Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH:10]3OC(C)(C)C(C)(C)O3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:32]([NH:34][C:35]([C:37]2[N:38]=C(Cl)[S:40][CH:41]=2)=[O:36])[CH3:33])[CH:23]=[C:24]([F:31])[C:25]=1[NH:26][S:27]([CH3:30])(=[O:29])=[O:28].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:31][C:24]1[CH:23]=[C:22]([CH:32]([NH:34][C:35]([C:37]2[N:38]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[CH:5]=3)[S:40][CH:41]=2)=[O:36])[CH3:33])[CH:21]=[C:20]([F:19])[C:25]=1[NH:26][S:27]([CH3:30])(=[O:28])=[O:29]
Reactant: CC1(C)OC(c2cccc(C3CC3)c2)OC1(C)C
Reactant: CC(NC(=O)c1csc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1csc(-c2cccc(C3CC3)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 37 %

Procedure:
2-(3-Cyclopropyl-phenyl)-4,4,5,5-tetramethyl-[1,3]dioxolane (63 mg, 0.26 mmol) and 2-chloro-thiazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (55 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (23 mg, 38%) after purification by flash chromatography on silica gel (% EtOAc in hexane=25%˜100%).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]([C:23]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)=[O:24])[NH2:22]>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:22][NH:21][C:23]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)=[O:24])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Yield: 78.1 %

Procedure:
Following a procedure analogous to Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 and tert-butyl 4-(hydrazinecarbonyl)piperidine-1-carboxylate (642 mg, prepared following a procedure analogous to Reference Example 5 and Reference Example 6), 552.7 mg of the title compound was afforded (yield 78.1%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][C:6]=1[C:7]([N:9]1[CH2:13][CH2:12][CH:11]([O:14]S(C)(=O)=O)[CH2:10]1)=[O:8])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:29]=[C:30](O)[CH:31]=[CH:32][C:33]=1[Cl:34]>>[Cl:27][C:28]1[CH:29]=[C:30]([CH:31]=[CH:32][C:33]=1[Cl:34])[O:14][CH:11]1[CH2:12][CH2:13][N:9]([C:7]([C:6]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:5]=2[O:4][CH:1]([CH3:3])[CH3:2])=[O:8])[CH2:10]1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(OS(C)(=O)=O)C1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(Oc2ccc(Cl)c(Cl)c2)C1
Yield: 32 %

Procedure:
Prepared in analogy to Example 3(c) from rac-methanesulfonic acid 1-(2-isopropoxy-5-methanesulfonyl-benzoyl)-pyrrolidin-3-yl ester (Example 14(a)) and 3,4-dichlorophenol. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 32%). MS (m/e): 476.3 ({37Cl}M+H+, 10%), 474.3 ({37C,35Cl}M+H+, 80%), 472.2 ({35Cl}M+H+, 100%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[C:4]([F:13])[C:3]=1F.C(=O)([O-])[O-].[K+].[K+].[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(#N)C>[F:13][C:4]1[C:5]([O:11][CH3:12])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([F:1])[C:3]=1[N:24]1[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]1
Reactant: COc1c([N+](=O)[O-])cc(F)c(F)c1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c([N+](=O)[O-])cc(F)c(N2CCN(C(=O)OC(C)(C)C)CC2)c1F
Temperature: 80 °C

Procedure:
To a solution of the product of Example 52A (500 mg, 2.4 mmol) in acetonitrile (20 mL) was added potassium carbonate (660 mg, 4.8 mmol) and tert-butyl piperazine-1-carboxylate (900 mg, 4.8 mmol) and the mixture was heated to 80° C. for 3 hours. After cooling, the mixture was filtered, concentrated and purified by flash chromatography on silica gel (200-300 mesh) eluting with 20/1 petroleum ether/ethyl acetate to provide the title compound. MS: 374 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([CH:12]1[CH2:14][CH2:13]1)=[O:11].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:15][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:10]([CH:12]1[CH2:14][CH2:13]1)=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(Cc1ccc(F)cc1F)C1CC1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(C1CC1)C(Br)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 84.5 %

