Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([CH3:37])[CH2:33][CH2:32]2)[CH:30]=1)[C:25](O)=[O:26].CC1CCNCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C>CN(C=O)C.C(Cl)Cl>[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([CH3:37])[CH2:33][CH2:32]2)[CH:30]=1)[C:25]([NH:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([O:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=1)=[O:26]
Reactant: CC1CCN(c2cc(F)cc(C(=O)O)c2)CC1
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Agent: CC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1CCN(c2cc(F)cc(C(=O)Nc3ccc(OCCN4CCOCC4)c4ccccc34)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of [4-(2-morpholin-4-ylethoxy)-1-naphthyl]amine (0.60 g, 2.2 mmol) in DMF (2 ml) is added 3-fluoro-5-(4-methylpiperidin-1-yl)benzoic acid (0.63 g, 2.64 mmol), prepared from 4-methylpiperidine according to conditions described in general procedure E, HBTU (1.25 g, 3.3 mmol) and diisopropylamine (1.15 ml, 6.6 mmol). This mixture is stirred at room temperature overnight and diluted with CH2Cl2 (5 ml), washed with 0.05 N NaOH, dried over Na2SO4 and concentrated. The residue is purified by column chromatography on silica gel (90% EtOAc in hexane) to give 3-fluoro-5-(4-methylpiperidin-1-yl)-N-[4-(2-morpholin-4-ylethoxy)-1-naphthyl]benzamide as a white solid (0.53 g). Mp: 116-118° C.; 1H NMR (300 MHz, DMSO-d6) δ 0.91(d, 6.3 Hz, 3H), 1.15-1.25(m, 2H), 1.67(d, J=12 Hz, 2H), 2.55(bs, 4H), 2.74(t, J=12.3 Hz, 2H), 2.86(s, 2H), 3.59(t, J=4.5 Hz, 4H), 3.82(d, J=12.9 Hz, 2H), 4.29(t, J=5.7 Hz, 2H), 6.93(d, J=12.6 Hz, 1H), 7.00(d, J=8.1 Hz, 1H), 7.12(d, J=8.7 Hz, 1H), 7.37-7.43(m, 2H), 7.51-7.55(m, 2H), 7.81-7.84 (m, 1H), 8.17-8.20(m, 1H), 10.21 (s, 1H); MS 492 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:54]([CH3:56])[CH3:55])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[C:24]([C:29]2[CH:30]=[C:31]4[C:51](=[CH:52][CH:53]=2)[C:35]2[NH:36][C:37]([C@@H:39]5[CH2:43][CH2:42][CH2:41][N:40]5C(OC(C)(C)C)=O)=[N:38][C:34]=2[CH2:33][CH2:32]4)[CH:23]=[CH:22]3)=[CH:17][N:18]=1)=[O:8])=[O:4].Cl.[CH3:58][O:59][C:60]([NH:62][C@H:63]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:64]([OH:66])=O)=[O:61].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl.O.CN(C=O)C>[CH3:58][O:59][C:60]([NH:62][C@H:63]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:64]([N:40]1[CH2:41][CH2:42][CH2:43][C@H:39]1[C:37]1[NH:36][C:35]2[C:51]3[C:31]([CH2:32][CH2:33][C:34]=2[N:38]=1)=[CH:30][C:29]([C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([C:16]1[NH:15][C:14]([C@@H:10]4[CH2:11][CH2:12][CH2:13][N:9]4[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:54]([CH3:56])[CH3:55])=[N:18][CH:17]=1)[CH:28]=[CH:27]2)=[CH:53][CH:52]=3)=[O:66])=[O:61]
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc5c(c4)CCc4nc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]c4-5)ccc3c2)[nH]1)C(C)C
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc5c(c4)CCc4nc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]c4-5)ccc3c2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 64.1 %

Procedure:
(S)-tert-butyl 2-(7-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (246 mg, 0.325 mmol) was dissolved in dichloromethane (10 mL) and HCl (4 M in dioxane, 2 mL) was added. After stirring at RT for 1 h 40 min, the reaction mixture was concentrated. The crude residue was treated with (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (75 mg, 0.358 mmol), COMU (139 mg, 0.325 mmol) and DMF (6 mL). DIPEA was added to the stirred reaction mixture dropwise. After 35 min, 1 mL H2O was added and the crude solution was purified by HPLC to afford the title compound (177 mg, 64%). MS (ESI) m/z 849 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]([O:15]CC)=[O:14])=[CH:10][C:9]=2[S:18][CH:19]([F:21])[F:20])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][C:9]=2[S:18][CH:19]([F:21])[F:20])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(SC(F)F)c(-c2ccc(Cl)cc2)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(SC(F)F)c(-c2ccc(Cl)cc2)[nH]1
Temperature: 0 °C
Yield: 104 %

