Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:26][CH2:25][C:24]4=[O:33])[CH2:19][CH2:18]3)=[O:16])=[C:10]([O:34][CH3:35])[CH:9]=2)[CH2:3][CH2:2]1.[CH3:36][C:37]1[C:42]([CH2:43]Cl)=[CH:41][CH:40]=[CH:39][N:38]=1.CCN(C(C)C)C(C)C>>[CH3:43][C:42]1[C:37]([CH2:36][N:1]2[CH2:6][CH2:5][CH:4]([O:7][C:8]3[CH:13]=[CH:12][C:11]([CH2:14][C:15]([N:17]4[CH2:18][CH2:19][CH:20]([N:23]5[C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[CH2:26][CH2:25][C:24]5=[O:33])[CH2:21][CH2:22]4)=[O:16])=[C:10]([O:34][CH3:35])[CH:9]=3)[CH2:3][CH2:2]2)=[N:38][CH:39]=[CH:40][CH:41]=1
Reactant: Cc1ncccc1CCl
Reactant: COc1cc(OC2CCNCC2)ccc1CC(=O)N1CCC(N2C(=O)CCc3ccccc32)CC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC2CCN(Cc3ncccc3C)CC2)ccc1CC(=O)N1CCC(N2C(=O)CCc3ccccc32)CC1
Temperature: 50 °C

Procedure:
To a solution of 1-(1-(4-(4-piperidinyloxy)-2-methoxyphenylacetyl)piperidin-4-yl)-3,4-dihydro-2(1H)-quinolinone (200 mg, 0.34 mmol) from Example 195 in dry degassed DMF (5 mL) was added 2-methyl-3-chloromethylpyridine (100 mg, 0.68 mmol) and DIEA (0.10 mL, 0.66 mmol) and the reaction was warmed to 50° C. for 72 hours. The solvent was removed under reduced pressure and the residue was purified by pressurized silica gel column chromatography using 98:2 CH2Cl2 :MeOH as eluant. The product-containing fractions were combined and the solvent was removed under reduced pressure. The residue was lyophilized from acetonitrile-water to give the title compound as an amorphous solid.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:11]=1)(=O)OCC)C.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH:11]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1cccc(Oc2ccc(F)cc2)c1)OCC
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(F)cc3)c2)CC1
Yield: 78.2 %

Procedure:
Following the procedure in Example 1, Step 4, using [3-(4-fluoro-phenoxy)-benzyl]-phosphonic acid diethyl ester (1.2 g, 3.5 mmol) (Step 1) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (707 mg, 3.55 mmol) yielded the title compound (1.05 g).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>C(OCC)C>[C:23]([C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[NH:20][C:14](=[O:16])[C:13]([N:10]1[CH2:9][CH2:8][CH:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)=[O:17])#[N:24]
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: N#Cc1ccccc1N
Solvent: CCOCC
Product: N#Cc1ccccc1NC(=O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) and 2-amino-benzonitrile (Aldrich) according to the method described in Example 1c. Melting Point: 101-103° C. (diethylether)
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O.[CH2:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][NH:24]1>O>[F:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([N:24]2[CH2:25][CH2:26][C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23]2)=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)cnc1Cl
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)cnc1N1CCc2ccccc2C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
2-chloro-5-fluoro-3-nitropyridine (1.00 g, 5.66 mmol) prepared in Step 4 and sodium carbonate (1.25 g, 9.06 mmol) were added to anhydrous N,N-dimethylformamide (50 ml). 1,2,3,4-tetrahydroisoquinoline (712 μg, 5.66 mmol) was added to the reaction mixture. The reaction mixture was stirred for 1 hour at 100° C. and then cooled to room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with a sodium chloride solution three times, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v) to give 1.34 g of the titled compound as yellow solid. (Yield: 86%).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].C(OCC)(=O)C>[OH-].[Na+]>[CH2:11]([O:10][C:8]([NH:6][CH2:5][CH2:4][CH2:3][Br:2])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCBr
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(NCCCBr)OCc1ccccc1
Reaction time: 8 h
Yield: 100 %

