Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([O:5][C:6](=[O:12])OC(Cl)(Cl)Cl)(Cl)Cl.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15]C=1.O1CCC[CH2:20]1>>[ClH:1].[C:6]([O:5][CH2:2][C@@H:18]1[CH2:17][CH2:16][CH2:15][NH:13]1)(=[O:12])[CH3:20]
Reactant: c1ccncc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C1CCOC1
Product: CC(=O)OC[C@@H]1CCCN1
Product: Cl
Reaction time: 1 h

Procedure:
To a solution of bis(trichloromethyl)carbonate (0.50 g) in tetrahydrofuran (30 mL) was added dropwise a solution of pyridine (0.40 mL) in tetrahydrofuran (1 mL) under ice-cooling. The reaction solution was stirred for 1 hr under ice-cooling, and (S)-2-pyrrolidinylmethyl acetate hydrochloride (0.90 g) obtained in Reference Synthetic Example 31 was added thereto. A solution of triethylamine (0.70 mL) in tetrahydrofuran (1 mL) was added dropwise, and stirred at room temperature for 2 hrs. The reaction solution was concentrated under reduced pressure. To the residue was added water (50 mL), and extracted with ethyl acetate (50 mL), and then, dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (20 mL). To the solution were added (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.11 g), triethylamine (0.84 mL) and 4-dimethylaminopyridine (0.037 g), and stirred at 60° C. for 1 day, and then at room temperature for 2 days. The reaction solution was concentrated under reduced pressure, and to the residue was added water (50 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified with basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:1, then ethyl acetate), and further with silica gel column chromatography (eluted with ethyl acetate:hexane=3:1, then ethyl acetate, then acetone:ethyl acetate=1:4, then 2:3) to give title compound as pale yellow amorphous solid (0.80 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:20])[C:9]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:5]#N.[OH-:21].[Na+].C[OH:24]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:20])[C:9]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:5]([OH:24])=[O:21]
Reactant: [OH-]
Reactant: COc1ccc(CNc2c(F)cc(C#N)cc2F)cc1
Reactant: CO
Agent: [Na+]
Product: COc1ccc(CNc2c(F)cc(C(=O)O)cc2F)cc1

Procedure:
To 3,5-difluoro-4-(4-methoxy-benzylamino)-benzonitrile (26.2 g, 95.5 mmol) obtained in Step A, methanol (300 ml) and 5M-NaOH aqueous solution (150 ml) were added, followed by heating to reflux for 58 hours. The solvent was distilled off under reduced pressure, and dichloromethane (200 ml) was added, followed by extraction with 1M-NaOH aqueous solution (200 ml×3). To the aqueous layer, 6M−HCl aqueous solution was added to adjust the pH to 6, followed by extraction with ethyl acetate (300 ml×2). After the organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure. The resulting solid was washed with n-hexane, and the desired compound was obtained as a colorless solid (25.6 g, 91%).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([N:17]([S:26]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[F:25])[CH3:16])C.O[Li].O>C1COCC1.CO.O>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([S:26]([N:17]([CH:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:36])=[O:3])[CH3:16])[C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])(=[O:27])=[O:28])=[CH:34][CH:33]=1
Reactant: CCOC(=O)CCCOc1ccccc1C(C)N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(c1ccccc1OCCCC(=O)O)N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Yield: 40.7 %

Procedure:
A solution of ethyl-4-[2-(1-{[(4-chlorophenyl)sulfonyl]-2,5-difluoroanilino}ethyl)phenoxy]butanoate (1.16 g, 2.2 mmol) in THF (5.2 mL), methanol (1.7 mL) and H2O (1.7 mL) was treated with LiOH.H2O (91 mg, 2.2 mmol) at 25° C. for 3 h. The reaction was then quenched with 1 N HCl solution. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with H2O and sat. NaCl aqueous solution, then dried over MgSO4. Concentration and chromatography afforded the desired product (457 mg, 41%) as white crystal: m.p. 141.0-142.0° C.; Rf 0.14 (10:10, hexane-ethyl acetate); 1H NMR (CDCl3, 300 MHz) δ 11.08 (br s, 1H), 7.62 (d, 2H, J=8.4 Hz), 7.35 (d, 2H, J=8.7 Hz), 7.16 (t, 1H, J=7.5 Hz), 6.38-6.93 (m, 6H), 6.03 (br s, 1H), 4.06 (m, 2H), 2.70 (t, 2H, J=7.0 Hz), 2.17 (m, 2H), 1.57 (d, 3H, J=6.9 Hz); LCMS 3.05 min, m/z 527.2 (C24H22ClF2NO5S requires 509.95).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=1[NH2:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:19][C:20]([F:26])([F:25])[CH2:21][C:22](O)=[O:23].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=1[NH:12][C:22](=[O:23])[CH2:21][C:20]([F:26])([F:25])[F:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: O=C(O)CC(F)(F)F
