Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br/[CH:2]=[C:3]1\[C:4]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:5]=2[CH2:6][CH2:7][C:8]2[C:13]\1=[CH:12][CH:11]=[CH:10][N:9]=2.[F:19][C:20]1[CH:21]=[C:22]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH:23]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([NH:35][S:36]([CH3:39])(=[O:37])=[O:38])[CH:23]=[C:24](/[CH:2]=[C:3]2\[C:4]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:5]=3[CH2:6][CH2:7][C:8]3[C:13]\2=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:25]=1
Reactant: Fc1ccc2c(c1)CCc1ncccc1/C2=C/Br
Reactant: CC1(C)OB(c2cc(F)cc(NS(C)(=O)=O)c2)OC1(C)C
Product: CS(=O)(=O)Nc1cc(F)cc(/C=C2\c3ccc(F)cc3CCc3ncccc32)c1
Yield: 66.7 %

Procedure:
Following procedures essentially as desctribed in Example 219, beginning with (E)-5-bromomethylene-8-fluoro-10,11-dihydro-benzo[4,5]cyclohepta[1,2-b]pyridine (50 mg, 0.16 mmol) and N-[3-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanesulfonamide (62 mg, 0.20 mmol). After work-up, purify the crude product by flash chromatography (50% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) to provide 44 mg (65%) of purified product. LCMS (APCI-pos): 413.0 (M+H). LCMS (APCI-neg): 411.0 (M−H). Purity by LCMS 1 Area percent) 98%. 1HNMR (d6-DMSO, 400 MHz): δ9.91 (s, 1H), 8.42 (dd, 1H), 7.91 (dd, 1H), 7.29-7.25 (m, 2H), 6.92 (s, 2H), 6.90 (d, 1H), 6.77-6.74 (m, 2H), 6.52-6.49(m, 1H), 3.4-2.8 (m, 4H), 2.87 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:32](O)=[O:33])[CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([NH2:30])=[C:22]([Cl:31])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1.[N:39]1([CH:45]2[CH2:50][CH2:49][N:48](C(OCC3C=CC=CC=3)=O)[CH2:47][CH2:46]2)[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[C:23]([NH2:30])=[C:22]([Cl:31])[CH:21]=3)[C:32](=[O:33])[N:42]3[CH2:41][CH2:40][N:39]([CH:45]4[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]4)[CH2:44][CH2:43]3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCNCC2)CC1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCNCC3)CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.00 g (1.80 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1f), 546 mg (1.80 mmol) benzyl 4-piperazin-1-yl -piperidine-1-carboxylate (Example A17b), 643 mg (2.00 mmol) TBTU and 0.35 mL (2.50 mmol) triethylamine in 10 mL DMF was stirred overnight at RT. This was combined with 150 mL of 15% K2CO3 solution, the precipitate was removed by suction filtering, washed with 30 mL water and the crude product was dried at 40° C. in the drying cupboard.
Reaction SMILES: CN(C=O)C.[C:6]([O:14][C:15]1[C:23]([O:24][CH3:25])=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([N+:26]([O-:28])=[O:27])[CH:16]=1)(=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S(Cl)(Cl)=O.[N:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[N:35][CH:34]=1>C1C=CC=CC=1>[CH2:6]([O:14][C:15]1[C:23]([O:24][CH3:25])=[CH:22][C:18]([C:19]([N:46]2[CH2:47][CH2:48][N:43]([C:36]3[C:37]4[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:33]=[CH:34][N:35]=3)[CH2:44][CH2:45]2)=[O:21])=[C:17]([N+:26]([O-:28])=[O:27])[CH:16]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OC(=O)c1ccccc1
Reactant: c1ccc2c(N3CCNCC3)ncnc2c1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COc1cc(C(=O)N2CCN(c3ncnc4ccccc34)CC2)c([N+](=O)[O-])cc1OCc1ccccc1
Reaction time: 6 h
Yield: 84 %

