Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7](=[O:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH:49]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:50][CH3:51]>>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:7](=[O:10])[N:8]([CH:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:50][CH3:51])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCC(Br)c1ccccc1
Product: CCCCc1nn(C(CC)c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 50 %

Procedure:
The alkylation of 5-n-butyl-2,4-dihydro-4-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one (from Example 2, Step D) with 1-bromo-1-phenylpropane was carried out as described in Example 3, Step A. After work-up, the residue was flash chromatographed over silica gel (gradient elution using 0.2-1.0% MeOH/CH2Cl2) to give the desired material in 50% yield, homogeneous by TLC in 2% MeOH/CH2Cl2, mass spectrum (FAB) 736 (M+1)+.
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[C:5]=1[OH:26])(=[O:3])[CH3:2].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.[N:51]1[CH:56]=[CH:55][CH:54]=[C:53]([CH2:57][CH2:58][CH2:59][CH2:60][NH2:61])[CH:52]=1>CN(C=O)C>[C:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:61][CH2:60][CH2:59][CH2:58][CH2:57][C:53]3[CH:52]=[N:51][CH:56]=[CH:55][CH:54]=3)=[O:18])=[CH:19][CH:20]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[C:5]=1[OH:26])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCOc2ccc(C(=O)O)cc2)ccc(C(C)=O)c1O
Reactant: NCCCCc1cccnc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCc1c(OCCOc2ccc(C(=O)NCCCCc3cccnc3)cc2)ccc(C(C)=O)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a cold (0° C.) solution of 1.22 g of 4-[2-(4-Acetyl-3-hydroxy-2-propylphenoxy)ethoxy]benzoic acid in 15 mL of anhydrous DMF was added to 0.8 mL of diphenylphosphoryl azide and 1.05 mL of anhydrous triethylamine. The resulting mixture was stirred at 0° C. for one hour and then 0.56 g of 3-pyridine butanamine was added. The mixture was stirred in ice bath for 1 hour and at room temperature for 6 hours. The solvent was removed in vacuo, the residue was dissolved in methylene chloride and washed with sodium bicarbonate solution. The extract was dried (over magnesium sulfate) and concentrated in vacuo to an oil which was purified by HPLC using 7% methanol-ethyl acetate to give an oil which was triturated with ethyl acetate-ether and filtered to yield 1.0 g, mp 93° , (60% yield) of 4-[2-(4-Acetyl-3-hydroxy-2-propylphenoxy)-ethoxy]-N-[4-(3-pyridinyl)butyl]benzamide, the title compound.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[F:5][C:6]1[CH:21]=[CH:20][C:9]2[C:10](=O)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH:13]=[CH:14][C:8]=2[CH:7]=1.O.C(Cl)Cl>O1CCCC1>[F:5][C:6]1[CH:21]=[CH:20][C:9]2[CH2:10][C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH:13]=[CH:14][C:8]=2[CH:7]=1
Reactant: O=c1c2ccccc2ccc2cc(F)ccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Fc1ccc2c(c1)C=Cc1ccccc1C2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.9 %

Procedure:
LiA1H4 (0.0686 mol) was added dropwise to a suspension of AlCl3 (0.0718 mol) in tetrahydrofuran (75 ml), cooled on an ice-bath and under N2 atmosphere. The mixture was stirred for 10 minutes at 0° C. A solution of 2-fluoro-5H-dibenzo[a,d]cyclohepten-5-one (0.0653 mol and prepared as described in DE 3,644,462) in tetrahydrofuran (75 ml) was added dropwise and the resulting reaction mixture was allowed to warm to room temperature. Then, the reaction mixture was stirred and refluxed for 2 hours. The mixture was cooled on an ice-bath. Water and CH2Cl2 was added. The organic layer was washed with a saturated aqueous NaHCO3 solution, dried, filtered and the solvent was evaporated, yielding 13.16 g (96%) of 2-fluoro-5H-dibenzo[a.d]cycloheptene (intermediate 1)
Reaction SMILES: I.CS[C:4](=[NH:18])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH3:19][NH:20][CH3:21]>C(N(CC)CC)C>[CH3:19][N:20]([CH3:21])[C:4]([NH2:18])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CNC
Reactant: CSC(=N)Nc1ccccc1N1CCOCC1
Agent: I
Solvent: CCN(CC)CC
Product: CN(C)C(N)=Nc1ccccc1N1CCOCC1

