Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]=O.Cl.[CH3:11][NH:12][CH3:13]>>[CH3:11][N:12]([CH2:8][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:1]1=[O:7])[CH3:13]
Reactant: C=O
Reactant: CNC
Reactant: O=C1CCCCC1
Agent: Cl
Product: CN(C)CC1CCCCC1=O

Procedure:
The Mannich base (I) is prepared by reacting cyclohexanone with formaldehyde and dimethylamine hydrochloride to produce the hydrochloride salt of 2-dimethylamino methyl cyclohexanone. Methods of preparing this base are known in the art. For example, Mannich reported a method wherein excess cyclohexanone is reacted with one equivalent each of dimethylamine HCl and formaldehyde. (Ber. 53B, 1874-1880 (1920)). Grunenthal (Tramadol's innovator) reported a method wherein two equivalents of cyclohexanone were reacted with one equivalent each of dimethylamine HCl and formaldehyde, using glacial acetic acid as a solvent. This method used by Grunenthal was reported in the original work on Tramadol published in Arzneimittel-Forsch./Drug Res. Although either of these methods may be used in the inventive process to prepare the Mannich Base, the method of Grunenthal is preferred because it provides higher yields and is more manageable in the laboratory. For best results, the Mannich base hydrochloride is isolated from the Mannich reaction mixture by distillation, preferably vacuum distillation, followed by crystallization. Vacuum distillation was found to be an effective way to remove the impurities such as water, acetic acid and cyclohexanone from the system. Following distillation, acetone is added to the residue to produce a thick slurry. The slurry is cooled, collected and washed with acetone. The wetcake or dried material is then dissolved in water and converted to the free base by addition of 50% NaOH. The free base is extracted into toluene.
Reaction SMILES: [PH2](=O)O.C(N(CC)CC)C.C[Si](Cl)(C)C.[CH2:16]([O:23][C:24]([CH:26]([CH2:40][CH2:41][C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[CH2:27][P:28](CCCC1C=CC=CC=1)(=[O:30])[OH:29])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)(Cl)Cl>[CH2:16]([O:23][C:24]([CH:26]([CH2:40][CH2:41][C:42]([O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:43])[CH2:27][PH:28](=[O:29])[OH:30])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(CCC(CP(=O)(O)CCCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: O=[PH2]O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CCC(C[PH](=O)O)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C

Procedure:
Dry phosphinic acid (100 g, 1.52 mol) was dissolved in 100 ml of chloroform and treated with triethylamine (155 g, 1.52 mol). The mixture was evaporated and transferred to a three liter flask, containing 750 mL of chloroform. The solution was stirred by means of a mechanical stirrer and the flask cooled to 0° C. The clear solution was treated with triethylamine (277 g, 2.72 mol) followed by trimethylsilyl chloride (281 g, 2.58 mol). Once addition of trimethylsilyl chloride was complete dibenzyl 2-methylenepentanedioate (2) in 150 mL of chloroform was added dropwise over 20 minutes. The low temperature bath was removed and the mixture warmed to room temperature. After 6 hours the thick slurry was filtered and the filtrate cooled to 0° C. The filtrate was then quenched with 5% hydrochloric acid and the organic layer removed. The aqueous layer was extracted with chloroform, the organics combined, dried (MgSO4) and evaporated under reduced pressure to give 55 g of 2,4-di(benzyloxycarbonyl)butylphosphinic acid (6) as a light yellow liquid. The liquid was purified by flash chromatography and eluted using 3:1 hexanes/ethyl acetate containing 5-trifluoroacetic acid to give 40 g (7%) of the desired product. Rf 0.28 (3:1 Hex./EtOAc 5% TFA); 1H NMR (CDCl3): 7.3 ppm (m, 10H), 7.2 ppm (d, 1H), 5.12 ppm (s, 2H), 2.9 ppm (m, 1H), 2.4 ppm (t, 2H), 2.2 ppm (m, 1H), 2.0 ppm (m, 3H).
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([CH2:8][S:9][CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:5][CH:4]=1)=[O:2].[CH2:23](O)[CH2:24][OH:25]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:2]1[CH2:23][CH2:24][O:25][CH:1]1[C:3]1[O:7][C:6]([CH2:8][S:9][CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:5][CH:4]=1
Reactant: OCCO
Reactant: O=Cc1ccc(CSCCN2C(=O)c3ccccc3C2=O)o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCSCc1ccc(C2OCCO2)o1
Reaction time: 6 h
Yield: 79 %

