Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:8]1[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:11][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>[Pd].CO>[CH2:1]([C:8]1[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC#Cc1csc(C(=O)OCC)c1
Agent: [Pd]
Solvent: CO
Product: CCCCCCCc1csc(C(=O)OCC)c1
Reaction time: 12 h
Yield: 79.6 %

Procedure:
5% Palladium on carbon (2.52 g) was added to a solution of compound 1016 (5.94 g, 23.7 mmol) in methanol (100 mL). The reaction mixture was stirred under a hydrogen atmosphere (1 atm) for 12 hours. The reaction mixture was filtered through celite and the clear solution was concentrated under vacuum to give ethyl 4-heptylthiophene-2-carboxylate (1017, 4.80 g) which was directly used in the next step without further purification. Rf=0.78 (10% EtOAc in Hexane).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]1[N:11]=[C:10](C(Cl)(Cl)Cl)[O:9][N:8]=1.[NH3:16]>CCOCC>[NH2:16][C:10]1[O:9][N:8]=[C:7]([CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[N:11]=1
Reactant: N
Reactant: ClC(Cl)(Cl)c1nc(Cc2cccs2)no1
Solvent: CCOCC
Product: Nc1nc(Cc2cccs2)no1

Procedure:
124.8 g. (0.44 moles) of the 3-(2-thienylmethyl)-5-(trichloromethyl)-1,2,4-oxadiazole obtained in part (a) are dissolved in 100 ml. of ether and added dropwise to 200 ml. of liquid ammonia at -45° with stirring. This mixture is stirred for one more hour and then the ammonia and solvent are permitted to evaporate overnight. The solid residue is treated with water and filtered under suction. 75 g. of crude 5-amino-3-(2-thienylmethyl)-1,2,4-oxadiazole are obtained which is recrystallized from isopropanol, yield 52.5 g., m.p. 132°-133°.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23].[I-].[Li+].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1>[CH3:11][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:18]
Reactant: CC(C)=CCBr
Reactant: CC(C(=O)OCc1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)=CCC(C)(C(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.8 %

Procedure:
A solution of 2-phenyl-propionic acid benzyl ester (2.0 g, 8.32 mmol), 4-bromo-2-methyl-2-butene (1.21 mL, 9.99 mmol), and lithium iodide (1 g) in tetrahydrofuran (15 mL) at 0° C. was treated dropwise with the lithium hexamethyldisilazide (9.99 mL, 1M in tetrahydrofuran, 9.99 mmol). The reaction was allowed to warm to 25° C. and stirred for 18 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the ethyl acetate layers were combined, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, then 10% ethyl acetate in hexane, and 20% ethyl acetate in hexane to give the title compound (2.51 g, 98%). 1H NMR (300 MHz, CDCl3): δ ppm 1.53 (m, 6 H) 1.63 (m, 3 H) 2.60 (m, 1 H) 2.80 (m, 1 H) 4.94 (m, 1 H) 5.11 (m, 2 H) 7.26 (m, 10 H). MS (ESI+) m/z 326 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:14].[F:16][C:17]([F:29])([F:28])[CH:18](OS(C(F)(F)F)(=O)=O)[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:14][CH:18]([CH3:19])[C:17]([F:29])([F:28])[F:16]
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1O
Reactant: CC(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(S(C)(=O)=O)ccc1OC(C)C(F)(F)F
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of 21.7 mmol 2-hydroxy-5-methanesulfonyl-benzoic acid methyl ester (WO 2002074774), 32.5 mmol trifluoro-methanesulfonic acid 2,2,2-trifluoro-1-methyl-ethyl ester [212556-43-9] and 43.4 mmol potassium carbonate in 87 ml DMF was stirred at 80° C. for 48 hours. After cooling to room temperature, the mixture was concentrated in vacuo, resuspended in water and stirred for 1 hour. Filtration yielded the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C@@H:3]([OH:5])[CH3:4].[H-].[Na+].Cl[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1>CN(C=O)C>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([O:5][C@@H:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])=[N:12][CH:13]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C[C@H](O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](Oc1ccc([N+](=O)[O-])cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 4-neck flask, commercially available 2-chloro-5-nitropyridine (71.9 g) and (S)-1,1,1-trifluoropropan-2-ol (54.3 g) were dissolved in DMF (610 ml) and sodium hydride (20 g, 55%) was added at a temperature of 16 to 18° C. (ice cooling). Following addition, the mixture was allowed to stir for 1 hour. The mixture was poured into ice and was allowed to hydrolyze. The suspension was warmed to RT over a period of 12 hours and the solid was filtered and washed with additional water and then with a small amount of hexanes (50 mL). The brown solid was further dried in vacuo to provide the title compound. (81.9 g). 1H-NMR (δ, CDCl3): 9.06 (m, 1H), 8.43 (dd, 1H), 6.93 (d, 1H), 5.87 (m, 1H); 1.54 (m, 3H).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([O:12][CH3:13])(=[O:11])[C:8]([CH3:10])=[CH2:9]>CO>[CH3:13][O:12][C:7](=[O:11])[CH:8]([CH3:10])[CH2:9][NH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: C=C(C)C(=O)OC
Solvent: CO
Product: COC(=O)C(C)CNC1CCCC1
Yield: 82.7 %

