Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[NH:6][N:5]=[C:4]2[CH2:9][O:10][C:11]3[CH:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:14]([CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)=[CH:13][C:12]=3[N:3]12.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[CH3:1][CH:2]1[C:7](=[O:8])[NH:6][N:5]=[C:4]2[CH2:9][O:10][C:11]3[CH:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:14]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:13][C:12]=3[N:3]12
Reactant: CC1C(=O)NN=C2COc3cc(-c4ccccc4)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1C(=O)NN=C2COc3cc(-c4ccccc4)c(C4CCNCC4)cc3N21
Yield: 78 %

Procedure:
A solution of tert-butyl 4-(1-methyl-2-oxo-8-phenyl-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)piperidine-1-carboxylate (0.020 g, 0.042 mmol) in DCM (6 mL) and TFA (1 mL) was stirred at ambient temperature for 1.5 h. The solvent was removed in vacuo to give 1-methyl-8-phenyl-9-(piperidin-4-yl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acid (0.016 g, 78%) as a pale yellow solid. LC/MS (Table 1, Method 5) Rt=2.314 min.; MS m/z: 377 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH:6]=[CH:7][CH2:8][NH:9][CH2:10][CH2:11][NH:12][S:13]([C:16]2[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][C:22]=3[CH:23]=[CH:24][CH:25]=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.Br[CH2:29][CH2:30]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[CH2:30][CH2:29][N:12]([S:13]([C:16]3[C:17]4[CH:18]=[CH:19][N:20]=[CH:21][C:22]=4[CH:23]=[CH:24][CH:25]=3)(=[O:14])=[O:15])[CH2:11][CH2:10]2)=[CH:26][CH:27]=1
Reactant: BrCCBr
Reactant: O=S(=O)(NCCNCC=Cc1ccc(Cl)cc1)c1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(c1cccc2cnccc12)N1CCN(CC=Cc2ccc(Cl)cc2)CC1
Reaction time: 24 h
Yield: 25.5 %

Procedure:
1.31 g of the product of Example 172 was dissolved in 3 ml of dimethylformamide, to the solution were added 644 mg of 1,2-dibromoethane and 1.13 g of anhydrous potassium carbonate at a room temperature, and the mixture was stirred for 24 hours. After adding 100 ml of ethyl acetate, the ethyl acetate layer was sequentially washed with water and a saturated sodium chloride aqueous solution twice in each case, and dried over magnesium sulfate. The solution was filtered and evaporated under a reduced pressure, and resulting residue was purified on a silica gel column (silica gel 50 g, eluant: 5% methanol in chloroform), to obtain 356 mg of the title compound in a colorless amorphous form, while recovering the residual starting material.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[CH:6][C:5]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28].C(=O)([O-])[O-].[K+].[K+].I[CH2:37][CH2:38][CH2:39][CH3:40]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][N:12]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:13][C:14]2[CH:15]=[C:16]([F:21])[CH:17]=[C:18]([F:20])[CH:19]=2)=[CH:6][C:5]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28]
Reactant: COC(=O)c1ccc(CONCc2cc(F)cc(F)c2)cc1-c1ccccc1C
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCN(Cc1cc(F)cc(F)c1)OCc1ccc(C(=O)OC)c(-c2ccccc2C)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a stirred solution at ambient temperature under N2 of 4-(N-(3,5-difluorobenzyl)aminooxymethyl)-2-(2-methylphenyl)benzoic acid methyl ester (254 mg, 0.640 mmol), prepared as in Example 1176 C, in DMF (2 mL) was added potassium carbonate (265 mg, 1.92 mmol) and 1-iodobutane (0.146 mL, 1.28 mmol). Reaction stirred vigorously at 80° C. overnight. Reaction diluted with EtOAc and washed with water and brine. Organic layer dried with Na2SO4, filtered, and concentrated in vacuo. Residue was purified by flash chromatography on silica gel eluting with 7% EtOAc/Hexanes to 30% EtOAc/Hexanes to afford the desired product. (44 mg, 15%). m/e (ESI) 454 (MH+)
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][CH:6]1Br)(=[O:3])[CH3:2].[OH:20][C:21]1[C:29]2[O:28][CH:27]=[CH:26][C:25]=2[CH:24]=[CH:23][CH:22]=1>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1[O:20][C:21]1[C:29]2[O:28][CH:27]=[CH:26][C:25]=2[CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Br)[C@@H]1OC(C)=O
Reactant: Oc1cccc2ccoc12
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc2ccoc12
Yield: 14 %

