Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6]Br.Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[P:21]([O-:28])(OCC)OCC.Cl>C1COCC1.C1(C)C=CC=CC=1>[C:9]1([C:6]2[CH:5]=[CH:17][CH:16]=[CH:15][CH:20]=2)[CH:14]=[CH:13][C:12]([PH:21](=[O:28])[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)=[CH:11][CH:10]=1
Reactant: CCOP([O-])OCC
Reactant: BrCCBr
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=[PH](c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
Under an argon atmosphere, a solution of magnesium (2.60 g, 1.0 equivalent), a small amount of iodine and a small amount of 1,2-dibromoethane in THF (20 mL) was stirred at room temperature for 30 min. A solution of 4-bromobiphenyl (25 g, 0.107 mol) in THF (20 mL) was added at 35° C. and the mixture was stirred at 40° C. for 1 hr. and then stirred at 5° C. for 30 min. A solution of diethyl phosphite (7.39 g, 0.5 equivalent) in THF (10 mL) was added at 5° C., and the mixture was stirred at 5° C. for 2 hrs. Toluene (60 mL) was added at 3° C. and 3M—HCl (30 mL) was added. The mixture was stirred at room temperature for 30 min. THF (50 mL) was added, and the reaction mixture was partitioned. The organic layer was washed with 5% aqueous NaCl solution (10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered by gravity, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether to give the title compound (12.47 g, white crystals). yield 65.8%.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].[H-].[Na+].BrC[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([O:21][CH3:22])=[O:20].[CH3:23]N(C=O)C>>[CH3:22][O:21][C:19](=[O:20])[C:14]1[CH:13]=[CH:18][CH:17]=[C:16]([CH2:23][N:5]2[C:6](=[O:7])[CH2:8][N:2]([CH3:1])[C:3]2=[O:4])[CH:15]=1
Reactant: CN(C)C=O
Reactant: CN1CC(=O)NC1=O
Reactant: COC(=O)c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cccc(CN2C(=O)CN(C)C2=O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To methylhydantoine (50 mg, 0.438 mmol) in DMF (2 mL) is added at 0° C. sodium hydride (23 mg, 0.525 mmol). After stirring at 0° C. during 1 h, methyl 2-bromomethylphenylcarboxylate (121 mg, 0.525 mmol) is added and the mixture is stirred at rt during 2 h before quenching with an aqueous saturated NaHCO3 solution and DCM. The organic phase is dried and evaporated to give a crude compound before purification by preparative HPLC (Column Waters C18 ODB 5 μm 19×50, Gradient: 0-2.5 min 5% ACN, 2.5-12.5 min 5-100% ACN, 12.5-15 min 100% ACN) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.O.O[N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30]C=2N=N1.CN(C)CCCN=C=NCC.C1(CCN)CC1>ClCCl>[CH:28]1([CH2:27][CH2:26][NH:22][C:8]([C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:10])[CH2:29][CH2:30]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(Cl)nn1
Agent: CCN=C=NCCCN(C)C
Agent: NCCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(NCCC1CC1)c1ccc(Cl)nn1
Reaction time: 0.25 h
Yield: 55.1 %

Procedure:
To a solution of 6-chloropyridazine-3-carboxylic acid (15.8 mmol) in dichloromethane (95 mL) was added diisopropylethylamine (46.7 mmol), 1-hydroxybenzotriazole monohydrate (23.7 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (23.7 mmol) under nitrogen atmosphere at ambient temperature. The resulting mixture was stirred for 15 minutes and 2-cyclopropylethylamine (20.2 mmol) was added. After stirring for 36 hours at ambient temperature, the reaction mixture was diluted with dichloromethane (100 mL), then washed with water and dried over anhydrous Na2SO4. The solvent was removed in vacuo. Purification via column chromatography (30% ethyl acetate in hexanes) afforded the title compound (8.70 mmol). Yield 55%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7](F)[C:6]=1[N+:13]([O-:15])=[O:14])[CH3:2].C(=O)([O-])[O-].[NH4+:21].[NH4+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([NH2:21])[C:6]=1[N+:13]([O-:15])=[O:14])[CH3:2]
Reactant: CCOC(=O)c1cc(F)cc(F)c1[N+](=O)[O-]
Reactant: [NH4+]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(F)cc(N)c1[N+](=O)[O-]
Yield: 75 %

