Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Cu+2].CN(C=O)C>[C:14]1([N:11]2[CH:12]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:8]=[CH:9][C:10]2=[O:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=c1ccc(-c2ccccn2)c[nH]1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=c1ccc(-c2ccccn2)cn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
While stirring 5-Pyridin-2-yl-2(1H)-pyridone (185 g), PhB(OH)2(261 g), Cu(OAc)2(19.4 g), pyridine (173 ml) and DMF (1480 ml) at room temperature, air was blown at 2.0 L/minute therein, to initiate the reactions. Since 26% of the reactant remained unreacted 7 hours after the initiation of the reaction, flow of air was stopped to suspend the reactions. On the next day, air was blown into the solution to restart the reactions, and the reactant was consumed to 0.57% of the initial weight in 5.5 hours. The reaction solution was poured into ice-cooled 10% aqueous ammonia (7.5 L), to give MA045. The resulting precipitates were collected by filtration under reduced pressure, and washed with water (3 L). The resulting crystals were suspended into 10% aqueous ammonia (3.6 L) under stirring at room temperature for 1 hour. Then the crystals were collected by filtration under reduced pressure, and washed with water (2 L). The resulting crystals were air-dried overnight, to give 187 g (68%) of the title compound as brown crystals.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3CCCC[O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)O>C(O)=O.[Zn]>[CH:15]([O:14][CH2:13][CH2:12][CH2:11][N:8]1[C:9](=[O:10])[C:4]2[C:3]([CH2:25][C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)=[C:2]([Br:1])[CH:24]=[N:23][C:5]=2[N:6]([CH3:22])[C:7]1=[O:21])=[O:16]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Br)cnc21
Agent: [Zn]
Solvent: O=CO
Product: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(Br)cnc21
Temperature: 60 °C
Yield: 72.7 %

Procedure:
To a solution of 6-bromo-5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (300 mg, 0.56 mmol) in HCOOH (10 mL) was added Zn dust (182 mg, 2.78 mmol). The reaction was heated at 60° C. for 1 h then cooled to RT and filtered. The filtrate was concentrated to a residue which was purified by Prep TLC eluted with PE/EA (1:2) to give 3-(6-bromo-5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (190 mg, 73% yield) as a white solid. LCMS: MH+ 468 and TR=1.893 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11])[NH2:5].C(N(CC)CC)C.[CH3:21][C:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:25]([C:22]2([CH3:21])[CH2:24][CH2:23]2)=[O:26])[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:11])([F:12])[F:13]
Reactant: Nc1ccc(OC(F)(F)F)c(Cl)c1
Reactant: CC1(C(=O)Cl)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C(=O)Nc2ccc(OC(F)(F)F)c(Cl)c2)CC1
Yield: 89.2 %

Procedure:
To a solution of 3-chloro-4-trifluoromethoxyaniline (2.1 g) in methylene chloride (50 ml), triethylamine (1.1 g) was added, and a solution of 1-methylcyclopropanecarbonyl chloride (1.2 g) in methylene chloride was dropwise added thereto while stirring and ice-cooling. After stirring at room temperature for 1 hour, the reaction mixture was washed with 1 N hydrochloric acid, sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The crude crystals (2.9 g) were recrystallized from ethanol to give N-(3-chloro-4-trifluoromethoxyphenyl)-1-methylcyclopropanecarboxamide (2.6 g). M.P., 101°-102° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:11]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-])=O)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].O.O.Cl[Sn]Cl>CO>[NH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][N:11]([S:22]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)(=[O:24])=[O:23])[CH:3]([CH2:2][OH:1])[C:4]([O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:5]
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2[N+](=O)[O-])C(CO)C(=O)OC(C)(C)C)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2N)C(CO)C(=O)OC(C)(C)C)cc1
Temperature: 90 °C
Yield: 53.7 %

