Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]([N+:13]([O-])=O)=[CH:7][CH:8]=2)[N:3]1[CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([O:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:22][CH2:21]1>Cl.O.C(O)C.O1CCCC1.[Zn]>[NH2:13][C:6]1[CH:5]=[C:4]2[C:9]([C:10](=[O:12])[NH:11][C:2](=[O:1])[N:3]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([O:26][CH:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:22][CH2:21]2)=[CH:8][CH:7]=1
Reactant: O=c1[nH]c(=O)n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c2cc([N+](=O)[O-])ccc12
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc2c(=O)[nH]c(=O)n(CCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)c2c1
Yield: 68.9 %

Procedure:
2,4-Dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-7-nitro-1,2,3,4-tetrahydroquinazoline (3.00 g) obtained in Example 11 was dissolved in a mixture of concentrated hydrochloric acid (10.0 ml), water (50.0 ml), ethanol (50.0 ml) and tetrahydrofuran (50.0 ml) and an excess of zinc powder was added in portions. After completion of the reaction, the reaction mixture was filtered, and the filtrate was made basic with 25% aqueous ammonia solution and extracted with ethyl acetate. After the extract was washed with water and dried (Na2SO4), the solvent was distilled off under reduced pressure to give the title compound (1.95 g, 69%). Recrystallization from ethyl acetate yielded a yellow crystal having a melting point of 162 to 164° C.
Reaction SMILES: CN(C)S(N1C(S[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=CN=C1[Si](C(C)(C)C)(C)C)(=O)=O.[Li]CCCC.[CH3:31][N:32]([CH3:50])[S:33]([N:36]1[C:40]([CH:41]=O)=[CH:39][N:38]=[C:37]1[Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])(=[O:35])=[O:34].C(OCC)(=O)C.CCCCCC>C1COCC1>[CH:12]1([CH2:41][C:40]2[N:36]([S:33](=[O:35])(=[O:34])[N:32]([CH3:50])[CH3:31])[C:37]([Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])=[N:38][CH:39]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CN(C)S(=O)(=O)n1c(C=O)cnc1[Si](C)(C)C(C)(C)C
Reactant: CN(C)S(=O)(=O)n1c(Sc2ccccc2)cnc1[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1c(CC2CCCCC2)cnc1[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
2-Tert-butyldimethylsilyl-1-dimethylsulfamoyl imidazole (1) (4.1 g, 14.2 mmol) is taken up in 47 mL of anhydrous THF and cooled to −20° C. n-BuLi (8.9 mL, 14.2 mmol) is added dropwise to the solution of (1). The resultant solution is stirred at −20° C. for 45 min. Cyclohexylmethyl iodide (2) (3.14 g, 14 mmol) is then added dropwise to the reaction mixture. Then reaction is warmed to rt and stirred overnight. The next day the reaction is quenched with saturated ammonium chloride and diluted with water. The mixture is extracted with ethyl acetate (3×100 mL). The organic layers are combined and washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (4:1 ethyl acetate/hexane) affords 2.26 g (5.6 mmol) of 5-cyclohexylmethyl-2-tert-butyldimethylsilyl-1-dimethylsulfamoyl imidazole (3). (3) (2.26 g, 5.6 mmol) is taken up in 56 mL of THF and cooled to 0° C. A 1M solution of TBAF in THF (5.6 mL, 5.6 mmol) is added dropwise to the solution of (3). The reaction is warmed to rt and stirred overnight. The next day the reaction is quenched with water and then extracted with ethyl acetate. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (1:1 ethyl acetate/hexane) affords 1.2 g (4.42 mmol) of 5-cyclohexylmethyl-1-dimethylsulfamoyl imidazole (4). (4) (1.2 g, 4.42 mmol) is taken up in 25 mL of a 1.5N HCl solution and heated at reflux for 2 h. The reaction is cool to rt and diluted with ethyl acetate. The mixture is brought to pH 13 with 2N NaOH and then extracted with chloroform (4×100 mL). The organic layers are combined and washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (9:1 chloroform/methanol) affords 700 mg (4.27 mmol) of 4(5)-cyclohexylmethyl-1H-imidazole (5) (J-1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N+:11]([O-])[CH:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[C-:24]#[N:25].[K+].C(Cl)(=O)C1C=CC=CC=1.O.C(Cl)(Cl)Cl>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([C:24]#[N:25])=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: [C-]#N
Reactant: COc1ccc(-c2cc[n+]([O-])nc2-c2ccc(OC)cc2)cc1
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O=C(Cl)c1ccccc1
Solvent: O
Product: COc1ccc(-c2cc(C#N)nnc2-c2ccc(OC)cc2)cc1
Yield: 64 %

