Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][O:6][CH:5]([CH2:8][OH:9])[CH2:4][O:3]1.[OH-].[K+].[Mn]([O-])(=O)(=O)=[O:14].[K+]>O>[CH3:1][C:2]1([CH3:10])[CH2:7][O:6][CH:5]([C:8]([OH:14])=[O:9])[CH2:4][O:3]1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC1(C)COC(CO)CO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC1(C)COC(C(=O)O)CO1
Temperature: 5 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of (5,5-dimethyl-[1,4]dioxan-2-yl)-methanol (657 mg, 4.5 mmol) in 1 M potassium hydroxide solution (6.7 mL, 6.7 mmol) was stirred at 5° C. A solution of potassium permanganate (1.42 g, 9 mmol) in water (10 mL) was added dropwise maintaining the internal temperature below 10° C. The reaction mixture was stirred at 5° C. for 1 h and then at room temperature for 18 h. The reaction mixture was filtered through Celite and the filter pad was washed with water and methanol and the filtrate was evaporated. The residue was acidified to pH 2 with hydrochloric acid (2 M) and the mixture was extracted with ethyl acetate and chloroform. The organic extracts were combined and washed with a small volume of brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford crude 5,5-dimethyl-[1,4]dioxane-2-carboxylic acid (694 mg, 4.5 mmol) as a waxy solid. LCMS (m/z) 159.1 [M−H], Tr=0.88 min. A solution of 5,5-dimethyl-[1,4]dioxane-2-carboxylic acid (750 mg, 4.7 mmol), oxalyl chloride (600 mg, 0.4 mL, 4.7 mmol) and N,N-dimethylformamide (2 drops) in dichloromethane (15 mL) was stirred at room temperature under nitrogen for 2 h. A solution of benzyl alcohol (508 mg, 0.5 mL, 4.7 mmol) in dichloromethane (2 mL) was added and the reaction mixture was stirred at room temperature for 20 h. Additional benzyl alcohol (0.5 mL, 4.7 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated and the residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 9:1 to 1:1 to afford the title compound (870 mg, 74%) as an oil. 1H NMR (300 MHz, CDCl3) δ 1.19 (s, 3H), 1.32 (s, 3H), 3.43 (d, J=11.4 Hz, 1H), 3.72 (d, J=11.4 Hz, 1H), 3.88-3.92 (m, 2H), 4.21 (dd, J=8.2, 4.7 Hz, 1H), 5.24 (s, 2H), 7.34-7.39 (m, 5H). LCMS (m/z) 273.1 [M+Na], Tr=2.41 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23](=[O:24])[C:22]4[CH:25]=[CH:26][C:27]5[N:28]=[C:29]([CH3:32])[NH:30][C:31]=5[C:21]=4[O:20][C:19]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:40](OC(=O)NC1(C2C=CC(C3C(=O)C4C(=C(NC)C(N)=CC=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C>>[C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23](=[O:24])[C:22]4[CH:25]=[CH:26][C:27]5[N:28]=[C:29]([CH3:32])[N:30]([CH3:40])[C:31]=5[C:21]=4[O:20][C:19]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c2[nH]1
Reactant: CNc1c(N)ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Product: Cc1nc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c2n1C
Yield: 39 %

Procedure:
Following the procedure used to prepare {1-[4-(2-methyl-6-oxo-8-phenyl-1,6-dihydro-chromeno[7,8-d]imidazol-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, {1-[4-(7-amino-8-methylamino-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a white solid (40 mg, 39%). LCMS (Method H): RT=3.34 min, [M+H]+=536.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=4)=[C:15]4[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]1([NH:38][C:39]2[CH:40]=[CH:41][C:42]3[N:43]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[C:44]4[C:49]([C:50]=3[CH:51]=2)=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.C(O[Na])(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>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].C1(C)C=CC=CC=1>[C:28]1([N:38]([C:4]2[CH:3]=[CH:2][C:1]([C:7]3[C:20]4[C:15]([C:14]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[C:13]5[C:8]=3[CH:9]=[CH:10][CH:11]=[CH:12]5)=[CH:16][CH:17]=[CH:18][CH:19]=4)=[CH:6][CH:5]=2)[C:39]2[CH:40]=[CH:41][C:42]3[N:43]([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[C:44]4[C:49]([C:50]=3[CH:51]=2)=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: Brc1ccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)cc1