Procedure:
4.64 g (20 mmol) of 3,5-difluoro-2-nitro-benzoic acid ethyl ester in DMF and 2.1 g (22 mmol) of ammonium carbonate was heated at 60° C. for 6 h. The reaction mixture was treated with water. The resulting solid was collected by filtration and washed with water to produce 3.4 g (15.0 mmol, 75%) of 3-amino-5-fluoro-2-nitro-benzoic acid ethyl ester. LCMS: 229 (M+1)+.
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:4]=2[O:3]1.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15]C([O-])=O>>[F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[CH:15][C:14]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][C:4]=2[O:3]1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Product: CCOC(=O)C=Cc1ccc2c(c1)OC(F)(F)O2
Yield: 81.3 %

Procedure:
2,2-difluoro-1,3-benzodioxole-5-carboxaldehyde (5.0 g, 26.9 mmol) and mono-ethyl malonate (4.1 ml, 34.9 mmol) were reacted as described under General Procedure A to furnish the title compound (5.6 g, 82%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.61 (d, J=16.0 Hz, 1H), 7.26-7.22 (m, 2H), 7.06 (d, J=7.9 Hz, 1H), 6.33 (d, J=16.0 Hz, 1H), 4.26 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](=[S:9])[NH2:8])([O-:3])=[O:2].Cl[CH2:14][CH:15]=O.C(O)(=O)C.[OH-].[Na+]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]2[S:9][CH:14]=[CH:15][N:8]=2)[CH:10]=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: NC(=S)c1cccc([N+](=O)[O-])c1
Reactant: O=CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(-c2nccs2)c1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A yellow suspension of 3-nitrobenzothioamide (2.0 g, 10.98 mmol), 2-chloroacetaldehyde (45% in H2O) (2.01 g, 11.53 mmol), and acetic acid (7.32 mL) was heated to reflux for 1 hour. The mixture was cooled to room temperature, poured into ice water, and rendered alkaline using 30 mL of 12 N NaOH solution. Ethyl acetate was then added, and the resulting emulsion was filtered through CELITE®. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were dried over magnesium sulfate. Filtration and concentration under reduced pressure afforded Intermediate 57A (2.107 g, 91% yield) as a brown solid. HPLC: Rt=3.331 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=207.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.68 (1H, t, J=1.89 Hz), 8.34-8.41 (1H, m), 8.28-8.34 (1H, m), 8.00-8.05 (1H, m), 7.94 (1H, d, J=3.27 Hz), 7.80 (1H, t, J=8.06 Hz).
Reaction SMILES: ClN1C(=O)CCC1=O.N1C=CC=CC=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]=[N:22][OH:23].[CH2:24]([O:26][C:27](=[O:36])/[CH:28]=[C:29](/N1CCCC1)\[CH3:30])[CH3:25].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:24]([O:26][C:27]([C:28]1[C:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)=[N:22][O:23][C:29]=1[CH3:30])=[O:36])[CH3:25]
Reactant: CCOC(=O)/C=C(\C)N1CCCC1
Reactant: ON=Cc1ccccn1
Agent: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(-c2ccccn2)noc1C
Temperature: 50 °C
Reaction time: 3 h
Yield: 10.7 %

