Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][CH2:5][CH:6]=[O:7].[O:12]=[C:13]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17]>C(Cl)(Cl)Cl>[CH2:4]([C@H:5]1[C@@H:15]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[C:13]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[O:12][C:6]1=[O:7])[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:2]=1
Reactant: COC(=O)/C=C/C(=O)C1CCCCC1
Reactant: O=CCCc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1C=C(C2CCCCC2)OC(=O)[C@H]1Cc1ccccc1
Yield: 76 %

Procedure:
Prepared according to the general procedure from 2-chloro-hydrocinnamaldehyde and (E)-methyl 4-oxo-4-cyclohexylbut-2-enoate using 0.5 mol % 1 as the catalyst in 76% yield as a single diasteromer (white solid). [α]D20 (c 1.06, CHCl3)=+178.6; mp=87-89° C.; 1H NMR (400 MHz, CDCl3) δ 7.32-7.25 (m, 3H), 7.15-7.13 (m, 2H), 4.98 (d, 1H, J=6.9 Hz), 3.73 (s, 3H), 3.47 (dd, 1H, J=14.3, 4.8 Hz), 3.06 (t. 1H, J=6.3 hz), 2.86-2.81 (m, 1H), 2.67 (dd, 1H, J=14.3, 10.1 Hz), 2.06-2.03 (m, 1H), 1.88-1.83 (m, 5H), 1.28-1.13 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 171.4, 169.6, 170.3, 138.3, 129.1, 128.9, 127.0, 96.2, 52.6, 43.0, 41.0, 40.0, 33.4, 30.2, 30.0, 26.1, 26.0, 25.9; IR (thin film) ν 3086, 3027, 2929, 2854, 1773, 1737, 1452, 1436, 1155, 1056 cm−1; HRMS (ESI) calcd for C20H24O4 [M+Na]+ 351.1566, found 351.1574; 86% ee (3S,4S)-isomer as determined by HPLC(OD-H, 9:1 hexanes/i-PrOH), tr (3S,4S)=8.5 min, tr (3R,4R)=7.7 min.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:37]([CH3:38])[C:36]4[CH:39]=[CH:40][C:41]([CH3:43])=[CH:42][C:35]=4[N:34]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:37]([CH3:38])[C:36]4[CH:39]=[CH:40][C:41]([CH3:43])=[CH:42][C:35]=4[N:34]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccc(-c3nc4cc(C)ccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2ccc(-c3nc4cc(C)ccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-propyl-6-(1,5-dimethyl-benzimidazol-2-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH3:1]O.C[Si](C=[N+]=[N-])(C)C.[Br:10][CH:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[C:12]([OH:14])=[O:13]>C1(C)C=CC=CC=1>[CH3:1][O:13][C:12](=[O:14])[CH:11]([Br:10])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21]
Reactant: O=C(O)C(Br)c1ccccc1Cl
Reactant: CO
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: COC(=O)C(Br)c1ccccc1Cl
Yield: 86 %

Procedure:
Methanol (1 mL) was added to toluene (10 mL) under an argon atmosphere at room temperature. The flask was cooled in a water bath and 2M (trimethylsilyl)diazomethane (5 mL, 10 mmol) was added, followed by α-bromo-2-chlorophenyl acetic acid (2.2 g, 8.81 mmol) in portions over 5 minutes. After 10 additional minutes, the toluene/methanol was removed under reduced pressure. The crude oil was purified by MPLC (companion) on a silica cartridge (40 g) with a gradient of ethyl acetate in heptane (10% to 50%) over 20 minutes. The product containing fractions were combined, concentrated, and dried under high vacuum for 1 hour at room temperature to provide bromo-(2-chlorophenyl)-acetic acid methyl ester (2.0 g, 86% yield) as a clear liquid that solidified at low temperatures (−10° C.). 1H NMR (300 MHz, CDCl3/TMS): δ=7.75 (d, 1H, J=6.9 Hz), 7.39-7.26 (m, 3H), 5.91 (s, 1H), 3.80 (s, 3H). 13C NMR (75 MHz, CDCl3/TMS): δ=168.29, 133.82, 133.30, 130.93, 130.47, 129.83, 127.66, 53, 80, 43.08.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:32])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]#[N:31])[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:14]1([C:12]2[C:11]([Cl:18])=[CH:10][C:9]3[NH:19][C:20](=[O:32])[CH2:21][C:22]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([C:30]#[N:31])[CH:25]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCC2)c(Cl)cc1NC(=O)CC(=O)c1ccnc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(C2=Nc3cc(N4CCC4)c(Cl)cc3NC(=O)C2)ccn1

