Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH2:15][CH2:14][O:13][N:12]=2)=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[OH:27][C:28]1[N:32]([CH3:33])[N:31]=[CH:30][CH:29]=1>O1CCOCC1>[Cl:1][C:2]1[C:10]([C:11]2[CH2:15][CH2:14][O:13][N:12]=2)=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=[CH:7][C:3]=1[C:4]([C:29]1[CH:30]=[N:31][N:32]([CH3:33])[C:28]=1[OH:27])=[O:5]
Reactant: Cn1nccc1O
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c(Cl)c1C1=NOCC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C3=NOCC3)c2Cl)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
43.60 g (0.13 mol) of 2-chloro-3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoyl chloride in 375 ml of anhydrous dioxane and 13.56 g (0.134 mol) of triethylamine in 375 ml of anhydrous dioxane are simultanouesly added dropwise at room temperature under a protective gas atmosphere to a solution 12.74 g (0.13 mol) of 5-hydroxy-1-methylpyrazole and 300 ml of anhydrous dioxane. After the reaction mixture had been stirred for 2 hours at room temperature, it was filtered through silica gel and the residue was washed with dioxane. The eluate was concentrated in vacuo to approxmately 500 ml, and 17.94 g (0.13 mol) of dried, finely powdered potassium carbonate were added. After the mixture had been refluxed for 6 hours, the solvent was distilled off in vacuo and the residue was taken up in approximately 700 ml of water. Insoluble constituents were filtered off, and the pH of the filtrate was brought to 2–3 by slow addition of 10% strength hydrochloric acid. The precipitate which formed was filtered off with suction. This gave 46.16 g (92% of theory) of 4-[2-chloro-3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoyl]-5-hydroxy-1-methyl-1H-pyrazole.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:29][C:28]3[C:23](=[N:24][CH:25]=[CH:26][C:27]=3Cl)[CH:22]=2)=[CH:17][CH:16]=1)[CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][O:10]1)([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:38]=[C:37]([N+:39]([O-:41])=[O:40])[CH:36]=[CH:35][C:34]=1[OH:42].C(=O)([O-])[O-].[K+].[K+]>O(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl>[F:32][C:33]1[CH:38]=[C:37]([N+:39]([O-:41])=[O:40])[CH:36]=[CH:35][C:34]=1[O:42][C:27]1[CH:26]=[CH:25][N:24]=[C:23]2[CH:22]=[C:21]([C:18]3[CH:19]=[CH:20][C:15]([CH2:14][N:7]([CH2:8][CH:9]4[CH2:13][CH2:12][CH2:11][O:10]4)[C:6](=[O:31])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:16][CH:17]=3)[S:29][C:28]=12
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(-c2cc3nccc(Cl)c3s2)cc1)CC1CCCO1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cc1)CC1CCCO1
Temperature: 180 °C
Yield: 19.8 %

Procedure:
To a solution of 77 (1.0 g, 2.18 mmol) in Ph2O (10 ml) was added 2-fluoro-4-nitrophenol (856 mg, 5.45 mmol) and potassium carbonate (904 mg, 6.55 mmol). The reaction mixture was heated at 180° C. for 4 hrs, cooled to room temperature, diluted with DCM, filtered and concentrated. The residue was purified by column chromatography, eluent EtOAc:hexane 8:2, to afford title compound 78 (250 mg, 20% yield). MS (m/z): 580.3 (M+H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:20](=[O:21])[CH:19]=[C:18]([CH3:22])[NH:17][C:16]=3[CH3:23])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[Cl:28]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:28][C:19]1[C:20](=[O:21])[C:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:26])[F:27])=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)=[C:16]([CH3:23])[NH:17][C:18]=1[CH3:22]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(=O)c(-c2ccc(Oc3ccc(OC(F)(F)F)cc3)cc2)c(C)[nH]1