Procedure:
To a solution of 2-(2,4-difluorophenyl)-1-cyclopropylethanone (329 mg) in carbon tetrachloride (10 ml) was added N-bromosuccinimide (360 mg) and 75% benzoyl peroxide with stirring at room temperature, and the resulting mixture was refluxed for 3.5 hours. After the reaction mixture was filtrated, 1N aqueous sodium hydroxide solution was added to the filtrate. The resulting mixture was extracted with ethyl acetate, and the extract was washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to afford the title compound (390 mg, yield: 84%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([N:13]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20]([C:22]3[NH:23][C:24]([CH3:29])=[C:25]([Cl:28])[C:26]=3[Cl:27])=[O:21])[C@H:15]([O:30][CH3:31])[CH2:14]2)=[N:4][CH:3]=1.[CH3:32][O:33][C:34](Cl)=[O:35]>N1C=CC=CC=1>[Cl:27][C:26]1[C:25]([Cl:28])=[C:24]([CH3:29])[NH:23][C:22]=1[C:20]([NH:19][C@H:16]1[CH2:17][CH2:18][N:13]([C:5]2[CH:6]=[C:7]([C:2]([NH:1][C:34]([O:33][CH3:32])=[O:35])=[CH:3][N:4]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:14][C@H:15]1[O:30][CH3:31])=[O:21]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)c1cc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)ncc1N
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)ncc1NC(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methylchlorofomate (15 μl, 0.19 mmol) was added to a solution of 60 mg (0.13 mmol) of Cis(±)-ethyl 5-amino-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)isonicotinate (Example 194) in 3 ml pyridine. After stirring at room temperature overnight, 7 μl more methylchloroformate was added. Solvent was removed and the residue was partitioned between EtOAc and NaHCO3 (aqueous). The EtOAc was separated and washed with water and brine. Drying (MgSO4) and removal of solvent gave 43 mg of product. NMR (d6-DMSO): 1.3 (t, 3H), 1.7 (m, 2H) 2.2 (s, 3H), 3.1 (m, 2H), 3.3 (s, 3H), 3.5 (m, 1H), 3.6 (s, 3H), 4.0-4.3 (m, 4H), 4.6 (m, 1H), 7.05 (m, 1H), 7.15 (m, 1H), 8.2 (s, 1H), 9.1 (s, 1H), 12.2 (s, 1H).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH:27]2[CH2:29][CH2:28]2)[CH2:25][SH:26])[C:5]1=[O:30])[CH:2]=[CH2:3].Br[CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35].[H-].[Na+]>CN(C=O)C>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH:27]2[CH2:29][CH2:28]2)[CH2:25][S:26][CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: CCC(Br)CC
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CS)C2CC2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CSC(CC)CC)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-mercaptoethyl)-3-methylpiperidin-2-one (49 mg, 0.10 mmol; Example 366, Step A) and 3-bromopentane (51 μl, 0.41 mmol) in DMF (0.52 mL) was added 60% sodium hydride in mineral oil (17 mg, 0.41 mmol) at 25° C. The reaction was stirred at 25° C. for 1 h and then heated to 60° C. After being stirred at 60° C. overnight, the reaction was quenched (10% aq. citric acid), extracted (2×EtOAc), and washed (3× brine). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (4 g SiO2, 9% and 18% EtOAc/hex) provided the title compound.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[N:5]1[C:14]2N[CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[CH:21]([OH:23])[CH3:22])[CH:6]=1>>[OH:23][CH:21]([C:20]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[C:7]1[CH:8]=[C:9]2[C:14](=[N:5][CH:6]=1)[N:1]([C:2]([NH2:4])=[O:3])[CH2:12][CH2:11][CH2:10]2)[CH3:22]
Reactant: NC(N)=O
Reactant: CC(O)c1ccncc1-c1cnc2c(c1)CCCN2
Product: CC(O)c1ccncc1-c1cnc2c(c1)CCCN2C(N)=O

