Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12][C:13]3[C:14]([C:26]([NH:28][C:29]4[S:33][N:32]=[C:31]([CH3:34])[N:30]=4)=[O:27])=[N:15][C:16]([S:19][C:20]4[N:24]([CH3:25])[CH:23]=[N:22][N:21]=4)=[CH:17][CH:18]=3)=[CH:8][CH:7]=2)[CH2:2]1.[CH3:35][C:36]([CH3:38])=O>>[CH:36]([N:1]1[CH2:2][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12][C:13]3[C:14]([C:26]([NH:28][C:29]4[S:33][N:32]=[C:31]([CH3:34])[N:30]=4)=[O:27])=[N:15][C:16]([S:19][C:20]4[N:24]([CH3:25])[CH:23]=[N:22][N:21]=4)=[CH:17][CH:18]=3)=[CH:8][CH:7]=2)[CH2:4]1)([CH3:38])[CH3:35]
Reactant: Cc1nsc(NC(=O)c2nc(Sc3nncn3C)ccc2Sc2ccc(OC3CNC3)cc2)n1
Reactant: CC(C)=O
Product: Cc1nsc(NC(=O)c2nc(Sc3nncn3C)ccc2Sc2ccc(OC3CN(C(C)C)C3)cc2)n1

Procedure:
Starting from 3-{[4-(azetidin-3-yloxy)phenyl]thio}-N-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]pyridine-2-carboxamide obtained in Example 2 (step 2) and using acetone, the entitled compound was obtained as a yellow solid in the same method as in Example 2 (step 3) or in accordance with the method or by combining it with an ordinary method.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]3[C:15](=[O:18])[NH:16][N:17]=[C:10]3[C:9]=2[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1.ClC1C=CC(C2N=C(N3CC(NCC)(C(N)=O)C3)N3C(=O)N(CC4C=CC(C(F)(F)F)=CC=4)N=C3C=2C2C=CC(Cl)=CC=2)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]3[C:15](=[O:18])[N:16]([CH2:32][C:31]4[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:36])[F:37])=[CH:35][CH:34]=4)[N:17]=[C:10]3[C:9]=2[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2n[nH]c(=O)n12
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3nn(Cc4ccc(C(F)(F)F)cc4)c(=O)n23)C1
Product: Cc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2nn(Cc3ccc(C(F)(F)F)cc3)c(=O)n12

Procedure:
The title compound was prepared by coupling 7,8-bis(4-chlorophenyl)-5-methyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one with 4-trifluoromethylbenzyl bromide in a manner analogous to that in which 1-(7,8-bis(4-chlorophenyl)-3-oxo-2-(4-(trifluoromethyl)benzyl)-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(ethylamino)azetidine-3-carboxamide was prepared. HPLC/MS: retention time=4.485 min, [M+H]30 =529.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]=[CH2:6].C(N(CC)CC)C.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]([CH2:3][CH2:4][CH:5]=[CH2:6])[C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=CCCNC
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCN(C)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 56.2 %