Solvent: ClC(Cl)Cl
Product: Cc1[nH]c(C)c(-c2ccc(Oc3ccc(OC(F)(F)F)cc3)cc2)c(=O)c1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.8 %

Procedure:
A mixture of 3-(4-(4-trifluoromethoxyphenoxy)phenyl)-2,6-dimethylpyridin-4(1H)-one (0.37 g) and N-chlorosuccinimide (0.16 g) in chloroform was stirred at room temperature for 3 days. The precipitate was filtered off and recrystallised from DMF to afford the title compound (0.1 g), m.p. 298°-302°, NMR δH (d6 -DMSO) 7.35-7.5 (2H, m), 7.1-7.3 (4H, m), 7-7.1 (2H, m), 2.38 (3H, s), 2.1 (3H, s).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:35][O:36][CH3:37])[O:5][C:6]1[CH:7]=[C:8]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][N:26]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21](O)=[O:22])[CH2:18][N:19]=1)=[CH:11]2.Cl.[CH2:39]([N:41]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[Cl-].C[NH3+]>CN(C)C=O.C(N(CC)CC)C>[CH3:37][O:36][CH2:35][CH:4]([CH2:3][O:2][CH3:1])[O:5][C:6]1[CH:7]=[C:8]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][N:26]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([NH:41][CH3:39])=[O:22])[CH2:18][N:19]=1)=[CH:11]2
Reactant: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: CCN=C=NCCCN(C)C
Agent: C[NH3+]
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cn4)cc(OC(COC)COC)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 60.7 %

Procedure:
A mixture of [2-(7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (280 mg), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (195 mg), 1-hydroxybenzotriazole (138 mg), methylammonium chloride (69 mg), triethylamine (0.14 mL) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 2.5 h. The mixture was concentrated under reduced pressure. The residue was dissolved in water and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=0/100 to 5/95, volume ratio) to give a pale yellow amorphous solid. The amorphous solid was crystallized from acetonitrile-diethyl ether to give white crystals. The crystals were recrystallized from ethyl acetate-diethyl ether to give the title compound (174 mg, 61%) as colorless crystals. MS 563 (MH+). mp 123-125° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:14][C:15](=[O:31])[CH2:16][P:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18])[CH2:10][C:11]([OH:13])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CI.[C:34](=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[Si:1]([O:8][C@H:9]([CH2:14][C:15](=[O:31])[CH2:16][P:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18])[CH2:10][C:11]([O:13][CH3:34])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CC(=O)O)CC(=O)CP(=O)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CI
Product: COC(=O)C[C@@H](CC(=O)CP(=O)(c1ccccc1)c1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To 0.92 g (2 mmol.) of (R)-3-t-butyldimethylsilyloxy-6-diphenylphosphinoyl-5-oxohexanoic acid prepared above, 0.28 g of methyl iodide, 0.28 g of potassium carbonate and 10 ml of acetone were added, and then the mixture was stirred for 8 hours at room temperature. After 16 ml of water was added to the solution, the solution was extracted with two portions of 20 ml of ethyl acetate. The ethyl acetate portions were combined and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation in vacuo to give 0.81 g of methyl (R)-3-t-butyldimethylsilyloxy-6-diphenylphosphinoyl-5-oxohexanoate as a colorless oil (optical purity: 98% ee; yield: 85% based on the amount of (R)-3-t-butyldimethylsilyloxy-6-diphenylphosphinoyl-5-oxohexanoic acid).