Procedure:
The title compound was prepared from {5-azetidin-1-yl-4-chloro-2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-phenyl}-carbamic acid tert. -butyl ester (Example M50) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an orange solid (66 mg).
Reaction SMILES: C(N[NH:9][CH2:10][CH:11]([OH:28])[CH:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C1C=CC=CC=1.[OH-].[Na+].O.[Cl:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[CH2:12]([N:9]([CH2:10][CH:11]([OH:28])[CH:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:34](=[O:35])[CH2:33][Cl:32])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccccc1OC(c1ccccc1)C(O)CNNCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1OC(c1ccccc1)C(O)CN(Cc1ccccc1)C(=O)CCl
Temperature: -50 °C
Yield: 93 %

Procedure:
To a solution of N-benzylamino-2-hydroxy-3-(2-methoxy-phenoxy)-3-phenyl-propylamine (3.5 g) in CH2Cl2 (60 ml), NaOH (0.6 g) and water (16 ml) were added at 0° C. The whole was cooled to -50° C. and chloroacetyl chloride (1.1 ml) diluted in CH2Cl2 (10 ml) was added dropwise. The organic extracts were combined and washed with a saturated solution of NaCl, drying was carried out over Na2SO4 and the solution was then evaporated to dryness, so obtaining N-benzyl-N-chloroacetyl-2-hydroxy-3-(2-methoxy-phenoxy)-3-phenylpropylamine (4.0 g; yield 93%) as an oil, chromatographically pure, which is used as such.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:5][N:4]2[C:18]([C:21]#[N:22])=[CH:19][CH:20]=[C:3]12.[OH-:23].[Li+].OO>O1CCCC1.O>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:5][N:4]2[C:18]([C:21]([NH2:22])=[O:23])=[CH:19][CH:20]=[C:3]12
Reactant: [OH-]
Reactant: N#Cc1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)cn12
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.5 %

Procedure:
A mixture of 1-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-pyrrolo[1,2-a]pyrazine-6-carbonitrile, (Example 2), (0.03 g, 98.9 82 mol), suspended in tetrahydrofuran (1 mL) was treated with a solution of lithium hydroxide (7.11 mg, 0.29 mmol) in water (500 μL) and 30 wt % aqueous hydrogen peroxide (40.4 μL, 0.39 mmol). The reaction was stirred at room temperature overnight. At this time, the reaction was concentrated in vacuo. The resulting residue was triturated with water. The resulting solid was collected by filtration and then dried in vacuo to afford 1-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-pyrrolo[1,2-a]pyrazine-6-carboxylic acid amide (20 mg, 61%) as light yellow solid. 1H NMR (methanol-d4) δ ppm 7.94 (d, J=1.5 Hz, 1H), 7.85-7.90 (m, 2H), 7.80-7.84 (m, 2H), 7.77 (s, 1H), 7.52 (d, J=0.8 Hz, 1H). LC-MS calcd. for C15H11F3N3O2 [(M+H)+] 322, obsd. 322.0.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[Al+3].[Cl-].[Cl-]>O.CN(C=O)C>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:5]([OH:6])[CH2:4][CH2:3][C:2]([F:9])([F:8])[F:1])=[CH:19][CH:18]=1
Reactant: Brc1ccccc1
Reactant: O=C(O)CCC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: OC(CCC(F)(F)F)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 4,4,4-trifluorobutanoic acid (1.0 g), oxalyl dichloride (0.820 mL) and bromobenzene (3.71 mL) was added DMF (0.008 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added aluminum chloride (1.408 g) at 0° C., and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added water at 0° C., the mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a mixture of the residue, ethanol (15 mL) and THF (5 mL) was added sodium borohydride (0.266 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water at 0° C., the mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.49 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH:15]=[C:16]([CH3:18])[CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.CCOC(C)=O>[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C[C@H](C=C(C)C)c1ccc(O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](CC(C)C)c1ccc(O)cc1
Temperature: 23 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a stirred solution of (R)-ethyl 3-(4-hydroxyphenyl)-5-methylhex-4-enoate 14.2 (0.200 g, 0.8 mmol) in EtOAc (5 mL, 51 mmol) at 0° C. was added Pd/C (0.09 g, 0.8 mmol). See Example 14—it is possible that 14.3 is the R enantiomer and that 14.2 is the S enantiomer although it is believed that 14.2 is the enantiomer shown. The reaction mixture was placed under an atmosphere of hydrogen and stirred at 23° C. for 2 hours. The reaction mixture was filtered and concentrated in vacuo. The resulting product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford (S)-ethyl 3-(4-hydroxyphenyl)-5-methylhexanoate 45.1 (0.200 g, 99% yield) as a colorless oil.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]([NH:12][OH:13])=[NH:11])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=O)=[CH:18][CH:17]=1)#[N:15]>>[CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]3[N:11]=[C:20]([C:19]4[CH:23]=[CH:24][C:16]([C:14]#[N:15])=[CH:17][CH:18]=4)[O:13][N:12]=3)[CH2:6][CH2:5]2)[CH2:2][CH2:3]1
Reactant: N=C(NO)C1CCN(C2CC2)CC1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: N#Cc1ccc(-c2nc(C3CCN(C4CC4)CC3)no2)cc1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 35a, starting from 1-cyclopropyl-N-hydroxypiperidine-4-carboxamidine and 4-cyanobenzoyl chloride.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:12][N:13]1C(=O)CCC1>>[C:12]([C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1)#[N:13]
Reactant: CN1CCCC1=O
Reactant: Brc1ccc2ccncc2c1
Product: N#Cc1ccc2ccncc2c1
Temperature: 25 °C

