Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([C:11](OC)=[O:12])=[CH:8][C:7]=2[CH:15]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1.[O-2].[O-2].[Mn+4]>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([CH:11]=[O:12])=[CH:8][C:7]=2[CH:15]=1
Reactant: COC(=O)c1cc2cc(C(F)(F)F)ccc2s1
Agent: [Mn+4]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc2cc(C(F)(F)F)ccc2s1
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution (40 mL) of methyl 5-(trifluoromethyl)-1-benzothiophene-2-carboxylate (2.00 g) in tetrahydrofuran was added lithium aluminum hydride (292 mg) at 0° C., and the mixture was stirred for 1 hr. Water (300 μL) was added to quench the reaction, 1N aqueous sodium hydroxide solution (300 μL) was added, and the mixture was stirred at room temperature for 3 hr. The resulting insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give a white solid. To a solution of the obtained solid in tetrahydrofuran (40 mL) was added active manganese dioxide (9.00 g), and the mixture was stirred overnight at room temperature. Manganese dioxide was filtered off, and the filtrate was concentrated under reduced pressure to give the title object compound (1.15 g, 65%) as a brown solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]([CH3:17])[C:12]([O:14]CC)=[O:13])=[CH:10][C:4]=2[O:3]1.[OH-].[Na+].O.C(O)(=O)C>CCO>[O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]([CH3:17])[C:12]([OH:14])=[O:13])=[CH:10][C:4]=2[O:3]1
Reactant: CCOC(=O)C(C)c1ccc2[nH]c(=O)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(C(=O)O)c1ccc2[nH]c(=O)oc2c1
Temperature: 45 °C
Reaction time: 24 h

Procedure:
A solution of Ethyl 2-(2,3-dihydro-2-oxobenzo[d]oxazol-6-yl)propanoate (95 mg, 0.404 mmol) in 90% aq. EtOH (5 mL) was added sodium hydroxide (82 mg, 2.05 mmol) at room temperature. The reaction mixture was stirred for 24 hours at 45° C. and cooled to room temperature. The mixture was added water (10 mL) and acidified with acetic acid (pH=4). The mixture was extracted with methylene chloride. The organic layer was dried with MgSO4 and filtered. The filtrate was concentrated in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[N+:23]([O-])=O.[H][H]>[Pd].CO>[NH2:23][C:3]1[CH:4]=[C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[CH:12]=2)=[O:10])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
Under argon, 5% palladium on carbon (850 mg) was added to N-(4-methyl-3-nitrophenyl)-2-morpholinopyridine-4-carboxamide (8.5 g) in methanol (300 ml). Hydrogen gas was introduced to the reaction via a balloon and stirred at ambient temperature for 18 hours. Methanol (200 ml) was added and the reaction mixture was filtered through celite. The filtrate was evaporated, then stirred in ethyl acetate, filtered again and washed with a small amount of methanol to yield N-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide (5.12 g); NMR: 2.01 (s, 3H), 3.52 (m, 4H), 3.73 (m, 4H), 4.83 (s, 2H), 6.78 (d, 1H), 6.84 (d, 1H) 7.04-7.08 (m, 2H), 7.20 (s, 1H), 8.24 (d, 1H), 9.95 (s, 1H); m/s: M+H+ 313.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:23]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)([CH3:25])[CH3:24]>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([CH:23]([CH3:25])[CH3:24])[CH:31]=4)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)c1cccc(-c2cc(-c3cnc4c(F)c(C(C)(C)O)ccn34)ccc2F)c1
Yield: 4 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 3-isopropylbenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[8-fluoro-3-(2-fluoro-3′-isopropylbiphenyl-5-yl)imidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (7 mg, 4%): m/z (ES+) 406 [MH+].
Reaction SMILES: [CH:1]([C:3]1[O:7][N:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)[N:4]=1)=[CH2:2].[CH3:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CO>[CH3:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:2][CH2:1][C:3]2[O:7][N:6]=[C:5]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH3:17])[CH:9]=3)[N:4]=2)[CH2:21][CH2:20]1
Reactant: CC1CCNCC1
Reactant: C=Cc1nc(-c2cn(C)c3ccccc23)no1
Solvent: CO
Product: CC1CCN(CCc2nc(-c3cn(C)c4ccccc34)no2)CC1
Reaction time: 16 h

