Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([CH:6]([Cl:13])[CH2:7][NH:8]C(C)(C)C)=[CH:4][C:3]=1[Cl:17].CO.Cl.[CH:21]([OH:24])(C)C>CCO>[ClH:13].[NH2:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([CH:6]([O:24][CH3:21])[CH2:7][NH2:8])=[CH:4][C:3]=1[Cl:17]
Reactant: CC(C)O
Reactant: CC(C)(C)NCC(Cl)c1cc(Cl)c(N)c(Cl)c1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: COC(CN)c1cc(Cl)c(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under N2 atmosphere, 11 g of 4-amino-α-[(tert-butylamino)methyl]-3,5-dichlorobenzyl chloride is added to 75 ml of methanol at 0° C. After 20 minutes, the cooling bath is removed and the reaction mixture is stirred at ambient temperature. After the reaction is completed, the mixture is evaporated to dryness in vacuo. The residue is stirred in 75 ml of H2O and the mixture is made alkaline with 6N NaOH solution and extracted with CH2Cl2 (3×50 ml). The organic phases are dried over MgSO4 and evaporated to dryness to afford an orange oil. This oil is dissolved in 150 ml of absolute EtOH and acidified with HCl/isopropyl alcohol solution to pH 2. The solution is evaporated to dryness and the residue is stirred in 75 ml of ethyl acetate. After cooling, this affords a pale yellow solid which is collected to give 6.97 g of the title compound, m.p. 195°-198° C. dec.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH:17]4[C:19]([OH:22])([CH3:21])[CH3:20])[N:13]([CH3:23])[C:12]=3[CH:24]=2)[C:4](=[O:25])[CH:3]=1.[F:26][C:27]1[CH:28]=[C:29]([CH2:34]O)[CH:30]=[CH:31][C:32]=1[F:33].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>CCOC(C)=O.C1COCC1>[F:26][C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:34][O:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH:17]4[C:19]([OH:22])([CH3:20])[CH3:21])[N:13]([CH3:23])[C:12]=3[CH:24]=2)[C:4](=[O:25])[CH:3]=1
Reactant: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1ccc(F)c(F)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(OCc4ccc(F)c(F)c4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-hydroxy-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (3,4-difluorophenyl)methanol (0.066 ml), tributylphosphine (0.219 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (223 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, and quenched with water. The organic layer was separated, washed with water and brine successively, dried over MgSO4, filtered through NH silica gel pad, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from IPA-IPE to give the title compound (51.4 mg) as an off-white solid.
Reaction SMILES: C(O[C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])C.[CH2:18]([C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23])[CH2:19][CH3:20]>CS(C)=O>[CH2:18]([C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[CH2:19][CH3:20]
Reactant: CCOc1c(Nc2ccccc2O)c(=O)c1=O
Reactant: CCCc1ccccc1N
Solvent: CS(C)=O
Product: CCCc1ccccc1Nc1c(Nc2ccccc2O)c(=O)c1=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethoxy-4-(2-hydroxyanilino)-cyclobut-3-ene-1,2-dione (50 mg, 0.21 mmol) in DMSO (1.5 mL) was added 2-propylaniline (0.030 mL, 0.21 mmol) and reaction was stirred at 110° C. overnight. Reaction was purified on HPLC (acetonitrile:water) and product was concentrated down. Solid was dried in vacuo. LC-MS (m/z) 323 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[O:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[CH:21]3[O:17][CH:18]([CH:19]=[CH:20]3)[CH:13]2[C:14]([OH:16])=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: c1ccoc1
Reactant: COc1ccc(S(=O)(=O)C=CC(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(S(=O)(=O)C2C3C=CC(O3)C2C(=O)O)cc1
Temperature: 55 °C

Procedure:
3-(4-Methoxyphenylsulfonyl)propenoic acid (200 mgs), excess furan (5.0 ml), and dry toluene (5.0 ml) were combined and warmed to 55° C. (at which time starting material went into solution) for overnight. The cooled reaction was concentrated in vacuo to a tan solid which was a mixture of starting material and product. The material was taken up in toluene (5 ml) and furan (10 ml) and heated to 69° C. overnight. The cooled reaction mixture was concentrated in vacuo to give 251 mgs of crude 3-(4-Methoxyphenylsulfonyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid as a dark tan solid.