Reactant: c1ccc(-n2c3ccccc3c3cc(Nc4cccc5ccccc45)ccc32)cc1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: c1ccc(-c2c3ccccc3c(-c3ccc(N(c4ccc5c(c4)c4ccccc4n5-c4ccccc4)c4cccc5ccccc45)cc3)c3ccccc23)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
2.0 g (5.0 mmol) of 9-phenyl-10-(4-bromophenyl)anthracene (PA), 1.9 g (5.0 mmol) of 3-[N-(1-naphthyl)amino]-9-phenylcarbazole (PCN), 2.1 g (20 mmol) of t-butoxysodium (abbreviation: t-BuONa) were put in a 100 mL three neck flask, and nitrogen was substituted for air in the flask, and then 40 mL of toluene and 0.1 mL of tri(t-butyl)phosphine (10 wt % hexane solution) (abbreviation: P(tBu)3) were added, and the 100 mL three neck flask was depressurized and degassed. After degassing, 30 mg (0.05 mmol) of bis(dibenzylideneacetone)palladium(0) was added, and stirred for 3 hours at 80° C. After reaction, a reaction solution was washed with water and saturated saline in this order, and then an organic layer was dried with magnesium sulfate. After natural filtration, a solid which was obtained by concentrating the filtrate was purified with silica gel column chromatography (hexane:toluene=7:3). When a target substance was recrystallized with dichloromethane hexane, 1.5 g of a yellow-solid target substance was obtained in a yield of 43% (Synthesis Scheme (g-2)). This compound was measured by a nuclear magnetic resonance (NMR) method and confirmed to be was PCNPA.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OO)(=[O:14])C.C(C1C=CC=CC=1O)CCC>C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[C:9]([OH:14])[C:8](=[CH:7][CH:6]=1)[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CC(=O)OO
Agent: CCCCc1ccccc1O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(O)c(O)c1
Yield: 77 %

Procedure:
After the manner of the procedure of Comparative Example 1, the reaction was carried out by using 20 ml of ethyl acetate as a solvent for para-tert.-butyl phenol and 0.5% by weight of Na5R'5 (P3O10)2 (R' = 2-ethylhexyl, tradename "Victor Wet 35B") as a peracetic acid stabilizer based on the amount of butyl phenol used. Consequently, the conversion of parta-tert.-butyl phenol was 7.2%, 4-tert.-butyl pyrocatechol was formed in a yield of 77% based on the converted butyl phenol and the conversion of peracetic acid was 98.5%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=3)=[CH:25][N:24]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:44]1[CH2:48][CH2:47][CH2:46][C@H:45]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC(=O)OCC>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[N:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=3)=[CH:25][N:24]=2)=[CH:21][CH:22]=1)[C:13]([N:44]1[CH2:48][CH2:47][CH2:46][C@H:45]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)OCc4ccccc4)C(=O)O)cc3)nc2)cc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)OCc4ccccc4)C(=O)N4CCC[C@H]4C(=O)OC(C)(C)C)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
Prepared using General Procedure 7. A stirred solution of (S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoic acid (419 mg, 0.738 mmol), (S)-tert-butyl pyrrolidine-2-carboxylate HCl (153 mg, 0.738 mmol) and TEA (257 μl, 1.845 mmol) in DMF (6 mL) was cooled to 0° C. and HATU (295 mg, 0.775 mmol) was slowly added over 5 minutes. The reaction was stirred at room temperature for 2 h, then diluted with 1M citric acid (30 mL) and iso-hexanes (20 mL). EA (100 mL) was added and the organic layer was isolated, washed with brine (100 mL), dried with MgSO4. The solvent was removed and the crude product was purified by chromatography 0-20% ACN in DCM to afford 436 mg (81%) of (S)-tert-butyl 1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylate INT-25 as a viscous oil. LCMS-ESI (m/z) calculated for C43H52N4O6: 720.4; no m/z observed, tR=11.45 min (Method 10).