Procedure:
5-Ethenyl-3-(1-methyl-1-H-indol-3-yl)-1,2,4-oxadiazole (D2)(0.0254 g, 1.13 mmol) was dissolved in methanol (5 ml) and 4-methyl piperidine (0.167 ml, 1.69 mmol) was added. The mixture was left standing at room temperature for 16 hours, before being evaporated under reduced pressure to give a colourless oil, which was purified by silica-gel chromatography, eluting with ethyl acetate to afford the title compound as a colourless oil that crystallised on standing. The material was then converted to its hydrochloride salt, mp 192°-192° C.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[CH3:15][O:16][C:17](=O)[C@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:19][CH:20]=O>C(Cl)(Cl)Cl>[CH2:22]([C:18]1[N:19]=[CH:20][S:2][C:17]=1[O:16][CH3:15])[CH:23]([CH3:25])[CH3:24]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)[C@H](CC(C)C)NC=O
Solvent: ClC(Cl)Cl
Product: COc1scnc1CC(C)C
Temperature: 25 °C

Procedure:
A 500 ml flask equipped with heating mantle, condenser, and drying tube is charged with 27.25 g (0.125 mole) of phosphorus pentasulfide, 17.3 g (0.1 mole) of N-formylleucine methyl ester, and 250 ml of chloroform, and the contents are refluxed for 24 hours. The reaction mixture is thereupon cooled to room temperature, washed with 250 ml of 10% potassium hydroxide, and then washed with 250 ml of distilled water.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([Br:13])[CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH3:14]I>CN(C=O)C>[CH3:14][N:9]1[C:10]2[C:6](=[CH:5][C:4]([CH3:3])=[CH:12][C:11]=2[Br:13])[CH:7]=[CH:8]1
Reactant: CI
Reactant: Cc1cc(Br)c2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)c2c(ccn2C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a suspension of sodium hydride (60%, 0.91 g, 22.9 mmol) in DMF (70 mL) was added a solution of 5-methyl-7-bromoindole (4.0 g, 19.05 mmol) in DMF (10 mL). The mixture was stirred at room temperature for 1 h, and then methyl iodide (1.78 mL, 28.6 mmol) was added with cooling in an ice-water-bath. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water and extracted with ethyl acetate. The extract was washed with water and brine, dried (sodium sulfate) and concentrated to give a crude product (4.1 g, 96%), which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 2.38 (s, 3H), 4.12 (s, 3H), 6.36 (d, J=3.12 Hz, 1H), 6.95 (d, J=3.13 Hz, 1H), 7.18 (d, J=1.56 Hz, 1H), 7.31 (dd, J1=0.79 Hz, J2=1.56 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[CH:3]=1.[F:10][C:11]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=1[NH2:13]>>[F:10][C:11]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=1[NH:13][C:2]1[CH:3]=[C:4]([NH:8][CH3:9])[N:5]=[CH:6][N:7]=1
Reactant: CNc1cc(Cl)ncn1
Reactant: Nc1ccc(F)cc1F
Product: CNc1cc(Nc2ccc(F)cc2F)ncn1

