Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1([C:11]([NH:13][C@H:14]([C:33]([OH:35])=[O:34])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:32])=[O:24])=[CH:18][CH:17]=2)=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[N+]=[N-].CP(C)C>C1COCC1>[NH2:1][CH2:4][CH2:5][C:6]1([C:11]([NH:13][C@H:14]([C:33]([OH:35])=[O:34])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:32])=[O:24])=[CH:18][CH:17]=2)=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: [N-]=[N+]=NCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)CCCC1
Agent: CP(C)C
Solvent: C1CCOC1
Product: NCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of N-[[1-(2-azidoethyl)cyclopentyl]carbonyl]-4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine on Wang resin (9.33 mmol, 13.43 g, 0.695 mmol per g) in THF (60 mL) was added a solution of 1.0 M trimethylphosphine in THF (37.3 mmol, 37.3 mL) at 0° C. The mixture was allowed to warm to room temperature and stir for 4 h at which time a Kaiser test was possible for amine. The resin was filtered and was washed with DMF (4×20 mL), dichloromethane (4×10 mL), isopropanol (4×10 mL), DMF (2×20 mL) and dichloromethane (2×20 mL), respectively. After drying under high vacuum, 13.43 g of N-[[1-(2-aminoethyl)cyclopentyl]carbonyl]-4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine on Wang resin was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11](O)=[O:12])=[CH:5][CH:4]=1)#[N:2].[CH2:28]([O:30][C:31]([CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([CH:33]1[CH2:38][CH2:37][N:36]([C:11](=[O:12])[C:10]2[CH:9]=[C:8]([O:7][C:6]3[CH:26]=[CH:27][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:14]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]
Reactant: CCOC(=O)C1CCNCC1
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Product: CCOC(=O)C1CCN(C(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 64.9 %

Procedure:
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.6 g (1.68 mmol) and piperidine-4-carboxylic acid ethyl ester (0.31 g, 2.02 mmol) were used to afford 0.54 g of the required product. 1H NMR (DMSO-d6): δ 1.18 (3H, t), 1.5 (2H, m), 1.82 (2H, m), 2.6 (1H, m), 2.90 (1H, m), 3.12 (1H, m), 3.52 (1H, m), 4.08 (2H, q), 4.25 (1H, m), 6.96 (2H, d), 7.06 (1H, t), 7.26 (4H, d), 7.88 (4H, d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]([CH3:14])[C:11]([CH3:15])=[N+:10]1[O-].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:20]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]([CH2:14][OH:20])[C:11]([CH3:15])=[N:10]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1nn(-c2ccc(F)cc2F)[n+]([O-])c1C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nn(-c2ccc(F)cc2F)nc1CO
Temperature: 110 °C
Reaction time: 1.25 h

Procedure:
To a solution of 2-(2,4-difluorophenyl)-4,5-dimethyl-2H-1,2,3-triazole 1-oxide (i.e. the product of Step A, 1.78 g, 7.0 mmol) in tetrahydrofuran (14 mL) was added trifluoroacetic anhydride (2.5 mL, 17.5 mmol). The reaction mixture was stirred at 110° C. in the microwave for 75 min. The mixture was diluted with ethyl acetate, washed successively with 1.0 M aqueous sodium hydroxide and 50% aqueous sodium hydroxide, dried (MgSO4) and concentrated under reduced pressure to afford the crude product. The crude material was purified by chromatography on silica gel eluting with 0 to 100% ethyl acetate in hexanes to obtain the title compound (0.59 g) as a colorless solid.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)C.C(O)C.O.[NH2:17][NH2:18]>O>[Br:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([NH:17][NH2:18])=[O:3]
Reactant: NN
Reactant: CCOC(=O)c1cccc(Br)c1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cccc(Br)c1
Yield: 86 %

