Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][C:13]2([O:15][CH:14]2[CH3:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[FH:25]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][C:13]([F:25])([CH:14]([OH:15])[CH3:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: F
Reactant: CC1OC12CCN(C(=O)OCc1ccccc1)C2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(O)C1(F)CCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 0.247 g, (1 mmol) of 2-methyl-1-oxa-5-azaspiro[2,4]-heptane-5-carboxylic acid benzyl ester (Example A9) in dichloromethane (3 mL) is added to a polypropylene flask containing 0.5 mL of hydrogen fluoride-pyridine at −40° C. The reaction is allowed to come to room temperature and stirring is continued for 3 hours. The reaction mixture is poured into an aqueous ice-cold ammonium hydroxide solution (30 mL) and extracted with dichloromethane. The organic layer is dried, filtered and concentrated to afford the title compound (0.267 g). 1H NMR (200 MHz, CDCl3): δ 7.35 (s, 5H), 5.13 (s, 2H), 3.96–3.34 (m, 5H), 2.20–1.98 (m, 3H), 1.33–1.26 (m, 3H).
Reaction SMILES: [Br-].[Br:2][CH2:3][CH2:4][CH2:5][P+:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>C(O)C.O>[Br-:2].[N:25]([CH2:3][CH2:4][CH2:5][P+:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: BrCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=NCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
(3-Bromo-propyl)-triphenyl-phosphonium bromide was dissolved in ethanol/water (1/1). To it sodium azide was added. The reaction mixture was heated up to reflux overnight. Solvents were removed by evaporation. The residue was extracted by dry ethanol. Filtered and evaporated to give crude (3-azido-propyl)-triphenyl-phosphonium bromide and was used directly for the next step reaction without further purification.
Reaction SMILES: [CH:1]1[C:13]2C[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:14]([Cl:18])(Cl)(Cl)[Cl:15]>>[Cl:15][C:14]1([Cl:18])[C:4]2[CH:3]=[CH:2][CH:1]=[CH:13][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: ClC(Cl)(Cl)Cl
Product: ClC1(Cl)c2ccccc2-c2ccccc21

Procedure:
To the reactor which has been purged with nitrogen is charged a volume of carbon tetrachloride (400 mL) such that its level just comes to the bottom of the sixth stage. NaOH solution (the same solution used in the previous run (Example 49), Part A), 25 percent by weight, 6.14 moles, 245.6 g dry weight, 983 g solution weight, 774.0 mL) is then charged to the reactor, and fills all six of the stirred zones. The stirrer is started and its speed adjusted to 1500 rpm. Fluorene (0.185 moles, 30.75 g) dissolved in carbon tetrachloride (2.24 moles, 344.8 g, 225.35 mL) is fed into the catalyst saturator containing the catalyst solution using a metering pump at a rate of 5.5 mL/min. The product solution is collected at the overflow and washed and dried as in Part A. The total product solution collected in this fashion amounts to 1056 g which is evaporated to dryness on a rotary evaporator leaving 42.66 g of very light yellow crystals, 9,9-dichlorofluorene (98.1 percent of the theoretical yield of 43.49 g).
Reaction SMILES: COC1C=CC(C([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[Si:39]([O:38][C@@H:25]1[C@@H:24]([CH2:23][OH:22])[O:28][C@@H:27]([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:26]1)([C:42]([CH3:45])([CH3:43])[CH3:44])([CH3:40])[CH3:41]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]c1=O
Yield: 0.1 %