Procedure:
By carrying out the process in a manner similar to example 7, starting from 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide and 7-hydroxybenzofuran, the desired product is obtained in the form of a white solid with a yield of 14%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:3]=1[C:14](=[O:16])[CH3:15].[O:17]=[C:18]1[NH:27][C:26]2[N:25]=[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH:32]=O)[CH:23]=[CH:22][C:21]=2[CH2:20][CH2:19]1>>[C:14]([C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:24]2[N:25]=[C:26]3[C:21]([CH2:20][CH2:19][C:18](=[O:17])[NH:27]3)=[CH:22][CH:23]=2)[CH2:10][CH2:9]1)(=[O:16])[CH3:15]
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Reactant: CC(=O)c1c(Cl)cccc1N1CCNCC1
Product: CC(=O)c1c(Cl)cccc1N1CCN(CCCCOc2ccc3c(n2)NC(=O)CC3)CC1

Procedure:
In a manner similar to that of other examples, above, 1-(2-chloro-6-piperazin-1-yl-phenyl)-ethanone was coupled by reductive amination to 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound, mp 115° C. MS: APCI: M+1: 457.2 (Exact Mass: 456.19).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C([Li])CCC.[C:27]1(=[O:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C1(C)C=CC=CC=1.C(OCC)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[CH:12]=[C:11]([C:27]3([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[S:10][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:15][CH:16]=1
Reactant: O=C1CCCCC1
Reactant: COc1ccc(-c2ccsc2-c2ccc(OC)cc2)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc(C3(O)CCCCC3)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A solution of 2,3-bis(4-methoxyphenyl)thiophene (5.92 g, 20 mmole) in toluene (20 ml)/diethyl ether (120 ml) was treated with 1.6M n-butyl lithium (14 ml, 1.1 equiv.) and heated at reflux for 1.5 hours. The reaction mixture was cooled to 0° and treated with a solution of cyclohexanone (2.3 ml, 1.1 equiv.) in 5 ml of diethyl ether. The mixture was stirred for 1.5 hours at 0° and 1 hour at room temperature, quenched with water, and extracted with ethyl acetate. The organic extracts were washed with brine, dried and concentrated in vacuo. Chromatography on a Waters Prep 500 (hexane/ethyl acetate, 3:1) provided the title compound (5.8 g, 74%) as an oil.
Reaction SMILES: NC(CCCCCCCCC(N)CCC)CCC.C(C1CC=CCCC=CCC(CCC)N=N1)CC.[CH2:37]([CH:42]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH:45]([CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[NH:44][NH:43]1)[CH2:38][CH2:39][CH2:40][CH3:41]>>[NH2:43][CH:42]([CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH:45]([NH2:44])[CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCC1CCCCCCCCC(CCCCC)NN1
Agent: CCCC(N)CCCCCCCCC(N)CCC
Agent: CCCC1CC=CCCC=CCC(CCC)N=N1
Product: CCCCCC(N)CCCCCCCCC(N)CCCCC
Yield: 61.3 %

Procedure:
If there are used in the manner described under (a), instead of 942 g (3.79 mols) of 3,12-dipropyl-1,2-diaza-1,5,9-cyclododecatriene, 220 g (0.71 mol) of 3,12-dipentyl-1,2-diazacyclododecane (diastereoisomeric mixture) and correspondingly reduced amounts of catalyst and solvent, with otherwise the same procedure, there is obtained, as the main fraction, 136 g (61.3% of theory) of 6,15-diaminoeicosane as colourless oil [b.p. 167°-170° C./0.001 Torr; nD20 =1.4603; IR (liquid) inter alia bands at 3378, 3289 and 1613 cm-1 ].
Reaction SMILES: [H-].[Na+].O[CH:4]([C:7]1([NH:10][C:11](=[O:17])[O:12]C(C)(C)C)[CH2:9][CH2:8]1)[CH2:5][OH:6]>C1COCC1>[OH:6][CH2:5][CH:4]1[C:7]2([CH2:8][CH2:9]2)[NH:10][C:11](=[O:12])[O:17]1
Reactant: CC(C)(C)OC(=O)NC1(C(O)CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NC2(CC2)C(CO)O1
Temperature: 30 °C
Reaction time: 16 h

