Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[N:9]=[C:8]([C:10]3[C:11]([O:17]C)=[N:12][CH:13]=[CH:14][C:15]=3I)[NH:7][C:6]=2[CH:19]=1.[ClH:21]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[N:9]=[C:8]([C:10]3[C:11](=[O:17])[NH:12][CH:13]=[CH:14][C:15]=3[Cl:21])[NH:7][C:6]=2[CH:19]=1
Reactant: COc1nccc(I)c1-c1nc2c(C)cc(Br)cc2[nH]1
Reactant: Cl
Solvent: C1COCCO1
Product: Cc1cc(Br)cc2[nH]c(-c3c(Cl)cc[nH]c3=O)nc12
Temperature: 80 °C
Yield: 100 %

Procedure:
The suspension of 6-bromo-2-(4-iodo-2-methoxy-pyridin-3-yl)-4-methyl-1H-benzimidazole (4 g, 9.03 mmol) and 60 mL of 4 M HCl in dioxane was heated to 80° C. for 6 h and cooled to room temperature. The precipitate was filtered and dried to yield the title compound (3.0 g, 100%) as a brown powder. The crude product was used for the next step without purification. 1H NMR (300 MHz, CD3OD) δ 7.55 (1H, s), 7.42 (1H, d, J=6.0 Hz), 7.17 (1H, s), 6.91 (1H, d, J=6.0 Hz), 2.55 (3H, s). LC MS (M+H)+ m/z 338 (t=1.33 min.).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=2)[C:3]1=[O:24].[C:25]([O:28][CH2:29][C:30]1[C:35]([N:36]2[CH2:48][CH2:47][N:39]3[C:40]4[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=4[CH:46]=[C:38]3[C:37]2=[O:49])=[CH:34][C:33]([F:50])=[CH:32][C:31]=1Br)(=[O:27])[CH3:26].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:25]([O:28][CH2:29][C:30]1[C:35]([N:36]2[CH2:48][CH2:47][N:39]3[C:40]4[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=4[CH:46]=[C:38]3[C:37]2=[O:49])=[CH:34][C:33]([F:50])=[CH:32][C:31]=1[C:6]1[CH:5]=[C:4]([NH:17][C:18]2[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=2)[C:3](=[O:24])[N:2]([CH3:1])[CH:7]=1)(=[O:27])[CH3:26]
Reactant: Cc1cc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)n[nH]1
Reactant: CC(=O)OCc1c(Br)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cc(Nc3cc(C)[nH]n3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 120 °C
Yield: 28.6 %

Procedure:
A mixture of 124a (330 mg, 1 mmol), 2-bromo-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzyl acetate 197d (434 mg, 1 mmol), PdCl2(dppf) (82 mg, 0.1 mmol), 2.0M Na2CO3 (2.0 equiv) in DME (10 mL) was heated at 120° C. under microwave irradiation for 0.5 h. The solvent was evaporated in vacuo. The residue was purified on reverse phase Combi-flash to give the title compound (160 mg, 29%). LCMS: [M+H]+ 559
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]([O:15]C)=[O:14])[CH:9]=1.[Li+].[OH-]>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]([OH:15])=[O:14])[CH:9]=1
Reactant: COC(=O)c1cc(-c2ccccc2O)on1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1cc(-c2ccccc2O)on1
Reaction time: 3 h
Yield: 65 %