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (3.8 g), a 33% ethanolic solution of dimethylamine (5 ml) and triethylamine (25 ml) was heated at 80° C. for 8 hours. Triethylamine was removed by evaporation under reduced pressure and the residue treated with a mixture of ice and water to give 1,1-dimethyl-2-(2-morpholinophenyl)guanidine (m.p. 141°-143° C.) which was recrystallised from hexane.
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2)[CH3:2].Br[CH:14]([CH3:19])[C:15]([O:17]C)=[O:16]>>[CH3:2][O:1][C:3]1[CH:4]=[C:5]2[C:9]([C:8]([CH:14]([CH3:19])[C:15]([OH:17])=[O:16])=[CH:7][CH2:6]2)=[CH:10][CH:11]=1
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: COC(=O)C(C)Br
Product: COc1ccc2c(c1)CC=C2C(C)C(=O)O
Yield: 68 %

Procedure:
This substrate was prepared using the same procedures as described for Examples 1 and 2a, starting with 5-methoxyl-1-indanone and methyl 2-bromopropionate. Yield: 68%. 1H NMR (CD2Cl2) δ 7.34 (d, J=9, 1H), 7.07 (d, J=2, 1H), 6.85 (dd, J=9, J=2, 1H), 6.32 (m, 1H), 3.82 (m, 4H), 3.36 (m, 2H), 1.56 (d, J=7, 3H).
Reaction SMILES: [O:1]1[C:5]2([CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][N:8]2[CH2:9][CH2:10][CH2:11][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: C1CNCCC2(C1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(CCN2CCCC3(CC2)OCCO3)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A mixture of intermediate (5) (0.114 mol), 1-(2-bromoethyl)-4-methoxy-benzene (0.172 mol) and K2CO3 (0.219 mol) in ACN (200 ml) was stirred at 80° C. for 2 hours. Water was added and the mixture was extracted with DCM. The organic layer was separated, dried , filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.2). The pure fractions were collected and the solvent was evaporated, yielding 28.5 g of 8-[2-(4-methoxyphenyl)ethyl]-1,4-dioxa-8-azaspiro[4.6]undecane (intermediate 6).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([C@H:25]([NH2:29])[C:26]([OH:28])=[O:27])[CH2:11][C:12]([NH:14][C@H:15]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[CH2:16][SH:17])=[O:13]>CC(C)=O.O>[NH2:29][C@H:25]([C:26]([OH:28])=[O:27])[CH2:10][CH2:11][C:12]([NH:14][C@H:15]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[CH2:16][S:17][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: CC(C)=O
Product: N[C@@H](CCC(=O)N[C@@H](CSC(=O)c1ccccc1)C(=O)NCC(=O)O)C(=O)O
Temperature: 25 °C
Yield: 78 %

Procedure:
Using in the procedure of Example 1 benzoyl chloride in place of pivaloyl chloride, L-glutathione reduced (15.4 g) affords a crude white solid which is suspended in boiling acetone/water (3/1; 400 ml) for thirty minutes. After cooling at room temperature the white precipitate is collected by filtration and washed with acetone (20 ml). Under vacuum drying yields γ-L-glutamyl-S-benzoyl-L-cysteinyl-glycine (16 g yield=78%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[O:17])=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH:2]=1.[CH3:18][N:19]1[CH2:24][CH2:23][N:22](C2C=CC(B3OC(C)(C)C(C)(C)O3)=CN=2)[CH2:21][CH2:20]1>>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:6]2[N:1]=[CH:2][C:3]([C:7]3[C:15]4[C:10](=[CH:11][C:12]([CH:16]=[O:17])=[CH:13][CH:14]=4)[NH:9][N:8]=3)=[CH:4][CH:5]=2)[CH2:21][CH2:20]1
Reactant: O=Cc1ccc2c(-c3cccnc3)n[nH]c2c1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: CN1CCN(c2ccc(-c3n[nH]c4cc(C=O)ccc34)cn2)CC1

Procedure:
According to the procedure for the synthesis of 3-(pyridin-3-yl)-1H-indazole-6-carbaldehyde, except substituting 1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)pyridin-2-yl)piperazine (67 mg, 0.22 mmol), the title compound was obtained as a beige solid (57 mg, 99%). 1H NMR (400 MHz, CD3OD) δ ppm 10.11 (s, 1H), 8.73 (d, J=2.3 Hz, 1H), 8.16 (dd, J=8.8, 2.3 Hz, 1H), 8.14 (s, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 3.83-3.78 (m, 4H), 3.01 (t, J=5.0 Hz, 4H), 2.67 (s, 3H); MS ESI 322.1 (100) [M+H]+, calcd for [C18H19N5O+H]+ 322.16.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:17][C@@H:16]2[CH2:18][C@H:13]1[CH2:14][N:15]2C(OC(C)(C)C)=O)=[O:11].C([O-])([O-])=O.[Na+].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C@H:13]12[CH2:18][C@H:16]([NH:15][CH2:14]1)[CH2:17][N:12]2[C:10]([C:2]1[NH:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1nc2ccccc2[nH]1)N1C[C@@H]2C[C@H]1CN2
Yield: 45.9 %

