Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]2[C@H:12]([CH2:13][CH2:14][C:15]=1[CH:16]=O)[C@H:11]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]2=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-].[O:28]=[C:29]1[CH:33]([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:32][CH2:31][N:30]1[CH2:53][C:54]([F:57])([F:56])[F:55]>O1C(CC)C1>[C:1]([O:5][C:6]([C:8]1[N:9]2[C@H:12]([CH2:13][CH2:14][C:15]=1/[CH:16]=[C:33]1/[C:29](=[O:28])[N:30]([CH2:53][C:54]([F:55])([F:56])[F:57])[CH2:31][CH2:32]/1)[C@H:11]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]2=[O:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)(C)C)=C(C=O)CC[C@H]12
Reactant: O=C1C([P+](c2ccccc2)(c2ccccc2)c2ccccc2)CCN1CC(F)(F)F
Agent: CCC1CO1
Agent: [Br-]
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)(C)C)=C(/C=C3\CCN(CC(F)(F)F)C3=O)CC[C@H]12

Procedure:
A mixture of 0.50 g (6R, 7S)-7-tert-butoxycarbonylamino-3-formyl-8-oxo-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid tert-butyl ester (10) and 0.96 g rac-[2-oxo-1-(2,2,2-trifluoroethyl)-3-pyrrolidinyl]-triphenylphosphonium bromide in 6.0 ml 1,2 epoxybutane was heated to reflux for 6 h. The solvent was evaporated and the residue was purified by chromatography on silica gel using n-hexane:ethyl acetate=3:1 as eluent. The title compound, (E)-(6R, 7S)-7-tert-butoxycarbonylamino-8-oxo-3-[2-oxo-1-(2,2,2-trifluoro-ethyl)-pyrrolidin-3-ylidenemethyl]-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid tert-butyl ester, was obtained as white foam (0.55 g;78% Th).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH2:13][CH3:14])[CH:5]=1.[Li]CCCC>>[CH2:13]([O:12][C:6]1[CH:5]=[C:4]([C:3]#[CH:2])[CH:9]=[CH:8][C:7]=1[O:10][CH3:11])[CH3:14]
Reactant: CCOc1cc(C=C(Br)Br)ccc1OC
Agent: [Li]CCCC
Product: C#Cc1ccc(OC)c(OCC)c1
Yield: 99.2 %

Procedure:
According to the General Procedure E, 2,2-Dibromo-1-(3-ethoxy-4-methoxyphenyl)ethene (5.00 g, 14.88 mmol) and n-BuLi (20.46 ml, 32.74 mmol) are converted to give after workup and chromatography (SiO2, PE/EE=5:1, Rf=0.31) the title compound (2.60 g, 14.76 mmol, 99%) as a colorless solid. M.p. 95-96° C.;
Reaction SMILES: [C:1]([N:5]([C:13]1[N:23]=[CH:22][C:21]2[C:20]3[S:24][C:25]([C:27](=[O:36])[NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[Cl:35])=[CH:26][C:19]=3[CH2:18][CH2:17][O:16][C:15]=2[CH:14]=1)[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:37]I.[H-].[Na+]>>[C:1]([N:5]([C:13]1[N:23]=[CH:22][C:21]2[C:20]3[S:24][C:25]([C:27](=[O:36])[N:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[Cl:35])[CH3:37])=[CH:26][C:19]=3[CH2:18][CH2:17][O:16][C:15]=2[CH:14]=1)[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N(c1cc2c(cn1)-c1sc(C(=O)Nc3ccccc3Cl)cc1CCO2)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: CN(C(=O)c1cc2c(s1)-c1cnc(N(C(=O)OC(C)(C)C)C(C)(C)C)cc1OCC2)c1ccccc1Cl
Yield: 78 %