Procedure:
To a stirred solution of methyl ester 4 (32 mg, 0.15 mmol) in THE (2 mL) was added a solution of 1.0 M LiOH (2 mL) in one portion. The corresponding reaction was monitored by HPLC for consumption of the starting material. After 3 hours at room temperature, the reaction was complete. To the reaction was added EtOAc (2 mL) and water (2 mL) and the layers were allowed to separate. The aqueous layer was transferred to clean flask and then acidified to pH=1 using 2.0 N HCl. This was then extracted with EtOAc (5 mL) and the aqueous layer was discarded. The organic layer was washed with water (2 mL) and brine (2 mL) followed by drying over Na2SO4. Concentration gave 20 mg (65% yield) of the desired product 5 that was used “as is” in the next step.
Reaction SMILES: [C:1]([CH2:4][N:5]([CH2:17][C:18]([OH:20])=[O:19])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7])([OH:3])=O.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(OC(=O)C)(=O)C>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([S:6]([N:5]([CH2:17][C:18]([OH:20])=[O:19])[CH2:4][C:1]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:3])(=[O:8])=[O:7])=[CH:10][CH:11]=1
Reactant: COc1ccc(S(=O)(=O)N(CC(=O)O)CC(=O)O)cc1
Reactant: C1COCCN1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(S(=O)(=O)N(CC(=O)O)CC(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[Carboxymethyl(4-methoxybenzenesulfonyl)amino]acetic acid (0.5 grams, 1.65 mmol) in acetic anhydride (15 mL) was dissolved in acetic anhydride by gentle warming. The resulting solution was stirred at room temperature overnight. The acetic anhydride was removed by evaporation under vacuum; the residue was dissolved in methylene chloride and morpholine (0.16 mL, 1.82 mmol) was added. The mixture was stirred overnight at room temperature and then concentrated under vacuum. The residue was dissolved in ethyl acetate, washed with 1N hydrochloric acid solution, water and brine, dried over magnesium sulfate and concentrated to afford [(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino]acetic acid as an oil, 0.33 grams (54%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)CCl
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2ccccc2C(F)(F)F)CC1
Product: CN(C)C(=O)Cn1cc(C(=O)N2CCC(c3ccccc3C(F)(F)F)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure I, the coupling of (6-chloro-1H-indol-3-yl)-[4-(2-trifluoromethyl-phenyl)-piperidin-1-yl]-methanone (prepared herein) with (commercially available) 2-chloro-N,N-dimethyl-acetamide gave the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:10][C:11]1[CH:16]=[C:15]([CH2:17]Cl)[CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:10][C:11]1[CH:16]=[C:15]([CH2:17][N:7]2[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]2)[CH:14]=[CH:13][N:12]=1
Reactant: ClCc1ccnc(Cl)c1
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(Cc2ccnc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Acetylpiperazine (1.0 equiv) was mixed with compound 2-chloro-4-(chloro-methyl)pyridine (1.0 equiv) and K2CO3 (4 equiv) in DMF. The mixture was stirred for 1 h at rt. After removing most of the solvent, the residue was partitioned in water and EtOAc. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography to give the title compound as a solid.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:8])[CH2:4][C:5](O)=[O:6].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.Cl.Cl.[NH2:35][CH2:36][C:37]1[N:42]=[C:41]([C:43]2[N:44]=[C:45]([N:48]=[C:49]([NH2:51])[NH2:50])[S:46][CH:47]=2)[CH:40]=[CH:39][CH:38]=1>CN(C)C=O.C(N(CC)CC)C>[NH2:50][C:49](=[N:48][C:45]1[S:46][CH:47]=[C:43]([C:41]2[CH:40]=[CH:39][CH:38]=[C:37]([CH2:36][NH:35][C:5](=[O:6])[CH2:4][N:3]([CH3:8])[CH3:2])[N:42]=2)[N:44]=1)[NH2:51]
Reactant: NCc1cccc(-c2csc(N=C(N)N)n2)n1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)NCc1cccc(-c2csc(N=C(N)N)n2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
A mixture of N,N-dimethylglycine hydrochloride (1.5 g), 1-hydroxybenzotriazole hydrate (1.5 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.1 g) in N,N-dimethylformamide (15 ml) was stirred for 1 hour at ambient temperature. The above mixture was added to a mixture of 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole trihydrochloride (3.0 g) and triethylamine (3.5 ml) in N,N-dimethylformamide (45 ml) and the mixture was stirred for 2 hours at ambient temperature. The solvent was removed by concentration and the residue was dissolved in a mixture of tetrahydrofuran, ethyl acetate and water. The mixture was adjusted to pH 13.5 With 5N-sodium hydroxide. The separated organic layer was washed with brine and evaporated in vacuo. The residue was triturated with ethyl acetate to give 2-(diaminomethyleneamino)-4-(6-dimethylaminoacetylaminomethylpyridin-2-yl)thiazole (1.96 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][OH:13])[CH:7]=1)[CH2:2][CH2:3][CH3:4]>[O-2].[O-2].[Mn+4]>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH:12]=[O:13])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccnc(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Product: CCCCOc1ccnc(C=O)c1
Yield: 83.1 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 17(d) using (4-butoxypyridin-2-yl)methanol (0.82 g, 4.50 mmol, obtained from Example 18(c)) and activated manganese dioxide (3.50 g, 40.5 mmol). 0.67 g of title compound (82% yield) was obtained as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[S:18](Cl)(=[O:20])=[O:19].[OH:22][CH2:23][CH2:24][CH2:25][CH:26]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:27][C@@H:28]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[NH:29][C:30]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[S:18]([O:22][CH2:23][CH2:24][CH2:25][CH:26]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:27][C@@H:28]([C:49]([O:51][C:52]([CH3:54])([CH3:55])[CH3:53])=[O:50])[NH:29][C:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)(=[O:19])=[O:20]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)C(CCCO)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(CCCOS(=O)(=O)c1ccc2ccccc2c1)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
At 0° C. triethylamine (0.68 mL, 4.90 mmol) and naphthalene-2-sulfonyl chloride (0.370 g, 1.63 mmol) were added to a solution of di-tert-butyl 4-(3-hydroxypropyl)-N-trityl-L-glutamate (0.457 g, 0.816 mmol) in dichloromethane (10 mL). The resulting mixture was stirred at 0° C. for 2 h and for 16 h at room temperature. The solution was concentrated and the crude product was purified by flash chromatography (silica, ethyl acetate/hexane) to afford di-tert-butyl 4-{3-[(2-naphthylsulfonyl)oxy]propyl}-N-trityl-L-glutamate (0.479 mg, 78%) as a mixture of (4S,4S)/(2S,4R) diastereoisomers. The isomers were separated by chiral HPLC (Chiralpak IC 5 μm 250×30 mm, ethanol/methanol 1:1, 30 mL/min):
Reaction SMILES: O[Li].O.C([O:7][CH:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:11]=2[C@H:10]([CH3:30])[CH2:9]1)(=O)C.C1COCC1.[NH4+].[Cl-]>O>[OH:7][CH:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:11]=2[C@H:10]([CH3:30])[CH2:9]1
Reactant: CC(=O)OC1C[C@@H](C)c2c1ncnc2N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [Li]O
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CC(O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.4 %