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)=[O:6].[CH3:19]COCC>CC(O)=O>[I:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14]([O:16][CH3:19])=[O:15])=[CH:9][CH:8]=1)=[O:6]
Reactant: CCOCC
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)CCCI)cc1
Solvent: CC(=O)O
Product: COC(=O)C(C)(C)c1ccc(C(=O)CCCI)cc1
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 12.6 g of 4-(4-iodo-1-oxobutyl)-α,α-dimethylphenylacetic acid, prepared in accordance with Example 3, in 100 mL of Et2O cooled in an ice bath, was added 40 mL of ethereal CH2N2. The mixture was stirred at 0 C for few minutes, then let stand for 2 hr. A few drops of AcOH were added to decompose excess CH2N2, then the mixture was filtered and stripped to afford 12.6 g (96%) of methyl 4-(4-iodo-1-oxobutyl)-α,α-dimethylphenylacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:41][S:42]([CH2:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)(=[O:44])=[O:43]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:38])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:51]3[CH2:52][CH2:53][N:48]([CH2:47][CH2:46][CH2:45][S:42]([CH3:41])(=[O:43])=[O:44])[CH2:49][CH2:50]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH2:33][CH3:34])(=[O:31])=[O:32])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(S(=O)(=O)CC)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(S(=O)(=O)CC)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(4-ethanesulfonyl-2-ethoxy-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide) gave the title compound. HR-MS (ES, m/z) calculated for C36H53N4O4SCl2 [(M+H)+] 763.2152, observed 763.2150.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=2)=[CH:5][CH:4]=1)=O.C(O)(=O)C.[CH3:26][CH:27]([CH3:31])[CH2:28][CH2:29][NH2:30].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[ClH:46].O1CCOCC1>C(Cl)Cl.CCOCC>[ClH:46].[CH3:26][CH:27]([CH3:31])[CH2:28][CH2:29][NH:30][CH2:1][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=2)=[CH:5][CH:4]=1
Reactant: CC(C)CCN
Reactant: N#Cc1ccc(Oc2ccc(C=O)c3ccccc23)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)CCNCc1ccc(Oc2ccc(C#N)cn2)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-(4-formylnaphthalen-1-yloxy)nicotinonitrile (Preparation 1) (1.50 g, 5.47 mmol) in DCM (15 mL) was added acetic acid (0.98 mL, 16.42 mmol) and 3-methylbutylamine (1.91 mL, 16.42 mmol). After 1 h NaBH(OAc)3 (3.48 g, 16.42 mmol) and DCM (20 mL) were added. The reaction was stirred at rt for a further 16 h. The mixture was partitioned between DCM (150 mL) and saturated NaHCO3 (200 mL), the organic phase washed with water (200 mL) and dried (MgSO4). Solvent removed in vacuo. To the residue was added ether (10 mL) followed by 4M HCl in dioxane (1.0 mL, 4.0 mmol). A further 40 mL of ether was added and the resulting precipitate filtered and dried under vacuum to give the title compound: RT=2.84 min; m/z (ES+)=346.2 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@@H:13]([NH2:15])[CH2:12]1.[Cl:16][C:17]1[C:18]([C:23]([CH3:28])([CH3:27])[C:24](O)=[O:25])=[N:19][CH:20]=[CH:21][N:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]1[CH2:12][C@H:13]([NH:15][C:24](=[O:25])[C:23]([C:18]2[C:17]([Cl:16])=[N:22][CH:21]=[CH:20][N:19]=2)([CH3:28])[CH3:27])[CH2:14]1
Reactant: N[C@H]1C[C@@H](Nc2nc3ccccc3s2)C1