Procedure:
A mixture of 42.575 g (0.50 mole) of cyclopentylamine (Aldrich), 60.072 g (0.60 mole) of methyl methacrylate (Aldrich) and 250 mL of methanol was heated at reflux under an argon atmosphere for 29 hours, then ca 250 mL of solvent was distilled out at atmospheric pressure. The residue was distilled under vacuum (11 mm Hg, bp 114-116 degrees) to give 76.570 g (82%) of (rac)-3-cyclopentylamino-2-methyl-propanoic acid methyl ester.
Reaction SMILES: [N:1]1([C:7]2[C:18]3=[C:19]4[N:14]([CH2:15][CH2:16][CH2:17]3)[CH:13]=[C:12]([C:20]([OH:22])=[O:21])[C:11](=[O:23])[C:10]4=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].O.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CC(C)=O>[C:30]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[C:18]3=[C:19]4[N:14]([CH2:15][CH2:16][CH2:17]3)[CH:13]=[C:12]([C:20]([OH:22])=[O:21])[C:11](=[O:23])[C:10]4=[CH:9][CH:8]=2)[CH2:2][CH2:3]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)c1cn2c3c(c(N4CCNCC4)ccc3c1=O)CCC2
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1cn2c3c(c(N4CCN(C(=O)c5ccccc5)CC4)ccc3c1=O)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
2.0 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid and 1.2 g of sodium hydrogen carbonate were added to 30 ml of water and the mixture was stirred at room temperature for 30 minutes. 5 ml of acetone having dissolved therein 1.0 g of benzoyl chloride was added dropwise to the mixture while ice-cooling followed by stirring at the same temperature as above for 30 minutes and then at room temperature for 1.5 hours to precipitate crystals, which were separated by filtration and washed with water. Recrystallization of the crystals thus-treated from dimethylformamide gave 2.4 g of 8-(4-benzoyl-1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white needles having a melting point of not lower than 300° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:22](OCCC(C)C)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:7][CH:8]=1)[NH:6][N:22]=[CH:9]2
Reactant: CC(C)CCON=O
Reactant: Cc1cc(Br)ccc1N
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: Brc1ccc2[nH]ncc2c1
Temperature: 68 °C
Reaction time: 0.83 h
Yield: 94 %