Procedure:
LiOH—H2O (6.577 g, 156.7 mmol) was added to a 0° C. solution of (5R)-tert-butyl 4-(7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (23.6 g, 62.69 mmol) in 2:1 THF:H2O (320 mL). The reaction mixture was stirred for 10 minutes, and then warmed to room temperature. LC/MS looked the same at 3 hours and 4.5 hours. The reaction mixture was cooled to 0° C., and then saturated NH4Cl was added to the mixture. The mixture was stirred for 5 minutes, and most of the THF was removed by rotary evaporation. The mixture was extracted with EtOAc (3×250 mL), and the combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was flashed on Biotage 65M: 4:1 DCM:ethyl acetate, then gradient to 1:1 to 1:4 DCM:ethyl acetate. Once the product was eluting, then ethyl acetate was flushed through the column. Then 30:1 DCM:MeOH eluted the rest of the product (8.83 g). The mixed fractions were re-flashed with Biotage 40M using the same conditions to give another 2.99 g which gave a combined yield of (5R)-tert-butyl 4-(7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (11.82 g, 56.38% yield) as a brown foam. LC/MS (APCI+) m/z 335.1 [M+1-1]+.
Reaction SMILES: [OH:1][C:2]1[C:7]([I:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:14])[CH:11]([CH3:13])[CH3:12].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:15]([O:1][C:2]1[C:7]([I:8])=[C:6]([O:9][CH2:10][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[CH:5]=[CH:4][C:3]=1[C:10](=[O:14])[CH:11]([CH3:12])[CH3:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)C(=O)c1ccc(O)c(I)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)c1ccc(OCc2ccccc2)c(I)c1OCc1ccccc1
Reaction time: 1 h
Yield: 158.7 %