Reaction SMILES: [NH2:1][C@H:2]([CH3:22])[CH2:3][O:4][C:5]1[C:20](Br)=[CH:19][C:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13][C:7]=2[CH:6]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:22][C@@H:2]1[CH2:3][O:4][C:5]2[C:20](=[CH:19][C:8]3[CH2:9][CH2:10][N:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13][C:7]=3[CH:6]=2)[NH:1]1
Reactant: CCOC(=O)N1CCc2cc(Br)c(OC[C@@H](C)N)cc2CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCc2cc3c(cc2CC1)OC[C@@H](C)N3
Temperature: 100 °C
Reaction time: 24 h
Yield: 47.6 %

Procedure:
Under an argon atmosphere, to a solution of 1.64 g of ethyl 7-{[(2R)-2-aminopropyl]oxy}-8-bromo-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in 41 ml of toluene were added 509 mg of sodium t-butoxide, 275 mg of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, and 202 mg of tris(dibenzylideneacetone)dipalladium (0) in this order, followed by heating at 100° C. for 24 hours. Further, 509 mg of sodium t-butoxide, 275 mg of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, and 202 mg of tris(dibenzylideneacetone)dipalladium (0) were added thereto, followed by stirring at 100° C. for additional 24 hours. The reaction mixture was returned to room temperature, then filtered through celite, and washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: Hex-AcOEt) to obtain 610 mg of ethyl (3R)-3-methyl-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[F:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17](OC)=[O:18]>C1COCC1.C(O)(=O)C.O>[F:13][C:14]1[CH:15]=[C:16]([C:17](=[O:18])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH:21]=[CH:22][CH:23]=1
Reactant: COP(C)(=O)OC
Reactant: COC(=O)c1cccc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)c1cccc(F)c1)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
To a stirred solution of dimethyl methylphosphonate (10.1 g, 81.2 mmol) in 100 ml of anhydrous THF was added dropwise n-butyl lithium (1.58N, 51.4 ml, 81.2 mmol) at -78° C. under argon atmosphere. After 30 minutes, methyl m-fluorobenzoate (5.0 g, 32 mmol) was further added dropwise and the mixture was stirred for 30 minutes. The reaction solution was allowed to warm to 0° C., diluted with 4.9 ml of acetic acid and 10 ml of water, and concentrated. 30 ml of water was added to the residue and the mixture was extracted with ethyl acetate (50 ml×2). The combined ethyl acetate layers were washed with water (20 ml×1) and brine (20 ml×1), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled under reduced pressure to give an oil of dimethyl 2-m-fluorophenyl-2-oxo-ethylphosphonate (6.6 g, 26.8 mmol, yield 83.8%, b.p. 132°-134° C./0.17 mmHg), which was assigned the structure by the following data:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.Br[C:26]1[N:34]2[C:29]([CH:30]=[N:31][C:32]([NH:35]C3C=CC(N4CCC(N5CCN(C)CC5)CC4)=CC=3OC)=[N:33]2)=[CH:28][CH:27]=1.[N:57]1[CH:62]=[CH:61][CH:60]=[C:59](B(O)O)[CH:58]=1.C(=O)([O-])[O-].[Na+].[Na+].O.C(O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:57]1[CH:62]=[CH:61][CH:60]=[C:59]([C:26]2[N:34]3[C:29]([CH:30]=[N:31][C:32]([NH2:35])=[N:33]3)=[CH:28][CH:27]=2)[CH:58]=1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc2ccc(Br)n2n1
Reactant: OB(O)c1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Nc1ncc2ccc(-c3cccnc3)n2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 133.7 %

Procedure:
Palladium Acetate (0.009 g, 0.00004 mol) and Triphenylphosphine (0.013 g, 0.000050 mol) were dissolved in Tetrahydrofuran (4 mL, 0.05 mol) and the mixture was allowed to stir at room temperature for 10 minutes. (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-{2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine (0.10 g, 0.00020 mol) (For preparation see Example 242) was then added and the reaction was again allowed to stir for 10 minutes. 3-Pyridylboronic acid (0.034 g, 0.00028 mol) was added followed by 1 M of Sodium carbonate in Water (0.70 mL, 0.0007 mol) and Ethanol (2 mL, 0.03 mol). The reaction mixture was then heated at 80° C. overnight. The solvent was removed under vacuum. The product was worked up with brine and DCM. Purification by prep plate chromatography gave 2-Methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-(7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine as a tan solid (0.0565 g, 56%). MP: 68-70° C.; 1H-NMR (DMSO, 400 MHz) δ 9.30 (d, 1H, J=2.16 Hz), 8.95 (s, 1H), 8.56 (d, 1H, J=8.08 Hz), 8.52 (d, 1H, J=4.76 Hz), 7.89 (s, 1H), 7.64 (d, 1H, J=5.97Hz), 7.47 (q, 1H, J=4.76 Hz), 7.29 (d, 1H, J=4.80 Hz), 6.95 (d, 1H, J=4.80 Hz), 6.67 (d, 1H, J=2.36 Hz) 6.51 (q, 1H, J=2.48 Hz), 3.82 (s, 3H), 3.72 (d, 2H, J=12.48 Hz), 2.7 (t, 1H, J=11.44 Hz), 2.33-2.30 (m, 4H, J=10.32 Hz), 1.54 (q, 2H).
