Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.BrC1C=C(C)C=CN=1>>[CH3:33][C:31]1[CH:30]=[CH:29][N:28]=[C:27]([C:24]2[O:23][C:22]([C:9](=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:26][CH:25]=2)[CH:32]=1
Reactant: Cc1ccnc(-c2cnc(C(CCCCCCc3ccccc3)O[Si](C)(C)C(C)(C)C)o2)c1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: Cc1ccnc(Br)c1
Product: Cc1ccnc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)c1
Yield: 59 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)-5-(4-methylpyridin-2-yl)oxazole. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (130 mg, 0.196 mmol) and 2-bromo-4-methylpyridine following General Procedure A. Flash chromatography (10% EtOAc/hexanes) yielded the title compound as a thick oil (41 mg, 59%): 1H NMR (CDCl3, 400 MHz) δ 8.48 (d, 1H, J=5 Hz), 7.63 (s, 1H), 7.50 (d, 1H, J=0.6 Hz), 7.29-7.25 (m, 2H), 7.18-7.15 (m, 3H), 7.05 (ddd, 1H, J=5.0, 1.5, 0.6 Hz), 4.86 (dd, 1H, J=7.3, 5.8 Hz), 2.59 (t, 2H, J=7.8 Hz), 2.41 (s, 3H), 1.93 (m, 2H), 1.61 (m, 2H), 1.36 (m, 4H), 0.91 (s, 9H), 0.11 (s, 3H), 0.01 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 165.5, 150.7, 149.6, 148.1, 147.2, 142.7, 128.2, 125.5, 125.0, 123.8, 119.9, 68.7, 36.4, 35.9, 31.4, 29.1, 25.7, 25.7, 25.1, 21.1, 18.2, −5.0, −5.2.
Reaction SMILES: FC(F)(F)S(O[CH:7]1[CH:11]=[C:10]([O:12][CH3:13])[C:9](=[CH:14][C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:8]1)(=O)=O.C(OC([N:33]1[CH:37]=[CH:36][CH:35]=[C:34]1B(O)O)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C(OCC)(=O)C>[CH3:13][O:12][CH:10]1[C:9](=[CH:14][C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:8][C:7]([C:34]2[NH:33][CH:37]=[CH:36][CH:35]=2)=[CH:11]1
Reactant: COC1=CC(OS(=O)(=O)C(F)(F)F)NC1=Cc1cc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC1C=C(c2ccc[nH]2)NC1=Cc1cc2ccccc2[nH]1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
The crude triflate 78 was mixed with about 3 equivalent of boronic acid 8, 8 equivalents of potassium carbonate and about 0.1 equivalent of tetrakistriphenylphosphine palladium under argon. Anhydrous 1,4-dioxane (10 mL) was added to the reaction mixture, and it was heated at 90° C. in a sand bath. After three hours, the mixture was cooled and added to ethyl acetate (100 mL). The organic layer was washed with brine (3×100 mL) and was then dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude mixture was passed through a short column of neutral alumina using 50/50 hexanes/ethyl acetate as an eluent. The relevant fractions were combined and concentrated, and the resulting crude product was purified using a preparative plate of neutral alumina and eluted using 80/20 hexanes/ethyl acetate. The alumina band containing Compound 79 was washed with ethyl acetate and concentrated to provide the Compound 79 as a red dark solid (2 mg, 20%). (500 MHz, CD3OD) : δ (ppm), 7.55 (m, 2H); 7.20 (t, 1H); 7.13 (s, 1H); 7.03 (t, 1H); 6.90 (s, 1H), 6.88 (s, 1H); 6.85 (s, 1H); 6.32 (s, 1H), 6.17 (s, 1H); 3.97 (s, 3H). MS (M+H): 290.0.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21].N1C2C(=CC=CC=2)C=CC=1>[Cu-]=O.S1C=CC=C1C([O-])=O.[Cu+2].S1C=CC=C1C([O-])=O.C(O)C.N1C=CC=CC=1>[N+:20]([C:11]1[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=1[S:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Br
Reactant: Oc1ccc(S)cc1
Agent: O=[Cu-]
Agent: [Cu+2]
Agent: O=C([O-])c1cccs1
Solvent: c1ccc2ncccc2c1
Solvent: c1ccncc1
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Sc1ccc(O)cc1
Temperature: 70 °C

