Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]=[CH:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](I)[CH:20]=[CH2:21].O>CN(C=O)C>[F:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]=[CH:7][C:8](=[O:10])[N:9]([CH2:21][CH:20]=[CH2:19])[C:4]=2[CH:3]=1
Reactant: O=c1cnc2ncc(F)cc2[nH]1
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)cnc2ncc(F)cc21
Yield: 46.5 %

Procedure:
7-Fluoropyrido[2,3-b]pyrazin-2(1H)-one (306 mg, 1.855 mmol) was suspended in dry DMF (10 mL) under argon at rt, and the stirred suspension was treated with K2CO3 (845 mg, 6.12 mmol) and allyl iodide (223 μl, 2.41 mmol). It was then stirred for 1 h before addition of water (100 ml). The mixture was then extracted with DCM (2×200 ml) and 5% MeOH/DCM (100 ml). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated and purified by column chromatography on silica with a 0-10% MeOH in DCM gradient to give the desired product as a yellow solid (177 mg, 47%).
Reaction SMILES: C(O[C:4](=[O:6])C)=O.C(O)=O.[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[N:18]1[CH2:22][CH2:21][N:20]([C:23]2[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:30])[C:19]1=[NH:31].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[CH3:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:23]=1[N:20]1[CH2:21][CH2:22][N:18]([C:12]2[C:11]([CH3:10])=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:17])[C:19]1=[N:31][CH:4]=[O:6]
Reactant: Cc1cccc(C)c1N1CCN(c2c(C)cccc2C)C1=N
Reactant: CC(=O)OC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=CO
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C)c1N1CCN(c2c(C)cccc2C)C1=NC=O
Reaction time: 4 h

Procedure:
A solution of 7.5 g (85 mmoles) of acetyl formate (a mixed anhydride of formic acid and acetic acid) in 30 ml of dry chloroform is added dropwise, at room temperature, to a solution of 5.0 g (17.0 mmoles) of 1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine, prepared as described in Method (a) of Example 1, in 50 ml of dry chloroform. The resulting mixture is stirred at 45° to 50° C. for 4 hours, thereafter it is cooled with ice, and 10 ml of a 10% aqueous sodium hydrogencarbonate solution are added dropwise to the stirred mixture at a temperature not exceeding +10° C. The aqueous phase is separated, the chloroform phase is washed thrice with 50 ml of water each, dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure, 4.6 g (84.2%) of 1,3-bis(2',6'-dimethylphenyl)-2-formylimino-imidazolidine are obtained; the product melts at 306°-308° C. after recrystallization from methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[OH2:12].[OH2:13].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O.CCCCCC>O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[C:11]([OH:13])=[O:12]
Reactant: O
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCCCCC
Product: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-fluoro-4-nitrotoluene (22.45 g, 144.7 mmol) and sodium dichromate dihydrate (60.38 g, 202.6 mmol) in water at 0° C. was added concentrated sulfuric acid (140 mL) dropwise over 3 h. When the addition was complete, the solution was allowed to warm to room temperature over 1 h, and then brought to 90° C. for 1 h. The mixture was allowed to cool to room temperature, diluted with 300 mL water and extracted with ethyl acetate (3×250 mL). The combined organic extracts were concentrated down to 300 mL and extracted with 1 N NaOH (3×250 mL). The aqueous extracts were acidified with 6 N HCl and extracted with ethyl acetate (3×300 mL). The combined organic extracts were dried over MgSO4 and concentrated to give a gummy solid. Trituration with hexane gave the 3-fluoro-4-nitrobenzoic acid as a solid that was collected by filtration (6.51 g, 24%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:18]2[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:19]=2[O:25][CH2:26][CH3:27])[N:3]=1.[N:28]1([OH:37])C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.NO.C(N(CC)CC)C>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:28][OH:37])=[O:14])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:18]2[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:19]=2[O:25][CH2:26][CH3:27])[N:3]=1
Reactant: CCOc1ccc(Br)cc1-c1cc(Nc2ccc(C(=O)O)cc2)nc(N)n1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1ccc(Br)cc1-c1cc(Nc2ccc(C(=O)NO)cc2)nc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
To a stirred solution of 4-[2-amino-6-(5-bromo-2-ethoxy-phenyl)-pyrimidin-4-ylamino]-benzoic acid (0.086 g, 0.20 mmol) in dimethylformamide (3.0 ml) was added benzotriazol-1-ol (0.054 g, 0.40 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.086 g, 0.44 mmol). After stirring at room temperature for 1 hour, hydroxylamine hydrochloride (0.070 g, 1.0 mmol) was added followed by triethylamine (0.1 g, 1.0 mmol). After stirring for 16 hours, the solvent was evaporated under reduced pressure and the residue was treated with 1 M aqueous sodium carbonate solution (10 ml). Filtration provided the title compound (0.065 g, 73% yield) as a light brown solid. 1H NMR (DMSO-d6) δ 1.38 (t, 3H, J=6.9 Hz, CH3), 4.12 (q, 2H, J=6.9 Hz, CH2), 6.32 (s, 2H, NH2), 6.79 (s, 1H, Ar), 7.08 (d, 1H, J=8.9 Hz, Ar), 7.52 (dd, 1H, J=8.9 Hz, J=2.6 Hz, Ar), 7.66 (b, 4H, Ar), 8.04 (d, 1H, J=2.6 Hz, Ar), 9.24 (s, 1H, NH).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26]C(NC2CCNCC2)=O)=[CH:22][CH:21]=1)([CH3:19])[CH3:18].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[OH-].[K+]>C(O)(CC)(C)C.CCOC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: CC(C)c1ccc(NC(=O)NC2CCNCC2)cc1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCC(C)(C)O
Product: CC(C)c1ccc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 28.2 %