Reactant: COc1ccc(N)c(CO[Si](C)(C)C(C)(C)C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(NC(=O)CC(F)(F)F)c(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A mixture of 2-((tert-butyldimethylsilyloxy) methyl)-4-methoxyaniline (14.0 g), 3,3,3-trifluoro-propionic acid (7.30 g, 57.0 mmol), EDCI (15.0 g, 76.5 mmol), HOBT (11.0 g, 80.2 mmol) and NMM (22 mL, 157 mmol) in anhydrous CH2Cl2 (200 mL) was stirred at 20° C. for 2 hours. The mixture was diluted with CH2Cl2 (100 mL), the organic layer was washed with 1M HCl (100 mL), H2O (100 mL) and brine (100 mL), dried over Na2SO4 and concentrated to give the product.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31]C(=O)OC(C)(C)C)[CH2:26]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])=[CH:13][CH:12]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:31][C@@H:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:7]2[CH:6]=[CH:5][C:4]([C:1]([NH2:2])=[O:3])=[C:9]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])=[CH:15][CH:16]=3)[N:8]=2)[CH2:26]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1ccc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
A solution of (R)-tert-butyl 1-(5-carbamoyl-6-(4-(morpholine-4-carbonyl)phenylamino)pyridin-2-yl)piperidin-3-ylcarbamate (1.7 g) in CH2Cl2 (3 ml) was treated with 3 ml of TFA and stirred at rt for 2 h. The reaction mixture was concentrated, basified with 1N NaOH, and extracted three times with CH2Cl2. The resulting organic layer was concentrated to obtained 1.367 g of (R)-6-(3-aminopiperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide as a pale yellow solid. LCMS: (M+H)+=425.08. 1H NMR (400 MHz, CDCl3) δ ppm 11.21 (1H, s), 7.71 (2H, d, J=8.56 Hz), 7.52 (1H, d, J=8.81 Hz), 7.38 (2H, d, J=8.56 Hz), 6.06 (1H, d, J=8.80 Hz), 5.62 (2H, s), 4.19 (1H, d, J=9.57 Hz), 4.06-4.14 (1H, m, J=13.35 Hz), 3.59-3.79 (8H, m), 3.03-3.13 (1H, m), 2.78-2.92 (2H, m), 1.95-2.06 (1H, m), 1.73-1.86 (1H, m), 1.51-1.64 (1H, m), 1.30-1.46 (1H, m).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[N:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][N:45]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: COc1ccc(CCl)nc1
Agent: Cl
Product: COc1ccc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)nc1
Yield: 69.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 6-chloromethyl-3-methoxypyridine (0.47 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(5-methoxypyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.63 g) was obtained.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([O:26][CH2:27][CH3:28])[C:24]=1[OH:25])[CH:20]=O.[NH2:29][C:30]([NH2:32])=[O:31].Cl>CCO>[Br:16][C:17]1[CH:18]=[C:19]([CH:20]2[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:32][C:30](=[O:31])[NH:29]2)[CH:22]=[C:23]([O:26][CH2:27][CH3:28])[C:24]=1[OH:25]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: NC(N)=O
Reactant: CCOc1cc(C=O)cc(Br)c1O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc(Br)c1O
Yield: 11.4 %

Procedure:
To a solution of 1,2-diphenylethanone (4.80 g, 25 mmol), 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (5.00 g, 20 mmol) and urea (3.68 g, 61 mmol) in EtOH (250 mL) was added conc. HCl (10 mL). The mixture was heated at reflux for 112 h. Followed standard aqueous workup procedure and purified by silica gel column chromatography (PE:EA=1:3) to afford Compound 100 as a white solid (1.06 g, 11%). 1H NMR (MeOH-d4 500 MHz TMS): δ 7.24 (s, 5H), 7.09 (s, 1H), 7.04 (s, 3H), 6.85 (s, 3H), 5.17 (s, 1H), 4.03 (m, 2H), 1.37 (t, J=7.5 Hz, 3H); MS (ESI): m/z 465.0 [M+1]+.