Procedure:
A mixture of 0.60 g (1.28 mmol) of 3-hydroxy-2-[(4-methoxybenzenesulfonyl)-(2-nitrobenzyl)amino]propionic acid, tert-butyl ester and 1.45 g (6.45 mmol) of SnCl2.2H2O in 20 ml of methanol was heated in an oil bath at 90° C. for 2 hours. The solvent was removed under vacuum and ethyl acetate added to the residue. The mixture was neutralized with saturated sodium bicarbonate solution and filtered through diatomaceous earth. The ethyl acetate layer was separated and washed with H2O, brine and dried with Na2SO4. The solvent was removed under vacuum to give 0.30 g (53%) of a gum. Anal. for C21H28N2O6S: Calc'd: C, 57.8; H,6.5; N,6.4; Found: C, 57.8; H,7.0; N,6.2.
Reaction SMILES: C(O[CH:5]1[CH:9]([CH:10]([OH:13])[CH2:11][OH:12])[CH2:8][CH2:7][O:6]1)(C)C.CS(O)(=O)=O.C(N(CC)CC)C.C(OCC)(=O)C>O1CCCC1>[O:12]1[CH:5]2[O:6][CH2:7][CH2:8][CH:9]2[CH:10]([OH:13])[CH2:11]1
Reactant: CC(C)OC1OCCC1C(O)CO
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OC1COC2OCCC12
Temperature: 0 °C

Procedure:
In a 50 mL round bottom flask, 1-(2-iso-propoxytetrahydro-3-furanyl)-1,2-ethanediol (2.21 g; 8.89 mmoles, 1 eq.) was dissolved in tetrahydrofuran (9 mL). After cooling at 0° C., methanesulfonic Acid (65 mg; 676.33 mmoles) was added to the mixture. The reaction mixture was thereafter heated at 45° C. for 30 min. After cooling at room temperature, triethylamine (0.3 g; 2.96 mmoles) was added to the mixture. The solvent was evaporated and ethyl acetate (9 mL; 91.98 mmoles) was added to the mixture at room temperature. Then the mixture was filtered over dicalite and the solvent was evaporated under reduced pressure to afford endo/exo bis-THF (1.562 g; GC: 71 area %) in a diastereomeric ratio of 15/85 endo/exo diastereoisomers.
Reaction SMILES: [F:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(Cl)Cl.O>[CH2:22]([O:21][C:19](=[O:20])[CH:18]=[C:10]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:2]=1[F:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:23]
Reactant: Nc1cccc(Cl)c1F
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=C(Nc1cccc(Cl)c1F)c1ccccc1
Reaction time: 3 h

Procedure:
2-Fluoro-3-chloroaniline (7.55 mL, 0.0687 mole), ethyl benzoylacetate (13.2 g, 0.0687 mole) and p-toluenesulfonic acid (1.18 g, 0.007 mole) were combined in a 250 mL round bottom flask with toluene (60 mL) and a magnetic stir-bar. The reaction was stirred at reflux with a Dean-Stark water trap. Reflux was stopped after 3 h. The product mixture was allowed to cool, and was then passed through a short pad of silica gel with methylene chloride, and concentrated in vacuo. Standing under high vacuum for 1 h afforded an oil. The oil was stirred in 100 mL of hexanes overnight, then suction filtered to remove a solid impurity. The filtrate was concentrated, and put on high vacuum to afford an oil. The oil was chromatographed with hexanes, ethyl acetate (8:1), and put under high vacuum for 1 h to afford the title compound as a yellow oil; 1H NMR (CDCl3, 400 MHz) δ 1.30-1.34 (t, 3H, J=7.1 Hz), 4.20-4.25 (Q, 2H, J=7.1 Hz), 5.13 (s, 1H), 6.19-6.23 (t, 1H), 6.60-6.65 (t of d, 1H, J=1.7 & J=8.2), 6.88-6.92 (t of d, 1H, J=1.5 & J=6.6), 7.29-7.37 (m, 5H), 10.21 (bs, 1H); MS(ES+): 319.99 (100) [MH+], 322.02 (30) [(M+2)H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](C(O)CC(OC(C)(C)C)=O)[C:5]([NH:18][C:19](=[O:24])[C:20]([CH3:23])(C)C)=[CH:4][N:3]=1.[H][H]>O1CCOCC1.Cl.O>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][N:3]=1)[NH:18][C:19](=[O:24])[CH:20]=[CH:23]2
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)CC(O)c1cc(Cl)ncc1NC(=O)C(C)(C)C
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=c1ccc2cc(Cl)ncc2[nH]1