Procedure:
A mixture containing 12.6 g. (0.10 mole) of 4-mercaptophenol, 7.15 g. (0.05 mole) of copper (I) oxide, and 100 ml. of absolute ethanol is heated at reflux under an atmosphere of dry nitrogen until conversion to the copper thiphenate is complete, as indicated by discharge of the reddish color of the copper (I) oxide. The resultant yellow mixture is cooled to 25°, 27.0 g. (0.10 mole) of 4-bromo-3-nitrobenzotrifluoride, 100 ml. of quinoline, and 10 ml. of pyridine are added, and the reaction vessel is equipped with a Newman still head. The reaction is now slowly heated with concomitant removal of the ethanol to 90° and maintained at this temperature until the conversion is complete, as indicated by vpc techniques. The dark liquid is cooled to 70° C., cautiously poured into 500 ml. of an ice cold 3.0 molar hydrochloric acid solution, and filtered, whereupon the residue is extracted with several portions of ether. the combined ether extracts are washed with a 3.0 molar hydrochloric acid solution, water until neutral, a saturated sodium chloride solution, dried (magnesium sulfate), and concentrated in vacuo to afford a quantitative yield of crude product as a dark solid. Recrystallization foam ether-hexane provides yellow crystals, mp 131°-134° of 4-(2-nitro-4-trifluoromethylphenylthio)phenol. This phenol is then reacted with 2-bromopropionate by the procedure of Example 3 above to provide the desired ethyl 2-[4-(2-nitro-4-trifluoromethylphenylthio)phenoxy]propionate, mp 63°-64° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:16][CH2:15][C:10]2(OCC[O:11]2)[CH2:9][CH2:8]1.S(=O)(=O)(O)O.N>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][C:10](=[O:11])[CH2:15][CH2:16]1
Reactant: c1ccc(N2CCC3(CC2)OCCO3)nc1
Agent: N
Agent: O=S(=O)(O)O
Product: O=C1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
A solution of 8-(2-pyridinyl)-1,4-dioxa-8-azaspiro[4.5]decane (23 g, 0.1 mol) (preparation 36) in 10% w/v sulphuric acid was stirred at room temperature for 8 hr. The reaction mixture was cooled in ice and then the solution adjusted to pH>7 with 0.88 ammonia. The solution was extracted with diethyl ether and the solvent removed from the organic extracts under reduced pressure to give the title compound (14.7 g) as an oil.
Reaction SMILES: [C:1]12([C:11]([OH:13])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:14]O.OS(O)(=O)=O>O>[CH3:14][O:12][C:11]([C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2)=[O:13]
Reactant: CO
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 77.5 %

Procedure:
A mixture of 1-adamantanecarboxylic acid (572 gm.), methanol (2.2 liters), and H2SO4 (90 ml.) was refluxed 5 hours and then cooled to room temperature overnight. The reaction mixture was poured into 28 liters of water and extracted with chloroform (2 × 150 ml. for each 3.5 liters of solution). The chloroform extracts were combined, washed with water, dried, and concentrated. The residual oil was distilled to give 476 gm. product (77.5% yield) b17 approx. 143°.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[C:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)N1CCCC1Cc1ccccc1
Agent: O=S(=O)(O)O
Product: CC(=O)N1CCCC1Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
Dissolve 5.0 g of 1-acetyl-2-benzylpyrrolidine (at 0°) in 25 ml of concentrated sulfuric acid. At this temperature add (dropwise, with stirring) 20 ml of concentrated nitric acid to the thus-prepared solution. After warming the obtained reaction mixture to room temperature, pour it into 200 ml of ice water and extract it with diethyl ether. After drying over sodium sulfate, treat the extract with activated charcoal and then distil off the solvent to obtain the title compound as reddish oil.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][NH2:23])[CH:17]=[C:18]([F:20])[CH:19]=1.[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:23][CH2:22][CH2:21][C:16]2[CH:17]=[C:18]([F:20])[CH:19]=[C:14]([F:13])[CH:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: NCCc1cc(F)cc(F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2cc(F)cc(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
0.67 ml of 4-tert-butylbenzaldehyde (3.87 mmol) and 500 mg 2-(3,5-difluoro-phenyl)-ethylamine (2.58 mmol) were dissolved in 7.5 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 4 h. After cooling down to rt, 147 mg (3.87 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 2.5 h. After cooling down to rt, the reaction mixture was treated with 10 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:2) to give 653 mg light yellow oil (83%). MS (ISP) 304.2 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH:3](=[O:8])[CH2:4][CH2:5][CH2:6][CH3:7]>O>[CH2:5]([C:4](=[CH:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:3]=[O:8])[CH2:6][CH3:7]
Reactant: CCCCC=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCC=C(C=O)CCC
Temperature: 80 °C
Yield: 88.4 %