Reaction SMILES: Cl.[C:2]([NH:5][C@@H:6]1[CH2:10][NH:9][C@@H:8]([CH3:11])[CH2:7]1)(=[O:4])[CH3:3].C(N(CC)CC)C.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:2]([NH:5][C@@H:6]1[CH2:10][N:9]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:8]([CH3:11])[CH2:7]1)(=[O:4])[CH3:3]
Reactant: CC(=O)N[C@@H]1CN[C@@H](C)C1
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@H]1C[C@H](C)N(Cc2ccccc2)C1

Procedure:
(2S,4S)-4-acetamido-2-methylpyrrolidine hydrochloride from the previous step is suspended in methylene chloride, triethylamine and benzyl bromide are added and the mixture heated at reflux. The product is obtained after washing and evaporation of the solvent.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([O:9][CH2:10][CH:11]=O)[CH2:6][CH:7]=[CH2:8])[CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].Cl.[NH2:19][OH:20]>C(O)C.O>[CH:1]1([CH2:4][CH:5]([O:9][CH2:10]/[CH:11]=[N:19]/[OH:20])[CH2:6][CH:7]=[CH2:8])[CH2:3][CH2:2]1
Reactant: NO
Reactant: C=CCC(CC1CC1)OCC=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCC(CC1CC1)OC/C=N/O
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
[(1-Cyclopropylpent-4-en-2-yl)oxy]acetaldehyde (C67) (17 g from the previous step, ≦83 mmol) was dissolved in a 2:1 mixture of ethanol and water (450 mL). Sodium acetate (41 g, 500 mmol) was added; after the reaction mixture had been stirred for 15 minutes, hydroxylamine hydrochloride (98%, 21 g, 300 mmol) was added. The reaction mixture was heated to 60° C. for 24 hours. The reaction mixture was concentrated under reduced pressure to remove ethanol and extracted with dichloromethane (3×140 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo at 22° C. Silica gel chromatography (Gradient: 0% to 20% ethyl acetate in petroleum ether) provided the product as a colorless oil. By 1H NMR analysis, this material consisted of a roughly 1:1 mixture of E and Z oxime isomers. Yield: 10 g, 55 mmol, 49.6% over two steps.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]([CH3:24])[CH2:13][C:14]2[CH2:15][C:16]3[C:21]([C:22]=2[CH3:23])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:11])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[C:30](OC(=O)C)(=[O:32])[CH3:31]>C1COCC1>[C:30]([NH:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]([CH3:24])[CH2:13][C:14]2[CH2:15][C:16]3[C:21]([C:22]=2[CH3:23])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:11])=[CH:4][CH:3]=1)(=[O:32])[CH3:31]
Reactant: CC1=C(CN(C)C(=O)/C=C/c2ccc(N)nc2)Cc2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(/C=C/C(=O)N(C)CC2=C(C)c3ccccc3C2)cn1
Yield: 249 %

Procedure:
To a solution of (E)-3-[6-aminopyridin-3-yl]-N-methyl-N-(3-methyl-1H-inden-2-ylmethyl)acrylamide (0.159 g, 0.5 mmole), from Example 26, in anhydrous THF (20 mL) was added NaHCO3 (0.126 g, 1.5 mmole) followed by acetic anhydride (0.153 g, 0.15 mmole). The mixture was heated at reflux for 40 hr, then was concentrated under vacuum. The residue was partitioned between H2O and EtOAc, and the organic layer was dried over MgSO4, filtered and concentrated. The residue was triturated with diethyl ether to give the title compound (0.135 g, 74.8%) as an off-white solid: MS (ES) m/e 362.2 (M+H)+. Anal. Calcd for C22H23N3O2.0.25 H2O: C, 72.20; H, 6.47; N, 11.47. Found: C, 72.42; H, 6.45; N, 11.07.