Reaction SMILES: CN.[CH2:3]([N:5](CC)CC)C.[Cl:10][C:11]([Cl:17])([S:15]Cl)[CH:12]([Cl:14])[Cl:13].[C:18]([Cl:21])(Cl)=[O:19]>C(#N)C>[Cl:10][C:11]([S:15][N:5]([CH3:3])[C:18]([Cl:21])=[O:19])([Cl:17])[CH:12]([Cl:14])[Cl:13]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)Cl
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Agent: CN
Solvent: CC#N
Product: CN(SC(Cl)(Cl)C(Cl)Cl)C(=O)Cl
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 3.1 g (0.1 mole) methylamine and 10.1 g (0.1 mole) triethylamine in 100 ml acetonitrile was added dropwise to a solution of 23.4 g (0.1 mole) 1,1,2,2-tetrachloroethylsulfenyl chloride in 200 ml acetonitrile at about 0°-5° C. Into the reaction mixture was then bubbled 9.9 g (0.1 mole) phosgene. The reaction was stirred at about 25° C for about 17 hours. The acetonitrile solvent was evaporated under reduced pressure and the residue was diluted with benzene and filtered to give a filtrate solution of N-1,1,2,2-tetrachloroethylthio N-methyl carbamoyl chloride in benzene.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].Cl.[C:10]([O-])(O)=O.[Na+].[CH3:15][CH2:16]O>O.CCOC(C)=O>[N:1]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:15]=[CH:16][CH:10]=[N:2]1
Reactant: O=C([O-])O
Reactant: CCO
Reactant: NNc1ccccn1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc(-n2cccn2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Hydrazinopyridine (7.6 g, 70 mmol), malondialdehyde-bis-(dimethylacetal) (11.5 mL, 70 mmol) and HCl (10 M, 7 mL) in EtOH (100 mL) were heated at 75° C. After 2 h, the resulting reaction mixture was cooled to ambient temperature and concentrated in vacuo to a give a brown solid. This was suspended in H2O (100 mL) and EtOAc (100 mL), and NaHCO3 added until there was no further effervescence. The EtOAc layer was then separated and the aqueous layer shaken with EtOAc (3×100 mL). The combined organic layers were dried over Na2SO4 and concentrated to afford 2-(1H-pyrazol-1-yl)pyridine as a brown oil which was used without further purification. MS (ESI) 147 (M+H)+
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C>[CH2:24]([O:23][C:21](=[O:22])[CH:20]([O:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=1)[CH3:26])[CH3:25]
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(OC(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
4-Trifluoromethoxyphenol (0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: O[CH:2]1[C:11](=C)[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[C:3]1=O.[NH:16]([CH2:18][CH:19]([OH:21])[CH3:20])[NH2:17].O.[C:23]1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:14][O:13][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][CH2:11][C:2]3[CH:23]=[N:17][N:16]([CH2:18][CH:19]([OH:21])[CH3:20])[C:3]=3[C:4]=2[CH:5]=1
Reactant: C=C1Cc2ccc(OC)cc2C(=O)C1O
Reactant: CC(O)CNN
Reactant: Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COc1ccc2c(c1)-c1c(cnn1CC(C)O)CC2
Yield: 74 %

Procedure:
A solution of 1.63 g (7.98 mmol) of 2-hydroxy-methylene-7-methoxy-1-tetralone, 0.87 g (9.65 mmol) of (RS)-1-hydrazino-2-propanol and 100 mg of p-toluenesulfonic acid in 100 ml of anhydrous toluene was heated on a water separator for 1.5 hours. After concentration in a vacuum, the reaction mixture S was purified by column chromatography on silica gel (ethyl acetate/hexane 1:1). 1.52 g (74%) of (RS)-1-(4,5-dihydro-8-methoxy-1H-benz[g]indazol-1-yl)-propan-2-ol were obtained as a yellow oil which was used directly in the next reaction.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].CC1[O:8][CH:9]=[CH:10][CH:11]=1.C1[O:14]C1.[Cl-].[NH4+]>C1COCC1>[CH3:5][C:4]1[O:8][C:9]([CH2:10][CH2:11][OH:14])=[CH:2][CH:3]=1
Reactant: C1CO1
Reactant: [Li]CCCC