Procedure:
A flask containing 4-bromo-2-methylaniline (95.0 g) in chloroform (0.70 L) was treated with acetic anhydride (0.109 L) at <40° C. The solution was stirred for 50 minutes and potassium acetate (14.6 g) and isoamyl nitrite (0.147 L) was charged. The solution was refluxed at 68° C. for 20 h. The temperature was cooled to 25° C. and the volatiles distilled at 30 mmHg vacuum (T=30-40° C.). Once most of the solvents had distilled, a total of 225 mL of water was charged in portions and the azeotrope of water and the various volatiles distilled. The product mass was transferred back into the reaction vessel using water (50 mL) and concentrated hydrochloric acid (400 mL) charged. The mixture was heated to 50-55° C. and another 100 mL acid charged in portions over 2 h. The solution was cooled to 20° C. and 50% sodium hydroxide (520 g) was charged at <37° C. to bring the pH to 11. Water (100 mL) and ethyl acetate (350 mL) was added and the mixture filtered through a Celite pad. The layers were separated and the aqueous phase further extracted with ethyl acetate (2×200 mL). The combined organic layers were mixed with brine (240 mL), filtered through a Celite pad and separated. The organic solution was dried over magnesium sulfate (3 g) and filtered through a silica gel pad (45 g) with ethyl acetate. The eluant was concentrated by rotary evaporation, adding a total of 0.45 L of heptane during the distillation and continueing until only dry solids remain. The solids were slurried with heptane (0.1 L), filtered and dried under vacuum at 45° C. to produce 91.9 g of 5-bromoindazole (94% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][CH2:38][CH2:39][CH2:40]I)=[CH:32][CH:31]=1>CN(C=O)C>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH:37]([C:12]2([S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:10])=[O:11])[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])[CH2:38][CH2:39][CH3:40])=[CH:32][CH:31]=1
Reactant: COc1ccc(S(=O)(=O)C2SC(=O)NC2=O)cc1
Reactant: Clc1ccc(C#CCCCI)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(Cc1ccc(Cl)cc1)C1(S(=O)(=O)c2ccc(OC)cc2)SC(=O)NC1=O
Reaction time: 0.25 h

Procedure:
To a solution of 5-(4-methoxyphenylsulfonyl)-thiazolidine-2,4-dione [U.S. Pat. No. 5,605,918; February 1997; Wrobel, et al.]((2.74 g, 9.5 mMol) in DMF (50 ml) was added sodium hexamethyldisilazide (1.0 M solution in THF—19.0 ml, 19.0 mmol) at room temperature, under nitrogen, and this was stirred for 15 minutes. To this was added 1-(4-chlorophenyl)-5-iodo-1-pentyne (2.70 g, 9.5 mmol) over 5 minutes, and this solution was stirred overnight at room temperature. The reaction mixture was quenched in water, and the solid that was obtained was recrystallized from methanol to give 1.59 g of the title compound as colorless crystals, m.p. 172-174°; NMR (CDCl3) δ 1.59 (m, 1H); 2.0 (m, 1H); 2.36 (dq (doublet of quartets?), 1H); 2.5 (t, 2H); 2.67 (dq, 1H); 3.88 (s, 3H); 7.0 (d, 2H); 7.26 (s, 4H) 7.86 (d, 2H).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:21]([C:26](O)=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1>>[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:21]([C:26]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1ccccc1-c1ccccc1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with Biphenyl-2-carboxylic acid. LC-MS (basic): tR=1.34 min; [M+H]+=457.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH:10]1[CH2:16][CH:15]2[N:17]([CH3:18])[CH:12]([CH2:13][CH2:14]2)[CH2:11]1)=O.[ClH:19].[NH2:20][OH:21].C([O-])(=O)C.[NH4+]>C(O)C.O>[ClH:19].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](/[CH:10]1[CH2:16][CH:15]2[N:17]([CH3:18])[CH:12]([CH2:13][CH2:14]2)[CH2:11]1)=[N:20]\[OH:21]
Reactant: CN1C2CCC1CC(C(=O)c1ccccc1F)C2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN1C2CCC1CC(/C(=N/O)c1ccccc1F)C2

Procedure:
A mixture of (2-fluorophenyl)(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)methanone (29.5 g), hydroxylamine hydrochloride (16.5 g) and ammonium acetate (27.5 g) were heated in 80 ml of refluxing ethanol-water (3:1 mixture) for 19 hours. The mixture was cooled and the precipitated product was collected (25.2 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:5]=[C:4]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:3]=1.[NH:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:15][C:14]([NH:13][C:4]1[N:5]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:7]=[C:2]([N:18]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=1)([CH3:17])[CH3:16]
Reactant: CC(C)(C)Nc1cc(Cl)nc(NC(C)(C)C)n1
Reactant: C1CNCCNC1
Product: CC(C)(C)Nc1cc(N2CCCNCC2)nc(NC(C)(C)C)n1
Yield: 55.3 %