Procedure:
To a solution of N-chlorosuccinimide (46.58 g, 349 mmol) in chloroform (211 mL) and pyridine (2.8 mL, 35 mmol) was added at room temperature within 15 min a solution of pyridine-2-carbaldehyde oxime (42.6 g, 349 mmol) in chloroform (1090 mL). The reaction mixture was stirred at 50° C. for 3 h and then cooled to room temperature. Within 15 min a solution of (E)-3-pyrrolidin-1-yl-but-2-enoic acid ethyl ester (63.9 g, 349 mmol) in chloroform (42 mL) was added to the reaction mixture, which then was heated again to 50° C. and a solution of triethylamine (48.6 mL, 349 mmol) in chloroform (42 mL) was added dropwise within 1 h. After stirring at 50° C. for 1 h the reaction mixture was cooled to room temperature and then poured on ice water (2 L). Extractive workup followed by drying over sodium sulfate, filtering and evaporation of the organic solvent furnished a dark brown oil. Chromatographic purification (silica, heptane:AcOEt=80:20 to 50:50) afforded the title compound (8.7 g, 11%) as a yellow oil MS: m/e=233.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:11]([O-])=O)=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].Cl>C(O)C.C(O)(=O)C.O.[Fe]>[CH3:1][O:2][C:3]1[C:4]([NH2:11])=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7]
Reactant: COc1cccc(C=O)c1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc(C=O)c1N
Yield: 112.6 %

Procedure:
5 g of 3-methoxy-2-nitrobenzaldehyde are dissolved in a solution of 100 ml of ethanol, 100 ml of acetic acid and 50 ml of water. After addition of 11.4 g of iron and of 1.4 ml of concentrated hydrochloric acid, the reaction medium is heated at reflux for 10-15 minutes. After having cooled the reaction medium, 150 ml of water are added and the reaction mixture is extracted with 3×200 ml of dichloromethane. The organic phases are combined, washed with 500 ml of a saturated sodium hydrogencarbonate solution, dried over magnesium sulfate, filtered and evaporated under vacuum to provide 4.7 g of 3-methoxy-2-aminobenzaldehyde in the form of a colorless oil, used without purification in the following stage. (Yield: quantitative)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[C:10]([O:14][C:15]([N:17]1[C@@H:21]([C@H:22]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:19][C@H:18]1[CH2:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[CH:40][CH:39]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Si:30]([O:29][C@H:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C@H:21]1[CH2:20][CH2:19][C@@H:18]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([C:42](=[O:43])[NH:1][CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=3)=[CH:45][CH:46]=2)[N:17]1[C:15]([O:14][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:16])([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:32])[CH3:31]
Reactant: NCCc1ccccn1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)NCCc3ccccn3)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(2-Aminoethyl)pyridine (0.034 mL, 0.29 mmol) was added to a stirred, room temperature mixture of 4-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acid (100 mg, 0.190 mmol), HATU (87 mg, 0.228 mmol), and DIPEA (0.166 mL, 0.951 mmol) in DMF (1.9 ml). The resulting mixture was stirred at room temperature overnight. Upon completion, as determined by LC-MS, water was added, and the mixture was partitioned with EtOAc. The aqueous layer was extracted with EtOAc (3×), and the combined organic layers were washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo to give the product that was used directly in the next step. LC-MS=630.3 (M+1)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([CH2:11]O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:15])=O>C(OCC)C>[ClH:15].[Cl:15][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:1]2
Reactant: OCc1cccc2ncccc12
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: Cl
Product: ClCc1cccc2ncccc12

Procedure:
A solution of 190 mg (1.19 mmol) of quinolin-5-ylmethanol in 5 ml of thionyl chloride is stirred for 10 minutes at room temperature and then refluxed for 2 hours. The reaction mixture is evaporated, the solid obtained is taken up in ethyl ether and the solution is filtered, washed with ethyl ether and dried to give 255 mg of 5-chloromethylquinoline hydrochloride, corresponding to the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[NH2:17])=[N:6][CH:7]=1.[C:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[C:25]([O:32][CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>N1C=CC=CC=1.ClCCl>[C:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:17][C:11]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=2[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:18])=[O:28])=[C:25]([O:32][CH:33]2[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38]2)[CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: Nc1cc(Cl)ccc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)Cl)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)Nc2cc(Cl)ccc2C(=O)Nc2ccc(Cl)cn2)CC1

