Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:28]=[C:11]3[N:12]=[C:13]([CH3:27])[C:14]([C@H:17]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:18]([O:20][CH3:21])=[O:19])=[C:15](I)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:29]([N:32]1[CH2:37][CH2:36][O:35][C:34]2[CH:38]=[C:39]([CH3:51])[C:40](B3OC(C)(C)C(C)(C)O3)=[CH:41][C:33]1=2)[CH:30]=[CH2:31].C([O-])([O-])=O.[Na+].[Na+].N#N>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:29]([N:32]1[CH2:37][CH2:36][O:35][C:34]2[CH:38]=[C:39]([CH3:51])[C:40]([C:15]3[N:10]4[N:9]=[C:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=5)[CH:28]=[C:11]4[N:12]=[C:13]([CH3:27])[C:14]=3[C@H:17]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:18]([O:20][CH3:21])=[O:19])=[CH:41][C:33]1=2)[CH:30]=[CH2:31]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Br)c3)nn2c1I
Reactant: C=CCN1CCOc2cc(C)c(B3OC(C)(C)C(C)(C)O3)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: C=CCN1CCOc2cc(C)c(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(Br)c5)nn34)cc21
Temperature: 90 °C
Yield: 25.1 %

Procedure:
A solution of (S)-methyl 2-(2-(3-bromophenyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.100 g, 0.179 mmol), 4-allyl-7-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.062 g, 0.197 mmol) and 2.0 M Na2CO3 (0.179 mL, 0.358 mmol) in dry DMF (3 mL) was sparged with N2 for 10 min, treated with Pd(Ph3P)4 (0.014 g, 0.013 mmol), sparged for 5 minutes, then heated (90° C.) for 48 h. The reaction was cooled, filtered (0.45 μm syringe tip filter) and purified by prep-HPLC to afford the desired product (0.028 g, 0.045 mmol, 25.2% yield) as a yellow oily film. 1H NMR (500 MHz, CDCl3) δ 7.99 (t, J=1.7 Hz, 1H), 7.78 (dt, J=7.7, 1.3 Hz, 1H), 7.49-7.42 (m, 1H), 7.26-7.22 (m, 1H), 6.87-6.80 (m, 2H), 6.61 (s, 1H), 5.86-5.73 (m, 1H), 5.22 (dd, J=17.2, 1.6 Hz, 1H), 5.17 (dd, J=10.2, 1.4 Hz, 1H), 5.11 (s, 1H), 4.42-4.30 (m, 2H), 3.87-3.78 (m, 1H), 3.75-3.68 (m, 1H), 3.66 (s, 3H), 3.42-3.34 (m, 1H), 3.32-3.24 (m, 1H), 2.76 (s, 3H), 1.90 (s, 3H), 1.17 (s, 9H). LCMS (M+H)=621.3.
Reaction SMILES: [C:1]([NH:4][C@H:5]([CH2:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[C:6](O)=[S:7])(=[O:3])[CH3:2].[N+]([O-])(O)=O.[N+:20]([O:23][CH2:24][CH2:25][NH2:26])([O-:22])=[O:21]>>[N+:20]([O:23][CH2:24][CH2:25][NH:26][C:6](=[S:7])[C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])([O-:22])=[O:21]
Reactant: NCCO[N+](=O)[O-]
Reactant: CC(=O)N[C@H](CC(=O)C(C)(C)C)C(O)=S
Solvent: O=[N+]([O-])O
Product: CC(=O)N[C@H](CC(=O)C(C)(C)C)C(=S)NCCO[N+](=O)[O-]
Yield: 74.5 %

Procedure:
The procedures of Example 1 were analogously repeated using 0.70 g of (2R)-2-acetylamino-3-pivaloylthiopropionic acid and 574 mg of 2-nitrooxyethylamine nitrate to give 0.72 g of the title compound as colorless crystals.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34].C(=O)([O-])[O-].[Na+].[Na+]>[I-].[Na+].C(C(C)=O)C(C)C>[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:21][CH2:22][CH2:23][N:24]3[C:28](=[O:29])[C:27]4=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]4[C:25]3=[O:34])[CH2:12][CH2:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=C1c2ccccc2C(=O)N1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 95.4 %