Procedure:
A solution of 3,4-bis-(4-methoxyphenyl)pyridazine 1-oxide [Eur. J. Med. Chem.-Chimica Therapeutica, 14, 53-60 (1979)] (5.01 g, 16.25 mmol) and potassium cyanide (3.17 g, 48.75 mmol) in water (90 ml) was ice-cooled. After benzoyl chloride (7.77 g, 55.25 mmol) was added dropwise with vigorous stirring under a nitrogen gas atmosphere, the resulting mixture was stirred at room temperature for 20 hours. Water-chloroform was added to the reaction mixture, and subsequent to alkalinization, the thus-obtained mixture was extracted with chloroform. The organic layer was washed with water, and was then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue (oil) was separated and purified by chromatography on a silica gel column [hexane/ethyl acetate (5/1)]. Relevant fractions were crystallized from ethyl acetate-diethyl ether-hexane, whereby the title compound was obtained as slightly yellow prisms (3.30 g, 64.0%). Melting point: 113-115° C.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:20]([O:22][C:23]1[N:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=1)[CH3:21]>>[CH2:20]([O:22][C:23]1[N:28]=[CH:27][C:26]([CH2:29][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:25][CH:24]=1)[CH3:21]
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CCOc1ccc(C=O)cn1
Product: CCOc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cn1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 6-ethoxypyridine-3-carbaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(6-ethoxypyridin-3-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:21]([N:24](CC2C=CC(OC)=CC=2)[C:25]2[S:26][CH:27]=[CH:28][N:29]=2)(=[O:23])=[O:22])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[O:19][CH3:20].Cl[CH:40]([CH3:44])[C:41](Cl)=[O:42].ClCC(Cl)=O>>[CH3:20][O:19][C:10]1[CH:11]=[C:12]([C:15]([F:17])([F:18])[F:16])[CH:13]=[CH:14][C:9]=1[N:8]1[C:41](=[O:42])[CH:40]([CH3:44])[O:1][C:2]2[CH:3]=[C:4]([S:21]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:23])=[O:22])[CH:5]=[CH:6][C:7]1=2
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(Nc3ccc(C(F)(F)F)cc3OC)c(O)c2)cc1
Reactant: CC(Cl)C(=O)Cl
Agent: O=C(Cl)CCl
Product: COc1cc(C(F)(F)F)ccc1N1C(=O)C(C)Oc2cc(S(=O)(=O)Nc3nccs3)ccc21