Procedure:
First, 10 g (44 mmol) of ethyl-3-bromobenzoate was put in a 200-mL three-neck flask, 50 mL of ethanol was added therein, and the mixture was stirred. Thereafter, 12 mL of hydrazine monohydrate was added therein, and the mixture was stirred at 78° C. for 5 hours so as to be reacted. After the reaction, water was added to the reaction solution, and a solid was precipitated. The precipitated solid was collected by suction filtration. The obtained solid was put in approximately 500 mL of water, washed, and again collected by suction filtration; thus, 8.1 g of a white solid that was an object was obtained (yield: 86%).
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([C:7]2[S:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH2:4][CH2:3]1.[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[N+:16]([C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([CH:5]3[CH2:4][CH2:3][C:2](=[O:1])[O:6]3)[S:8][C:9]=2[CH:15]=1)([O-:18])=[O:17]
Reactant: O=C1CCC(c2nc3ccccc3s2)O1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1CCC(c2nc3ccc([N+](=O)[O-])cc3s2)O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
504 g of the 2-(5-oxotetrahydrofuran-2-yl)-benzothiazole obtained in the Preparation Example 6 was dissolved in 2,000 ml of concentrated sulfuric acid. 188 ml of concentrated nitric acid was added dropwise to the solution at -5° to 0° C. and the mixture was stirred under the same conditions for 30 min. After stirring at 0° C. for additional 2 h, the reaction mixture was poured into about 30 l of ice/water. The precipitates thus formed were recovered by filtration, washed with water and then with ethanol and dried to give 488 g of the titled compound.
Reaction SMILES: [C:1]1([C:13](=O)[CH2:14][C:15]#[N:16])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[BH4-].[Na+]>CN(C)C=O>[C:1]1(/[CH:13]=[CH:14]/[C:15]#[N:16])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: N#CCC(=O)c1cn2c3c(cccc13)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#C/C=C/c1cn2c3c(cccc13)CCC2