Procedure:
A solution of 1,1-Dimethylethyl (1S,4S)-5-(1H-benzimidazol-2-ylcarbonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (20 g, 58.5 mmol) in 200 ml TFA/DCM (20%) was stirred at room temperature for 1 h. The reaction mixture was basified by addition of sat. aqueous Na2CO3 and then extracted with DCM (4×200 mL). The DCM solution was dried over anhydrous Na2SO4 and concentrated to give the title compound (6.5 g) as a pale yellow solid. LCMS (m/z): 243.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH:30]1(O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C(Cl)(Cl)Cl.CO>[CH:30]1([O:24][C:23]([C:18]2([C:20]([O:22][CH:30]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: OC1CCCCCCC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OC1CCCCCCC1)(C(=O)OC1CCCCCCC1)O2)NC[C@H](O)c1cccc(Cl)c1
Yield: 84 %

Procedure:
The title compound was prepared as a white gum from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and cyclooctanol according to the procedure of Example 1; yield 84%; Rf =0.30 (10/1 CHCl3 /MeOH); 1H NMR (300 MHz, CDCl3): δ 1.30-1.39 (brd, 3H), 1.40-1.92 (m, 28H), 2.72-2.87 (m, 1H), 3.06-3.30 (m, 2H), 3.39-3.52 (m, 2H), 3.80-3.91 (m, 1H), 5.02-5.13 (m, 1H), 5.40-5.80 (m, 1H), 6.71-6.89 (m, 4H), 7.21-7.37 (m, 2H), 7.44 (s, 1H), 8.73 (brs, 1H), 10.11 (brs, 1H); MS (ES) m/z (relative intensity): 679 (M+, 100).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[N-:12]=[N+:13]=[N-:14].[Na+]>CS(C)=O>[N:12]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4])=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC(=O)c1ccc(F)cc1
Yield: 80.9 %

Procedure:
A solution of 2-bromo-1-(4-fluoro-phenyl)-ethanone (2.5 g, 11.5 mmol) in DMSO (15 mL) at 10° C. was vigorously stirred and sodium azide (0.94 g, 14.4 mmol) was added. The mixture was stirred for I hour then quenched with water (20 mL) and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure to give 2-azido-1-(4-fluoro-phenyl)-ethanone (1.7 g, 9.3 mmol) as a viscous yellow-red liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH2:9][C:8]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[N:6][CH:7]=1.Cl[C:17]1[C:26]2[C:21](=[C:22]([Cl:27])[CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([CH3:28])[C:18]=1[CH3:29].[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([C:17]3[C:26]4[C:21](=[C:22]([Cl:27])[CH:23]=[CH:24][CH:25]=4)[N:20]=[C:19]([CH3:28])[C:18]=3[CH3:29])[CH2:9][C:8]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2c(c1)NCC21CCOCC1
Reactant: Cc1nc2c(Cl)cccc2c(Cl)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2c(Cl)cccc2c(N2CC3(CCOCC3)c3ncc(Br)cc32)c1C