Procedure:
3-Bromopropylamine hydrobromide (5.0 g, 22.8 mmol) was dissolved in an aqueous NaOH solution (15 wt %, 80 ml) and cooled to 0° C. under nitrogen before benzyl chloroformate was added dropwise. The reaction was left to stir overnight then ethyl acetate (100 ml) was added and the phases were separated. The organic phase was further washed with a HCl solution (2 M, 100 ml), a NaOH solution (2 M, 100 ml), brine (100 ml), dried over Na2SO4, and evaporated to yield 12 as a clear oil (6.22 g, 22.8 mmol, 100%). Rf=0.31 (8:2 Hexane/Ethyl acetate); 1H NMR (300 MHz, CDCl3) δ=7.40-7.33 (m, 5H, ArCH), 5.11 (s, 2H, CH2Ph), 4.94 (bs, 1H, NHCbz), 3.45 (t, 3J(H,H)=6.4 Hz, 2H, CH2Br), 3.36 (q, 3J(H,H)=6.4 Hz, 2H, CH2NHCbz), 2.08 (q, 3J(H,H)=6.4 Hz, 2H, CH2CH2CH2); 13C NMR (75 MHz, CDCl3) δ=156.4 (CO), 136.4 (ArCCH2), 128.5 (ArCH), 128.2 (ArCH), 127.0 (ArCH), 66.8 (CH2Ph), 39.4 (CH2NHCbz), 32.4 (CH2CH2CH2), 30.6 (CH2Br); HRMS (ESI+): m/z calculated for C11H14BrNO2Na [M+Na]+: 294.0106, found 294.0099.
Reaction SMILES: [N:1]([C:4]1[C:5]([C:9]([O:11]CC)=O)=[CH:6][S:7][CH:8]=1)=[C:2]=[S:3].[F:14][C:15]([F:26])([F:25])[CH2:16][O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.CC(C)([O-])C.[K+]>C(#N)C.C(O)C>[S:3]=[C:2]1[NH:1][C:4]2=[CH:8][S:7][CH:6]=[C:5]2[C:9](=[O:11])[N:22]1[C:21]1[CH:23]=[CH:24][C:18]([O:17][CH2:16][C:15]([F:14])([F:25])[F:26])=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1cscc1N=C=S
Reactant: Nc1ccc(OCC(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: O=c1c2cscc2[nH]c(=S)n1-c1ccc(OCC(F)(F)F)cc1
Yield: 86 %

Procedure:
Ethyl 4-isothiocyanatothiophene-3-carboxylate (1.1 g) and 4-(2,2,2-trifluoroethoxy)aniline (0.99 g) were dissolved in acetonitrile (40 ml), and the solution was heated under reflux for 1 hr, and allowed to be cooled. Potassium tert-butoxide (1.27 g) was dissolved in ethanol (15 ml), and the solution was poured into the reaction mixture at room temperature. The reaction mixture was heated under reflux for 10 min, allowed to be cooled, and concentrated under reduced pressure. The obtained brown residue was dissolved in ethanol (10 ml), and the solution was poured into 0.3M hydrochloric acid (35 ml) under ice-cooling. The resulting precipitate was collected by filtration, washed with water, and dissolved in tetrahydrofuran (40 ml). The solution was diluted with ethyl acetate (80 ml). This organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a solid. This solid was washed with a mixed solvent of tetrahydrofuran/isopropyl ether (1/10) to give the title compound (1.59 g) as a solid.
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[C:30]1([C:36]2[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:30]1([C:36]2[CH:37]=[CH:38][C:39]([C:40]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:3])=[O:29])[CH2:19][C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][CH:21]=3)=[O:18])[CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:41])=[CH:43][CH:44]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Product: CN(C(=O)c1ccc(-c2ccccc2)cc1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 4-phenylbenzoic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(4-phenylbenzoyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 546 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N:20]2[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]2)=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]1[CH2:32][CH2:31][CH2:30][CH:29]=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:1]([O:8][C:9]1[C:10]([N:20]2[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]2)=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([C:28]1[CH2:32][CH2:31][CH2:30][CH:29]=1)[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CCCC1
Reactant: O=C1CN(c2cc3cc(Br)ccc3cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CN(c2cc3cc(C4=CCCC4)ccc3cc2OCc2ccccc2)S(=O)(=O)N1
Reaction time: 0.25 h
Yield: 13 %