Procedure:
A mixture of 500 mg (1.98 mmole) of 4-(diphenylmethyl)piperazine, 530 mg (1.98 mmole) of N-(3-bromopropyl)phthalimide, 840 mg (7.92 mmole) of sodium carbonate, 10 mg of sodium iodide and 12 ml of methyl isobutyl ketone was heated under reflux overnight. The reaction mixture was then filtered, and the solvent was removed from the filtrate by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to afford 830 mg (yield 96%) of the title compound as an oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(C(C)C)C(C)C)C.[C:22]([C:25]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][C:40]([CH2:43][C:44](O)=[O:45])=[CH:39][C:38]=3[Cl:47])=[CH:33][CH:32]=2)[C:28]([CH3:48])=[N:27][C:26]=1[CH3:49])(=[O:24])[NH2:23].Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[C:22]([C:25]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][C:40]([CH2:43][C:44]([NH:2][C@@H:3]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:45])=[CH:39][C:38]=3[Cl:47])=[CH:33][CH:32]=2)[C:28]([CH3:48])=[N:27][C:26]=1[CH3:49])(=[O:24])[NH2:23]
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)O)cc3Cl)cc2)nc1C(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](CC(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: 80.2 %

Procedure:
A mixture of (S)-ethyl 2-amino-4-methylpentanoate hydrochloride (111 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 was incomplete so the temperature was increased to 50° C. and the reaction mixture was stirred for a further 3 hours. The reaction mixture was diluted with EtOAc (20 mL), and washed sequentially with water (50 mL), saturated brine (50 mL), and water (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford (S)-ethyl 2-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetamido)-4-methylpentanoate (224 mg, 81%) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][NH:11]2)=[C:7]([NH:14][CH2:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:6]=1)=[O:4].[H-].[Na+].CC([O:34][C@H:35]1[CH:39]=[CH:38][C@@H:37](O)[CH2:36]1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)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]>[CH3:1][O:2][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:38]2[CH2:39][C@H:35]([OH:34])[CH:36]=[CH:37]2)=[C:7]([NH:14][CH2:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Reactant: CC(=O)O[C@H]1C=C[C@@H](O)C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Product: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@H]3C=C[C@@H](O)C3)c2n1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To 6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester (5 g 13.4 mmol) under an atmosphere of argon is added dry deoxygenated tetrahydrofuran (100 ml) and dry dimethyl sulfoxide (2 ml). Sodium hydride 95% (0.32 g, 13.4 mmol) is then added and the solution is stirred at 40° C. Separately to (1S,4R)-cis 4-Acetoxy-2-cyclopenten-1-ol (1.89 g. 13.4 mmol), triphenylphosphine (0.53 g, 2.0 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.69 g, 0.67 mmol) is added dry deoxygenated tetrahydrofuran (20 ml) and the mixture stirred at room temperature for 10 minutes. This solution is added to the anion solution via syringe and the resulting mixture is then stirred at 80° C. The reaction is shown to be complete by LCMS after 2 hours. The reaction mixture is allowed to cool, methanol is added and a solid is filtered. The filtrate is concentrated in vacuo and the title compound is obtained by precipitation from dichloromethane/hexane. 1H NMR (MeOD, 400 MHz); 8.15(s, 1H), 7.40-7.15(m, 10H), 6.20(m, 1H), 5.95(m, 1H), 5.50(m, 2H), 4.75(m, 2H), 4.55(m, 1H), 4.10(m 2H), 3.90(s, 2H), 3.80(s, 1H), 2.9(m, 1H), 1.75(m, 1H).
Reaction SMILES: [O-]CC.[Na+].C(OP([CH2:13][C:14]([O:16]CC)=[O:15])(OCC)=O)C.[CH3:19][C:20]([CH3:24])([CH3:23])[CH:21]=O.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[CH3:19][C:20]([CH3:24])([CH3:23])[CH:21]=[CH:13][C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)(C)C=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)C=CC(=O)O
Reaction time: 1.5 h

Procedure:
To 20% sodium ethoxide in ethanol (1.02 L) was added ethyl diethylphosphonoacetate (516 mL) dropwise at ice temperature. After the mixture was stirred at ice temperature for 1.5 hr, a solution of 2,2-dimethylpropionaldehyde (260 mL) in tetrahydrofuran (510 mL) was added to the mixture at ice temperature. The mixture was stirred at RT for 3.5 hr and aqueous 4 N sodium hydroxide (885 mL) was added to the mixture at ice temperature. After the mixture was stirred overnight at RT, 6 N hydrochloric acid (802 mL) was added to the reaction mixture at ice temperature. The mixture was extracted with ethyl acetate (1 L), washed with water (1 L×5) and brine (500 mL), then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (289 g) as a crude product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]2[N:9]([CH3:19])[CH:10]=[C:11]([C:14](OCC)=[O:15])[C:12](=[O:13])[C:7]=2[S:6][CH:5]=1)[CH3:2].[NH3:20]>C(O)C>[CH2:1]([O:3][C:4]1[C:8]2[N:9]([CH3:19])[CH:10]=[C:11]([C:14]([NH2:20])=[O:15])[C:12](=[O:13])[C:7]=2[S:6][CH:5]=1)[CH3:2]
Reactant: N
Reactant: CCOC(=O)c1cn(C)c2c(OCC)csc2c1=O
Solvent: CCO
Product: CCOc1csc2c(=O)c(C(N)=O)cn(C)c12
Temperature: 25 °C