Procedure:
A solution of 4.63 g (13 mmoles) of 2-chloro-5-((2,2-dimethyl-1-oxopropyl)amino)-β-hydroxy-4-pyridine propanoic acid, 1,1-dimethylethyl ester in 70 ml of dioxane and 30 ml of 3N HCl in water was warmed at reflux for a period of 4 hours. The solution was diluted with 100 ml of water and cooled to give a white precipitate. The crystals were filtered, washed with water and dried in a vacuum oven to give 2.18 g (93% of theoretical) of the above-captioned compound having a melting point of 304°-306° C. The carbon, hydrogen and nitrogen content calculated for C8H5ClN2O is C, 53.20; H, 2.79; and N, 15.52 percent by weight which compares to that actually found upon analysis of C, 53.55; H, 2.79; and N, 15.47.
Reaction SMILES: [CH2:1]([N:5]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[C:8]([O:14][CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:20]([C:22]1[C:23](=[C:38]([C:41]#[N:42])[C:39]#[N:40])[O:24][C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:28]([F:31])([F:30])[F:29])[C:26]=1[CH3:27])#[N:21]>C(O)C>[CH2:1]([N:5]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH:27][C:26]2[C:25]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)([C:28]([F:31])([F:29])[F:30])[O:24][C:23](=[C:38]([C:41]#[N:42])[C:39]#[N:40])[C:22]=2[C:20]#[N:21])=[C:8]([O:14][CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1ccc(C=O)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC2=C(C#N)C(=C(C#N)C#N)OC2(c2ccccc2)C(F)(F)F)c(OC)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
In 5 ml of ethanol were dissolved 150 mg (0.57 mmol) of 4-dibutylamino-2-methoxybenzaldehyde and 197 mg (0.63 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. After the mixture was stirred at 50° C. for 2 hours, ethanol was evaporated off. The residue was purified by silica gel column chromatography to give 272 mg of a dark brown crystal (yield: 85.2%; mp: 191-194° C.)
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[CH3:20][C:21]1[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=1>>[CH3:20][C:21]1[CH:25]=[C:24]([CH3:26])[N:23]([C:2]2[N:11]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[N:22]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Nc1ccccn1
Product: Cc1cc(C)n(-c2nc(Nc3ccccn3)c3ccccc3n2)n1

Procedure:
Was prepared according to Method B from 2,4-dichloroquinazoline, 2-aminopyridine and 3,5-dimethylpyrazole. Mp. 126.1-126.8° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:17]=2)[C:14]([OH:16])=O)[S:3]1.C(N(CC)CC)C.C(Cl)(=O)OCC.[N+:33]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1)([O-:35])=[O:34]>C(Cl)Cl>[N+:33]([C:36]1[CH:37]=[CH:38][C:39]([CH2:40][NH:41][C:14](=[O:16])[C:13]2[CH:17]=[C:9]([CH2:8][CH:4]3[S:3][C:2](=[O:1])[NH:6][C:5]3=[O:7])[CH:10]=[CH:11][C:12]=2[O:18][CH3:19])=[CH:42][CH:43]=1)([O-:35])=[O:34]
Reactant: COc1ccc(CC2SC(=O)NC2=O)cc1C(=O)O
Reactant: NCc1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CC2SC(=O)NC2=O)cc1C(=O)NCc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 75.7 %