Procedure:
In a microwave vial is added 5-(3-benzyloxy-7-bromonaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (0.100 g, 0.224 mmol), cyclopentene (0.04 mL, 0.453 mmol), palladium acetate (0.010 g, 0.0445 mmol), triethylamine (0.063 mL, 0.448 mmol) and acetonitrile (2 mL). The vial is capped and placed in the microwave for 15 min at 110° C. The reaction mixture is filtered over Celite and washed with acetonitrile. The filtrate is concentrated and the residue is purified via Biotage Sp1, eluting with 15-60% EtOH/H2O to afford 5-(3-benzyloxy-7-cyclopent-1-enyl-naphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (0.0127 g): (M−H)−=433.
Reaction SMILES: C(O[C:4]1[CH:9]=[CH:8][N:7]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[S:12][CH2:11]2)[C:6](=[O:17])[N:5]=1)C.[NH3:18].CO>>[OH:16][CH2:15][C@@H:13]1[S:12][CH2:11][C@H:10]([N:7]2[CH:8]=[CH:9][C:4]([NH2:18])=[N:5][C:6]2=[O:17])[O:14]1
Reactant: N
Reactant: CCOc1ccn([C@H]2CS[C@@H](CO)O2)c(=O)n1
Solvent: CO
Product: Nc1ccn([C@H]2CS[C@@H](CO)O2)c(=O)n1
Temperature: 70 °C
Yield: 89 %

Procedure:
A solution of (2S*,5R*)-4-ethoxy-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one (0.21 g) in ammonia/methanol (8 mL of methanol saturated with ammonia gas at 0° C. for 45 minutes) was placed in a steel bomb with a teflon liner, sealed and heated at 70° C. for 18 hours. Solvent was evaporated in vacuo and the residue subjected to flash chromatography to give the desired product (0.16 g, 89%) as a white solid: mp 184-185° C.; 1H NMR (DMSO-d6): δ 3.00 (dd, J=11.8, 5.0 Hz, 1H), 3.38 (dd, J=11.8, 5.5 Hz, 1H), 3.63-3.80 (m, 2H), 5.15 (t, J=4.5 Hz, 1H), 5.30 (t, J=6.0 Hz, 1H), 5.70 (d, J=7.3 Hz, 1H); 6.18 (t, J=5.0 Hz, 1H), 7.20 (brd, 2H, NH2), 7.79 (d, J=7.3 Hz, 1H); MS m/z 229.8 (M+1, 4%), 112 (100%). Anal. Calcd. for C8H11N3O3S: C, 41.91; H, 4.84; N. 18.33; S, 13.99. Found: C, 41.97; H, 4.83; N, 18.24; S, 13.93
Reaction SMILES: [H-].[Na+:2].[C:3]([C:11]1[C:15]2=[C:16]([C:21]([OH:23])=[O:22])[C:17]([OH:20])=[CH:18][CH:19]=[C:14]2[O:13][C:12]=1[C:24]([F:27])([F:26])[F:25])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:28][O:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[N:33]=[C:32](S(C)(=O)=O)[N:31]=1.O>CN(C)C=O>[C:3]([C:11]1[C:15]2=[C:16]([C:21]([O-:23])=[O:22])[C:17]([O:20][C:32]3[N:33]=[C:34]([O:36][CH3:37])[CH:35]=[C:30]([O:29][CH3:28])[N:31]=3)=[CH:18][CH:19]=[C:14]2[O:13][C:12]=1[C:24]([F:27])([F:25])[F:26])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[Na+:2]
Reactant: O=C(O)c1c(O)ccc2oc(C(F)(F)F)c(C(=O)c3ccccc3)c12
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2ccc3oc(C(F)(F)F)c(C(=O)c4ccccc4)c3c2C(=O)[O-])n1
Reaction time: 1 h
Yield: 40.5 %