Procedure:
A mixture of N-[2-[(5-formyl-2-furanylmethyl)thio]ethyl ]-1H-isoindole-1,3-(2H)-dione (15 g), p-toluenesulphonic acid (0.12 g) and 1,2-ethanediol (6.2 g) in benzene (160 ml) was refluxed under Dean-Starke conditions. After 6 hours, the solution was washed with a solution of sodium carbonate (1.2 g) in water (25 ml), dried (Na2CO3), decolourised (charcoal) and evaporated in vacuo. The semi-solid residue was suspended in ether (200 ml) and filtered off to give the title compound (13.5 g), m.p. 83°-85°.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:14][CH:13]([CH2:15][OH:16])[CH:12]2[CH2:17][OH:18])=[C:4]([O:19]CC2C=CC=CC=2)[N:3]=1.C[O-].[Na+].Cl.CS(C)=O>CO>[NH2:1][C:2]1[NH:3][C:4](=[O:19])[C:5]2[N:6]=[CH:7][N:8]([CH:11]3[CH2:14][CH:13]([CH2:15][OH:16])[CH:12]3[CH2:17][OH:18])[C:9]=2[N:10]=1
Reactant: Nc1nc(OCc2ccccc2)c2ncn(C3CC(CO)C3CO)c2n1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: Nc1nc2c(ncn2C2CC(CO)C2CO)c(=O)[nH]1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A solution of [1S-(1α, 2β, 3α)]-3-[2-amino -6-(phenylmethoxy)-9H-purin-9-yl]-1,2-cyclobutanedimethanol, dibenzoate ester (20.0 g.) in 550 ml. of methanol under argon was treated with 5 ml. of 25% sodium methoxide in methanol and heated at 40° C. for 2 hours. Aqueous hydrochloric acid (3N, 275 ml.) was then added to the reaction mixture, and heating was continued at 50° C. for 2 hours. This mixture was concentrated to 100 ml. and the solution was transferred to a separatory funnel, with addition of another 100 ml. of water. The solution was extracted with ether (3×100 ml.) and the pH of the aqueous layer was adjusted to 8.5 with the slow addition of 360 ml. of 2N potassium hydroxide. The resulting thick precipitate was filtered and the damp solid was recrystallized by dissolving in 200 ml. of hot water, filtering while hot, and chilling at 5° C. overnight. Drying in vacuo over phosphorus pentoxide gave 7.65 g. of an impure white solid. Chromatography on 750 ml. of CHP-20P resin with gradient elution using acetonitrile and water, concentration of the pertinent product fractions until turbid, and chilling this turbid solution for 1 hour at 0° C. gave crystals which were filtered. Drying in vacuo at room temperature over phosphorus pentoxide gave 6.3 g. of the title compound as a white crystalline solid, m. p. >270° C., [α]D =-27° (c=1.0, DMSO).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16](C=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[CH3:30][NH:31][CH2:32][CH:33]([OH:36])[CH2:34][OH:35].[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:30][N:31]([CH2:32][CH:33]([OH:36])[CH2:34][OH:35])[CH3:37])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: CNCC(O)CO
Agent: [Na+]
Solvent: ClCCl
Product: CN(Cc1ccc2c(c1)cc(-c1ccc(Cl)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C)CC(O)CO

