Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([S:14]([F:19])([F:18])([F:17])([F:16])[F:15])[CH:13]=1)[C:8]([OH:10])=[O:9].[CH3:20][O:21][CH2:22][CH2:23]Br.CO>CN(C=O)C>[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([S:14]([F:19])([F:15])([F:16])([F:17])[F:18])[CH:13]=1)[C:8]([O:10][CH2:23][CH2:22][O:21][CH3:20])=[O:9]
Reactant: COCCBr
Reactant: O=C(O)c1cc(CO)cc(S(F)(F)(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COCCOC(=O)c1cc(CO)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.1 %

Procedure:
At 0° C., 86 mg (2.16 mmol) of sodium hydride (60% strength suspension in mineral oil) were added to a solution of 200 mg (0.719 mmol) of the compound of Example 37A in 5.7 ml of anhydrous DMF, and the mixture was then warmed to RT. 300 mg (2.16 mmol) of 2-bromoethyl methyl ether were then added, and the reaction mixture was stirred at 60° C. for about 16 h. After cooling to RT, 1 ml of methanol was added. In two portions, the reaction mixture was then separated into its components by preparative HPLC (Method 33). The product fractions were combined and concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 58 mg (20% of theory) of the title compound. In addition, 138 mg (57% of theory) of 2-methoxyethyl 3-(hydroxymethyl)-5-(pentafluoro-λ6-sulphanyl)benzoate were isolated, which were then reacted once more in the manner described above with 2-bromoethyl methyl ether to give a further 30 mg of the title compound.
Reaction SMILES: CN(C)C(OC(C)(C)C)N(C)C.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:14][CH3:15].[CH3:20][N:21]([CH:23]=O)[CH3:22]>>[CH3:22][N:21]([CH3:20])/[CH:23]=[C:14](\[CH3:15])/[C:13]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CC
Reactant: CN(C)C=O
Agent: CN(C)C(OC(C)(C)C)N(C)C
Product: CCOC(=O)/C(C)=C/N(C)C
Yield: 30 %

Procedure:
A solution of N,N,N′,N′-tetramethyl-1-[(2-methylpropan-2-yl)oxy]methanediamine (2.47 g, 14.19 mmol), ethyl propionate (2.17 g, 21.27 mmol) and DMF (2 mL) in a sealed tube was heated to 90° C. for 24 h. Then extracted with ethyl acetate, collected the organic phase and washed with water, brine and dried with anhydrous sodium sulfate. Organic phase was concentrated and purified by silica gel chromatograph to give 0.68 g of the title compound (30%). 1H NMR (400 MHz, CDCl3): δ 1.24 (3H, t, J=7.2 Hz), 1.95 (3H, s), 3.00 (6H, s), 4.11 (2H, q, J=7.2 Hz), 7.28 (1H, s). [M+H] Calc'd for C8H15NO2, 158. Found, 158.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]#[N:21].C(#N)C>O>[CH:4]([C:3]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:2]=1[O:1][CH2:19][C:20]#[N:21])=[O:5]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(C=O)c(OCC#N)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.6 %