Procedure:
Sodium hydride (197 mg, 4.92 mmol) was added to a solution of tert-butyl [1-(1,2-dihydroxyethyl)cyclopropyl]carbamate (100 mg, 0.46 mmol) in THF (1 mL) at room temperature. The mixture was stirred at 30° C. under a nitrogen atmosphere for 16 hours. After being cooled to 20° C., the mixture was diluted with ice water (1 mL) and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (methanol/dichloromethane) to give 7-(hydroxymethyl)-6-oxa-4-azaspiro[2.4]heptan-5-one. 1H NMR (300 MHz, DMSO-d6): δ 7.62 (br s, 1H), 5.00-4.96 (m, 1H), 4.40-4.35 (m, 1H), 3.51-3.40 (m, 2H), 1.01-0.88 (m, 1H), 0.80-0.55 (m, 3H).
Reaction SMILES: [CH3:1][C@H:2]([C:15]([OH:17])=[O:16])[C:3]1[CH:8]=[CH:7][C:6]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:5]=2[CH:4]=1.[F:18][C:19]([F:27])([C:23]([F:26])([F:25])[F:24])[CH:20](O)[CH3:21].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:14][O:13][C:10]1[CH:9]=[C:6]2[C:5](=[CH:12][CH:11]=1)[CH:4]=[C:3]([CH:2]([CH3:1])[C:15]([O:17][C@H:20]([C:19]([F:27])([F:18])[C:23]([F:26])([F:25])[F:24])[CH3:21])=[O:16])[CH:8]=[CH:7]2
Reactant: CC(O)C(F)(F)C(F)(F)F
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc2cc(C(C)C(=O)O[C@@H](C)C(F)(F)C(F)(F)F)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-naproxen (9.23 g, 40.1 mmol), racemic 3,3,4,4,4-pentafluoro-2-butanol (6.58 g, 40.1 mmol), EDC (9 20 g, 48.0 mmol) and DMAP (4.89 g, 40.0 mmol) was dissolved in CH2Cl2 (40 mL) at room temperature. After stirring for 8 h at room temperature, the mixture was diluted with CH2Cl2, then washed successively with 1 N HCl, sat. NaHCO3, and brine. After drying over Na2SO4 and concentrating, a mixture of diastereomeric naproxen esters was obtained as a white solid.
Reaction SMILES: IC.[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:8][CH2:7]2.[C:26](=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:26][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:9]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:8][CH2:7]2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1c2ccc(O)cc2CCN1C(=O)OC(C)(C)C
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCOC(=O)C1c2ccc(OC)cc2CCN1C(=O)OC(C)(C)C
Reaction time: 2.5 h
Yield: 100.5 %

Procedure:
Iodomethane (3.04 mL, 48.85 mmol) was added to a solution of 1-ethyl 2-tert-butyl 6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (7.85 g, 24.43 mmol) and cesium carbonate (10.35 g, 31.75 mmol) in DMF (50 mL) at room temperature, and the mixture was stirred for 2.5 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with 0.1% aqueous sodium thiosulfate solution and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 1-ethyl 2-tert-butyl 6-methoxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (8.23 g, 24.54 mmol, 100%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](C2ON=C3C=CC(C(C4N(C)C=NC=4)O)=CC=23)=[CH:4][CH:3]=1.[C:25]([O-:28])([O-])=O.[K+].[K+]>O.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[O:28])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1cncc1C(O)c1ccc2noc(-c3ccc(Cl)cc3)c2c1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
TiCl3/15% in H2O (200 ml) was added at room temperature to a solution of intermediate (6-c) (38 g) in THF (300 ml). The mixture was stirred at room temperature for 90 minutes. The mixture was poured out on ice, basified with K2CO3, filtered over celite, washed with ethyl acetate and decanted. The organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1 and 95/5/0.1), yielding 18.7 g (49%) of (±)-[2-amino-5-[4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]phenyl](3-chlorophenyl)methanone (interm. 6-d).
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:9]([CH2:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:12][CH3:13])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:15].[Cl:28][CH2:29][CH2:30][C:31](=O)[CH3:32].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[Cl-:28].[CH2:12]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH3:11])[C:4]=1[N+:3]1[C:30]([CH3:29])=[C:31]([CH3:32])[S:15][CH:1]=1)[CH3:13]
Reactant: CC(=O)CCCl
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCc1cccc(CC)c1NC=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1cccc(CC)c1-[n+]1csc(C)c1C
Product: [Cl-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.4 %