Procedure:
Compound 83 (100 mg, 0.43 mmol), 1-(4-isopropyl-phenyl)-3-piperidin-4-yl-urea (136 mg, 0.52 mmol), Pd(OAc)2 (5 mg, 0.02 mmol), X-Phos (21 mg, 0.04 mmol), and KOH (73 mg, 1.30 mmol) were suspended in tert-amyl alcohol (2 mL), and stirred overnight at 100° C. The reaction mixture was diluted with EtOAc/H2O. The resulting precipitate was filtered, washed with EtOAc/H2O, and dried under vacuum to provide 159 (40 mg, 28% yield) as a tan solid. LC-MS (M+H=330, obsd.=330).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[F:57][C:58]([F:69])([F:68])[C:59]1[CH:64]=[CH:63][C:62]([C:65](=[O:67])[CH3:66])=[CH:61][CH:60]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:66][C:65]([C:62]2[CH:63]=[CH:64][C:59]([C:58]([F:57])([F:68])[F:69])=[CH:60][CH:61]=2)=[O:67])=[CH:4][CH:3]=1
Reactant: Clc1ccc(I)cc1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(Cc1ccc(Cl)cc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
A solution of 3 g of 1-Chloro-4-iodo-benzene, 9 g of Cs2CO3, 36 mg of Pd(dba)2 (Bis(dibenzylidenacetonpalladium), 72 mg of Xantphos (9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene) and 4.7 g of 1-(4-Trifluoromethyl-phenyl)ethanone in 45 ml of dioxane was heated under argon for 30 min at 150° C. by microwave irradiation. After cooling to room temperature and dilution with saturated aqueous sodium hydrogen carbonate solution the reaction mixture was filtered through a chem Elut® cartridge by eluting with ethyl acetate The solvents were removed under reduced pressure and the crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 3.7 g.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.[Cl:16][C:17]1[C:22]([CH3:23])=[C:21]([CH:24]2[CH2:26][CH2:25]2)[N:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C.Cl.CCOCC>CN1CCCC1=O.C(OCC)(=O)C>[ClH:16].[CH:24]1([C:21]2[N:20]=[CH:19][N:18]=[C:17]([NH:12][CH2:11][C:9]3[CH:10]=[C:5]4[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[NH:13][C:6]4=[N:7][CH:8]=3)[C:22]=2[CH3:23])[CH2:26][CH2:25]1
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Reactant: Cc1c(Cl)ncnc1C1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: Cc1c(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)ncnc1C1CC1
Temperature: 120 °C
Yield: 5 %