Procedure:
(+/−)-4-(2-methoxy-4-(trifluoromethyl)phenyl)-2-methyl-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide was prepared in a similar fashion to Example 223, starting from 3-hydroxy-4-((2-methoxy-4-(trifluoromethyl)phenyl)amino)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide) (from Step 1, Example 223) and 2-chloropropanoyl chloride instead chloroacetyl chloride. Purification was achieved using reverse-phase HPLC with a Waters-Xbridge C18, 19×100 mm, 10 m column with a gradient 5-95% acetonitrile and water with 0.1% ammonium hydroxide modifier. 1H NMR (500 MHz, DMSO-d6) δ 1.53 (dd, J=16.93, 6.73 Hz, 3 H) 2.54 (s, 3 H) 3.79 (s, 1 H) 4.97-5.04 (m, 1 H) 6.40 (d, J=8.48 Hz, 1 H) 6.83 (d, J=4.58 Hz, 1H) 7.26 (d, J=4.52 Hz, 1 H) 7.30-7.42 (m, 2 H) 7.45-7.63 (m, 3 H). m/z ESI 500.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:33])[C:9]1[N:24]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])[C:12]2[N:13]=[C:14]([NH:17][CH:18]([CH3:23])[C:19]([CH3:22])([OH:21])[CH3:20])[N:15]=[CH:16][C:11]=2[CH:10]=1.C(N(CC)CC)C.[C:41](Cl)(=[O:43])[CH3:42].C(OCC)(=O)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:33][C:41](=[O:43])[CH3:42])[C:9]1[N:24]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])[C:12]2[N:13]=[C:14]([NH:17][CH:18]([CH3:23])[C:19]([OH:21])([CH3:22])[CH3:20])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CC(Nc1ncc2cc(C(O)c3ccccc3Cl)n(-c3c(F)cccc3F)c2n1)C(C)(C)O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OC(c1ccccc1Cl)c1cc2cnc(NC(C)C(C)(C)O)nc2n1-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-[6-[(2-chloro-phenyl)-hydroxy-methyl}-7-(2,6-difluoro-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-2-methyl-butan-2-ol, 9, (0.47 g, 1.00 mmol) and triethylamine (0.60 ml, 4.0 mmol), in pyridine (5 ml) is added dropwise acetyl chloride (0.08 ml, 2.20 mmol). The reaction mixture is stirred under argon at room temperature for 48 hours. Ethyl acetate is added to the mixture and the resulting mixture is washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting residue is purified over silica (40% EtOAc/hexanes) to afford 30 mg of the desired: 1H NMR (300 MHz, CDCl3) δ 8.42 (s, 1H), 7.52-7.10 (m, 7H), 6.11 (d, J=5.3 Hz, 1H), 4.00-3.91 (m, 1H), 1.97 (d, J=5.9 Hz, 3H), 1.50 (br s, 1H), 1.23 (s, 3H), 1,19 (s, 3H); HRMS calcd for C26H25ClF2N4O3 (M+H)+ 515.1662, found 515.1644.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[P:6](=[S:12])(Cl)([O:9][CH3:10])[O:7][CH3:8]>ClCCl>[CH2:1]([N:3]([CH2:4][CH3:5])[P:6](=[S:12])([O:9][CH3:10])[O:7][CH3:8])[CH3:2]
Reactant: COP(=S)(Cl)OC
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)P(=S)(OC)OC
Reaction time: 1 h

Procedure:
A solution of diethylamine (7.31 g, 100 mmol) in dichloromethane (250 ml) at 5° C. was treated with O,O-dimethyl phosphorochloridothioate (8.03 g, 50 mmol) in dichloromethane (50 ml) in a dropwise fashion. The resulting mixture was stirred 1 h and then washed with 1N HCl (2X 100 ml) and water (100 ml). The dichloromethane solution was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give an oil. Distillation employing a Kugelrohr apparatus at 45°-50° C. and less than 1 mm Hg pressure gave 5.27 g (53 percent of theory) of the desired product; nD25 1.4735.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.O=P(Cl)(Cl)Cl.O.CN([CH:21]=[O:22])C>>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[C:7]=1[CH:21]=[O:22]
Reactant: COc1cc(Br)cc(OC)c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1cc(Br)c(C=O)c(OC)c1
Temperature: 100 °C
Yield: 65 %