Procedure:
To a room temperature stirred solution of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-oxo-propionitrile (1.0 g, 4.5 mmol) in anhydrous N,N-dimethylformamide (20 ml) was added excess sodium borohydride in small portions over 3 days. After 5 days the mixture was quenched with 1M hydrochloric acid (50 ml) and extracted with ethyl acetate (3×100 ml). The organic layer was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue obtained was purified by flash column chromatography (SiO2, 20% EtOAc in hexanes) to afford (E)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-acrylonitrile as an off white solid (348 mg). 400 MHz 1H NMR (CDCl3) δ: 7.55 (d, J=8.0 Hz, 1H), 7.5 (d, J=16.4 Hz, 1H), 7.3 (s, 1H), 7.18 (t, J=7.6 Hz, 1H), 7.03 (dd, J=0.8 and 6.8 Hz, 1H), 5.7 (d, J=16.4 Hz, 1H), 4.17 (t, J=5.6 Hz, 2H), 3.0 (t, J=6.4 Hz, 2H), 2.28-2.22 (m, 2H); LCMS: 208 [M+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:37][CH2:38][C@@H:39]([OH:41])[CH3:40]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:37][CH2:38][C@@H:39]([OH:41])[CH3:40])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O
Reactant: C[C@H](O)CN
Product: C[C@H](O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxohexahydro-1H-azepin-1-yl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2S)-1-amino-2-propanol using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.08-1.13 (m, 3 H), 1.55 (d, J=2.74 Hz, 4 H), 1.63 (s, 2 H), 1.65-1.78 (m, 2 H), 2.41 (d, J=10.11 Hz, 2 H), 3.19 (s, 1 H), 3.38 (d, J=6.95 Hz, 5 H), 3.81 (s, 1 H), 4.16-4.25 (m, 4 H), 4.96 (d, J=4.63 Hz, 1 H), 7.11-7.17 (m, 2 H), 7.38-7.44 (m, 2 H), 8.00 (s, 1 H), 8.56 (d, J=1.47 Hz, 1 H), 10.44 (t, J=6.21 Hz, 1 H), 17.21 (s, 1 H); ES+ MS: 525 (M+H+).
Reaction SMILES: [CH2:1]([N:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=O)[O:8]C1=O)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:18][N:19]([CH3:21])[NH2:20]>C1(C)C=CC=CC=1>[CH3:18][N:19]([CH3:21])[NH:20][C:9](=[O:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CN(C)N
Reactant: CCCCCn1c(=O)oc(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: CCCCCNc1ccccc1C(=O)NN(C)C
Temperature: 100 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
The obtained 1-pentyl-3,1-benzoxazin-2,4-(1H)-dione (0.301 g, 1.29 mmol) was dissolved in toluene (4 ml), N,N-dimethylhydrazine (0.10 ml, 1.32 mmol) was added, and the mixture was stirred at 100° C. for 2 hr. The reaction mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give N′,N′-dimethyl-2-pentylaminobenzohydrazide (0.218 g, 0.87 mmol, yield 67%). This was dissolved in methanol (3 ml), 36% formalin (0.35 ml, 4.31 mmol), sodium cyanoborohydride (0.174 g, 2.62 mmol) and acetic acid (0.1 ml) were added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added. The mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give an acylhydrazine compound N′,N′-dimethyl-2-(N-methyl-N-pentylamino)benzohydrazide (0.103 g, 0.39 mmol, yield 45%).
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:32])([CH3:31])[CH2:4][C:5]1[N:6]=[C:7]([C:16]([OH:30])([CH3:29])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[N:8](S(N(C)C)(=O)=O)[CH:9]=1>CO>[CH3:2][C:3]([CH3:32])([CH3:31])[CH2:4][C:5]1[N:6]=[C:7]([C:16]([OH:30])([CH3:29])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[NH:8][CH:9]=1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(C)(O)Cc1ccc(-n2cccn2)cc1
Agent: Cl
Solvent: CO
Product: CC(C)(C)Cc1c[nH]c(C(C)(O)Cc2ccc(-n3cccn3)cc2)n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (0.25 mL, 1 mmol) was added to an ambient temperature solution of 4-(2,2-dimethylpropyl)-2-{1-hydroxy-1-methyl-2-[4-(1H-pyrazol-1-yl)phenyl]ethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (25 mg, 0.06 mmol) in methanol (2 mL). After stirring at 80° C. for 2 h, volatiles were removed in vacuo. The residue was partitioned between 1 N hydrochloric acid and diethyl ether. The aqueous phase was basified with 4 N aqueous sodium hydroxide and extracted with ethyl acetate. The combined organic extracts were dried (sodium sulfate) and concentrated in vacuo to afford the title compound. Chiral HPLC eluting with IPA/heptane afforded the two individual enantiomers. 1H NMR (500 MHz, CD3OD) δ 7.84 (s, 1H), 7.7 (s, 1H), 7.5 (d, J=7 Hz, 2H), 7.05 (d, J=7 Hz, 2H), 6.6 (s, 1H), 6.4 (s, 1H), 3.35 (d, J=12 Hz, 1H), 3.05 (d, J=12 Hz, 1H), 2.40 (s, 2H), 1.63 (s, 3H), 0.85 (s, 9H); (M+H) found: 339.
Reaction SMILES: [CH3:1][C:2]([C:6]1[NH:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1)([CH3:5])[CH2:3][NH2:4].[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:32]=2)[C:29](O)=[O:30])[N:20]=1>>[CH3:5][C:2]([C:6]1[NH:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1)([CH3:1])[CH2:3][NH:4][C:29](=[O:30])[C:28]1[CH:32]=[C:24]([C:21]2[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=2)[CH:25]=[N:26][CH:27]=1
Reactant: CC(C)(CN)c1nc(-c2ccccc2)n[nH]1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Product: CC(C)(CNC(=O)c1cncc(-c2noc(C(F)(F)F)n2)c1)c1nc(-c2ccccc2)n[nH]1
Yield: 23 %