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 3-methylamino-1,2-propanediol (21 mg, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[N-(2,3-dihydroxypropyl)-N-methylaminomethyl]indol-2-yl}isoindolinone.
Reaction SMILES: [F:1][C:2]1([F:14])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([OH:13])=[O:12])[C:4]=2[O:3]1.C([Li])CCC.[Cl:20]C(Cl)(Cl)C(Cl)(Cl)Cl.Cl>O1CCCC1.CCCCCC>[Cl:20][C:7]1[C:5]2[O:6][C:2]([F:1])([F:14])[O:3][C:4]=2[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(O)c1cccc2c1OC(F)(F)O2
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1ccc(Cl)c2c1OC(F)(F)O2
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
7.5 g (0.038 mol) of 2,2-difluoro-1,3-benzodioxole-4-carboxylic acid, prepared according to the process described in European Application 0,333,658, are dissolved, with stirring and under an argon atmosphere, in 75 ml of dry tetrahydrofuran (THF). ml (0.081 mol) of n-butyllithium in solution in hexane are run in dropwise at -70° C. After stirring for 1 hour, 8.9 g (0.038 mol) of hexachloroethane in solution in 50 ml of dry tetrahydrofuran (THF) are run in. After 2 hours at -70° C., the temperature is allowed to return to 10° C. The reaction mixture is hydrolysed with 150 ml of ice-cold water and brought to a pH of approximately 1 by addition of 1N hydrochloric acid. The aqueous phase is extracted with ether, dried over magnesium sulphate and concentrated under vacuum. The solid is washed with heptane to give 3.7 g (0.016 mol) of 7-chloro-2,2-difluoro-1,3-benzodioxole-4-carboxylic acid (yield: 42%; melting point: 185° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[I:12][Cl:13]>C(O)(=O)C>[ClH:13].[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccccc1N
Reactant: ClI
Solvent: CC(=O)O
Product: COC(=O)c1cc(I)ccc1N
Product: Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.5 %

Procedure:
To a solution of 25 g (0.165 mol) of methyl 2-aminobenzoate in 3 L of glacial acetic acid was added a second solution of 26.82 g (0.165 mol)iodine monochloride in 250 mL of glacial acetic acid over 20-30 min. The resulting mixture was stirred at room temperature for 24 h. The ensuing precipitate was filtered, washed with glacial acetic acid followed by diethyl ether, and dried to provide 43.2 g of the title compound, which was generally used without further purification in subsequent steps, m.p. 188-192° C.; 1H NMR (300 MHz, Me2SO--d6): δ3.79 (s,3H); 6.67 (d,1H); 7.50 (dd,1H); 7.93 (d,1H). Anal. Calcd. for C8H9NO2ICl: C, 30.65; H, 2.89; N, 4.47; O, 10.21; Cl, 11.31; I, 40.48. Found: C, 31.19; H, 2.85; N, 4.48; 0, 10.27; Cl, 11.72; I, 40.15.
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.S1[CH2:17][CH2:16][C:15](=[O:18])NC1=O.[OH-].C([N+:25](CCCC)(CCCC)CCCC)CCC.CS(O)(=O)=O>>[CH:5]1[N:6]=[CH:7][NH:8][C:4]=1[CH2:3][C@H:2]([NH:1][C:15]([CH2:16][CH2:17][NH2:25])=[O:18])[C:9]([OH:11])=[O:10]
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: O=C1CCSC(=O)N1
Agent: CS(=O)(=O)O
Agent: [OH-]
Product: NCCC(=O)N[C@@H](Cc1cnc[nH]1)C(=O)O
Yield: 79.6 %

Procedure:
Following the procedure of Example 1., 1.55 g. (10 mmol) of L-histidine and 2.62 g. (20 mmol) of tetrahydro-1,3-thiazin-2,4-dione were reacted, using 40% aqueous tetra-n-butylammonium hydroxide solution to raise pH and methanesulfonic acid to lower pH, to give 1.80 g. (79.6% yield) of L-carnosine.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[CH2:5]([O:12][C@:13]1([CH3:36])[C@H:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:16]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:15][C@@H:14]1O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CO>C(N(CC)CC)C>[CH2:28]([O:27][CH2:26][C@@H:16]([OH:15])[C@@H:17]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@@:13]([O:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH:36]=[N:4][O:3][CH3:2])[CH3:14])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CON
Reactant: C[C@@]1(OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H]1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CON=C[C@](C)(OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.7 %

