Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([O:56][C:57]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)=[O:58])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C(Cl)Cl.O>[CH2:49]([O:56][C:57]([N:59]1[CH2:64][CH2:63][N:62]([C:6](=[O:8])[C@@H:2]([NH:1][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:3]([CH3:4])[CH3:5])[CH2:61][CH2:60]1)=[O:58])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of Boc-(L)-Val-OH (2 g) in DCM (5 mL) was added DIPEA (4.7 mL) and HATU (5.2 g). After stirring at RT for 10 min, a solution of piperazine-1-carboxylic acid benzyl ester in DCM (5 mL) was added and the resulting reaction mixture was stirred at RT for 2 h. Water was added and the phases were separated. The org. phase was washed with brine, dried (MgSO4) and evaporated off to give 9.3 g of the desired compound as beige oil.
Reaction SMILES: [CH:1]([S:4][C:5]1[C:6]([C@H:11]2[C@@H:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13][N:12]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[OH:28]OS([O-])=O.[K+].[OH2:34]>CCO.CCOC(C)=O>[CH:1]([S:4]([C:5]1[C:6]([C@H:11]2[C@@H:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13][N:12]2[C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])=[N:7][CH:8]=[CH:9][CH:10]=1)(=[O:28])=[O:34])([CH3:3])[CH3:2]
Reactant: O
Reactant: O=S([O-])OO
Reactant: CCOC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1ncccc1SC(C)C
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1ncccc1S(=O)(=O)C(C)C
Reaction time: 18 h
Yield: 81 %

Procedure:
To 65E (0.45 g, 1.15 mmol) in EtOH (8 mL) at 0° C. was added Oxone® (0.99 g, 1.6 mmol, 1.4 eq.) in water (8 mL). The mixture was stirred from 0° C. to rt over 18 h. It was quenched with sat. NaHCO3 and Na2S2O3. The precipitate was removed by filtration and the filtrate was condensed, diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4. After removal of solvent, the crude was purified by silica column chromatography using gradient EtOAc in hexanes to give 65J (0.44 g, 81% yield). 1H NMR (400 MHz, 90° C., DMSO-d6) δ ppm 0.88 (t, J=7.15 Hz, 3H) 1.13-1.17 (m, 3H) 1.19-1.27 (m, 9H) 1.34 (d, J=7.15 Hz, 3H) 2.10 (dd, J=7.42, 4.67 Hz, 1H) 2.39 (br s, 1H) 3.45-3.56 (m, 2H) 3.59-3.69 (m, 1H) 3.70-3.80 (m, 3H) 5.86 (d, J=8.25 Hz, 1H) 7.50 (dd, J=7.97, 4.67 Hz, 1H) 8.15 (d, J=7.70 Hz, 1H) 8.76 (d, J=4.40 Hz, 1H), LC-MS 427 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][CH:13]([O:16][CH2:17][C:18]([OH:20])=O)[CH2:12][CH2:11]2)=[CH:5][C:4]=1[C:21]([F:24])([F:23])[F:22])#[N:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[F:54][C:55]([F:73])([F:72])[C:56]1[CH:57]=[CH:58][C:59]2[O:63][CH:62]([CH2:64][N:65]3[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]3)[CH2:61][C:60]=2[CH:71]=1>ClCCl>[O:20]=[C:18]([N:68]1[CH2:69][CH2:70][N:65]([CH2:64][CH:62]2[CH2:61][C:60]3[CH:71]=[C:56]([C:55]([F:73])([F:54])[F:72])[CH:57]=[CH:58][C:59]=3[O:63]2)[CH2:66][CH2:67]1)[CH2:17][O:16][CH:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:21]([F:23])([F:22])[F:24])[CH:5]=2)[CH2:15][CH2:14]1
Reactant: FC(F)(F)c1ccc2c(c1)CC(CN1CCNCC1)O2
Reactant: N#Cc1ccc(NC2CCC(OCC(=O)O)CC2)cc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(NC2CCC(OCC(=O)N3CCN(CC4Cc5cc(C(F)(F)F)ccc5O4)CC3)CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To a solution of 2-[(4-[[4-cyano-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]acetic acid (100 mg, 0.29 mmol) in dichloromethane (30 ml) was added EDAC.HCl (84.2 mg, 0.44 mmol, 1.5 eq), HOBt (59.2 mg, 0.44 mmol, 1.5 eq), triethylamine (59.1 mg, 0.58 mmol, 2 eq) and 1-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]piperazine (92.0 mg, 0.32 mmol, 1.1 eq). The reaction mixture was stirred overnight at room temperature and then quenched by the addition of water (30 ml). The crude product was extracted with ethyl acetate (3×20 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and then concentrated under vacuum. The crude material was purified by Pre-TLC with 20% ethyl acetate in dichloromethane to afford 4-([4-[2-oxo-2-(4-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]piperazin-1-yl)ethoxy]cyclohexyl]amino)-2-(trifluoromethyl)benzonitrile as a white solid (76 mg, 43%); (ES, m/z): [M+H]+ 611.30; 1H NMR (300 MHz, CDCl3): δ 7.55 (d, J=8.7 Hz, 1H), 7.42 (m, 2H), 6.81-6.86 (m, 2H), 6.64-6.68 (dd, J=2.1 Hz, 8.4 Hz, 1H), 5.08-5.13 (m, 1H), 4.29 (d, J=7.8 Hz, 1H), 4.21 (s, 2H), 3.65-3.78 (m, 3H), 3.30-3.48 (m, 3H), 3.01-3.06 (dd, J=8.4 Hz, 15.9 Hz, 2H), 2.51-2.90 (m, 4H), 2.10-2.19 (m, 4H), 1.44-1.58 (m, 3H), 1.21-1.33 (m, 3H).
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.Cl[C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]2[CH3:36])[CH:27]=[C:26]([C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=2[S:44]([CH3:47])(=[O:46])=[O:45])[N:25]=1.[F:48][C:49]1[CH:50]=[C:51]([NH:64][C:65]([NH:67][CH2:68][CH2:69][F:70])=[O:66])[CH:52]=[CH:53][C:54]=1B1OC(C)(C)C(C)(C)O1>>[F:48][C:49]1[CH:50]=[C:51]([NH:64][C:65]([NH:67][CH2:68][CH2:69][F:70])=[O:66])[CH:52]=[CH:53][C:54]=1[C:24]1[N:25]=[C:26]([C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=2[S:44]([CH3:47])(=[O:46])=[O:45])[CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]2[CH3:36])[N:29]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCF)cc2F)OC1(C)C
Reactant: C[C@H]1COCCN1c1cc(-c2cc(F)ccc2S(C)(=O)=O)nc(Cl)n1
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Product: C[C@H]1COCCN1c1cc(-c2cc(F)ccc2S(C)(=O)=O)nc(-c2ccc(NC(=O)NCCF)cc2F)n1

