Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:52])[C:10]([CH3:51])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]([CH3:35])([CH3:34])[CH2:26][O:27]C(=O)C(C)(C)C)[CH:17]=[C:16]4[CH2:36][N:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][C@H:38]3[CH3:50])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:52])[C:10]([CH3:51])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]([CH3:34])([CH3:35])[CH2:26][OH:27])[CH:17]=[C:16]4[CH2:36][N:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][C@H:38]3[CH3:50])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)COC(=O)C(C)(C)C)cc(CN3CCN(C(=O)OC(C)(C)C)C[C@H]3C)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(CN3CCN(C(=O)OC(C)(C)C)C[C@H]3C)c2c1
Temperature: 67 °C
Yield: 72.2 %

Procedure:
(3R)-tert-Butyl 4-((6-(5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl)-2-(2,2-dimethyl-3-(pivaloyloxy)propyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)-3-methylpiperazine-1-carboxylate (50.8 g) was dissolved in methanol (600 mL) and a solution of potassium carbonate (29.3 g) in water (100 mL) was added. The reaction was heated at reflux (internal temperature 67° C.) for 16 h. After cooling to 50° C., further water was slowly added until the mixture became opaque and the mixture was cooled to 23° C. over 1 h. The precipitate was collected by filtration, washed with water (100 mL) and isohexane (100 mL) and dried in vacuo at 45° C. to give the subtitle product (32.4 g).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]Br.[S:13]([O-:16])([O-:15])=[O:14].[Na+:17].[Na+].C(O)C.BrCCS([O-])(=O)=O.[Na+]>O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:13]([O-:16])(=[O:15])=[O:14].[Na+:17]
Reactant: BrCCCCCCCCCCBr
Reactant: O=S([O-])[O-]
Agent: O=S(=O)([O-])CCBr
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])CCCCCCCCCCBr

Procedure:
1,10-Dibromodecane (7.5 g, 25 mmol), sodium sulfite (1.4 g, 11 mmol), ethanol (25 mL) and water (20 mL) were reacted and worked up analogously to sodium 2-bromoethane sulfonate. Yield: 1.8 g (23%) colorless solid, melting point 342° C., IR (ATR): {tilde over (ν)}=3541 (s), 3481 (s), 2916 (s), 2874 (m), 2853 (s), 2095 (w), 1627 (m), 1472 (m), 1307 (w), 1281 (w), 1250 (w), 1230 (m), 1197 (m), 1178 (s), 1055 (m), 1044 (m), 968 (w), 796 (m), 721 (w), 640 (w), 608 cm−1 (m). HRMS (ESI) (C10H21BrNaO3S+): calculated 323.0287. found 323.0602, Δ=31.5 mmu.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[NH:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH2:14]>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[N:14][NH:13][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=Cc1ccc2ccccc2n1
Solvent: CCO
Product: CC(C)(C)OC(=O)NN=Cc1ccc2ccccc2n1

Procedure:
A solution of 10.70 g 2-quinolinecarboxaldehyde and 9.00 g tert-butyl hydrazinecarboxylate in 200 ml of ethanol is refluxed for 2 h with stirring. Then the solution is evaporated to dryness and the residue is triturated with diisopropylether, separated off and dried at 50° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH2:10][O:11][CH3:12])([CH3:9])[CH3:8])[O:4][N:3]=1.[CH3:13][N:14]=[C:15]=[O:16]>CCOCC>[CH3:13][NH:14][C:15]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:9])([CH3:8])[CH2:10][O:11][CH3:12])[O:4][N:3]=1)=[O:16]
Reactant: COCC(C)(C)c1cc(N)no1
Reactant: CN=C=O
Solvent: CCOCC
Product: CNC(=O)Nc1cc(C(C)(C)COC)on1

Procedure:
A solution of 1.0 g of 3C and 1.0 g of methyl isocyanate in 15 ml of anhydrous ether was held at room temperature for 3 days. Then the solvent was evaporated and the residue was crystallized from hexane to give 1-methyl-3-(5-(1,1-dimethyl-2-methoxyethyl)-1,2-oxazol-3-yl)urea (3D), as a colorless solid, m.p.: 113°-115° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[Si:10](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1.CCOC(C)=O>[OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][O:7][Si:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]([CH3:26])([CH3:24])[CH3:25])[CH2:4][OH:5]
Reactant: OCC(CO)(CO)CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCC(CO)(CO)CO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.2 %