Procedure:
A solution of ethyl 5-(p-chlorophenyl)-4-[(difluoromethyl)thio]pyrrole-2-carboxylate (166 mg, 0.5 mmol) in ethanol is treated under nitrogen with a solution of sodium hydroxide (100 mg, 2.5 mmol) in water. The reaction mixture is refluxed for three hours, poured into ice-water, treated with hydrochloric acid and extracted with ethyl acetate. The combined organic extracts are washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the title product as an orange solid (158 mg, mp 165° C. (dec)) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [O:1]([CH2:8][CH2:9][Br:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1>>[Br:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]([C:15]2[CH:19]=[CH:20][C:12]([OH:11])=[CH:13][CH:14]=2)=[O:17])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: BrCCOc1ccccc1
Product: O=C(c1ccc(O)cc1)c1ccc(OCCBr)cc1

Procedure:
Melting points (mp) were obtained on a capillary melting point apparatus and are uncorrected. Elemental analyses of all compounds prepared were within ±0.4% of calculated theoretical values. Reaction progress and purity of products were checked by analytical TLC using 0.2 mm silica gel plastic backed layers, and viewed under light of 254 nm wavelength. Proton NMR spectra were obtained at 90 mHz and EIMS were obtained using a direct ion probe. 4-(2-Bromoethoxy)-4'-hydroxybenzophenone was prepared by acylation of 2-phenoxyethyl bromide with 4-hydroxybenzoic acid: mp 136°-138° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[C:5]([O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:4]=1.[C-:19]#[N:20].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:18][O:17][CH2:16][CH2:15][O:14][C:5]1[CH:4]=[C:3]([CH2:2][C:19]#[N:20])[CH:8]=[CH:7][C:6]=1[O:9][CH2:10][CH2:11][O:12][CH3:13]
Reactant: COCCOc1ccc(CCl)cc1OCCOC
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1ccc(CC#N)cc1OCCOC
Temperature: 60 °C
Yield: 91.7 %