Procedure:
The mixture of 2-hydroxy-4-methoxybenzaldehyde (9.50 g), potassium carbonate (17.3 g), bromoacetonitrile (11.2 g) and acetonitrile (100 ml) was stirred at room temperature for 12 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate), and then recrystallized from ethyl acetate-hexane to obtain the entitled compound (10.7 g).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:7]([F:35])=[C:8]([CH:12]2[C:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[F:26])([C:17]#[N:18])[CH:15]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[NH:14][CH:13]2[C:32](O)=[O:33])[CH:9]=[CH:10][CH:11]=1.[NH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[C:42](=[O:46])[NH:41][C:40]2=[O:47]>C(N(CC)CC)C>[O:46]=[C:42]1[C:43]2[C:39](=[CH:38][C:37]([NH:36][C:32]([CH:13]3[CH:12]([C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[C:7]=4[F:35])[C:16]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=4[F:26])([C:17]#[N:18])[CH:15]([CH2:27][C:28]([CH3:31])([CH3:29])[CH3:30])[NH:14]3)=[O:33])=[CH:45][CH:44]=2)[C:40](=[O:47])[NH:41]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1ccc2c(c1)C(=O)NC2=O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc3c(c2)C(=O)NC3=O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of thionyl chloride (2 mL), rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (110 mg, 0.24 mmol) was added and the mixture was stirred at rt for 2 hrs. The excess thionyl chloride was removed and the residue was dissolved in methylene chloride (5 mL) and 5-amino-isoindole-1,3-dione (Aldrich, 0.30 mmol) was added followed by the addition of triethylamine (0.2 mL). The mixture was stirred overnight. The solvent was removed and the residue was purified on an ISCO machine (24 g column, eluent, 40-80% EtOAc/hexanes) to give a pale yellow solid. 10 mg.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([CH2:22][S:23][CH3:24])[CH:21]=1)[NH:18][CH:17]=[CH:16]2.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[C:33]([CH:36]1[CH2:38][CH:37]1[C:39]#[N:40])(O)[CH3:34]>ClCCl>[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[C:33]([CH:36]1[CH2:38][CH:37]1[C:39]#[N:40])([C:16]1[C:15]2[C:19](=[C:20]([CH2:22][S:23][CH3:24])[CH:21]=[C:13]([F:12])[CH:14]=2)[NH:18][CH:17]=1)[CH3:34]
Reactant: CSCc1cc(F)cc2cc[nH]c12
Reactant: CC(O)(c1ccc(F)cc1F)C1CC1C#N
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cc(F)cc2c(C(C)(c3ccc(F)cc3F)C3CC3C#N)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
273 mg (1.23 mmol) of indium(III) chloride and 0.1 ml (1.34 mmol) of trifluoroacetic acid were added to 250 mg (1.12 mmol) of the compound from Example 11A and 437 mg (2.24 mmol) of the compound from Example 133A were introduced into 44 ml of dichloromethane, and the mixture was stirred at RT overnight. The reaction mixture was concentrated in a rotary evaporator. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 313 mg (69% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC(C)=O>[CH2:34]([O:27][C:23]1[CH:22]=[C:21]([CH2:20][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:26]=[CH:25][CH:24]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(Cc1cccc(O)c1)C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC(Cc1cccc(OCc2ccccc2)c1)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 71 %

Procedure:
171 (580 mg, 1 equivalent) was dissolved in 15 ml of acetone, then potassium carbonate (238 mg, 1.1 equivalent) and benzylbromide (1.1 équivalent, 206 μl) were added successively. The reaction mixture was let overnight at room temperature. The reaction mixture is concentrated and 50 ml of AcOEt are added. The organic phase are washed with 10% citric acid, saturated NaHCO3 and brine then dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (AcOEt/Hexane 2/8) to afford 172 as white solid (513 mg, 71%). 1H NMR (CDCl3): δ 1.46 (s, 9H), 2.64 (s, 1H), 3.05 (m, 1H), 3.18 (m, 1H), 4.39 (m, 1H), 5.20 (s, 1H), 5.25 (s, 4H), 6.95 (d, 1H, J=7.1 Hz), 7.00 (d, 1H, J=7.9 Hz), 7.07 (s, 1H), 7.20 (m, 2H), 7.27 (d, 2H, J=7.4 Hz), 7.32 (t, 1H, J=7.9 Hz), 7.50 (m, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH2:9][CH2:8]1.[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1.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:23]1([C:18]2[CH:17]=[CH:16][C:15]([O:21][CH3:22])=[C:14]([CH2:13][N:10]3[CH2:11][CH2:12][N:7]([C:2]4[N:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:8][CH2:9]3)[CH:19]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(Br)cc1CN1CCN(c2ncccn2)CC1
Reactant: Br[Mg]c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccc2)cc1CN1CCN(c2ncccn2)CC1
Temperature: 25 °C

