Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([CH3:11])[CH2:9]O)=[C:4]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[C:18]([F:21])[CH:17]=[CH:16][CH:15]=3)[CH:3]=1.CCOC(/N=N/C(OCC)=O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]([CH3:11])[CH2:9][N:13]3[C:14]4[CH:15]=[CH:16][CH:17]=[C:18]([F:21])[C:19]=4[CH:20]=[C:12]3[C:4]=2[CH:3]=1
Reactant: CC(CO)c1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC1Cn2c(cc3c(F)cccc32)-c2cc(Cl)ncc21
Reaction time: 12 h
Yield: 49.8 %

Procedure:
To a suspension of 2-(6-chloro-4-(4-fluoro-1H-indol-2-yl)pyridin-3-yl)propan-1-ol (60 mg, 0.21 mmol) and DEAD (111 mg, 0.63 mmol) in THF (4 mL) was added PPh3 (156 mg, 0.63 mmol) at 0° C. under N2, and the mixture was stirred for 12 hours. Then the mixture was diluted with H2O and extracted with EA. The combined organic layer was washed with H2O, brine, dried over Na2SO4, filtrated and concentrated to give 2-chloro-11-fluoro-5-methyl-5,6-dihydroindolo[2,1-a][2,6]naphthyridine (30 mg, yield: 56%). 1H-NMR (CDCl3, 400 MHz) δ 8.26 (s, 1H), 7.54 (s, 1H), 7.05˜7.15 (m, 3H), 6.73˜6.77 (m, 1H), 4.16˜4.20 (m, 1H), 4.00˜4.04 (m, 1H), 3.31˜3.35 (m, 1H), 1.30 (d, J=8.0 Hz, 3H). MS (M+H)+: 287/289.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([N:9]2[CH:14]=[CH:13][C:12](=[O:15])[NH:11][C:10]2=[O:16])[CH:6]=[CH:7][CH:8]=1.[I:19]I.[N+]([O-])([O-])=O.[NH4+].[Ce]>C(#N)C>[I:19][C:13]1[C:12](=[O:15])[NH:11][C:10](=[O:16])[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=2)[CH:14]=1
Reactant: II
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)c(=O)[nH]1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Product: O=c1[nH]c(=O)n(-c2cccc(C(F)(F)F)c2)cc1I
Temperature: 80 °C
Yield: 160.9 %

Procedure:
To a suspension of 1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 113) (5.09 g) in acetonitrile (75 ml) were added iodine (3.03 g) and cerium ammonium nitrate (6.54 g) and the resulting mixture was stirred at 80° C. for thirty minutes. The resulting mixture was cooled to 0° C. and thereto were then added ethyl acetate (150 ml), saturated saline (50 ml) and 5% sodium hydrogen sulfite solution (100 ml) so as to separate the layer. Furthermore, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with 5% aqueous sodium hydrogen sulfite solution and saturated saline. The resulting mixture was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To the residue were added ethyl acetate (50 ml) and hexane (100 ml) and the resulting mixture was stirred for fifteen minutes, and the precipitated solids were then collected by filtration and washed with hexane to afford 5-iodo-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (7.34 g).