Procedure:
4-(Chloromethyl)-1,2-bis{[2-(methyloxy)ethyl]oxy}benzene (0.65 g, 2.4 mmol) was dissolved in N,N-dimethyl formamide (2 mL) followed by the addition potassium cyanide (0.20 g, 3.1 mmol), and the resulting mixture was heated at 60° C. for 18 hours. After cooling to room temperature, it was diluted with ethyl acetate (50 mL), washed with water and brine (20 mL each), dried over sodium sulfate, filtered and concentrated to give an oily residue which was purified by flash chromatography (50% ethyl acetate-hexane) to provide (3,4-bis{[2-(methyloxy)ethyl]oxy}phenyl)acetonitrile (0.59 g, 2.2 mmol, 92% yield). 1H NMR (400 MHz, CDCl3): 6.89-6.93 (m, 3H), 4.16-4.13 (m, 4H), 3.78-3.75 (m, 4H), 3.67 (s, 2H), 3.45 (s, 3H), 3.44 (s, 3H).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:68]=[N:69][C:70]([F:73])=[CH:71][CH:72]=2)[C:56]=1[CH3:74].CC(C)([O-])C.[Na+]>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]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:68]=[N:69][C:70]([F:73])=[CH:71][CH:72]=4)[C:56]=3[CH3:74])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccc(F)nc2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(F)nc2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.025 g, 0.052 mmol), 2,5-dimorpholinopyridin-3-amine (0.103 g, 0.39 mmol), 4-chloro-5,7-difluoro-2-(6-fluoropyridin-3-yl)-3-methylquinoline (0.1 g, 0.32 mmol), Pd2dba3 (0.012 g, 0.013 mmol) and sodium tert-butoxide (0.078 g, 0.81 mmol) in toluene (3.2 mL) at 100° C. for 2.1 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-2-(6-fluoropyridin-3-yl)-3-methylquinolin-4-amine. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.52 (1H, d, J=2.4 Hz), 8.27 (1H, td, J=8.2, 2.4 Hz), 7.82 (1H, d, J=5.9 Hz), 7.67 (1H, d, J=10.0 Hz), 7.56 (1H, d, J=2.7 Hz), 7.47-7.53 (1H, m), 7.38 (1H, dd, J=8.4, 2.6 Hz), 6.47 (1H, d, J=2.7 Hz), 3.61-3.77 (8H, m), 3.15 (2H, br. s.), 2.96-3.05 (4H, m), 2.83 (2H, br. s.), 2.06 (3H, s). Mass Spectrum (ESI) m/e=563.3 (M+1).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]([CH3:32])[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:33]([O-])([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34].B(F)(F)F>ClCCl>[P:33]([O:11][C@@H:10]1[O:12][C@@H:13]([CH3:32])[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:9]1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:34]
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Reactant: C[C@@H]1OC(O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Product: C[C@@H]1O[C@@H](OP(=O)(OCc2ccccc2)OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of 2,3,4-tri-O-benzyl-L-fucopyranose (prepared, for example, according to Wegmann et al., supra.) (0.50 g, 0.86 mmol) in 20 ml of dry dichloromethane and commercially available dibenzyl phosphate which is not further purified (0.24 g, 0.86 mmol) is stirred under a nitrogen atmosphere at room temperature for about 2 h. In the case of very pure dibenzyl phosphate, a catalytic amount of boron trifluoride is added to the mixture. The solution is then concentrated and purified by chromatography (toluene/acetone 9:1). Dibenzyl 2,3,4-tri-O-benzyl-α-L-fucopyranosyl phosphate (4) is obtained in a yield of 90% as a colorless oil (0.54 g). TLC (toluene/acetone 7:1) gives an Rf of 0.60, [α]578 =-68.2 (c=1, chloroform).
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].I([O-])(=O)(=O)=O.[Na+].CC(O)C>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)(Cl)Cl.O.[Ru](Cl)(Cl)Cl>[CH2:1]([CH:6]1[CH2:7][CH2:8][CH:9]([CH:12]=[O:13])[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1CCC(CO)CC1
Agent: Cl[Ru](Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCC1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a slurry of (4-pentyl-cyclohexyl)-methanol (21) (1 equi.), benzyltriethylammonium chloride (0.05 equi.), potassium carbonate (0.15 equi.), and sodium periodate (1.5 equi.) in chloroform-water (1:1) (2 mL/mmole), ruthenium chloride (0.03 equi.) was added at room temperature. The reaction mixture was stirred at 60 C for 2 h. 2-Propanol (0.3 equi.) was added and the reaction mixture was stirred for another 30 min at 60 C, cooled to room temperature, filtered through celite, extracted with dichloromethane, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (dichloromethane) afforded 4-pentyl-cyclohexanecarboxaldehyde (22) as a colorless oil (83%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[N:11]=[N:10]1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:29][C:30]1[C:31](=[O:44])[N:32]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[F:43])[N:33]([CH3:36])[C:34]=1[CH3:35].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([CH3:14])=[C:12]([C:15]([NH:29][C:30]2[C:31](=[O:44])[N:32]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[F:43])[N:33]([CH3:36])[C:34]=2[CH3:35])=[O:17])[N:11]=[N:10]1
Reactant: Cc1c(N)c(=O)n(-c2ccccc2F)n1C
Reactant: Cc1c(C(=O)O)nnn1-c1ccc(Cl)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Nc2c(C)n(C)n(-c3ccccc3F)c2=O)nnn1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(2,4-dichlorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (100 mg, 0.368 mmol), oxalyl chloride (0.048 ml, 0.551 mmol) and DMF (0.057 ml, 0.735 mmol) in DCM (5 ml) was stirred at RT for 15 mins. 4-Amino-2-(2-fluorophenyl)-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate B) (89 mg, 0.404 mmol) was added followed by triethylamine (0.154 ml, 1.103 mmol) and the mixture was stirred at RT for 30 mins. The resulting mixture was diluted with DCM, washed with 0.1M HCl(aq) and sat. NaHCO3(aq) and the organic extracts were passed through a phase separating cartridge and concentrated under reduced pressure. The resultant brown oil was absorbed onto silica and purified by chromatography eluting with 0-10% MeOH in TBME. The product fractions were combined and concentrated under reduced pressure to give a pale pink solid which was triturated with diethylether. The resulting solid was collected by filtration and dried in the vacuum oven to give the title compound as a pale pink solid.
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=2[N:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:11][CH:10]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([O:39]CC)=[O:38])[CH:32]=2)=[O:29])[C:9]1=[O:42])=[O:6])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>O1CCCC1.C(O)C>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=2[N:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:11][CH:10]([NH:27][C:28](=[O:29])[NH:30][C:31]2[CH:32]=[C:33]([CH:34]=[CH:35][CH:36]=2)[C:37]([OH:39])=[O:38])[C:9]1=[O:42])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(c3ccccc3)c3ccc(OC)cc3N(CC(=O)C(C)(C)C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(NC(=O)Nc1cccc(C(=O)O)c1)CN2c1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 55.4 %

