80 %

Procedure:
This compound was synthesized by refluxing 2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine prepared in accordance with Example A-299 in 4-methoxybenzylamine overnight. The product, 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-[(4-methoxyphenyl)methyl]-2-pyrimidinamine, was obtained as a off-white solid in 80% yield, mp: 183–185° C.; Anal. Calc'd for C21H18FN5O: C, 67.19; H, 4.83; N, 18.66. Found: C, 67.01; H, 5.11; N, 18.93.
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([I:10])[N:4]2[N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:26]=2[O:40][CH3:41])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:2]3[S:6][C:5]4=[N:7][CH:8]=[C:9]([I:10])[N:4]4[N:3]=3)=[CH:27][C:26]=2[O:40][CH3:41])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Brc1nn2c(I)cnc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2nn3c(I)cnc3s2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 115 °C
Yield: 47.5 %

Procedure:
To a suspension of 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (0.262 g, 0.794 mmol, 1 eq) in 1,4-dioxane (13 mL), 4-[2-Methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (0.413 g, 0.953 mmol, 1.2 eq), Cs2CO3 (0.517 g, 1.588 mmol, 2 eq), dichlorobis(triphenylphosphine)palladium(II) (0.056 g, 0.079 mmol, 0.1 eq) and water (6 ml) were added. The resulting mixture was heated at 115° C. overnight. Solvents were removed and the crude was purified in an (solute Flash Si II column (25 g silica gel, 10%-21% EtOAc in c-hexane) to give the desired product (0.21 g). HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=4.98 min, [M+H]+ m/z 557.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]=2[C:18]#[N:19].[OH-:20].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[C:6]=2[C:18]([NH2:19])=[O:20]
Reactant: [OH-]
Reactant: N#Cc1c2ccc(Br)cc2nn1-c1ccc(F)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)c1c2ccc(Br)cc2nn1-c1ccc(F)cc1
Temperature: 70 °C
Yield: 93.5 %

Procedure:
To a stirred suspension of compound (xiv) (50 mg, 0.16 mmol) in ethanol:water (1:1, 6 mL) was added sodium hydroxide (63 mg, 0.16 mmol) and the reaction mixture was heated at 70° C. for 2 h. The reaction mixture was cooled to RT and the volatiles were removed under reduced pressure. The residue was acidified to pH 2 upon addition of 2N hydrochloric acid. The resulting precipitate was filtered, washed with water (2×20 mL) and dried (Na2SO4) to give 6-bromo-2-(4-fluorophenyl)-2H-indazole-3-carboxamide (xv) (50 mg, 94%) as white solid. ESI-MS m/z calculated for [M+H]+: 334.00; found: 334.00.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:19][CH2:18][C:17]3[CH:16]=[C:15]([C:20]([OH:22])=O)[CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH2:6][CH2:5]1.[CH2:23]1[NH:28][CH2:27][CH2:26][N:25]2[CH2:29][CH2:30][CH2:31][CH:24]12>>[CH2:23]1[N:28]([C:20]([C:15]2[CH:14]=[CH:13][C:12]3[CH2:11][CH:10]([N:7]4[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][CH2:6]4)[CH2:19][CH2:18][C:17]=3[CH:16]=2)=[O:22])[CH2:27][CH2:26][N:25]2[CH2:29][CH2:30][CH2:31][CH:24]12
Reactant: CN1CCN(C2CCc3cc(C(=O)O)ccc3C2)CC1
Reactant: C1CC2CNCCN2C1
Agent: Cl
Product: CN1CCN(C2CCc3cc(C(=O)N4CCN5CCCC5C4)ccc3C2)CC1

Procedure:
(Hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-[6-(4-methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-methanone is prepared from 6-(4-methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid dihydrochloride and Octahydro-pyrrolo[1,2-a]pyrazine in a manner substantially analogous to Procedure B (See herein Example 8). Observed mass 383 (M++1).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:34])[C:6]1[CH:11]=[C:10]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]CCC[Si](C)(C)C)=[O:22])=[C:16]([F:31])[CH:15]=2)[CH:9]=[C:8]([C:32]#[CH:33])[CH:7]=1)([CH3:3])[CH3:2].O>CS(C)=O>[CH:1]([O:4][C:5](=[O:34])[C:6]1[CH:7]=[C:8]([C:32]#[CH:33])[CH:9]=[C:10]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[C:16]([F:31])[CH:15]=2)[CH:11]=1)([CH3:3])[CH3:2]
Reactant: C#Cc1cc(C#Cc2ccc(CC(=O)OCCC[Si](C)(C)C)c(F)c2)cc(C(=O)OC(C)C)c1
Solvent: CS(C)=O
Solvent: O
Product: C#Cc1cc(C#Cc2ccc(CC(=O)O)c(F)c2)cc(C(=O)OC(C)C)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38.6 %

