Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2[CH:19]=[CH:18][C:11]3[C:12](O)=[N:13][S:14](=[O:16])(=[O:15])[C:10]=3[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1.C(C1C=CC(N)=CC=1)(C)(C)C>>[F:28][C:27]([F:30])([F:29])[C:2]1[C:3]([C:8]2[CH:19]=[CH:18][C:11]3[C:12]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][N:22]=4)=[N:13][S:14](=[O:16])(=[O:15])[C:10]=3[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S1(=O)N=C(O)c2ccc(-c3ncccc3Cl)cc21
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: CC(C)(C)c1ccc(N)cc1
Product: O=S1(=O)N=C(Nc2ccc(C(F)(F)F)cn2)c2ccc(-c3ncccc3C(F)(F)F)cc21

Procedure:
The title compound was prepared using the procedure as described in Example 1C, substituting the product of Example 7B for the product of Example 1B, and substituting 2-amino-5-trifluoromethylpyridine for 4-tert-butylaniline. 1H NMR (300 MHz, CDCl3) δ 8.92 (d, 1H), 8.72 (d, 1H), 8.67 (s, 1H), 8.45 (brs, 1H), 8.15-8.19 (m, 2H), 8.11 (dd, 1H), 7.95 (d, 1H), 7.89 (d, 1H), 7.57 (dd, 1H). MS (m/z) 473.1.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1OS(C)(=O)=O)(=O)[CH3:2].[CH3:16][O:17][CH2:18][CH2:19][CH2:20][NH:21][NH2:22].C([O-])(=O)C.[NH4+].O>CC1C=CC=CC=1C>[Br:10][C:7]1[CH:6]=[C:5]2[C:4]([C:1]([CH3:2])=[N:22][N:21]2[CH2:20][CH2:19][CH2:18][O:17][CH3:16])=[CH:9][CH:8]=1
Reactant: CC(=O)c1ccc(Br)cc1OS(C)(=O)=O
Reactant: COCCCNN
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1C
Product: COCCCn1nc(C)c2ccc(Br)cc21
Temperature: 25 °C

Procedure:
A mixture of 10.90 g methanesulfonic acid 2-acetyl-5-bromo-phenyl ester, 7.75 g of (3-methoxy-propyl)-hydrazine and 7.17 g of ammonium acetate in 100 ml of o-xylene is refluxed for 3 days with continuous separation of the water which is formed during the reaction. The reaction mixture is then cooled to room temperature and concentrated by evaporation. The title compound is obtained as an orange-yellow oil from the residue by means of flash chromatography (SiO2 60 F). Rf=0.38 (1:1 EtOAc-heptane). Rt=4.52 (gradient I).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[C:3]=1[C:4]#[N:5].O=[C:19]([CH3:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[N:1]=[C:19]([CH3:26])[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCCC(CCC)Oc1cccc(N)c1C#N
Reactant: CCOC(=O)CC(C)=O
Product: CCCC(CCC)Oc1cccc2nc(C)c(C(=O)OCC)c(N)c12

Procedure:
Prepared as in Example 2a from 2-amino-6-(heptan-4-yloxy)benzonitrile (Example 23b) and ethyl 3-oxobutanoate as a pale yellow solid (65%). 1H NR (400 MHz, DMSO-d6) δ 0.87 (t, J=7.2 Hz, 6H), 1.31 (t, J=7.2 Hz, 3H), 1.47-1.33 (m, 4H), 1.77-1.59 (m, 4H), 2.54 (s, 3H), 4.30 (q, J=7.2 Hz, 2H), 4.67-4.64 (m, 1H), 6.92 (d, J=7.6 Hz, 1H), 7.19 (dd, J=0.8, 8.4 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 8.13 (brs, 2H). MS 345 (MH+).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(CN)OCC
Product: CCOC(CNCc1ccccc1)OCC
Yield: 42.5 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-2, 2,2-diethoxyethanamine (72.7 ml, 500 mmol) was reacted with benzaldehyde (50.7 ml, 500 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=50:50 and 0:100) to obtain the title compound (47.5 g, 42%).