Procedure:
1-(1-tert-Butylcarbonylmethyl-2-oxo-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea (1.17 g) was dissolved in a mixed solvent of tetrahydrofuran (20 ml) and ethanol (20 ml), aqueous lithium hydroxide monohydrate (428 mg) solution (10 ml) was added, and the mixture was stirred for 7 hours at room temperature. The reaction mixture was concentrated under reduced pressure, the residue was weakly acidified with 1N hydrochloric acid, extracted with chloroform. The organic layer was successively washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was suspended in ethyl acetate for trituration, collected by filtration, to thereby obtain 616 mg of the titled compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[CH:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:23][NH2:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][NH:24][C:13]([C@@H:9]1[CH:10]=[CH:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CC=C[C@H]1C(=O)O
Reactant: NOCc1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C[C@H]1C(=O)NOCc1ccccc1
Yield: 86 %

Procedure:
(S)-tert-Butyl 2-(benzyloxycarbamoyl)-2,5-dihydro-1H-pyrrole-1-carboxylate is prepared from (S)-1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (Boc-3,4-dehydro-proline) and O-benzylhydroxylamine following Method G (yield=86%). 1H NMR (300 MHz, CHCl3) δ 9.38 (s, 0.5H), 8.46 (s, 0.5H), 7.52-7.22 (m, 5H), 6.01-5.77 (m, 2H), 5.04-4.79 (m, 3H), 4.38-3.99 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.[Br:16][C:17]1[C:22]2[NH:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=[C:19]([O:27][CH3:28])[CH:18]=1>>[Br:16][C:17]1[C:22]2[N:23]([C:2]3[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=3)[CH2:24][CH2:25][O:26][C:21]=2[CH:20]=[C:19]([O:27][CH3:28])[CH:18]=1
Reactant: COc1cc(Br)c2c(c1)OCCN2
Reactant: CC[C@H](COC)n1cc(Br)nc(Br)c1=O
Product: CC[C@H](COC)n1cc(Br)nc(N2CCOc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 556 using 3,5-dibromo-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5-bromo-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine as the starting materials to give an oil. 1H NMR (300 MHz, CDCl3): δ 7.14 (s, 1H), 6.75 (d, J=2.5 Hz, 1H), 6.46 (d, J=2.5 Hz, 1H), 5.08–4.86 (m, 1H), 4.50–3.88 (m, 4H), 3.77 (s, 3H), 3.70–3.52 (m, 2H), 3.36 (s, 3H), 1.92–1.70 (m, 2H), 0.93 (t, J=7.5 Hz, 3H); HRMS (ESI) m/z 501.9992 [(M+H)+, calcd for C18H22N3O4Br2 501.9977].
Reaction SMILES: [OH-].[Li+].[O:3]=[C:4]1[C:13]2[C:8](=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH:5]1[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=1>C1COCC1>[O:3]=[C:4]1[C:13]2[C:8](=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH:5]1[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=1
Reactant: COC(=O)c1ccc(CC2CCc3c(cccc3-c3cccc(C(F)(F)F)c3)C2=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CC2CCc3c(cccc3-c3cccc(C(F)(F)F)c3)C2=O)cc1
Temperature: 40 °C
Reaction time: 24 h
Yield: 92.2 %