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)(=O)C>CC(OC)(C)C>[CH2:11]([C@@:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])([OH:4])[CH:2]=[O:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccccc1
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: COC(C)(C)C
Solvent: CC(=O)Cl
Product: O=C[C@](O)(Cc1ccccc1)[C@H](O)[C@H](O)CO
Temperature: 35 °C
Reaction time: 8 h

Procedure:
D-Arabinose (50 kg, 330.04 moles) and benzyl alcohol (132.2 kg, 4.33 equivalents) were stirred and heated to 35° C. Acetyl chloride (10.9 kg, 0.42 equivalents), keeping the temperature <45° C., then stirred 50° C. overnight. The mixture was cooled to 20° C. and diluted with MTBE (600 kg). The mixture was stirred for 0.5−5 h. The solids were collected by filtration and washed with MTBE (2×40 kg). The material was dried in a filter drier. 2-Benzyl-D-arabinose was obtained as an off-white solid, 70.9 kg (88.6%). 1H NMR (300 MHz, DMSO-d6): δ 7.32 (m, 5H), 4.76 (s, 1H), 4.66 (d, J=12 Hz, 1H), 4.59 (m, 3H), 4.45 (d, J =12 Hz, 1H), 3.70 (m, 4H), 3.47(dd, J=12, 3 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Cl[CH2:21][C:22]1[S:26][C:25]([CH3:27])=[N:24][C:23]=1[CH3:28].C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>CO>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22]1[S:26][C:25]([CH3:27])=[N:24][C:23]=1[CH3:28])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: Cc1nc(C)c(CCl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nc(C)c(CN2C(=O)C(C)(C)c3cc(N)c([N+](=O)[O-])cc32)s1
Yield: 61.8 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1.77 g) is alkylated using 5-chloromethyl-2,4-dimethyl-thiazole (1.09 g; 6.74 mmol) (Zh. Obshch. Khim. 1956, engl. transl. 3835) and K2CO3 (1.05 g; 7.41 mmol) at 60° C. for 3 days. After aqueous work-up the crude material is de-acetylated in MeOH (70 ml) using DBU (2.2 ml) at reflux. After aqueous work-up 5-amino-1-(2,4-dimethyl-thiazol-5-ylmethyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (1.44 g) is obtained and used without further purification.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[C:13]([O:17][CH3:18])(=[O:16])[CH2:14][SH:15]>O1CCCC1>[CH3:18][O:17][C:13]([CH2:14][S:15][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:16]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CSc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
First, 0.8 g of sodium hydride was added to a mixture of 3.17 g of 2-chloro-3-nitropyridine, 2.12 g of methyl thioglycolate, and 20 ml of tetrahydrofuran at 0° C. After stirring at room temperature for 2 hours, the reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was washed with diisopropyl ether and hexane to give 3.1 g of 2-(methoxycarbonyl)methylthio-3-nitropyridine.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[CH:15]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(OCc3ccccc3)cc2CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(COc2ccc3c(c2)CCNCC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
7-Benzyloxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (D1) (1.06 g, 3 mmol) was dissolved in dichloromethane (15 ml) and treated with trifluoroacetic acid (15 ml). The solution was stirred at room temperature for 2 hours, concentrated in vacuo and then twice co-evaporating with dichloromethane. The residue was dissolved in methanol and applied to a SCX ion exchange column (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia/methanol. The combined basic fractions were reduced in vacuo and the residue purified by column chromatography, eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title compound (D2) (702 mg, 93%), MS (ES+) m/e 254 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=23)[CH:3]=[N:2]1.