Procedure:
To a stirring solution of N-(5-chloropyridin-2-yl)-2-amino-4-chlorobenzamide (0.74 g, 26.5 mmol) in pyridine (1 mL) and dichloromethane (20 mL) at 0° C. was added a solution of 4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzoyl chloride (1.05 g, 26.5 mmol) in dichloromethane (10.5 mL). The cold bath was then removed and after 72 h, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate and washed with water, followed by satd aq NaHCO3 and then brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo. The residue was chromatographed over silica gel, eluting with a solution of 20% ethyl acetate in hexanes.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:24](O)=[O:25]>>[CH:24]([C:11]1[CH:10]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7])=[O:25]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: COC(=O)c1ccc(O)c(C=O)c1

Procedure:
Methyl 4-hydroxybenzoate (1.52 g) is dissolved in trifluoroacetic acid (20 ml), and thereto is added hexamethylenetetramine (700 mg). The mixture is heated under reflux for 2 hours. The reaction solution is concentrated under reduced pressure, and thereto is poured ice-water. The mixture is then extracted with ethyl acetate. The organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is dissolved in chloroform, and filtered to remove the insoluble materials. The filtrate is concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1) to give the title compound (540 mg). ESI-MS M/Z:179[M−H]−
Reaction SMILES: [N+:1]([C:4]1[C:12]2[S:11][N:10]=[CH:9][C:8]=2[C:7]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)([O-])=O.O.C(O)(=O)C.N>[Fe].C(O)CC>[NH2:1][C:4]1[C:12]2[S:11][N:10]=[CH:9][C:8]=2[C:7]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c2cnsc12
Agent: [Fe]
Agent: N
Solvent: CCCO
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(OCc2ccccc2)c2cnsc12
Yield: 98 %

Procedure:
28.6 g of 7-nitro-4-benzyloxy-1,2-benzisothiazole are added in portions to a boiling mixture of 67 ml of water, 30 g of iron powder, 3 ml of glacial acetic acid and 167 ml of n-propanol and the mixture is then refluxed for a further hour. When it has cooled, it is neutralized with concentrated ammonia solution and filtered. The filter residue is washed with methylene chloride and the combined wash solutions are dried over magnesium sulfate and freed from the solvent under reduced pressure. 25.1 g (100% of theory) of 7-amino-4-benzyloxy-1,2-benzisothiazole of melting point 126°-128° C. are obtained.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].Cl[CH2:6][CH2:7][CH2:8][Si:9]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])([O:15][CH2:16][CH2:17][CH2:18][CH3:19])[O:10][CH2:11][CH2:12][CH2:13][CH3:14].[Cl-].[K+]>C(O)CCC>[S:1]([CH2:6][CH2:7][CH2:8][Si:9]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])([O:10][CH2:11][CH2:12][CH2:13][CH3:14])[O:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:2]#[N:3]
Reactant: N#C[S-]
Reactant: CCCCO[Si](CCCCl)(OCCCC)OCCCC
Agent: [Cl-]
Agent: [K+]
Solvent: CCCCO
Product: CCCCO[Si](CCCSC#N)(OCCCC)OCCCC
Reaction time: 20 h
Yield: 85 %