Procedure:
DMF was added to a stirred suspension of 4-benzoyloxy-5-methoxy-2-nitro benzoic acid (6) (0:500 mg, 1.65 mmol) and thionyl chloride (3 ml) in dry benzene (30 ml) and the stirring was continued for 6 h. The benzene was evaporated in vacuum and the resultant oil dissolved in dry THF (50 ml) and added dropwise over a period of 1 h to a stirred suspension of (4-quinazolinyl)piperazine (350 mg, 1.65 mmol) triethyl amine (5 ml). After the completion of addition, the reaction mixture was brought to ambient temperature and stirred for an additional hour. The THF was evaporated in vacuum and the aqueous layer was washed with ethyl acetate. The aqueous phase was then adjusted to pH 3 using 6 N HCl and extracted with ethyl acetate and washed with brine, dried over Na2SO4 and evaporated in vacuum to afford the crude product of (7d), (700 mg in 84% yield). 1H NMR (CDCl3) δ 3.15-3.30 (m, 4H), 3.65-3.75 (m, 4H), 3.95 (s, 3H), 5.20 (s, 2H), 6.45-6.55 (t, 1H) 6.70 (s, 1H), 7.30-7.50 (m, 5H), 7.55-7.65 (t, 1H), 7.65 (s, 1H), 7.70-7.90 (m, 2H), 7.85-7.95 (m, 2H); FABMS: 500 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([CH3:29])([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)(=O)=O.[N-:30]=[N+:31]=[N-:32].[Na+]>>[N:30]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([CH3:29])([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)=[N+:31]=[N-:32]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCOS(C)(=O)=O)cc1)Oc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CCOC(=O)C(C)(Cc1ccc(OCCN=[N+]=[N-])cc1)Oc1ccccc1

Procedure:
In a similar manner to that described in Reference example 3(h), a reaction was carried out using ethyl 3-[4-(2-methanesulfonyloxyethoxy)phenyl]-2-methyl-2-phenoxypropionate (i1.42 g), which is the product of Reference example 8(e), and sodium azide (0.66 g) and the reaction mixture was treated to afford the desired compound (0.82 g) as a syrup.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH2:19][CH3:20])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][CH2:24][CH2:25][P:26]([O:31][CH2:32][CH3:33])(=[O:30])[O:27][CH2:28][CH3:29]>>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:22][CH2:23][CH2:24][CH2:25][P:26](=[O:30])([O:31][CH2:32][CH3:33])[O:27][CH2:28][CH3:29])[C:13](=[O:18])[N:12]([CH2:19][CH3:20])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Reactant: CCOP(=O)(CCCCCl)OCC
Product: CCOP(=O)(CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(CC)c1=O)OCC

Procedure:
The title substance was prepared from 0.04 mol of 7-benzyl-3-ethyl-xanthine and 0.048 mol of diethyl 4-chlorobutanephosphonate analogously to Example 23.
Reaction SMILES: [C:1]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:23][C:24]([C:26]2[N:27]=[N:28][NH:29][CH:30]=2)=[O:25])[CH2:9][C@@:10]([CH3:22])([CH2:14][O:15]C2CCCCO2)[C:11](O)=[O:12])=[CH:3][CH:2]=1.[CH2:37]([OH:43])[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].Cl.O1CCOCC1>>[CH2:37]([O:43][C:11](=[O:12])[C@@:10]([CH2:14][OH:15])([CH3:22])[CH2:9][C@H:8]([NH:23][C:24]([C:26]1[N:27]=[N:28][NH:29][CH:30]=1)=[O:25])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:6][CH:5]=1)[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: C[C@@](COC1CCCCO1)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1c[nH]nn1)C(=O)O
Reactant: CCCCCCO
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCCOC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1c[nH]nn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
(2S,4R)-5-Biphenyl-4-yl-2-methyl-2-(tetrahydropyran-2-yloxymethyl)-4-[(1H-1,2,3-triazole-4-carbonyl)amino]pentanoic acid (100 mg, 0.2 mmol) was combined with 1-hexanol (0.3 mL, 2 mmol) and 4 M HCl in 1,4-dioxane (0.3 mL, 1 mmol). The mixture was stirred for 2 hours at 60° C. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase chromatography to yield the title compound (51 mg). MS m/z [M+H]+ calc'd for C28H36N4O4, 493.27. found 493.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][C:6]([CH2:9][N:10]=[C:11]=[O:12])([CH3:8])[CH2:5][CH:4]([N:13]=[C:14]=[O:15])[CH2:3]1.[OH2:17].[CH3:18][CH:19]([OH:21])[CH3:20]>>[CH3:1][C:2]1([CH3:16])[CH2:7][C:6]([CH2:9][N:10]=[C:11]=[O:12])([CH3:8])[CH2:5][CH:4]([N:13]=[C:14]=[O:15])[CH2:3]1.[CH3:3][CH:4]([NH2:13])[CH2:5][O:17][CH2:18][CH:19]([O:21][CH2:18][CH:19]([O:21][CH2:5][CH:4]([NH2:13])[CH3:3])[CH3:20])[CH3:20]
Reactant: CC(C)O
Reactant: O
Agent: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Product: CC(N)COCC(C)OCC(C)OCC(C)N