Procedure:
2,2-bis(hydroxymethyl)propane-1,3-diol (10.55 g, 77 mmole) was taken up in dry pyridine (100 mL). Tert-butyldiphenylsilyl chloride (4.26 g, 15 mmole, 0.2 eq) was then added dropwise over 10 minutes to the pyridine solution at ambient temperature. The reaction mixture was stirred at ambient temperature for 24 hours. TLC (EtOAc) indicated that the reaction was complete. The reaction was diluted with EtOAc (250 mL), washed with 10% HCl (3×200 mL). The organic layer was dried over sodium sulfate and then concentrated in vacuo to afford a thick pale yellow oil. Column chromatography on silica gel (200 g), eluted with EtOAC followed by concentration of the appropriate fractions gave 5.01 g of the title compound as a clear colorless oil which solidified very slowly upon standing (86%). 1H NMR (300 MHz, CDCl3) δ 7.65 (m, 4H), 7.42 (m, 6H), 3.74 (s, 6H), 3.66 (s, 2H), 1.08 (s, 9H); MS (70 eV, EI) 392 (M+NH4)+.
Reaction SMILES: C([C:4]1([CH:8]([O:10][CH:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:22](=[O:23])[C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]5[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=5)=[CH:27][CH:26]=4)=[C:20]([CH2:39][CH2:40][CH3:41])[N:19]4[N:42]=[CH:43][N:44]=[C:18]34)[CH2:13][CH2:12]2)[CH3:9])[CH2:7][CH2:6][CH2:5]1)(=O)C.OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:50].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[OH:50][C:4]1([CH:8]([O:10][C@@H:11]2[CH2:12][CH2:13][C@H:14]([N:17]3[C:22](=[O:23])[C:21]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([C:31]5[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=5)=[CH:29][CH:30]=4)=[C:20]([CH2:39][CH2:40][CH3:41])[N:19]4[N:42]=[CH:43][N:44]=[C:18]34)[CH2:15][CH2:16]2)[CH3:9])[CH2:5][CH2:6][CH2:7]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OC(C)C3(C(C)=O)CCC3)CC2)c2ncnn12
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: OO
Solvent: ClC(Cl)Cl
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@@H](OC(C)C3(O)CCC3)CC2)c2ncnn12
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To a mixture of 4′-[(4-{4-[1-(1-acetylcyclobutyl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (9.20 g), 30% aqueous hydrogen peroxide solution (77.5 mL) and chloroform (80 mL) was added trifluoroacetic acid anhydride (42.8 mL), and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution and 1 M sodium thiosulfate were added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution of the obtained residue in tetrahydrofuran (15 mL)-methanol (15 mL) was added 2 N aqueous sodium hydroxide solution (15 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was acidified with 1 N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=80/20→40/60 (volume ratio)] to give the title compound as a colorless amorphous compound (0.50 g, 6%).
Reaction SMILES: C([Sn]([C:14]1[N:15]([CH3:19])[CH:16]=[CH:17][CH:18]=1)(CCCC)CCCC)CCC.C(C1(C)C(O)=C(C(C)(C)C)C=CC1)(C)(C)C.Cl[C:37]1[O:38][C:39]2[C:40](=[C:42]([C:54]#[N:55])[C:43]([CH3:53])=[C:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:45]=2[F:46])[N:41]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[F:46][C:45]1[C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[C:43]([CH3:53])[C:42]([C:54]#[N:55])=[C:40]2[C:39]=1[O:38][C:37]([C:14]1[N:15]([CH3:19])[CH:16]=[CH:17][CH:18]=1)=[N:41]2
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)C1=C(O)C(C)(C(C)(C)C)CC=C1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2)c(F)c2oc(-c3cccn3C)nc2c1C#N