Procedure:
Method as described for intermediate 5 using (S)-4-(2-chloro-6-(5-fluoro-2-(methylsulfonyl)phenyl)pyrimidin-4-yl)-3-methylmorpholine (intermediate 10) and 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-fluoroethyl)urea (intermediate 14). Material was purified by using a TsOH cartridge (500 mg) followed by prep HPLC (low pH) to afford a white solid, (26 mg, 14%).
Reaction SMILES: [C:1]1([N:7]2[C:11]([SH:12])=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:33][C@@H:34]1[NH:38][C:37](=[O:39])[CH2:36][CH2:35]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1.O>[C:1]1([N:7]2[C:11]([S:12][CH2:33][C@@H:34]3[NH:38][C:37](=[O:39])[CH2:36][CH2:35]3)=[N:10][N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: O=C1CC[C@H](CO)N1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CC[C@H](CSc2nnnn2-c2ccccc2)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.4 %

Procedure:
1-Phenyl-1H-tetrazole-5-thiol (9.0 g) and triphenylphosphine (13.2 g) were added to a solution of (R)-(−)-5-(hydroxymethyl)-2-pyrrolidinone (4.5 g) in tetrahydrofuran (90 mL), followed by ice-cooling. A solution of 2.2 M diethyl azodicarboxylate in toluene (23 mL) was added dropwise thereto, and the mixture was stirred at room temperature overnight. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=4:1→1:1→0:1) to give (R)-5-{[(1-phenyl-1H-tetrazol-5-yl)sulfanyl]methyl}pyrrolidin-2-one (1.98 g) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:30][C:31]1[CH:39]=[CH:38][C:34]([CH2:35][CH2:36]O)=[CH:33][CH:32]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:30][C:31]1[CH:39]=[CH:38][C:34]([CH2:35][CH2:36][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[CH:33][CH:32]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: OCCc1ccc(F)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(CCOc2ccc3[nH]ccc3c2)cc1
Reaction time: 8 h
Yield: 25.7 %