Reactant: Cc1ccco1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(CCO)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of n-BuLi (83.0 mL, 133 mmol, 1.6 M in hexanes) was added to a stirred solution of 2-methylfuran (10.0 mL, 111 mmol) in THF (85 mL) at 0° C. under nitrogen. The reaction mixture was stirred for 4 h at room temperature and cooled to 0° C. Ethylene oxide (8.30 mL, 166 mmol) was added drop wise and the reaction mixture was allowed to warm to room temperature over 16 h. Saturated aqueous ammonium chloride was added, the resulting layers were separated, and the aqueous layer was extracted with diethyl ether (2×250 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. Distillation at atmospheric pressure (170-185° C.) gave 10.1 g (80.3 mmol, 72%) of Preparation 1A as a light yellow oil.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.[C:6]([O:10][C:11]([N:13]1[CH2:16][CH:15]([C:17]([OH:19])=O)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH:15]([C:17]([N:2]2[CH2:5][CH2:4][CH2:3]2)=[O:19])[CH2:16]1)=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(C(=O)N2CCC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Azetidine hydrochloride salt (515 mg, 5.50 mmol) was added to a solution of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (1.0 g, 4.97 mmol), HATU (2.09 g, 5.50 mmol) and DIPEA (2.18 mL, 12.52 mmol) in DMF (100 mL) and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give 3-(azetidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil. TFA (3 mL) was added to a solution of 3-(azetidine-1-carbonyl)-azetidine-1-carboxylic acid tert-butyl ester in DCM (15 mL) and the mixture stirred at ambient temperature for 1 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a colourless oil (260 mg, 37%). 1H NMR (CD3OD, 400 MHz) δ 4.19-4.08 (m, 2 H); 4.07-3.92 (m, 2 H); 3.91-3.78 (m, 2 H); 3.72-3.52 (m, 3 H) and 2.36-2.21 (m, 2 H).
Reaction SMILES: C(N1[C:12]2[C:7](=[CH:8]C=CC=2)[C:6](=O)[C:5]1=O)CC.[NH:15]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18](=[O:19])[C:16]1=[O:17].BrCCC(C)C>>[CH2:5]([N:15]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18](=[O:19])[C:16]1=[O:17])[CH2:6][CH:7]([CH3:12])[CH3:8]
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Reactant: O=C1Nc2ccccc2C1=O
Solvent: CC(C)CCBr
Product: CC(C)CCN1C(=O)C(=O)c2ccccc21

Procedure:
Was prepared in an analogous manner to 1-propylindoline-2,3-dione using commercially available isatin (purchased from Fisher Scientific) and 1-bromo-3-methyl butane (purchased from Fisher Scientific). 1H NMR δ 7.58 (m, 2H), 7.10 (t, 1H), 6.89 (d, 1H), 3.73 (t, 2H), 1.58 (m, 3H), 1.00 (d, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1F)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][CH2:21][CH2:22][OH:23].C([O-])([O-])=O.[Cs+].[Cs+].CCCCCC.C(OCC)(=O)C>O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[O:23][CH2:22][CH2:21][O:20][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c(OCc2ccccc2)c1
Reactant: COCCO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COCCOc1ccc([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Into a 25 mL 3-neck RBF equipped with reflux condenser and thermo pocket were charged 2-(benzyloxy)-1-fluoro-4-nitrobenzene (3.3 g), 2-methoxy ethanol (16.0 mL) and Cs2CO3 (8.67 g). The reaction mixture was heated at 80° C. for 2 hr. The reaction was monitored on TLC using hexane:ethyl acetate (5:5) as mobile phase. The reaction was complete after 2 hr. After completion, the reaction mixture was cooled to room temperature and poured into cold water. Solid precipitate was filtered and washed with water. Solid was dried under reduced pressure. The obtained 3.90 g of solid 2-(benzyloxy)-1-(2-methoxyethoxy)-4-nitrobenzene was taken onto the next step without further purification. 1H NMR: DMSO-d6 (400 MHz): 3.34 (s, 3H), 3.722-3.700 (t, 2H, J=4.4), 4.269-4.291 (t, 2H, J=4.4), 5.256 (s, 2H), 7.216-7.239 (d, 1H, J=9.2), 7.328-7.364 (m, 1H), 7.393-7.430 (m, 2H), 7.471 (s, 1H), 7.489 (s, 1H), 7.849-7.855 (d, 1H, J=2.4), 7.889-7.971 (dd, 1H, J=2.4, 6.4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C@H:33]3[O:38][B:37]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:36][C@@H:35]([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:34]3)[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19](=S)[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[OH-].