Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[C:16]([N+:18]([O-])=O)[CH3:17])=[CH:11][C:10]=1[O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH2:18])[CH3:17])=[CH:11][C:10]=1[O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C=C(C)[N+](=O)[O-])ccc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CC(C)N)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
A tetrahydrofuran solution of 6.78 g of 1-(4-benzyloxy-3-methoxy-phenyl)-2-nitropropene is added dropwise to a suspension of 2.15 g of lithium aluminum hydride in tetrahydrofuran. The mixture is stirred at room temperature and then refluxed. After the reaction, excess lithium aluminum hydride is decomposed with ice water, and inorganic materials are filtered off. The filtrate is washed, dried and then condensed to dryness. 6 g of 1-(4-benzyloxy-3-methoxyphenyl)-2-aminopropane are obtained as pale yellow viscous oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([N:8]=[C:9]=S)=[N:6][CH:7]=1.C(N(CC)CC)C.Cl.Cl.[NH2:21][CH2:22][C@@:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([NH:8][C:9]2[O:31][C@:23]3([CH2:22][N:21]=2)[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]3)=[N:6][CH:7]=1
Reactant: Cc1cc(N=C=S)ncc1Cl
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(NC2=NC[C@@]3(CN4CCC3CC4)O2)ncc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 30.5 %

Procedure:
To 5-chloro-2-isothiocyanato-4-methylpyridine (0.37 g, 2.0 mmol) in N,N-dimethylformamide (20 mL) was added triethylamine (0.7 mL, 5.0 mmol) and (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (from Step B of Example 17) (0.47 g, 2.0 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH). The product was then treated with N,N-dimethylformamide (20 mL) and N,N′-diisopropylcarbodiimide (0.94 mL, 6.0 mmol). The reaction was heated to 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated to yield the crude product. The crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (R)—N-(5-chloro-4-methylpyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.19 g, 0.61 mmol, 30.3% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.79 (s, 1H), 8.08-8.15 (m, 2H), 6.78 (s, 1H), 3.82 (d, J=8.55 Hz, 2H), 3.55 (d, J=10.38 Hz, 2H), 2.93-3.02 (m, 5H), 2.71-2.80 (m, 5H), 2.66 (t, J=7.63 Hz, 4H), 2.23-2.29 (m, 7H), 1.94-2.02 (m, 2H), 1.92 (s, 1H), 1.86 (s, 2H), 1.53-1.62 (m, 5H), 1.41-1.49 (m, J=12.55, 9.88, 7.02, 2.29 Hz, 2H). MS (LC/MS) R.T.=0.72; [M+H]+=307.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9](=[O:31])[NH:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:38][C:39]([F:50])([F:49])I1C2C=CC=CC=2CO1>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([O:31][C:39]([F:50])([F:49])[F:38])=[N:10][N:11]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:4]=2[CH:3]=1
Reactant: Cc1nc(Cl)cc2c1c(=O)[nH]n2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: FC(F)(F)I1OCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(Cl)cc2c1c(OC(F)(F)F)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
A mixture of 6-chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3(2H)-one (Intermediate 4B, 207.1 mg, 0.486 mmol), potassium carbonate (217.6 mg, 1.574 mmol) and 1-trifluoromethyl-1,2-benziodoxol-3-(1H-one (227.3 mg, 0.719 mmol) in DMF (2 ml) was stirred at RT for 16.5 hr, then heated to 60° C. for 5 hr. Added water and filtered to collect precipitate, which was purified via flash chromatography (0-100% EtOAc/Hex) to provide 6-chloro-4-methyl-3-(trifluoromethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine. MS: [M+H]+ m/z 494.
Reaction SMILES: C([O:4][C@@H:5]([CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[C:6]([OH:8])=[O:7])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[OH:4][C@@H:5]([CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[C:6]([OH:8])=[O:7]
Reactant: CC(=O)O[C@@H](CC1CCCC1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H](O)CC1CCCC1
Temperature: 25 °C
Reaction time: 30 h
Yield: 92.1 %