Procedure:
Tributylstannyl-1-methylpyrrole (389 mg, 1.05 mmol), bis(triphenylphosphine)palladium(II) dichloride (49 mg, 0.07 mmol), and a catalytic amount of 2,6-di-tert-butylcresol (2 mg) were added to a toluene (20 ml) solution of 2-chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (200 mg, 0.70 mol), followed by stirring under heat under nitrogen atmosphere for 3 hours. After cooling, the reaction liquid was filtered, and the solvent of the filtrate was evaporate away under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of n-hexane/ethyl acetate (9:1, v/v→5:1, v/v) to obtain a main product. After washing with isopropyl ether, the entitled compound (50 mg, 22%) was collected by filtration as a pale yellow solid.
Reaction SMILES: [C:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][S:13][C:12]2=[CH:17][N+:18]([O-:20])=[O:19])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21]N1C(=O)CCC1=O>>[C:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][S:13][C:12]2=[C:17]([Cl:21])[N+:18]([O-:20])=[O:19])(=[O:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=[N+]([O-])C=C1SCCCN1S(=O)(=O)Cc1ccccc1
Product: O=[N+]([O-])C(Cl)=C1SCCCN1S(=O)(=O)Cc1ccccc1

Procedure:
was prepared, as a yellow solid, m.p.: 150°-151° C. (with decomposition), by treating (5A) with N-chlorosuccinimide according to the procedure described in Example 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[C:13][Si](C)(C)C)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CC(O)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOCC>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][C:12]#[CH:13])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(CC#C[Si](C)(C)C)cc(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C#CCc1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 101.2 %

Procedure:
To a stirred solution of 7 (5.37 g, 21.6 mmol, 1 equiv) was dissolved in THF (100 mL) and AcOH (4.99 mL, 86.5 mmol, 4 equiv) was added followed by dropwise addition of TBAF (1 M in THF; 86.5 mL, 86.5 mmol, 4 equiv). The resulting reaction was allowed to stir at room temperature for 24 h. The reaction was diluted with Et2O, washed with brine (×2), dried (MgSO4), filtered, and concentrated under reduced pressure. The crude mixture was purified by chromatography on SiO2 (EtOAc/hexanes, 1:10) to give 3.85 g (100% yield) of the desired product as a colorless oil: Rf 0.36 (EtOAc/hexanes, 1:10); IR (CDCl3) 3286, 2999, 2954, 1593, 1457, 1428, 1344, 1323, 1288, 1204, 1154, 1064, 827; 1H NMR (400 MHz, CDCl3) δ 6.53 (d, 2 H, J=2.4 Hz), 6.35 (t, 1 H, J=2.4 Hz), 3.79 (s, 6 H), 3.56 (d, 2 H, J=2.8 Hz), 2.20 (t, 1H, J=2.8 Hz); 13C NMR (100 MHz, CDCl3) δ 160.9, 138.3, 105.9, 98.7, 81.7, 70.6, 55.3, 25.0; HRMS (EI+) m/z calcd for C11H12O2 176.0837, found 176.0834.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:29]=[CH:28][C:12]([O:13][CH2:14][C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20](=O)[CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:29]=[CH:28][C:12]([O:13][CH2:14][C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)CCC(=O)N1CCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCCN1CCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Yield: 49.5 %

Procedure:
To a solution of methyl 4-{(S)-2-[4-(4-chloro-phenyoxy)-phenoxymethyl]-pyrrolidin-1-yl}-4-oxo-butyrate (d4) (500 mg, 1 mmol, 1 eq.) in THF (14 ml) was added BH3 (1M in THF, 2 ml, 2 mmol, 2 eq.). The mixture was stirred under reflux overnight. After cooling to ambient temperature, THF was removed and the crude product was purified by chromatography on silica gel using dichloromethane as eluent to give the title product (200 mg, 49% yield).
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][NH:30][C:29](=[O:33])[CH:28]=7)=[C:24]([C:34]([NH:36][CH3:37])=[O:35])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.[C:45]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][N:30]([CH3:45])[C:29](=[O:33])[CH:28]=7)=[C:24]([C:34]([NH:36][CH3:37])=[O:35])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1c(-c2cc[nH]c(=O)c2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccn(C)c(=O)c2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.1 %