Procedure:
This compound was synthesized from 2-methyl-2-(3-phenyl-1H-1,2,4-triazol-5-yl)propan-1-amine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (20 mg, yield 23%). 1H NMR (400 MHz, MeOD) δ 9.37 (m, 1H), 9.16 (m, 1H), 8.84-8.13 (m, 1H), 8.02-7.99 (m, 2H), 7.48-7.42 (m, 3H), 3.77 (s, 2H), 1.54 (m, 6H). MS (ESI) m/z: Calculated for C21H18F3N7O2: 457.15. found: 458.2 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16].[CH2:19]=[C:20]1[O:24][C:22](=[O:23])[CH2:21]1>CO>[C:22]([NH:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])(=[O:23])[CH2:21][C:20]([CH3:19])=[O:24]
Reactant: C=C(C)C(=O)NCCCN
Reactant: C=C1CC(=O)O1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)NCCCNC(=O)CC(C)=O
Temperature: 0 °C
Reaction time: 20 h
Yield: 50 %

Procedure:
Triethylamine (24 g, 0.24 mole) was added dropwise at 0° C. to a solution of N-(3-aminopropyl)methacrylamide hydrochloride (40 g, 0.24 mole) and diketene (20 g, 0.24 mole) in methanol (800 ml). After addition, the temperature was maintained at 0° C. for 2 hours under stirring. Stirring was continued at 20° C. for 20 hours. The solvent was then removed. The residue was dissolved in chloroform (1 liter), washed with 5% hydrochloric acid (200 ml), washed with saturated NaHCO3 (200 ml), dried over anhydrous magnesium sulfate, and filtered. Excess solvent was removed. The residue was recrystallized from benzene (500 ml) and ethyl ether (500 ml) to give N-(3-acetoacetamidopropyl)methacrylamide (m.p.=93°-94° C.) at a yield of 50%.
Reaction SMILES: [O:1]=[S:2]1(=[O:35])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[C:11]([C:31]([F:34])([F:33])[F:32])=[N:12][C:13]([NH:16][C:17]34[CH2:26][CH:21]5[CH2:22][CH:23]([CH2:25][C:19]([C:27]([O:29]C)=[O:28])([CH2:20]5)[CH2:18]3)[CH2:24]4)=[N:14][CH:15]=2)=[O:9])[CH2:4][CH2:3]1.CO.[OH-].[Na+]>O1CCCC1>[O:35]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([C:8]([C:10]2[C:11]([C:31]([F:34])([F:33])[F:32])=[N:12][C:13]([NH:16][C:17]34[CH2:24][CH:23]5[CH2:22][CH:21]([CH2:20][C:19]([C:27]([OH:29])=[O:28])([CH2:25]5)[CH2:18]3)[CH2:26]4)=[N:14][CH:15]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: COC(=O)C12CC3CC(CC(Nc4ncc(C(=O)N5CCS(=O)(=O)CC5)c(C(F)(F)F)n4)(C3)C1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(c1cnc(NC23CC4CC(C2)CC(C(=O)O)(C4)C3)nc1C(F)(F)F)N1CCS(=O)(=O)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
To a mixture of methyl 3-({5-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]-4-(trifluoromethyl)pyrimidin-2-yl}amino)adamantane-1-carboxylate (500 mg) and methanol (2 mL), and tetrahydrofuran (2 mL) was added a 1 M aqueous sodium hydroxide solution (1.9 mL) at room temperature, followed by stirring at 60° C. for 3 hours. The solvent was evaporated under reduced pressure, and to the obtained residue were added water and 1 M hydrochloric acid, followed by stirring at room temperature for 30 minutes. The obtained precipitate was filtered and washed with water to obtain 3-({5-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]-4-(trifluoromethyl)pyrimidin-2-yl}amino)adamantane-1-carboxylic acid (446 mg) as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([Li])CCC.C([O:16][C:17](=O)[C:18]([F:21])([F:20])[F:19])C>O1CCCC1.C1(C)C=CC=CC=1.[Cl-].[NH4+]>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:17](=[O:16])[C:18]([F:21])([F:20])[F:19])=[N:3][CH:4]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: Brc1ccc(Br)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Br)cn1)C(F)(F)F
Reaction time: 0.29 h
Yield: 68.8 %