[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#[N:24].CN(C=O)C.N1C=CC=CC=1>C(OCC)(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cu+2]>[CH3:20][Si:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][O:16][CH2:15][N:12]1[C:8]2=[N:9][CH:10]=[CH:11][C:6]([C:4]3[CH:5]=[N:1][N:2]([C:29]4[CH:30]=[C:25]([CH:26]=[CH:27][CH:28]=4)[C:23]#[N:24])[CH:3]=3)=[C:7]2[CH:14]=[CH:13]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ccnc21
Reactant: N#Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(-c4cccc(C#N)c4)c3)ccnc21
Temperature: 125 °C
Yield: 75.2 %

Procedure:
4-(1H-Pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (0.025 g, 0.000080 mol) and (3-cyanophenyl)boronic acid (0.023 g, 0.00016 mol) were combined in DMF (1.50 mL, 0.0194 mol). Then copper(II) diacetate (0.002 g, 0.00001 mol) and pyridine (0.019 mL, 0.00024 mol) were added. The reaction was heated in an open tube to 125° C. for 40 minutes, allowed to cool to rt, taken up in ethyl acetate, and washed with water saturated with sodium carbonate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give 3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-benzonitrile (0.025 gm, 92%) as an oily residue, LC/MS (M+H)+: 316.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH2:6]([O:8][C:9](=[O:15])[CH:10]([Cl:14])C(=O)C)[CH3:7].[CH2:16]([O:20][C:21]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:22]=1[NH2:23])[CH2:17][C:18]#[CH:19].[N:29]([O-])=O.[Na+]>C(O)C.Cl.O1CCCC1.O>[CH2:16]([O:20][C:21]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:22]=1[NH:23][N:29]=[C:10]([Cl:14])[C:9]([O:8][CH2:6][CH3:7])=[O:15])[CH2:17][C:18]#[CH:19]
Reactant: O=N[O-]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: C#CCCOc1ccc(I)cc1N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: C#CCCOc1ccc(I)cc1NN=C(Cl)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
A mixture of sodium acetate (1.29 g, 15.7 mmol) and 2-chloro-3-oxo-butyric acid ethyl ester (1.4 ml, 10.0 mmol) in ethanol (125 ml) was stirred at room temperature for 1 hours and then cooled to 0° C. In a separate flask a mixture of 2-(but-3-yn-1-yloxy)-5-iodoaniline (2.81 g, 9.79 mmol) in hydrochloric acid (6 M, 6.8 ml) and tetrahydrofuran (2 ml) was cooled to 0° C. before a solution of sodium nitrite (685 mg, 9.79 mmol) in water (−10 ml) was added slowly. After stirring for 30 minutes in the cold the diazonium salt mixture was washed into the ethanol solution with a small amount of water. The resulting solution was stirred for one hour at 0° C. before being added to water (600 ml) and ethyl acetate (200 ml). After separation the aqueous layer was further extracted with ethyl acetate (2×200 ml) and the combined extracts were washed with brine (200 ml), dried over MgSO4, filtered and concentrated. The residue was co-evaporated with ethyl acetate (2×) to give 3.96 g (96%) of the title compound as a crystalline solid. 1H NMR (500 MHz, CDCl3) 8 ppm 1.43 (3H, t, J=7.17 Hz), 2.06 (1H, t, J=2.67 Hz), 2.73 (2H, td, J=6.49, 2.59 Hz), 4.17 (2H, t, J=6.48 Hz), 4.41 (2H, q, J=7.17 Hz), 6.64 (1H, d, J=8.39 Hz), 7.27 (1H, dd, J=8.70, 2.14 Hz), 7.82 (1H, d, J=2.14 Hz), 8.81 (1H, s); M+23=443.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([NH:11][CH3:12])[CH3:10])[CH:6]=[CH:7][CH:8]=1.C1[C:22]2[C:17](=[CH:18]C=CC=2)[CH:16]=CN=1.Cl[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:30])[OH:29].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:17]([O:29][C:28](=[O:30])[NH:27][CH2:26][CH2:25][CH2:24][N:11]([CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:10])[CH3:12])([CH3:22])([CH3:18])[CH3:16]