Procedure:
1-[2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 185 mg, 0.516 mmol), 4-chloro-6-cyclopropyl-5-methylpyrimidine (Intermediate 52, 122 mg, 0.722 mmol) and DIPEA (0.180 ml, 1.032 mmol) were added together in N-methyl-2-pyrrolidone (NMP) (2 ml) and the resulting mixture was heated at 120° C. for 18 hours and allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by SP4 column chromatography eluting with a gradient of 0-100% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure. The residue, contaminated with NMP, was dissolved in methanol and passed down an SCX column (1 g) eluting with methanol, followed by 2M ammonia/methanol. Product containing fractions were combined and evaporated under reduced pressure. The resulting residue was dissolved in methanol (1 mL), treated with 1M hydrochloric acid in ether (0.05 ml, 0.050 mmol), the solvent removed under reduced pressure and the residue dried under high vacuum at 40° C. for 4 hours to give the title compound as a yellow solid, (10 mg);
Reaction SMILES: [CH2:1]([N:8]([CH3:25])[C:9]([CH2:11][CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20](=[O:24])[C:21]([OH:23])=O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([N:28](CC)CC)[CH3:27].ClC(OCC(C)C)=O.C(N)C>C1COCC1.O>[CH2:1]([N:8]([CH3:25])[C:9]([CH2:11][CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20](=[O:24])[C:21]([NH:28][CH2:26][CH3:27])=[O:23])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(=O)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)C(=O)[C@@H]1CCCN1C(=O)CCC(=O)N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 2 [(2S)-1-[3-(N-benzyl-N-methylcarbamoyl) propanoyl]pyrrolidin-2-yl]-2-oxoacetic acid (98 mg) in THF (3 ml) was cooled to -20° C. Triethylamine (188 μl) and isobutyl chloroformate (77 μl) were added dropwise to the solution. The mixture was stirred for 20 mins at the same temperature. An aq. solution of ethylamine (70% ; 200 μl) was added dropwise to the solution at the same temperature. The solution was stirred for 1 hr, while the temperature of the solution was raised to room temperature gradually. Water was added to the reaction solution. The mixture was extracted with EtOAc. The extract was washed, dried and evaporated. The residue was purified by column chromatography on silica gel (CH2Cl2 --CH3OH) to give the title compound (62 mg) having the following physical data:
Reaction SMILES: [N:1]1([C:7]2C=CC(NC(C3C(C4C=CC(C(F)(F)F)=CC=4)=CC=CC=3)=O)=CC=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:32]([O-:35])([O-])=[O:33].[Na+].[Na+].BrC(C1C=CC=CC=1)C(OC)=O>CN(C=O)C>[N:1]1([CH2:7][C:32]([OH:35])=[O:33])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: O=C([O-])[O-]
Agent: COC(=O)C(Br)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CN1CCNCC1

Procedure:
A mixture of intermediate (2) (0.019 mol) and Na2CO3 (0.019 mol) in DMF (125 ml) was stirred. Methyl 2-bromo-2-phenylacetate (0.019 mol) was added dropwise. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated. The residue was stirred in DCM and washed with water. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was stirred in DIPE. The precipitate was filtered off, dried and separated by high performance liquid chromatography over Chiralcel OD (eluent:hexane/EtOH 70/30) in its enantiomers. The desired fractions were collected and the solvent was evaporated, yielding 1-piperazineacetic acid, α-phenyl-4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-, methyl ester, (α1A)-(intermediate 33) after crystallisation from 2-propanol, and 1-piperazineacetic acid, α-phenyl-4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-, methyl ester, (α1B)-(intermediate 34) after crystallisation from 2-propanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:14])[C:3]=1[C:15]1[NH:16][C:17]2[CH:23]=[C:22]([C:24]([NH:26][NH:27][C:28](=O)[C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[O:25])[CH:21]=[CH:20][C:18]=2[N:19]=1.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1COCC1.O.CCCCCCC>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:28]2[O:25][C:24]([C:22]3[CH:21]=[CH:20][C:18]4[N:19]=[C:15]([C:3]5[C:2]([CH3:1])=[CH:7][C:6]([N:8]6[CH2:13][CH2:12][O:11][CH2:10][CH2:9]6)=[CH:5][C:4]=5[CH3:14])[NH:16][C:17]=4[CH:23]=3)=[N:26][N:27]=2)=[CH:34][CH:33]=1
Reactant: Cc1cc(N2CCOCC2)cc(C)c1-c1nc2ccc(C(=O)NNC(=O)c3ccc(Cl)cc3)cc2[nH]1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: Cc1cc(N2CCOCC2)cc(C)c1-c1nc2ccc(-c3nnc(-c4ccc(Cl)cc4)o3)cc2[nH]1