Procedure:
To a stirred solution of 2, 5-Dibromo-pyridine (4 g, 6.87 mmol) in dry tetrahydrofuran (30 mL) and dry toluene (40 mL) is added drop wise n-Butyl lithium (1.62 g, 25.31 mmol) at −78° C. After stirring for 15-20 minutes, added trifluoro-acetic acid ethyl ester (3.56 g, 25.31 mmol) at −78° C. then stirred at −78° C. for another 30 minutes. The reaction mixture is diluted with saturated ammonium chloride solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by column chromatography eluting in 20% ethyl acetate in hexane to afford the title compound (1.2 g). 1HNMR (400 MHz, DMSO-d6) δ: 7.72 (d, J=8.32 Hz, 1H), 7.85-7.88 (dd, J1=8.32 Hz, J2=2.44 Hz 1H), 8.52 (d, J=2.36 Hz, 1H). LC-MS (m/z): [M+H]=255.8.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C@H:13]([NH:18]C(=O)OC(C)(C)C)[C:14]([CH3:17])([CH3:16])[CH3:15])=[N:11][C:10]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:8]1[C:12]([C@H:13]([NH2:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[N:11][C:10]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](c1nc(-c2cc(F)ccc2F)nn1Cc1ccccc1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@@H](N)c1nc(-c2cc(F)ccc2F)nn1Cc1ccccc1

Procedure:
(R)-tert-Butyl 1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropylcarbamate (3.25 g, 7.13 mmol) was treated with TFA (10 mL) in CH2Cl2 (30 ml). Once the reaction was complete, the reaction was concentrated in vacuo and then partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organics were separated, then washed with H2O, brine, then dried over Na2SO4, filtered, and evaporated under reduced pressure to give (R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropan-1-amine which was directly used for the next step without further purification (2.32 g, 91%). LC/MS (uplc): MH+ 357.1, 0.82 min.
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][CH:5]=1.[CH2:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:11](=[O:13])[C@@H:2]([NH:1][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:3][C:4]2[CH:5]=[CH:6][C:7]([I:10])=[CH:8][CH:9]=2)[CH2:30][CH2:29]1)=[O:27])[CH2:22][CH2:23][CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Reactant: CCCCOC(=O)N1CCNCC1
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](Cc2ccc(I)cc2)NC(=O)OC(C)(C)C)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 8, step 8.5 Boc-Phe(4-I)-OH replacing 2-phenoxyphenylboronic acid and piperazine-1-carboxylic acid butyl ester replacing intermediate 8.4.
Reaction SMILES: O1[C:5]2([CH2:9][CH2:8][CH:7]([CH2:10][CH:11]([C:22]3[NH:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[CH:23]=3)[C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH2:6]2)[O:4]CC1>O1CCCC1.Cl.C(OCC)(=O)C>[CH3:21][S:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:11]([C:22]2[NH:30][C:25]3=[N:26][CH:27]=[CH:28][CH:29]=[C:24]3[CH:23]=2)[CH2:10][CH:7]2[CH2:8][CH2:9][C:5](=[O:4])[CH2:6]2)=[CH:17][CH:16]=1)(=[O:19])=[O:20]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC3(C2)OCCO3)c2cc3cccnc3[nH]2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)c2cc3cccnc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 18.9 %