Reaction SMILES: [Cl:1][C@@H:2]([CH3:22])[CH2:3][C@H:4]([CH3:21])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:23]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)#[N:24].N1(C2C=CN=CC=2)CCCC1>C(Cl)Cl>[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:17][C:16](=[O:18])[C:15]2[CH:19]=[CH:20][C:12]([C:9]3[CH:8]=[CH:7][C:6]([O:5][C@@H:4]([CH3:21])[CH2:3][C@@H:2]([Cl:1])[CH3:22])=[CH:11][CH:10]=3)=[CH:13][CH:14]=2)=[CH:27][CH:26]=1)#[N:24]
Reactant: N#Cc1ccc(O)cc1
Reactant: C[C@H](Cl)C[C@H](C)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: C[C@H](Cl)C[C@H](C)Oc1ccc(-c2ccc(C(=O)Oc3ccc(C#N)cc3)cc2)cc1
Yield: 60.7 %

Procedure:
Methyl (R,S)-4-[4'-(3"-hydroxy-1"-methylbutoxy)-phenyl]benzoate, which had been obtained from methyl 4(4'-hydroxyphenyl)benzoate and monotosylate of (R,R)-2,4-pentadiol, was chlorinated and hydrolyzed. 0.5 g of the (S,S)-4-[4'-(3"-chloro-1"-methylbutoxy)phenyl]-benzoic acid thus obtained, 0.19 g of 4-cyanophenol, 0.04 g of 4-pyrrolidinopyridine, 0.34 g of dicycylohexylcarbodiimide and 6 ml of methylene chloride were stirred at room temperature for five hours. The dicyclohexyl urea thus precipitated was filtered and the filtrate was desolvated. The obtained crude product was recrystallized from ethyl alcohol to thereby give 0.4 g of the title compound (m.p.: 103.8° C.).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]3[N:27]=[N:26][N-:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]([CH2:28][OH:29])=[C:7]([Cl:30])[N:6]=1.[K+].[N+:32]([O:35][C@@H:36]([CH2:43][O:44][N+:45]([O-:47])=[O:46])[CH2:37][CH2:38][CH2:39][C:40](O)=[O:41])([O-:34])=[O:33].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.OP([O-])(O)=O.[Na+].OP([O-])([O-])=O.[Na+].[Na+]>CN(C)C1C=CN=CC=1.CO.ClCCl.ClCCl>[N+:32]([O:35][C@@H:36]([CH2:43][O:44][N+:45]([O-:47])=[O:46])[CH2:37][CH2:38][CH2:39][C:40]([O:29][CH2:28][C:8]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]3[N:24]=[N:25][NH:26][N:27]=3)=[CH:15][CH:16]=2)[C:5]([CH2:4][CH2:3][CH2:2][CH3:1])=[N:6][C:7]=1[Cl:30])=[O:41])([O-:34])=[O:33]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[n-]n2)cc1
Reactant: O=C(O)CCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CO
Product: CCCCc1nc(Cl)c(COC(=O)CCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Reaction time: 2 h
Yield: 74.8 %

Procedure:
To a dichloromethane (50 mL) suspension of Losartan potassium (4.72 g, 10.24 mmol), (5R)-5,6-bis(nitrooxy)hexanoic acid (1.23 g, 5.16 mmol), and 4-dimethylaminopyridine (0.075 g, 0.614 mmol) was added N-methylmorpholine (1.2 mL, 10.91 mmol), followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.2 g, 6.26 mmol). After 2 hours, the reaction mixture was mixed with pH 5 buffer (sodium phosphate monobasic/sodium phosphate dibasic, 250 mL) and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (magnesium sulfate), and concentrated in vacuo. Chromatography over silica eluting with 2-12% methanol/dichloromethane afforded the title compound as a white solid (2.485 g, 3.86 mmol, 74.8% yield). 