Procedure:
Aqueous lithium hydroxide (1 N, 0.11 mL, 0.11 mmol) was added to a solution of methyl 4-((1-oxo-5-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydronaphthalen-2-yl)methyl)benzoate (10 mg, 0.023 mmol) in THF (0.23 mL) in a 1 dram vial. The vial was sealed and heated at 40° C. After 24 h, the reaction mixture was allowed to cool and the volatiles were evaporated under a stream of nitrogen. The residue was diluted with water (0.5 mL), acidified with 1 N aqueous HCl (0.5 mL) and extracted with EtOAc (3×2 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford 9 mg of the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8][C:9]([C:11]([O:14][NH2:15])([CH3:13])[CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:22][C:23]1[S:24][CH:25]=[C:26]([C:28](=O)[C:29]([OH:31])=[O:30])[N:27]=1>CO>[NH2:22][C:23]1[S:24][CH:25]=[C:26](/[C:28](=[N:15]/[O:14][C:11]([C:9]([O:8][CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:10])([CH3:13])[CH3:12])/[C:29]([OH:31])=[O:30])[N:27]=1
Reactant: CC(C)(ON)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: Nc1nc(C(=O)C(=O)O)cs1
Solvent: CO
Product: CC(C)(O/N=C(\C(=O)O)c1csc(N)n1)C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 12 h
Yield: 78.3 %

Procedure:
21.5 g of O-(1-diphenylmethoxycarbonyl-1-methylethyl)hydroxylamine and 12 g of (2-amino-4-thiazolyl)glyoxylic acid are refluxed for 3 hours in 1500 ml of methanol. The cloudy reaction mixture is filtered whilst hot, and then stirred for 12 hours at 10°. The resultant crystalline deposit is filtered off by suction and washed with methanol. 24 g (80%) of the title compound are obtained.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:16]=2[CH3:28])=[O:14])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].C(=O)([O-])[O-].[K+].[K+].Cl[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>O.O1CCCC1>[NH2:4]/[C:2](=[N:3]\[C:36](=[O:37])[O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)/[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[C:16]=2[CH3:28])=[O:14])=[CH:7][CH:6]=1
Reactant: Cc1cc(C(=O)NCc2ccc(C(=N)N)cc2)c(C)n1-c1ccc(F)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NCc2ccc(/C(N)=N/C(=O)OCc3ccccc3)cc2)c(C)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
115 mg of N-[(4-carbamimidoylphenyl)methyl]-1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carboxamide hydrochloride and 115 mg of potassium carbonate were dissolved in 1.4 ml of water and 7 ml of tetrahydrofuran. The mixture was stirred at room temperature, and 0.04 ml of benzyl chloroformate (Sigma-Aldrich) added. Stirring was continued for 1 h, following which the organic layer is removed, and dried in vacuo to obtain the synthetic target. The mass of the compound was verified using LC/MS/MS.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([Cl:19])[C:16]=1[O:17][CH3:18])[O:13][C:12]([CH3:21])([CH3:20])[CH2:11][C:10]2=O.CN1CCCN(C)C1=O>C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([Cl:19])[C:16]=1[O:17][CH3:18])[O:13][C:12]([CH3:21])([CH3:20])[CH:11]=[C:10]2[CH:1]([CH3:3])[CH3:2]
Reactant: COc1c(Br)cc2c(c1Cl)OC(C)(C)CC2=O
Reactant: CC(C)[Mg]Cl
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COc1c(Br)cc2c(c1Cl)OC(C)(C)C=C2C(C)C
Reaction time: 12 h

Procedure:
Following General Procedure C, isopropylmagnesium chloride (2.0 M in THF, 3.15 mL, 6.29 mmol), 6-bromo-8-chloro-7-methoxy-2,2-dimethyl-chroman-4-one (Compound 9, 400 mg, 1.26 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 2 mL) in THF was reacted then quenched with 10% HCl, and stored at room temperature for 12 h. Purification by flash chromatography (silica gel, 95:5 hexane/ethyl acetate) afforded the title compound as a yellow oil.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20](=[O:28])[CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[CH:14]=1)[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>>[O:1]=[C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20](=[O:28])[CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[CH:14]=1)[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:11])[CH3:9]
Reactant: CCCC(CCC)C(=O)Nc1cccc(C(O)CCNC(=O)OC(C)(C)C)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: CCCC(CCC)C(=O)Nc1cccc(C(=O)CCNC(=O)OC(C)(C)C)c1

Procedure:
Oxidation of tert-butyl 3-hydroxy-3-(3-(2-propylpentanamido)phenyl)propylcarbamate by PCC following the method used in Example 16 gives tert-butyl 3-oxo-3-(3-(2-propylpentanamido)phenyl)propylcarbamate.