Procedure:
To a suspension of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)-2-(2-oxo-1,2-dihydropyridin-4-yl)benzofuran-3-carboxamide (20 mg, 0.03 mmol) and K2CO3 (10 mg, 0.06 mmol) in DMF (1 mL) was added CH3I (5 mg, 0.03 mol) at 0° C. under N2, and then the mixture was stirred for 12 hours at room temperature. After being concentrated in vacuo, the resulting residue was suspended in H2O and extracted with DCM. The combined organic layer was washed with H2O and dried over Na2SO4. After concentration, the residue was purified by prep-HPLC to give the product of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (10 mg, yield: 49%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.7˜28.74 (m, 1H), 8.10 (s, 1H), 7.84˜7.86 (m, 2H), 7.70˜7.72 (m, 1H), 7.59˜7.62 (m, 1H), 7.50˜7.53 (m, 1H), 7.24˜7.28 (m, 1H), 7.23 (s, 1H), 6.96˜7.09 (m, 2H), 6.67˜6.91 (m, 1H), 6.27 (s, 2H), 3.48 (s, 3H), 3.31 (s, 3H), 2.97 (s, 3H), 2.85 (d, J=4.4 Hz, 3H). MS (M+H)+: 628.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].Br[CH2:11][CH2:12][CH2:13][CH2:14][Cl:15]>>[Cl:15][CH2:14][CH2:13][CH2:12][CH2:11][O:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: ClCCCCBr
Reactant: Cc1ccc(O)cc1C
Product: Cc1ccc(OCCCCCl)cc1C

Procedure:
Prepared by Procedure U and Scheme AK using 3,4-dimethylphenol and 1-bromo-4-chlorobutane.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:29](=[O:44])[C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:11][CH2:10][N:9]1[C:29](=[O:44])[C:30]1[CH:31]=[C:32]([C:40]([F:41])([F:42])[F:43])[CH:33]=[C:34]([C:36]([F:38])([F:39])[F:37])[CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N(CCc2ccccc2)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](NCCc2ccccc2)C[C@H]1Cc1ccccc1

Procedure:
0.190 g (0.301 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-bis(trifluoromethyl)benzoyl)-N-(2-phenylethyl)-N-trifluoroacetyl-4-piperidinamine is reacted with 0.046 g (1.21 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR82## is obtained (0.123 g, 76%) as oil. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.22, FD-MS: M+ =534, IR: 1630 cm-1.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][N:30]=[C:29]([O:33]C)[CH:28]=7)=[C:24]([C:35]([NH:37][CH3:38])=[O:36])[C:23]=6[CH:39]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.Br.CC(O)=O>CC(O)=O>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][NH:30][C:29](=[O:33])[CH:28]=7)=[C:24]([C:35]([NH:37][CH3:38])=[O:36])[C:23]=6[CH:39]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CNC(=O)c1c(-c2ccnc(OC)c2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Agent: Br
Solvent: CC(=O)O
Product: CNC(=O)c1c(-c2cc[nH]c(=O)c2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 48.9 %

