Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C[C:4](P(OC)(O)=O)([C:6]([O-:8])=[O:7])[CH3:5].C([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:17]=1)=O.Cl.[CH3:30]N(C)C=O>>[O:22]([C:18]1[N:17]=[C:16]([CH:5]=[CH:4][C:6]([O:8][CH3:30])=[O:7])[CH:21]=[CH:20][CH:19]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=Cc1cccc(Oc2ccccc2)n1
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C=Cc1cccc(Oc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, 0.53 g of sodium hydride (60% oil dispersion) was added to 20 ml of dry dimethylformamide, and 2.77 g of trimethylphosphonoacetate were added dropwise over 5 minutes with ice-cooling. After dropwise addition, stirring was continued at room temperature for 30 minutes. A solution of 2.02 g of 2-formyl-6-phenoxypyridine in 5 ml of dry dimethylformamide was added dropwise thereto over 5 minutes with ice-cooling. After dropwise addition, stirring was continued at room temperature for 14 hours. The reaction solution was poured into ice water, neutralized to a pH of 6.8 with aqueous dilute hydrochloric acid, and then extracted twice with diethyl ether. The ether layers were combined, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was then removed by evaporation under reduced pressure, and the residue was column-chromatographed on silica gel (developing solvent, n-hexane:ethyl acetate=7.1) to obtain 2.1 g of the desired methyl 3-(6-phenoxypyridin-2-yl)propenate.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:27]([NH:34][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Brc1ccc(CN2CCCC2)cc1
Reactant: NCc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(CNc2ccc(CN3CCCC3)cc2)cc1
Temperature: 70 °C

Procedure:
The mixture of 4-bromobenzyl-pyrrolidine (1 equiv, 120 mg), Pd2(dba)3 (2.0% equiv, 9.15 mg), t-Bu3P (1.6% equiv, 1.6 mg), benzylamine (1 equiv, 53.6 mg) and NaOtBu3 (1.5 equiv, 72 mg) in toluene (5 mL) was heated at 70° C. for 8 h.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1CCC[C@@H]1C(O)=O)(OC(C)(C)C)=O.[N+:30]([C:33]1[CH:34]=[C:35](O)[CH:36]=[CH:37][CH:38]=1)([O-:32])=[O:31].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([N+:30]([O-:32])=[O:31])[CH:38]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc([N+](=O)[O-])c1
Reaction time: 16 h

Procedure:
A 1.5 g (7.46 mmol) sample of (R)-1-t-butoxycarbonyl-2-pyrrolidinemethanol (prepared as in Example 1b above, except starting with the N-BOC-D-proline (Sigma) instead of the N-BOC-L-proline) and 1.56 g (11.19 mmol) of 3-nitrophenol (Aldrich) were added to a complex of TPP and DEAD (prepared as in Example 1 above, 11.2 mmol of each) in 50 mL of THF. The reaction was stirred for 16 hr, the solvents were removed under vacuum, and the residue was chromatographed on silica gel, eluting with 1:1 chloroform:hexane to give 670 mg of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:37](=[O:38])[N:12]2[C:13]([C:21]([O:23]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:22])=[C:14]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:15][S:16][C@H:11]12)=[O:8].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>CCCCCCC>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:37](=[O:38])[N:12]2[C:13]([C:21]([OH:23])=[O:22])=[C:14]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CCC(=O)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: CCCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCC(=O)C1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 5 °C
Yield: 92 %