Procedure:
By reacting 4-chloro-2,6-bis(1,1-dimethylethylamino)-pyrimidine with hexahydro-1H-1,4-diazepine as described in Example 4, the title product is obtained in a yield of 55.3%, m.p.: 127°-132° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([NH:16][CH:17]=[O:18])[CH:6](O)[C:7](=[CH2:14])[CH2:8][CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH3:2].S(Br)([Br:22])=O.O>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([NH:16][CH:17]=[O:18])[CH:6]=[C:7]([CH2:14][Br:22])[CH2:8][CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH3:2]
Reactant: C=C(CCOC(C)=O)C(O)C(NC=O)C(=O)OCC
Reactant: O=S(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C=C(CBr)CCOC(C)=O)NC=O
Reaction time: 1 h

Procedure:
9.19 g (35.9 mmol) of 6-acetoxy-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 100 ml of dichloromethane, and 3.34 ml (43.1 mmol) of thionyl bromide are added dropwise at room temperature. After one hour, 10 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, saturated potassium hydrogen carbonate solution and again with water, dried over magnesium sulfate, filtered and concentrated by evaporation. 6-acetoxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a brownish oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:8]([CH3:9])[C:7]([CH2:10][OH:11])=[N:6][CH:5]=1.I[CH3:13]>C1COCC1.CCOC(C)=O>[Br:3][C:4]1[N:8]([CH3:9])[C:7]([CH2:10][O:11][CH3:13])=[N:6][CH:5]=1
Reactant: Cn1c(Br)cnc1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCc1ncc(Br)n1C
Reaction time: 0.25 h
Yield: 27.4 %

Procedure:
NaH (60%, 30 mg) was added to a solution of (5-bromo-1-methyl-1H-imidazol-2-yl)methanol (120 mg, 0.63 mmol) in THF (4 mL). After stirring for 15 minutes, iodomethane (35 uL, 0.57 mmol) was added. The resulting solution was stirred at 60° C. under microwave irradiation for 60 minutes. The reaction mixture was diluted with EtOAc, filtered and concentrated in vacuo. The residue was purified using Biotage silica gel column chromatography eluting with EtOAc to give the title compound as light brown oil (32 mg, 25%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.Cl.[NH2:16][OH:17]>N1C=CC=CC=1>[OH:17][N:16]=[C:7]([C:6]1[O:5][CH:4]=[N:3][C:2]=1[CH3:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ncoc1C(=O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ncoc1C(=NO)c1ccccc1
Temperature: 50 °C
Yield: 40.1 %

Procedure:
To a stirred solution of (4-methyl-1,3-oxazol-5-yl)(phenyl)methanone (1.34 g, 7.15 mmol) in pyridine (40 mL), was added hydroxylamine hydrochloride (1.24 g, 17.9 mmol) and the reaction mixture was heated at 50° C. for 15 h. The reaction mixture was concentrated in vacuo. Water (60 mL) was added and the mixture was extracted with ethyl acetate (3×30 ml). The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude material on silica gel afforded N-hydroxy-1-(4-methyl-1,3-oxazol-5-yl)-1-phenylmethanimine (0.58 g, 39%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1)[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH2:22][C:23]([N:28]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:34]#[N:35])=[CH:36][CH:37]=2)[CH2:26][CH3:27])=[O:24])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CCNCc1ccc(C#N)cc1
Product: CCN(Cc1ccc(C#N)cc1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 4-ethylaminomethyl-benzonitrile
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8](=[O:26])[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[C:10]([CH3:17])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[CH:40]([CH3:42])[CH3:41]>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:26][CH:40]([CH3:42])[CH3:41])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[C:10]([CH3:17])=[N:11]2
Reactant: CC(C)I
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(C)c(Cc3ccc(F)cc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(F)cc3)c(OC(C)C)c12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of [8-chloro-3-(4-fluorobenzyl)-2-methyl-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.020 g), N,N-dimethylformamide (1.0 mL), potassium carbonate (0.020 g) and 2-iodopropane (0.050 g) was stirred at room temperature for 2 days. The mixture was diluted with water, extracted with ethyl acetate and the combined extracts washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:9 by volume) to afford title compound as a light brown oil, 0.024 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[C:12]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22](Cl)=[O:23])[CH2:17][CH2:16]1)(=[O:14])[CH3:13].Cl>>[C:12]([N:15]1[CH2:16][CH2:17][CH:18]([CH2:21][C:22]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:23])[CH2:19][CH2:20]1)(=[O:14])[CH3:13]
Reactant: CC(=O)N1CCC(CC(=O)Cl)CC1
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)N1CCC(CC(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a stirred mixture of 50 parts of fluorobenzene and 32 parts of aluminium trichloride is added dropwise (slowly) a solution of 26.5 parts of 1-acetyl-4-piperidineacetyl chloride in 50 parts of fluorobenzene. Upon completion, stirring is continued for 2 hours at reflux temperature. The reaction mixture is cooled to room temperature and poured onto a mixture of crushed ice and a hydrochloric acid solution. The aqueous phase is separated and extracted with methylbenzene. The combined organic phases are dried, filtered and evaporated, yielding 31 parts (90%) of 2-(1-acetyl-4-piperidinyl)-1-(4-fluorophenyl)ethanone as a residue.
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[NH3:14]>>[NH2:14][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: N
Reactant: O=C(O)c1cnc(Cl)c([N+](=O)[O-])c1
Product: Nc1ncc(C(=O)O)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to example 154a from 6-chloro-5-nitro-nicotinic acid and conc. ammonia (aq).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[F:16][CH2:17][C:18]([C:22]1[O:26][N:25]=[C:24]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[CH:23]=1)([CH3:21])[CH2:19][F:20].CCN(C(C)C)C(C)C>C1COCC1.CN(C1C=CN=CC=1)C>[F:20][CH2:19][C:18]([C:22]1[O:26][N:25]=[C:24]([NH:27][C:28](=[O:29])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:6][CH:7]=2)[CH:23]=1)([CH3:21])[CH2:17][F:16]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)no1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)Nc2cc(C(C)(CF)CF)on2)cc1
Temperature: 65 °C
Yield: 100.3 %