Procedure:
To a solution of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(2-methoxypyridin-4-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (30 mg, 0.05 mmol) in HOAc (1 mL) was added HBr—HOAc (1 mL) at 0° C. Then the mixture was stirred at 80° C. for 2 hours. The solvent was removed by vacuum and NaHCO3 (a.q.) was added. The mixture was extracted with DCM, and the organic phase was dried over Na2SO4. After concentrated in vacuo, the residue was purified by prep-HPLC to give the product of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)-2-(2-oxo-1,2-dihydropyridin-4-yl)benzofuran-3-carboxamide (15 mg, yield: 52%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.73˜8.75 (m, 1H), 8.11 (s, 1H), 7.85 (s, 1H), 7.73 (q, J=8.8 Hz, 1H), 7.59˜7.62 (m, 2H), 7.51˜7.61 (m, 2H), 7.25˜7.27 (m, 1H), 7.11 (s, 1H), 6.88˜6.96 (m, 1H), 6.65 (d, J=2.8 Hz, 1H), 6.27 (s, 2H), 3.31 (s, 3H), 2.97 (s, 3H), 2.85 (d, J=4.0 Hz, 3H). MS (M+H)+: 614.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][C:19]([OH:23])=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1.Br[CH2:35][CH2:36][OH:37]>>[CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:35][CH2:36][OH:37])=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1
Reactant: OCCBr
Reactant: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3cc(O)ccc32)cc1
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3cc(OCCO)ccc32)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 106 using N-[(4-dimethylaminophenyl)methyl]-6-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66 g) and 2-bromoethanol (0.16 mL) as starting materials, N-[(4-dimethylaminophenyl)methyl]-6-(2-hydroxyethoxy)-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.28 g) was obtained. melting point: 141.4° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([NH:23][CH:24]1[CH2:29][S:28][C@H:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:26]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:25]1=[O:42])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1C(=O)C2=CC=CC=C2C1=O)=[O:5])[CH3:2].O.NN>O1CCOCC1.C1(C)C=CC=CC=1>[NH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][P:4]([NH:23][CH:24]1[CH2:29][S:28][C@H:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:26]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:25]1=[O:42])([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)CN1C(=O)C(NP(=O)(CCCCCCN2C(=O)c3ccccc3C2=O)OCC)CS[C@@H]1c1ccccc1
Agent: NN
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)CN1C(=O)C(NP(=O)(CCCCCCN)OCC)CS[C@@H]1c1ccccc1
Temperature: 25 °C

Procedure:
A solution of (R)-dihydro-5-[[ethoxy(6-phthalimidohexyl)phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester in dioxane is treated with hydrazine hydrate and stirred at room temperature under argon. After the reaction is completed, the mixture is diluted with toluene and the solvents decanted. The residue is triturated with methylene chloride and filtered. The combined filtrate is evaporated to dryness to give (R)-dihydro-5-[[(6-aminohexyl)ethoxyphosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]([N:8]1[C@@H:11]([S:12]SC2SC3C=CC=CC=3N=2)[C@@H:10]([O:23][CH3:24])[C:9]1=[O:25])=[C:5]([CH3:7])[CH3:6].[BH4-].[Na+].[C:29](Br)(=[O:31])[CH3:30].C1C=CC=CC=1>CN(C)C=O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:26])[C:4]([N:8]1[C@H:11]([S:12][C:29](=[O:31])[CH3:30])[C@@H:10]([O:23][CH3:24])[C:9]1=[O:25])=[C:5]([CH3:6])[CH3:7]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H](OC)[C@@H]1SSc1nc2ccccc2s1
Reactant: CC(=O)Br
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H](OC)[C@H]1SC(C)=O
Reaction time: 0.5 h

Procedure:
A solution of 372 mg of 2-[(3S,4S)-4-(benzthiazol-2-yldithio)-3-methoxy-2-oxoazetidin-1-yl]-3-methylcrotonic acid methyl ester in 10 ml of dimethylformamide is cooled to -20°, 10 ml of a solution of 2 g of sodium borohydride in 200 ml of dimethylformamide are added and the mixture is stirred at the same temperature for 30 minutes. 5 ml of freshly distilled acetyl bromide are added to the reaction mixture and the mixture is further stirred for 110 minutes at 0°. After adding 150 ml of benzene, the reaction mixture is washed in successsion with sodium bicarbonate solution and water, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue yields, after chromatography over silica gel with toluene/ethyl acetate (9:1), the title compound in the form of a slightly yellowish oil.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[C:29]1([S:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[ClH:20].[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][S:35]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)(=[O:36])=[O:37])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=S(=O)(CCCCCCl)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCS(=O)(=O)c2ccccc2)CC1
Yield: 48.2 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (0.48 g) as starting compound, potassium carbonate (0.80 g) and 5-phenylsulfonylpentyl chloride (0.40 g) were reacted and treated in the same manner as in Example 199 to give 0.17 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-phenylsulfonylpentyl)piperidin-4-yl)methyl)-benzamide hydrochloride.