Procedure:
Combine 1-(2,4-dihydroxy-3-iodo-phenyl)-2-methyl-propan-1-one (1357 g, 4.43 mol), benzyl bromide (1345 mL, 11.28 mol), and cesium carbonate (2460 g, 7.55 mol) in dimethylformamide (12 L) in a 22-L Morton flask and stir at room temperature overnight. Filter the salts and concentrate the filtrate (8 L of dimethylformamide is evaporated off). Combine residue with the salts, dilute with water (10 L) and extract with 2:1 ethyl acetate/toluene (2×6 L). Wash extracts with water (3×4 L), brine, dry with magnesium sulfate, filter, and evaporate. Stir the resulting solid in 9 L of 10% ethyl acetate in hexane for 1 hr, filter, wash solid with hexanes and air dry to provide the title compound (1710 g, 79% yield) as an off-white solid. HPLC Rt=6.60 min; 1H NMR (DMSO-d6) δ 7.61 (d, J=8.0 Hz, 1H), 7.4 (m, 10H), 6.99 (d, J=8.0 Hz, 1H), 5.27 (s, 2H), 4.84 (s, 2H), 3.43 (hept, J=8.0 Hz, 1H), 0.99 (d, J=8.0 Hz, 6H).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH3:4][C:5]([O:8][C:9]([O:11]C(OC(C)(C)C)=O)=O)([CH3:7])[CH3:6].[OH-].[Na+]>O1CCCC1.O>[CH3:4][C:5]([CH3:7])([O:8][C:9]([N:2]([CH3:1])[NH2:3])=[O:11])[CH3:6]
Reactant: CNN
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(N)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
A solution of methylhydrazine (2.3 g, 50 mmole) in 100 ml of tetrahydrofuran and 100 ml of water was treated with BOC anhydride (10.91 g, 50 mmole) at 20° C. and the pH was maintained at 8-9 with the dropwise addition of 2N sodium hydroxide. After the pH stabilized, the solution was stirred overnight at 20° C. and pH 8-9. The organic solvent was evaporated in vacuo and the residue was extracted with ethyl acetate. The organic solution was washed with water, dried over sodium sulfate and evaporated. The residual oil was flash-distilled in vacuo to give 3.68 g of the title compound as a colorless oil.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:10]=2[C:22](OCC)=[O:23])=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:23][CH2:22][C:10]1[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:14][C:9]=1[C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=C(c2ccnn2C(C)C)CN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)n1nccc1C1=C(CO)CCN(C(=O)OC(C)(C)C)C1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
To a solution of 1-(tert-butyl) 4-ethyl 5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydropyridine-1,4(2H)-dicarboxylate (450 mg, 1.24 mmol) in THF (6 mL) was added LiAlH4 (1M in THF, 1.49 mL, 1.49 mmol) at −20° C., the reaction was stirred at −20° C. for 30 min, and was quenched with Sat. NH4Cl, the aqueous layer was extracted with EtOAc, the combined organics were washed with brine, dried and concentrated to give crude oil, which was purified by column (Hexanes/EtOAc=100:0 to 40:60) to give tert-butyl 4-(hydroxymethyl)-5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (370 mg, 91%).
Reaction SMILES: [C@H:1]1([CH2:11][OH:12])[C@@H:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.O>CN(C=O)C>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:12][CH2:11][C@H:1]2[C@@H:10]3[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]3)[CH2:4][CH2:3][CH2:2]2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OC[C@@H]1CCCN2CCCC[C@H]12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC[C@@H]2CCCN3CCCC[C@H]23)cc1
Reaction time: 2 h

Procedure:
(1R,9aR)-1-(Octahydroquinolizin-1-yl)methanol (2.5 g) was added to a suspension of sodium hydride (60% in oil, 710 mg) in DMF (20 ml) and, after gas evolution ceased, 4-fluoronitrobenzene (2.51 g) was added. After 2 hours, the reaction mixture was hydrolyzed with water and then partitioned between ethyl acetate and dilute hydrochloric acid. The aqueous phase was made alkaline with sodium hydroxide solution and extracted twice with ethyl acetate. The two ethyl acetate phases were combined, dried over magnesium sulfate and concentrated. The product with the molecular weight of 290.37 (C16H22N2O3); MS (ESI): 291 (M+H+) was obtained in this way.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[NH2:29][CH:30]1[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(O[Na])(C)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[C:37]([O:36][C:34]([N:32]1[CH2:33][CH:30]([NH:29][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][C:11]4[CH:10]=[C:9]([C:15]5[N:16]([C:20]6[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=6[F:27])[N:17]=[CH:18][N:19]=5)[S:8][C:7]=4[C:6]=3[N:28]=2)[CH2:31]1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(Nc2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C1
Temperature: 112 °C
Yield: 63.6 %