Procedure:
A solution of 395 mg (1.97 mmol) of 2-(S)-acetoxy-3-(cyclopentyl)propanoic acid (from Step E) in 10 mL MeOH and 1 mL of H2O was treated with 1.29 g (9.33 mmol) of K2CO3 and stirred at rt for 30 h. The volatiles were removed under reduced pressure. The crude product was partitioned between 100 mL of ether and 100 mL of H2O and the layers were separated. The aqueous layer was acidified to pH 1-2 using 2.0 N HCl and extracted with 3×150 mL of EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to give 287 mg (92%) of the title compound: 1H NMR (300 MHz) δ 1.11-2.15 (m, 11H), 4.27 (dd, J=8.1, 4.7, 1H), 6.5 (br, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10]Br.[OH-:12].[K+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH:4]([CH3:3])[C:5]([OH:8])=[O:12]
Reactant: [OH-]
Reactant: COc1ccc(Br)c(CBr)c1
Agent: [K+]
Solvent: O
Product: COc1ccc(Br)c(CC(C)C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 168.9 %

Procedure:
To a solution of sodium ethoxide obtained from 15.2 g (0.661 mol) of sodium and 540 ml of dry ethanol 115 g (0.658 mol) of diethyl methylmalonate was added. This mixture was stirred for 15 min; then, 184 g (0.659 mol) of 1-bromo-2-(bromomethyl)-4-methoxybenzene was added with vigorous stirring at such a rate to maintain gentle reflux. This mixture was refluxed for an additional 2 h and then cooled to room temperature. A solution of 130 g of KOH in 400 ml of water was added. The resulting mixture was refluxed for 4 h to saponificate the formed ester. Ethanol and water were distilled off until the vapor temperature reached 95° C. To the residue cooled to room temperature 1500 ml of water and then 12 M HCl (to pH 1) were added. The formed precipitate of (2-bromo-5-methoxybenzyl)(methyl)malonic acid was filtered off, washed with 2×200 ml of cold water, and dried on air. Decarboxylation of the substituted methylmalonic acid at 180° C. gave 152 g (84%) of the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].Cl.N([O-])=O.[Na+].[N-:15]=[N+:16]=[N-].[Na+]>O.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:6]=[N+:15]=[N-:16])[CH:7]=[CH:8][CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cccc(N)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: COc1cccc(N=[N+]=[N-])c1
Reaction time: 2 h

Procedure:
A solution of 9.26g. (0.08 mole) of 3-methoxyaniline in 40 ml. of water and 20 ml. of concentrated HCl was cooled to 0° C. There was then added a solution of 6.07g. (0.088 mole) of NaNO2 in 20 ml. of water, and the reaction mixture was aged for 1/2 hour. There was next added 70 ml. of hexane followed by dropwise addition of a solution of 5.72g. (0.088 mole) of NaN3 in 20 ml. of water. After addition was complete, the reaction mixture was aged for 2 hours at room temperature. The aqueous and organic components were separated and the aqueous component was extracted with 50 ml. of hexane. The hexane component and extract were dried over MgSO4 and concentrated under reduced pressure to 10.77g. (50.5%) of a yellow oil. Structure of the product as 3-methoxyphenylazide was confirmed by IR.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].Cl[CH:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(COC)OC>[CH3:22][C:20]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]2[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: Nc1ccccn1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1c(C)nc2ccccn12
Yield: 61.6 %

Procedure:
To a stirred solution of 2-aminopyridine (15.0 g. 159.00 mmol) in dimethoxyethane (150 mL) was added NaHCO3 (14.72 g, 175 mmol) followed by ethyl 2-chloroacetoacetate (39.34 g, 239 mmol) at room temperature. After refluxing for 16 h the solvent was removed under reduced pressure. The residue was taken up in water (200 mL) and extracted with dichloromethane (2×200 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), and dried over anhydrous Na2SO4. Evaporation of solvents under reduced pressure afforded crude product which was further purified by column chromatography to give 20 g of the product as an off-white solid; 1H NMR (300 MHz, CDCl3) δ 1.44 (t, J=6.9 Hz, 3H), 2.72 (s, 3H), 4.43 (q, J=7.2 Hz, 2H), 6.98 (t, J=6.6 Hz, 1H), 7.38 (t, J=8.7 Hz, 1H), 7.62 (d, J=8.7 Hz, 1H), 9.31 (d, J=6.9 Hz, 1H); ESI-MS (m/z) 205.13 (MH)+.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]([C:28](=[O:39])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=2)[CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21](OCCCC)=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].[NH2:42][C:43]1[NH:47][N:46]=[N:45][N:44]=1>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]([C:28](=[O:39])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=2)[CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([NH:42][C:43]4[NH:47][N:46]=[N:45][N:44]=4)=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCOC(=O)c1ccc2c(c1)CCC2N(C(=O)Cc1ccc(C(C)C)cc1)[C@H]1CC[C@H](C(C)(C)C)CC1
Reactant: Nc1nnn[nH]1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)c1ccc(CC(=O)N(C2CCc3cc(C(=O)Nc4nnn[nH]4)ccc32)[C@H]2CC[C@H](C(C)(C)C)CC2)cc1