Procedure:
The title compound is prepared analogously as described in Example 114A from (6-chloro-pyrimidin-4-yl)-methylamine and 2,4-difluoroaniline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]2)=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:26]2)=[N:23][CH:24]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(N)cn2)C1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Yield: 93 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with (S)-tert-butyl 1-(5-aminopyridin-2-yl)piperidin-3-ylcarbamate (439 mg, 1.5 mmol) to afford the desired product (527 mg, 93%) as a yellow solid: ESI MS m/z 566 [C28H32BrN5O3+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([S:13]([CH2:16][CH2:17][SH:18])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:20]1[N:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:21]=1[C:22]([NH:24][CH2:25][C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)=[O:23].CCCCCC.CC(=O)OCC>CN(C=O)C>[C:7]1([S:13]([CH2:16][CH2:17][S:18][C:20]2[N:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:21]=2[C:22]([NH:24][CH2:25][C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)=[O:23])(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=S(=O)(CCS)c1ccccc1
Reactant: Cc1ccc(C(=O)NCc2cccs2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1ccc(C(=O)NCc2cccs2)c(SCCS(=O)(=O)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
336 mg (3.0 mmol) of potassium tert-butoxide were added at 0° C. to a solution of 607 mg (3.0 mmol) of 2-(phenylsulfonyl)ethanethiol in DMF (10 ml). After stirring for 10 min at 0° C., 534 mg (2.0 mmol) of 2-chloro-6-methyl-N-(thiophen-2-ylmethyl)nicotinamide were added and the mixture was then heated for 16 h at 50° C. Dilution with EA and washing with brine were then carried out. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 7:3) of the residue yielded 556 mg (1.28 mmol, 64%) of 2-[2-(benzenesulfonyl)ethylthio]-6-methyl-N-(2-thienylmethyl)-nicotinamide. MS: m/z 433.1 [M+H]+
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([N:21]2[CH2:26][CH2:25][C:24]([CH2:31][CH:32]3[CH2:34][CH2:33]3)([CH2:27][C:28]([CH3:30])=[CH2:29])[O:23][C:22]2=[O:35])[CH3:20])=[CH:15][CH:14]=1>C(Cl)Cl>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([N:21]2[CH2:26][CH2:25][C:24]([CH2:31][CH:32]3[CH2:34][CH2:33]3)([CH2:27][C:28]3([CH3:30])[CH2:29][O:9]3)[O:23][C:22]2=[O:35])[CH3:20])=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)CC1(CC2CC2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Solvent: ClCCl
Product: C[C@@H](c1ccc(Br)cc1)N1CCC(CC2CC2)(CC2(C)CO2)OC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
m-Chloroperbenzoic acid (455 mg) was added to a solution of 3-[(S)-1-(4-bromophenyl)-ethyl]-6-(cyclopropylmethyl)-6-(2-methylallyl)-1,3-oxazinan-2-one (516 mg) in CH2Cl2 (15 mL) at 0° C. The mixture was stirred at room temperature overnight. The mixture was then washed with 3% aqueous Na2S2O3 solution and saturated aqueous NaHCO3 solution. The aqueous washing phase was extracted with ethyl acetate (3×30 mL) and the combined organic layer was washed with brine, dried (Na2SO4), and concentrated to afford the crude title compound which was used without further purification. Yield: 490 mg (91% of theory).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][C@H:10]2[C@@H:12]([C@:13]([C:18]3[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:19]=3[F:25])([CH:15]([F:17])[F:16])[N:14]=1)[CH2:11]2)(C)(C)C.[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([CH:34]=O)=[N:32][CH:33]=1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCCl.CCOC(C)=O.O>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][NH:24][C:22]2[CH:21]=[CH:20][C:19]([F:25])=[C:18]([C@:13]3([CH:15]([F:16])[F:17])[C@@H:12]4[C@@H:10]([CH2:11]4)[O:9][C:8]([NH2:7])=[N:14]3)[CH:23]=2)=[N:32][CH:33]=1
Reactant: O=Cc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(N)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: O
Product: NC1=N[C@@](c2cc(NCc3ccc(Cl)cn3)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
To a solution of tert-butyl((1R,5S,6R)-5-(5-amino-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate (16i-B, 0.072 g, 0.194 mmol) and 5-chloropicolinaldehyde (0.028 g, 0.198 mmol) in DCE (1 mL) at RT was added HOAc (0.011 ml, 0.194 mmol) and sodium triacetoxyborohydride (0.050 g, 0.236 mmol). The reaction mixture was stirred at RT for 1.5 h. Trifluoroacetic acid (2.0 ml, 26.9 mmol) was added and after 15 min, and the reaction mixture was diluted with EtOAc and water. The pH was adjusted to 9 with 10 M NaOH. The aqueous phase was extracted with EtOAc and the combined organic extracts were washed with brine and dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (60% to 100% EtOAc in heptane) to give the title compound (0.064 g, 0.161 mmol, 83% yield) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]([C:11]1[CH:29]=[C:14]2[C:15]([C:21]3[CH:22]([CH3:28])[CH2:23][C:24](=[O:27])[NH:25][N:26]=3)=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[N:13]2[N:12]=1)[CH3:10]>CS(C)=O>[C:9]([C:11]1[CH:29]=[C:14]2[C:15]([C:21]3[CH:22]([CH3:28])[CH2:23][C:24](=[O:27])[NH:25][N:26]=3)=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[N:13]2[N:12]=1)(=[O:8])[CH3:10]
Reactant: COc1ccc(C2=NNC(=O)CC2C)c2cc(C(C)O)nn12
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(C2=NNC(=O)CC2C)c2cc(C(C)=O)nn12
Temperature: 25 °C
Yield: 59.8 %