Procedure:
A mixture of 2-[2-(1,4-dioxa-spiro[4.4]non-7-yl)-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (80 mg, 0.18 mmol) in tetrahydrofuran (12 mL) and aqueous hydrochloric acid solution (2 N, 6 mL) was stirred at 25° C. for 5 h. The mixture was diluted with ethyl acetate (50 mL), washed with a saturated aqueous sodium bicarbonate solution (2×20 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% dichloromethane/ethyl acetate) afforded 3-[2-(4-methanesulfonyl-phenyl)-2-(1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl]-cyclopentanone (diastereomer 2, 13 mg, 18%) as a white solid: LC/MS m/e calcd for C21H22N2O3S [M+H]+ 383.49, observed 383.0; 1H NMR (400 MHz, CD3OD) δ ppm 8.09 (d, J=4.5 Hz, 1H), 7.87-7.94 (m, 3H), 7.60-7.66 (m, 2H), 7.03-7.10 (m, 1H), 6.44 (d, J=3.0 Hz, 1H), 4.35-4.41 (m, 1H), 3.06-3.11 (m, 3H), 2.38-2.49 (m, 1H), 2.07-2.31 (m, 5H), 1.87-1.99 (m, 1H), 1.59-1.71 (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:11])[CH:5]([O:7][CH2:8][CH:9]=[CH2:10])[CH3:6])C.[OH-].[Na+]>O>[CH2:8]([O:7][CH:5]([CH3:6])[C:4]([OH:11])=[O:3])[CH:9]=[CH2:10]
Reactant: C=CCOC(C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCOC(C)C(=O)O
Reaction time: 5.5 h
Yield: 79.1 %

Procedure:
2-Allyloxypropionic acid ethyl ester (147.2 g, 0.93 mol), water (300 ml) and NaOH (44.7 g) were fed into a flask, followed by agitating the mixture for about 5 to 6 hours while the reaction temperature was kept at about 60° C., thereafter dropwise adding conc. hydrochloric acid (90 ml) under ice cooling, extracting the resulting deposited oily substance with isopropyl ether, drying over MgSO4 and carrying out vacuum distillation to obtain 2-allyloxypropionic acid (95.7 g, 108° C./5 mmHg). Yield: 79%.
Reaction SMILES: [N:1]([C:4]1[C:13]2[CH2:12][CH2:11][N:10]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:9][C:8]=2[N:7]=[CH:6][CH:5]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[CH2:14]([N:10]1[CH2:9][C:8]2[N:7]=[CH:6][CH:5]=[C:4]([NH2:1])[C:13]=2[CH2:12][CH2:11]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [N-]=[N+]=Nc1ccnc2c1CCN(Cc1ccccc1)C2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccnc2c1CCN(Cc1ccccc1)C2

Procedure:
4-azido-7-benzyl-5,6,7,8-tetrahydro-1,7-naphthyridine (0.06 g, 0.226 mmol) was treated with 0.5 g of PS-PPh3 resin in a 8 ml mixture THF:H2O (18:1) at 32° C. ON. The reaction was monitored by LCMS and TLC. The reaction mixture was filtered and washed with THF and methanol. The combined filtrate was concentrated and used directly in the next step.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]=[CH:11][C:10]=2[CH:14]=1.C([Li])CCC.C1C(=O)N([Cl:27])C(=O)C1.O>C1COCC1.C(OCC)(=O)C>[Cl:27][C:12]1[O:13][C:9]2[CH:8]=[CH:7][C:6]([CH:2]3[O:3][CH2:4][CH2:5][O:1]3)=[CH:14][C:10]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: c1cc2cc(C3OCCO3)ccc2o1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1cc2cc(C3OCCO3)ccc2o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
5-[1,3]Dioxolan-2-yl-benzofuran (50 mg, 0.26 mmol) was dissolved in TIE (2 mL) and the solution was cooled down to −78° C. Butyl lithium (180 uL, 1.1 eq.) was added dropwise. This mixture was stirred 30 min at 25° C. Then the reaction mixture was cooled down to −78° C. and NCS (39 mg, 1.1 eq.) dissolved in 1 mL THF was added dropwise to the reaction mixture. After 1 h30 at −78° C. only small amount of starting material could be detected. The temperature was increased slowly to room temperature overnight. Water and ethyl acetate were added to the mixture and the aqueous layer was extracted 3 times. Combined organic phases was dried over MgSO4, filtrated and evaporated to give 2-Chloro-5-[1,3]dioxolan-2-yl-benzofuran (48.1 mg, 81%) sufficiently pure to be used in the next step.