Reactant: CC(C)(C(=O)O)c1nccnc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C(=O)N[C@H]1C[C@@H](Nc2nc3ccccc3s2)C1)c1nccnc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a round bottomed flask was added cis-N1-(benzo[d]thiazol-2-yl)cyclobutane-1,3-diamine (Intermediate 32, 0.3010 g, 1.030 mmol), 2-(3-chloropyrazin-2-yl)-2-methylpropanoic acid (Intermediate 29, 0.248 g, 1.236 mmol), HATU (0.509 g, 1.339 mmol, GenScript Corp), and triethylamine (0.573 ml, 4.12 mmol, Sigma-Aldrich Chemical Company, Inc.) in DCM (2.060 ml) to stir at room temperature for 4 hours. The reaction mixture was diluted with water and extracted with CH2Cl2. The organic extract was washed with water, saturated NaHCO3, saturated NaCl, dried over MgSO4, filtered and concentrated in vacuo. The crude product (592.4 mg) was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (50 g), eluting with a gradient of 10% to 100% EtOAc in hexane, to provide the title compound (0.3181 g, 0.791 mmol, 77% yield). LCMS showed product peak at 1.536 min (m+1=401.9). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52 (s, 4 H) 1.88-2.03 (m, 1 H) 2.60-2.69 (m, 1 H) 3.87-4.03 (m, 1 H) 6.97-7.07 (m, 1 H) 7.18-7.26 (m, 1 H) 7.39 (d, J=7.43 Hz, 1 H) 7.63-7.71 (m, 1 H) 7.76 (d, J=6.65 Hz, 1 H) 8.27 (d, J=6.26 Hz, 1 H) 8.45 (d, J=2.54 Hz, 1 H) 8.68 (d, J=2.54 Hz, 1 H)
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].C(N(CC)CC)C.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:23]>C(O)C>[CH3:1][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:23]
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CNCc1ccccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(CC(=O)c1ccc(F)cc1)Cc1ccccc1[N+](=O)[O-]

Procedure:
135.8 g (0.67 mol) of methyl-(2-nitrobenzyl)-amine and 187.5 ml (1.339 mols) of triethylamine are dissolved in 1.87 liters of ethanol at room temperature, with stirring, and 148 g (0.682 mol) of 2-bromo-1-(4-fluorophenyl)ethanone are then added in portions. The reaction mixture is stirred for 3 hours. The solvent is then stripped off on a rotary evaporator and the residue is dissolved in 1.3 liters of toluene. The toluene phase is washed several times with H2O and dried over Na2SO4, and HCl/diethyl ether is added. The glutinous precipitate is separated from the toluene by decanting and crystallized with acetone. The colorless precipitate is filtered off with suction and dried.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH2:20][OH:21])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:22])[CH2:6][C@@H:5]1[CH3:23])(=[O:3])[CH3:2].N1C=CN=C1.Cl[Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C)C=O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH2:20][O:21][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:22])[CH2:6][C@@H:5]1[CH3:23])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3cn(CCO)nn3)cc2[C@H](N)C[C@@H]1C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3cn(CCO[Si](C)(C)C(C)(C)C)nn3)cc2[C@H](N)C[C@@H]1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.1 %

Procedure:
To 2-{4-[(2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]-1H-1,2,3-triazol-1-yl}ethanol (for a preparation see intermediate 45) (358 mg, 0.834 mmol) and imidazole (114 mg, 1.667 mmol) in N,N-dimethylformamide (DMF) (15 mL), was added chloro(1,1-dimethylethyl)dimethylsilane (151 mg, 1.0 mmol) and the resulting reaction mixture was stirred at room temperature for 16 h. Another equivalent of imidazole (114 mg, 1.667 mmol) and chloro(1,1-dimethylethyl)dimethylsilane (151 mg, 1.000 mmol) were then added and after 15 min the resulting mixture was partitioned between EtOAc and water. The layers were separated and the aqueous phase was extracted three times with EtOAc. The combined organic layers were washed twice with brine, dried over MgSO4 and concentrated in vacuovacuo. Purification of the residue on SP4 using a 25 G silica cartridge (gradient:0 to 10% MeOH in DCM) gave (2S,4R)-1-acetyl-6-[1-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-1H-1,2,3-triazol-4-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (202 mg, 0.451 mmol, 54.1% yield) as a yellow oil.