Reactant: c1ccc2cnccc2c1
Reactant: O=C(O)NCCCCl
Reactant: CNC(C)c1cccc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(C(C)N(C)CCCNC(=O)OC(C)(C)C)c1
Yield: 40 %

Procedure:
A solution of [1-(3-methoxy-phenyl)-ethyl]-methyl-amine (IV) (Grethe, Guenter; Lee, Hsi Lin; Uskokovic, Milan; Brossi, Arnold. Syntheses in the isoquinoline series. Synthesis of 2,3-dihydro-4(1H)-isoquinolones. Journal of Organic Chemistr 1968, 33, 491-494) (320 mg, 1.9 mmol), (3-chloro-propyl)-carbamic acid tert-butylic ester (370 mg, 1.9 mmol), K2CO3 (260 mg, 1.9 mmol) and a catalytic quantity of KI in DMF (5 mL) was stirred under reflux conditions for 24 h. Evaporation of the solvent afforded a residue which was purified by gravity column. Elution with CHCl3/MeOH/aqueous 30% ammonia solution (9:1:0.005) afforded V as an oil: 40% yield, 1H NMR (200 MHz, CDCl3) δ 7.20 (t, J=8.0 Hz, 1H); 6.74-6.95 (m, 3H), 5.38 (br s, 1H, exchangeable with D2O), 3.80 (s, 3H); 3.50 (q, J=7.0 Hz, 1H), 3.13 (q, J=6.2 Hz, 2H), 2.30-2.52 (m, 2H), 2.19 (s, 3H), 1.54-1.68 (m, 2H), 1.44 (s, 9H), 1.35 (d, J=6.6 Hz, 3).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].N1C=CC=CC=1.[OH:13][C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20](=[O:22])[CH:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]=2[CH:29]=1>ClCCl>[O:22]=[C:20]1[CH:19]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:18]2[CH:29]=[C:14]([O:13][C:1](=[O:5])[C:2]([Cl:4])=[O:3])[CH:15]=[CH:16][C:17]=2[O:21]1
Reactant: O=C1Oc2ccc(O)cc2C1c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cl)C(=O)Oc1ccc2c(c1)C(c1ccccc1)C(=O)O2

Procedure:
Oxalyl chloride (17.5 parts) and pyridine (0.5 parts) were added to a suspension of 5-hydroxy-2-oxo-3-phenyl-2,3-dihydrobenzfuran (22.6 parts) in dichloromethane (200 parts). After six hours reflux, chloro-oxo-acetic acid 2-oxo-3-phenyl-2,3-dihydro-benzofuran-5-yl ester was isolated and phenol (9.9 parts) added and the mixture refluxed for eighteen hours. Removal of the solvent gave the crude product oxalic acid (2-oxo-3-phenyl-2,3-dihydro-benzofuran-5-yl)ester phenyl ester (33.3 parts; 89%). Trituration in methanol and recrystallisation from ethyl acetate gave a pure product. Analysis C,70.4; H,3.7; C22H13O6 requires C,70.8; H,3.5%. M.pt.134° C., 1H and 13Cnmr gave spectra consistent with structure.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7](N)=[CH:6][CH:5]=1)([O-:3])=[O:2].N([O-])=O.[Na+].[OH-].[Na+].[CH2:17]=[CH:18][C:19](=[O:23])[CH2:20][CH2:21][CH3:22].[ClH:24]>O.CC(C)=O>[Cl:24][CH:18]([C:19](=[O:23])[CH2:20][CH2:21][CH3:22])[CH2:17][C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: C=CC(=O)CCC
Reactant: Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCC(=O)C(Cl)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
60 g of 4-nitroaniline are dissolved in 485 ml of 20% hydrochloric acid. The solution is cooled to 0°-5° C. and a solution of 26.7 g of sodium nitrite in 65 ml of water is then added slowly, with cooling. The pH is raised to 3 with a 25% solution of sodium hydroxide (300 ml), the temperature being kept at 5°-10° C. A solution of 11.6 g of CuCl2 in 75 ml of water is added, followed by a solution of 44.3 g of hex-1-en-3-one in 390 ml of acetone. The reaction mixture is allowed to return to room temperature, when the evolution of nitrogen and a temperature increase are observed. The reaction mixture is left overnight. It is decanted and the organic phase is concentrated. The residue is taken up with water and extracted with chloroform. After drying, the filtrate is concentrated to give a red oil, which is purified by chromatography on a silica column (eluent: cyclohexane) to give 57.9 g of 2-chloro-1-(4-nitrophenyl)hexan-3-one in the form of an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([N+:15]([O-])=O)[CH2:13][C:12]([CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20]2)=[CH:11][CH2:10]1>CO.C(O)(=O)C.