Procedure:
A solution of 5 g (7.6 mol) 5′-O-(4,4′-dimethoxytrityl)-3′-O-(tert-butyldimethylsilyl)thymidine 17 in 100 ml 80% aq. acetic acid was stirred until the removal of dimethoxytrityl group was completed. Saturated Na2CO3 was then added to adjust the pH of the solution to 6-7. The solution was then extracted with ethyl acetate. The extract was dried and the mixture was chromatographed on a silica gel column (CH2Cl2:MeOH=20:1) to give 2.5 g of 3′-O-(tert-butyldimethylsilyl) thymidine 18 (92.6%).: m.p. 93-95° C. (lit. 83-84° C.); H NMR (200 MHz, CDCl3) δ 9.18 (s, 1H, NH), 7.36 (b, 1H, H-6), 6.12 (t, J=6.8 Hz, 1H, H-1′), 4.44-4.48 (m, 1H, H-3′), 3.69-3.91 (m, 3H, H-4′, H-5′), 2.87 (m. 1H, OH), 2.15-2.35 (m, 2H, H-2′), 1.87 (s, 3H, C═CMe), 0.86 (s, 9H, CMe3), 0.05 (s, 6H, SiMe2); 13C NMR (125 MHz, CDCl3) δ 163.9 (C-4), 150.4 (C-2), 137.1 (C-6), 110.9 (C-5), 87.6 (C-4′), 86.8 (C-1′), 71.5 (C-3′), 61.9 (C-5′), 40.4 (C-2′), 25.7 (SiCMe3), 17.9 (SiCMe), 12.5 (C═CMe), −4.7 (SiMe2), −4.9 (SiMe2).
Reaction SMILES: [C:1]([O:10][CH2:11][P:12]([CH3:15])([CH3:14])=[O:13])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].Cl[C:17]1[C:26]2[C:21](=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1>C(O)(C)C.Cl>[F:30][C:27]([F:28])([F:29])[C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:21]=1[N:20]=[CH:19][CH:18]=[C:17]2[NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([O:10][CH2:11][P:12]([CH3:15])([CH3:14])=[O:13])=[O:9]
Reactant: FC(F)(F)c1cccc2c(Cl)ccnc12
Reactant: CP(C)(=O)COC(=O)c1ccccc1N
Agent: Cl
Solvent: CC(C)O
Product: CP(C)(=O)COC(=O)c1ccccc1Nc1ccnc2c(C(F)(F)F)cccc12

Procedure:
4.6 grams (0.02 mol) of dimethylphosphinylmethyl anthranilate and 4.6 grams (0.02 mol) of 4-chloro-8-trifluoromethylquinoline are kept at 80° C for about 31/2 hours in 15 ml of isopropanol and 2.3 ml of concentrated aqueous hydrochloric acid. After removing the solvents and excess hydrochloric acid, the free base of the ester is liberated at 0° C. The dimethylphosphinyl-methyl N-(8-trifluoromethyl-4-quinolyl)-anthranilate obtained is identical to that prepared in Example (2a). Yield 7.6 grams (90% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[SH:17]>>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[S:17][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: Sc1cccs1
Product: O=[N+]([O-])c1ccc(Sc2cccs2)c(Cl)c1
Yield: 32 %

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Example 8 which is concerned with the preparation of starting materials, 3-chloro-4-fluoronitrobenzene was reacted with 2-thiophenethiol to give 2-chloro-4-nitrophenyl 2-thienyl sulphide in 32% yield.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])[N:9]2[CH:22]=[CH:23][CH:24]=[C:8]2[C:7]=1[OH:25])=[O:5])C.[NH2:26][CH2:27][C:28]([O-:30])=[O:29].[Na+]>>[F:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([F:21])[C:14]=1[CH2:13][N:10]1[C:11](=[O:12])[C:6]([C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5])=[C:7]([OH:25])[C:8]2=[CH:24][CH:23]=[CH:22][N:9]12
Reactant: NCC(=O)[O-]
Reactant: CCOC(=O)c1c(O)c2cccn2n(Cc2c(F)cccc2F)c1=O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cccn2n(Cc2c(F)cccc2F)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 1-(2,6-difluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 378 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][C:10]3[CH:14]=[C:15]([S:18](Cl)(=[O:20])=[O:19])[CH:16]=[CH:17][C:9]2=3)=[C:4]([C:22]#[N:23])[CH:3]=1.[F:24][C:25]1[C:30]([OH:31])=[C:29]([F:32])[C:28]([F:33])=[C:27]([F:34])[C:26]=1[F:35].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][C:10]3[CH:14]=[C:15]([S:18]([O:31][C:30]4[C:29]([F:32])=[C:28]([F:33])[C:27]([F:34])=[C:26]([F:35])[C:25]=4[F:24])(=[O:20])=[O:19])[CH:16]=[CH:17][C:9]2=3)=[C:4]([C:22]#[N:23])[CH:3]=1
Reactant: N#Cc1cc(Cl)ccc1N1CCOc2cc(S(=O)(=O)Cl)ccc21
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(Cl)ccc1N1CCOc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
To a solution of 4-(4-chloro-2-cyanophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (480 mg, 1.30 mmol) in DCM (5 mL) was added pentafluorophenol (240 mg, 1.30 mmol) at 0° C. Triethylamine (0.27 mL, 1.95 mmol) was added at 0° C. and the reaction mixture was stirred at room temperature for 1 h. After completion, the reaction mixture was diluted with DCM (3 mL) and concentrated under reduced pressure. The crude mass was purified by combi flash column chromatography (12 g column; elution: 7% ethyl acetate in hexane) to provide perfluorophenyl 4-(4-chloro-2-cyanophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (370 mg, 54.9%) as clear liquid. 1H NMR (400 MHz, DMSO) δ 8.22 (d, J=2.5 Hz, 1H), 7.96 (dd, J=8.7, 2.5 Hz, 1H), 7.70 (d, J=8.7 Hz, 1H), 7.38 (d, J=2.2 Hz, 1H), 7.31 (dd, J=8.7, 2.3 Hz, 1H), 6.59 (d, J=8.7 Hz, 1H), 4.41 (s, 2H), 3.86 (s, 2H); LCMS (ESI) m/z; 516.02 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:28]([NH2:32])[CH:29]([CH3:31])[CH3:30]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([NH:32][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:15])[CH:10]([CH3:11])[CH3:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)CN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reaction time: 0.83 h
Yield: 83 %

