Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:35]=[CH:34][C:13]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]4[CH:32]=[C:31]5[C:27]([CH2:28][C:29](=[O:33])[NH:30]5)=[CH:26][CH:25]=4)[CH:18]=3)=[O:15])=[CH:12][C:11]=2[C:36]([F:39])([F:38])[F:37])[CH2:5][CH2:4]1)[CH3:2].[NH:40]1[CH:44]=[CH:43][CH:42]=[C:41]1[CH:45]=O.N1CCCCC1>CCO>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:35]=[CH:34][C:13]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]4[CH:32]=[C:31]5[C:27]([C:28](=[CH:45][C:41]6[NH:40][CH:44]=[CH:43][CH:42]=6)[C:29](=[O:33])[NH:30]5)=[CH:26][CH:25]=4)[CH:18]=3)=[O:15])=[CH:12][C:11]=2[C:36]([F:38])([F:39])[F:37])[CH2:5][CH2:4]1)[CH3:2]
Reactant: O=Cc1ccc[nH]1
Reactant: CCN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4ccc5c(c4)NC(=O)C5)c3)cc2C(F)(F)F)CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4ccc5c(c4)NC(=O)C5=Cc4ccc[nH]4)c3)cc2C(F)(F)F)CC1
Temperature: 80 °C
Yield: 59.5 %

Procedure:
To a suspension of 4-(4-ethyl-piperazin-1-ylmethyl)-N-[3-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-phenyl]-3-trifluoromethyl-benzamide (200 mg, 0.372 mmol) in EtOH (10 mL) are added pyrrole-2-carboxaldehyde (42 mg, 0.446 mmol) and piperidine (74 μL, 0.74 mmol). The mixture is heated at 80° C. for 2 hours. All the solvent is evaporated to dryness. The crude is recrystallized in EtOH to give 136 mg of the desired compound: 1H NMR (400 MHz, DMSO) δ 10.74 (s, 1 H), 10.34 (s, 1 H), 8.37 (s, 1 H), 8.18-8.24 (m, 2 H), 7.92 (d, 1 H); 7.67 (s, 1 H), 7.46-7.50 (t, 2 H), 7.24-7.28 (m, 3 H), 6.84 (d, 1 H), 6.76 (s, 1 H), 6.72 (m, 1 H), 6.67 (d, 1 H), 6.29-6.31 (m, 1 H), 3.69 (s, 2 H), 3.30 (s, 2 H), 2.30-2.48 (m, 8H), 1.00 (t, 3H); LC-MS: 615.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](=[O:12])[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([Cl:13])[N:3]=1.[H-].[Na+].[CH3:16]I.CO>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:16])[CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([Cl:13])[N:3]=1
Reactant: CI
Reactant: O=c1[nH]cnc2cc(Cl)nc(Cl)c12
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1cnc2cc(Cl)nc(Cl)c2c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5,7-dichloropyrido[4,3-d]pyrimidin-4(3H)-one (1 g, 4.65 mmol) was dissolved in anhydrous DMF 15 mL, and NaH (60% mineral oil, 205 mg, 5.11 mmol) was slowly added into the reaction solution. The reaction was stirred at room temperature for 15 minutes, then CH3I (730 mg, 5.11 mmol) in DMF was added drop-wise into the solution. The reaction was heated to 50° C. for 1 hour and then cooled down to room temperature. Methanol was then added to quench the reaction and the solvent was removed under the vacuum. The crude product was purified by silica column chromatography using hexane/ethyl acetate 1:1 to obtain the final compound 5,7-dichloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one. 1H NMR (DMSO-d6) δ 8.64 (s, 1H), 7.74 (s, 1H), 3.46 (s, 3H); ESI-MS m/z 230.1 (MH+).