[Zn]>[NH2:15][C@@H:14]1[CH2:13][C:12]([CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20]2)=[CH:11][CH2:10][C@H:9]1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: CCOC(=O)[C@@H]1CCCN(CC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H]([N+](=O)[O-])C2)C1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)[C@@H]1CCCN(CC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H](N)C2)C1
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of Example 18A (100 mg, 0.24 mmol) in a mixture of methanol/acetic acid (1.0 mL/1.0 mL), Zn powder (170 mg, 2.6 mmol) was added at room temperature. The reaction mixture was stirred for 30 minutes, filtered, concentrated under reduced pressure and purified by high pressure liquid chromatography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (78 mg, 78%). 1H NMR (400 MHz, methanol-d4) δ ppm 7.62 (br s, 1H), 7.51 (br s, 1H), 7.39 (br s, 1H), 6.30-6.20 (m, 1H), 4.21 (q, 2H), 3.95-3.85 (m, 1H), 3.8-3.5 (m, 4H), 3.15-2.80 (m, 4H), 2.75-2.40 (m, 3H), 2.35-2.20 (m, 2H), 2.10-1.90 (m, 2H), 1.65-1.50 (m, 1H), 1.30 (t, 3H). MS (DCI) m/z 411 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][C:11](=O)[C:10]([CH3:16])([CH3:15])[CH2:9]1.[C-:28]#[N:29].[Na+].[F:31][C:32]1[C:38]([F:39])=[C:37]([F:40])[CH:36]=[CH:35][C:33]=1[NH2:34]>>[F:31][C:32]1[C:38]([F:39])=[C:37]([F:40])[CH:36]=[CH:35][C:33]=1[NH:34][C:11]1([C:28]#[N:29])[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([N:17]3[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]3=[O:27])=[CH:3][C:2]=2[F:1])[CH2:9][C:10]1([CH3:16])[CH3:15]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)C(C)(C)C3)c(F)c2)C(=O)O1
Reactant: [C-]#N
Reactant: Nc1ccc(F)c(F)c1F
Agent: [Na+]
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(C#N)(Nc4ccc(F)c(F)c4F)C(C)(C)C3)c(F)c2)C(=O)O1
Yield: 50 %

Procedure:
By using procedure as described in Example 45 and by reacting (S)-N-{3-[3-fluoro-4-(4-oxo-3,3-dimethylpiperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide with sodium cyanide and 2,3,4-trifluoroaniline the compound was obtained in 50% yield.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C(#N)C>[C:24]([O:23][C:21](=[O:22])[CH2:20][O:1][C:2]1[C:3]2[CH2:4][CH2:5][CH2:6][C:7](=[O:12])[C:8]=2[CH:9]=[CH:10][CH:11]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C1CCCc2c(O)cccc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)COc1cccc2c1CCCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a stirred mixture of 5-hydroxy-3,4-dihydro-2H-naphthalen-1-one (10.0 g, 61.7 mmol) and cesium carbonate (58.5 g, 180 mmol) in acetonitrile (300 mL) was added tert-butyl bromoacetate (29.0 g, 148 mmol) at room temperature under nitrogen. After being stirred at room temperature overnight, the reaction mixture was filtered through a pad of Celite® (a diatomite filter), and washed with ethyl acetate (100 mL). The combined filtrates were concentrated under reduced pressure. The residue was partitioned between ethyl acetate (500 mL) and water (200 mL×3). The organic layer was concentrated under reduced pressure. Column chromatography (silica gel, 100-200 mesh, 5-10% ethyl acetate in hexane) gave (5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (12.1 g, 71%). MS cald. for C16H20O4 276, obsd. 277 [(M+H)+].