Procedure:
A solution of 7-bromoisoquinoline (1.80 g, 8.65 mmol) and cuprous cyanide (1.16 g, 12.97 mmol) in N-methyl pyrrolidinone (17 mL) was heated to 200° C. for 2 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous phase was back-extracted with additional ethyl acetate and the combined organic layers were washed with saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to yield 7-cyano-isoquinoline (770 mg): 1H NMR (300 MHz, CDCl3) δ 9.35 (s, 1H), 8.70 (d, J=5 Hz, 1H), 8.40 (s, 1H), 7.95 (d, J=8 Hz, 1H), 7.84 (d, J=8 Hz, 1H), 7.73 (d, J=5 Hz, 1H); ESI MS m/z 155 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][S:11]1(=[O:20])=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[O:20]=[S:11]1(=[O:19])[N:12]([CH2:41][CH2:42][N:43]2[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[CH2:45][CH2:44]2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]1[C:3]1[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=1[F:1]
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Reactant: O=S1(=O)Nc2ccccc2N1c1ccc(F)c(F)c1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCN2c3ccccc3N(c3ccc(F)c(F)c3F)S2(=O)=O)CC1
Yield: 61.3 %

Procedure:
In an analogous manner as general VI, a solution of 1-(2,3,4-trifluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.21 g, 0.7 mmol) in tetrahydrofuran (10 mL) was cooled to 0° C., treated with triphenylphosphine (0.27 g, 1.0 mmol), tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (0.38 g, 1.4 mmol) were added followed by diisopropylazodicarboxylate (0.2 mL, 1.0 mmol to provide tert-butyl 4-{2-[2,2-dioxido-3-(2,3,4-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperazine-1-carboxylate (0.22 g, 625) as white solid:
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:6]1[N:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]2[C:14]([CH2:15][C:16]#[N:17])=[C:13]([F:18])[CH:12]=[CH:11][C:9]=2[N:10]=1)[CH3:5].[NH2:25][C:26]1[C:31]([C:32]#[N:33])=[C:30](Cl)[N:29]=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:25][C:26]1[C:31]([C:32]#[N:33])=[C:30]([NH:3][C@H:4]([C:6]2[N:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]3[C:14]([CH2:15][C:16]#[N:17])=[C:13]([F:18])[CH:12]=[CH:11][C:9]=3[N:10]=2)[CH3:5])[N:29]=[CH:28][N:27]=1
Reactant: C[C@H](N)c1nc2ccc(F)c(CC#N)c2n1-c1ccccc1
Reactant: N#Cc1c(N)ncnc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(CC#N)c2n1-c1ccccc1
Temperature: 90 °C
Yield: 106.9 %