Procedure:
252 mg of 4-Chloro-benzoic acid N′-[2-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3H-benzoimidazole-5-carbonyl]-hydrazide was placed in a microwave tube and dissolved in 4 ml of THF. 300 mg of (methoxycarbonylsulfamoyl)triethylammonium hydroxide (Burgess Reagent) was added and the tube was sealed and microwaved at 150° C. for 30 minutes. The reaction was then diluted with water and heptane. The precipitates were collected by filtration and purified by column chromatography (heptane:ethyl acetate=1:1 to 1:2) to provide the title compound. LCMS ret T=1.44 min, m/z=486.1, method 10. 1H NMR (400 MHz, MeOD) □ ppm 2.29 (br. s., 6 H) 3.36 (br. s., 5 H) 3.99 (br. s., 4 H) 6.95 (br. s., 2 H) 7.81 (s, 2 H) 7.95 (br. s., 1 H) 8.25 (br. s., 1 H) 8.32 (br. s., 2 H) 8.56 (br. s., 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13])[S:5][C:6]=1[CH3:7].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13])[S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[S:5][C:6]=1[CH3:7]
Reactant: COC(CNCc1cc(Br)c(C)s1)OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: ClCCl
Product: COC(CN(Cc1cc(Br)c(C)s1)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
N-((4-bromo-5-methylthiophen-2-yl)methyl)-2,2-dimethoxyethanamine (14.5 g, 49 mmol) was dissolved in DCM (100 ml) and TEA (14 ml, 99 mmol) was added. The reaction was cooled to 0° C. with an ice bath and 4-tosyl chloride (8.5 ml, 59 mmol) was added portionwise. The reaction was allowed to warm up to RT and stirred overnight. The reaction was then diluted with DCM and water. The layers were separated and the organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 30 to 70% EtOAc in hexanes to give N-((4-bromo-5-methylthiophen-2-yl)methyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide as light brown oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10](O)=O)=[CH:5][CH:4]=1.[CH3:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[CH3:23])[NH2:19].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.B.O1CCCC1.Cl>ClCCl.C(OCC)(=O)C>[CH3:15][C:16]1[CH:17]=[C:18]([NH:19][CH2:10][CH2:9][C:6]2[CH:7]=[N:8][C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][CH:5]=2)[CH:20]=[CH:21][C:22]=1[CH3:23]
Reactant: O=C(O)Cc1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc(N)cc1C
Agent: B
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(NCCc2ccc(C(F)(F)F)nc2)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.3 %

Procedure:
To a suspension of (6-trifluoromethyl-pyridin-3-yl)-acetic acid (257 mg, 1.25 mmol), 3,4-dimethylaniline (167 mg, 1.38 mmol) and 1-hydroxybenzotriazole in dichloromethane (2 mL) was added under a nitrogen atmosphere 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (264 mg, 1.37 mmol) and N,N-diisopropyl ethyl amine (322 μl, 1.88 mmol). After stirring for 3 h at ambient temperature it was concentrated and a solution of borane-tetrahydrofuran complex (1 M in THF, 5 mL, 5 mmol) was added and the reaction mixture was stirred for 18 h at 60° C. Further solution of borane-tetrahydrofuran complex (1 M in THF, 5 mL, 5 mmol) was added and the reaction mixture was stirred for 4 h at 80° C. An aqueous solution of hydrochloric acid (1 M, 2 mL) was carefully added and stirring was continued for 15 min. at reflux. After cooling it was diluted with ethyl acetate (15 mL) and washed with aqueous Na2CO3 (saturated, 15 mL). The aqueous layer was extracted with EtOAc (15 mL) and the combined organic layers dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (218 mg, 64%) as a light yellow oil. MS m/e: 295.2 [M+H]+.
Reaction SMILES: C(O)CCCCCCCCCO.C(Br)C1C=CC=CC=1.[CH2:21]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCCCCCCCCCC(O)=O)C1C=CC=CC=1.Cl.Cl.[CH2:62]([O:69][C:70](=[O:78])[CH2:71][C@@H:72]([NH2:77])[CH2:73][N:74]([CH3:76])[CH3:75])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>>[CH2:62]([O:69][C:70](=[O:78])[CH2:71][C@@H:72]([NH:77][C:38](=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:28][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:73][N:74]([CH3:75])[CH3:76])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: OCCCCCCCCCCOCc1ccccc1
Agent: BrCc1ccccc1
Agent: Cl
Agent: O=C(O)CCCCCCCCCOCc1ccccc1
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCCOCc1ccccc1