Procedure:
A solution of 1-bromo-3,5-dimethoxybenzene (10.0 g, 46.1 mmol) in DMF (40 mL) was treated with POCl3 (6.32 mL, 69.1 mmol) at 0° C. and heated to 100° C. for 6 h. The reaction was cooled to room temperature and water (40 mL) was added. The resulting mixture was heated to 50° C. 1 h. The reaction was cooled down and extracted with ethyl acetate. The organic layer was separated, dried (Na2SO4), and concentrated. The residue was purified by flash column chromatography (silica, hexanes/ethyl acetate=2:1) to give the title compound (7.26 g, 65%). 1H NMR (300 MHz, CDCl3) δ 10.24 (s, 1H), 6.81 (s, 1H), 6.42 (s, 1H), 3.96 (s, 3H), 3.93 (s, 3H).
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[O:19]([C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.C>O1CCOCC1.C(O)(C)C>[O:19]([C:26]1[CH:27]=[C:28]([NH:29][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:30]=[CH:31][CH:32]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1cccc(Oc2ccccc2)c1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(Oc2ccccc2)c1)c1ccn2c1CSC2c1cccnc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 34 %

Procedure:
7-chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (4.5 g) is added, at a temperature between 60° C. and 68° C., to a solution of 3-phenoxyaniline (2.8 g) and triethylamine (3.05 g) in dioxane (100 cc) heated to a temperature in the vicinity of 60° C., in the course of 5 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 6 hours and 15 minutes and is then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (250 cc) and the solution obtained is washed twice with distilled water (200 cc in total), twice with an aqueous 4N sodium hydroxide solution (200 cc in total) and twice with distilled water (200 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. Crude product (6.7 g) is thereby obtained. This product is dissolved in boiling isopropanol (25 cc). Decolourizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 3 hours. The crystals formed are separated by filtration, washed 4 times with ispropanol (20 cc in total) and then 3 times with diethyl ether (75 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-(3-phenoxyphenyl)-3(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (2.1 g) in the form of creamcoloured crystals, m.p. 144° C., is thereby obtained.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]1([C:21]2[CH:34]=[CH:33][C:24]([C:25]([NH:27][CH2:28][CH2:29][CH2:30][CH:31]=O)=[O:26])=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:35][O:36][C:37]1[CH:46]=[C:45]2[C:40]([CH2:41][CH2:42][NH:43][CH2:44]2)=[CH:39][CH:38]=1.ClCCl>ClCCCl>[CH3:35][O:36][C:37]1[CH:46]=[C:45]2[C:40]([CH2:41][CH2:42][N:43]([CH2:31][CH2:30][CH2:29][CH2:28][NH:27][C:25](=[O:26])[C:24]3[CH:33]=[CH:34][C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:22][CH:23]=3)[CH2:44]2)=[CH:39][CH:38]=1
Reactant: O=CCCCNC(=O)c1ccc(-c2ccccc2)cc1
Reactant: COc1ccc2c(c1)CNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc2c(c1)CN(CCCCNC(=O)c1ccc(-c3ccccc3)cc1)CC2
Reaction time: 16 h
Yield: 82.7 %

Procedure:
Sodium triacetoxyborohydride (4.66 g, 22 mmol) was added to a stirred mixture of 4-(4-phenylbenzoylamino)butyraldehyde (3.92 g, 15 mmol) and 7-methoxy-1,2,3,4-tetrahydroisoquinoline [Daniel J. Sall et al., J. Med. Chem., 1987, 30, 2208] (2.40 g, 14.7 mmol) in 1,2-dichloroethane (200 ml) at room temperature. After stirring for 16 h, dichloromethane (100 ml) was added and the mixture was then washed with saturated aqueous K2CO3 (2×100 ml) and brine (100 ml). Drying (Na2SO 4) and evaporation in vacuo afforded a viscous oil which was chromatographed on silica gel, eluting with ethyl acetate, to give the title compound as a pale pink solid (5.04 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)=O)=[CH:4][CH:3]=1.[C:20]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)(=[O:22])[CH3:21].[OH-].[Na+]>CCCCCCCC>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2ccc(Cl)cc2)cc1OC
Reactant: CC(=O)N1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCCC
Product: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccc(Cl)cc2)cc1OC
Temperature: 127 °C
Reaction time: 10 h