Procedure:
A mixture of 8d (3.545 g, 20 mmol) and phosphorus pentasulfide (0.900 g, 2.02 mmol) in dry 1,4-dioxane (5 mL) was stirred at room temperature for 15 min under an argon atmosphere. 4-Chloro-2-butanone (1.422 g, 20 mmol) was added and the resulting slurry was heated at 100° C. The reaction mixture was refluxed for 50 min, initially becoming clear yellow and finally deep red. After cooling at room temperature, the crude mixture was diluted with H2O (20 mL). Na2CO3 was added to the reaction mixture until pH≈7. The solvent was evaporated under reduced pressure and the resulting solid was suspended in CH2Cl2 and purified by column chromatography (column packed with silica gel) eluting with EtOH/CH2Cl2 (15/85). Upon concentration of the last band, a viscous brownish oil was obtained. This was solidified when washed under vigorous stirring with diethyl ether (3×2 mL) to afford 9d as a tan solid (560 mg, 10%). 1H NMR (CDCl3. 300 MHz): δ=10.97 (s, 1H), 7.52 (t, J=8 Hz, 1H), 7.30 (d, J=8 Hz, 2H), 2.63 (s, 3H), 2.16 (q, J=8 Hz, 4H), 2.06 (s, 3H), 1.14 (t, J=8 Hz, 6H); 13C{1H} NMR (CDCl3, 75 MHz): δ=161.92, 141.63, 139.62, 135.04, 134.20, 132.30, 127.65, 23.97, 14.18, 13.16, 11.82; HRMS (FAB+) calculated for C15H20NS [M]+ 246.1316, observed 246.1326.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:34]1([CH2:40][CH2:41][S:42][CH:43]([C:47](O)=[O:48])[C:44](O)=[O:45])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[OH:48][C:47]1[CH:17]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:8])=[O:9])=[CH:15][CH:14]=2)[O:18][C:44](=[O:45])[C:43]=1[S:42][CH2:41][CH2:40][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)c2ccccc2)cc1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(S(=O)(=O)c3ccccc3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-(phenylsulfonyl)acetophenone (2.50 g, 9.61 mmol), lithium bis(trimethylsilyl)amide (2.41 g, 14.42 mmol), chlorotrimethylsilane (1.83 mL, 14.42 mmol), THF (96 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 194°-195° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.76 (t, 2 H), 3.01 (t, 2 H), 6.87 (s, 1 H), 7.19 (m, 5 H), 7.68 (m, 3 H), 8.04 (m, 6 H), 12.05 (bs, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Si:12]([O:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:7][CH:6]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([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
Reactant: COC(=O)CBr
Reactant: CC(C)(C)[Si](OCCCc1ccc(O)cc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1ccc(CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Yield: 94.2 %

Procedure:
A solution of 3(4-hydroxyphenyl)-1-(tert-butyldiphenylsilyloxy)propane (3.91 g, 10.0 mmol) and methyl bromoacetate (3.0 g, 19.7 mmol) in acetonitrile (100 ml) was treated with powdered anhydrous potassium carbonate (10 g) and the resulting mixture was heated under reflux for 1 h. The cooled mixture was filtered and the filtrate was concentrated in vacuo. Chromatography of the residue as silica gel (elution toluene-ethyl acetate, 98:2) gave 4.36 g (94%) of the title material as clear oil.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.Cl.[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1>>[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:12]([C:11]4[CH:10]=[CH:9][C:8]([N:3]5[C@H:2]([CH3:1])[CH2:6][O:5][C:4]5=[O:7])=[CH:16][CH:15]=4)=[O:14])[CH2:31][CH2:32]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1
Reactant: C[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Agent: Cl
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C)cc2)CC1
Yield: 70.5 %

Procedure:
By reaction and treatment in the same manner as in Example 49 and using (R)-4-(4-methyl-2-oxooxazolidin-3-yl)benzoic acid (221 mg) described in Preparation Example 37 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (254 mg) described in Preparation Example 49, the title compound (296 mg) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C@:3]([OH:21])([CH2:8][C:9]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH3:10])[C:4]([F:7])([F:6])[F:5].O1C2C(C(C)(C)C[C@@](CN[C@@H](C3C=CC=CC=3)C)(O)C(F)(F)F)=CC=CC=2CC1>>[NH2:1][CH2:2][C@@:3]([OH:21])([CH2:8][C:9]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH3:10])[C:4]([F:6])([F:7])[F:5]
Reactant: CC(C)(C[C@@](O)(CN)C(F)(F)F)c1cccc2c1OCC2
Agent: C[C@@H](NC[C@@](O)(CC(C)(C)c1cccc2c1OCC2)C(F)(F)F)c1ccccc1
Product: CC(C)(C[C@](O)(CN)C(F)(F)F)c1cccc2c1OCC2