Procedure:
To a solution of 1.06 g (8 mmol) 5-hydroxyindole and 2.09 g (8 mmol) triphenylphosphine in 40 ml anhydrous THF, cooled to 0° C. in ice, was added 1.0 mL (8 mmol) 4-fluorophenethylalcohol and 1.6 ml (8 mmol) diisopropylazodicarboxylate. The solution was allowed to gradually come to room temperature overnight. The solution was concentrated and the residue was chromatographed on silica using 20–25% EtOAc-hexane to afford 0.525 g 5-[2-(4-fluoro-phenyl)-ethoxy]-1H-indole as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([CH3:16])[CH:3]=1.[I:17]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([CH3:16])[C:3]=1[I:17]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(N)n(-c2c(Cl)cc(Cl)cc2Cl)n1
Solvent: CC#N
Product: Cc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1I

Procedure:
A stirred solution of 5-amino-3-methyl-1-(2,4,6-trichlorophenyl)pyrazole (WO-A-94/13643; 35 g) and N-iodosuccinimide (29 g) in acetonitrile (450 ml) was heated under reflux for 1.5 hours, then the reaction mixture allowed to cool and evaporated under reduced pressure. The residue was dissolved in dichloromethane and the solution washed successively with aqueous sodium thiosulphate solution, water and brine, then dried (Na2SO4) and evaporated under reduced pressure. The resulting dark coloured solid was triturated with hexane to yield the title compound as a pale orange solid, m.p. 135-137° C. δ(CDCl3): 2.25 (s,3H), 3.67 (br.s,2H), 7.49 (s,2H). MS (thermospray): M/Z [M+H] 401.4; C10H7Cl3 lN3 +H requires 401.88.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10][C:11]#N.[OH-:13].[Na+].[OH2:15]>CO>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([OH:15])=[O:13]
Reactant: [OH-]
Reactant: COc1cccc(CC#N)c1F
Reactant: O
Agent: [Na+]
Solvent: CO
Product: COc1cccc(CC(=O)O)c1F
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a mixture of 2-(2-fluoro-3-methoxyphenyl)acetonitrile (6.7 g, 40.6 mmol) in water (40 mL) and methanol (40 mL), sodium hydroxide (3.2 g, 81.1 mmol) was added. The resulting mixture was stirred at 60° C. for 5 h. After cooling to room temperature, methanol was evaporated under reduced pressure. The residue was acidified with 10% HCl until pH 5. The resulting precipitate was collected by filtration and dried to afford the title compound (6.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])[CH:5]=[N:6][C:7]=1[OH:8].Cl[C:16]1[CH:17]=[C:18]([CH:23]=[O:24])[CH:19]=[N:20][C:21]=1O.[C:25](#N)[CH2:26][C:27]#N.N1CCCCC1>CCO>[NH2:12][C:11]1[O:24][C:23]2[C:27]([CH:9]([C:4]3[CH:5]=[N:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=3)[C:10]=1[C:13]#[N:14])=[CH:26][CH:25]=[C:19]1[N:20]([CH3:21])[CH:16]=[CH:17][C:18]=21
Reactant: O=Cc1cnc(O)c(Cl)c1
Reactant: N#CCC#N
Reactant: N#CC(C#N)=Cc1cnc(O)c(Cl)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cn1ccc2c3c(ccc21)C(c1cnc(O)c(Cl)c1)C(C#N)=C(N)O3