Procedure:
A reactor equipped with a dropping funnel and a condenser was charged with 20 g (0.5 mol) of sodium hydroxide (manufactured by Kanto Chemical Co., Inc.) and 500 mL of water. 2434 g (28.3 mol) of n-pentanal (“Valeraldehyde” manufactured by Tokyo Chemical Industry Co., Ltd.) was added dropwise to the mixture from the dropping funnel over 3.5 hours while stirring the mixture at 80° C. The mixture was stirred at 95° C. for 2 hours, and the aqueous layer was removed from the reaction product. The reaction product was purified by distillation (b.p.: 70° C./0.7 kPa) to obtain 1930 g of 2-propyl-2-heptenal.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:11]I.O>CN(C=O)C>[Br:1][C:2]1[C:7]([O:8][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CI
Reactant: Oc1cccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccnc1Br
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, to a solution of 2-bromo-3-hydroxypyridine (10.00 g) in DMF (100 ml) was added sodium hydride (60% oil, 2.5 g) at 0° C., and the mixture was stirred for 30 minutes. To the reaction mixture was added methyl iodide (4.0 ml), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated. Under reduced pressure, the residue was separated and purified with column chromatography (ethyl acetate/hexane=1:2) to give 2-bromo-3-methoxypyridine (9.24 g) as colorless crystals.
Reaction SMILES: [C:1]([CH2:3][CH:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:5]([OH:7])=[O:6])#[N:2].C([Sn]([N:29]=[N+:30]=[N-:31])(CCCC)CCCC)CCC>C1COCC1>[NH:29]1[C:1]([CH2:3][CH:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:5]([OH:7])=[O:6])=[N:2][N:31]=[N:30]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NC(CC#N)C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1nnn[nH]1)C(=O)O
Reaction time: 72 h
Yield: 84.9 %

Procedure:
17.5 g (82 mmol, 1 equiv.) of the compound of Example 39 (3-cyano-2-(1,1-dimethylethoxy)methanamido-propionic acid) was dissolved in 125 mL of THF and 40.5 g (129 mmol, 1.5 equiv.) tributyltin azide was added. The reaction mixture was brought to reflux and held there for 3 days. The reaction mixture was cooled and the volatiles removed in vacuo on the rotary evaporator. The residue was dissolved in 300 mL of 0.5M NaOH and this aqueous solution was washed with ethyl acetate (4×100 mL). The aqueous layer was passed through a 125 mL bed of Dowex 50X8-400 ion exchange resin and the resin washed with four column volumes of 1:1 methanol:water. The volatiles were removed in vacuo on the rotary evaporator to yield 17.9 g of the title compound as a white solid (85% yield). 1H-NMR (CD3OD) : 4.55 p.p.m (m, 1H); 3.40 p.p.m. (m, 2H); 1.40 p.p.m. (s, 9H). This material is suitable for use in solid-phase peptide synthesis.
Reaction SMILES: C1(S(O)(=O)=[O:8])C=CC=CC=1.[CH3:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][CH2:17][C:18]2=[N:23]O.C(O)(=O)C>O>[CH3:11][O:12][C:13]1[C:14]2[CH2:15][CH2:16][CH2:17][C:18](=[O:8])[NH:23][C:19]=2[CH:20]=[CH:21][CH:22]=1
Reactant: O=S(=O)(O)c1ccccc1
Reactant: COc1cccc2c1CCCC2=NO
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc2c1CCCC(=O)N2
Yield: 75.7 %

Procedure:
9.7 g (0.029 mole) of 5-methoxy-tetralone-1-oxime benzenesulfonate in 800-900 ml of 50% strength acetic acid are kept on a waterbath until completely dissolved (about 60 minutes). The solution is then diluted with twice its volume of water and the mixture is repeatedly extracted with ether. The combined ether extracts are washed first with aqueous bicarbonate solution and then repeatedly with water, and are dried and concentrated. The residue which remains crystallizes on being left to stand, and is analytically pure. 4.2 g of 6-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (75.7% yield), of melting point 162° C., are obtained.
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][CH:21]=[C:22]([CH2:24][C:25](=O)[N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[N:23]=2)=[CH:15][CH:14]=1.II.[OH-].[K+]>O1CCCC1.CO>[CH3:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[O:20][CH:21]=[C:22]([CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)[N:23]=2)=[CH:17][CH:18]=1
Reactant: CC1CCCN1CCCOc1ccc(-c2nc(CC(=O)N3CCCC3)co2)cc1
Agent: II
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1CCCN1CCCOc1ccc(-c2nc(CCN3CCCC3)co2)cc1
Temperature: 0 °C
Yield: 15.6 %