Reaction SMILES: FC(F)(F)C([NH:5][C@H:6]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:7]([OH:10])([CH3:9])[CH3:8])=O.[OH-].[K+].O>CO>[NH2:5][C@H:6]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[C:7]([CH3:9])([OH:10])[CH3:8]
Reactant: CC(C)(O)[C@H](NC(=O)C(F)(F)F)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(O)[C@H](N)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 87.1 %

Procedure:
5.6 g of 2,2,2-trifluoro-N—[(R)-1-(4-fluorophenyl)-2-hydroxy-2-methylpropyl]-acetamide and 2.27 g KOH are suspended in 60 ml of methanol. The reaction mixture is stirred for 20 hours at 60° C., then mixed with water and the product is extracted with dichloromethane. 3.2 g product are obtained in the form of an oil. Analytical HPLC-MS (method A): RT=0.79 min.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.CN(C)C=O.F[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27]>O>[N+:26]([C:17]1[CH:18]=[C:19]([C:22]([F:23])([F:24])[F:25])[CH:20]=[CH:21][C:16]=1[N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: c1ccc2c(c1)CNC2
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isoindoline (679 μl, 5.98 mmol, commercially available product) was added at 0° C. to an N,N-dimethylformamide (DMF; 2 ml) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (508 mg, 2.43 mmol, commercially available product). The resulting mixture was warmed to room temperature and stirred for two hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 g, hexane/ethyl acetate=15/1). Thus, 2-[2-nitro-4-(trifluoromethyl)phenyl]isoindoline (749 mg, quant.) was yielded as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[CH2:25]([C:27]1[N:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:31](=[O:39])[C:30]([C:40](O)=[O:41])=[CH:29][CH:28]=1)[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:40]([C:30]5[C:31](=[O:39])[N:32]([C:33]6[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=6)[C:27]([CH2:25][CH3:26])=[CH:28][CH:29]=5)=[O:41])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: CCc1ccc(C(=O)O)c(=O)n1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 59.2 %

Procedure:
To a solution of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.306 mmol) and 6-ethyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (89 mg, 0.366 mmol) in N,N-dimethylformamide (1.0 mL) were added HATU (151 mg, 0.397 mmol) and N,N-diisopropylethylamine (105 μL, 0.612 mmol), and the mixture was stirred at room temperature for 17 hr. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give a white solid. The obtained white solid was washed with ethyl acetate to give the title compound (100 mg, 59%) as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([N:21]1[CH2:42][CH2:41][C:24]2([C:28](=[O:29])[N:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)[CH:23]([OH:43])[CH2:22]1)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([N:21]1[CH2:42][CH2:41][C:24]2([C:28](=[O:29])[N:27]([C:30]3[CH:31]=[CH:32][C:33]([O:36][C:37]([F:39])([F:40])[F:38])=[CH:34][CH:35]=3)[CH2:26][CH2:25]2)[C:23](=[O:43])[CH2:22]1)(=[O:19])=[O:20]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1CN(S(=O)(=O)c2ccccc2Cl)CCC12CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
In a 10 mL round-bottomed flask, oxalyl chloride (46.1 mg, 31.8 μl, 356 μmol) was combined with DCM (5 mL) to give a colorless solution. DMSO (27.8 mg, 25.3 μl, 356 μmol) was added drop wise at −78° C. The reaction was stirred for 15 min. A solution of 8-(2-chlorophenylsulfonyl)-6-hydroxy-2-(4-(trifluoromethoxy)phenyl)-2,8-diazaspiro[4.5]decan-1-one (124 mg, 246 μmol) in DCM (1 mL) was added. The reaction mixture was stirred for 30 min at −40° C. Triethylamine (74.6 mg, 103 μl, 737 μmol) was added drop wise and the reaction mixture was heated to r.t. and stirred for 3 h. The reaction mixture was poured into 15 mL DCM and washed with H2O (2×10 mL).The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by flash chromatography (0 to 100% AcOEt in heptane) to afford the title compound as an off-white solid (73 mg, 59%). MS (ESI): 503.1 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:4]([O:6]C)=[O:5].[OH-].[Li+]>O1CCCC1.CO>[OH:1][CH2:2][CH:3]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C(CO)NC(=O)N1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(CO)NC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