Procedure:
While stirring 0.35 g of sodium hydride in 30 ml of N,N-dimethylformamide at room temperature, 1.73 g of 3-benzoyl-5-hydroxy-2-trifluoromethylbenzofuran-4-carboxylic acid was gradually added thereto. After completion of the addition, the mixture was further stirred for one hour. While stirring this mixture at room temperature, 1.08 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine was added thereto, and then the mixture was stirred at 70° C. for 3 hours. The mixture was returned to room temperature and poured into water. Precipitated crystals were separated by filtration and washed with water and acetone to obtain 1.02 g (yield: 40.5%) of the desired compound.
Reaction SMILES: Cl.[CH:2]1([NH:8][NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:10]([O:12][C:13](=[O:21])[C:14]([C:19]#[N:20])=[CH:15]OCC)[CH3:11].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[CH:15]=[N:9][N:8]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[C:19]=1[NH2:20])=[O:21])[CH3:11]
Reactant: NNC1CCCCC1
Reactant: CCOC=C(C#N)C(=O)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnn(C2CCCCC2)c1N
Temperature: 80 °C

Procedure:
To a round bottom flask is added cyclohexyl-hydrazine hydrochloride (4.5 g, 30 mmol), 2-cyano-3-ethoxy-acrylic acid ethyl ester (5.1 g, 30 mmol), sodium bicarbonate (2.6 g, 30.9 mmol) and 40 mL of ethanol. The mixture is heated to 80° C. for 1 hour, cooled down to room temperature and concentrated. The residue is dissolved in chloroform and washed with water, dried over sodium sulfate. After removal of the solvent, the solid is recrystallized from ethyl acetate: 1HNMR (CDCl3): δ 7.40 (1 H, s), 4.77 (2 H, brs), 4.05 (2 H, q, J=7.2 Hz), 3.50 (1 H, m), 1.61-1.71 (6 H, m), 1.50 (1 H, m), 1.02-1.21 (3 H, m), 1.13 (3 H, t, J=7.2 Hz).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][CH2:6][N:7]([CH2:14][CH2:15][O:16][CH2:17][O:18][CH3:19])[CH2:8][CH2:9][O:10][CH2:11][O:12][CH3:13].ClC1C=CC=C(C(OO)=[O:28])C=1>ClCCl>[CH3:19][O:18][CH2:17][O:16][CH2:15][CH2:14][N+:7]([O-:28])([CH2:6][CH2:5][O:4][CH2:3][O:2][CH3:1])[CH2:8][CH2:9][O:10][CH2:11][O:12][CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCOCCN(CCOCOC)CCOCOC
Solvent: ClCCl
Product: COCOCC[N+]([O-])(CCOCOC)CCOCOC
Reaction time: 1 h

Procedure:
28.1 g (0.1 mole) of tris(2-(methoxymethoxy)ethyl)-amine was dissolved in 85 g of dichloromethane, which was ice cooled. To the solution, 26.5 g (0.1 mole) of 65% pure m-chloroperbenzoic acid in 250 g of dichloromethane was added dropwise at such a rate that the mixture might not exceed 5° C. The mixture was allowed to mature for one hour at room temperature. The reaction solution was concentrated below 30° C. and the residue was purified by column chromatography (basic alumina, elute; dichloromethane/methanol). The eluate was concentrated whereupon the desired compound solidified. The amount was 27.3 g and the yield was 92*.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[CH2:9][N:10]([C:11]([NH:13][NH2:14])=[O:12])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:28]1([S:34][CH2:35][C:36](Cl)=[O:37])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[C:28]1([S:34][CH2:35][C:36]([NH:14][NH:13][C:11]([N:10]2[CH2:9][C:8]3[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=3[O:6][C:5]3[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]2=3)=[O:12])=[O:37])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)CSc1ccccc1
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CSc1ccccc1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 25 °C

Procedure:
To a stirred mixture of 5.89 g of 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carboxylic acid hydrazide (see U.S. Pat. No. 3,534,019) and 2.8 ml of triethylamine in 50 ml of cold (ca. 0° ) dichloromethane was slowly added 3.8 g of the title product of Example 1. The mixture was then stirred for twenty hours at room temperature. The solution was then washed three times with 50-ml portions of water, dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound, m.p. 172°-175°.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:7][CH:6]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][C:15]([C:18]([OH:20])=[O:19])=[CH:16][CH:17]=[C:10]3[C:9]2=[O:21])[CH2:5][C:4]([CH3:23])([CH3:22])[NH:3]1.[CH2:25]1[O:33][CH:26]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN(C)C=O>C(Cl)Cl>[CH3:22][C:4]1([CH3:23])[CH2:5][CH:6]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][C:15]([C:18]([O:20][CH2:25][CH:26]([OH:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:19])=[CH:16][CH:17]=[C:10]3[C:9]2=[O:21])[CH2:7][C:2]([CH3:24])([CH3:1])[NH:3]1
Reactant: CC1(C)CC(N2C(=O)c3ccc(C(=O)O)cc3C2=O)CC(C)(C)N1
Reactant: c1ccc(C2CO2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)CC(N2C(=O)c3ccc(C(=O)OCC(O)c4ccccc4)cc3C2=O)CC(C)(C)N1