Procedure:
0.69 g of O-methylhydroxylamine hydrochloride was added to a mixture of 2.0 g of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-3-methyloxolan-2-ol and 10 mL of methanol, and thereafter, 0.56 g of triethylamine was added dropwise to the mixture. The obtained mixture was stirred at room temperature for 6 hours. Thereafter, the solvent was distilled away under reduced pressure, and 20 mL of ethyl acetate and 20 mL of water were then added to the obtained residue. The organic layer was fractionated, and was then washed with water twice. The solvent was distilled away under reduced pressure, so as to obtain 2.0 g of (2R,3R,4S)-1,3,4-tris(benzyloxy)-4-((methoxyimino)methyl)pentan-2-ol in the form of a colorless oily product.
Reaction SMILES: [Mg].[CH3:2][CH2:3][O:4][C:5]([C@H:7]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:6].O.Br[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[C:23]=1[F:30]>O1CCCC1>[C:16]([O:15][C:13]([NH:8][C@H:7]([CH2:11][CH2:10][C:9]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[C:23]=1[F:30])=[O:12])[C:5]([O:4][CH2:3][CH3:2])=[O:6])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Fc1ccc(Br)c(F)c1F
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](CCC(=O)c1ccc(F)c(F)c1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of magnesium (0.452 g) in tetrahydrofuran (20 mL), 1-bromo-2,3,4-trifluorobenzene (2.21 mL) was added dropwise at 55° C. over 15 minutes, and the reaction solution was stirred at room temperature for 30 minutes. This solution was added dropwise to a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (4.0 g) in tetrahydrofuran (25 mL) at −40° C. over 10 minutes, and the reaction solution was stirred at −40° C. to 0° C. for one hour. Water was added to the solution in small portions at 0° C., followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 4.2 g of the title compound as a colorless oil. The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:16]2[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1.[Cl:23][C:24]1[C:29]([C:30](O)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:26][CH:25]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:29]([C:30]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[N:10]=[CH:9][CH:8]=[C:7]3[O:6][C:5]2[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:26][CH:25]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)ccnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4cccc(C(F)(F)F)c4)ccnc23)c1F
Yield: 21.3 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(3-(trifluoromethyl)phenoxy)quinolin-8-amine (Intermediate-11, 100 mg, 0.327 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 200 mg, 0.699 mmol), oxalyl chloride (125 mg, 0.99 mmol), DMF (1 drop) and DIPEA (126 mg, 0.98 mmol) in CH2Cl2 (5 mL) to afford 40 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.77 (s, 1H), 8.79 (d, J=8.7 Hz, 1H), 8.73 (d, 1H), 8.17 (br t, 1H), 8.08 (d, J=8.7 Hz, 1H), 7.78-7.67 (m, 5H), 7.41-7.35 (m, 2H), 6.83 (d, 1H), 4.32 (d, 2H), 1.14 (s, 9H); MS [M+H]+: 574.31.
Reaction SMILES: O=[CH:2][CH2:3][N:4]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:5](=[O:17])[CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.[NH2:33][CH2:34][CH2:35][C:36]1[C:44]2[S:43][C:42](=[O:45])[NH:41][C:40]=2[C:39]([OH:46])=[CH:38][CH:37]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[OH:46][C:39]1[C:40]2[NH:41][C:42](=[O:45])[S:43][C:44]=2[C:36]([CH2:35][CH2:34][NH:33][CH2:2][CH2:3][N:4]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:5](=[O:17])[CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:37][CH:38]=1
Reactant: O=CCN(CCCCCOCCc1ccccc1)C(=O)CCOCCc1ccccc1
Reactant: NCCc1ccc(O)c2[nH]c(=O)sc12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: O=C(CCOCCc1ccccc1)N(CCCCCOCCc1ccccc1)CCNCCc1ccc(O)c2[nH]c(=O)sc12
Reaction time: 8 h