Reaction SMILES: [Si:1]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[Mg]Br.CCCCC>C1COCC1>[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[Si:1]([O:5][CH2:6][CH3:7])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13]
Reactant: CCO[Si](OCC)(OCC)OCC
Reactant: Cc1cc(C)c([Mg]Br)c(C)c1
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCO[Si](OCC)(OCC)c1c(C)cc(C)cc1C
Temperature: 23 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To tetraethyl orthosilicate (3.30 mL, 15.0 mmol, 3.00 equiv) in 10 mL of THF at −30° C. was added 2,4,6-trimethylphenylmagnesium bromide solution (1.0 M in THF, 5.0 mL, 5.0 mmol, 1.0 equiv) dropwise over 10 min. After stiffing at −30° C. for 1 h, the reaction mixture was warmed to 23° C. and was further stirred for 12 h. The reaction mixture was poured into 100 mL of pentane, and was washed three times with water (3×20 mL) and dried over Na2SO4. After filtration, the solvent was removed under reduced pressure. Bulb-to-bulb distillation (125° C., 0.5 Torr) afforded 0.87 g of the title compound as a colorless oil (62% yield). Rf=0.14 (hexanes). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23° C., δ): 6.80 (s, 2H), 3.83 (q, J=7.0 Hz, 6H), 2.51 (s, 6H), 2.26 (s, 3H), 1.24 (t, J=7.0 Hz, 9H). 13C NMR (125 MHz, CDCl3, 23° C., δ): 145.92, 139.79, 128.81, 124.99, 58.10, 23.73, 21.08, 18.15.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=[CH:7]2.[CH2:15]([NH2:21])[C:16]1[O:20][CH:19]=[CH:18][CH:17]=1.C(OP(C#N)(=O)OCC)C.C(N(CC)CC)C>CN(C=O)C>[O:20]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:15][NH:21][C:12]([C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([Br:1])[CH:3]=[N:4][CH:5]=2)[N:10]=1)=[O:14]
Reactant: O=C(O)c1ccc2cncc(Br)c2n1
Reactant: NCc1ccco1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1ccco1)c1ccc2cncc(Br)c2n1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
8-Bromo-[1,6]naphthyridine-2-carboxylic acid (1) is stirred in DMF (20 mL) and furfurylamine (1 equiv.) is added. The reaction mixture is cooled to 0° C. (ice bath) and diethylcyanophosphonate (1 equiv.) is added followed immediately by triethylamine (2 equiv.). The reaction mixture is removed from the ice bath and stirred at room temperature for 26 hrs. The mixture is diluted with water (50 mL) and extracted with methylene chloride (3×50 mL). The combined organic layers are dried over sodium sulfate, filtered, and concentrated in vacuo to afford a tan solid, which is purified via silica gel chromatography (1:1; hexanes:EtOAc to 1:3.) LC/MS (M+H) 332.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([S:8]([C:11]1[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=1)(=[O:10])=[O:9])([CH3:7])[CH3:6])[CH3:2].CN1C=CN=C1S.ClC[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:7])([S:8]([C:11]1[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=1)(=[O:10])=[O:9])[CH2:6][C:36]1[CH:37]=[CH:38][C:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:27]=2)=[CH:34][CH:35]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)c1nccn1C
Reactant: ClCc1ccccc1-c1ccccc1
Agent: Cn1ccnc1S
Product: CCOC(=O)C(C)(Cc1ccc(-c2ccccc2)cc1)S(=O)(=O)c1nccn1C

Procedure:
3-Biphenyl-4-yl-2-methyl-2-(1-methyl-1H-imidazole-2-sulfonyl)-propionic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-methyl-(1-methyl-1H-imidazolesulfonyl)-propionic acid ethyl ester Prepared from (1-Methyl-2-mercapto imidazole and 2-bromo ethyl propionate) (3.0 g, 12.2 mmol) and 4 chloromethylbiphenyl (2.97 g,15 mmol). Yield 5.0 g (99 %); low melting solid; MS 413 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([CH2:19][O:20][C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24]([O:26][CH3:27])=[O:25])[N:16]([CH3:31])[C:15]=3[CH:32]=2)=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1Cl.[CH3:33][O-:34].[Na+].O>CO>[Br:1][C:2]1[C:3]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([CH2:19][O:20][C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24]([O:26][CH3:27])=[O:25])[N:16]([CH3:31])[C:15]=3[CH:32]=2)=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[O:34][CH3:33]
Reactant: C[O-]
Reactant: COC(=O)c1cccc(OCc2nc3ccc(Oc4ncc(Br)c(Cl)c4Br)cc3n2C)c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc(OCc2nc3ccc(Oc4ncc(Br)c(OC)c4Br)cc3n2C)c1
Yield: 8.4 %

Procedure:
The reaction and post-treatment were carried out according to Example (3b) using methyl 3-({6-[(3,5-dibromo-4-chloropyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoate produced in Example (14c) (1.56 g, 2.68 mmol), sodium methoxide (5.0 M solution in methanol, 5.36 mL, 26.8 mmol), water (5 mL) and methanol (100 mL) to obtain the title compound (0.13 g, 8%) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:26])[NH2:25])=[CH:20][CH:19]=2)([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:27]1([CH2:33][NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:27]1([CH2:33][NH:34][C:14]([C:11]2([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24](=[O:26])[NH2:25])=[CH:22][CH:23]=3)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:16])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(C(N)=O)cc2)(C(=O)O)CC1
Reactant: NCC1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc(CC2(C(=O)NCC3CCCCC3)CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of solution of 4-(4-carbamoylbenzyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.38 mmol; 0.5 g) in DMF (5 mL) was added cyclohexylmethylamine (1.18 mmol; 0.154 mL), N,N-diisopropyl-N-ethylamine (2.81 mmol; 0.50 mL) and HBTU (1.38 mmol; 0.51 g), and the resulting mixture was stirred at room temperature overnight. The mixture was purified via reverse phase HPLC. The desired fractions were combined and lyophilized. The residue was dissolved in tetrahydrofuran (2 mL) and a 4N HCl in 1,4-dioxane solution (3 mL), and the resulting mixture was stirred for 4 hours at room temperature and evaporated. The residue was triturated with diethyl ether and dried under vacuum to yield 4-(4-carbamoylbenzyl)-piperidine-4-carboxylic acid cyclohexylmethyl amide as a hydrochloride salt. MS (ESI) m/z 358.40 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:12][NH:13][O:14][CH3:15].[OH-].[Na+]>O1CCCC1.O>[CH3:15][O:14][N:13]([CH3:12])[C:8](=[O:10])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: CNOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CON(C)C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
Based on a procedure found in the literature (Guanti, G.; Banfi, L.; Riva, R. Tetrahedron 50(41), 1994, 11945-11966), a solution of phenylacetic acid (10 g, 73 mmol) in tetrahydrofuran (150 mL) is combined with a solution of N,O-dimethylhydroxylamine hydrochloride (13 g, 130 mmol) in water (150 mL). The pH is adjusted to 4.5 by the addition of 1 N aqueous sodium hydroxide solution. To the mixture is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimine hydrochloride (36 g, 190 mmol) as a solution in water (510 mL) dropwise over 30 minutes. Over the course of the addition, pH is maintained at 4.5 by the addition of 1 N aqueous sodium hydroxide solution. The reaction mixture is allowed to stir for 3 hours at room temperature and is then saturated with sodium chloride and extracted thrice with ethyl acetate. The combined extracts are washed with saturated aqueous sodium hydrogen carbonate (×2), water, and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a golden liquid (13 g, 100%). MS (ES+): (M+H)=180.1
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.N[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1O.ClC1C=CC=CC=1CC(Cl)=O>>[C:12]1([CH:2]2[CH2:3][NH:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:1]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc2c(c1)NCCO2
Reactant: Nc1ccccc1O
Agent: O=C(Cl)Cc1ccccc1Cl
Product: c1ccc(C2CNc3ccccc3O2)cc1

Procedure:
By a procedure similar to that described for the synthesis of 3,4-dihydro-2H-1,4-benzoxazine (Example 142), o-aminophenol and 2-chlorophenylacetyl chloride produces 3,4-dihydro-2-phenyl-2H-1,4-benzoxazine, m.p. 113°-116° which, according to the reaction scheme of Example 110 is converted to the title compound, m.p. 311°-313°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:14]([NH:16][N:17]([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:19][N:17]([CH3:18])[NH:16][C:14]([C:11]1([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:15]
Reactant: CN(C)NC(=O)C1(Cc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)NC(=O)C1(Cc2ccccc2)CCNCC1
Reaction time: 1 h

Procedure:
To a solution of 4-benzyl-4-(N′,N′-dimethylhydrazinocarbonyl)piperidine-1-carboxylic acid tert-butyl ester (0.76 g, 2.02 mmol) in methylene chloride (2 ml) at 0° C. was added trifluoroacetic acid (5 ml) and the mixture was stirred for 60 min. The mixture was quenched with ethanol (20 ml), concentrated in vacuo and stripped three times with methylene chloride to give 4-benzylpiperidine-4-carboxylic acid N′,N′-dimethylhydrazide in quantitative yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH3:27])[CH:3]=1.C([Li])CCC.CN(C)[CH:35]=[O:36].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Si:10]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH:35]=[O:36])=[CH:3][C:4]=1[CH3:27])([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(Br)ccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-bromo-4-(tert-butyldiphenylsilyloxymethyl)-3-methylbenzene (2.19 g) in tetrahydrofuran (30 ml) was added 1.6 M butyllithium in hexane (4.69 ml) by syringe under nitrogen atmosphere at −78° C. After 30 minutes of stirring at −78° C., N,N-dimethylformamide (1.16 ml) was added to the solution at −78° C. and then the mixture was allowed to warm to 5° C. over 1.5 hours. Saturated ammonium chloride solution (10 ml) was added to the mixture and the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give 4-(tert-butyldiphenylsilyloxymethyl)-3-methylbenzaldehyde (1.90 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[N:12]([S:21]([N:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])[CH:13]=[C:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:15]=2)=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[C:36]([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[N:35]1.O>CN(C)C=O.O>[C:51]([O:50][C:49](=[O:55])[NH:48][C:36]1[C:37]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]3[N:12]([S:21]([N:24]([CH3:26])[CH3:25])(=[O:22])=[O:23])[CH:13]=[C:14]([CH2:16][C:17]([CH3:18])([CH3:19])[CH3:20])[N:15]=3)=[O:10])=[CH:4][CH:3]=2)=[CH:38][N:34]([CH3:33])[N:35]=1)([CH3:54])([CH3:53])[CH3:52]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c(NC(=O)OC(C)(C)C)n1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(-c2cn(C)nc2NC(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (23 mg, 0.03 mmol) was added to a degassed, ambient temperature solution of 2-[(4-bromophenyl)acetyl]-4-(2,2-dimethylpropyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (Intermediate 7) (123 mg, 0.28 mmol), sodium carbonate (89 mg, 0.84 mmol) and tert-butyl [1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-3-yl]carbamate (90 mg, 0.28 mmol) in N,N-dimethylformamide/water (2:1) (7.5 mL). After stirring at 80° C. overnight, the reaction mixture was cooled, poured into water and extracted with diethyl ether. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-30% acetone/methylene chloride afforded tert-butyl[4-(4-{2-[1-[(dimethylamino)sulfonyl]-4-(2,2-dimethylpropyl)-1H-imidazol-2-yl]-2-oxoethyl}phenyl)-1-methyl-1H-pyrazol-3-yl]carbamate.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[CH:39]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40]1>>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:44]([CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[O:45])[CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[O:4])(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(N)cc1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)C1CCCC1)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (product of example 49) as described in general procedure D using cyclopentanecarbonyl chloride. The final product was obtained in 57% yield.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C@@H:14]3[CH2:18][C@H:17]([O:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH2:16][NH:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH2:27]=O.[Na]>C(O)C.[OH-].[Na+]>[CH3:27][N:15]1[CH2:16][C@@H:17]([O:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:18][C@H:14]1[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][N:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH2:6][CH2:7]1)=[O:13]
Reactant: O=C([C@@H]1C[C@H](Oc2ccc(F)cc2)CN1)N1CCCN(C2CCC2)CC1
Reactant: C=O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: CN1C[C@@H](Oc2ccc(F)cc2)C[C@H]1C(=O)N1CCCN(C2CCC2)CC1
Reaction time: 18 h
Yield: 63 %

Procedure:
To a solution of (2S,4S)-2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(4-fluoro-phenoxy)-pyrrolidine (26 mg, 0.072 mmol) in ethanol (EtOH; 1 mL) was added formaldehyde (37% in H2O; 150 μL) and sodium triacetoxyborohyrdide (46 mg, 0.216 mmol). After 18 h, the mixture was diluted with 1 M NaOH and, stirred for 1 h, and extracted with CH2Cl2 (3×). The combined organic layers were dried and concentrated. Purification by FCC provided the desired product (17 mg, 63%). MS (ESI): mass calcd. for C21H30FN3O2, 375.23; m/z found, 376.6 [M+H]+. 1H NMR (CDCl3): 6.97-6.91 (m, 2H), 6.80-6.73 (m, 2H), 4.77-4.70 (m, 1H), 3.85-3.53 (m, 4H), 3.37 (dd, J=10.7, 3.8 Hz, 1H), 3.15 (ddd, J=8.9, 8.8, 2.7 Hz, 1H), 2.88-2.78 (m, 1H), 2.66-2.57 (m, 1H), 2.51-2.44 (m, 3H), 2.40 (dd, J=10.9, 5.2 Hz, 2H), 2.35 (s, 3H), 2.16-2.07 (m, 1H), 2.06-1.98 (m, 2H), 1.91-1.78 (m, 4H), 1.71-1.56 (m, 2H).