1H NMR (500 MHz, CD3CN) δ 7.69 (dd, J=1.1, 7.6 Hz, 1H), 7.64 (dt, J=1.3, 7.6 Hz, 1H), 7.53 (dt, J=1.1, 7.6 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.09 (d, J=8.3 Hz, 2H), 6.91 (d, J=8.3 Hz, 2H), 5.27 (dq, J=2.8, 6.3 Hz, 1H), 5.15 (s, 2H), 4.95 (s, 2H), 4.75 (dd, J=2.8, 12.8 Hz, 1H), 4.51 (dd, J=6.1, 12.9 Hz, 1H), 2.48 (t, J=7.7 Hz, 2H), 2.08 (t, J=7.3 Hz, 2H), 1.5-1.7 (m, 6H), 1.28 (pent, J=7.4 Hz, 2H), 0.83 (t, J=7.5 Hz, 3H). LCMS: m/e 643.2 (M+H).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[NH:6][C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([CH:17]4[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.C([NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)(=[O:29])=[O:28])(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.FC(F)(F)C(O)=O>[CH:17]1([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][C:7]3[NH:6][C:5]4[CH:20]=[CH:21][C:2]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[S:27]([NH2:26])(=[O:29])=[O:28])=[CH:3][C:4]=4[N:8]=3)=[CH:12][CH:13]=2)[CH2:19][CH2:18]1
Reactant: Brc1ccc2[nH]c(COc3ccc(C4CC4)cc3)nc2c1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C4CC4)cc3)nc2c1
Temperature: 90 °C

Procedure:
A mixture of 5-bromo-2-(4-cyclopropyl-phenoxymethyl)-1H-benzoimidazole (0.030 g, 0.0874 mmol), 2-(tert-butylamino)sulfonylphenylboronic acid (0.029 g, 0.114 mmol), sodium carbonate (0.079 g, 0.524 mmol), and 1,1′-[bis(di-tert-butylphosphino)ferrocene]-palladium dichloride (0.006 g, 0.00874 mmol) in DME (2 mL) and H2O (0.5 mL) was heated at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to provide a residue, which was purified by chromatography (silica, hexanes:EtOAc, 1:1) to afford the product. It was then dissolved in trifluoroacetic acid (3 mL) and heated to 60° C. for 2 hours. The reaction mixture was concentrated and the residue was purified by chromatography (silica, hexanes: EtOAc, 1:2) to afford the title compound as a light brown solid. 1H NMR (400 MHz, CD3OD) δ (ppm): 8.14 (dd, 1H, J=8.0 Hz, J=1.2 Hz), 7.77 (s, 1H), 7.73 (d, 1H, J=9.2 Hz), 7.65 (td, 1H, J=8.2 Hz, J=1.6 Hz), 7.50 (td, 1H, J=8.4 Hz, J=1.6 Hz), 7.51 (dd, 1H, J=8.8 Hz, J=1.2 Hz), 7.41 (dd, 1H, J=6.0 Hz, J=1.2 Hz), 7.08-6.99 (m, 4H), 5.50 (s, 2H), 1.90-1.84 (m, 1H), 0.92-0.90 (m, 2H), 0.62-0.58 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C23H22N3O3S: 420.5 (M+H), Found 420.4.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[C:20]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:10]1=[O:29])[CH2:6][CH2:7][OH:8].CC1C2C(CN3C4C=CC=CC=4N(C4CCOC(=O)C4)C3=O)=CSC=2C=CC=1.[OH-].[Na+].Cl>O1CCOCC1>[OH:8][CH2:7][CH2:6][CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[C:20]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:10]1=[O:29])[CH2:4][C:3]([OH:30])=[O:2]
Reactant: COC(=O)CC(CCO)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Agent: Cc1cccc2scc(Cn3c(=O)n(C4CCOC(=O)C4)c4ccccc43)c12