Procedure:
2-(5-Chloro-6-hydroxy-pyridin-3-ylmethylene)-malononitrile: The title compound was prepared from 5-chloro-6-hydroxy-pyridine-3-carbaldehyde (0.170 g, 1.08 mmol), anhydrous EtOH (1.00 mL), malononitrile (0.071 g, 1.08 mmol), and piperidine (4.3 μL, 0.043 mmol), similar to Example 8a, and yielded 0.130 g (59%) of a brown solid. 1H NMR (DMSO-d6): 8.31 (d, 1H), 8.21 (s, 1H), 8.13 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][CH2:12]OS(C)(=O)=O)=[CH:4][CH:3]=1.Br[C:19]1[CH:24]=C[C:22]([C@@H]2C[C@@H]2CCOS(C)(=O)=O)=[CH:21][CH:20]=1.[NH3:35]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][CH2:12][N:35]2[CH2:22][CH2:21][CH2:20][C@H:19]2[CH3:24])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCC[C@@H]1C[C@H]1c1ccc(Br)cc1
Reactant: CS(=O)(=O)OCC[C@H]1C[C@H]1c1ccc(Br)cc1
Reactant: N
Product: C[C@@H]1CCCN1CC[C@@H]1C[C@H]1c1ccc(Br)cc1

Procedure:
The title compound was prepared according to the methods outlined in Example 26I substituting the product from Example 27A, (1R,2R)-methanesulfonic acid 2-[2-(4-bromo-phenyl)-cyclopropyl]-ethyl ester, for the product from Example 26H. 1H NMR (300 MHz, CDCl3, free base): δ 0.75-0.9 (m, 2H), 0.97-1.04 (m, 1H), 1.15 (d, J=6 Hz, 3H), 1.5-1.65 (m, 8H), 1.85-2.35 (m, 3H), 2.85-2.95 (m 1H), 3.12-3.20 (m, 1H), 6.9 (d, J=9 Hz, 2H), 7.33 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 310 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[CH2:34][OH:35]>>[F:24][C:22]1[CH:21]=[CH:20][C:19]([O:25][C:30]2[CH:31]=[CH:32][C:33]([CH2:34][OH:35])=[C:28]([F:27])[CH:29]=2)=[C:18]2[C:23]=1[C@H:15]([O:14][C:12]1[CH:11]=[CH:10][C:9]3[C@H:5]([CH2:4][C:3]([OH:2])=[O:26])[CH2:6][O:7][C:8]=3[CH:13]=1)[CH2:16][CH2:17]2
Reactant: OCc1ccc(B(O)O)cc1F
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: O=C(O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc(CO)c(F)c5)ccc(F)c43)ccc21

Procedure:
The methyl ester of the title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-fluoro-4-hydroxymethyl-phenylboronic acid following a procedure analogous to that described for Intermediate 6. The title compound is obtained after saponification of the methyl ester as described for Example 1. LC (method 6): tR=1.02 min; Mass spectrum (ESI−): m/z=467 [M−H]−.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].C(N(CC)CC)C.Cl>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:4]
Reactant: NCCCCCCCCCCC(=O)O
Reactant: CC(Br)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Br)C(=O)NCCCCCCCCCCC(=O)O

Procedure:
30.65 g (178.8 mmol) of α-bromopropionic acid chloride is added in drops at 0° C. to 30 g (149 mmol) of 11-aminoundecanoic acid and 45.24 g (447.1 mmol) of triethylamine in 600 ml of methylene chloride. In this case, the temperature remains between 0° C.-5° C. 800 ml of 5% aqueous hydrochloric acid is added, and the organic phase is separated. The organic phase is extracted once more with 300 ml of 5% aqueous hydrochloric acid, dried on magnesium sulfate and evaporated to dryness in a vacuum. The residue is recrystallized from acetone/diisopropyl ether.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:11]([O:12]C(=O)C)[C@:10]2([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([C:24](=[O:34])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH3:33])=[CH:27][CH:26]=4)[CH:18]=3)[O:16][C@@:7]([CH2:35][O:36]C(=O)C)([CH2:8][O:9]2)[C@H:6]1[O:40]C(=O)C)(=O)C.C[O-].[Na+]>CO.O1CCCC1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C@@:10]23[O:16][C@@:7]([CH2:35][OH:36])([CH2:8][O:9]2)[C@@H:6]([OH:40])[C@H:5]([OH:4])[C@H:11]3[OH:12])=[CH:18][C:19]=1[C:24]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH3:33])=[CH:29][CH:30]=1)=[O:34]
Reactant: CCOc1ccc(C(=O)c2cc([C@]34OC[C@](COC(C)=O)(O3)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc2Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(C(=O)c2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.7 %