Procedure:
Triethylamine (1.46 mL) was added to a solution of the compound of Example 238 (315 mg) in DMSO (10 mL). While the mixture was stirred at room temperature, sulfur trioxide-pyridine complex (829 mg) was added at once and the mixture was further stirred at room temperature for 1 hour. Subsequently, the reaction was quenched by adding water (100 mL). Filtration of the resulting crystals afforded the title compound as a colorless powder (187 mg).
Reaction SMILES: CC1C(CN[C@@H]2C3N=CC=CC=3CCC2)=NC=C(C)C=1.[CH3:21][O:22][C:23](=[O:36])[C:24]1[CH:33]=[CH:32][C:31](CBr)=[C:26]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=1.CCN(C(C)C)C(C)C>CC#N>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][CH:33]=[C:24]([C:23]([O:22][CH3:21])=[O:36])[CH:25]=1
Reactant: COC(=O)c1ccc(CBr)c(C(=O)OC)c1
Agent: Cc1cnc(CN[C@H]2CCCc3cccnc32)c(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cccc(C(=O)OC)c1

Procedure:
Using General Procedure A: Reaction of (S)-(3,5-Dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine, 4-bromomethyl-isophthalic acid dimethyl ester (Egbertson, M. S. et al. Bioorg. Med. Chem. Lett. 1996, 6, 2519-2524), DIPEA and KI in CH3CN gave 4-1[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-isophthalic acid dimethyl ester as a tan oily foam. 1H NMR (CDCl3) δ 1.64 (m, 1H), 2.01 (m, 2H), 2.14 (s+m, 4H), 2.27 (s, 3H), 2.68 (m, 1H), 2.79 (m, 1H), 3.89 (s, 6H), 3.92 (s, 2H), 4.09 (t, 1H, J=6.0 Hz), 4.26 (m, 2H), 6.97 (s, 1H), 7.03 (m, 1H), 7.30 (d, 1H, J=9.0 Hz), 7.89 (dd, 2H, J=7.5, 4.5 Hz), 8.02 (s, 1H), 8.25 (s, 1H), 8.50 (d, 1H, J=3.0 Hz). 13C NMR (CDCl3) δ 18.1, 18.7, 22.2, 26.8, 29.7, 52.5, 54.7, 57.1, 63.3, 121.9, 128.0, 130.7, 131.4, 131.9, 133.3, 134.5, 136.7, 138.8, 146.3, 148.5, 166.8, 168.1. HPLC: 96%. ES-MS m/z 474 [M+H]+, 496 [M+Na]+. Anal. Calcd. for C28H31N3O4.1.1H2O: C, 68.30; H, 6.59; N, 8.53. Found: C, 68.23; H, 6.41; N, 8.60.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].O=C1CC[CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:4]=[C:3]1[CH2:8][CH2:9][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:1][CH2:2]1
Reactant: [Li]CCCC
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCC(C(=O)OCC)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
To a solution of (methyl)triphenylphosphonium bromide (5.18 g, 14.51 mmol) in THF (50 mL) at 0° C. was added n-butyllithium (9.07 mL, 14.51 mmol). The reaction mixture was stirred at 0° C. for 30 min. Ethyl 4-oxocyclohexanecarboxylate (1.9 g, 11.16 mmol) in THF (8 mL) was then added at 0° C. and the reaction was warmed to rt and stirred for 2 h. The reaction was quenched with sat′d aq. NH4Cl and diluted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on SiO2 (0 to 50% EtOAc:hexanes) to afford the title compound (1.58 g, 84% yield) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 4.65 (s, 2H), 4.17-4.11 (m, 2H), 2.44 (tt, J=11.1, 3.8 Hz, 1H), 2.35 (dt, J=13.7, 4.0 Hz, 2H), 2.11-1.96 (m, 4H), 1.64-1.54 (m, 2H), 1.28-1.23 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:51])[CH:5]=[C:6]([Cl:50])[C:7]=1[CH2:8][C@@H:9]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)[CH:36]=1)[O:10][C:11](=[O:34])[CH2:12][CH2:13][O:14]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl.Br>[Cl:50][C:6]1[CH:5]=[N+:4]([O-:51])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)[CH:36]=1)[O:10][C:11](=[O:34])[CH2:12][CH2:13][OH:14]
Reactant: O=C(CCOC(c1ccccc1)(c1ccccc1)c1ccccc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: Br
Solvent: ClCCl
Product: O=C(CCO)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a mixture of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(trityloxy)propanoyloxy)ethyl)pyridine 1-oxide (0.600 g, 0.817 mmol) and Amberlyst 15 (4.7 meq/g, 0.050 g) in dry DCM (20 ml), 3 drops of HBr 48% were added at RT. After 1 hour, the reaction mixture was washed with NaHCO3 sat. sol. and with brine. The organic layer was dried over Na2SO4, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel column (DCM:MeOH:32% aq. NH4OH=90:10:1) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(3-hydroxy propanoyloxy)ethyl)pyridine 1-oxide (0.311 g, 0.632 mmol, 77% yield, MS/ESI+ 492.1 [MH]+).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1)([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:20])=[O:19])=[CH:16][CH:17]=1)([O-:11])=[O:10]
Reactant: Cc1noc(N)c1Br
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Product: Cc1noc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1Br
Yield: 34 %