Procedure:
To a cooled (5° C.), stirred slurry of 0.168 g. of benzhydryl 7-(2-thienylacetamido)-3-propionyl-3-cephem-4-carboxylate in 2 ml. of anisole was added 1 ml. of cold trifluoroacetic acid. The reaction mixture was allowed to stir with cooling for 20 minutes after which time 30 ml. of n-heptane was added. After the resulting solution was evaporated in vacuo to a low volume to remove excess trifluoroacetic acid, an additional 30 ml. of n-heptane was added. After stirring the reaction mixture in an ice bath for five minutes the mixture was filtered. The solid was dissolved in acetone, and the acetone solution was filtered. The filtrate was evaporated to low volume and subsequently transferred to a separatory funnel with the aid of cold ethyl acetate. The ethyl acetate solution was extracted twice with cold aqueous sodium bicarbonate solution. The aqueous extracts were combined, layered with cold ethyl acetate, and acidified with cold 1N.HCl. The organic layer was separated and washed twice with brine and dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness provided 0.108 g. (92 percent) of the title product as a white solid:
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[C:10]([O:13][CH:14]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]([OH:22])=O)[C:15]1=[O:23])(=[O:12])[CH3:11].[CH3:24][C@H:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([CH3:31])[N:26]1[CH2:32][CH2:33][NH2:34].C(N(CC)CC)C>C(Cl)Cl>[CH3:24][C@H:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([CH3:31])[N:26]1[CH2:32][CH2:33][NH:34][C:20](=[O:22])[CH2:19][N:16]1[CH2:17][CH2:18][CH:14]([O:13][C:10](=[O:12])[CH3:11])[C:15]1=[O:23]
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Reactant: CC(=O)OC1CCN(CC(=O)O)C1=O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1CCN(CC(=O)NCCN2[C@H](C)CCC[C@@H]2C)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.81 g of 2-chloro-1-methyl-pyridinium iodide are suspended in 10 ml of methylene chloride and thereto there are added at room temperature 1.20 g of (R/S)-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetic acid. Within 15 minutes there is added dropwise at 0° a solution of 0.98 g of 94.7% cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine and 3.02 ml of triethylamine in 20 ml of methylene chloride, whereupon the mixture is stirred at room temperature for 18 hours. Thereupon, the mixture is evaporated and the residue is chromatographed on aluminum oxide (activity grade III, neutral). The material which is eluted with chloroform is chromatographed on silica gel (granular size 0.2-0.5 mm). The (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetamide which is eluted with alcohol has a melting point of 120°-122° after crystallization from diethyl ether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]([CH2:19][CH3:20])[CH:9]([O:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][N+:11]([O-:13])=O)([CH3:4])([CH3:3])[CH3:2].C1(N=C=O)C=CC(N=C=O)=CC=1.[CH3:34][CH:35]([CH3:38])[C:36]#[CH:37].O>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]([CH:9]([C:10]1[CH:37]=[C:36]([CH:35]([CH3:38])[CH3:34])[O:13][N:11]=1)[O:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH2:19][CH3:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: C#CC(C)C
Reactant: CCC(NC(=O)OC(C)(C)C)C(C[N+](=O)[O-])O[Si](C)(C)C
Agent: O=C=Nc1ccc(N=C=O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCC(NC(=O)OC(C)(C)C)C(O[Si](C)(C)C)c1cc(C(C)C)on1