200 mg (0.869 mmol) of methyl 3-hydroxy-2-[(1-piperidinylcarbonyl) amino]propionate was dissolved in 6 ml of a solvent mixture of methanol tetrahydrofuran (1:1). 1.04 ml (1.04 mmol) of 1 N aqueous lithium hydroxide solution was added to the obtained solution, and they were stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the concentrate was acidified with 1 N aqueous hydrochloric acid solution. After extracting with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C@H:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=[C:3]([N:13]([CH2:17][CH2:18][Cl:19])[CH2:14][CH2:15][Cl:16])[CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:26](OC(=O)C)(=[O:28])[CH3:27].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.O1CCOCC1>[CH3:27][C:26]([NH:12][CH:8]([C:9]([OH:11])=[O:10])[CH2:7][C:6]1[CH:5]=[CH:4][C:3]([N:13]([CH2:14][CH2:15][Cl:16])[CH2:17][CH2:18][Cl:19])=[CH:2][CH:1]=1)=[O:28]
Reactant: N[C@@H](Cc1ccc(N(CCCl)CCCl)cc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)NC(Cc1ccc(N(CCCl)CCCl)cc1)C(=O)O

Procedure:
600 mg of melphalan (63) is suspended in 25 ml of water containing 500 mg of sodium carbonate. 10 ml of dioxane is added and 1 ml of acetic anhydride. After stirring at ambient temperature for 1 h citric acid is added and the mixture extracted with ethyl acetate. After washing with water and brine the organic phase is dried (sodium sulfate) and concentrated in vacuum. Removal of all volatiles yields the crude N-acetylmelphalan that is carried on to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:10][CH2:11][C:12](=[O:14])[N:13]=2)[CH:6]=[CH:7][CH:8]=1.N1C(C)=CC=CC=1C.[O:23](S(C(F)(F)F)(=O)=O)[S:24]([C:27]([F:30])([F:29])[F:28])(=O)=[O:25]>C(Cl)Cl>[F:28][C:27]([F:30])([F:29])[S:24]([O:14][C:12]1[N:13]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[O:10][CH:11]=1)(=[O:25])=[O:23]
Reactant: COc1cccc(C2=NC(=O)CO2)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COc1cccc(-c2nc(OS(=O)(=O)C(F)(F)F)co2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
Compound 16 (516 mg, 1 eq) was dissolved in CH2Cl2. To the resulting solution, at 0° C., was added 501 μL (1.6 eq) of 2,6-lutidine, followed by the dropwise addition of Tf2O (681 ml, 1.5 eq). The resulting mixture was stirred for 4 h at RT, then an additional 501 μL (1.6 eq) of 2,6-lutidine and 681 ml (1.5 eq) of Tf2O were added. After 1 h, the mixture was evaporated and the residue purified by flash chromatography (SiO2, CH2Cl2/hexane, 9/1) giving 17 as a red oil in 75% yield.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH2:9])=[O:8])=[C:4]([NH:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[CH:3]=1.[CH3:20][C:21]1(C)C2(CS(O)(=O)=O)C(C[CH:22]1CC2)=O.COC(OC)(C)C.C([O-])(O)=O.[Na+]>O.CC(N(C)C)=O>[Br:1][C:2]1[S:6][C:5]2[C:7](=[O:8])[NH:9][C:21]([CH3:22])([CH3:20])[N:10]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[O:13])[C:4]=2[CH:3]=1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: NC(=O)c1sc(Br)cc1NCC(=O)N1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: COC(C)(C)OC
Product: CC1(C)NC(=O)c2sc(Br)cc2N1CC(=O)N1CCOCC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 394.9 %

Procedure:
A mixture of 5-bromo-3-[(2-(morpholin-4-yl)-2-oxoethyl)amino]thiophene-2-carboxamide (120 mg, 0.345 mmol), CSA (10 mg), 2,2-dimethoxypropane (1.0 mL) and DMA (1 mL) was stirred at 80° C. for 0.5 h. Then, water and saturated aqueous NaHCO3 were added to quench the reaction. The precipitate was collected by filtration to afford the title compound (66 mg) as a pale brown solid. From the filtrate, the organic layer was collected, washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford the title compound (50 mg) as a pale brown solid. Total yield of the title compound (66+50 mg) was 87%:
Reaction SMILES: [OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.[C:31](OC(=O)C)(=[O:33])[CH3:32].N1C=CC=CC=1>O>[C:31]([O:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3ccccc32)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5-hydroxy-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.58 g) are added acetic anhydride (8.0 ml) and pyridine (2.0 ml). The mixture is stirred at room temperature for 1 hour. Water is added to the reaction mixture and the precipitated crystal is collected by filtration, and recrystallized from ethyl acetate/n-hexane to give 5-acetyloxy-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.56 g) as white powder, m.p. 193-194° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([C:10]2[S:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[C:14]([C:19]2([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:21][CH2:20]2)[N:13]=3)[CH:7]=[C:6]([CH3:28])[C:3]=1[CH:4]=O.[NH:29]1[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(Cl)Cl.CO>[CH3:1][C:2]1[CH:9]=[C:8]([C:10]2[S:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[C:14]([C:19]2([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][CH2:21]2)[N:13]=3)[CH:7]=[C:6]([CH3:28])[C:3]=1[CH2:4][N:29]1[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]1
Reactant: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc(C)c1C=O
Reactant: O=C(O)C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc(C)c1CN1CC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2,6-dimethyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzaldehyde (22.4 mg, 0.058 mmol), azetidine-3-carboxylic acid (29.5 mg, 0.29 mmol), and acetic acid (26.9 μl, 0.466 mmol) in 1:1 CH2Cl2/MeOH (2.0 mL) was stirred at 25° C. for 1 h. Sodium cyanoborohydride (6.59 mg, 0.105 mmol) was then added, and the resulting mixture was stirred at 25° C. for 15 h. The reaction mixture was then concentrated in vacuo, dissolved in DMSO (2 mL)+trifluoroacetic acid (20 μL), filtered, and purified by rpHPLC (10-100% acetonitrile/water+0.1% TFA) to provide 1-((2,6-dimethyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylic acid as a light yellow solid. MS (ESI) m/z: Calculated: 469.2; Observed: 470.1 (M++1). (2,6-
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][CH:19]([CH2:21][C:22]([OH:24])=O)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[NH:26][C:27]([CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[NH:28].O>CN(C)C=O>[CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]4[O:24][N:28]=[C:27]([CH:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[N:26]=4)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N=C(NO)C1CCCC1
Reactant: O=C(O)CC1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Solvent: CN(C)C=O
Solvent: O
Product: c1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](Cc4nc(C5CCCC5)no4)CS3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
[(7-Cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]acetic acid (140 mg, 0.41 mmol) prepared in Example 75 was dissolved in N,N-dimethylformamide (5 mL). 1,1′-Dicarbonyldiimidazole (73 mg, 0.45 mmol) was added thereto, and the mixture was stirred for 30 min at room temperature. N-hydroxy-cyclopentanecarboxamidine (260 mg, 2.03 mmol) was added thereto, and the mixture was stirred for 5 h at 80° C. After completion of the reaction, water was added. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and the residue was purified by column chromatography to give the title compound (100 mg, Yield 56%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:6]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14][C:13]=2[CH:20]=1)([O-:8])=[O:7].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[N+:6]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][CH:16]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:15][CH2:14][C:13]=2[CH:20]=1)([O-:8])=[O:7]