Procedure:
The titled product is synthesized according to the procedure of Urea Formation Method II using 1-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-4-yl]-ethanol.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][C:27]([O:26][C:25]([F:24])([F:36])[F:37])=[CH:28][CH:29]=3)[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(CNC(=O)c3ccc(OC(F)(F)F)cc3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.5 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.49 g, 1.5 mmol) in acetonitrile (10 mL), was added 4-trifluoromethoxy-benzoyl chloride (0.34 mL, 2.2 mmol) and N,N-diisopropyl ethylamine (0.63 mL, 3.6 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-4-trifluoromethoxy-benzamide as a white solid (370 mg, 54% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.54 min (98.6%); mp, 258-260° C.; 1HNMR (DMSO-d6) 2.18-2.23 (m, 1H, CHH), 2.59-2.92 (m, 6H, CHCH2, CH3), 4.98-5.09 (m, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, Ch), 7.34-8.07 (m, 7H, Ar), 9.05 (t, J=5 Hz, 1H, CH2NH), 11.05 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.82, 23.29, 30.60, 42.22, 56.54, 117.66, 120.70, 124.15, 125.52, 129.59, 133.30, 133.96, 140.65, 148.51, 150.33, 154.84, 161.10, 165.05, 169.54, 172.63. LCMS MH=489; Anal Calcd For C23H19N4O5F3: C, 56.56; H, 3.92; N, 11.47; F, 11.67. Found: C, 56.32; H, 3.60; N, 11.23; F, 11.56.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:14]=[CH:13][C:12]3[NH:11][CH2:10][C@@H:9]4[CH2:15][C@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=2[C:8]=34)=[N:2]1.ClCl>O=[Mn]=O>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:14]=[CH:13][C:12]3[NH:11][CH:10]=[C:9]4[CH2:15][C@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=2[C:8]=34)=[N:2]1
Reactant: CCCN(CCC)[C@@H]1Cc2c(-c3ccon3)ccc3c2[C@H](CN3)C1
Agent: O=[Mn]=O
Agent: ClCl
Product: CCCN(CCC)[C@H]1Cc2c[nH]c3ccc(-c4ccon4)c(c23)C1
Reaction time: 4 h
Yield: 14.2 %

Procedure:
A mixture of (-)(2aR,4S)-6-(3-isoxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (400 mg, 1.2 mmol) and 1 g of MnO2 in 100 ml of CH2 Cl2 was sonicated at 50-55 KHz for four hours. The reaction mixture was warmed to reflux during the time period. After four hours, the reaction mixture was filtered through a celite pad and the filtrate was concentrated to dryness in vacuo. The resulting residue was chromatographed (flash column, silica gel, EtOAc) to provide 55 mg of title product as an oil. MS m/e 323(FD) NMR (300 MHz, CDCl3) δ 0.90 (t, 6H); 1.2-1.6 (m, 5H); 2.2-3.6 (m, 8H); 6.6 (s, 1H); 6.9 (s, 1H); 7.2 (d, 1H); 7.4 (d, 1H); 8.0 (bs, 1H); 8.4 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3].[CH3:31][C:32]1[NH:33][CH:34]=[CH:35][N:36]=1>CO.[Cu-]=O>[CH3:3][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N:33]3[CH:34]=[CH:35][N:36]=[C:32]3[CH3:31])[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:1]
Reactant: Cc1ncc[nH]1
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: O=[Cu-]
Solvent: CO
Product: CC(=O)N1c2ccc(-n3ccnc3C)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 37 %