Temperature: 50 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a solution of (1-Ethyl-3-nitro-2-trimethylsilanyloxy-propyl)-carbamic acid tert-butyl ester (918 mg, 2.86 mmol), 1,4-Phenylene diisocyanate (1.38 g, 8.5 mmol) and 3-methyl-1-butyne (586 mg, 8.5 mmol) in dry toluene (15 mL) under N2 is added triethylamine (10 drops). The mixture is heated to 50° C. in a sealed vial for 28 h, and then cooled to room temperature Water (1 mL) is added and the mixture is stirred for an additional 2 h, then filtered. The filtrate is concentrated in vacuum and the residue is purified over 35 g silica gel, eluted with ethyl acetate: heptane (1:5) to afford {1-[(5-Isopropyl-isoxazol-3-yl)-trimethylsilanyloxy-methyl]-propyl}-carbamic acid tert-butyl ester (764 mg, 72%) as an oil.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:28][CH2:29][CH:30]([C:32]1[CH:33]=[C:34]2[C:38](=[C:39]([C:41]([NH2:43])=[O:42])[CH:40]=1)[NH:37][CH:36]=[CH:35]2)[OH:31]>>[C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([NH:28][CH2:29][CH:30]([C:32]4[CH:33]=[C:34]5[C:38](=[C:39]([C:41]([NH2:43])=[O:42])[CH:40]=4)[NH:37][CH:36]=[CH:35]5)[OH:31])[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)(=[O:16])=[O:17])=[CH:19][CH:20]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: NCC(O)c1cc(C(N)=O)c2[nH]ccc2c1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NCC(O)c4cc(C(N)=O)c5[nH]ccc5c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and 5-(2-amino-1-hydroxy-ethyl)-1H-indole-7-carboxamide according to the procedure of Example 255 as a pale grey solid; 1H NMR (300 MHz, DMSO-d6) δ 1.60–1.80 (m, 2 H), 2.00–2.15 (m, 2 H), 2.06 (s, 3 H), 2.50–2.70 (m, 2 H), 3.10–3.20 (m, 3 H), 3.60–3.75 (m, 2 H), 4.95–5.05 (m, 1 H), 6.13 (brs, 1 H), 6.49 (t, J=2.7 Hz, 1 H), 6.81 (d, J=9.0 Hz, 2 H), 6.88 (d, J=9.0 Hz, 2 H), 7.35 (t, J=2.7 Hz, 1 H), 7.42 (brs, 1 H), 7.59 (d, J=9.0 Hz, 2 H), 7.69 (d, J=9.0 Hz, 2 H), 7.77 (s, 1 H), 8.11 (s, 1 H), 9.72 (s, 1 H), 10.40 (s, 1 H); MS (ES) m/z: 591.1 (MH+); HRMS Calcd. for C30H35N6O5S (MH+): 591.2390. Found: 591.2392.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[CH:25]=[CH:24][NH:23][C:18]4=[N:19][C:20]=3[O:21][CH3:22])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:28](Cl)(=[O:32])[C:29](Cl)=[O:30].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.O>ClCCl>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:25]([C:28](=[O:32])[C:29]([N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)=[O:30])=[CH:24][NH:23][C:18]4=[N:19][C:20]=3[O:21][CH3:22])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C1CCNC1
Reactant: COc1nc2[nH]ccc2cc1C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: O
Solvent: ClCCl
Product: COc1nc2[nH]cc(C(=O)C(=O)N3CCCC3)c2cc1C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
[4-(4-Fluoro-benzyl)-piperidin-1-yl]-(6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)-methanone (368 mg, 1 mmol) was dissolved in dry dichloromethane (5 mL). It was cooled in an ice-bath and oxalyl chloride (4.5 mL, 2 M solution in dichloromethane) was added. The mixture was stirred for 1 h at 0° C. and for another 4 h at room temperature. It was evaporated to dryness, redissolved in dichloromethane and treated with pyrrolidine (3 mmol). After stirring for 30 min, water was added and the product was extracted with dichloromethane (3×25 mL). The combined extracts were dried over sodium sulfate. After evaporation of the solvent, the product was purified via radial chromatography using chloroform-methanol (0-3% methanol) to yield 340 mg of the desired product. LCMS: 493, M+1.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([F:10])=[C:8]([O:11][CH3:12])[N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[N:6]=1)=[O:4].[OH-].[Li+].O.Cl>O1CCOCC1>[F:10][C:9]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:8]=1[O:11][CH3:12]
Reactant: COC(=O)c1nn(-c2ccccc2F)c(OC)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(F)c(C(=O)O)nn1-c1ccccc1F
Temperature: 56 °C
Reaction time: 0.5 h
Yield: 101.4 %