Reaction SMILES: II.[CH2:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][N:12]1[CH2:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH2:14][CH2:13]1.Cl>CCOCC.C(Cl)C1C=CC=CC=1.O>[CH2:3]([CH:15]1[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH:16]1[C:18]([O:20][CH3:21])=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C1=CCCN(C)C1
Reactant: ClCc1ccccc1
Agent: Cl
Agent: II
Solvent: CCOCC
Solvent: O
Product: COC(=O)C1CN(C)CCC1Cc1ccccc1
Temperature: -15 °C

Procedure:
To a solution of 480 mg of Mg in 2 mL of dry ether was added a little bit of I2 and several drops of benzyl chloride (about 0.5 mL) of the solution of 2.3 mL (20 mmol) of benzyl chloride in 10 mL of ether. The mixture was gentle stirred, as soon as the reaction sets in, the reminder of benzyl chloride in ether was added at the rate that the reaction went vigorously by cooling the flask with water. Then the resulting solution was stirred at gentle reflux for fifteen minutes after all the benzyl chloride has been added. Another 5 mL of dry ether was added to the Grignard reagent solution and it was cooled to −15° C., the arecoline (1.5 g) in 20 mL of dry ether was added dropwise to it. The resulting mixture was stirred at −15° C. for another 0.5 hour. The mixture was cooled to about −40° C. and treated slowly with 10% HCl (22 mL). The aqueous layer was separated, extracted with ether (20 mL), and then basified with saturated sodium bicarbonate solution when cooled in an ice bath. The mixture was extracted with ether and the combined organic extracts were washed with brine, dried and concentrated under reduced pressure. Flash chromatography afforded a mixture of cis isomer 76 and trans isomer 77 (500 mg, 21%).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Na].Br.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][CH2:22]Br)[CH:15]=1>C(O)C>[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][CH2:22][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:15]=1
Reactant: BrCCCc1cccnc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Br
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCCc1cccnc1)C(=O)OCC

Procedure:
To a solution of 48 mL (0.37 mole) of diethyl malonate in 960 mL ethanol is added 14.03 g (0.61 mole) sodium metal and the mixture is stirred until all of the metal dissolved. The solution is heated to reflux and a solution of 80.04 g (0.28 mole) of 3-(3-pyridyl)-propyl bromide hydrobromide in 960 mL ethanol is added rapidly and the mixture is maintained at reflux for 10 hours. The reaction mixture is evaporated and the residue is taken up in 400 mL of 1N aqueous hydrochloric acid and washed with 400 mL hexane. The aqueous phase is adjusted to pH 8 using solid sodium bicarbonate. The mixture is then extracted with methylene chloride (3×200 mL). Combined organic extracts are dried (MgSO4), filtered and evaporated to dryness to give diethyl [3-(3-pyridyl)-propyl]-malonate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][NH:5][C:6]([C:8]1([CH2:21][OH:22])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)=[O:7].[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1.Cl>C1COCC1.CN(C1C=CN=CC=1)C.CO>[F:27][C:28]([F:38])([F:39])[C:29]1[CH:30]=[CH:31][C:32]([NH:35][C:36](=[O:37])[O:22][CH2:21][C:8]2([C:6](=[O:7])[NH:5][CH2:4][C:3]3[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=3[Cl:1])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:33][CH:34]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(C(=O)NCc2ccccc2Cl)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(C(F)(F)F)cc1)OCC1(C(=O)NCc2ccccc2Cl)CCNCC1
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a solution of tert-butyl 4-(2-chlorobenzylcarbamoyl)-4-(hydroxymethyl)piperidine-1-carboxylate (500 mg, 1.3 mmol), in THF were added DMAP (32 mg, 0.26 mmol, 0.2 equiv.) and 4-trifloromethylphenylisocyanate (0.28 mL, 1.97 mmol, 1.5 equiv.). The reaction mixture was stirred for 1 h. The reaction mixture was concentrated to dryness. To a solution of the above crude mixture in CH3OH (3 mL) was added HCl (4 M in dioxane, 1 mL, 4 mmol, 3 equiv.). The reaction mixture was stirred overnight. The white solid was filtered and dried to give (4-(2-chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-(trifluoromethyl)phenylcarbamate (615 mg, 93%). LRMS (M-Boc+H+) m/z 470.1.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F-].[Na+].[F:19]C1(F)N(C)CCN1C>ClCCl>[C:1]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[C:14]([F:19])=[O:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(=O)O