Procedure:
Following Scheme 4, tert-butyl tert-butyl(2-(2-chlorophenylcarbamoyl)-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepin-8-yl)carbamate, methyl iodide and sodium hydride were reacted to give tert-butyl tert-butyl(2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepin-8-yl)carbamate (78%). MS: (ESI+) 542.3
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1.[CH3:18][CH:19]([OH:23])[CH2:20][CH2:21][CH3:22].[H-].[Na+]>>[CH3:18][CH:19]([O:23][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1)[CH2:20][CH2:21][CH3:22]
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Reactant: CCCC(C)O
Agent: [H-]
Agent: [Na+]
Product: CCCC(C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
In a separate flask, a suspension of 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (500 mg) and 2-pentanol (3.8 mL) was heated to 50° C. Sodium hydride (396 mg, 60% dispersion) was added in portions and the reaction was stirred at 50° C. for 72 h. The reaction was cooled and quenched with water (10 mL) and was extracted with EtOAc (3×25 mL). The combined organics were washed with brine (30 mL), dried over MgSO4, filtered and concentrated in vacuo to give crude title compound as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:7])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:14][CH:15]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(C(=O)c2ccccc2)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 55.1 %

Procedure:
To a solution of 4-hydroxybenzophenone (200 mg, 1 mmol) in DMF (3 mL) at 0-5° C. was added 60% NaH (70 mg, 1.75 mmol) at 0-5° C. The reaction mixture was stirred at rt for 15 min at 0-5° C. A solution of (R)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (358 mg, 1 mmol) in DMF (2 mL) was added to the above mixture at 0-5° C. The reaction mixture was warmed to rt and then heated at 90° C. for 15 h. The mixture was concentrated, diluted with saturated aq NaHCO3 and extracted with ethyl acetate. The aqueous layer was re-extracted with ethylacetate. The combined organic layers were dried over anhy. MgSO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (210 mg, 54%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([F:34])=[C:30](F)[CH:31]=3)[C:26](=[O:35])[N:25]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:24]2=[O:44])[CH:20]=[CH:21][CH:22]=1>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([F:34])=[C:30]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH:31]=3)[C:26](=[O:35])[N:25]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:24]2=[O:44])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(F)cc32)c1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Product: COc1cccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(N4CCN(C)CC4)cc32)c1
Yield: 81.5 %

Procedure:
Using General Method 4, the reaction of N-methylpiperazine (0.1 mL, 0.9 mmol), triethylamine (0.12 mL, 0.9 mmol), and 1-(3-methoxyphenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example E-1, 0.12 g, 0.3 mmol) provided 0.12 g of the title compound as a solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23](=[CH:29]O)[C:24](=[O:28])[NH:25]2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23](=[CH:29][NH:17][C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:16][CH:15]=3)[C:24](=[O:28])[NH:25]2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(OCCCN2CCCCC2)cc1
Reactant: O=C1Nc2cc(F)ccc2C1=CO
Product: O=C1Nc2cc(F)ccc2C1=CNc1ccc(OCCCN2CCCCC2)cc1
Yield: 58.8 %