Procedure:
Ethyl 3-ethoxy-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate (3 g) and a saturated solution of ammonia in ethanol (70 ml) were stirred together in a sealed stainless steel pressure vessel at 130° for 24 hours. After allowing to cool to ambient temperature the mixture was filtered and the solid was dried to give the novel compound 3-ethoxy-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide, m.p. 286°-287°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1.[C:11]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)OC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[CH:9][N:8]([CH3:11])[C:6]=2[CH:7]=1
Reactant: CNc1cc(Br)ccc1N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Product: Cn1cnc2ccc(Br)cc21
Temperature: 100 °C
Yield: 93 %

Procedure:
To a solution of 5-bromo-N1-methylbenzene-1,2-diamine (7.4 g, 37 mmol) in trimethyl orthoformate (100 mL) was added p-toluenesulfonic acid (0.36 g, 1.9 mmol). The reaction mixture was heated at 100° C. for 4 h, cooled, concentrated, dissolved in ethyl acetate, washed with brine, dried over sodium sulfate and concentrated. The crude product was used in next step without further purification. (7.3 g, yield 93%) MS (ESI+) e/z: 212.1.
Reaction SMILES: Br[C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[CH:8]=[O:9].[CH2:10]([O:12][C:13]([C:15]1([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27](B4OC(C)(C)C(C)(C)O4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:17][CH2:16]1)=[O:14])[CH3:11]>>[CH2:10]([O:12][C:13]([C:15]1([C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:2]4[CH:6]=[N:5][N:4]([CH3:7])[C:3]=4[CH:8]=[O:9])=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH2:17][CH2:16]1)=[O:14])[CH3:11]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Reactant: Cn1ncc(Br)c1C=O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnn(C)c4C=O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: 4-bromo-2-methyl-2H-pyrazole-3-carbaldehyde and 1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([SH:4])[CH:2]=[CH2:3].[OH-].[Na+].C([O:9][C:10]([NH:12][N:13]([CH2:16][CH3:17])[C:14]#[N:15])=O)C.C(O)(=O)C>O>[CH2:16]([N:13]1[C:14]([S:4][CH2:1][CH:2]=[CH2:3])=[N:15][C:10]([OH:9])=[N:12]1)[CH3:17]
Reactant: CCOC(=O)NN(C#N)CC
Reactant: C=CCS
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: C=CCSc1nc(O)nn1CC
Yield: 42.9 %

Procedure:
244 g of allyl mercaptan is added to a solution of 132 g of sodium hydroxide in 750 ml of water, and subsequently at room temperature 514 g of 2-ethyl-2-cyanohydrazinecarboxylic acid ethyl ester is added dropwise. After one hour's refluxing, there is added to the cooled solution 198 g of glacial acetic acid. The oily phase is separated and concentrated in vacuo to dryness. There is obtained 260 g (43% of theory) of 1-ethyl-5-allylthio-3-hydroxy-1,2,4-triazole, m.p. 74°-76° C.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH2:14]([N:21]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[C:27](Br)[CH:28]=2)[N:23]=[CH:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[Cu](I)I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[CH2:14]([N:21]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:28]=2)[N:23]=[CH:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=c1c2cc(Br)ccc2ncn1Cc1ccccc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc2ncn(Cc3ccccc3)c(=O)c2c1
Temperature: 100 °C
Reaction time: 14 h
Yield: 107.9 %