Procedure:
N-(2-Oxoethyl)-3-phenethyloxy-N-(5-phenethyloxypentyl)propanamide (Example 9c), 0.12 g) was dissolved in methanol (5 mL) and treated with 7-(2-aminoethyl)-4-hydroxy-3H-benzothiazol-2-one hydrochloride (0.32 g), acetic acid (0.1 mL) and water (0.3 mL). The resultant mixture was stirred for 2 hours and then sodium cyanoborohydride (0.01 g) was added and the reaction mixture was stirred overnight. The mixture was concentrated in vacuo and the residue was taken up in methanol (5 mL) and adsorbed onto silica gel. The product was purified by flash chromatography eluting with 5% methanol, 1% ammonia in dichloromethane. Collected fractions were concentrated and the resultant residue was taken up in dichloromethane (5 mL) and treated with 4N hydrogen chloride in dioxane (0.2 mL). The mixture was stirred vigorously and concentrated. The resulting gum was azeotroped with dichloromethane (3×5 mL) to give the titled compound (0.13 g) as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[N:45]=[C:44]([CH3:46])[CH:43]=[CH:42][CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[CH:41]=[CH:42][CH:43]=[C:44]([CH3:46])[N:45]=5)=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Reactant: Cc1cccc(Br)n1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1cccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)n1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 6-bromo-2-picoline (344 mg, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 100° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature and purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (425 mg, 82%) as a yellow oily substance.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].Br[CH2:35][C:36](N)=[O:37].[OH-:39].[Li+]>>[C:36]([CH2:35][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([NH:14][C:5]2([C:3]([OH:2])=[O:4])[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)=[O:33])=[CH:17][C:18]=1[O:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1)([OH:37])=[O:39]
Reactant: COC(=O)C1(NC(=O)c2ccc(O)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1
Reactant: [OH-]
Reactant: NC(=O)CBr
Agent: [Li+]
Product: Cc1cccc(CCOc2cc(C(=O)NC3(C(=O)O)Cc4ccccc4C3)ccc2OCC(=O)O)c1

Procedure:
The title compound was prepared in analogy to example 270 from the compound of step 1 of example 254 and 2-bromo-acetamide. In the final hydrolysis step, 6 equivalents of lithium hydroxide were used, resulting in the hydrolysis of the ester moiety and the acetamide moiety.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(O)(O)(=O)=O.[NH2:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1.C(N(CC)CC)C>ClCCl.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[NH:16]1[CH:17]=[CH:18][N:19]=[C:15]1/[N:14]=[CH:1]/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ncc[nH]1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C(=N/c1ncc[nH]1)\c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of benzaldehyde (1.92 ml, 18.8 mmol) in dichloromethane (15 ml) were added sequentially 2-aminoimidazole sulfate (3.77 g, 14.3 mmol), tetraisopropyl orthotitanate (6.83 ml, 23.3 mmol) and triethylamine (3.90 ml, 2.81 mmol). The reaction mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was taken up in ethyl acetate and water and the mixture filtered. The filtrate phases were separated and the organic phase dried over sodium sulfate and concentrated in vacuo to yield the title compound as a yellow solid which was used in the next step without further purification (3.03 g, 95%); MS (ISP): 172.1 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.[C:10]([O-:13])(=O)C.[K+].[Se].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1>O1CCCC1>[C:20]1([CH3:23])[CH:21]=[CH:22][C:17]([NH:16][C:10]([NH:1][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:13])=[CH:18][CH:19]=1
Reactant: CC(=O)[O-]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: Cc1ccc(N)cc1
Agent: [K+]
Agent: [Se]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)Nc2ccccc2)cc1
Temperature: 180 °C

Procedure:
Ten milliliters of nitrobenzene, 100 milliliters of tetrahydrofuran, 1.0 gram potassium acetate, 1.0 gram selenium and 21.4 grams of p-toluidine are charged to the autoclave which is then flushed and pressured to 800 psig with carbon monoxide. The temperature is raised to 180° C. for one hour giving 1-p-tolyl-3-phenylurea as product.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:34]([N:41]1[C:46](=[O:47])[C:45]([CH2:48]OS(C)(=O)=O)=[CH:44][C:43]([C:54]2[CH:59]=[CH:58][C:57]([F:60])=[C:56]([CH3:61])[CH:55]=2)=[N:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN1CCNCC1>>[CH2:34]([N:41]1[C:46](=[O:47])[C:45]([CH2:48][N:11]2[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]2)=[CH:44][C:43]([C:54]2[CH:59]=[CH:58][C:57]([F:60])=[C:56]([CH3:61])[CH:55]=2)=[N:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccccc3)n2)ccc1F
Agent: CN1CCNCC1
Product: Cc1cc(-c2cc(CN3CCN(C)CC3)c(=O)n(Cc3ccccc3)n2)ccc1F
Yield: 81.3 %

Procedure:
Following the procedure of Example 1 (10), 2-benzyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 81.3%).