Procedure:
A solution of 182 mg 2-[(4-(2-pyrimidinyl)-piperazinyl)methyl]-4- bromoanisole in 1 mL of tetrahydrofuran heated to 60° C. and 6 mg of Pd(PPh3)4 was added. To this mixture 0.5 mL of a 1M solution of phenylmagnesium bromide in tetrahydrofuran was added dropwise. The reaction mixture was heated at relux temperature under nitrogen for 1 hr, cooled to room temperature and the solvent removed by evaporation under reduced pressure to yield 4-phenyl-2-[(4-(2-pyrimidinyl)-piperazinyl)methyl]anisole which was purified by chromatography on silica gel using 5% methanol in dichloromethane as eluent. Evaporation of the solvent yielded 140 mg of a solid which was treated with ethyl acetate-HCl to give 50 mg of 4-phenyl-2-[(4-(2-pyrimidinyl)piperazinyl)methyl]anisole dihydrochloride (Compound 1 ), mp 205°-207° C.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](=[O:16])([S:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[CH3:6].Cl[C:18](=[O:30])[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.Cl>C(Cl)Cl>[C:5]([S:7][C:8]1[CH:9]=[C:10]([O:14][CH3:15])[CH:11]=[CH:12][C:13]=1[C:18](=[O:30])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=1)(=[O:16])[CH3:6]
Reactant: COc1cccc(SC(C)=O)c1
Reactant: COC(=O)c1ccc(CC(=O)Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc(CC(=O)c2ccc(OC)cc2SC(C)=O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 20.3 %

Procedure:
To a suspension of aluminum trichloride (9.9 g, 74.08 mmol) in DCM (100 ml) was added S-3-methoxyphenyl ethanethioate (step 1) (4.5 g, 30.57 mmol) at 0-5° C., followed by a solution of methyl 4-(2-chloro-2-oxoethyl)benzoate (step 2) (4.5 g, crude, 24.69 mmol) in DCM (20 ml). The mixture was stirred at room temperature for 3 days. The mixture was poured carefully into icy 1 N HCl (200 ml) and extracted with EtOAc (50 ml×2). The combined organic layers were washed with water (100 ml×2) and brine (100 ml), dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (PE/EtOAc=15/1 to 10/1) to afford Intermediate F as a yellow solid (1.8 g, 14%). MS (ESI): m/z 359.0 [M+1]+.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:17][S:18]([C:21]2[CH:22]=[C:23]([CH:27]=[CH:28][C:29](Cl)=[O:30])[CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=1>O1CCCC1>[OH:3][NH:2][C:29](=[O:30])[CH:28]=[CH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([S:18](=[O:20])(=[O:19])[NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH3:9])[CH:12]=2)[CH:22]=1
Reactant: NO
Reactant: COc1cccc(NS(=O)(=O)c2cccc(C=CC(=O)Cl)c2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(NS(=O)(=O)c2cccc(C=CC(=O)NO)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (0.39 g, 5.7 mmol) in tetrahydrofuran (6 ml) a saturated NaHCO3 solution (4.5 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-[3-(3-methoxy-phenylsulfamoyl)-phenyl]-acryloyl chloride (6i) (0.40 g) in tetrahydrofuran (4 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was crystallised from ethyl acetate-acetonitrile affording the title compound (0.15 g, 39%) as a lightly pink crystals. M.p. 137° C. 1H NMR (DMSC-d6, HMDSC) δ: 3.65 (3H, s); 6.38-6.78 (4H, m); 6.98-7.27 (1H, m); 7.34-8.03 (5H, m); 9.14 (1H, br s); 10.30 (1H, s); 10.83 (1H, br s). HPLC analysis on Symmetry C8 column: impurities 5% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 40:60; sample concentration 0.5 mg/ml; flow rate 1.2 ml/min; detector UV 254 nm). Anal. Calcd for C16H16N2O5S containing 1% of inorganic impurities, %: C 54.67, H 4.50, N 8.09. Found, %: C 54.61, H 4.58, N 7.96.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][C:17]([CH3:22])=[CH:18][C:19](Cl)=[O:20]>CC(C)=O.O>[CH3:16][C:17]([CH3:22])=[CH:18][C:19]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:20]
Reactant: CC(C)=CC(=O)Cl
Reactant: COc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(NC(=O)C=C(C)C)cc1
Temperature: 0 °C
Yield: 74.6 %