Procedure:
70 mg (0.26 mmol) of 4-fluoro-1-(2-fluoro-phenyl)-5-methoxy-1H-pyrazole-3-carboxylic acid methyl ester were dissolved in 1.3 ml of dioxane and 1.305 ml of a 1 M aqueous solution of lithium hydroxide were added. The mixture was stirred at 56° C. for 30 min, then water and 2 N hydrochloric acid were added and the mixture extracted with diethyl ether. The organic phase was evaporated to give 67 mg (33%) of the title compound.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:2]=12.C(Cl)(=O)C(Cl)=O.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:23][CH2:22]1>C(Cl)Cl.CN(C)C=O>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]([NH:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:23][CH2:22]3)=[O:12])[CH:8]=[CH:9][C:2]=12
Reactant: O=C(O)c1ccc2nonc2c1
Reactant: NCC1CCN(CCc2ccccn2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCC1CCN(CCc2ccccn2)CC1)c1ccc2nonc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a suspension of benzofurazan-5-carboxylic acid (150 mg, 0.91 mmol) in methylene chloride (3.3 ml) was added dimethylformamide (1 drop) followed by dropwise addition of oxalyl chloride (89 μl, 1.0 mmol). The resulting solution was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The brown oil was redissolved in methylene chloride (3.3 ml) and was added to a cooled (0° C.) solution of 4-(aminomethyl)-1-(2-pyridylethyl)piperidine (0.21 g, 0.95 mmol) in methylene chloride (1.6 ml). The reaction mixture was stirred at 0° C. for 11/2 hours. Solvent evaporation, flash chromatography (silica gel, chloroform-methanol-ammonium hydroxide, 95/5/1/2) and trituration with hexane-ethyl acetate gave 4-[N-(benzofurazan-5-carbonyl)aminomethyl]-1-(2-pyridylethyl)piperidine (133 mg, 40%);
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19]>>[Cl:17][C:4]1[CH:3]=[C:2]([C:24]2[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=2)[C:18]#[N:19])[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4cccc(C#N)c4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (76 mg, 91%), MS (ISP) m/z=336.5 [(M+H)+], mp 199° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 3-cyano-phenylboronic acid (47.8 mg, 0.325 mmol).
Reaction SMILES: O.[NH2:2][C@H:3]([C:14]([NH:16][C@H:17]([C:20]([NH:22][C@H:23]([C:32]([OH:34])=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)=[O:21])[CH2:18][OH:19])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.CC(O)=O.C([O-])(O)=O.[Na+].C1C(=O)N([O:51][C:52]([O:54][CH2:55][CH:56]2[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[C:62]3[C:57]2=[CH:58][CH:59]=[CH:60][CH:61]=3)=O)C(=O)C1>O1CCOCC1>[NH:2]([C:52]([O:54][CH2:55][CH:56]1[C:57]2[C:62](=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:63]2[C:68]1=[CH:67][CH:66]=[CH:65][CH:64]=2)=[O:51])[C@H:3]([C:14]([NH:16][C@H:17]([C:20]([NH:22][C@H:23]([C:32]([OH:34])=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)=[O:21])[CH2:18][OH:19])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reaction time: 4 h