Procedure:
24.3 grams of potassium thiocyanate were dissolved in 900 ml. of n-butanol and the solution heated to boiling. Then there were added dropwise in about 30 minutes 81.3 grams of 3-chloropropyl tri-n-butoxy silane. After a further 20 hours of boiling at reflux temperature the precipitated potassium chloride was separated off with a Seitz filter. The solvent was distilled off from the filtrate and the 3-thiocyanatopropyl tri-n-butoxy silane distilled in vacuo. B.P. 0.1 128°-129° C., yield 85% based on the weight of the 3-chloropropyl tri-n-butoxy silane.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([C:13]1[C:22]([OH:23])=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[N:20]2)=[CH:15][N:14]=1)=[O:12].CO.CO.O>C(Cl)(Cl)Cl>[CH3:9][O:10][C:11]([C:13]1[C:22]([OH:23])=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[N:20]2)=[C:15]([Br:1])[N:14]=1)=[O:12]
Reactant: COC(=O)c1ncc2cccnc2c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: COC(=O)c1nc(Br)c2cccnc2c1O
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
N-bromosuccinimide (7.83 g, 44.0 mmol) was added to a solution of 8-hydroxy-1,6-naphthyridine-7-carboxylic acid methyl ester (5, 8.17 g, 40.0 mmol) in chloroform (32 mL) over 20 min maintaining the temperature at 20-50° C. and the mixture was aged for 30 min at 50° C. The mixture became a thick, stirrable slurry and HPLC analysis indicated <2% starting material remaining. The mixture was cooled to 30° C. over 15 min. MeOH (64 mL) was added over 30 min then a 1:1 mixture of MeOH-water (64 mL) was added over 30 min. The mixture was cooled to −40° C. over 30 min and aged at −40° C. for 30 min. The cold mixture was filtered and the solid was washed with 1:1 MeOH:water (100 mL) at 10-20° C. The off white crystalline solid was dried under a stream of nitrogen to provide 10.48 g (93% yield) of 5-bromo-8-hydroxy-1,6-naphthyridine-7-carboxylic acid methyl ester (6).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+].[K+].Br[CH:19](C(OCC)=O)[C:20]([O:22]CC)=[O:21].Cl>O>[CH3:11][O:10][C:8]1[CH:7]=[CH:6][C:3]2[CH:4]=[C:19]([C:20]([OH:22])=[O:21])[O:1][C:2]=2[CH:9]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc2cc(C(=O)O)oc2c1
Yield: 46.7 %

Procedure:
To a suspension of 2-hydroxy-4-methoxybenzaldehyde (20.0 g) and potassium carbonate (20.0 g) in2-butanone (80 ml) was added diethyl bromomalonate (39.3 g), and the mixture was refluxed under nitrogen atmosphere for 7 hours and cooled. To the mixture was added water, and the mixture was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the resulting dark brown oil was suspended in a solution of potassium hydroxide (20.0 g) in ethanol (200 ml). The suspension was refluxed for 1 hour and cooled, and to the mixture was added water. The mixture was made acidic with 1N hydrochloric acid and extracted with ethylacetate(twice). The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the resulting solid was washed with hexane to give yellow solid of 6-methoxybenzofuran-2-carboxylic acid (11.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[CH:17](I)([CH3:19])[CH3:18].[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][CH:17]([CH3:19])[CH3:18])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-c2ccccc2)cc1NC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
A DMF (15 mL) solution of 3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (500 mg, 21.5 mmol) was cooled to 0° C. and then isopropyl iodide (2.57 mL) and NaH (60%, 775 mg, 32.3 mmol) were added under an atmosphere of N2. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. The mixture was partitioned between ether and water, the ether layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (5:95) as eluent to obtain 3-isopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (189 mg, 32%) as a solid. 1H NMR (CDCl3, 400 MHz): 7.62 (d, 2H), 7.40 (m, 3H), 6.91 (s, 1H), 3.84 (s, 3H), 1.35 (d, 6H).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>C1(C)C=CC=CC=1>[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH:2]([N:13]([CH:14]([CH3:19])[CH3:15])[CH3:11])[C:1]([OH:5])=[O:4])=[CH:16][CH:15]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: O=CC(=O)O
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)N(C)C(C(=O)O)c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 62 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with glyoxylic acid (618 mg, 6.72 mmol), toluene (20 mL), N,N-isopropylmethylamine (486 mg, 6.60 mmol) and 4-(tert-butoxycarbonylamino)phenylboronic acid (1.58 g, 6.66 mmol). The reaction was sealed with a plastic cap under a nitrogen atmosphere and stirred at room temperature for 7 d. After this time, the reaction was concentrated under reduced pressure. The resulting residue was subjected to flash chromatography to afford 25 in 62% yield (1.34 g) as a light brown solid: mp 320° C. dec, 1H NMR (300 MHz, DMSO-d6) δ 9.42 (s, 1H), 7.42 (d, 2H, J=8.7 Hz), 7.37 (d, 2H, J=8.7 Hz), 4.23 (s, 1H), 3.28 (m, 1H), 3.17 (s, 1H), 2.23 (s, 3H), 1.47 (s, 9H), 1.15 (d, 3H, J=6.6 Hz), 1.11 (d, 3H, J=6.6 Hz); MS (ESI+) m/z 323 (M+H).