Procedure:
To a solution of acetic acid (1R,2S,3S,4R,5S)-3,4-diacetoxy-1-acetoxymethyl-5-[4-chloro-3-(4-ethoxy-benzoyl)-phenyl]-6,8-dioxa-bicyclo[3.2.1]oct-2-yl ester (see Example 11 for preparation; 65 mg, 0.10 mmol) in methanol (3 mL) and tetrahydrofuran (2 mL) was added sodium methoxide in methanol (25% wt) until pH 12 was obtained and the resulting mixture was stirred at room temperature. After 16 hours, the reaction mixture was neutralized by the addition of Dowex Monosphere 650C (H) cation exchange resin until the pH of the solution was <7, filtered and concentrated under reduced pressure. The resulting material was precipitated from ethyl acetate and heptanes and the resulting white solid was washed with heptane 2 times and dried under reduced pressure to yield the desired product (44.5 mg, 94% yield). MS (LCMS) 451.1 (M+H+; positive mode) 1H NMR (400 MHz, METHANOL-d4) delta ppm 1.40 (t, J=6.9 Hz, 3H), 3.55 (d, J=8.0 Hz, 1H), 3.60 (d, J=7.4 Hz, 1H), 3.65 (t, J=8.1 Hz, 1H), 3.67 (d, J=12.5 Hz, 1H), 3.77 (d, J=8.0 Hz, 1H), 3.83 (d, J=12.5 Hz, 1H), 4.12 (q, J=7.0 Hz, 2H), 4.14 (d, J=7.6 Hz, 1H), 6.98 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.4 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.65 (dd, J=8.4, 2.0 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H). HRMS calculated for C22H23O8Cl (M) 450.1081. found 450.1079.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:9]2[CH2:11][O:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1)#[N:21]>CC#N>[C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][CH2:11][C@@H:9]([OH:10])[C@@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:24][CH:23]=1)#[N:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H]1CO1
Reactant: N#Cc1ccc(CN)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H](O)CNCc1ccc(C#N)cc1
Yield: 57.8 %

Procedure:
To a solution of tert-butyl (S)-2-cyclohexyl-1-((S)-oxiran-2-yl)ethylcarbamate (67.3 mg, 0.25 mmol) in CH3CN (8 mL) was added 4-cyanobenzylamine (39.6 mg, 0.3 mmol) and the mixture was heated under reflux overnight. The solvent was removed in vacuo and the residue was purified by the preparative HPLC to give tert-butyl (2S,3R)-4-(4-cyanobenzylamino)-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate (58 mg, 58%). 1H NMR: 0.82 (m, 1H), 0.95 (m, 1H), 1.10-1.48 (m, 5H), 1.45 (s, 9H), 1.55-1.68 (m, 5H), 1.76 (m, 1H), 2.65 (m, 2H), 3.46 (m, 1H), 3.85 (m, 2H), 4.49 (m, 1H), 7.42 (d, 2H), 7.59 (d, 2H). MS (E/Z): 402 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:18])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.[CH3:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([CH3:26])[NH:21]1>C(O)C>[ClH:1].[CH3:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([CH3:26])[N:21]1[CH2:2][CH:3]([OH:18])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1
Reactant: OC(CCl)COc1ccccc1Cc1cccs1
Reactant: CC1CCCC(C)N1
Solvent: CCO
Product: CC1CCCC(C)N1CC(O)COc1ccccc1Cc1cccs1
Product: Cl
Yield: 53.6 %

Procedure:
A solution of 2.8 g of 1-chloro-3[2-(2-thienylmethyl)phenoxy]-2-propanol, 2.3 g of 2,6-dimethylpiperidine in 30 ml of ethanol is refluxed for 15 hours. The ethanol is then removed, and the residue is dissolved in ether. The insoluble matter is filtered off, and the filtrated is extracted with two 50 ml portions of 10% hydrochloric acid. The aqueous layer is made alkaline with sodium hydroxide, and separated oil is extracted with ether. The ether layer is dried over anhydrous potassium carbonate, and the solvent is removed. The residue (crude product) is purified by column chromatography and converted into the hydrochloride in the same manner as in above method (a) to give 2.1 g of 1-(2,6-dimethylpiperidino)-3-[2-(2-thienylmethyl)phenoxy]-2-propanol hydrochloride as colorless crystals, melting at 152°-153°C.
Reaction SMILES: O=[C:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.COC(OC)[N:26]([CH3:28])C.[NH2:31]N>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:2]1[C:3]([N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)=[CH:28][NH:26][N:31]=1
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)c2ccccn2)CC1
Reactant: NN
Product: CC(C)(C)OC(=O)N1CCN(c2c[nH]nc2-c2ccccn2)CC1
Temperature: 25 °C
Yield: 38.1 %