Procedure:
To a stirred solution of tert-butyl 4-aminophenylcarbamate (176 mg, 0.85 mmol) in 5 mL of THF was added phenyl 5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (250 mg, 0.85 mmol), DIEA (147 mL, 0.85 mmol), and DMAP (5.2 mg, 0.043 mmol). The resulting mixture was heated at 65° C. for 90 min. LC-MS indicated that the reaction was complete. The organic solvent was removed under reduced pressure and the residue was purified with silica gel column chromatography, eluting with 0-50% EtOAc in hexanes, to give tert-butyl 4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenylcarbamate (350 mg, 95%). LC-MS (ESI) m/z 411 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:18]#[N:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[CH2:20]([NH:22][CH3:23])[CH3:21]>C(#N)C.[I-].[K+]>[CH2:20]([N:22]([CH3:23])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:18]#[N:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH3:21]
Reactant: N#CC1(c2ccc(OCCCCl)cc2)CCOCC1
Reactant: CCNC
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCN(C)CCCOc1ccc(C2(C#N)CCOCC2)cc1
Temperature: 60 °C
Yield: 61.7 %

Procedure:
A mixture of 4-[4-(3-chloro-propoxy)-phenyl]-tetrahydropyran-4-carbonitrile (3.0 g, 10.7 mmol), potassium iodide (100 mg, 0.60 mmol) and ethylmethylamine (5.0 ml, 58.3 mmol) in acetonitrile (30 mL) was heated to 60° C. overnight. The mixture was cooled, concentrated in vacuo and partitioned between dilute Na2CO3 solution (40 ml) and ethyl acetate (80 ml). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the crude material was carried out with flash chromatography (silica gel, ethyl acetate/methanol/aqueous ammonia 98:2:0.2 to 85:15:1.5) to afford 4-(4-{3-[ethyl(methyl)amino]propoxy}phenyl)tetrahydro-2H-pyran-4-carbonitrile as a pale yellow oil (2.0 g, 6.6 mmol, 62%). 1H NMR (400 MHz CDCl3) δ 1.06 (t, 3H), 1.91-2.00 (m, 2H), 2.00-2.14 (m, 4H), 2.25 (s, 3H), 2.40-2.50 (m, 2H), 2.53 (t, 2H), 3.89 (m, 2H), 4.00-4.11 (m, 4H), 6.91 (d, 2H), 7.38 (d, 2H).