Procedure:
In a manner similar to that described in Example 231, 4-(3-Piperidin-1-yl-propoxy)-phenylamine (0.61 g, 1.3 equiv.) and 6-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (0.358 g, 2.00 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (465 mg, 59%).
Reaction SMILES: COCCOC[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([C:20]#[N:21])[C:17]3[N:22]=[N:23][N:24]([CH3:25])[C:16]=3[CH:15]=2)=[CH:10][C:9]=1[C:26]([F:29])([F:28])[F:27].Cl.CCOC(C)=O.N>C1COCC1>[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([C:20]#[N:21])[C:17]3[N:22]=[N:23][N:24]([CH3:25])[C:16]=3[CH:15]=2)=[CH:10][C:9]=1[C:26]([F:29])([F:28])[F:27]
Reactant: COCCOCOc1ccc(-c2cc3c(nnn3C)c(C#N)n2)cc1C(F)(F)F
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1nnc2c(C#N)nc(-c3ccc(O)c(C(F)(F)F)c3)cc21
Temperature: 65 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
6-(4-((2-Methoxyethoxy)methoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (6.31 mmol, 2.57 g) was dissolved in THF (42 ml) and hydrochloric acid (2M aq) (31.5 mmol, 15.77 ml) added. The mixture was heated to 65° C. for 4 hours, after which time LCMS indicated no reaction. THF (21 ml) was added and heating continued for 16 hours then EtOAc was added and the solution basified with aqueous ammonia. Organics were separated and solvent evaporated under reduced pressure. The resulting pale yellow solid was washed with EtOAc/ether (1:1) and dried to afford product 6-(4-hydroxy-3-(trifluoromethyl)-phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (82% yield). 1H NMR (DMSO) δ: 8.85 (s, 1H), 8.36 (s, 1H), 8.32 (d, 1H), 7.18 (d, 1H), 4.45 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:19]1C=CC=CC=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)(O)[O-].[NH4+]>O1CCOCC1>[C:16]([CH:9]1[CH2:10][C:11]([F:15])([F:14])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:18])[NH2:19]
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(F)CC1C(=O)O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(F)(F)CC1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-4,4-difluoro-piperidine-2-carboxylic acid, 13f, (1.67 g, 6.30 mmol) in 1,4-dioxane (12 mL) was added pyridine (0.35 mL, 4.33 mmol), followed by di-tert-butyl dicarbonate (1.78 g, 8.17 mmol) and ammonium bicarbonate (0.63 g, 7.86 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was taken up in EtOAc. The organic phase was washed with water, aqueous saturated KHSO4 solution, brine, dried over Na2SO4, filtered and evaporated to dryness. The crude residue was used without further purification.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]1=[O:11].[H-].[Na+].CS(O[CH2:19][CH2:20][CH2:21][C:22]1([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)(=O)=O.Cl>O.C(OCC)(=O)C.CN(C)C=O>[O:11]=[C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]1[CH2:19][CH2:20][CH2:21][C:22]1([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:24][CH2:23]1
Reactant: O=c1cnc2ccccc2[nH]1
Reactant: CCOC(=O)C1(CCCOS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(CCCn2c(=O)cnc3ccccc32)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To 5 mL of an N,N-dimethylformamide suspension containing 0.25 g of quinoxalin-2(1H)-one, 0.10 g of 60% sodium hydride was added at room temperature, and the mixture was stirred at 50° C. for 30 minutes. Thereto was dividedly added 0.68 g of 1-tert-butyl 4-ethyl 4-(3-((methanesulfonyl)oxy)propyl)piperidine-1,4-dicarboxylate at the same temperature, and the mixture was stirred at 80 to 90° C. for 2 hours. The reaction mixture was cooled to room temperature, ethyl acetate and water were added thereto, and the resultant solution was adjusted to pH 2.0 with 6 mol/L hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=1:1] to obtain 0.18 g of a yellow brown oily substance, 1-tert-butyl 4-ethyl 4-(3-(2-oxoquinoxalin-1(2H)-yl)propyl)piperidine-1,4-dicarboxylate.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[CH:14][C:13]([C:16]([NH2:18])=O)=[CH:12][N:11]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].P(Cl)(Cl)(Cl)=O>>[C:16]([C:13]1[CH:12]=[N:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=2)=[N:15][CH:14]=1)#[N:18]
Reactant: CCCc1ccc(-c2ncc(C(N)=O)cn2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1ccc(-c2ncc(C#N)cn2)cc1