Reaction SMILES: C(=O)(O)[O-].[Na+].[I-].[Li+].[CH2:8]([C:10]1[C:11](=[O:27])[NH:12][C:13](=[O:26])[NH:14][C:15]=1[C:16](=[O:25])[C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1)[CH3:9].C1(C)C(S(O[CH2:38][CH2:39][C:40]2[CH2:44][CH2:43][CH2:42][CH:41]=2)(=O)=O)=CC=CC=1>CN(C)C=O>[C:40]1([CH2:39][CH2:38][N:14]2[C:15]([C:16](=[O:25])[C:17]3[CH:18]=[C:19]([CH3:24])[CH:20]=[C:21]([CH3:23])[CH:22]=3)=[C:10]([CH2:8][CH3:9])[C:11](=[O:27])[NH:12][C:13]2=[O:26])[CH2:44][CH2:43][CH2:42][CH:41]=1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: Cc1ccccc1S(=O)(=O)OCCC1=CCCC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(CCC2=CCCC2)c(=O)[nH]c1=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
A mixture of sodium bicarbonate (0.10 g, 1.2 mmol) and lithium iodide (13 mg, 0.1 mmol) were added to dimethylformamide solution (10 ml) of 5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione (0.27 g, 1.0 mmol) and 2-(cyclopent-1-en-1-yl)ethyl toluenesulfonate (0.27 g, 1.0 mmol). And then, the reaction mixture was stirred at 90° C. for overnight, concentrated for removement of dimethylformamide, extracted with dichloromethane, dried, filtered and separated by column chromatography to give a desirable product as a white solid (148 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[C:24]([O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:40])[CH:23]=3)[CH2:18][CH2:17]2)[CH3:15])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:32]=[CH:31][C:25]([C:26]([OH:28])=[O:27])=[C:24]([O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:40])[CH:23]=3)[CH2:20][CH2:21]2)[CH3:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(N2CCN(C(C)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1Oc1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(c1ccccc1-c1ccc(Cl)cc1)N1CCN(c2ccc(C(=O)O)c(Oc3ccccc3Cl)c2)CC1
Reaction time: 8 h

Procedure:
A mixture of EXAMPLE 110D (300 mg) in tetrahydrofuran (10 mL) and methanol (10 mL) at 50° C. was treated with 10% NaOH (2085 μL), stirred overnight, neutralized with HCl and concentrated. The concentrate was taken up in water and extracted with dichloromethane. The organic layer was dried over Na2SO4, filtered and concentrated.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH3:29][N:30]([CH3:34])[C:31](Cl)=[S:32]>O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][C:31](=[S:32])[N:30]([CH3:34])[CH3:29])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1
Reactant: CN(C)C(=S)Cl
Reactant: COC(=O)Cc1cc(O)c2cc(F)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cc(OC(=S)N(C)C)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71.4 %

Procedure:
A mixture of (6-fluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (500 mg, 2.14 mmol), finely ground potassium carbonate (591 mg, 4.28 mmol), and N,N-dimethylformamide (10 mL) was stirred at room temperature for 20 minutes. Dimethylthiocarbamoyl chloride (290 mg, 2.35 mmol) was added in one portion. After being stirred for 2 hours, the resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with water (15 mL) and brine (20 mL), then dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (gradient elution with 0-30% ethyl acetate in hexanes) to afford (4-dimethylthiocarbamoyloxy-6-fluoro-naphthalen-2-yl)-acetic acid methyl ester (491 mg, 71.5%) as a yellow oil.