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[CH2:8][C@H:9]1[CH2:14][N:13]([S:15]([C:18]2[S:19][CH:20]=[CH:21]C=2)(=[O:17])=[O:16])[CH2:12][CH2:11][NH:10]1.C([N:25](CC)CC)C.S1C=CN=C1S(Cl)(=O)=O>C(Cl)Cl>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[CH2:8][C@H:9]1[CH2:14][N:13]([S:15]([C:18]2[S:19][CH:20]=[CH:21][N:25]=2)(=[O:16])=[O:17])[CH2:12][CH2:11][NH:10]1
Reactant: C[C@H]1COCCN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1
Reactant: CCN(CC)CC
Agent: O=S(=O)(Cl)c1nccs1
Solvent: ClCCl
Product: C[C@H]1COCCN1C[C@H]1CN(S(=O)(=O)c2nccs2)CCN1
Temperature: 0 °C
Yield: 121.2 %

Procedure:
A 50-mL round-bottomed flask was cooled to 0° C. and charged with (3S)-3-methyl-4-((2R)-2-piperazinylmethyl)morpholine (100 mg, 0.5 mmol, Example 82, Step 2), CH2Cl2 (5 mL) and triethylamine (0.07 mL, 0.5 mmol). Thiazole-2-sulfonyl chloride (92 mg, 0.5 mmol, Bioorg. Med. Chem., 2006, 14, 6628) was added and after 10 min the reaction was concentrated and acidified with 4 N HCl in dioxane (5 mL). The HCl salt was collected after filtration and the crude material was purified via column chromatography (40 g silica gel, 0 to 10% (2M NH3 in MeOH) in CH2Cl2) to give (3S)-3-methyl-4-(((2S)-4-(1,3-thiazol-2-ylsulfonyl)-2-piperazinyl)methyl)morpholine (210 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:6]([CH:8]=[C:9]([C@@H:11]3[CH2:13][C@@H:12]3[C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[N:10]=2)[N:7]=1.Br[C:31]1[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:6]([C:8]([C:31]3[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[CH:33][CH:32]=3)=[C:9]([C@@H:11]3[CH2:13][C@@H:12]3[C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[N:10]=2)[N:7]=1
Reactant: Clc1cc(N2CCOCC2)c2nc([C@@H]3C[C@@H]3c3ccc4ccccc4n3)cn2n1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Product: CC(C)(C)OC(=O)c1ccc(-c2c([C@@H]3C[C@@H]3c3ccc4ccccc4n3)nc3c(N4CCOCC4)cc(Cl)nn23)cc1

Procedure:
Compound 79d (33 mg, 0.081 mmol) was coupled with tert-butyl 4-bromobenzoate (29 μL, 0.12 mmol) using the procedure described in Example 20, Step A to afford title compound 146. 1H NMR (400 MHz, CD3OD) δ (ppm): 7.93-8.08 (m, 4H), 7.72-7.85 (m, 3H), 7.66 (t, J=7.6 Hz, 1H), 7.41-7.50 (m, 1H), 7.24-7.31 (m, 1H), 6.12 (s, 1H), 4.05 (br. s., 4H), 3.95 (d, J=3.9 Hz, 4H), 2.80-2.93 (m, 2H), 1.87-2.00 (m, 2H), 1.58 (s, 9H) Mass Spectrum (LCMS, ESI pos.): Calcd. for C33H32ClN5O3: 582.2 (M+H). found: 582.2.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[C:13]([CH2:15][C:16]([NH2:18])=[S:17])#[N:14]>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:18]=[C:16]([CH2:15][C:13]#[N:14])[S:17][CH:2]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: N#CCC(N)=S
Product: COc1ccc(-c2csc(CC#N)n2)cc1
Yield: 75 %

Procedure:
This compound was synthesized from 2-bromo-1-(4-methoxyphenyl)ethanone and 2-cyanothioacetamide as described in example 1 step 1 (1.5 g, yield 75%). 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=8.9 Hz, 2H), 7.35 (s, 1H), 6.98 (d, J=8.9 Hz, 2H), 4.17 (s, 2H), 3.86 (s, 3H). MS (ESI) m/z: Calculated for C12H10N2OS: 230.05. found: 231.2 (M+H)+.