Procedure:
To a solution of [2-((S)-1-aminoethyl)-5-fluoro-3-phenyl-3H-benzoimidazol-4-yl]acetonitrile dihydrochloride (100 mg, 0.27 mmol) in IPA (2 mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (44 mg, 0.28 mmol) and DIPEA (139 μL, 0.82 mmol) and the reaction mixture heated at 90° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue purified by prep HPLC (C18 phenomenex column, 10-90% MeCN in water 0.1% formic acid, 20 min gradient) to give 345 as a white solid (119 mg, 66%). 1H NMR 400 MHz δ (d6-DMSO): 7.73 (1H, dd, J=8.8, 4.8 Hz), 7.67 (1H, d, J=7.2 Hz), 7.63-7.58 (1H, m), 7.56-7.45 (4H, m), 7.18 (1H, dd, J=10.6, 8.8 Hz), 7.14 (2H, br s), 5.22 (1H, quin, J=5.2 Hz), 3.38-3.21 (2H, m), 1.47 (3H, d, J=6.8 Hz), LCMS (Method K): RT=3.56 min, [M+H]+=413
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:15]=[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]2[N:8]=1.[C:16](=O)([O-])[O-:17].[K+].[K+]>CN(C)C=O>[CH:16]([C:15]1[C:7]([CH3:6])=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12)=[O:17]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc2ccccn2n1
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nn2ccccc2c1C=O
Temperature: 0 °C

Procedure:
To 116.6 ml of dimethylformamide was added 105 ml of phosphorus oxychloride, followed by 99 g of 2-methylpyrazolo[1,5-a]pyridine under stirring at keeping the temperature below 20° C. The reaction mixture was stirred at 50°-60° C. for 1 hours, then poured into ice water. Acidic aqueous solution was neutralized with potassium carbonate, then extracted with dichloromethane, washed with salt water, dried over anhydrous sodium sulfate and then concentrated. The resulting residue was recrystallized from methanol to give the title compound in a yield of 54.8 g (46%) as colorless crystals, mp 77°-79° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[C:19]2[C:14](=[C:15]([O:20][CH3:21])[N:16]=[CH:17][CH:18]=2)[N:13]([CH3:22])[CH:12]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[OH:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[O:31][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[C:19]2[C:14](=[C:15]([O:20][CH3:21])[N:16]=[CH:17][CH:18]=2)[N:13]([CH3:22])[CH:12]=1
Reactant: Oc1ccc(F)cc1F
Reactant: COc1nccc2c(-c3cc([N+](=O)[O-])ccc3F)cn(C)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COc1nccc2c(-c3cc([N+](=O)[O-])ccc3Oc3ccc(F)cc3F)cn(C)c12
Yield: 95.3 %

Procedure:
A mixture of Example 2B (0.123 g, 0.408 mmol), 2,4-difluorophenol (0.069 g, 0.531 mmol) and cesium carbonate (0.173 g, 0.531 mmol) in dimethylsulfoxide (5 mL) was heated at 110° C. for 1 hour. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, 20-50% ethyl acetate in hexanes) to provide 0.16 g (95%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[OH:9]O>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N+:3]=1[O-:9]
Reactant: Cc1ccc(Cl)nc1
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(Cl)[n+]([O-])c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of 2-chloro-5-methylpyridine (10 mL) in 155 mL of glacial acetic acid was added 19 mL of 30% aqueous hydrogen peroxide. The mixture was stirred at 80° C. for 8 hours. The mixture was diluted with 100 mL of water and then concentrated in a vacuum. The residue was made strongly alkaline with anhydrous sodium carbonate and shaken with 200 mL of chloroform. The solids were removed via filtration, and the filtrate was dried over sodium sulfate, filtered and concentrated to give 10.8 g of the 2-chloro-5-methylpyridine-N-oxide (82%). Mass Spec. M+H=144.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:20])C(F)(F)F)=[CH:10][CH:9]=1)=[O:6].I([O-])(=O)(=O)=O.[Na+].[OH2:31]>>[C:4]([O:20][C:15](=[O:31])[NH:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:21]=[CH:22][CH:23]=[CH:24][C:3]=2[S:2][CH3:1])=[CH:9][CH:10]=1)([CH3:21])([CH3:5])[CH3:3]
Reactant: O
Reactant: CSc1ccccc1C(=O)Nc1ccc(NC(=O)C(F)(F)F)cc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Product: CSc1ccccc1C(=O)Nc1ccc(NC(=O)OC(C)(C)C)cc1
Reaction time: 12 h

Procedure:
To a solution of 2-methylsulfanyl-N-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-benzamide (234 mg) is added a saturated solution of sodium periodate (5 mL) and the mixture is stirred for 12 hours. The purple mixture is poured into water, extracted with ethyl acetate, dried over anhydrous potassium carbonate and evaporated to yield a red solid, 101 mg.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:19]2[CH2:23][C:22](=[O:24])[NH:21][C:20]2=[O:25])C=CC=CC=1>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[C:19]2/[C:20](=[O:25])[NH:21][C:22](=[O:24])[CH2:23]/2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=C1CC(=P(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N1
Reactant: CCOc1ccc(C=O)cc1
Product: CCOc1ccc(/C=C2\CC(=O)NC2=O)cc1