Reactant: CN1CCN(C)C1(F)F
Agent: [F-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(=O)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71.9 %

Procedure:
(2S,4S)—N-Boc-4-fluoropyrrolidine-2-carboxylic acid (1.17 g, 5 mmol) and sodium fluoride (0.63 g, 15 mmol) were put in a fluoropolymer (PFA) vessel, and 10 ml of dichloromethane was added into the vessel. The mixture was cooled with ice. A solution of 2,2-difluoro-1,3-dimethylimidazolidine (817 mg, 6 mmol) in 2 ml of dichloromethane was added slowly. After 5 minutes of addition, the ice bath was removed and the mixture warmed to room temperature. The reaction mixture was stirred for a total 20 min. 19F NMR analysis of the reaction mixture showed that (2S,4S)—N-Boc-4-fluoropyrrolidine-2-carbonyl fluoride (Id) was produced in 85% yield. The mixture was diluted with 10 ml of dichloromethane and washed with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. Removal of solvent followed by washing with a small amount of water and then drying gave 846 mg (yield 72%) of (2S,4S)—N-Boc-4-fluoropyrrolidine-2-carbonyl fluoride (Id): Oil: 19F-NMR (CDCl3) (as a 6:4 mixture of two rotamers) δ 28.22 (s, 0.6 F, COF), 28.14 (s, 0.4 F, COF), −173.18 (m, 1 F, CF): 1H-NMR (CDCl3) 8 (as a mixture of two rotamers) 1.40 (s, 0.55×9H, t-Bu), 1.43 (s, 0.45×9H, t-Bu), 2.2-2.6 (m, 2H), 3.45-3.95 (m, 2H), 4.5-4.7 (m, 1H), 5.22 (br.d, J=51.9 Hz, 1H, CHF): 13C-NMR (CDCl3) 8 (as a mixture of two rotamers); 90.94 (d, J=177.0 Hz, 1H, CF), 92.02 (d, J=177.0 Hz, CF), 153.06 (s, CON), 153.82 (s, CON), 161.50 (d, J=372.1 Hz, COF), 161.66 (d, J=372.8 Hz, COF): High Resolution Mass/ESI-APCI method (solvent; methanol); (M-F+OCH3+Na)+ 270.1109 [calcd 270.1112 for (C11H18FNO4+Na)].
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([NH2:13])[C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH:12]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([NH2:13])[C:7]2[CH:8]=[N:9][N:10]([S:21]([C:18]3[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=3)(=[O:23])=[O:22])[C:11]=2[CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(Br)cc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ncc3c(N)cc(Br)cc32)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a suspension of sodium hydride (5.66 g) in anhydrous DMF (75 ml) stirring at 0° C. was added a solution of 6-bromo-1H-indazol-4-amine (30 g), also in anhydrous DMF (125 ml), dropwise. The reaction mixture was stirred for 1 h at 0° C. then a solution of 4-methylbenzenesulfonyl chloride (27 g) in anhydrous DMF (100 ml) was added dropwise. The reaction was stirred for 2 h. A further portion of sodium hydride (0.57 g) was added followed by 4-methylbenzenesulfonyl chloride (2.70 g). The reaction mixture was left to stand overnight at room temperature, before pouring onto ice/water (1800 ml). A precipitate formed that was collected by filtration, tritrurated using diethyl ether:methanol (1:1, v/v), then re-collected by filtration and dried in vacuo at 40° C. over the weekend to give title compound, (26.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[Cl:12][C:13]1[C:14](F)=[CH:15][C:16]2[O:21][CH:20]([C:22]([F:25])([F:24])[F:23])[C:19]([C:26]([O:28]CC)=[O:27])=[CH:18][C:17]=2[CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:5]([C:4]1[CH:8]=[CH:9][C:10]([O:11][C:14]2[C:13]([Cl:12])=[CH:31][C:17]3[CH:18]=[C:19]([C:26]([OH:28])=[O:27])[CH:20]([C:22]([F:24])([F:25])[F:23])[O:21][C:16]=3[CH:15]=2)=[C:2]([Cl:1])[CH:3]=1)([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc(C(=O)O)cc3Cl)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 3-chloro-4-hydroxybenzoic acid and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4. (Note: In the step similar to Example 183, Step 3, an additional equivalent of potassium carbonate was added.) mp >300° C. 1H NMR (acetone-d6/ 300 MHz) 8.18 (d, 1H, J=2.0 Hz), 8.03 (dd, 1H, J=8.5 Hz 2.0 Hz), 7.93 (s, 1H), 7.78 (s, 1H), 7.23 (d, 1H, J=8.7 Hz), 6.77 (s, 1H), 5.87 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz) −79.4 (d, J=6.5 Hz). ESHRMS m/z 446.9625 (M−H, Calc'd 446.9650). Anal. Calc'd for C18H9Cl2F3O6: C, 48.13; H, 2.02; Cl, 15.79. Found: C, 47.96; H, 1.90; Cl, 15.65.