Procedure:
Enantiomer A of butyl 1-{(trans-4-tert-butylcyclohexyl)[(4-isopropylphenyl)acetyl]amino}indane-5-carboxylate (36 mg) was saponified with aqueous LiOH and then coupled to 5-amino tetrazole following the procedure described (Step D., Example 1/2) to give 1-{(Trans-4-tert-butylcyclohexyl)[(4-isopropylphenyl)acetyl]amino}-N-1H-tetrazol-5-ylindane-5-carboxamide. HPLC/MS: m/z=543.5 (M+1), Rt=2.67 min. 1H NMR (DMSO-d6): δ 12.30 (1H, br s), 7.90 (1H, s), 7.85 (1H, d, J=8.0 Hz), 7.17 (2H, d, J=8.0 Hz), 7.10 (2H, d, J=8.0 Hz), 7.03 (1H, d, J=8.0 Hz), 4.79 (1H, m), 3.74 (2H, m), 3.06 (1H, m), 2.88 (1H, m), 2.36 (1H, m), 2.21 (1H, m), 1.74 (2H, m), 1.54 (2H, m), 1.36-0.86 (13H, m), 0.84 (9H, s).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31](Cl)=[O:32])[C@H:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:39])[CH3:38]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31]([N:43]3[CH2:44][CH2:45][N:40]([C:37](=[O:39])[CH3:38])[CH2:41][CH2:42]3)=[O:32])[C@H:13]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(=O)N1CCNCC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(C(C)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-acetyl-piperazine (Aldrich) to give the title compound. LC-MS: 635.2 [(M+H)+]
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].S(C1C=CC(C)=CC=1)(O[CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH:14]1([CH2:13][O:2][C:1]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Oc1ccccc1OCC1CCCC1
Yield: 44 %

Procedure:
This compound was prepared in 44% yield from catechol and cyclopentylmethyl tosylate according to the general procedure for 2p in Example IX, except that potassium carbonate was used in place of cesium carbonate. Yellow oil; 1H NMR (CDCl3): δ 1.33 (m, 2H), 1.58-1.69 (m, 4H), 1.82-1.89 (m, 2H), 2.40 (s-7, J=7.70 Hz, 1H), 3.91 (d, J=7.15 Hz, 2H), 5.66 (s, 1H), 6.81-6.88 (m, 3H), 6.92-6.94 (m, 1H); 13C NMR (CDCl3): δ 25.53, 29.54, 39.11, 73.20, 111.78, 114.49, 120.16, 121.40, 145.90, 146.16.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:16])[N:6]=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=2)[N:3]=1>C(N)CCC>[CH2:2]([NH:3][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:16])[N:6]=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=2)[N:3]=1)[CH2:11][CH2:10][CH3:9]
Reactant: Nc1nc2ccccc2c2ccc(Cl)nc12
Solvent: CCCCN
Product: CCCCNc1ccc2c(n1)c(N)nc1ccccc12
Temperature: 110 °C

Procedure:
A solution of 3-chlorobenzo[f][1,7]naphthyridin-5-amine (Example 20) (1.0 eq.) was dissolved in n-butylamine (0.1 M) and heated at 110° C. overnight. The reaction mixture was concentrated en vacuo, and the residue was purified by a COMBIFLASH® system (ISCO) using 0-90% ethyl acetate in hexane to give N3-butylbenzo[f][1,7]naphthyridine-3,5-diamine. 1H NMR (methanol d-4): δ 8.42 (d, 1H), 8.13 (d, 1H), 7.53 (d, 1H), 7.38-7.42 (dd, 1H), 7.25-7.29 (dd, 1H), 6.96 (d, 1H), 3.48 (t, 2H), 1.63-1.71 (m, 2H), 1.43-1.52 (m, 2H), 0.99 (t, 3H). LRMS [M+H]=267.2
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([CH3:9])[C:5](OC)=[O:6].[C:10]([O:13][CH3:14])(=[O:12])[CH3:11].Cl>>[F:3][CH:4]([CH3:9])[C:5](=[O:6])[CH2:11][C:10]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(C)F
Reactant: COC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)CC(=O)C(C)F
Temperature: 32.5 °C
Yield: 92 %