Procedure:
Prepared according to procedure M by using 6′-bromo-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (150 mg, 0.56 mmol), 4,8-dichloro-2,3-dimethylquinoline (126 mg, 0.56 mmol) and NaH (48.6 mg, 1.11 mmol, 55% dispersion in oil) in DMF (2.5 mL) while heating the reaction at 60° C. for 14 h. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 6′-bromo-1′-(8-chloro-2,3-dimethylquinolin-4-yl)-1′,2,2′,3,5,6-hexahydrospiro-[pyran-4,3′-pyrrolo[3,2-b]pyridine]. Mass Spectrum (ESI) m/e=458.0 [(M+1) (79Br)] and 460.0 [(M+1) (81Br)].
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:9])[C:5]([OH:19])=[CH:4][CH:3]=1.[C:20]([O-])([O-])=O.[Cs+].[Cs+].ClCI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:19][CH2:20][N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:8](=[O:9])[C:6]=2[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)ccc1O
Agent: ClCI
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1c2nc(Br)ccc2OCN1Cc1ccc(F)cc1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of 6-bromo-N-(4-fluorobenzyl)-3-hydroxypicolinamide (100 mg, 0.31 mmol) and Cs2CO3 (219 mg, 0.62 mmol) in DMF (10 mL) was added chloroiodomethane (87 mg, 0.46 mmol) dropwise at 110° C. under N2. The mixture was stirred at 110° C. for 0.5 hour. Then the mixture was concentrated and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-TLC (PE:EtOAc=2:1) to afford the product of 6-bromo-3-(4-fluorobenzyl)-2H-pyrido[2,3-e][1,3]oxazin-4(3H)-one (70 mg, yield: 67.3%). 1H-NMR (CDCl3, 400 MHz) δ 7.46˜7.48 (m, 1H), 7.26˜7.29 (m, 2H), 7.18˜7.20 (m, 1H), 6.96 (t, J=8.4 Hz, 2H), 5.16 (s, 2H), 4.70 (s, 2H). MS (M+H)+: 337/339.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:10]([OH:13])=[CH:11][N:12]=1)[C:8]#[N:9])([CH3:4])([CH3:3])[CH3:2].[CH3:14]CN(C(C)C)C(C)C.C[Si](C=[N+]=[N-])(C)C>CC#N.CO>[C:1]([C:5]1[CH:6]=[C:7]([C:10]([O:13][CH3:14])=[CH:11][N:12]=1)[C:8]#[N:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C#N)c(O)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC#N
Product: COc1cnc(C(C)(C)C)cc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
To a solution of 10.0 g (73.5 mmol) of 2-tert-Butyl-5-hydroxy-isonicotinonitrile ((a) J. Med. Chem. 1981, 24, 115 (b) U.S. Pat. No. 4,123,537) in MeCN/MeOH (9:1, 20 mL) was added iPr2NEt (1.48 mL, 8.52 mmol) followed by (trimethylsilyl)diazomethane (2.0 M in hexane, 4.30 mL, 8.52 mmol). The red solution was stirred 18 h at rt then concentrated. The residue was dissolved in CH2Cl2, washed with saturated NaHCO3, dried over Na2SO4, filtered, and concentrated to provide 2-tert-Butyl-5-methoxy-isonicotinonitrile (1.10 g, 99%) as a pale yellow oil which was utilized without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]1([CH2:14][CH:15]([C:18]2[CH:19]=[N:20][C:21]([CH:24]([F:26])[F:25])=[CH:22][CH:23]=2)[CH2:16][NH2:17])[CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][CH2:16][CH:15]([C:18]1[CH:19]=[N:20][C:21]([CH:24]([F:26])[F:25])=[CH:22][CH:23]=1)[CH2:14][CH:11]1[CH2:12][CH2:13]1)=[O:6]
Reactant: NCC(CC1CC1)c1ccc(C(F)F)nc1
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(NCC(CC1CC1)c1ccc(C(F)F)nc1)c1ccccc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=365.1, tR (minutes, Method F)=2.97. [α]D20=+21.00 (c=3.00 mg/mL,CHCl3)
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:7])[CH2:5][Cl:6].[CH3:8][N:9]=[C:10]=[O:11]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C1C=CC=CC=1>[Cl:6][CH2:5][C:4]([O:7][C:10](=[O:11])[NH:9][CH3:8])=[N:3][O:2][CH3:1]
Reactant: CONC(=O)CCl
Reactant: CN=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: c1ccccc1
Product: CNC(=O)OC(CCl)=NOC

Procedure:
N-Methoxychloroacetamide (3.5 grams), benzene (60 ml) and dibutyltin dilaurate (1 drop) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Methyl isocyanate (2.0 grams) dissolved in benzene (15 ml) was added dropwise to the reaction mixture at room temperature and with stirring. After the addition was completed the reaction mixture was heated at reflux, with stirring for a period of about 2 hours. After this time the reaction mixture was distilled to remove benzene and unreacted isocyanate leaving an oily residue. The residue was subjected to vacuum (0.1 mm Hg) whereupon it solidified. The solid was recrystallized from a carbon tetrachloride-hexane mixture to yield a white crystalline solid. The solid was washed with hexane and dried to yield the desired product 1-chloro-2-(N-methylcarbamoyloxy)-2-methoxyiminoethane having a melting point of 80°-82°C.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(Cl)Cl.C(N(CC)CC)C.[C:15](N=[N+]=[N-])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>O>[C:15]([CH:3]=[CH:2][CH2:1][NH2:4])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Reactant: C=CCN
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C=CCN
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
A mixture of 3.00 ml of allylamine, 30 ml of CH2Cl2, 5.85 ml of triethylamine and 5.81 ml of BOC-azide is prepared at 0° C. and stirred at 25° C. for 16.5 hours while protected from moisture. It is then treated with 2 ml of water for 20 minutes, evaporated, treated with ethyl acetate, extracted successively with water, aqueous pH 2 phosphate buffer, water, aqueous K2HPO4 and brine, dried with MgSO4, filtered and evaporated to afford 5.54 g of product, m.p. 37° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[C:19]1[C:23]([C:24](Cl)=[O:25])=[C:22]([CH3:27])[O:21][N:20]=1>>[CH3:2][O:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:24]([C:23]1[C:19]([C:13]2[C:14]([F:18])=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])=[N:20][O:21][C:22]=1[CH3:27])=[O:25]
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Reactant: COC(=O)CCCCN
Agent: Cl
Product: COC(=O)CCCCNC(=O)c1c(-c2c(F)cccc2Cl)noc1C
Yield: 89.1 %