Procedure:
Under a nitrogen atmosphere, a solution of N-methyl-3-buten-1-amine (6.86 g, 80.6 mmol) in dichloromethane (100 mL) was cooled to 0° C., and triethylamine (17.93 g, 177.2 mmol) and 4-(N,N-dimethylamino)pyridine (207 mg) were added. A solution of benzoyl chloride (11.89 g, 84.6 mmol) in dichloromethane (60 mL) was added drop-wise via addition funnel over 1 h at 0-5° C. The resulting turbid mixture was stirred 3 h at 0° C. The mixture was then washed in succession with 1M HCl solution (3×75 mL), 5% NaHCO3 solution (3×100 mL), and water (100 mL). The organic phase was dried (Na2SO4), filtered, and concentrated on a rotary evaporator to a yellow oil (12.66 g). Vacuum distillation using a 6 in. Vigreaux column and a short path distillation apparatus afforded 8.58 g (56.3%) of a colorless oil, bp 100-103° C. at 0.1 mm Hg.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](=O)[CH3:4].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1.C(N(CC)CC)C>C(OCC)C.CCCCCC.Cl[Ti](Cl)(Cl)Cl>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:15]=[C:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])=[CH:12][CH:11]=1
Reactant: COc1ccc(CN)cc1
Reactant: CC(=O)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1ccc(CN=C(C)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirring solution of trifluoroacetone (7.75 g, 69.2 mmol) in diethyl ether (60 ml) at −40° C. was added 4-methoxybenzyl amine (9.49 g, 69.2 mmol) and triethylamine (14 g, 138 mmol) in diethyl ether (40 ml). A cooled (0° C.) mixture of TiCl4 (6.56 g, 34.6 mmol) in hexane (40 ml) at was added dropwise over 10 minutes and the resulting mixture was allowed to warm up to ambient temperature over 20 mins and stirred at 50° C. for 2.5 h. The inorganic precipitate was removed by filtration and washed with diethyl ether. The filtrate was concentrated in vacuo to afford a yellow oil. Purification of the crude product by chromatography on silica eluting with 0% to 25% EtOAc in iso-hexane afforded the title product.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2.[N:19]1([C:25]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:26]=2[C:27](O)=[O:28])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(OCC)(=O)C>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:14][CH2:15][N:16]([C:27]([C:26]3[CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[CH:32]=[CH:33][C:25]=3[N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:28])[CH2:17][CH2:18]1)[CH:7]=[CH:6]2
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Reactant: Clc1ccc2nc(N3CCNCC3)ccc2c1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 6-chloro-2-piperazin-1-yl-quinoline hydrochloride (Example 1.20b) and 2-morpholin-4-yl-5-nitro-benzoic acid (Example 2.1) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid.
Reaction SMILES: [Li]CCCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C([O:16][C:17](=O)[CH:18]([F:20])[F:19])C.Cl>C1COCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([C:17](=[O:16])[CH:18]([F:20])[F:19])[CH:8]=1
Reactant: CCOC(=O)C(F)F
Reactant: Fc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1cc(Br)ccc1F)C(F)F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of diisoprpopylamine (343 g, 3.39 mol) in THF (4 L) was added slowly n-BuLi (1.4 L, 3.5 mol, 2.5 M in hexane) at −78° C. while keeping reaction temperature under −55° C. After addition, the mixture was stirred at −78° C. for 15 min. At this point, a solution of 4-bromo-1-fluorobenzene (540 g, 3.08 mol) in THF (1 L) was cooled to −60° C. before adding to the reaction mixture gradually while keeping reaction temperature under −55° C. and the resulting yellow solution was stirred at −78° C. for 150 min. Ethyldifluoroacetate (421 g, 3.39 mol) was added to the reaction mixture over 15 min and then the mixture was stirred at −78° C. for 15 min. 1 M HCl (6.0 L) was added to the reaction mixture with stirring. Aqueous layer was extracted with TBME (3×4 L). The combined organic phases were washed with water, dried (MgSO4) and evaporated in vacuo. The resulting residue was distilled under vacuum (90˜95° C./0.19 mbar) and fraction at 54˜62° C. was collected to obtain the title compound as a colorless liquid. ESIMS: 253 [(M+H)+]; 1H NMR (400 MHz, CDCl3): δ 8.06 (dd, 1H), 7.75 (ddd, 1H), 7.13 (dd, 1H), 6.41 (dt, 1H).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])(O)=[O:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:43]12([CH2:53][NH2:54])[CH2:52][CH:47]3[CH2:48][CH:49]([CH2:51][CH:45]([CH2:46]3)[CH2:44]1)[CH2:50]2>C(#N)C>[C:43]12([CH2:53][NH:54][C:1]([CH2:4][N:5]3[CH2:27][CH2:26][CH2:25][C@H:6]3[C:7]([N:9]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])=[O:2])[CH2:50][CH:49]3[CH2:48][CH:47]([CH2:46][CH:45]([CH2:51]3)[CH2:44]1)[CH2:52]2
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Reactant: NCC12CC3CC(CC(C3)C1)C2
Agent: CC(C)COC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)NCC12CC3CC(CC(C3)C1)C2
Yield: 10.2 %