Reactant: C1CCNC1
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc2c(c1)CCC(N1CCCC1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyrrolidine (0.85 g, 12 mmol) and 2-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one (2.05 g, 10 mmol) were mixed in 1,2-dichloroethane (35 mL) and then treated with NaBH(OAc)3 (3.18 g, 15 mmol) and AcOH (0.60 g, 10 mmol). The mixture was stirred at ambient temperature under a N2 atmosphere overnight. The reaction mixture was quenched with saturated NaHCO3, and the product was extracted with EtOAc (3×30 mL). The organic layers were combined and dried over NaSO4. The solvent was evaporated and the residue was purified by flash column chromatography eluting with CH2Cl2/DMA=1/1 (DMA=CH2Cl2/MeOH/30% NH3=80/19/1) to afford 1-(2-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)pyrrolidine, a yellow oil (2.2 g, 85%); MS (m/e): 261 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](O)([C:15]3[C:23]([OH:24])=[CH:22][C:18]4[O:19][CH2:20][O:21][C:17]=4[CH:16]=3)[C:7]2=[O:26])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH:1]1([CH2:4][CH2:5][N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]([C:15]3[C:23]([OH:24])=[CH:22][C:18]4[O:19][CH2:20][O:21][C:17]=4[CH:16]=3)[C:7]2=[O:26])[CH2:3][CH2:2]1
Reactant: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C(c2cc3c(cc2O)OCO3)c2ccccc2N1CCC1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
To a solution of 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (2.22 g, 6.27 mmol) in dichloromethane (30.0 mL) was added trifluoroacetic acid (2.12 g, 18.8 mmol) and triethylsilane (2.14 g, 18.8 mmol). The brown solution was stirred at ambient temperature for 0.5 h and concentrated in vacuo to dryness. The residue was diluted with dichloromethane (100 mL), washed with water (3×50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with ethyl acetate/hexane (20/80) to give the title compound (1.69 g, 80%) as a brown solid: 1H NMR (300 MHz, CDCl3) δ 9.21-9.10 (br, 1H), 7.38-7.30 (m, 2H), 7.16 (t, 1H), 6.96 (d, 1H), 6.63 (s, 1H), 6.33 (s, 1H), 5.84 (dd, 2H), 5.01 (s, 1H), 3.87-3.72 (m, 2H), 1.66-1.46 (m, 2H), 0.69-0.59 (m, 1H), 0.43-0.30 (m, 2H), 0.09-0.06 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 178.8, 151.3, 147.6, 144.1, 141.5, 128.7, 126.2, 123.1, 115.2, 109.5, 109.4, 106.5, 101.5, 101.2, 47.4, 40.5, 32.2, 8.6, 4.3, 4.2; MS (ES+) m/z 338.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4](F)[N:3]=1.[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CN1C(=O)CCC1.CCN(C(C)C)C(C)C>CCOC(C)=O>[Br:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(F)nc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1Br
Temperature: 120 °C

Procedure:
To microwave vial was added 2-bromo-6-fluoro-3-methylpyridine (1355 mg, 7.13 mmol), tert-butyl piperazine-1-carboxylate (1338 mg, 7.18 mmol), anhydrous NMP (3.5 mL), and DIPEA (1.65 ml, 9.45 mmol). The resulting mixture was heated at 120° C. for 16 hours. The reaction mixture was allowed to cool to room temperature. The mixture was then diluted with EtOAc (100 mL), washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered and concentrated. The crude residue was purified by flash chromatography (80 g SiO2, 0-25% EtOAc in hexanes) to afford tert-butyl 4-(6-bromo-5-methylpyridin-2-yl)piperazine-1-carboxylate (46-1) as a waxy tan solid. HRMS m/z (M+H) 356.0971 measured, 356.0968 calculated.