Procedure:
Into a 125 ml reaction flask equipped with a magnetic stirrer, thermometer, condenser and nitrogen atmosphere were placed the HALS of Example 1 (5.0 g, 0.015 mol), styrene oxide (1.6 g, 0.013 mol), ADOGEN® (Ashland Chemical Co.) (0.15 g) and 60 ml of dimethylformamide. The reaction was refluxed for 5 hours then cooled. The mixture was transferred to a separatory funnel with 100 ml methylene chloride and washed with 200 ml of 2.5% sodium hydroxide. Additional methylene chloride, 100 ml, was added and the solution extracted with two 100 ml portions of 5% sodium hydroxide and then 100 ml water. The organic solution was then dried with anhydrous magnesium sulfate and the solvent stripped using aspirator and high vacuum systems. The solid residue (2.9 g) was recrystallized from aqueous ethanol, then recrystallized again from methyl t-butyl ether/hexanes. After high vacuum removal of residual solvent, the product weighed 0.6 g and melted at 144°-146° C. The infrared spectrum (in chloroform) showed a broad carbonyl absorption at 1710 cm-1 (imide and ester). The structure of this material was further confirmed using proton NMR spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:21]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][S:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:21])[N:3]=1
Reactant: Cc1cccc(CSc2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: Cc1cccc(CS(=O)c2ccccc2)n1

Procedure:
A solution of 2-methyl-6-((phenylthio)methyl)pyridine is reacted with m-chloroperoxybenzoic acid according to the method of Example 18 to give the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:22]=[CH:21][C:13]3[N:14]([CH:18]([CH3:20])[CH3:19])[C:15](=[O:17])[O:16][C:12]=3[CH:11]=2)[CH2:5]1.C(N(CC)CC)C.[Cl:30][C:31]1[S:35][C:34]([C:36](Cl)=[O:37])=[CH:33][CH:32]=1>O1CCCC1>[Cl:30][C:31]1[S:35][C:34]([C:36]([NH:2][CH2:3][C@@H:4]2[O:8][C:7](=[O:9])[N:6]([C:10]3[CH:22]=[CH:21][C:13]4[N:14]([CH:18]([CH3:20])[CH3:19])[C:15](=[O:17])[O:16][C:12]=4[CH:11]=3)[CH2:5]2)=[O:37])=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccc(Cl)s1
Reactant: CC(C)n1c(=O)oc2cc(N3C[C@H](CN)OC3=O)ccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)n1c(=O)oc2cc(N3C[C@H](CNC(=O)c4ccc(Cl)s4)OC3=O)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg (0.61 mmol) of 6-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-3-isopropyl-1,3-benzoxazol-2(3H)-one hydrochloride (EP 738726) are suspended in 5 ml of tetrahydrofuran and admixed with 0.26 ml (1.83 mmol) of triethylamine and 132 mg (0.73 mmol) of 5-chlorothiophene-2-carbonyl chloride. The reaction mixture is stirred at room temperature overnight and then concentrated. The product is isolated by column chromatography (silica gel, methylene chloride/ethanol=50/1 to 20/1). This gives 115 mg (43% of theory) of the desired compound.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][NH:10][CH2:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:23]
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CNCCC(c1ccccc1)c1ccccc1
Reaction time: 18 h
Yield: 69.1 %