Procedure:
Similarly prepared to Intermediate 24 by hydrogenolysis of (2S)-4-(2,3-dihydro-1-benzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-({[(1R)-1-phenylethyl]amino}methyl)-2-pentanol (Intermediate 22).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](NCC1C=CC=CC=1)=[O:15].COCCCCCCCCCCCC(O)=O.C(Cl)(=O)C([Cl:43])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([Cl:43])=[O:15]
Reactant: COCCCCCCCCCCCC(=O)NCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: COCCCCCCCCCCCC(=O)O
Solvent: Cc1ccccc1
Product: COCCCCCCCCCCCC(=O)Cl

Procedure:
Reaction Scheme 4 illustratively shows the preparation of 12-methoxy-N-(phenyl-methyl)dodecanamide wherein 12-methoxydodecanoic acid (8) is treated with oxalyl chloride in anhydrous toluene to form 12-methoxydodecanoyl chloride (9) which in turn reacts with benzylamine in methylene chloride to give the desired fatty acid amide (10).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]1([NH2:20])[CH2:19][CH2:18][CH2:17]1.C([BH3-])#N.[Na+]>CO>[CH:16]1([NH:20][CH2:12][C:11]2[CH:14]=[CH:15][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: NC1CCC1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(Oc2ccc(CNC3CCC3)cc2)cc1
Reaction time: 48 h
Yield: 88.9 %

Procedure:
4-Phenoxybenzaldehyde (5.0 g, 25.0 mmol) and cyclobutylamine (1.8 g, 25.0 mmol) were dissolved in methanol (85 mL) under nitrogen at room temperature. Sodium cyanoborohydride (1.57 g, 25.0 mmol) was added, and stirring was continued for 48 hours. The solvent was evaporated, and the residue was suspended in ether, washed with brine, and dried over Na2SO4. The ether was evaporated, and the crude product was chromatographed on silica gel eluting with 3% methanol in methylene chloride to provide 5.63 g (89%) of the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 1.56-1.80 (m, 5H), 2.15-2.30 (m, 2H), 3.25-3.39 (m, 1H), 3.68 (s, 2H), 6.94-7.04 (m, 4H), 7.05-7.15 (tt, J=7.5, 1.5 Hz, 1H), 7.25-7.38 (m, 4H). MS (DCl/NH3) m/e 254 (M+H)+.
Reaction SMILES: [C:1]([C:9]1[C:10]([CH3:33])=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)=[CH:16][C:15]([O:29][CH3:30])=[C:14]([O:31][CH3:32])[CH:13]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:34]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]([C:9]1[C:10]([CH2:33][Br:34])=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)=[CH:16][C:15]([O:29][CH3:30])=[C:14]([O:31][CH3:32])[CH:13]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-c2c(C(=O)c3ccccc3)c(C)nc3cc(OC)c(OC)cc23)cc1OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(-c2c(C(=O)c3ccccc3)c(CBr)nc3cc(OC)c(OC)cc23)cc1OC
Yield: 42.1 %

Procedure:
A mixture of 3-benzoyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-methylquinoline (5.5 g), N-bromosuccinimide (2.42 g), 2,2'-azobis(isobutyronitrile)(0.815 g) and carbon tetrachloride (250 ml) was stirred under reflux for 1.5 hours. The reaction mixture was cooled, and then the insoluble material was filtered off. The filtrate was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-ethyl acetate (10:1, v/v) gave 3-benzoyl-2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline (2.73 g, 42%). This compound was recrystallized from ethyl acetate-hexane to give colorless prisms, mp. 182°-183° C.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][CH:5]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:19]2[C@:21]3([C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:30])[CH2:20]2)[CH:14]=1>>[O:30]=[C:22]1[C@:21]2([CH2:20][C@@H:19]2[C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]1[CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:12])=[CH:5][CH:6]=1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1cccnc1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: O=C(O)c1ccc(CN2C(=O)[C@]3(C[C@@H]3c3cccnc3)c3ccccc32)cc1

Procedure:
The title compound was prepared in analogy to Example 1 starting from 4-bromomethyl-benzoic acid methyl ester (commercially available), (1R,2S) and (1S,2R)-2-(pyridin-3-yl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C23H18ClN2O3: 370, observed (M+H)+: 371.2 1H NMR (400 MHz, DMSO-d6) δppm 2.14-2.23 (m, 1 H) 3.30 (t, 1 H) 5.10 (s, 2 H) 6.14 (d, 1 H) 6.70 (t, 1 H) 6.93 (d, 1 H) 7.10 (t, 1 H) 7.45 (d, 2 H) 7.57-7.65 (m, 1 H) 7.93 (d, 2 H) 8.06 (d, 1 H) 8.61 (d, 1H) 8.71 (s, 1 H).