Procedure:
8.3 G. of 2-(p-n-propylphenyl)-5-pyrimidinecarboxamide are boiled under reflux with 100 ml. of phosphorus oxychloride with the exclusion of moisture for 2 hours. Then, the excess phosphorus oxychloride is removed in vacuo and the mixture evaporated twice with toluene in vacuo. The residue is taken up in methylene chloride and chromatographed on 100 g. of silica gel in methylene chloride. Elution with methylene chloride and methylene chloride/2% acetone yields the 5cyano-2-(4-n-propylphenyl)-pyrimidine, which is recrystallized from acetone/hexane up to a constant melting point and is sublimed at 120° C. in a high vacuum for purification. The pure, colorless 5-cyano-2-(4-n-propylphenyl)-pyrimidine has a melting point of 125.9°-126.0° C. and on cooling is liquid crystalline (monotropic) at 106.4° C. The substance is identical with the compound obtained according to Example 6.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[OH-].[Na+].[CH2:13]([OH:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl>O.C1(C)C=CC=CC=1>[CH2:13]([O:20][C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCO
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCOc1cc[n+]([O-])c(C)c1C
Temperature: 25 °C
Yield: 157.2 %

Procedure:
15.8 g (0.1 mol, 1.0 eq.) of 4-chlor-2,3-dimethylpyridine-N-oxide, 8.0 g (0.2 mol, 2.0 eq.) of caustic soda, and 23.2 g (0.2 mol, 2.0 eq.) of 1-heptanol were added to 64 mL of toluene, and the mixture was heated to reflux for 3 hours, and then cooled to room temperature. 15 mL of water was added to the reaction liquid, and then the mixture was neutralized with concentrated hydrochloric acid (8 mL). Subsequently, the resultant was extracted three times with 670 mL of chloroform. The extract was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, to obtain 37.3 g of 4-heptyloxy-2,3-dimethylpyridine-N-oxide as a black brown oily matter.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.Cl[CH2:18][C:19]1[N:20]=[C:21](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[O:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.CO>[F:35][C:32]([F:33])([F:34])[C:29]1[CH:30]=[CH:31][C:26](/[CH:25]=[CH:24]/[C:21]2[O:22][CH:23]=[C:19]([CH2:18][O:16][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[N:2]4)=[CH:15][CH:14]=3)[N:20]=2)=[CH:27][CH:28]=1
Reactant: FC(F)(F)c1ccc(/C=C/c2nc(CCl)co2)cc1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCn4ccnn4)cc3)co2)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 92.7 %

Procedure:
4-[4-(1H-1,2,3-Triazol-1-yl)butyl]phenol (400 mg, 1.84 mmol) and 4-(chloromethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole (529 mg, 1.84 mmol) were dissolved in dimethylformamide (3 ml), potassium carbonate (279 mg, 2.02 mmol) was added and the mixture was stirred at 65-75° C. for 4 hours. 4-[4-(1H-1,2,3-Triazol-1-yl)butyl]phenol (40 mg, 0.184 mmol) was added and the mixture was stirred at 65-75° C. for 3 more hours. After cooling to room temperature, water (5 ml) and methanol (3 ml) were added in this order, and the mixture was stirred at room temperature for 40 min. The precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to give 1-[4-[4-[[2-[(E)-2-[-4-(trifiuoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole (799 mg, yield 93%).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[OH:20])#[N:2].[H-].[Na+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1COCC1>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][O:20][C:4]1[CH:5]=[C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)[CH:18]=[CH:19][C:3]=1[C:1]#[N:2])[CH3:29]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1cc(Oc2ccc3c(c2)COB3O)ccc1C#N
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-hydroxy-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzonitrile (D10) (300 mg, 1.12 mmol) in THF (50 mL) was added NaH (95 mg, 60%, 2.36 mmol) portion-wise. The mixture was stirred at room temperature for 5 minutes, followed by the slow addition of ethyl bromoacetate (0.262 mL, 2.36 mmol). The reaction was heated at 70° C. overnight.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C@@H:18]([CH3:42])[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2)=[O:20]>>[CH2:1]([NH:8][C:9]([NH:10][O:11][CH2:12][C:13]([NH:17][C@@H:18]([CH3:42])[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2)=[O:20])=[O:15])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CONC(=O)NCc1ccccc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)N
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)NC(=O)CONC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-benzylureidooxy)acetic acid (Compound VI-1) 94 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-11) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([OH:15])=[CH:7][C:6]=1[C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH:28]=[CH2:29]>CC(C)=O>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:9][C:8]([O:15][CH2:29][CH:28]=[CH2:27])=[CH:7][C:6]=1[C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(O)cc1C(C)(C)C
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1