Procedure:
2.132 g (10.1 mmol) 3,3-diphenylpropylamine (Aldrich, Milwaukee, Wis.) was added to a mixture of 0.853 g (5.11 mmol) ethyl bromoacetate (Aldrich) and 2.7 g (19.57 mmol) potassium carbonate in 14 ml acetonitrile at rom temperature. The mixture was stirred under argon for 18 hours. The reaction mixture was filtered, the solvent evaporated and the residue chromatographed on a silica gel column with 40% ethyl acetate in hexanes to give 1.05 g (yield 69%) N-[(3,3-diphenyl)propyl]glycine ethyl ester (Compound A22) as an oil. NMR spectra of the product showed: 1H NMR (CDCl3, 300 MHz) 7.40–7.10 (m, 10 H), 4.14 (q, 2 H), 4.03 (t, 1 H), 3.33 (s, 2 H), 2.56 (t, 2 H), 2.24 (dt, 2 H), 1.22 (t, 3 H); 13C NMR (CDCl3, 75 MHz) 172.44, 144.66, 128.43, 127.75, 126.15, 60.63, 50.93, 48.80, 47.92, 35.85, 14.17, 0.019 g of A28 was also isolated from the silica gel column.
Reaction SMILES: [F:1][C:2]([F:14])([S:11]([OH:13])=[O:12])[CH2:3][O:4][C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7].[Na:15].[OH:16]O>O>[F:14][C:2]([F:1])([S:11]([OH:16])(=[O:13])=[O:12])[CH2:3][O:4][C:5](=[O:10])[C:6]([CH3:8])([CH3:9])[CH3:7].[Na:15]
Reactant: OO
Reactant: CC(C)(C)C(=O)OCC(F)(F)S(=O)O
Agent: [Na]
Solvent: O
Product: CC(C)(C)C(=O)OCC(F)(F)S(=O)(=O)O
Reaction time: 1 h
Yield: 91 %

Procedure:
A glass flask equipped with a thermometer, a condenser and a dropping funnel was charged with 290 g (0.74 mole) of 65% purity sodium 1,1-difluoro-2-(pivaloyloxy)ethane-1-sulfinic acid obtained by Comparative Example 1-2, a catalytic amount of sodium tungstate(IV) dehydrate and 600 ml of water, followed by stirring. Then, 170 g (1.5 moles) of 30% hydrogen peroxide solution was added dropwise in an iced bath. After the termination of the dropping, stirring was conducted for 1 hour at room temperature. Then, the termination of the reaction was confirmed by 19F NMR. The reaction solution was condensed and then rinsed with 500 ml of diisopropyl ether. Subsequently, filtration was conducted and a solid obtained therewith was dried, thereby obtaining 278 g of sodium 1,1-difluoro-2-(pivaloyloxy)ethanesulfonic acid in the form of a white solid (91% yield, 65% purity). In this case, 2-bromo-2,2-difluoroethyl pivalate was detected to be formed as a by-product in an amount of 8%.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[C:14]([Cl:15])=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=1[Cl:17])[CH3:5].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[Cl:15][C:14]1[CH:13]=[C:12]([Cl:16])[CH:11]=[C:10]([Cl:17])[C:9]=1[C@@H:7]1[CH2:8][C@H:6]1[CH:4]([NH:3][O:2][CH3:1])[CH3:5]
Reactant: CON=C(C)C1CC1c1c(Cl)cc(Cl)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CONC(C)[C@@H]1C[C@H]1c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1-[2-(2,4,6-trichloro-phenyl)-cyclopropyl]-ethanone O-methyl-oxime (0.19 mmol), prepared as described in example P23, in ethanol (1 ml) and acetic acid (1 ml) was treated at ambient temperature with sodium cyanoborohydride (200 mg, 3.18 mmol) added in one portion. The resulting solution was stirred at ambient temperature for 20 hours. The solvent was evaporated under reduced pressure (co-evaporation with toluene twice) and the residue was slurried with 1 M NaOH (5 ml). The aqueous phase was extracted with ether (3×10 ml), washed with brine and dried over anhydrous Na2SO4. After removal of the solvent, the residue was purified by flash chromatography over silica gel (5 g) (eluent: c-hexane/ethyl acetate 5:1). 25 mg (45.0% of theory) of trans-N-{1-[2-(2,4,6-trichlorophenyl)-cyclopropyl]-ethyl}-O-methyl-hydroxylamine as a mixture of diastereomeres was obtained in form of a clear liquid.