Procedure:
A mixture of p-anisidine (10 g, 81 mmol, Aldrich) and potassium carbonate (13.5 g, 97.5 mmol, Aldrich) in acetone (125 mL) was cooled to 0° C. and treated with dimethyl acryloyl chloride (10.2 mL, 89.3 mmol). The mixture was allowed to warm to room temperature overnight. The reaction was diluted with water and extracted with dichloromethane. The organic layer was separated, dried over magnesium sulfate, filtered, concentrated, and purified by chromatography on SiO2 (0 to 100% ethyl acetate/dichloromethane) to give 3-methyl-N[4-(methyloxy)phenyl]-2-butenamide (12.4 g, 67%) as a light violet solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.84 (s, 3 H), 2.13 (s, 3 H), 3.71 (s, 3 H), 5.82 (s, 1 H), 6.85 (d, J=9.0 Hz, 2 H), 7.52 (d, J=9.0 Hz, 2 H), 9.67 (s, 1 H); ESIMS (M+H)+=206.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Cl-].[Cl-].[Al+3].C[O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][C:16](=[O:20])[NH:17]2)=[CH:13][CH:12]=1>C(=S)=S>[C:1]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:11]=1[OH:10])[NH:17][C:16](=[O:20])[CH2:15]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)NC(=O)C2
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1cc2c(cc1O)NC(=O)C2
Reaction time: 0.04 h
Yield: 86.6 %

Procedure:
Acetyl chloride (4.09 mL, 0.0575 mol) was added to a slurry of aluminum trichloride (AlCl3) (35.36 g, 0.265 mol) in carbon disulfide (CS2) (250 mL). After 2-3 min, 6-methoxyoxindole (7.22 g, 0.0442 mol) was added. The resulting mixture was heated to reflux for 2.5 hours. (A black tar developed with time). Excess solvent was decanted and ice water was added carefully to the residue. The resulting mixture was stirred overnight. The pale yellow solid obtained was collected, washed with water and dried under high vacuum to give the title compound (7.32 g, 87%).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH:27][CH2:28][CH:29]([CH2:31]O)[OH:30].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CCOCC>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:31][CH:29]([OH:30])[CH2:28][OH:27])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: OCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1
Temperature: 120 °C

Procedure:
A mixture of 722 mg of 4-(n-hexadecylamino)benzoic acid, 736 mg of glycerol, and 412 mg of p-toluene sulfonic acid is heated for 4 hours at 120° C., allowed to cool, and then is treated with ether and 2% aqueous sodium carbonate solution. Filtration affords a white solid which is recrystallized from chloroform to yield 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate, mp 112° C.
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]([CH2:10][C:11]([OH:13])=O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:14]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:9])[CH2:10][C:11]([NH:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)CC(=O)N(c1ccccc1)c1ccccc1
Reactant: NCCN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CC(=O)N(c1ccccc1)c1ccccc1)NCCN1CCOCC1

Procedure:
A solution of 13 g (0.05 mol) of N,N-diphenylcarbamoylacetic acid and 7.1 g (0.055 mol) of N-(2-aminoethyl)morpholine in 120 ml of methylene chloride is refluxed with agitation. A solution of 11 g (0.055 mol) of dicyclohexylcarbodiimide in 30 ml of CH2Cl2 is slowly added and the mixture is maintained under reflux for 3 hours.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[F:18])[CH:3]=[CH:2]1.[C:19]1([CH2:25][C:26]([N:28]=[C:29]=[S:30])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:29]([NH:28][C:26](=[O:27])[CH2:25][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[S:30])=[CH:13][C:12]=2[F:18])[CH:3]=[CH:2]1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: Nc1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.6 %

Procedure:
A mixture of 268 (20 mg, 0.08 mmol) and 2-phenylacetyl isothiocyanate (16 □L, 0.08 mmol) in THF (1 mL) was stirred at room temperature for 2 hours and concentrated. The residue was purified by flash column chromatography (eluent EtOAc) followed by preparative HPLC (column Aqusil C18, gradient elution with 60-95% MeOH in water, 45 min) to afford the title compound 269a (13 mg, 40% yield) as an off-white solid. 1H NMR (CD3OD) δ (ppm): 8.41 (s, 1H), 8.16 (d, 1H, J=5.6 Hz), 8.02 (dd, 1H, J1=2.3Hz, J2=12.2 Hz), 7.62 (d, 1H, J=3.3 Hz), 7.44 (m, 1H), 7.37-7.33 (m, 4H) 7.31-7.26 (m, 1H), 6.65(d, 1H, J=3.1 Hz), 6.52(d, 1H, J=5.7 Hz), 3.76 (s, 2H), MS (m/z): 421.1 (M+H) (found).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O-:20])=[O:19].C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:17][CH2:16][CH2:15][NH:14][C:4]1[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:30]2[CH2:31][CH2:32][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N+:18]([O-:20])=[O:19])[CH2:28][CH2:29]2)[N:3]=1
Reactant: O=[N+]([O-])c1ccccc1N1CCNCC1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCCO)nc(NCCO)nc1N1CCN(c2ccccc2[N+](=O)[O-])CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-(2-nitro-phenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 60° C. to yield 2,4-bis-(2-hydroxy-ethylamino)-6-[4-(2-nitro-phenyl)-piperazin-1-yl]-pyrimidine-5-carbonitrile as a yellowish lyophilisate; MS: [M+H]+=429.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:10])=[O:9])[CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>CC(N(C)C)=O>[C:8]([C:4]1[CH:3]=[C:2]([O:18][C:15]2[CH:16]=[CH:17][C:12]([NH2:11])=[CH:13][CH:14]=2)[CH:7]=[CH:6][N:5]=1)(=[O:9])[NH2:10]
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1
Solvent: CC(=O)N(C)C
Product: NC(=O)c1cc(Oc2ccc(N)cc2)ccn1