Procedure:
A solution of 3-ethynyl-5-[3-fluoro-4-(3-trimethylsilanyl-propoxycarbonylmethyl)-phenylethynyl]-benzoic acid isopropyl ester (Intermediate 207, 0.15 g, 0.32 mmol) in anhydrous dimethysulfoxide (4 mL) was treated with tetra-n-ethyl ammonium fluoride (0.19 mL, 1.3 mmol) and the resulting reaction mixture was stirred at ambient temperature for 5 min. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated to an oil that was purified by recrystallization from ethyl acetate/hexane to afford the title compound as a white solid (0.045 g, 38%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7])[CH3:2].[H-].[Na+].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27]I)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.Cl>CN(C=O)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH:5]([S:6]([CH3:9])(=[O:8])=[O:7])[C:4]([O:3][CH2:1][CH3:2])=[O:10])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1
Reactant: Fc1ccc(-c2ccc(CCI)cc2)cc1
Reactant: CCOC(=O)CS(C)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCc1ccc(-c2ccc(F)cc2)cc1)S(C)(=O)=O
Temperature: 25 °C
Yield: 70.3 %

Procedure:
A mixture of ethyl(methylsulphonyl)acetate (330 mg, 1.99 mmol) in 4 mL of DMF was treated with sodium hydride (88 mg, 60% dispersion in mineral oil, 2.19 mmol), until effervescence ceased in an ice bath under nitrogen. To this was added 4-fluoro-4′-(2-iodoethyl)biphenyl (650 mg, 1.99 mmol) as a solid and the residual material was dissolved by the addition of DMF (2 mL). The mixture was warmed to room temperature, then heated at 50° C. for 2 hours. The mixture was then cooled to room temperature, poured into 60 mL of 0.5N aqueous HCl and extracted 2×60 mL with ethyl acetate. The organic phase was dried over sodium sulfate filtered and concentrated in vacuo to yield a light yellow oil with some white solid particulates. The crude yield was 840 mg. The material was purified by flash chromatography on a 40 mm flash column using 120 g silica gel eluting with 0-50% ethyl acetate/heptane. This afforded the title compound as an oil (510 mg, 70.2%). MS (LC/MS) m/z 365.2 (M+1).
Reaction SMILES: Cl[Si](C)(C)C.[Cl:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[N:22])[CH:19]=2)[NH:14][CH:13]=1)=O.C(#N)C.C([BH3-])#N.[Na+]>O>[Cl:6][CH2:7][CH2:8][CH2:9][CH2:10][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[N:22])[CH:19]=2)[NH:14][CH:13]=1
Reactant: N#Cc1ccc2[nH]cc(C(=O)CCCCl)c2c1
Agent: C[Si](C)(C)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc2[nH]cc(CCCCCl)c2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Chlorotrimethylsilane (137 g) was added to a mixture of 3-(4-chlorobutyryl)-1H-indole-5-carbonitrile (50 g) and acetonitrile (750 ml) at 25-30° C. The resulting mixture was cooled to 0° C., followed by portion wise addition of sodium cyanoborohydride (75 g) while maintaining the temperature at 0-5° C. during the time period of 30 minutes to 1 hour. The resulting mass was stirred for 1 hour at the same temperature. The temperature of the reaction mass was then raised to 25-30° C., followed by stirring for 6-16 hours at the same temperature. The reaction mass was slowly poured into water (5 Lt) at 25-30° C. and then stirred for 30 minutes to 1 hour at the same temperature. The separated solid was filtered and then dissolved in dichloromethane (900 ml) and the resulting organic layer was washed with 20% sodium chloride solution (400 ml×10). The resulting organic layer was subjected to carbon treatment, followed by distillation of the organic layer at 50-55° C. under vacuum to produce the titled compound as a residue. The resulting residue was dissolved in 5% aqueous methanol (4 to 5 times to the weight of the residue), followed carbon treatment at 50-55° C. The resulting filtrate was finally cooled to 25-30° C., the separated solid was filtered, washed with chilled 5% aqueous methanol (50 ml) and then dried the material at 60-65° C. to produce 31 g of 3-(4-chlorobutyl)-1H-indole-5-carbonitrile (First Crop). The resulting filtrate was cooled to 0-5° C. and then stirred for 30 minutes at the same temperature. The separated solid was filtered, washed with chilled 5% aqueous methanol and then dried the material at 60-65° C. to produce 10.5 g of the titled compound (Second Crop) (Purity by HPLC: 99.3; Total yield: 87.2%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][N:4]1[C:8]([CH2:9]O)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.P(Br)(Br)[Br:15].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.ClCCl>[Br:1][CH2:2][CH2:3][N:4]1[C:8]([CH2:9][Br:15])=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1
Reactant: BrP(Br)Br
Reactant: O=[N+]([O-])c1cc(CO)n(CCBr)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