Procedure:
Part B: A solution of tert-butyl 4-(2-oxo-2-(pyridin-2-yl)ethyl)piperazine-1-carboxylate (1.46 g, 4.78 mmol) and N,N-dimethylformamide dimethyl acetal (10.00 mL, 75 mmol) was heated at reflux for 5 h. After cooling to room temperature the mixture was concentrated under vacuum. The residue was dissolved in 20 mL of ethanol. To this solution was added anhydrous hydrazine (1.50 mL, 47.8 mmol), and the mixture was heated at reflux for 2 h. After cooling to room temperature the reaction mixture was concentrated under vacuum, and the residue was dissolved in ethyl acetate. The solution then was washed with aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 1-5% isopropanol/chloroform w/0.5% conc. ammonia) provided 0.600 g (38%) of tert-butyl 4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)piperazine-1-carboxylate as an oil; Mass Spec.: m/e: 330.30 (M+H)+ [calc'd: 330.19]; 1H NMR (300 MHz, DMSO-D6) δ 13.19 (br s, 1H), 8.60 (m, 1H), 8.09 (m, 1H), 7.90 (m, 1H), 7.53 (m, 1H), 7.31 (m, 1H), 3.50 (m, 4H), 2.82 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[C:4]([C:3]1[C:6]([F:11])=[CH:7][CH:8]=[C:9]([F:10])[C:2]=1[N:1]=[CH:14][N:15]([CH3:17])[CH3:16])#[N:5]
Reactant: N#Cc1c(F)ccc(F)c1N
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1c(F)ccc(F)c1C#N
Yield: 797.9 %

Procedure:
A solution of 2-amino-3,6-difluorobenzonitrile (1.92 g, 12.5 mmol) and N,N-dimethylformamide dimethyl acetal (2.2 mL, 1.3 mmol) in 15 mL of toluene was heated to reflux for 1 h. The reaction was complete based on GC-MS. The solvent was removed in vacuo and the oily residue was suspended in hexane and a small amount of ether. The mixture was then cooled in a freezer for 20 min. The resulting solid was suction filtered, washed with hexane and dried to give 2.17 g (83% yield) of the product as a tan solid, M.P. 56-60°; GC/MS: m/z 209. 1H NMR (CDCl3): δ 7.86 (s, 1H), 7.16 (m, 1H), 6.63 (m, 1H), 3.12 (s, 3H), 3.10 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([C:8]1[CH:9]=[CH:10][C:11]([Cl:16])=[C:12]([CH:15]=1)[C:13]#[N:14])[CH2:3][N:4]1[CH2:7][CH2:6][CH2:5]1.O[C:18]1[C:19]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([NH2:30])=[O:29])[C:20]=2[N:21]=[N:22][N:23]=1>>[N:4]1([CH2:3][C@@H:2]([NH:1][C:18]2[C:19]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([NH2:30])=[O:29])[C:20]=3[N:21]=[N:22][N:23]=2)[C:8]2[CH:9]=[CH:10][C:11]([Cl:16])=[C:12]([C:13]#[N:14])[CH:15]=2)[CH2:7][CH2:6][CH2:5]1
Reactant: N#Cc1cc([C@H](N)CN2CCC2)ccc1Cl
Reactant: NC(=O)c1cccc2c(O)nnnc12
Product: N#Cc1cc([C@@H](CN2CCC2)Nc2nnnc3c(C(N)=O)cccc23)ccc1Cl

Procedure:
Compound 18 was prepared following general synthetic scheme 7 wherein (S)-5-(1-amino-2-(azetidin-1-yl)ethyl)-2-chlorobenzonitrile was reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the title compound. LC-MS [408 (M+1)], 1H NMR (400 MHz, DMSO-d6): δ 9.31 (s, 1H), 8.82 (d, 1H), 8.63 (d, 1H), 8.55 (d, 1H), 8.12 (d, 1H), 8.03 (t, 2H), 7.85 (dd, 1H), 7.72 (d, 1H), 5.54 (d, 1H), 3.21-3.12 (m, 4H), 3.02-2.97 (m, 1H), 2.83-2.79 (m, 1H).