Procedure:
4-Acetoxy-3,5-di-tert-butylphenol (10 g) and potassium carbonate (15.6 g) were dissolved in acetone (300 ml). After addition of 3-bromo-1-propene (6.55 ml), the mixture was refluxed for 24 h. The reaction mixture was concentrated under reduced pressure and water was added to the concentrate. The mixture was subjected to extraction with diethyl ether and the organic layer was washed with water and saturated brine, then dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 4-acetoxy-3,5-di-tert-butyl-1-(2-propenyloxy)benzene (11 g) as a colorless liquid in a quantitative yield.
Reaction SMILES: C([N:3](CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:54]=[CH:55][C:56]=1[N+:57]([O-:59])=[O:58])[C:40]([C:42]1[N:46]2[CH:47]=[C:48]([C:51](O)=[O:52])[CH:49]=[CH:50][C:45]2=[CH:44][N:43]=1)=[O:41].N>CN(C)C=O.O1CCCC1>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:54]=[CH:55][C:56]=1[N+:57]([O-:59])=[O:58])[C:40]([C:42]1[N:46]2[CH:47]=[C:48]([C:51]([NH2:3])=[O:52])[CH:49]=[CH:50][C:45]2=[CH:44][N:43]=1)=[O:41]
Reactant: COc1cc(C(=O)c2ncc3ccc(C(=O)O)cn23)ccc1[N+](=O)[O-]
Reactant: CCN(CC)CC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2ncc3ccc(C(N)=O)cn23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.16 ml (1.12 mmol) of triethylamine and then 0.49 g (1.12 mmol) of BOP are added to 0.346 g (1.01 mmol) of 3-(3-methoxy-4-nitrobenzoyl)imidazo[1,5-a]pyridine-6-carboxylic acid obtained in example 182 in 10 ml of N,N-dimethylformamide. The reaction medium is stirred at ambient temperature for 30 minutes, then 1.35 ml of a 1N solution of ammonia in tetrahydrofuran are added and the mixture is stirred at ambient temperature for 18 hours. The precipitate formed is filtered off and then washed with water. 0.25 g of a yellow solid is collected. Melting point: 289° C.; 1H NMR (d6-DMSO): 4.02 (3H, s), 7.82 (1H, d), 7.98 (1H, s), 8.06-8.10 (3H, m), 8.15 (1H, s), 10.21 (1H, s)
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([NH:23][C:24]2[C:29]([F:30])=[C:28](Cl)[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:32][C:33]1([CH3:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@@H:35]([NH2:42])[CH2:34]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([NH:23][C:24]2[C:29]([F:30])=[C:28]([NH:42][C@@H:35]3[C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:33]([CH3:43])([CH3:32])[CH2:34]3)[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Nc2ncnc(Cl)c2F)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CC1(C)C[C@H](N)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)C[C@H](Nc2ncnc(N[C@@H]3C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C3)c2F)c2ccccc21
Temperature: 180 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
A mixture of N-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]-6-chloro-5-fluoropyrimidin-4-amine (205 mg, 0.38 mmol), (1S)-3,3-dimethylindan-1-amine (243 mg, 1.51 mmol), and sodium carbonate (160 mg, 1.51 mmol) was stirred at 180° C. for 3 h in an oil bath. The reaction mixture was diluted with DCM and the suspension was filtered. The filtrate was concentrated under vacuum and the residue was purified by flash chromatography (5 to 10% ethyl acetate/hexanes) to afford the title compound (213 mg, 70%) as a colorless amorphous solid.