To as solution of (1-(2-bromoethyl)-3-nitro-1H-pyrazol-5-yl)methanol (482 mg, 1.93 mmol) in chloroform (20 mL) was cooled to 0° C. was added phosphorus tribromide (522 mg, 0.18 mL, 1.93 mmol) drop wise via syringe. The resulting solution was warmed to room temperature and stirred for 1 h. The resulting solution was cooled to 0° C. and diluted with dichloromethane (50 ml). The resulting solution was made basic (pH 8.5) with saturated aqueous sodium bicarbonate was (20 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate. The resulting mixture was filtered and concentrated in vacuo to give 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole (469 mg, 78%) as a yellow solid.
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[C:8]3[N:13]([C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH2:12][CH2:11][CH2:10][CH2:9]3.C1C(=O)N([Br:21])C(=O)C1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:21][C:7]1[C:6]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[N:13]2[C:8]=1[CH2:9][CH2:10][CH2:11][CH2:12]2
Reactant: O=C1CCC(=O)N1Br
Reactant: c1cnc2cc3n(c2c1)CCCC3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1c2n(c3cccnc13)CCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
To a solution of 6,7,8,9-tetrahydropyrido[2,3-b]indolizine (170 mg) in DMF (3 mL) was added NBS (193 mg) at 0° C. The mixture was stirred at 0° C. for 30 min. The mixture was added saturated NaHCO3 aqueous solution at 0° C. and extracted with AcOEt. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (217 mg).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:46][C@@H:47]([C:49]2[CH:54]=[CH:53][C:52]([O:55][CH2:56][C:57]3C=CC=CC=3)=[C:51]([NH:63][CH:64]=[O:65])[CH:50]=2)[OH:48])[CH2:26][C@H:27]([OH:45])[C:28]2[CH:33]=[CH:32][C:31]([O:34]CC3C=CC=CC=3)=[C:30]([NH:42][CH:43]=[O:44])[CH:29]=2)=[CH:17][CH:16]=1)C1C=CC=CC=1.C[OH:68]>C(O)(=O)C.[OH-].[OH-].[Pd+2].ClCCl>[C:56]([OH:68])(=[O:55])[CH3:57].[C:56]([OH:68])(=[O:55])[CH3:57].[OH:34][C:31]1[CH:32]=[CH:33][C:28]([C@@H:27]([OH:45])[CH2:26][N:25]([CH2:46][C@H:47]([OH:48])[C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[C:51]([NH:63][CH:64]=[O:65])[CH:50]=2)[CH2:24][CH2:23][CH2:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH2:10])=[CH:20][CH:19]=2)=[CH:29][C:30]=1[NH:42][CH:43]=[O:44]
Reactant: O=CNc1cc([C@@H](O)CN(CCCCc2ccc(CCCCNC(=O)OCc3ccccc3)cc2)C[C@H](O)c2ccc(OCc3ccccc3)c(NC=O)c2)ccc1OCc1ccccc1
Reactant: CO
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: NCCCCc1ccc(CCCCN(C[C@H](O)c2ccc(O)c(NC=O)c2)C[C@H](O)c2ccc(O)c(NC=O)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A mixture of {4-[4-(4-{bis-[2-(4-benzyloxy-3-formylaminophenyl)-2-(R)-hydroxyethyl]-amino}butyl)phenyl]butyl}carbamic acid benzyl ester (10) (0.17 g, 0.19 mmol), palladium dihydroxide (50 mg, 10% Pd(OH)2 on carbon, 50% wet), eight drops of acetic acid, methanol (10 mL), and dichloromethane (5 mL) was stirred at rt for 18 h under atmospheric hydrogen pressure. The catalyst was filtered through a Celite pad and the filtrate was concentrated by rotary evaporation and further dried under high vacuum to give the desired amine diacetic acid salt 13 as a white solid (0.10 mg, 98%); m/z (ESI) 579 [C32H42N4O6+H]+.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[C:28](O)(=[O:31])[CH2:29][CH3:30]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: CCC(=O)O
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (88 mg, 76%), MS (ISP) m/z=387.4 [(M+H)+], mp 196° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (132 mg, 0.3 mmol) and propionic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][NH:23][C:24](=[O:27])[CH2:25]Cl)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[CH3:28][NH:29][CH3:30]>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][NH:23][C:24](=[O:27])[CH2:25][N:29]([CH3:30])[CH3:28])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: CNC
Reactant: Cc1nnc(CNC(=O)CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1nnc(CNC(=O)CN(C)C)n1-c1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
To a solution of 5-chloro-2-[3-(2-chloroacetamidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone (0.4 g) in methanol (4 ml) and chloroform (8 ml), 40% aqueous dimethylamine (0.5 g) is added, and the resultant mixture is stirred at room temperature for 24 hours. The reaction mixture is evaporated under reduced pressure, and the residue is shaken with methylene chloride (20 ml). The methylene chloride layer is washed with aqueous sodium bicarbonate and water in order, dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The residue is chromatographed on a column of silica gel, whereby 5-chloro-2-[3-(2-dimethylaminoacetamidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone is obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Cc1cccc(C(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)N2CCOCC2)n1
Yield: 83 %