Procedure:
Using the procedure described previously, a solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (106 mg, 0.28 mmol), triethylamine (158 uL, 1.13 mmol, 4 eq) in acetonitrile (1.5 mL, was cooled to 0° C. and treated with isobutyl chloroformate (40.5 uL, 0.31 mmol, 1.1 eq) followed by 1-adamantanemethylamine (100 uL, 0.57 mmol, 2 eq). After TLC indicated the reaction was complete, the mixture was purified by HPLC to provide 15 mg (10%) of L-isoleucine, N-[1-(adamant-1-ylmethylcarbamoylmethyl)-L-prolyl] benzylamide.
Reaction SMILES: [CH2:1]([CH2:11][C:12](=[CH:14][CH2:15][CH2:16]/[C:17](=[CH:19]/[CH2:20][OH:21])/[CH3:18])[CH3:13])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[CH3:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][C:41](O)=[O:42].CCCCCC>C(CC(C)(C)C)(C)C>[C:41]([O:21][CH2:20]/[CH:19]=[C:17](/[CH2:16][CH2:15]/[CH:14]=[C:12](\[CH3:13])/[CH2:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4])\[CH3:18])(=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=[CH:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: CC(C)=CCC/C(C)=C/CCC(C)=CCC/C(C)=C/CO
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Solvent: CCCCCC
Solvent: CC(C)CC(C)(C)C
Product: CCCCCCCCCC=CC=CC=CC=CC=CC(=O)OC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CCC=C(C)C
Temperature: 60 °C
Reaction time: 24 h

Procedure:
There were dissolved, in 1 g of isooctane, 100 mg of geranyl geraniol and 600 mg of ethyl ester of eicosapentaenoic acid, followed by the addition of lipase in an amount of 1% relative to the total amount of the resulting solution and then stirring the mixture at 60° C. for 24 hours. After confirming whether the reaction system reached its equilibrium state or not by the GC technique, the reaction solution was diluted by the addition of hexane to the solution in an amount of 10 times the volume thereof, followed by the removal of the lipase from the reaction solution through filtration and then the removal of the hexane through distillation to thus give a crude reaction product. The crude product was purified by silica gel column chromatography to give 102 mg of geranyl-geranyl eicosapentaenoate.
Reaction SMILES: IC.[F:3][C:4]1[CH:5]=[C:6]([SH:11])[CH:7]=[CH:8][C:9]=1[F:10].[C:12](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:3][C:4]1[CH:5]=[C:6]([S:11][CH3:12])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(S)cc1F
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(F)c(F)c1
Reaction time: 8 h