Procedure:
4-Chloro-3', 4'-dimethoxybenzophenone (276.7 g; 1 mol), N-acetyl morpholine (387.6 g; 3 mol) and powdered sodium hydroxide (40.0 g; 1 mol) in n-octane (600 ml) were refluxed under stirring for 10 hours at a column internal temperature of 127° C. The refluxing condensate (3 l/h) was passed through a column packed with molecular sieves (4 A, 150 g). Subsequently, n-octane (450 ml) was distilled off and toluene (1 l) was added. The mixture was heated to 80° C. and extracted once with 500 ml water and twice with 250 ml water. The organic layer was separated, and dried by azeotropic distillation of a part of the solvent (125 ml) under reduced pressure. On cooling to room temperature, crystallisation already started. Under continuous stirring, 750 ml petroleum ether (bp. 58°-63° C.) was added over a period of 30 minutes. After standing overnight, the crystals were collected by vacuum filtration washed with toluene/petroleum ether (1:3; 400 ml) and dried. Yield: 268 g (69.1%). Mp.: 140°-152° C. The product was 98.1% pure and contained 0.9% of the original ketone. The mother liquor contained an additional 25.2 g of the title compound and 42.2 g of the original ketone. The water washings contained 207 g =1.6 mol N-acetyl morpholine.
Reaction SMILES: [C:1]1([CH:7]([N:12]([CH2:18][CH:19]([O:22][CH3:23])[O:20][CH3:21])[C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[C:8]([O:10]C)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:1]1([CH:7]([N:12]([CH2:18][CH:19]([O:22][CH3:23])[O:20][CH3:21])[C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(c1ccccc1)N(CC(OC)OC)C(=O)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(CN(C(=O)C(C)C)C(C(=O)O)c1ccccc1)OC
Reaction time: 2.5 h
Yield: 97.2 %

Procedure:
A solution of methyl 2-phenyl-2-[N-(2,2-dimethoxyethyl)-2-methylpropanamido]acetate (72.3 g) in methanol (800 ml) was treated with a solution of sodium hydroxide (30 g) in water (200 ml). The mixture was stirred for 2.5 hours and then left to stand at room temperature for 18 hours. It was then concentrated to 500 ml and diluted with water (500 ml), washed with diethyl ether (2×200 ml), cooled to below 10° C., and acidified by treatment with hydrochloric acid (4N), maintaining the temperature below 10° C. The precipitated product was extracted with ethyl acetate (3×750 ml) and the combined extracts were washed with brine (300 ml), and evaporated, to give an off-white solid, which was recrystallised from a mixture of ethanol and ethyl acetate and washed with light petroleum, to give 2-phenyl-2-[N-(2,2-dimethoxyethyl)-2-methylpropanamido]acetic acid (67.2 g), in the form of a white solid, m.p. 147°-149° C. [Elemental analysis: C,62.3;H,7.6;N,4.54%; calculated: C,62.1; H,7.4;N,4.53%].
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH2:10])=[O:4].C1OC1C.CN(C)C(=O)C.[N:21]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[N:24][N:23]=[N:22]1>C(OCC)C>[CH3:1][O:2][C:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:27](=[O:28])[CH2:26][N:21]1[CH:25]=[N:24][N:23]=[N:22]1)=[O:4]
Reactant: COC(=O)[C@H]1NC(=O)[C@H]1N
Reactant: O=C(Cl)Cn1cnnn1
Agent: CC1CO1
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@H]1NC(=O)[C@H]1NC(=O)Cn1cnnn1
Temperature: -30 °C
Yield: 79.3 %