Procedure:
N-t-butoxycarbonylvaline (2.2 g, 10 mmol) is dissolved in, dry THF under nitrogen, and to this is added 2.0 g (12 mmol) of carbonyldiimidazole. After this mixture is stirred for 50 min, 2.0 mL (20 mmol) of isobutylamine is added. After 1 week, the mixture is concentrated, dissolved in ethyl acetate, and washed successively with aqueous potassium hydrogen sulfate, water, and brine. It is dried over anhydrous sodium sulfate and concentrated to 2.27 g (8.3 mmol, 83%) of the title compound as a white solid. NMR (CDCl3) δ 6.0 (br, 1H), 5.07 (br d, 1H), 3.83 (m, 1H), 3.10 (m, 2H), 2.14 (m, 1H), 1.77 (m, 1H), 1.44 (s, 9H), 1.01-0.90 (overlapping d, 12H). HRMS (ESI) calcd for C14H28N2O3+H1 273.2178, found 273.2180
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15]O.Cl.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N)CC1

Procedure:
1-t-Butoxycarbonyl piperidine-4-one (commercially available from Lancaster Chem) (39.9 g, 0.20 mol), THF (150 mL), H2O (300 mL), and H2NOH HCl (55.2, 0.80 mol) were dissolved together and Na2CO3 (55.2 g, 0.53 mol) was added in small portions. The mixture was stirred at 23° for 14 h, most of the THF was evaporated in vacuo, adjusted to pH>10 with 50% aq NaOH, extracted with EtOAc(5×50 mL) and concentrated to a white foam. Triturated with hexane, filtered and the solid was dried in vacuo to afford 40.31 g of the title compound.
Reaction SMILES: [C:1]([C:4]1[N+:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:7][NH:6][C:5]=1[O-:19])(=[O:3])[NH2:2].[C:20]([O:23][C@@H:24]1[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@@H:28]([O:34][C:35](=[O:37])[CH3:36])[C@@H:27]([CH2:38][O:39][C:40](=[O:42])[CH3:41])[O:26][C@@H:25]1Br)(=[O:22])[CH3:21]>>[N+:16]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:8]2[C:4]([C:1]([NH2:2])=[O:3])=[C:5]([O:19][C@@H:25]3[O:26][C@H:27]([CH2:38][O:39][C:40](=[O:42])[CH3:41])[C@H:28]([O:34][C:35](=[O:37])[CH3:36])[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]3[O:23][C:20](=[O:22])[CH3:21])[N:6]=[CH:7]2)=[CH:15][CH:14]=1)([O-:18])=[O:17]
Reactant: NC(=O)c1c([O-])[nH]c[n+]1Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2ncn(Cc3ccc([N+](=O)[O-])cc3)c2C(N)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 65.1 %