Procedure:
5-[(2,4-Dioxothiazolidin-5-yl)methyl]-2-methoxybenzoic acid (422 mg, 1.50 mmol), triethylamine (0.732 mL, 5.25 mmol) and methylene chloride (7 mL) were mixed and ethyl chlorocarbonate (0.158 mL, 1.50 mmol) was added under cooling with ice and stirring. After stirring for 10 minutes under cooling with ice, 4-nitrobenzylamine (283 mg, 1.50 mmol) was added. The mixture was stirred for 2 hours at room temperature, and then allowed to stand overnight. After washed with water, the reaction mixture was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved into water (20 mL), which was made acidic with 10% hydrochloric acid and stirred for 2 hours. The precipitated crystals were collected by filtration, washed with water and dried, then they were recrystallized from ethanol to obtain 472 mg (75%) of the title compound as pale yellow prisms.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:17]1[O:27][C:20]2([CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)[O:19][CH2:18]1>C1COCC1.CCOCC>[CH3:10][N:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([C:23]2([OH:26])[CH2:24][CH2:25][C:20]3([O:27][CH2:17][CH2:18][O:19]3)[CH2:21][CH2:22]2)=[N:7][CH:6]=1)[CH3:11]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CN(C)Cc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(C2(O)CCC3(CC2)OCCO3)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
1-(6-Bromopyridin-3-yl)-N,N-dimethylmethanamine (1.15 g, 5.4 mmol) was dissolved in 30 mL of THF and 80 mL of anhydrous ether. After the solution was cooled to −78° C. 2.60 mL of n-butyllithium (2.5 M, 6.40 mmol) was slowly dropped through a syringe in 10 min. After being stirred at −78° C. for 30 minutes, 1,4-cyclohexanedione mono-ethylene ketal (1.01 g, 6.4 mmol) was added. The reaction mixture was allowed to wram up to room temperature during two hours and then quenched by addition of 10 mL of water. The mixture was extracted twice using EtOAc. The combined extracts were dried and concentrated. After flash column using 20-40% methanol in EtOAc and 0.5% NH4OH, 0.85 g of oil was obtained (54% yield), MS: 293.2.0 (M++1).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[CH2:1]([N:5]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13])[S:36]([C:33]1[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=1)(=[O:38])=[O:37])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ccc(F)cc1F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCN(c1ccc(F)cc1F)S(=O)(=O)c1ccc(C)cc1
Temperature: 90 °C
Reaction time: 48 h
Yield: 68.4 %

Procedure:
A solution of 14.8 g of N-butyl-2,4-difluoroaniline, 16.2 g of triethylamine and 0 5 g of dimethylaminopyridine in 150 ml of toluene is treated dropwise at 0-5° C. with a solution of 15.2 g of p-toluenesulphonyl chloride in 80 ml of toluene. The reaction mixture is then warmed to 90° C. and stirred at this temperature for 48 hours. After cooling, the mixture is washed with 5% strength HCl and with water, and the toluene solution is dried over Na2SO4 and evaporated. The residue is distilled at 0.01 mbar. 18.5 g of N-butyl-N-(2,4-difluorophenyl)-p-toluenesulphonamide are obtained at 150°-160° as a colourless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1F)[N:15]=[CH:14][C:13]([C:20]#[N:21])=[C:12]2[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][CH2:25][CH2:26][OH:27]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:27][CH2:26][CH2:25][O:24][CH3:23])[N:15]=[CH:14][C:13]([C:20]#[N:21])=[C:12]2[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCO
Reactant: N#Cc1cnc2cc(F)c(OCc3ccccc3)cc2c1O
Product: COCCOc1cc2ncc(C#N)c(O)c2cc1OCc1ccccc1
Yield: 86 %

Procedure:
Following the procedure used to prepare Reference Example 6, reaction of 6-benzyloxy-4-hydroxy-7-fluoro-3-quinolinecarbonitrile and 2-methoxyethanol provides 6-benzyloxy-4-hydroxy-7-(2-methoxyethoxy)-3-quinolinecarbonitrile in 86% yield, mp>250° C.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>>[F:10][C:7]1[CH:8]=[N:9][C:2]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc(F)cnc1Cl
Reactant: C1CCNC1
Product: N#Cc1cc(F)cnc1N1CCCC1
Yield: 90 %