Procedure:
The same experimental procedures were repeated. A mixture of IPDI (22.2 g, 0.10 M) in i-PrOH (11.2 g) was added into the solution of D-230 (46 g, 0.20 M) in i-PrOH (18 g)-and water (5 g) over a 3 hour period at 20°-30° C. The resulting product solution was analyzed to be 1.88 meq/g for amine (calc. 1.95 meq/g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]#[N:16].[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>ClCCl>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH3:13])[C:4](=[O:14])[C:3]([C:15]#[N:16])=[C:2]2[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: C1CNCCN1
Reactant: Cn1c(=O)c(C#N)c(Cl)c2cc(F)ccc21
Solvent: ClCCl
Product: Cn1c(=O)c(C#N)c(N2CCNCC2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
A solution of Compound 47 (750 mg, 3.17 mmol) in dichloromethane was added slowly to a stirred solution of piperazine (819 mg, 9.50 mmol) in dichloromethane at room temperature. The solution was stirred overnight at room temperature. The solvent was removed under reduced pressure. The residue was taken in water, sonicated briefly, and filtered. The solids were dissolved in ethyl acetate and washed by water. The organic layer was dried over Na2SO4 and concentrated to yield 780 mg (86%) of yellow solids. M.P. 211° C. 1H NMR (DMSO-d6): δ 2.91 (m, 4H), 3.47 (m, 4H), 3.56 (s, 3H), 7.54 (m, 1H), 7.63 (m, 2H). EIMS m/z 287 (M+1).
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[N:7]=[CH:6][C:5]2[CH:8]=[C:9](C(C)(C)C)[CH:10]=[C:11](Cl)[C:4]=2[O:3]1.O=S1(=O)N=CC2C=CC=CC=2O1>>[O:17]=[S:2]1(=[O:1])[NH:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[O:3]1
Reactant: CC(C)(C)c1cc(Cl)c2c(c1)C=NS(=O)(=O)O2
Agent: O=S1(=O)N=Cc2ccccc2O1
Product: O=S1(=O)NCc2ccccc2O1

Procedure:
This compound is prepared by essentially the same method as described in Example 9 except that the 2,2-dioxo-6-(1,1-dimethylethyl)-8-chloro-1,2,3-benzoxathiazine is replaced by 2,2-dioxo-1,2,3-benzoxathiazine. The following reagents are employed:
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]3[CH2:17][CH2:16][CH2:15][CH:12]32)=[CH:7][CH:6]=1)([O-])=O>C(O)C>[ClH:1].[CH2:15]1[CH:12]2[C:13]3[C:8]([CH2:9][CH2:10][N:11]2[CH2:17][CH2:16]1)=[CH:7][CH:6]=[C:5]([NH2:2])[CH:14]=3
Reactant: O=[N+]([O-])c1ccc2c(c1)C1CCCN1CC2
Agent: Cl
Solvent: CCO
Product: Nc1ccc2c(c1)C1CCCN1CC2

Procedure:
A suspension (+)-9-nitro-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline hydrochloride (1.83 g, 7.18 mmol) and 10% Pd--C (0.2 g) in ethanol (150 ml) was hydrogenated at 50 psi for 0.75 h. The solution was filtered and the filtrate was concentrated to a volume of 25 ml. It was then heated to reflux to dissolve all of the solid and upon cooling the product precipitated. The title compound was isolated as a white solid (1.37 g, 85%), m.p. 239-41.5° C.; [α]D +62.5° (c 1.13, MeOH). This salt was a single enantiomer by chiral CE.
Reaction SMILES: [C:1]([C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]([NH:12][C@H:13]([C@H:27]([OH:29])[CH3:28])[C:14]([NH:16][NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=O)=[CH:5][CH:4]=1)#[N:2].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.CO>C1COCC1>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]2[O:26][C:14]([C@H:13]([NH:12][C:6]3[C:7]4[CH:11]=[CH:10][S:9][C:8]=4[C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[C@H:27]([OH:29])[CH3:28])=[N:16][N:17]=2)=[CH:24][CH:23]=1
Reactant: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)NNC(=O)c1ccc(F)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)c1nnc(-c2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.5 %