Procedure:
9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (812 mg, 2.0 mmol), tert-butyl 3-aminoazetidine-1-carboxylate (412 mg, 2.4 mmol), Pd(OAc)2 (45 mg, 0.20 mmol), Xphos (95 mg, 2.0 mmol), t-BuONa (460 mg, 4.0 mmol) and dioxane (4.0 mL) were added into a 10 mL of sealed tube, and the mixture was heated by microwave at 112° C. for 7 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by column (DCM/EtOAc=10:1) to give 3-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}-azetidine-1-carboxylic acid tert-butyl ester (703 mg, yield: 64%). 1HNMR (Acetone-d6, 400 MHz): δ7.99 (s, 1H), 7.76-7.73 (m, 1H), 7.38-7.27 (m, 2H), 7.14 (s, 1H), 7.00 (d, J=8.8 Hz, 1H), 6.37 (d, J=8.8 Hz, 1H), 6.27 (d, J=5.2 Hz, 1H), 4.29-4.09 (m, 6H), 3.57 (s, 1H), 3.02 (t, J=4.8 Hz, 2H), 1.34 (s, 9H). ESI-MS: m/z=553 [M+H+]
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[S:17])[NH2:16])=[CH:11][C:10]=1[C:18]#[N:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:21]([CH:26]=O)[C:22]([O:24][CH3:25])=[O:23]>C(O)CCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:17][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][N:16]=2)=[CH:11][C:10]=1[C:18]#[N:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cc(C(N)=S)ccc1OCc1ccccc1
Reactant: COC(=O)C(Cl)C=O
Solvent: CCCCO
Product: COC(=O)c1cnc(-c2ccc(OCc3ccccc3)c(C#N)c2)s1

Procedure:
4-(Benzyloxy)-3-cyanobenzenecarbothioamide and methyl 2-chloro-3-oxopropionate were heated under reflux in 1-butanol in the presence of Molecular Sieves 4A to obtain methyl 2-[4-(benzyloxy)-3-cyanophenyl]-1,3-thiazole-5-carboxylate. AP: 373(Na).
Reaction SMILES: [CH2:1]([C:8]1[O:12][N:11]=[C:10]([CH2:13][S:14]([C:16]2[CH:24]=[CH:23][C:19]([CH2:20][CH2:21][NH2:22])=[CH:18][CH:17]=2)=[O:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([Si:29]([O:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH2:50][C@@H:51]2[CH2:53][O:52]2)=[CH:45][CH:44]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:28])([CH3:27])[CH3:26].ClCCl.C(Cl)(Cl)Cl.CO>CO.C1COCC1>[CH2:1]([C:8]1[O:12][N:11]=[C:10]([CH2:13][S:14]([C:16]2[CH:17]=[CH:18][C:19]([CH2:20][CH2:21][NH:22][CH2:53][C@H:51]([OH:52])[CH2:50][O:49][C:46]3[CH:45]=[CH:44][C:43]([O:42][Si:29]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:48][CH:47]=3)=[CH:23][CH:24]=2)=[O:15])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1ccc(S(=O)Cc2noc(Cc3ccccc3)n2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H]2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(S(=O)Cc3noc(Cc4ccccc4)n3)cc2)cc1)(c1ccccc1)c1ccccc1
Temperature: 45 °C
Yield: 41.2 %

Procedure:
A solution of the amine of Example 22 (0.705 g, 2.00 mmol) and the epoxide of Example 9 (0.640 g, 1.594 mmol) in a mixture of methanol (25 mL) and THF (5 mL) was heated to 45° C. for 23 h. TLC shows characteristic product spot at Rf=0.2 5(silica gel plate; dichloromethane/chloroform/methanol: 20/5/2). The reaction mixture was cooled, silica gel (5 g) was added and the methanol was remove in vacuo. The reaction mixture, preabsorbed onto silica gel was applied to the top of a flash chromatography column(silica gel; dichloromethane/chloroform/methanol: 12/3/1) and purified in the standard manner. This procedure afforded 0.490 g of the title compound as a white foam.