Procedure:
4-Nitro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 4-nitrobenzenesulfonyl chloride according to the procedures described in Example 30. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 146-149° C., yield 34%.
Reaction SMILES: I.[Cl:2][C:3]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]2[C:4]=1[CH:5]([CH3:16])[NH:6][C:7](SC)=[N:8]2.[OH-].[NH4+:18].[OH-].[Na+].OO>C(#N)C.O>[Cl:2][C:3]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]2[C:4]=1[CH:5]([CH3:16])[NH:6][C:7]([NH2:18])=[N:8]2
Reactant: CSC1=Nc2c(Cl)ccc(Cl)c2C(C)N1
Reactant: [NH4+]
Agent: I
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC1NC(N)=Nc2c(Cl)ccc(Cl)c21
Temperature: 170 °C

Procedure:
5,8-Dichloro-4-methyl-2-methylsulfanyl-3,4-dihydro-quinazoline hydroiodide (116 mg, 0.30 mmol) was suspended in a mixture of ammonium hydroxide (0.22 ml, 25% in H2O, 3 mmol) and acetonitrile (0.9 ml), and heated in a microwave oven to 170° C. (30 min). The reaction was cooled in an ice bath and treated with 1N aqueous sodium hydroxide solution (0.9 ml) and 5-6 drops of concentrated solution of aqueous hydrogen peroxide. A little water was added, and the title compound (36 mg, 52%) was filtered off as a white solid.
Reaction SMILES: [NH2:1][CH:2]([C:13]1[C:18]([Cl:19])=[N:17][CH:16]=[CH:15][N:14]=1)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[C:20]([CH2:22][C:23](O)=[O:24])#[N:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC(=O)OCC>C1COCC1>[Cl:19][C:18]1[C:13]([CH:2]([NH:1][C:23](=[O:24])[CH2:22][C:20]#[N:21])[C:3]2[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=2)=[N:14][CH:15]=[CH:16][N:17]=1
Reactant: N#CCC(=O)O
Reactant: COC(=O)c1ccc(C(N)c2nccnc2Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(NC(=O)CC#N)c2nccnc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of methyl 4-(amino(3-chloropyrazin-2-yl)methyl)benzoate (54 g, 195 mmol) in THF (500 mL) was added 2-cyanoacetic acid (16.6 g, 195 mmol) and TEA (39.4 g, 390 mmol). The mixture was added HATU (74.1 g, 195 mmol) at 0-5° C., and stirred at room temperature for 1 h. The reaction mixture was extracted with EA and water, the organic layer was dried and concentrated. The residue was purified by column chromatography on silica gel eluted with PE:EA=2:1 to give methyl 4-((3-chloropyrazin-2-yl)(2-cyanoacetamido)methyl)benzoate (67 g, yield 100%).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([O:13][C:14]([C:16]1([CH2:22][CH2:23][O:24][CH3:25])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])[CH3:12]>>[CH2:11]([O:13][C:14]([C:16]1([CH2:22][CH2:23][O:24][CH3:25])[CH2:17][CH2:18][N:19]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH2:20][CH2:21]1)=[O:15])[CH3:12]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2)CC1

Procedure:
This material was prepared in analogy to example 1 step C) from benzenesulfonyl chloride (0.115 g), 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.14 g) as a brown oil (0.13 g). MS (ESI): 356.1 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH2:21][OH:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH2:21][O:22][C:30](=[O:31])[C:29]1[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:34][CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1COC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
(2S,4R)-4-(Tert-butyl-dimethyl-silanyloxy)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 53, 51.4 g, 155 mmol) dissolved in 500 ml of dichloromethane was cooled to 0° C., then p-nitrobenzoic acid (28.5 g, 171 mmol), N,N′-dicyclohexylcarbodiimide (35.2 g, 171 mmol) and 4-dimethylaminopyridine (1.90 g, 1.60 mmol) were added. The mixture was maintained under stirring at room temperature for 18 hours, then filtrated; the filtrate was concentrated to obtain crude that was purified by silica gel chromatography (petroleum ether/ethyl acetate from 15/1 to 10/1). (2S,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(4-nitro-benzoyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester was obtained as white solid (70 g, yield: 94%).