Procedure:
To a solution of N′-((2R,3R)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)-4-fluorobenzohydrazide (0.41 g, 0.99 mmol) in THF (80 mL) was added PS-BEMP (1.36 g, 2.99 mmol, ˜2.2 mmol/g) and p-TsCl (191 mg, 1.0 mmol) at room temperature. The mixture was stirred at room temperature for 15 h, then methanol (5 mL) was added to quench the reaction. The resin was filtered and washed with MeOH. The combined filtrate was concentrated to give a residue, which was purified by flash chromatography to afford the title compound 4-((1R,2R)-1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)benzo[b]thiophene-7-carbonitrile (170 mg, 43%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.03 (dd, J=5.3, 8.8 Hz, 2H), 7.84 (d, J=5.6 Hz, 1H), 7.71 (d, J=5.6 Hz, 1H), 7.64 (d, J=8.2 Hz, 1H), 7.32 (t, J=8.8 Hz, 2H), 6.86 (d, J=8.2 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 5.13 (dd, J=6.4, 8.8 Hz, 1H), 4.66 (d, J=6.1 Hz, 1H), 4.57 (m, 1H), 1.48 (d, J=6.2 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]([NH:12][C:13](=[O:16])[CH2:14][Cl:15])([CH3:11])[CH2:9][OH:10])[CH:7]=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@@:8]([NH:12][C:13](=[O:16])[CH2:14][Cl:15])([CH3:11])[CH2:9][OH:10])[CH:7]=1
Reactant: CC(CO)(NC(=O)CCl)c1cc(Br)ccc1F
Solvent: ClCCl
Product: C[C@](CO)(NC(=O)CCl)c1cc(Br)ccc1F

Procedure:
A solution of (RS)-N-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide (2.7 g) in dichloromethane was divided in 100 mg aliquots which were separated on chiral HPLC (Reprosil Chiral NR 8 μm, 250×30 mm, Dr. Maisch GmbH) using a 85:15-mixture of heptane and isopropanol as the eluent. The first eluting enantiomer (retention time: 9.94 min), the (S)-(−)-N-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide, was obtained as a light yellow waxy solid (1.05 g, 39% of theory), and the second eluting enantiomer (retention time: 12.92 min), the (R)-(+)-N-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide, was also obtained as a light yellow waxy solid (1.07 g, 40% of theory), with e.e. >99% each.
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)=[C:18]([C:27]4[CH:28]=[C:29]5[C:33](=[CH:34][CH:35]=4)[C:32](=NO)[CH2:31][CH2:30]5)[CH:17]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N1CC[O:41]CC1.C(N(CC)CC)C>ClCCl>[N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]3[O:20][C:19]([C:21]4[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=4)=[C:18]([C:27]4[CH:28]=[C:29]5[C:33](=[CH:34][CH:35]=4)[C:32](=[O:41])[CH2:31][CH2:30]5)[CH:17]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=C(CN1CCOCC1)N1CCCC(c2cc(-c3ccc4c(c3)CCC4=NO)c(-c3ccncc3)o2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCc2cc(-c3cc(C4CCCN(C(=O)CN5CCOCC5)C4)oc3-c3ccncc3)ccc21
Yield: 54.7 %

Procedure:
A solution of the product of Step 1 (140 mg, 0.32 mmol) in dry dichloromethane (10 ml) was treated with morpholine (0.031 ml, 0.35 mmol) and triethylamine (0.049 ml, 0.35 mmol) and heated at reflux for 3 hours. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried, concentrated in vacuo and then purified by silica gel chromatography eluting with chloroform/ethanol/0.880 ammonia solution (98:1.8:0.2) to yield the title compound (85 mg, 55%); MS(ES+) m/e 486 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][O:3][CH2:4][C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2.C(N(CC)CC)C.C1C[O:25][CH2:24][CH2:23]1>>[Cl:1][CH2:2][O:3][CH2:4][C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2.[Cl:1][CH2:23][CH2:24][OH:25]
Reactant: C1CCOC1
Agent: ClCOCC12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Product: OCCCl