Procedure:
To a mixture of 288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester, 4 ml of propylene oxide and 3 ml of N,N-dimethylacetamide, which is stirred previously under ice-cooling, is added dropwise 400 mg of 1H-tetrazol-1-yl acetyl chloride, followed by stirring for 30 minutes. To the mixture is added 50 ml of ethyl ether, followed by stirring under cooling at -30° C., and then the upper layer is removed by decantation. The lower layer is subjected to the same procedure as above twice, followed by addition of 10 ml of acetone. The resultant solution is developed and purified by column-chromatography on silica-gel (40 g, 3×10 cm) using a mixture of acetone:methylene chloride (1:1) as eluent, followed by drying to give 403 mg (84%) of cis-3-(1H-tetrazol-1-ylacetamido)-2-oxoazetidine-4-carboxylic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.C([Li])CCC.Cl[C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:17]=[C:16]([N:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:29]=3[N:28]=[C:27]2[CH:37]([F:39])[F:38])[N:15]=1>C1COCC1.C(O)(=O)C.O>[F:39][CH:37]([F:38])[C:27]1[N:26]([C:16]2[N:17]=[C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:19]=[C:14]([NH:1][C:2]3[CH:3]=[N:4][CH:5]=[N:6][CH:7]=3)[N:15]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:29]=2[N:28]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: Nc1cncnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(Nc2cncnc2)nc(N2CCOCC2)n1
Reaction time: 0.17 h
Yield: 22.6 %

Procedure:
To 0.207 g (2.18 mmol) of 5-aminopyrimidine in THF (4 mL) was added 0.96 mL of n-butyllithium (2.5 M solution in hexanes) and the mixture stirred for 10 min. A solution of 0.260 g (0.66 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) in THF (5 mL) was added. The resulting mixture was stirred at room temperature for 1 hr. After neutralization with acetic acid, the mixture was diluted with water, and extracted with EtOAc. The organic layer was washed successively with water and aqueous NH3, and dried. Removal of the solvent, followed by chromatography on silica eluting with hexanes/EtOAc (1:1) gave a yellow powder. Recrystallization from ethanol/CH2Cl2 gave 0.068 g (20% yield) of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(5-pyrimidinyl)-1,3,5-triazin-2-amine: mp 293-295° C.; 1H NMR (CDCl3) δ 9.07 (s, 2H), 9.01 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.48 (t, JHF=53.2 Hz, 1H), 7.37 (t, J=8.2 Hz, 1H), 7.14 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 4.05 (s, 3H), 3.95-3.90 (m, 4H), 3.82-3.81 (m, 4H); Anal. Calcd. for C20H19F2N9O2: C, 52.75; H, 4.2; N, 27.7. Found: C, 52.9; H, 4.2; N, 27.7%.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:3]1=[O:13].[CH2:15]=[O:16].C1(C)C=CC=CC=1>C(O)(=O)C>[CH3:1][C:2]1([CH3:14])[CH2:6][N:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:4]([CH2:15][OH:16])[C:3]1=[O:13]
Reactant: C=O
Reactant: CC1(C)CN(c2ccccc2)NC1=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC1(C)CN(c2ccccc2)N(CO)C1=O
Temperature: 25 °C

Procedure:
4,4-Dimethyl-1-phenyl-3-pyrazolidone (152 g) was dissolved in 600 ml of acetic acid. To the solution as prepared above, 97 g of an aqueous solution containing 37% of formaldehyde was dropped with stirring at room temperature. The resultant mixture was stirred for 2 hours. At the end of the time, the solvent was distilled away under reduced pressure. To the residue thus obtained, 100 ml of toluene was added, and water was separated at the toluene azeotrope under reduced pressure. A mixture of 900 ml of hexane and 700 ml of ethyl acetate was added to the residue as obtained above which was then dissolved therein by heating. The resultant solution was allowed to cool to room temperature. Crystals precipitated were collected by filtration to obtain 120 g of 4,4-dimethyl-2-hydroxymethyl-1-phenyl-3-pyrazolidone.