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[C:3]1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[C:18](=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=2[O:11][CH3:18])[CH:4]=[C:3]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2c(C)ccc(O)c2n1C
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C)ccc(OC)c2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
A mixture of 3.50 g (15.5 mmol) of ethyl 1,4-dimethyl-7-hydroxy-2-indolecarboxylate, 4.14 g (30.0 mmol) of potassium carbonate, 4.26 g (30.0 mmol) of potassium iodide and dimethylformamide was stirred at room temperature for 2 hours. The reaction mixture was poured onto ice water followed by extraction with ethyl acetate. The extract was washed with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 3.21 g of ethyl 1,4-dimethyl-7-methoxy-2-indolecarboxylate.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH2:21])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7].[F:23][C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1.CC(C)CCNC(C1C(C2C=CC=CC=2C(S(C2C=CC=C(F)C=2)(=O)=O)N)=CC=CC=1)=O>>[CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH:21][S:30]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[CH:25]=2)(=[O:32])=[O:31])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC(C)CCNC(=O)c1ccccc1-c1ccccc1CN
Agent: CC(C)CCNC(=O)c1ccccc1-c1ccccc1C(N)S(=O)(=O)c1cccc(F)c1
Product: CC(C)CCNC(=O)c1ccccc1-c1ccccc1CNS(=O)(=O)c1cccc(F)c1

Procedure:
From 0.34 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid (3-methyl-butyl)amide (precursor 5c) and 3-fluorophenylsulfonyl chloride, according to the general working procedure 118 mg of 2′-(3-fluorophenylsulfonyl-aminomethyl)biphenyl-2-carboxylic acid (3-methylbutyl)amide were obtained; m.p. 141° C. MS (ES+): m/e=455 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[C@@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[O:11][C@H:10]([CH2:27][NH:28][CH2:29][C:30]([OH:32])=[O:31])[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].C(N(CC)CC)C>CO>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[C@@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[O:11][C@H:10]([CH2:27][N:28]([C:34](=[O:36])[CH3:35])[CH2:29][C:30]([OH:32])=[O:31])[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CNC[C@H]1O[C@H](c2ccccc2Cl)c2cc(Cl)ccc2N(Cc2ccccc2)C1=O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)N(CC(=O)O)C[C@H]1O[C@H](c2ccccc2Cl)c2cc(Cl)ccc2N(Cc2ccccc2)C1=O

Procedure:
In 4 ml of methanol was dissolved 60 mg of ethyl ester of N-[trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl]glycine obtained in Example 40. To the solution were added 0.2 ml of acetic anhydride and 0.2 ml of triethylamine. The mixture was heated for one hour under reflux while stirring. The reaction mixture was concentrated under reduced pressure, which was subjected to extraction with ethyl acetate. The organic layer was washed with an aqueous solution of potassium hydrogensulfate, an aqueous solution of sodium hydrogencarbonate and water, which was then dried, followed by distilling off the solvent. The residue was dissolved in 4 ml of methanol, to which was added 2 ml of a 5% aqueous solution of potassium carbonate. The mixture was stirred for 30 minutes at 60° C. The reaction mixture was concentrated under reduced pressure, to which was added 1N hydrochloric acid to acidify the solution, followed by extraction with ethyl acetate. The organic layer was washed with water and dried, then the solvent was distilled off under reduced pressure. From the residue, 45 mg of N-[trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl]-N-acetyl glycine was obtained as crystals, m.p. 143°-145° C.