Procedure:
Methyl-5-aminopentanoate hydrochloride (694 mg, 4.14 mmol) and 3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-oyl chloride (1.24 g, 4.52 mmol) were converted to 1.36 g of the title compound by the procedure of Preparation 10. (100%). EA calculated for: C17H18N2O4ClF: C, 55.37; H, 4.92; N, 7.60. Found: C, 55.44; H, 5.00; N, 7.52. MS(FD) m/z 368 (M+).
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:37]=[CH:36][CH:35]=[CH:34][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:39][C:40](=[O:50])[C@H:41]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)O>>[CH2:1]([C:8]1[O:9][C:10]2[CH:37]=[CH:36][CH:35]=[CH:34][C:11]=2[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C@@H:41]([CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:40]([OH:50])=[O:39])=[C:21]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[CH:20]=2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2cc(-c3ccc(-c4c(Cc5ccccc5)oc5ccccc45)cc3)ccc2O)cc1
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Product: COc1ccc(-c2cc(-c3ccc(-c4c(Cc5ccccc5)oc5ccccc45)cc3)ccc2O[C@@H](Cc2ccccc2)C(=O)O)cc1

Procedure:
The title compound was prepared from 4-(2-benzyl-benzofuran-3-yl)-4″-methoxy-[1,1′;3′,1″]terphenyl-4′-ol, and (S)-(−)-3-phenyllactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h , and was obtained as a white solid, mp 73-75° C.; MS m/e 629 (M−H)+;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23](O)=[O:24])=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN(C=O)C.[Cl:54][C:55]1[CH:61]=[CH:60][C:58]([NH2:59])=[CH:57][CH:56]=1>C1COCC1>[Cl:54][C:55]1[CH:61]=[CH:60][C:58]([NH:59][C:23]([C:15]2[C:16]3[O:20][C:19]([CH3:21])([CH3:22])[CH2:18][C:17]=3[C:11]3[NH:10][C:9]([NH:8][C:7]4[C:6]([Cl:26])=[CH:5][N:4]=[CH:3][C:2]=4[Cl:1])=[N:13][C:12]=3[CH:14]=2)=[O:24])=[CH:57][CH:56]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(Cl)cc3)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 9.8 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-3, 0.080 g, 0.203 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.128 g, 0.400 mmol), TEA (1.0 mL), DMF (1.0 mL), THF (5.0 mL) and 4-chloro aniline (0.052 g, 0.400 mmol) to afford 0.010 g of the desired product. 1HNMR (DMSO-d6): δ 1.57 (s, 6H), 3.07 (s, 2H), 7.14 (s, 1H), 7.40 (d, J=9.0 Hz, 2H), 7.72 (d, J=12.3 Hz, 2H), 8.45 (s, 2H), 9.72 (s, 1H), 11.00 (s, 1H), 11.45 (s, 1H); MS [M−H]−: 500.25.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][CH:25]=1)[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[O:19][CH2:20][C:21]#[N:22])[CH:12]=[CH:11]1>O1CCCC1.Cl.O>[CH:2]([C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][CH:25]=1)[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[O:19][CH2:20][C:21]#[N:22])[CH:12]=[CH:11]1)=[O:1]
Reactant: N#CCOc1cccc2ccn(Cc3cccc(C4OCCO4)c3)c12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: N#CCOc1cccc2ccn(Cc3cccc(C=O)c3)c12

Procedure:
A solution of 1-[3-(1,3-dioxolan-2-yl)benzyl]-7-cyanomethoxyindole (50 mg., 0.15 mmol) in tetrahydrofuran (1 ml) and 2M hydrochloric acid (0.5 ml) was stirred at room temperature for 1 hour, diluted with water and extracted with ethyl acetate. The extract was dried and evaporated to a dark oil.