Procedure:
Entry 14: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2. Step 4 using DMAC in place of DMF to give 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C4,2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 4-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH2:14][C:15]([NH2:17])=[O:16])[C:9]=2[CH:18]=1)[CH3:3].C[O:20][C:21](=O)[C:22]([C:24]1[C:32]2[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=O.CC([O-])(C)C.[K+]>C1COCC1.CCOC(C)=O>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH3:13])=[C:10]([C:14]3[C:15](=[O:16])[NH:17][C:21](=[O:20])[C:22]=3[C:24]3[C:32]4[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=4)[NH:26][CH:25]=3)[C:9]=2[CH:18]=1)[CH3:3]
Reactant: COC(=O)C(=O)c1c[nH]c2c(C)cccc12
Reactant: Cc1oc2ccc(CN(C)C)cc2c1CC(N)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1oc2ccc(CN(C)C)cc2c1C1=C(c2c[nH]c3c(C)cccc23)C(=O)NC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a solution of 2-(5-dimethylaminomethyl-2-methyl-benzofuran-3-yl)-acetamide (111 mg, 0.406 mmol) and (7-methyl-1H-indol-3-yl)-oxo-acetic acid methyl ester (132 mg, 0.608 mmol) in anhydrous THF (4.0 mL) is added dropwise a 1 M solution of t-BuOK in THF (2.0 mL) at 0° C. under an argon atmosphere. The resulting deep red reaction mixture is stirred for 1 h at 0° C., diluted with EtOAc, washed with a saturated aqueous NH4Cl solution and washed with brine. The combined aqueous phases are extracted with EtOAc and the combined organic phases are dried over Na2SO4, filtered and concentrated at reduced pressure to afford an orange solid. Purification by flash column chromatography (silica gel, EtOAc/acetic acid/water 7:1:1) affords the title compound as an orange solid (122 mg, 0.295 mmol, 73%). 1H NMR (400 MHz, DMSO-d6, 298 K): δ=11.88 (bs, 1H), 11.07 (bs, 1H), 7.91 (s, 1H), 7.38 (d, J=8.3 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 6.93 (s, 1H), 6.75 (d, J=6.8 Hz, 1H), 6.50 (t, J=7.5 Hz, 1H), 6.42 (d, J=7.8 Hz, 1H), 3.40-3.16 (m, 2H), 2.40 (s, 2H), 2.12 (s, 2H), 1.84 (s, 6H). MS (ES+): 414 (M(C26H23N3O3)+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11].Cl[C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:20]=2[N:21]=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:19]2[O:18][C:17]([NH:1][CH2:2][C@@H:3]3[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]3[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[N:21][C:20]=2[CH:22]=1
Reactant: Clc1ccc2oc(Cl)nc2c1
Reactant: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CN
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CNc1nc2cc(Cl)ccc2o1
Temperature: 40 °C

Procedure:
A mixture of (2S,3R)-allyl 2-(aminomethyl)-3-methylpiperidine-1-carboxylate (0.804 g, 3.787 mmol), 2,5-dichlorobenzo[d]oxazole (0.712 g, 3.787 mmol) and DIPEA (1 mL, 5.68 mmol) in acetonitrile (15 mL) was heated at 40° C. overnight. The solvent was removed in vacuo and the crude was purified via silica gel with 0˜100% EtOAc/hexanes to obtain the title compound. ESI-MS (m/z): 364 [M+1]+.