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]=[CH:44][C:43]([CH3:46])=[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:24]=[CH:25][C:26]([C:40]5[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][N:45]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Reactant: Cc1ccc(Br)nc1
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: COCCOC
Solvent: O
Product: Cc1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)nc1
Temperature: 25 °C
Yield: 20.5 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 6-bromo-3-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 (107 mg, 21%) as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3C(CC)=N[NH:19][C:18]3=[O:24])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[O:25]([CH2:32][CH2:33]Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:2][CH2:3][C:4]1[N:19]([CH2:33][CH2:32][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18](=[O:24])[N:17]([CH2:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:13][CH2:12]2)[N:8]=1
Reactant: CCc1n[nH]c(=O)n1CCCN1CCN(c2cccc(Cl)c2)CC1
Reactant: ClCCOc1ccccc1
Product: CCc1nn(CCCN2CCN(c3cccc(Cl)c3)CC2)c(=O)n1CCOc1ccccc1

Procedure:
Nefazodone and two processes for its preparation have) been described in Canadian Patent 1,198,436 and in PCT/EP93/03119 published May 26, 1994. The '436 patent relates to the preparation of 2-phenoxyalkyl-1,2,4 triazol-3-one derivatives Scheme 1 below depicts the two different methods described in the '436 patent. ##STR1## 5-Ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3-one, compound 1.3 is alkylated with 1-(3-chloropropyl)-4-(3-chlorophenyl)piperazine, compound 1.5 in the presence of base to give nefazodone. Alternatively, 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl-5-ethyl-4H-1,2,4-triazol-3-one, compound 1.4, is alkylated with 2-phenoxyethyl chloride in the presence of base to give nefazodone.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[F:42][C:43]([F:53])([F:52])[CH2:44][N:45]1[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47][CH2:46]1.Cl>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:51][CH:48]5[CH2:49][CH2:50][N:45]([CH2:44][C:43]([F:53])([F:42])[F:52])[CH2:46][CH2:47]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NC1CCN(CC(F)(F)F)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(CC(F)(F)F)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a mixture of 0.10 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.20 mL (1.1 mmole) of ethyldiisopropyl amine and 0.068 g (0.26 mmole) of 1-(2,2,2-trifluoro-ethyl)-piperidin-4-ylamine; hydrochloride in 4.0 mL of dimethylformamide was added 0.11 g (0.25 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate solution, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexane-ethylacetate (gradient, 80:20-0:100) gave 0.11 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-[1-(2,2,2-trifluoro-ethyl)-piperidin-4-yl]-benzamide (I-77) as a white solid.
Reaction SMILES: [CH2:1]([N:8]([CH3:34])[C:9]([CH:11]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=1)[C:12]([NH:14][C@@H:15]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:16](O)=[O:17])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC(C)=CC=1C.[NH2:68][CH2:69][CH:70]1[CH2:75][CH2:74][CH:73]([C:76]#[N:77])[CH2:72][CH2:71]1>CN(C)C=O>[CH2:1]([N:8]([CH3:34])[C:9](=[O:10])[CH:11]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=1)[C:12]([NH:14][C@H:15]([C:16](=[O:17])[NH:77][CH2:76][CH:73]1[CH2:74][CH2:75][CH:70]([C:69]#[N:68])[CH2:71][CH2:72]1)[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1CCC(CN)CC1
Reactant: CN(Cc1ccccc1)C(=O)C(Cc1ccc(C#N)cc1)C(=O)N[C@H](C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: CN(Cc1ccccc1)C(=O)C(Cc1ccc(C#N)cc1)C(=O)N[C@H](C(=O)NCC1CCC(C#N)CC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103 %

Procedure:
To [2-(R,S)-(Benzyl-methyl-carbamoyl)-3-(4-cyano-phenyl)-propionylamino]-(S)-cyclohexyl-acetic acid (910 mg, 1.97 mmol) in dimethylformamide (150 ml) were added HATU (825 mg, 2.17 mmol) and collidine (263 mg, 2.17 mmol) at 0° C. After 30 minutes at 0° C. 4-aminomethyl-cyclohexanecarbonitrile (272 mg, 1.97 mmol) was added. The mixture was stirred for 1 hour, then allowed to warm to room temperature, and stand at room temperature for 72 hours. After evaporation the residue was stirred with Na2CO3 solution and the precipitate was sucked off to yield 1.18 g of the desired product which was used for further reactions without purification.