Procedure:
To a liquid in which 1.31 g of a 62.8% sodium hydride had been suspended in 10 ml of tetrahydrofaran was added dropwise a mixed solution of 2.00 g of methyl 2-fluoropropionate and 2.10 g of methyl acetate over 10 minutes, and the mixture was then heated at 30 to 35° C. for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, neutralized with 1N-hydrochloric acid, and subjected to liquid separation. When the organic layer was quantitated by the gas chromatography internal standard method. As a result, it was found that 2.57 g of methyl 4-fluoro-3-oxopentanoate was formed (yield: 92%). When this organic layer was concentrated under reduced pressure and then distilled under reduced pressure, 2.03 g of methyl 4-fluoro-3-oxopentanoate could be obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15](/[CH:19]=[CH:20]\[CH2:21][NH:22][OH:23])[CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[CH:4][CH:3]=1.[Si]([N:28]=[C:29]=[O:30])(C)(C)C.CO>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15](/[CH:19]=[CH:20]\[CH2:21][N:22]([OH:23])[C:29]([NH2:28])=[O:30])[CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[CH:6][CH:7]=1
Reactant: ONC/C=C\c1cccc(C2=NOC(c3ccc(F)cc3)C2)c1
Reactant: C[Si](C)(C)N=C=O
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)N(O)C/C=C\c1cccc(C2=NOC(c3ccc(F)cc3)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of the product of Step 5, above (17, 0.66 g, 2.1 mmol), in THF (10 ml) was added TMSNCO (0.42 ml, 3.1 mmol) under a nitrogen atmosphere and the reaction mixture was stirred at room temperature for 1 hour. Methanol (5 ml) was then added and after stirring for 10 minutes, solvent was removed under reduced pressure. The residue was recrystallized from ethyl acetate/methanol to afford the title compound (18, 340 mg, 45% yield) as colorless solids.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:33])=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([NH:7][C:8]1[C:13]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:12][C:11]([C:19]([F:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[Br:29])=[O:6].[Cl:34][C:35]1[N:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37](Cl)=[O:38]>>[Br:29][C:9]1[CH:10]=[C:11]([C:19]([F:28])([C:20]([F:21])([F:22])[F:23])[C:24]([F:25])([F:26])[F:27])[CH:12]=[C:13]([O:14][C:15]([F:17])([F:18])[F:16])[C:8]=1[NH:7][C:5]([C:4]1[C:3]([F:33])=[C:2]([NH:1][C:37](=[O:38])[C:36]2[CH:40]=[CH:41][CH:42]=[N:43][C:35]=2[Cl:34])[CH:32]=[CH:31][CH:30]=1)=[O:6]
Reactant: Nc1cccc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2OC(F)(F)F)c1F
Reactant: O=C(Cl)c1cccnc1Cl
Product: O=C(Nc1cccc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2OC(F)(F)F)c1F)c1cccnc1Cl