Procedure:
To a mixture of 50 ml of water and 50 ml of dioxane, 19.96 g (38.8 mmol) of H-Trp-Ser-Tyr-OH acetate, 6.52 g (77.6 mmol) of NaHCO3 and 14.2 g (42 mmol) of Fmoc-OnSu are added successively. After allowing to stand for 4 hours at room temperature, insoluble material is filtered off and discarded next day. The filtrate is concentrated. The residue is triturated with petroleum ether, filtered off with suction and dried.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].C(N(C(C)C)C(C)C)C.[C:19]([C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][C:35]=3[Cl:44])=[CH:30][CH:29]=2)[C:25]([CH3:45])=[N:24][C:23]=1[CH3:46])(=[O:21])[NH2:20].Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1>CN(C=O)C>[C:19]([C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][C:41]([NH:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5])=[O:42])=[CH:36][C:35]=3[Cl:44])=[CH:30][CH:29]=2)[C:25]([CH3:45])=[N:24][C:23]=1[CH3:46])(=[O:21])[NH2:20]
Reactant: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)O)cc3Cl)cc2)nc1C(N)=O
Reactant: COC(=O)C(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)NC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 124.3 %

Procedure:
A mixture of methyl 2-amino-2-methylpropanoate hydrochloride (88 mg, 0.57 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.57 mmol) in DMF (342 μL) were treated with a solution of 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetic acid (Example 1; 205 mg, 0.52 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (124 mg, 0.65 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (70.0 mg, 0.52 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.57 mmol) in DMF (2049 μL) at RT. The resulting solution was stirred at RT for 20 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (5 mL), and washed with water (5 mL). The organic layer was evaporated to afford methyl 2-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetamido)-2-methylpropanoate (320 mg, 125%) which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:5]2.[F-].[Cs+].[CH2:23]1[CH2:27]OC[CH2:24]1.C(B1OC(C)(C)C(C)(C)O1)C=C>C(OCC)(=O)C>[CH2:27]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:5]2)[CH:23]=[CH2:24]
Reactant: C1CCOC1
Reactant: O=C(OCc1ccccc1)N1Cc2ccc(Br)cc2C1
Agent: C=CCB1OC(C)(C)C(C)(C)O1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Product: C=CCc1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Temperature: 72 °C
Reaction time: 4 h

Procedure:
To a mixture of benzyl 5-bromoisoindoline-2-carboxylate (332 mg, 1 mmol), tetrakistriphenylphosphine palladium (0) (80 mg, 0.07 mmol), and cesium fluoride (604 mg, 4 mmol) was added THF (7 mL). The system was degassed and flushed with argon. To this mixture was added allyl boronic acid pinacol ester (285 μL, 1.5 mmol). The resulting mixture was heated to 72° C. and stirred at this temperature for 4 hr then cooled to room temperature. The mixture was diluted with ethyl acetate, washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by silica chromatography (25 g silica eluted with 3-40% ethyl acetate in hexane) to give the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:12]([N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C1CCCCCN1
Reactant: CCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCCCN1CCCCCC1=O
Yield: 84.8 %

Procedure:
Following example 10, 10.2 g of 50% sodium hydride-mineral oil dispersion (5.1 g NaH, 0.2125 M), 20 g (0.177 M) of azacycloheptan-2-one and 44.2 g (0.2 M) of 1-bromodecane on 19 hr. reflux gave 38 g (84.7%) of product; b.p. 158°-163°/0.25-0.3 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C@H:15]2[C@H:24]([OH:25])[CH2:23][C:22]3[C:21]([OH:26])=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16]2)[CH2:11][CH2:10]1.[N+](=[CH2:29])=[N-]>CO>[CH3:29][O:26][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:22]=1[CH2:23][C@@H:24]([OH:25])[C@H:15]([N:12]1[CH2:11][CH2:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:14][CH2:13]1)[CH2:16]2
Reactant: C=[N+]=[N-]
Reactant: COc1ccccc1N1CCN([C@@H]2Cc3cccc(O)c3C[C@H]2O)CC1
Solvent: CO
Product: COc1ccccc1N1CCN([C@@H]2Cc3cccc(OC)c3C[C@H]2O)CC1
Reaction time: 48 h

Procedure:
A solution of 2.0 g of trans-5,6,7,8-tetrahydro-6-[4-(2-methoxyphenyl)-1-piperazinyl]-1,7-naphthalenediol in methanol is treated with about 2 equivalents of freshly prepared diazomethane. The solution is stored at 0° C for 48 hours. The solvent is removed in vacuo. The residue is dissolved in ethyl acetate, washed with dilute sodium hydroxide solution and dried. The solvent is removed in vacuo leaving an oil which crystallizes on trituration with a small amount of ether. This is washed with isopropyl ether and recrystallized from ether to give 1.7 g of the title compound, melting point 123°-125° C.
Reaction SMILES: C(S[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:23]([CH3:24])[C:14]2=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=[C:13]2[N:12]=1)CC.Cl[C:26]1C=CC=C(C(OO)=O)[CH:27]=1.C(=O)([O-])O.[Na+].[S:41]([O-:45])([O-])(=[O:43])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:26]([S:41]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:23]([CH3:24])[C:14]2=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=[C:13]2[N:12]=1)(=[O:45])=[O:43])[CH3:27]
Reactant: CCCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2-(2-propylsulfanylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.22 g) and chloroform (3 ml), 3-chloroperbenzoic acid (purity: not less than 65%, 0.33 g) was added under ice-cooling, and then heated to room temperature, and stirred for 1.5 hours. Into the reaction mixture, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution were poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced, pressure. The resulting residue was subjected to silica gel column chromatography to give 0.24 g of 2-(2-ethylsulfonylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 9).