Procedure:
Under nitrogen atmosphere, 947 mg of trimethylsilylacetylene, 54.7 mg of copper iodide (I), 54.2 mg bis(triphenylphosphine) palladium dichloride (II) and 3 ml of triethylamine were added sequentially to 1.5 ml solution of dimethylformamide with 501 mg of 3-benzyl-6-bromo4-oxo-3,4-dihydroquinazoline, and the mixture was stirred at 100° C. for 14 hours. After distilling out the solvents under reduced pressure, water was added to the reaction solution, and extracted with ether. Ether layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure, and the residues were separated and purified by silicagel column chromatography (ethyl acetate/hexane=3/7) to obtain 570 mg of the above compound as a colorless oily matter.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:21][C:22]([C:24]1([C:37](C)(C)[O:38][SiH2]C(C)(C)C)[CH2:28][CH2:27][N:26]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1)=[O:23])[CH3:20]>>[CH2:19]([O:21][C:22]([C:24]1([CH2:37][OH:38])[CH2:28][CH2:27][N:26]([CH2:29][C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:25]1)=[O:23])[CH3:20]
Reactant: CCOC(=O)C1(C(C)(C)O[SiH2]C(C)(C)C)CCN(CC(=O)OC(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CCOC(=O)C1(CO)CCN(CC(=O)OC(C)(C)C)C1
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
Tetrabutylammonium fluoride (1.8 ml, 1 M in THF) was added to 1-tert-butoxycarbonylmethyl-3-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (726 mg, 1.8 mmol). The reaction solution was stirred for half hour and purified by column chromatography using solution of ethyl acetate in hexanes (1:1), then ethyl acetate to provide the title product (350 mg, 68%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[H-].[Na+].I[CH2:18][CH2:19][CH3:20].O>CN(C=O)C>[CH2:18]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13])[CH2:19][CH3:20]
Reactant: CC(=O)c1cc2c(cc1O)OCCC2
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1cc2c(cc1C(C)=O)CCCO2
Reaction time: 0.17 h
Yield: 114.9 %

Procedure:
1-(7-Hydroxychroman-6-yl)ethanone (3.0 g, 15.6 mmol) was dissolved in DMF (20 ml). Sodium hydride (60% oil base, 686 mg, 1.1 equivalent weight) was added thereto while ice cooling, and then stirred for 10 minutes. 1-Iodopropane (2.92 g, 1.1 equivalent weight) was added to the mixture and then stirred at room temperature for 3 hours. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The thus-obtained organic layer was concentrated to dryness under reduced pressure, and the residue was then purified using silica gel column chromatography (n-hexane:ethyl acetate=1:0→0:1). The purified product was concentrated to dryness under reduced pressure, giving a white powder of 1-(7-propoxychroman-6-yl)ethanone (4.2 g, yield: quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][O:28]C(=O)C)[C@@H:20]([O:21]C(=O)C)[C@H:15]([O:16]C(=O)C)[C@H:10]2[O:11]C(=O)C)[OH:9])=[CH:4][C:3]=1[CH:32]([C:42]#[CH:43])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:40][CH3:41])=[CH:35][CH:34]=1.[OH-].[K+]>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][OH:28])[C@@H:20]([OH:21])[C@H:15]([OH:16])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH:32]([C:42]#[CH:43])[C:33]1[CH:34]=[CH:35][C:36]([CH2:39][O:40][CH3:41])=[CH:37][CH:38]=1
Reactant: C#CC(c1ccc(COC)cc1)c1cc([C@@]2(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#CC(c1ccc(COC)cc1)c1cc([C@@]2(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.11 g 1-chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos1-yl)-2-(4-methoxymethylethynyl-benzyl)-benzene in 2 mL methanol is added 0.85 mL of 1 M aqueous potassium hydroxide solution. The solution is stirred for 1 h at ambient temperature and then diluted with ethyl acetate. The resulting solution is washed with brine and dried over sodium sulfate. The solvent is evaporated and the residue is filtered through silica gel (dichloromethane/methanol 9:1->2:1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH3:10])[CH:5]=[C:6]([OH:8])[CH:7]=1>Cl.O.[Pd]>[CH2:9]([C:4]1[CH:5]=[C:6]([OH:8])[CH:7]=[C:2]([OH:1])[CH:3]=1)[CH3:10]
Reactant: CC(=O)c1cc(O)cc(O)c1
Agent: [Pd]
Agent: Cl
Solvent: O
Product: CCc1cc(O)cc(O)c1
Reaction time: 16 h
Yield: 52.2 %