Procedure:
Prepared in 90% yield from the product of Example 169A and pyrrolidine according to the procedure described for Example 178A. MS (ESI+) m/z 192.0 (M+H)+; 1H NMR (DMSO-d6) δ 1.90-1.96 (m, 4H), 3.61-3.65 (m, 4H), 8.05 (dd, J=8.5, 3.0 Hz, 1H), 8.38 (d, J=3.0 Hz, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11].[C:12]1([CH3:25])[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[S:20]([O:23][NH2:24])(=[O:22])=[O:21]>C(Cl)Cl>[NH2:24][N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[NH2+:11].[CH3:19][C:14]1[CH:15]=[C:16]([CH3:18])[CH:17]=[C:12]([CH3:25])[C:13]=1[S:20]([O-:23])(=[O:22])=[O:21]
Reactant: Nc1ccc2ncccc2n1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: Nn1c(=[NH2+])ccc2ncccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
To a solution of 1,5-naphthyridin-2-amine (2.0 g, 13.8 mmol) in DCM (10 mL) was added a solution of O-(mesitylsulfonyl)hydroxylamine (8.9 g, 41.3 mmol) in DCM (20 mL) at 0° C. The mixture was stirred at 0° C. for 3 h. The precipitate was filtered and collected to give the crude product as a yellow solid (4.2 g, yield 85%). ESI MS: m/z 161 [M+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:21]=[C:20]([C:22]3[S:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[O:19][N:18]=1)[C:11]([C:28]([O:30]CC)=[O:29])=[CH:10]2)=[O:6])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.CO>[CH:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:21]=[C:20]([C:22]3[S:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[O:19][N:18]=1)[C:11]([C:28]([OH:30])=[O:29])=[CH:10]2)=[O:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(C(=O)OC(C)C)ccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1ccc2c(c1)cc(C(=O)O)n2Cc1cc(-c2ccc(Cl)s2)on1
Reaction time: 2 h

Procedure:
To a solution of 6.21 g 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-indole-2,5-dicarboxylic acid 2-ethyl ester 5-isopropyl ester in 100 ml THF and 40 ml MeOH 52 ml of an aqueous 1M LiOH solution were added and stirred for 2 h. The organic solvents were removed under reduced pressure and the residue acidified with 2 M hydrochloric acid to pH 2. The precipitated product was collected by filtration and dried over P2O5 in vacuo to yield a white solid. Yield: 5.77 g.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH:8]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:7]1.[CH3:17]O>>[ClH:3].[NH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH:8]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:7]1
Reactant: NC1CCCC(CCC(=O)O)C1
Reactant: CO
Reactant: O=S(Cl)Cl
Product: COC(=O)CCC1CCCC(N)C1
Product: Cl
Reaction time: 0.17 h

Procedure:
At −5° C., 1.9 ml (25.7 mmol) of thionyl chloride were slowly added dropwise to 50 ml of methanol, and the mixture was stirred at this temperature for 10 min. 2 g (11.7 mmol) of 3-(3-aminocyclohexyl)propanoic acid were then added in one portion, and the reaction mixture was stirred at room temperature overnight. After the reaction had gone to completion, the solvent was evaporated under reduced pressure. This gave 2.46 g (11.1 mmol, 95% of theory) of a colorless solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.[Cl:9][C:10]1[CH:29]=[CH:28][C:13]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([OH:27])=[C:22](OC)[CH:23]=3)[N:18]=[CH:17][N:16]=2)=[C:12]([F:30])[CH:11]=1.[C:31](=O)([O-])[O-:32].[K+].[K+]>CN(C=O)C>[Cl:9][C:10]1[CH:29]=[CH:28][C:13]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH2:31][O:32][CH2:2][CH2:3][CH:4]4[O:8][CH2:7][CH2:6][O:5]4)=[CH:22][CH:23]=3)[N:18]=[CH:17][N:16]=2)=[C:12]([F:30])[CH:11]=1
Reactant: BrCCC1OCCO1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1cc(Cl)ccc1Nc1ncnc2cc(OCOCCC3OCCO3)ccc12
Temperature: 100 °C
Yield: 16.6 %