Procedure:
The title compound 12 was prepared from 4-ethoxybenzaldehyde (0.22 mL, 1.60 mmol) and compound 11 (1.03 g, 2.88 mmol) in a manner similar to that described for 3 in 92.5% (342 mg) yield as a yellow solid.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].CC1C=CC(S(O)(=O)=O)=CC=1.[CH:25]1[CH:30]=[CH:29][C:28]([CH2:31][O:32][C:33]([CH2:35][NH2:36])=[O:34])=[CH:27][CH:26]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C1COCC1>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([NH:36][CH2:35][C:33]([O:32][CH2:31][C:28]1[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=1)=[O:34])=[O:6])[CH3:3]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
To a solution of 5.68 g of BOC-Ala-OH, 10.12 g of H-Gly-OBzl.TosOH and 4.0 g of HOBT dissolved in 50 ml of THF, under cooling at -5° C., was added 5.5 ml of WSC, and the mixture was stirred at -5° C. for one hour and at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate layer was washed successively twice with 1N hydrochloric acid, twice with 5% aqueous sodium hydrogen carbonate and with water. After drying over anhydrous magnesium sulfate, the product was concentrated under reduced pressure. The residue was crystallized from n-hexane, then recrystallized twice from ethyl acetate-n-hexane to give 9.32 g (yield: 92.3%) of BOC-Ala-Gly-OBzl melting at 85°-87° C. Rf1 =0.54.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[N+:7]([C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([N+]([O-])=O)[C:11]=1[C:12]#[N:13])([O-:9])=[O:8]>>[OH:4][CH2:3][CH:2]([CH3:1])[CH2:5][O:6][C:14]1[CH:15]=[CH:16][CH:17]=[C:10]([N+:7]([O-:9])=[O:8])[C:11]=1[C:12]#[N:13]
Reactant: CC(CO)CO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CC(CO)COc1cccc([N+](=O)[O-])c1C#N
Yield: 37 %

Procedure:
Prepared as in Example 215c from 2-methylpropane-1,3-diol and 2,6-dinitrobenzonitrile in 37% yield. MS 237 (MH+).
Reaction SMILES: [N+:1]([O:4][C@@H:5]([CH2:12][O:13][N+:14]([O-:16])=[O:15])[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])([O-:3])=[O:2].[C:17](Cl)(=O)[C:18]([Cl:20])=O.C(=O)C>CN(C)C=O.ClCCl.[Cl-].[Zn+2].[Cl-]>[N+:1]([O:4][C@@H:5]([CH2:12][O:13][N+:14]([O-:16])=[O:15])[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH:18]([Cl:20])[CH3:17])=[O:10])([O-:3])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-]
Agent: CC=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(Cl)OC(=O)CCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a dichloromethane (10 mL) solution of (5R)-5,6-bis(nitrooxy)hexanoic acid (292 mg, 1.22 mmol) was added oxalyl chloride (0.54 mL, 6.12 mmol), followed by a few drops of N,N-dimethylformamide. After bubbling has stopped, the reaction mixture was concentrated in vacuo to afford a yellow slurry, which was redissolved in dichloromethane (5 mL). This solution was added to a mixture of zinc chloride (166 mg, 1.22 mmol) and acetaldehyde (0.15 mL, 2.66 mmol) in dichloromethane (5 mL) at 0° C. The reaction mixture turned cloudy immediately. It was warmed up to room temperature, stirred for 1 hour, and concentrated in vacuo to afford the crude product. Chromatography over silica eluting with ethyl acetate/hexanes afforded the diastereomeric 1-chloroethyl (5R)-5,6-bis(nitrooxy)hexanoate as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ 6.54 (q, J=5.8 Hz, 1H, D1), 6.54 (q, J=5.8 Hz, 1H, D2), 5.25-5.35 (m, 1H), 4.76 (dd, J=3.1, 13.0 Hz, 1H, D1), 4.76 (dd, J=3.0, 12.8 Hz, 1H, D2), 4.49 (dd, J=6.5, 12.9 Hz, 1H, D1), 4.49 (dd, J=6.4, 13.1 Hz, 1H, D2), 2.4-2.5 (m, 2H), 1.7-1.9 (m, 7H).