[Na+].OO.C(OCC)(=[O:59])C>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C@H:33]3[O:38][B:37]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:36][C@@H:35]([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:34]3)[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19](=[O:59])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: CC(C)c1c(C(=S)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OB(c2ccccc2)O1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OB(c2ccccc2)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2 g of t-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamothioyl)-1H-pyrrol-1-yl)ethyl)-2-phenyl-1,3,2-dioxaborinan-4-yl)acetate obtained in Example 5-3 was dissolved in 70 ml of ethanol, and 0.83 g of sodium hydroxide and 35 ml of 30% hydrogen peroxide were added thereto. The mixture was stirred at room temperature for 3 hours. 300 ml of ethyl acetate and 200 ml of purified water were added to the reaction mixture and stirred slowly for 30 minutes, and the organic layer was separated and washed one time with a saturated aqueous sodium chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, thus obtaining oil. The oil was crystallized from isopropylether and heptane, thus obtaining the target compound as a solid compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14](=[O:20])[N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH:13]=1)[C:7]([O:9]C)=[O:8])(=[O:3])[CH3:2].CO.O.[Li+].[OH-]>C1COCC1>[C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14](=[O:20])[N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH:13]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(C(C)=O)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(C(C)=O)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-acetyl-5-(methyl(propyl)carbamoyl)benzoate (107 mg, 0.386 mmol) in a mixture of THF (0.4 mL), MeOH (0.8 mL) and H2O (2.0 mL), was added LiOH (28 mg, 1.159 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated and partitioned between ethyl acetate and H2O. The aqueous layer was washed with ethyl acetate twice and acidified with 1N HCl solution to pH around 2˜3. The aqueous layer was extracted with ethyl acetate 3 times and the combined organic layers were dried over sodium sulfate and concentrated under vacuum to give the title compound which was ready for next step without further purification: HPLC retention time: 1.412 min (method A). MS (ESI) (M+H)+ 264.18.
Reaction SMILES: CCCCC([N:7]([C@H:26]([C:30]([OH:32])=[O:31])[CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[C:21]2NN=N[N:25]=2)=[CH:13][CH:14]=1)=O.Br[CH2:34]C1C=CC(C2C=CC=CC=2C#N)=CC=1.Cl.COC(=O)[C@H](C(C)C)N.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:34][O:32][C:30](=[O:31])[C@H:26]([CH:27]([CH3:28])[CH3:29])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[C:21]#[N:25])=[CH:11][CH:10]=1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C
Agent: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](NCc1ccc(-c2ccccc2C#N)cc1)C(C)C

Procedure:
Bioorganic & Medicinal Chemistry Letters (1994), 4(1), 29-34, reported a process for the preparation of Valsartan by reacting 4′-bromomethyl-2-cyanobiphenyl (II) with (L)-valine methyl ester hydrochloride (V) in the presence of diisopropylethylamine in methylenechloride to produce N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester (VI), followed by reacting with valeryl chloride in the presence of diisopropylethylamine in methylenechloride to produce N-valeryl-N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester (VII), which is further reacted with tributyltin azide in xylene to produce N-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-N-valeryl-(L)-valine methyl ester (VIII), followed by hydrolysis with aqueous base to produce Valsartan of formula (I).