Procedure:
Iodomethane (15 mL, 0.22 mol) was added to a stirred mixture of 3,4-difluorobenzenethiol (30 g, 0.21 mol) and potassium carbonate (32.6 g, 0.24 mol) in DMF (250 mL), and left overnight. The reaction mixture was diluted with water (100 mL) and extracted with ethyl ether (100 mL×3), the organic phases were dried over Na2SO4 and evaporated under reduced pressure to give (3,4-difluorophenyl)(methyl)sulfane as a yellow liquid. Yield: 30 g, 89.3%. 3-Chloroperoxybenzoic acid (85% in purity, 62.5 g, 0.305 mol) was added in portions to a solution of (3,4-difluorophenyl)(methyl)sulfane (25 g, 0.155 mol) in dichloromethane (650 mL), and the mixture was stirred at room temperature for 2 h. The mixture was washed with saturated aqueous sodium sulfite solution (200 mL). The organic phases were sequentially washed with aqueous sodium bicarbonate solution (100 mL×2) and water (100 mL), dried over Na2SO4 and evaporated under reduced pressure to give the title compound as a white solid. Yield: 18 g, 60%.
Reaction SMILES: C1N=CN([C:6]([N:8]2C=[N:11][CH:10]=[CH:9]2)=[S:7])C=1.N1C=CN=C1.[CH2:18]([O:20][C:21]([C:23]1[C:28]([O:29][CH2:30][CH3:31])=[C:27]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[N:26]=[C:25]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[N:24]=1)=[O:22])[CH3:19].[C:45]1(N)[C:46](N)=CC=[CH:49][CH:50]=1>CC#N>[CH2:18]([O:20][C:21]([C:23]1[C:28]([O:29][CH2:30][CH3:31])=[C:27]([N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)[N:26]=[C:25]([C:38]2[CH:39]=[CH:40][C:41]([NH:44][C:6]([NH:8][C:9]3[CH:49]=[CH:50][CH:45]=[CH:46][C:10]=3[NH2:11])=[S:7])=[CH:42][CH:43]=2)[N:24]=1)=[O:22])[CH3:19]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)c1nc(-c2ccc(N)cc2)nc(N2CCOCC2)c1OCC
Reactant: Nc1ccccc1N
Agent: c1c[nH]cn1
Solvent: CC#N
Product: CCOC(=O)c1nc(-c2ccc(NC(=S)Nc3ccccc3N)cc2)nc(N2CCOCC2)c1OCC
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 28.5 %

Procedure:
To a stirred solution of 1,1-thiocarbonyldiimidazole (216.5 mg, 1.5 eq.), imidazole (164.52 mg, 3 eq.) and CH3CN (10 ml) at 0° C., 2-(4-amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic acid ethyl ester (300 mg, 1 eq.) dissolved in CH3CN (10 ml) was added dropwise over 10 min. After 10 min, the cooling bath was removed. After 3 h, benzene-1,2-diamine (175.2 mg, 2 eq.) was added and the reaction was heated to 50° C. for 3 h, and then stirred at ambient temperature for 16 h. The solvent was removed by evaporation. The residue was chromatographed to give a thiourea (120 mg, 29%)
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][CH:10]1[CH2:14][CH2:13][N:12](C(OCC)=O)[CH2:11]1.[OH-].[K+]>CC(O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1
Reactant: CCOC(=O)N1CCC(Nc2cccc(C)c2C)C1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1cccc(NC2CCNC2)c1C
Yield: 63 %

Procedure:
A mixture of 13.10 parts of ethyl 3-[(2.3-dimethylphenyl)amino]-1-pyrrolidinecarboxylate, 28 parts of potassium hydroxide and 240 parts of 2-propanol was stirred and refluxed for 6 hours. The reaction mixture was evaporated. The residue was taken up in water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 6 parts (63%) of N-(2,3-dimethylphenyl)-3-pyrrolidinamine as a residue (intermediate 68).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:25])[CH:3]=1.COC1C=C[C:31]([CH2:32][NH2:33])=[CH:30]C=1.ClCCC[S:40](Cl)(=[O:42])=[O:41].NC1N=CC(C(N2CCN(C3C(C4CC4)=CC(C)=CN=3)CC2)=O)=C(C)C=1>>[O:41]=[S:40]1(=[O:42])[CH2:30][CH2:31][CH2:32][N:33]1[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:25])[CH:3]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Cc1cc(F)ncc1C(=O)N1CCN(c2nc(C)c(C)cc2C)CC1
Agent: Cc1cnc(N2CCN(C(=O)c3cnc(N)cc3C)CC2)c(C2CC2)c1
Product: Cc1cc(N2CCCS2(=O)=O)ncc1C(=O)N1CCN(c2nc(C)c(C)cc2C)CC1