Procedure:
A mixture of 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 52) (500 mg, 1.2 mmol), 2-methylimidazole (99 mg, 1.2 mmol) and copper(I) oxide (10 mg, 0.126 mmol) in methanol (10 mL) was stirred in air at room temperature for 24 h. A further portion of copper(I) oxide (10 mg, 0.126 mmol) was added and stirring was continued for 48 h. The reaction mixture was then filtered through celite and most of the solvent were removed in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 5% MeOH in DCM) gave 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(2-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (167 mg, 0.451 mmol, 37%) as a colourless foam.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH:15]3[CH2:19][CH2:18][O:17][CH2:16]3)[CH:11]=[C:10]([C:20](O)=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:25][C:26]1[N:31]=[CH:30][C:29]([C@H:32]([NH2:34])[CH3:33])=[CH:28][CH:27]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH:15]3[CH2:19][CH2:18][O:17][CH2:16]3)[CH:11]=[C:10]([C:20]([NH:34][C@@H:32]([C:29]3[CH:30]=[N:31][C:26]([CH3:25])=[CH:27][CH:28]=3)[CH3:33])=[O:21])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(OC3CCOC3)cc(C(=O)O)c2)cc1
Reactant: Cc1ccc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(OC3CCOC3)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(tetrahydrofuran-3-yloxy)biphenyl-3-carboxylic acid (40 mg, 0.13 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (60 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol), and N,N-diisopropylethylamine (400 μL, 2.3 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a light color solid.
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:2][CH2:3][CH:4]=CCCC.CSC.C[OH:17]>>[CH2:11]([O:10][C:1](=[O:9])[CH2:2][CH2:3][CH:4]=[O:17])[CH3:12]
Reactant: CO
Reactant: CCCC=CCCC(=O)OCC
Solvent: CSC
Product: CCOC(=O)CCC=O
Temperature: -60 °C
Reaction time: 4 h

Procedure:
A solution of ethyl 4-octenoate (34 mL, 173 mmol) in methanol (240 mL) was placed in a 3-neck round bottomed flask and cooled at −60° C., and then O3/O2 was bubbled through the reaction mixture. After 4 hours at ca. −60° C., the reaction mixture had a slight blue tint, and TLC (1:9 ethyl acetate:hexane, stained in phosphomolybdic acid (PMA)) showed no starting material remaining. The reaction mixture was then flushed with O2 for 10 minutes. To the above reaction mixture was added slowly dimethyl sulfide (26 mL, 345 mmol) while maintaining the reaction temperature below −55° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred overnight. Argon was then bubbled through for 2 hours. The reaction mixture was then concentrated in vacuo. Low pressure fractional distillation afforded 4-oxo-butyric acid ethyl ester (14.3 g, 63%, contained a small amount of dimethyl sulfoxide) as a clear, colorless oil. Alternatively, purification can be accomplished using silica gel chromatography (100% hexanes-20% ethyl acetate in hexane). 1H NMR (300 MHz, CDCl3) δ ppm 9.81 (s, 1 H), 4.14 (q, J=7.2 Hz, 2 H), 2.79 (t, J=6.6 Hz, 2 H), 2.62 (t, J=6.6 Hz, 2 H), 1.26 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[CH3:18][Si:19](Cl)([CH3:21])[CH3:20]>CN(C=O)C>[CH2:11]([O:10][C:8]([N:5]1[CH2:4][CH:3]=[C:2]([O:1][Si:19]([CH3:21])([CH3:20])[CH3:18])[CH2:7][CH2:6]1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: C[Si](C)(C)OC1=CCN(C(=O)OCc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a stirred solution of benzyl 4-oxopiperidine-1-carboxylate (4.0 g, 17.2 mmol) in DMF (20 mL) was added TEA (9.0 mL) and TMSCl (4.0 mL, 32 mmol). The mixture was stirred overnight at 80° C., cooled, diluted with hexanes and washed with water. The organics were dried over sodium sulfate, filtered, concentrated, and purified by column chromatography using 10% EtOAc in hexanes to give 4-trimethylsilanyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (5 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]#[CH:10])(=O)=O.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CC(=O)CC.O>[CH2:6]([N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)[CH2:7][CH2:8][C:9]#[CH:10]
Reactant: C#CCCCOS(C)(=O)=O
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Solvent: ClCCl
Product: C#CCCCn1ccnc1
Yield: 53.8 %