Procedure:
The title compound, m/e=405.6 ([M−H]−), was produced in analogy with example 1, steps 1 to 4. Thus, 1,10-decanediol was alkylated in step 1 with benzyl bromide, leading to 10-benzyloxy-decan-1-ol, which was oxidized in step 2 to 10-benzyloxydecanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-3-(10-benzyloxy-decanoylamino)-4-dimethylamino-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>CCO>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=[N:26][OH:27])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(OCCN2CCC(Cc3ccccc3)CC2)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=Cc1cccc(OCCN2CCC(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.3 %

Procedure:
To a solution of 3-((2-(4-benzylpiperidin-1-yl)ethyl)oxy)benzaldehyde (200 mg, 0.620 mmol) in 6 mL of 50% aqueous EtOH was added a solution of hydroxylamine hydrochloride (110 mg, 1.55 mmol) and sodium acetate (246 mg, 2.77 mmol) in 50% aqueous EtOH (10 mL). The resulting solution was allowed to stir at room temperature for 3 days. The EtOH was evaporated and a colorless solid was collected by filtration and dried to give the product (160 mg, 70%): mp 141-143° C.; 1H NMR (CDCl3) 1.40 (m, 2 H), 1.50 (m, 1 H), 1.64 (m, 2 H), 2.12 (m, 2 H), 2.54 (m, 2 H), 2.85 (s, 2 H), 3.08 (m, 2 H), 4.21 (m, 2 H), 6.88-7.28 (m, 9 H), 8.04 (s, 1 H), 10.00 (bs, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:34]1[CH:35]=[N:36][CH:37]=[C:38]([CH:42]=1)[C:39]([NH2:41])=[O:40].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(Cl)(Cl)Cl.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:34]4[CH:35]=[N:36][CH:37]=[C:38]([CH:42]=4)[C:39]([NH2:41])=[O:40])[CH:19]=3)[O:14]2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(B3OC(C)(C)C(C)(C)O3)ccc1O2
Reactant: NC(=O)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3cncc(C(N)=O)c3)ccc1O2
Temperature: 100 °C

Procedure:
1′-tert-butoxycarbonyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[chroman-2,4′-piperidin]-4-one (1.43 g, 3.23 mmol), 5-bromonicotinamide (778 mg, 3.87 mmol), Pd(PPh3)4 (372 mg, 0.322 mmol), and aqueous 2M Na2CO3 (10 ml) solution were suspended in dioxane (20 ml) and heated at 100° C. for 4 h. The reaction mixture was diluted with CHCl3 and H2O, the aqueous layer was extracted with CHCl3. The combined organic layer was dried over MgSO4. The desiccant was removed through celite filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified through silica gel column chromatography (EtOAc/Acetone) to obtain the intended compound as a pale yellow foam.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[F:18])=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].C(O)C>O1CCCC1>[F:18][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:12]=1[C:7]1[C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[O:9][N:8]=1
Reactant: CCOC(=O)c1c(-c2ccncc2F)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1onc(-c2ccncc2F)c1C(=O)O

Procedure:
Combine 3-(3-fluoro-pyridin-4-yl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (2.00 g, 0.008 mol) with aqueous sodium hydroxide (2N, 15.0 mL, 0.03 mol), ethanol (3 mL), and tetrahydrofuran (3 mL) and stir overnight at ambient temperature. Remove the organic solvents in vacuo and adjust the aqueous mixture to approx. pH 3.5 with aqueous hydrochloric acid. Extract with ethyl acetate and dry the combined extracts over sodium sulfate and concentrate in vacuo. Drying nets the desired isoxazole acid as an off white solid (1.35 g, 76%). MS(FD): M+ 223.2 m/z.