Procedure:
Using (6-fluoro-4-methylpyridin-3-yl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (220 mg) described in Preparation Example 182, 4-methoxybenzylamine (1.5 mL) and 3-chloropropane-1-sulfonyl chloride (0.16 mL) and by the reaction and treatment in the same manner as in Example 229, the title compound (175 mg) was obtained via (6-amino-4-methylpyridin-3-yl)[4-(3-cyclopropyl-5-methylpyridin-2-yl)piperazin-1-yl]methanone.
Reaction SMILES: Cl[C:2]1[NH:11][C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[S:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][NH:17][CH2:16][CH2:15]1.[O:25]1[CH2:28][C:27]([CH2:31][NH2:32])([CH2:29][NH2:30])[CH2:26]1>>[NH2:30][CH2:29][C:27]1([CH2:31][NH:32][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=3)[N:3]=[C:2]([N:17]3[CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[S:14][CH2:15][CH2:16]3)[N:11]=2)[CH2:28][O:25][CH2:26]1
Reactant: NCC1(CN)COC1
Reactant: Cc1ccc2nc(Cl)[nH]c(=O)c2c1
Reactant: c1ccc2c(c1)CNCCS2
Product: Cc1ccc2nc(N3CCSc4ccccc4C3)nc(NCC3(CN)COC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 62-1 in Scheme 23 by using 2-chloro-6-methylquinazolin-4(3H)-one, 2,3,4,5-tetrahydro-1,4-benzothiazepine and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 422. 1H NMR (400 MHz, CD3OD) δ ppm 7.66 (dd, J=1.6, 7.2 Hz, 1 H), 7.62 (s, 1 H), 7.44 (dd, J=1.2, 7.6 Hz, 1 H), 7.34-7.29 (m, 2 H), 7.18 (m, 1 H), 7.08 (m, 1 H), 4.99 (s, 2 H), 4.63 (d, J=6.4 Hz, 2 H), 4.45 (d, J=6.4 Hz, 2 H), 4.34 (s, 2 H), 4.02 (s, 2 H), 2.98 (s, 2 H), 2.90 (m, 2 H), 2.36 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)Cl.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>O>[CH3:23][S:24]([O:11][CH2:10][C@@H:9]([NH:12][C:13]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:19])[C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CO)c1ccc(F)c(Cl)c1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of (S)-tert-butyl 1-(3-chloro-4-fluorophenyl)-2-hydroxyethylcarbamate (0.75 g, 2.59 mmol) and DCM (15 mL) at RT was added TEA (0.541 mL, 3.88 mmol) and MsCl (0.210 mL, 2.72 mmol). The reaction was stirred at RT for 1 h then poured into water and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (500:5) to afford 0.8 g (84%) of (S)-2-(tert-butoxycarbonylamino)-2-(3-chloro-4-fluorophenyl)ethyl methanesulfonate (224).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][C:6]1[C:7]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:19][C:2]([F:1])([F:18])[CH2:3][NH:5][C:6]1[C:7]([N:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Nc1cccnc1N1CCNCC1)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: FC(F)(F)CNc1cccnc1N1CCNCC1
Reaction time: 0.17 h

Procedure:
1-[3-(2,2,2-Trifluoroacetamido)-2-pyridinyl]piperazine (PREPARATION 35), is dissolved in 5 ml of tetrahydrofuran and cooled to 0°. Then 4.84 ml of lithium aluminum hydride solution is added dropwise. After 10 min of stirring at 0°, the reaction is warmed to 20°-25° and stirred 45 min. The reaction is quenched at 0° with the dropwise addition of 0.4 ml of water. 0.6 ml of 10% aqueous sodium hydroxide, and 1 ml of water. The slurry is filtered through celite, washed with 20% methanol/chloroform and concentrated in vacuo to afford the title amine which is used without further purification, NMR (300 MHz, CDCl3) 7.82, 6.97-6.92, 4.86, 3.75, and 3.06-3.01 δ.
Reaction SMILES: C([CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1([CH2:15][CH:16]=[CH2:17])[OH:14])C1C=CC=CC=1.[CH:18]1[C:23]([C:24](OO)=[O:25])=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:24]([O:25][CH:17]=[CH:16][CH2:15][C:9]12[O:14][CH:10]1[CH:11]=[CH:12][CH:13]=[CH:8]2)[C:23]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(OO)c1ccccc1
Reactant: C=CCC1(O)C=CC=CC1Cc1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: C1=CC2OC2(CC=COCc2ccccc2)C=C1
Reaction time: 96 h
Yield: 70.1 %