Procedure:
According to the method of 1-7 of Example 1, a target compound was prepared from 3-amino-N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethoxy)phenyl)-2-fluorobenzamide and 2-chloronicotinoylchloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)/[S:6][C:5]1=[O:20].C(N(CC)CC)C.[C:28](OC(=O)C)(=[O:30])[CH3:29]>ClCCl>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11](/[CH:10]=[C:7]2/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][C:28](=[O:30])[CH3:29])[C:5](=[O:20])[S:6]/2)=[CH:12][CH:13]=1)[CH3:19]
Reactant: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(/C=C2\SC(=O)N(CCNC(C)=O)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a solution of compound 76 (101 mg, 0.25 mmol) in 5 mL of dichloromethane was added triethylamine (105 μL, 0.75 mmol) and acetic anhydride (26.0 μL, 0.28 mmol). After being stirred at room temperature overnight, the reaction solution was diluted with 50 mL of dichloromethane, washed with water, collected the organic layer, dried over Na2SO4, filtered, concentrated and purified by silica column chromatography (33% dichloromethane in ethyl acetate) to afford 74 mg (88.6%) of the title compound 25a as a light-yellow solid.
Reaction SMILES: [C:1]12([CH2:12][C:11](=[O:13])[O:10][C:8](=[O:9])[CH2:7]1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.N1C=CC=CC=1.[CH2:20]([OH:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC=CC=1>>[CH2:20]([O:27][C:11]([CH2:12][C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:13])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CC2(CCCCC2)CC(=O)O1
Reactant: OCc1ccccc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(O)CC1(CC(=O)OCc2ccccc2)CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
A mixture of 1,1-cyclohexanediacetic anhydride (5.0 g, 27 mmol), pyridine (2.2 mL, 27 mmol), and benzyl alcohol (2.8 mL, 27 mmol) and toluene (5.0 mL, 47 mmol) was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and 1 N HCl. The organic layer was washed three times with 1 N HCl and brine. The organic extract was dried over sodium sulfate, filtered, and concentrated to dryness to yield the title compound (7.06 g, 89% yield) as a clear oil. 1H NMR (DMSO-d6, 400 mHz) δ (ppm): 11.96 (s, 1H), 7.32 (m, 5H), 5.03 (s, 2H), 2.52 (s, 2H), 2.34 (s, 2H), 1.40 (m, 10H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[NH:25]1[CH:29]=[N:28][CH:27]=[N:26]1>>[N:25]1([CH2:2][C:3]2[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[CH:11]=3)=[O:8])=[CH:5][CH:4]=2)[CH:29]=[N:28][CH:27]=[N:26]1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)cc1
Reactant: c1nc[nH]n1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cn2cncn2)cc1

Procedure:
88 mg of 4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was coupled to 45 mg of 1H-1,2,4-triazole via Procedure P. The reaction was evaporated to dryness and purified by reverse phase HPLC to yield 4-((1H-1,2,4-triazol-1-yl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 390 (M)+.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)[CH2:12][N:11]([C:25]([O:27]C4C=CC([N+]([O-])=O)=CC=4)=O)[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1.Cl.[CH3:38][CH:39]1[CH2:42][NH:41][CH2:40]1>>[CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)[CH2:12][N:11]([C:25]([N:41]4[CH2:42][CH:39]([CH3:38])[CH2:40]4)=[O:27])[CH2:10]3)[O:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CC1CNC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Agent: Cl
Product: CC1CN(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(C4CC4)no3)C2)C1

Procedure:
95 mg (0.19 mmol) of the compound from Example 184A and 61 mg (0.57 mmol) of 3-methylazetidine hydrochloride were reacted according to the General Method 6. Work-up of the crude product was carried out initially by column chromatography on silica gel (mobile phase: dichloromethane->dichloromethane/methanol 100:5) and additionally by preparative HPLC. Yield: 14 mg (17% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: NCc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCc3ccccn3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 2-(aminomethyl)pyridine (0.010 mL, 0.097 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[(pyridin-2-ylmethyl)amino methyl]indol-2-yl)isoindolinone.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:14]2[C:15]([CH2:23][CH3:24])=[N:16][N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=23)[C:6]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=O)[CH2:3][CH2:2]1.O.Cl>O1CCCC1>[CH:1]1([CH2:4][N:5]([C:14]2[C:15]([CH2:23][CH3:24])=[N:16][N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=23)[CH2:6][CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH2:3][CH2:2]1
Reactant: CCc1nn2ccccc2c1N(CC1CC1)C(=O)C1CCOCC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCc1nn2ccccc2c1N(CC1CCOCC1)CC1CC1
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A solution of N4-cyclopropylmethyl-N4-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)tetrahydro-2H-4-pyrancarboxamide (220 g, 672 mmol) in tetrahydrofuran (1100 mL) was stirred at an external temperature of 55° C. (hot water bath). A borane-tetrahydrofuran complex (1M solution, 1748 mL) was added dropwise to the reaction mixture, and after heating and stirring for 2 hours, the reaction mixture was cooled in an ice bath and 2N hydrochloric acid (437 mL) was added. The reaction mixture was then stirred for 1 hour at an external temperature of 50° C. (hot water bath). After the reaction terminated, a 5N aqueous sodium hydroxide solution (299 mL) was added dropwise to the reaction mixture to adjust it to pH 8, and the aqueous layer was removed. Toluene (2200 mL) was then added to the organic extract, and after washing the organic extract twice with water, it was concentrated under reduced pressure to afford 209 g of the title compound (99.2% yield).