Procedure:
To a solution of sodium borohydride (0.05 g, 1.21 mmol, 2.4 eq) in tetrahydrofuran (0.5 ml) is added a solution of 2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-4-(2-oxo-2-pyrrolidin-1-ylethyl)-1,3-oxazole 52 (0.2 g, 0.5 mmol, 1 eq) in tetrahydrofuran (2 ml). The mixture is cooled down to 0° C. (ice bath) and a solution of iodine (0.13 g, 0.5 mmol, 1 eq) in tetrahydrofuran (1 ml) is added dropwise. When the release of gas has stopped, the mixture is heated to reflux overnight. Methanol is added to the mixture at 0° C. until complete dissolution. The solvent is removed under vacuum to give a white solid. The solid is taken up into a 20% methanolic solution of potassium hydroxide and the mixture is heated at 60° C. for 10 h. The mixture is poured onto water and extracted with dichloromethane. The organic layer is dried over magnesium sulfate and the solvent is removed in vacuum. The crude product is purified by chromatography over silica gel (eluent: gradient of dichloromethane/methanol/ammonia) to give 0.03 g of 2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-4-(2-pyrrolidin-1-ylethyl)-1,3-oxazole 55 as an orange oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.S(=O)(=O)(O)O.[N+:21]([O-])([O-:23])=[O:22].[K+].[OH-].[Na+]>>[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[C:7]([N+:21]([O-:23])=[O:22])[CH:8]=2)[CH2:3]1
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)c1cccc2c1CN(C)CC2
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: COC(=O)c1cc([N+](=O)[O-])cc2c1CN(C)CC2
Temperature: -7 °C
Reaction time: 1 h

Procedure:
A mixture of 1.04 g (5.0 mmol) 2-methyl-1,2,3,4-tetrahydro-8-methoxycarbonyl-isoquinoline and sulphuric acid is slowly combined at −7° C. with 0.57 g of potassium nitrate, then stirred for 15 min at −7° C. and for 1 h at ambient temperature. Then it is slowly poured onto ice water and made alkaline with NaOH. The crystals precipitated are filtered off and dried. A mixture of regioisomers is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8](CC1C=CC(OC)=CC=1)[C:7](=[O:21])[C:6]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)=[C:5]2[O:27][CH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.FC(F)(F)C(O)=O>C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:21])[C:6]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)=[C:5]2[O:27][CH2:28][CH:29]1[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1
Reactant: COc1ccc(Cn2c(=O)c(-c3cccs3)c(OCC3CCOCC3)c3cc(Br)ccc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2ccc(Br)cc2c(OCC2CCOCC2)c1-c1cccs1
Temperature: 100 °C

Procedure:
6-bromo-4-(tetrahydro-2H-pyran-4-ylmethoxy)-1-(4-methoxybenzyl)-3-(thiophen-2-yl)quinolin-2(1H)-one (160 mg, 0.30 mmol) was taken into neat trifluoroacetic acid (500 μL, 6.5 mmol). The reaction mixture was heated overnight at 100° C. The crude reaction mixture was poured into saturated sodium bicarbonate (50 mL). The product was extracted with dichloromethane (3×50 mL). The combined organic extractions were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified via flash chromatography (silica, 4:1 dichlormethane/ethyl acetate) to yield 6-bromo-4-(tetrahydro-2H-pyran-4-ylmethoxy)-3-(thiophen-2-yl)quinolin-2(1H)-one as an off white solid. LCMS (M+H)=419.8. 1H NMR (400 MHz, CDCl3) 12.0 (s, 1H), 8.00 (s, 1H), 7.88 (d, 1H), 7.62 (d, 1H), 7.54 (d, 1H) 7.30 (d, 1H), 7.18 (t, 1H), 4M (dd, 2H) 3.65 (d, 2H), 3.45 (t, 2H), 2.15 (m, 1H), 1.75 (d, 2H), 1.4 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.OS(O)(=O)=O.[C:15]([O-])(O)=O.[Na+].[OH-].[Na+]>CO.C(Cl)(Cl)Cl>[CH3:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:15])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: Cc1ccc(C(=O)O)o1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(C)o1
Temperature: 50 °C
Yield: 82 %

Procedure:
To a 200 mL round-bottomed flask with condenser was added 5-methyl-2-furancarboxylic acid (2.5 g, 19.82 mmol) in Methanol (100 mL). H2SO4 (10.5 mL, 197 mmol) was added slowly at room temperature. The reaction mixture was heated to 50° C. overnight. The reaction mixture was cooled to 0° C. and a saturated solution of NaHCO3 was added to neutral pH followed by 5N NaOH to pH 10. CHCl3 was added and the organic phase was separated, dried with Na2SO4 and concentrated affording the title compound (2.3 g, 16.3 mmol, 82%): LC-MS (ES) m/z=141 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:20])[C:15]([C:17]([OH:19])=O)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[C:46]([NH:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[NH2:60])([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:20])[C:15]([C:17](=[O:19])[NH:60][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=3[NH:53][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: Cn1c(C(=O)O)cc2c1CCN(C(=O)OC(C)(C)C)C2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cn1c(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc2c1CCN(C(=O)OC(C)(C)C)C2
Reaction time: 1 h