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cccc2scc(Cn3c(=O)n(C(CCO)CC(=O)O)c4ccccc43)c12
Reaction time: 2 h
Yield: 62 %

Procedure:
5-Hydroxy-3-[3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-pentanoic acid methyl ester and 1-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-3-(2-oxo-tetrahydro-pyran-4-yl)-1,3-dihydro-benzimidazol-2-one (51 mg) are dissolved in 1,4-dioxane (2.5 mL). Then 1.0 N NaOH solution (2.0 mL) is added and the mixture is stirred for 2 hr. Then 1.0 M HCl (3.0 mL) is added to make it acidic and the mixture is extracted with EtOAc (3×35 mL). The organic layers are combined, dried and concentrated to give crude product. Purification by preparative TLC using 7.5% MeOH in CH2Cl2 affords 43 mg (62% for two steps) of 5-Hydroxy-3-[3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-pentanoic acid. LCMS (ESMS): m/z 411.07 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[OH:33][CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]1>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:37]3[CH2:38][CH2:39][CH2:40][CH:35]([CH2:34][OH:33])[CH2:36]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: OCC1CCCNC1
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCCC(CO)C3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with 3-hydroxymethyl piperidine. A yellow solid 115 was obtained (0.0279 g, 60%). 1H-NMR (CDCl3, 400 MHz) δ 1.32–1.42 (m, 1H), 1.63–1.74 (m, 1H), 1.86–1.95 (m, 2H), 2.04–2.14 (m, 1H), 3.18–3.25 (m, 1H), 3.33–3.39 (m, 1H), 3.47–3.52 (m, 1H), 3.71 (dd, J=4.0 Hz, 11.0 Hz, 1H), 3.83 (s, 3H), 4.02–4.07 (m, 1H), 4.48–4.53 (m, 1H), 6.93 (d, J=6.6 Hz, 1H), 7.00–7.08 (m, 4H), 7.45–7.52 (m, 3H), 7.84 (s, 1H), 8.35 (d, J=6.5 Hz, 1H); MS (APCI) m/z 475 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]([CH3:9])([CH2:7][CH3:8])[C:4](O)=O)[CH3:2].[NH2:10][NH:11][C:12]([NH2:14])=[S:13].P(Cl)(Cl)(Cl)=O.[OH-].[NH4+]>O1CCOCC1>[NH2:14][C:12]1[S:13][C:4]([C:3]([CH2:7][CH3:8])([CH3:9])[CH2:1][CH3:2])=[N:10][N:11]=1
Reactant: CCC(C)(CC)C(=O)O
Reactant: NNC(N)=S
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CCC(C)(CC)c1nnc(N)s1
Temperature: 90 °C
Yield: 91.9 %

Procedure:
A solution containing 13.0 g of 2-ethyl-2-methylbutyric acid and 9.1 g of thiosemicarbazide in 125 ml of dioxane was stirred and heated to 90° C. To the stirred reaction mixture was added dropwise over thirty minutes 15.3 g of phosphorous oxychloride. Following complete addition, the reaction mixture was heated at 90° C. for six hours. The mixture was then cooled to about 30° C. and added to 100 g of ice. The aqueous mixture was made alkaline by the addition of ammonium hydroxide, and the alkaline solution was extracted several times with ethyl acetate. The extracts were combined, washed with water, dried, and the solvent was removed by evaporation under reduced pressure to afford 17.0 g of 2-amino-5-(1-ethyl-1-methylpropyl)-1,3,4-thiadiazole.