Procedure:
Following a procedure similar to that of Example 1 but using 2.622 g of 5-carbamoyl-1-(4-nitrobenzyl)imidazolium-4-olate and 8.220 g of 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide there was obtained 3.857 g of 1-(4-nitrobenzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)oxy-1H-imidazole-5-carboxamide.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1.[CH2:14](I)[CH3:15].CN(C)C=O>O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]([N:10]([CH2:14][CH3:15])[C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)Nc1cccc(Br)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCN(C(C)=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
820 mg (20.5 mmol, 1.1 eq) of 60% sodium hydride are added to a solution of 4.0 g (18.7 mmol, 1 eq) of N-(3-bromophenyl)acetamide and 1.80 mL (22.4 mmol, 1.2 eq) of ethyl iodide in 15 ml of tetrahydrofuran in the presence of 1.5 ml of dimethylformamide. The reaction medium is stirred at room temperature for 12 hours and then hydrolyzed with water and extracted with ethyl acetate. The organic phases are combined, washed with sodium chloride solution and dried over sodium sulfate. The solvents are evaporated off and the N-(3-bromophenyl)-N-ethylacetamide obtained in oil form is used in the following reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[O:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[CH2:43][NH:44][CH3:45]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:44]([CH2:43][C:39]3[O:38][CH:42]=[CH:41][CH:40]=3)[CH3:45])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: CNCc1ccco1
Product: CN(Cc1ccco1)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and furan-2-ylmethylmethylamine according to conditions described in general procedure C. Mp: 155-156° C.; 1H NMR (400 MHz, CDCl3) δ 1.61-1.69 (m, 6 H), 3.05 (s, 3 H), 3.25-3.28 (m, 4 H), 4.49 (s, 2 H), 6.12-6.18 (m, 2 H), 6.75 (d, J=11.1 Hz, 1 H), 6.98 (d, J=8.0 Hz, 1 H), 7.25-7.31 (m, 3H), 7.46-7.57 (m, 3 H), 7.88-7.97 (m, 3 H), 8.16-8.21 (m, 2 H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:7]=1.[O:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35]>>[CH3:28][C:27]1[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([C:5]3[CH:4]=[CH:3][C:2]([N:32]4[CH2:33][CH2:34][O:30][C:31]4=[O:35])=[CH:7][C:6]=3[N:8]3[CH2:12][CH2:11][CH2:10][C:9]3=[O:13])=[O:15])[CH2:17][CH2:18]2)=[N:23][CH:24]=[C:25]([CH3:29])[CH:26]=1
Reactant: O=C1NCCO1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCCC3=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3N3CCCC3=O)CC2)c(C)c1
Yield: 10.4 %