Procedure:
To a solution of compound 5-(tert-butoxycarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (1.0 eq) in DMF was added DCC (1.3 eq.), and HOBt (1.3 eq) and stirred for 1 hr. Monoboc phenylene diamine was added and reaction was stirred for 48 hrs. Reaction mixture was then quenched with water and extracted with ethyl acetate, dried over sodium sulphate and concentrated to dryness. Crude mass was then purified by silica gel column chromatography to afford 2-(2-tert-Butoxycarbonylamino-phenylcarbamoyl)-1-methyl-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester which was then reacted with hydrochloric acid saturated diethyl ether to get N-(2-aminophenyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17][C:4]=1[CH:5]=[C:6]1[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1>O1CCOCC1.O1CCOCC1.C(Cl)Cl>[NH:8]1[CH2:9][C:6](=[CH:5][C:4]2[CH:17]=[CH:18][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:20][C:3]=2[Cl:2])[CH2:7]1
Reactant: COC(=O)c1ccc(C=C2CN(C(=O)OC(C)(C)C)C2)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C=C2CNC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.5 %

Procedure:
A 4 M solution of HCl in dioxane (5 mL) was added to a solution of tert-butyl 3-(2-chloro-4-(methoxycarbonyl)benzylidene)azetidine-1-carboxylate (0.27 g, 0.66 mmol) in dioxane:DCM (1:1 v/v, 10 mL) and the mixture was stirred at room temperature for 3 h. Salt precipitation was observed. The reaction mixture was diluted with diethyl ether (20 mL). The precipitate was filtered, washed with ether and dried overnight to get the HCl salt of methyl 4-(azetidin-3-ylidenemethyl)-3-chlorobenzoate (0.12 g) as an off-white solid. ES+(M+H)+238
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([CH:13]([CH3:15])[CH3:14])[C:11]2[N:10]=[C:9]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:26]([OH:28])=O)=[C:21]4[C:25]=3[O:24][CH2:23][CH2:22]4)[N:8]=[CH:7][C:6]=2[N:5]([CH3:29])[C:4]1=[O:30])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH:62]1([CH2:65][N:66]2[CH2:71][CH2:70][N:69]([CH2:72][C@@H:73]([O:76][CH3:77])[CH2:74][NH2:75])[CH2:68][CH2:67]2)[CH2:64][CH2:63]1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH:62]1([CH2:65][N:66]2[CH2:67][CH2:68][N:69]([CH2:72][C@@H:73]([O:76][CH3:77])[CH2:74][NH:75][C:26]([C:20]3[CH:19]=[CH:18][C:17]([NH:16][C:9]4[N:8]=[CH:7][C:6]5[N:5]([CH3:29])[C:4](=[O:30])[C@@H:3]([CH2:1][CH3:2])[N:12]([CH:13]([CH3:15])[CH3:14])[C:11]=5[N:10]=4)=[C:25]4[O:24][CH2:23][CH2:22][C:21]=34)=[O:28])[CH2:70][CH2:71]2)[CH2:63][CH2:64]1
Reactant: CO[C@@H](CN)CN1CCN(CC2CC2)CC1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC[C@@H](CN4CCN(CC5CC5)CC4)OC)c4c3OCC4)nc2N1C(C)C
Reaction time: 2 h
Yield: 37.9 %

Procedure:
7-[[(7R)-7-Ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 22f (70 mg, 0.17 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (55 mg, 0.17 mmol) were dissolved in mL of anhydrous dichloromethane followed by the addition of diisopropylethylamine (0.1 mL, 0.58 mmol) and (2S)-3-[4-(cyclopropylmethyl)piperazin-1-yl]-2-methoxy-propan-1-amine 35d (39 mg, 0.17 mmol) successively. The reaction solution was stirred for 2 hours. The resulting solution was added with 30 mL of saturated sodium carbonate solution and extracted with dichloromethane (20 mL×3). The combined organic phase was washed with saturated sodium chloride solution (30 mL), then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound N-[(2S)-3-[4-(cyclopropylmethyl)piperazin-1-yl]-2-methoxy-propyl]-7-[[(7R)-7-ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxamide 36 (40 mg, yield: 38.0%) as a white solid.