Procedure:
A solution of 2-(2-bromoethyl)-1,3-dioxolane (258 mg, 1.4 mmol) in DMF (0.5 ml) was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (329 mg, 1.02 mmol) and potassium carbonate (264 mg, 2 mmol) in DMF (2 ml). The mixture was heated at 100° C. for 3 hours and allowed to cool. The volatiles were removed by evaporation, and the residue partitioned between aqueous sodium hydrogen carbonate solution and methylene chloride. The organic phase was separated and passed through phase separating paper. The solvent was removed by evaporation, and the residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 4-(4-chloro-2-fluoroanilino)-7-(2-(1,3-dioxolan-2-yl)ethoxy)methoxyquinazoline (71 mg, 17%).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH:7]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[C:20]3[C:21]([CH3:37])=[C:22]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([S:35][CH3:36])=[CH:31][CH:30]=4)[C:23]([CH3:26])=[C:24]([CH3:25])[C:19]=3[O:18][C:17]2([CH3:39])[CH3:38])=[CH:12][CH:11]=1)([CH3:9])[CH3:8].O.C(OCC)(=[O:43])C>C(O)C>[CH:7]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[C:20]3[C:21]([CH3:37])=[C:22]([O:27][CH2:28][C:29]4[CH:30]=[CH:31][C:32]([S:35]([CH3:36])=[O:43])=[CH:33][CH:34]=4)[C:23]([CH3:26])=[C:24]([CH3:25])[C:19]=3[O:18][C:17]2([CH3:39])[CH3:38])=[CH:14][CH:15]=1)([CH3:9])[CH3:8]
Reactant: CCOC(C)=O
Reactant: CSc1ccc(COc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1OCc1ccc(S(C)=O)cc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 79 %

Procedure:
Sodium periodate (0.766 g, 3.58 mmol) was added to a solution of 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-5-(4-methylthiobenzyloxy)-2,3-dihydrobenzofuran (1.50 g, 3.26 mmol) in a mixture of ethanol (80 mL) and water (8 mol), and the mixture was heated under reflux for 2 hours. To the reaction mixture were added ethyl acetate and water to separate it into two layers, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized from ethyl acetate-hexane to obtain the title compound (1.23 g, yield 79%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][O:11][CH3:12])[CH2:7][N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4].[Li+].[OH-].Cl.BrC[C:25]([C:27]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=1)=[O:26].C(N(CC)CC)C>CO>[C:16]([O:15][C:13]([N:6]1[CH2:7][CH:8]([CH2:10][O:11][CH3:12])[CH2:9][CH:5]1[C:3]([O:2][CH2:1][C:25]([C:27]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=1)=[O:26])=[O:4])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: COCC1CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Product: COCC1CC(C(=O)OCC(=O)c2ccc(Br)cc2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.3 %

Procedure:
4-Methoxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (461 mg, 1.68 mmol) was dissolved in MeOH (17 mL) and LiOH (1 M in H2O, 8.5 mL, 8.5 mmol) was added. After stirring at RT for 5 h, the MeOH was removed under reduced pressure. The aqueous solution was poured into a separatory funnel, diluted with 1 M HCl (9 mL, 9 mmol) and extracted with DCM (3×). The combined organics were dried over MgSO4, filtered and concentrated. The residue was dissolved in MeCN (17 mL) and treated with 2,4′-dibromoacetophenone (514 mg, 1.85 mmol), and triethylamine (0.258 mL, 1.85 mmol). After stirring for 2 h, the solvent was removed and the solid was suspended in EtOAc. The organic layer was washed with saturated aqueous NaHCO3 and brine then dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (15% to 35% EtOAc/Hex) to afford the title compound (746 mg, 97%).