Procedure:
A mixture of 1-(3,5-dihydroxy-phenyl)-ethanone (5 g, 32.89 mmol), 10% Pd—C (1 g) in 4% HCl—H2O (100 mL) was hydrogenated at 1 atmosphere for 16 hours. The mixture was extracted with EtOAc and the organic extracts was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give 5-ethyl-benzene-1,3-diol (2.37 g, 52%). 1H NMR (400 MHz, CDCl3δ 6.26 (s, 2H), 6.20 (s, 1H), 4.78 (s, 2H), 2.55 (m, 2H), 1.20 (m, 3H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][CH:6]2[NH:11][CH2:10][CH2:9][N:8]3[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=[C:7]23)[CH2:4][CH2:3]1.[C:19]([O:23][C:24]([NH:26][C@H:27]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41])[CH2:28][C:29](O)=[O:30])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([NH:26][C@H:27]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41])[CH2:28][C:29]([N:11]1[CH2:10][CH2:9][N:8]2[N:12]=[C:13]([C:15]([F:16])([F:18])[F:17])[N:14]=[C:7]2[CH:6]1[CH2:5][CH:2]1[CH2:4][CH2:3]1)=[O:30])=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: FC(F)(F)c1nc2n(n1)CCNC2CC1CC1
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2nc(C(F)(F)F)nc2C1CC1CC1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 35 mg portion of 8-(cyclopropylmethyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazine hydrochloride was coupled to (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid essentially following the procedure outlined in Example 2, Step D, with the following exception. The reaction mixture was stirred at ambient temperature for 24 h and then concentrated. The residue was purified by preparative TLC (silica gel, 10% methanol/dichloromethane) to provide 54 mg of the title compound as a mixture of diastereomers. The diastereomers were separated by HPLC (OD chiralcel column, 7% ethanol/hexane) to give the faster eluting diastereomer and the slower eluting diastereomer.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10](SC)[N:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[NH2:16][NH2:17]>CO.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:16][NH2:17])[N:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CSc1nncc(-c2ccc(F)cc2)n1
Reactant: NN
Solvent: CO
Solvent: C1CCOC1
Product: NNc1nncc(-c2ccc(F)cc2)n1

Procedure:
To a solution of 11.9 g. of 5-(p-fluorophenyl)-3-(methylthio)-1,2,4-triazine in 50 ml. of 1:1 methanol-tetrahydrofuran is added 2.1 ml. of 95% hydrazine. The mixture is refluxed for 12 hours and then cooled. The solid which forms is collected by filtration and washed with hexane, giving 5-(p-fluorophenyl)-3-hydrazino-1,2,4-triazine as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][NH:14][C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH:6]=1)=[O:4].[H-].[Na+].[CH3:25]OS(OC)(=O)=O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][N:14]([C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH3:25])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(=O)n(CCNC(=O)c2cccnc2)c1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(=O)n(CCN(C)C(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a round bottomed 25 ml flask fitted with a magnetic stirrer bar and nitrogen inlet was added 1,6-dihydro-l-[2-(3-pyridinylcarbonylamino)ethyl]-6-oxo-3-pyridinecarboxylic acid methyl ester (0.211 g, 0.70 mmol) and dimethylformamide (7.0 ml). At room temperature with stirring, sodium hydride (0.018 g, 0.77 mmol, 98% dry) was added. After 45 minutes, the reaction was quenched with dimethylsulfate (0.073 ml, 0.78 mmol). Stirring was continued for 3.75 hours at which time the mixture was concentrated. The crude product was purified by medium pressure liquid chromotography (silica gel, 3% methanol/dichloromethane) and triturated with ether to give the product, MP: 120°-122° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)([O-])=O.[NH4+].[Cl-]>CCO.O.[Fe]>[F:24][C:21]([F:22])([F:23])[C:18]1[CH:19]=[CH:20][C:15]([O:14][C:9]2[C:8]3[C:13](=[C:4]([NH2:1])[CH:5]=[CH:6][CH:7]=3)[N:12]=[CH:11][CH:10]=2)=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1cccc2c(Oc3ccc(C(F)(F)F)cc3)ccnc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccc2c(Oc3ccc(C(F)(F)F)cc3)ccnc12
Yield: 70.2 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-11, step-4 using 8-nitro-4-(4-(trifluoromethyl)phenoxy)quinoline (200 mg, 0.59 mmol), iron powder (335 mg, 5.98 mmol), and NH4Cl (260 mg, 4.70 mmol) in EtOH (5 mL) and water (1 mL) to afford 126 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.60 (d, J=4.8 Hz, 1H), 7.85 (d, J=8.7 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 7.31 (d, J=7.8 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 6.92 (d, J=7.2 Hz, 1H), 6.85 (d, J=5.4 Hz, 1H), 6.01 (s, 2H).