Procedure:
By reaction and treatment in the same manner as in Example 201 and using 1-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}pyrrolidin-2-one (206 mg) described in Preparation Example 121 and oxazolidin-2-one (43.5 mg), the title compound (24.1 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[CH:4][C:5]2[O:10][CH:9]=[CH:8][CH:7]([C:11]([OH:13])=[O:12])[C:6]=2[CH:14]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([Cl:15])=[CH:4][C:5]2[O:10][CH:9]=[CH:8][CH:7]([C:11]([O:13][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:12])[C:6]=2[CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)C1C=COc2cc(Cl)c(Cl)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C1C=COc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 6,7-dichloro-4H-1-benzopyran-4-carboxylic acid (16.8 gm), tetra (N-butyl)ammonium hydrogensulfate (23 gm), benzyl bromide (9.7 mL), saturated sodium bicarbonate (100 mL) and dichloromethane (100 mL) were stirred vigorously at room temperature for 14 hours, then diluted with dichloromethane, and the organic layer separated, washed with saturated sodium bicarbonate, water, brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (2:1 dichloromethane/hexanes, SiO2) to afford the title compound (11.8 gm, Rf=0.3 (2:1 dichloromethane/hexanes, SiO2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH2:15]O)[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.S(Cl)([Cl:19])=O.C1(C)C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][Cl:19])[CH:10]=2)=[N:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(Oc2ncc(Br)cn2)c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: ClCc1cccc(Oc2ncc(Br)cn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
(3-(5-Bromopyrimidin-2-yloxy)phenyl)methanol (0.790 g, 2.81 mmol) in dichloromethane (9 mL) was cooled to 0° C. and treated dropwise with thionyl chloride (0.215 mL, 2.95 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. Toluene (5 mL) was added and the mixture was concentrated to give the title compound (0.815 g, 97% yield) as a semi-solid. MS (APCI) M+1=299.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=O.[CH2:11]([O:13][P:14]([CH2:23][CH2:24][CH2:25][NH2:26])([CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[O:15])[CH3:12].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:11]([O:13][P:14]([CH2:23][CH2:24][CH2:25][NH:26][CH2:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[C:8]([Cl:10])[CH:7]=1)([CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[O:15])[CH3:12]
Reactant: CCOC(OCC)P(=O)(CCCN)OCC
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(OCC)P(=O)(CCCNCc1cc(Cl)cc(Cl)c1)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.41 g of 3,5-dichlorobenzaldehyde are added to a solution of 2.53 g of 3-aminopropyl(diethoxymethyl)-phosphinic acid ethyl ester in 10 ml of anhydrous methanol and the resulting clear solution is stirred at room temperature for 30 minutes. There are then added first 0.6 g of glacial acetic acid and then, dropwise, 0.21 g of sodium cyanoborohydride dissolved in 5 ml of methanol. An exothermic reaction begins. The reaction mixture is stirred for 3 hours at 20°, adjusted to pH 8, and the solvent is removed. The residue is dissolved in dichloromethane and washed with water. The organic phase is separated off, dried over sodium sulfate and concentrated to dryness by evaporation. The oil that remains behind is purified by chromatography on silica gel, yielding 3-(3,5-dichlorobenzylamino)propyl(diethoxymethyl)-phosphinic acid ethyl ester in the form of a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:3]=1[NH:4][S:5]([CH2:8][CH2:9][CH2:10][CH2:11]Cl)(=[O:7])=[O:6].[K].CC(C)([O-])C.O>CN(C=O)C>[Cl:1][C:2]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:3]=1[N:4]1[CH2:11][CH2:10][CH2:9][CH2:8][S:5]1(=[O:7])=[O:6]
Reactant: Cc1ccc(NS(=O)(=O)CCCCCl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCCCS2(=O)=O)c(Cl)c1

Procedure:
1.27 g (4.29 mmol) 2-chloro-N-(4-chlorobutyl-sulphonyl)-4-methyl-aniline are stirred together with 722 mg (6.43 mmol) potassium-tert.-butoxide in 50 ml DMF for 16 hours at 60° C. Then the reaction mixture is poured into water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down i. vac. The residue is purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate=3:2).
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]([CH3:51])[CH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:41][CH2:42][N:44]([CH3:51])[CH:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[CH:36][CH:37]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C(=O)CCl)C1CCOCC1
Product: CCN(Cc1ccc(OCCN(C)C2CCOCC2)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 23.7 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-N-methyl-N-(tetrahydropyran-4-yl)acetamide (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (4.1 mg) was obtained.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:27]([O:31][C:32]([O:34][C:35]1[C:47]([C:48]([F:51])([F:50])[F:49])=[CH:46][CH:45]=[C:44]([CH3:52])[C:36]=1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:33])([CH3:30])([CH3:29])[CH3:28]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:52][C:44]1[C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[C:35]([O:34][C:32]([O:31][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:33])[C:47]([C:48]([F:49])([F:50])[F:51])=[CH:46][CH:45]=1
Reactant: Cc1ccc(C(F)(F)F)c(OC(=O)OC(C)(C)C)c1C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Yield: 51.6 %

Procedure:
N-Bromosuccinimide (9.70 g, 54.5 mmol) and benzoyl peroxide (0.7 g) were added to a solution of tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-methyl-3-(trifluoromethyl)benzoate (18.6 g, 49.6 mmol) obtained in Example (28-4) in carbon tetrachloride (400 ml), and the mixture was heated under reflux for 5 hours. The temperature of the reaction mixture was returned to room temperature and the solvent was removed under reduced pressure. After n-hexane was added to the obtained residue and the mixture was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent: toluene) to give tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (11.66 g, yield: 52%).