Procedure:
6-Methylpicolinic acid (1.37 g) and morpholine (870 mg) was dissolved in 30 mL of DMF, and thereto 1.6 g of HOBt was added under stirring at ice temperature. After the mixture was stirred at same temperature for 15 minutes, additionally 2.3 g of WSC was added, and the solution was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, and then the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed. The resulting residue was purified by chromatography on silica gel (methylene chloride-methanol-triethylamine=900:30:1) to give 1.71 g of (6-methylpyridin-2-yl)morpholin-4-ylmethanone as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH2:18][C:17]3([CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)[O:16][N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[C:8]1([C:14]2[CH2:18][C:17]3([CH2:23][CH2:22][CH2:21][NH:20][CH2:19]3)[O:16][N:15]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1.[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCCC2(CC(c3ccccc3)=NO2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(C2=NOC3(CCCNC3)C2)cc1
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2 mL, 26.0 mmol) was added dropwise to a solution of tert-butyl 3-phenyl-1-oxa-2,7-diazaspiro[4.5]dec-2-ene-7-carboxylate (270 mg, 0.853 mmol) in CH2Cl2 (5 mL) at room temperature. After 1 h at room temperature, the mixture was concentrated to give the expected product as TFA salt (280 mg, 99% yield). LCMS: (M+H)+=217.15. 1H NMR (400 MHz, methanol-d4) δ ppm 7.62-7.78 (2H, m), 7.36-7.51 (3H, m), 3.35-3.49 (4H, m), 3.00-3.24 (2H, m), 2.04-2.22 (2H, m), 1.85-2.07 (2H, m).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][C:14]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[O:18][CH2:17][CH2:16][O:15]1.[O:28]([CH2:35][CH:36]1[O:40][C:39](=[O:41])[N:38]([CH2:42][CH2:43]O)[CH2:37]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:13][C:14]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:43][CH2:42][N:38]3[CH2:37][CH:36]([CH2:35][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:40][C:39]3=[O:41])=[CH:23][CH:22]=2)[O:18][CH2:17][CH2:16][O:15]1
Reactant: O=C1OC(COc2ccccc2)CN1CCO
Reactant: CC1(COc2ccc(O)cc2)OCCO1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(COc2ccc(OCCN3CC(COc4ccccc4)OC3=O)cc2)OCCO1
Reaction time: 64 h
Yield: 62.9 %

Procedure:
Diethyl azodicarboxylate (1.6 ml) was added dropwise to an ice-bath cooled, stirred, solution of 4-[(2-methyl-1,3-dioxolan-2-yl)methoxy]phenol (2.1 g), 5-phenoxymethyl-3-(2-hydroxyethyl)-oxazolidin-2-one (2.4 g) and triphenylphosphine (2.6 g) in anhydrous tetrahydrofuran (50 ml) under argon. The reaction mixture was left for 64 hours at 22° C. and then the solvent removed under reduced pressure. The residue was dissolved in dichloromethane and the solution seeded with 1,2-dicarbethoxyhydrazine. The solution was allowed to stand for 2 hours, the solid was collected and the filtrate was subjected to chromatography using 45% hexane in ethyl acetate grading to 40% hexane in ethyl acetate as eluent. The appropriate fractions were combined, evaporated, and the residue triturated with cyclohexane to give the 3-[2-(4-(2-methyl-1,3-dioxolan-2-ylmethoxy)phenoxy)ethyl]-5-(phenoxymethyl)oxazolidin-2-one (2.7 g) m.p. 75°-77° C.