Procedure:
A mixure of pent-4-ynyl methanesulfonate (1.06 g), imidazole (534 mg) and K2CO3 (3.66 g) in 2-butanone (11 mL) was heated to reflux overnight. Work-up (DCM, H2O), drying (Na2SO4) and concentration gave 1-(pent-4-ynyl)-1H-imidazole (472 mg).
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:6](=[O:17])[N:5]([CH3:18])[C:4](=[O:19])[CH:3]=1.CCOCC.[NH2:25][NH2:26]>CCO.CO>[NH:25]([C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:6](=[O:17])[N:5]([CH3:18])[C:4](=[O:19])[CH:3]=1)[NH2:26]
Reactant: NN
Reactant: COc1ccc(Cn2c(Cl)cc(=O)n(C)c2=O)cc1
Solvent: CO
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc(Cn2c(NN)cc(=O)n(C)c2=O)cc1
Yield: 84 %

Procedure:
To a solution of 6-chloro-1-(4-methoxybenzyl)-3-methylpyrimidine-2,4(1H,3H)-dione (2.4 g 8.6 mmol) in EtOH (25 mL) and MeOH (50 mL), anhydrous hydrazine (1.2 mL) is added slowly. The reaction mixture is refluxed for three hours, and then cooled. A large amount of ether is added into the reaction mixture, and then filtered to give 2.0 g of product as crystalline solids (Yield: 84%). 1H NMR (DMSO-d6) δ 3.13 (s, 3H), 3.73 (s, 3H), 4.42 (br, 1H), 5.03 (s, 2H), 5.15 (s, 1H), 6.88 and 7.15 (AB, 4H, J=6.4 Hz), 8.08 (br, 1H). MS (FAB) m/z 277.28 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](O)=[O:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:32][NH:33][C@H:34]([CH3:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](=[O:30])[N:33]([CH3:32])[C@@H:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH3:41])=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)O)cc3)cc2)CC1
Reactant: CN[C@H](C)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)N(C)[C@H](C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 98, Step 1, using 1-{4′-[4-(2-carboxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and (R)-(+)-N,α-dimethylbenzylamine.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5](=[O:14])[C:6]([CH3:13])([CH3:12])[C:7](=[O:11])[CH2:8][CH2:9][CH3:10]>C(Cl)(Cl)Cl>[CH3:3][O:4][C:5](=[O:14])[C:6]([CH3:13])([CH3:12])[C:7](=[O:11])[CH:8]([Br:1])[CH2:9][CH3:10]
Reactant: CCCC(=O)C(C)(C)C(=O)OC
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCC(Br)C(=O)C(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A solution of bromine (24 g, 150 mmol) in chloroform (30 mL) is added to 2,2-dimethyl-3-oxo-hexanoic acid methyl ester (25.9 g, 150 mmol) in chloroform (126 mL) at 0–5° C. dropwise. After the addition of bromine, the mixture is allowed to warm up to room temperature slowly and stirred overnight. The reaction is then quenched by ice water, the layers are separated. The organic layer is washed with cold water and brine, dried over sodium sulfate. Concentration gave the title compounds (36.9 g), which is used for next step without further purification.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:15]([CH3:16])[C:14](=[O:17])[CH2:13][N:12]=[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:10]=2[CH:25]=1.[H+].[B-:27]([F:31])([F:30])([F:29])[F:28]>O>[F:28][B-:27]([F:31])([F:30])[F:29].[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:11]1[C:10]2[CH:25]=[C:6]([N+:5]#[N:1])[CH:7]=[CH:8][C:9]=2[N:15]([CH3:16])[C:14](=[O:17])[CH2:13][N:12]=1
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(N)ccc21
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: CN1C(=O)CN=C(c2ccccc2F)c2cc([N+]#N)ccc21
Reaction time: 22 h

Procedure:
A solution of 2.9 g (42 mmol) of sodium nitrite in 7 ml of water is added while stirring to a solution, cooled in ice, of 11 g (38.8 mmol) of 7-amino-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one in 50 ml of water and 100 ml of 50 percent aqueous hydrofluoboric acid so that the sodium nitrite solution enters below the surface of the mixture (addition time ca 15 minutes). The mixture is stirred at 5° for a further 30 minutes and then left to stand at -24° for 22 hours. The precipitated crystals are filtered off, washed with isopropanol and ether and dried at 14 Torr and room temperature. There is obtained 5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepine-7-diazonium tetrafluoroborate (1:2) of melting point 120°-125°.