Procedure:
A two neck Kjeldahl flask of 50 ml into which a stirrer was put was charged with 2.15 g (10 mmol) of 1-adamantylmethyl chloromethyl ether obtained in (1), 0.97 g (12 mmol) of 2-chloroethanol, 1.52 g (15 mmol) of triethylamine and dried THF, and it was equipped with a coiled condenser to reflux and stir the solution for 8 hours. Triethylamine hydrochloride was filtered, and gas chromatographic analysis was carried out to find that chloroethyl chloromethyl ether was completely converted and that 2.25 g (8.7 mmol, isolation yield: 86.9%) of a colorless liquid which was the intended product was obtained at a selectivity of 98.5%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.[CH:11]1(O)[CH2:15][CH2:14][CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([O:8][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:7]=1
Reactant: OC1CCCC1
Reactant: COc1ccc(Br)cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A solution of 5-bromo-2-methoxyphenol (1 g), cyclopentanol (0.54 ml) and triphenylphosphine (1.55 g) in anhydrous tetrahydrofuran (20 ml), at 0° C., was treated with diethylazodicarboxylate (0.85 mi). The resulting yellow solution was stirred at 0° C. for 40 minutes then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of petroleum ether and ethyl acetate (19:1, v/v) to give the title compound (1.2 g) as a pale yellow oil. NMR (CDCl3): δ1.62 (m,2H), 1.78-2.20 (m,6H), 3.79 (s,3H), 4.72 (m,1H), 6.70 (d,1H), 7.00 (dd,2H). Mass spectrum (FAB): m/z 270/272 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[CH:5]=[N:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[N:11][CH:12]=1.[CH2:19]=[CH:20][C:21](=[CH2:23])[CH3:22]>CC#N.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[CH2:22][C:21]([CH3:23])([CH:20]=[CH2:19])[C:12]3[N:11]=[C:10]([C:13]#[N:14])[CH:9]=[CH:8][C:7]=3[NH:6]2)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: C=CC(=C)C
Reactant: N#Cc1ccc(N=Cc2ccc(F)c(Cl)c2)cn1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CC#N
Product: C=CC1(C)CC(c2ccc(F)c(Cl)c2)Nc2ccc(C#N)nc21
Temperature: 80 °C
Reaction time: 16 h
Yield: 5.3 %

Procedure:
To a stirred solution 5-[(3-chloro-4-fluoro-benzylidene)-amino]-pyridine-2-carbonitrile (3.7 g, 14.3 mmol) in MeCN (36 mL) were added isoprene (5.8 mL, 57.1 mol) and scandium(III) trifluoromethanesulfonate (Sc(OTf)3) (1.4 g, 2.9 mmol). The resulting mixture was stirred at 80° C. for 16 hours in sealed tube. The mixture was extracted with diethyl ether (80 mL) and washed with water (100 mL) and brine (100 mL) and then dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 0-20% ethyl acetate in petroleum ether) to afford 6-(3-chloro-4-fluoro-phenyl)-8-methyl-8-vinyl-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carbonitrile (0.25 g, 5.5%) as white powder. MS (ESI+) [(M+H)+] 328.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH2:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[F:31])[C:13]2[CH:22]=[CH:21][C:16]3[O:17][CH2:18][CH2:19][O:20][C:15]=3[CH:14]=2)[CH2:8][CH2:7]1)[CH3:5].[CH3:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[C:34]=1[C:35](O)=[O:36]>>[Cl:30][C:28]1[CH:27]=[CH:26][C:25]([F:31])=[C:24]([CH:29]=1)[CH2:23][N:12]([C:13]1[CH:22]=[CH:21][C:16]2[O:17][CH2:18][CH2:19][O:20][C:15]=2[CH:14]=1)[CH:9]1[CH2:8][CH2:7][N:6]([CH:4]([CH3:5])[CH2:3][CH2:2][NH:1][C:35](=[O:36])[C:34]2[C:38]([CH3:42])=[CH:39][CH:40]=[CH:41][C:33]=2[CH3:32])[CH2:11][CH2:10]1
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: CC(CCN)N1CCC(N(Cc2cc(Cl)ccc2F)c2ccc3c(c2)OCCO3)CC1
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cc(Cl)ccc2F)c2ccc3c(c2)OCCO3)CC1
Yield: 85.3 %