Procedure:
5.4 g of o-benzyl-1-allylphenol was added to 600 ml of chloroform solution containing perbenzoic acid prepared from 26.4 g of benzoyl peroxide and the mixture was allowed to stand at about 5° C for 4 days. The reslting mixture was washed with sodium hydroxide solution, water, Mohr's salt solution, then saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain the residue which was distilled under reduced pressure, and there was obtained 4.1 g (yield 70.1%) of o-benzyloxyallylbenzene oxide having a boiling point of 158° to 160° C/5 mmHg as colourless oil.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[C:28]([N:31]1[CH2:35][CH2:34][NH:33][C:32]1=[O:36])(=[O:30])[CH3:29]>>[C:28]([N:31]1[CH2:35][CH2:34][N:33]([C:24]2[CH:25]=[CH:26][C:21]([C:19]([N:16]3[CH2:15][CH2:14][N:13]([C:5]4[C:4]([CH:1]5[CH2:3][CH2:2]5)=[CH:9][C:8]([CH:10]5[CH2:11][CH2:12]5)=[CH:7][N:6]=4)[CH2:18][CH2:17]3)=[O:20])=[CH:22][CH:23]=2)[C:32]1=[O:36])(=[O:30])[CH3:29]
Reactant: CC(=O)N1CCNC1=O
Reactant: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C4CC4)CC3)cc2)C1=O
Yield: 85 %

Procedure:
Using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (1.34 g) described in Preparation Example 186 and 1-acetylimidazolidin-2-one (461 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (1.14 g) was obtained.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:23][CH2:22]1.N>C(OCC)(=O)C.CO.C1CCCCC1>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH:30]2[CH2:31][CH2:32][N:33]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:34][CH2:35]2)[CH2:23][CH2:22]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CN1CCN(CCCC2CCNCC2)CC1
Agent: N
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCCCC1
Product: CN1CCN(CCCC2CCN(C(=O)N3c4ccccc4C(=O)Nc4cccnc43)CC2)CC1
Yield: 17 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 4-[3-(4-methyl-1-piperazinyl)propyl]piperidine in a yield of 17% of theory. Colourless crystals, m.p. 213°-214° C.; Rf 0.25 (Merck DC ready-made TLC plates, silica gel 60 F254 ; eluant: ethyl acetate/methanol/cyclohexane/conc. ammonia 80/10/10/1 v/v/v/v).
Reaction SMILES: [Br:1][CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=1)=[O:4].C[C@@H](N)C[OH:17].[N:19]1C(C)=CC=[CH:21][C:20]=1[CH3:26]>C(#N)C>[BrH:1].[F:12][C:7]1[CH:6]=[C:5]([C@:3]2([OH:17])[O:4][CH2:21][C@@H:20]([CH3:26])[NH:19][C@H:2]2[CH3:13])[CH:10]=[CH:9][C:8]=1[F:11]
Reactant: CC(Br)C(=O)c1ccc(F)c(F)c1
Reactant: Cc1cccc(C)n1
Reactant: C[C@@H](N)CO
Solvent: CC#N
Product: Br
Product: C[C@@H]1CO[C@@](O)(c2ccc(F)c(F)c2)[C@H](C)N1
Yield: 43.7 %

Procedure:
To a solution of 2-bromo-3',4'-difluoropropiophenone (47.3 g, 0.19 mole) in acetronitrile (100 ml) was added a solution of R-2-amino-1-propanol (Aldrich Chemical Co., Milwaukee, Wis. 53233) (15 g, 0.20 mole) and 2,6-lutidine (23.6 g, 0.22 mole) in acetonitrile (50 ml). The reaction was worked up as in Example 1 to give 26.9 g of (2S,3S,5R)-2-(3,4-difluorophenyl)-3,5-dimethyl-2-morpholinol hydrobromide.