Procedure:
Using general procedure E, [1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(5-chloro-2-fluoro-benzyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amine (see EXAMPLE 215) (86 mg, 0.19 mmol) and 2,6-dimethyl-benzoic acid (40 mg, 0.27 mmol) gave COMPOUND 216 as a white foam (94 mg, 84%). 1H NMR (CDCl3) δ 0.83-1.14 (m, 2H), 0.98 (d, 3H, J=6.6 Hz), 1.47-1.57 (m, 1H), 1.66-1.81 (m, 3H), 2.06-2.17 (m, 1H), 2.30 (s, 6H), 2.46-2.57 (m, 1H), 2.69-2.90 (m, 3H), 3.22-3.33 (m, 1H), 3.36-3.47 (m, 1H), 3.75 (s, 2H), 3.81-3.93 (m, 1H), 4.12-4.23 (m, 4H), 6.07-6.17 (m, 2H), 6.66 (d, 1H, J=8.7 Hz), 6.87-7.04 (m, 4H), 7.10-7.18 (m, 2H), 8.36 (s, 1H). 13C NMR (CDCl3) δ 13.25, 18.99, 28.82, 30.02, 30.90, 39.54, 42.59 (d, J=3.8 Hz), 43.57, 52.01, 57.47, 60.23, 64.04, 64.56, 103.36, 107.81, 116.24 (d, J=23.2 Hz), 117.28, 127.13, 127.77 (d, J=8.1 Hz), 128.32 (d, J=5.5 Hz), 128.35, 129.20 (d, J=3.2 Hz), 129.35 (d, J=15.3 Hz), 133.61, 135.82, 138.27, 143.27, 143.66, 158.57 (d, J=245 Hz), 169.89. ESI-MS m/z 580 (MH)+, 582 (MH+2)+. Anal. Calcd. for C33H39ClFN3O3.0.3H2O.0.2CH2Cl2: C, 66.55; H, 6.72; N, 7.02; Cl, 7.70. Found: C, 66.44; H, 6.60; N, 7.12; Cl, 7.74.
Reaction SMILES: [CH2:1]1[O:9][C@H:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:20]=[C:19]([SH:21])[CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]>>[Cl:10][C:11]1[CH:20]=[C:19]([S:21][CH2:1][C@@H:2]([OH:9])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1ccc(S)cc1Cl
Reactant: c1ccc([C@H]2CO2)cc1
Product: COC(=O)c1ccc(SC[C@@H](O)c2ccccc2)cc1Cl

Procedure:
119 mg of (S)-styrene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford (S)-methyl 2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoate. 230 mg of (S)-methyl-2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoate was hydrolyzed via Procedure M to give (S)-2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoic acid. 180 mg of (S)-2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoic acid was reacted via Procedure R to give (S)-2-chloro-4-(2-hydroxy-2-phenylethylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (S)-2-chloro-4-(2-hydroxy-2-phenylethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (S)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxy-2-phenylethylsulfonyl)benzamide. MS (Q1) 527.0 (M)+.
Reaction SMILES: C([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:42])[CH2:15][CH2:16][CH2:17][C:18]2[N:19]=[CH:20][N:21](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:22]=2)=[CH:10][CH:9]=1)=O)(C)(C)C>S(Cl)(Cl)=O>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14](=[O:42])[CH2:15][CH2:16][CH2:17][C:18]2[N:19]=[CH:20][NH:21][CH:22]=2)=[CH:12][CH:13]=1)#[N:5]
Reactant: CC(C)(C)NC(=O)c1ccc(C(=O)CCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(C(=O)CCCc2c[nH]cn2)cc1
Temperature: 0 °C

Procedure:
A solution of 0.5 g of 1-(p-N-tert-butylaminocarbonylphenyl)-4-(1-trityl-4-imidazolyl)-1-butanone in 20 ml of thionyl chloride is refluxed for 3 h and poured into 100 ml of ice-water. The aqueous phase is extracted with ether (3×20 ml), adjusted to pH=10 and reextracted with methylene chloride. The organic phase is dried and evaporated to yield 1-(p-cyanophenyl)-4-(4-imidazolyl)-1-butanone.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O>C1COCC1.CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc(N)cc1
Reaction time: 24 h

Procedure:
A mixture of 1 (6.7 g, 1 mmol) in THF (100 ml) and EtOH (100 ml) is slowly added 10% Pd/C (680 mg) at room temperature. The reaction mixture is hydrogenated for 24 h with H2 balloon at room temperature. The mixture is filtered through celite pad and washed with EtOH. The filtrate is concentrated in vacuo.