Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([OH:24])=[CH:10][CH:11]=[C:12]([C:14]([OH:23])([C:18]3[N:19]=[CH:20][NH:21][CH:22]=3)[CH:15]([CH3:17])[CH3:16])[CH:13]=2)=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1.C(OCC)(=O)C.CO>[C:25]([O:24][C:9]1[CH:10]=[CH:11][C:12]([C:14]([OH:23])([C:18]2[N:19]=[CH:20][NH:21][CH:22]=2)[CH:15]([CH3:17])[CH3:16])=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)C(O)(c1ccc(O)c(-c2ccc(F)cc2)c1)c1c[nH]cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccc(C(O)(c2c[nH]cn2)C(C)C)cc1-c1ccc(F)cc1
Reaction time: 4 h

Procedure:
To a solution of 4′-fluoro-5-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-2-ol (390 mg) in pyridine (4 ml) was added dropwise acetic anhydride (0.135 ml) at room temperature, and the mixture was stirred for 4 h. Acetic anhydride (22.5 μl) was further added and the mixture was stirred for 15 h. The reaction mixture was subjected to azeotropic reaction with toluene for concentration, diluted with ethyl acetate, washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and to a solution of the residue (414 mg) in pyridine (4 ml) was added dropwise acetic anhydride (0.209 ml) at room temperature. The mixture was stirred for 15 h and the reaction mixture was subjected to azeotropic reaction with toluene for concentration. To a solution of the residue in methanol (15 ml) was added 0.1N aqueous p-toluenesulfonic acid solution (7.5 ml) at room temperature, and the mixture was stirred for 1 h. The reaction mixture was concentrated, diluted with ethyl acetate, neutralized with saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chomatography (eluent; ethyl acetate→ethyl acetate:methanol=20:1) to give the colorless amorphous title compound (337 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:18]=[CH:17][C:10]([C:11]([O:13]C(C)C)=[O:12])=[CH:9][N:8]=2)[CH2:3][CH2:2]1.Cl>[OH-].[Na+]>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:18]=[CH:17][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)OC(=O)c1ccc(N2CCOCC2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(N2CCOCC2)nc1
Temperature: 55 °C

Procedure:
A solution of isopropyl 6-chloronicotinate (6.0 g, 0.03 mol) and morpholine (13 mL, 0.15 mol) in isopropyl alcohol (60 mL) was heated at reflux for 72 hours. The solution was allowed to cool to ambient temperature overnight. The resulting precipitate was isolated by filtration, washed with isopropyl alcohol and dried to provide isopropyl 6-morpholinonicotinate. The filtrate was diluted with water. The resulting precipitate was isolated by filtration, washed with water and dried to provide isopropyl 6-morpholinonicotinate. The combined yield was 8.3 g. The isopropyl 6-morpholinonicotinate was combined with 1 N sodium hydroxide (40 mL) and the resulting suspension was stirred at 50-60° C. until all of the solid had dissolved. The solution was stirred at ambient temperature overnight during which time a precipitate formed. This material was isolated by filtration and identified as starting material. The filtrate was neutralized with concentrated hydrochloric acid. The resulting precipitate was isolated by filtration, washed with water and dried to provide 3.3 g of crude product. This material was recrystallized from methanol/dichloromethane to provide 6-morpholinonicotinic acid as a solid, m.p. 259-261° C. Analysis: Calculated for C10H12N2O3: % C, 57.19; % H, 5.81; % N, 13.48; Found: % C, 57.50; % H, 5.71; % N, 13.53.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[C:7]([OH:14])[C:8]([CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[CH3:15][C:16]([C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1F)=[O:17].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([O:14][C:7]2[C:8]([CH3:13])=[N:9][C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([F:1])[C:11]=3[F:12])[C:18]=1[C:16](=[O:17])[CH3:15]
Reactant: CC(=O)c1c(F)cccc1F
Reactant: Cc1nc2c(F)c(F)ccc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1c(F)cccc1Oc1cc2ccc(F)c(F)c2nc1C
Temperature: 100 °C
Reaction time: 4 h
Yield: 38.1 %

Procedure:
26.3 g of 7,8-difluoro-3-hydroxy-2-methylquinoline was dissolved in 200 mL of dimethylformamide. 27.2 g of 2,6-difluoroacetophenone and 24.0 g of potassium carbonate were added to the solution and the mixture was stirred for 4 hours at 100° C. After the thus obtained reaction solution was poured into ice water, and neutralized with dilute hydrochloric acid, the liquid was separated with ethyl acetate. The organic layer was concentrated and purified by silica gel column chromatography to obtain 17.0 g of 1-[2-fluoro-6-(7,8-difluoro-2-methylquinolin-3-yloxy)-phenyl]-ethanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][C:11]3=[N:13][N:14]=[C:15](S(C)(=O)=O)[N:10]3[CH:9]=[CH:8][C:7]=2[CH:20]=1.[CH3:21][O-:22].[Na+]>>[CH3:21][O:22][C:15]1[N:10]2[C:11]([CH2:12][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][C:7]=3[CH:8]=[CH:9]2)=[N:13][N:14]=1
Reactant: C[O-]
Reactant: COc1ccc2c(c1)C=Cn1c(nnc1S(C)(=O)=O)C2
Agent: [Na+]
Product: COc1ccc2c(c1)C=Cn1c(nnc1OC)C2

Procedure:
The reaction of 8-methoxy-3-methylsulfonyl-11H-s-triazolo[3,4-b][3]benzazepine with sodium methoxide yielded 3,8-dimethoxy-11H-s-triazolo[3,4-b][3]benzazepine. Colorless needles (as recrystallized from aqueous methanol), melting point: 185°-186° C.
Reaction SMILES: Cl[C:2]1[C:3](=[O:21])[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:5]=[CH:6][C:7]=1[N:8]([CH3:10])[NH2:9].[OH-].[Na+]>[Pd].C(O)C>[F:20][C:17]([F:18])([F:19])[C:13]1[CH:12]=[C:11]([N:4]2[C:3](=[O:21])[CH:2]=[C:7]([N:8]([CH3:10])[NH2:9])[CH:6]=[N:5]2)[CH:16]=[CH:15][CH:14]=1
Reactant: CN(N)c1cnn(-c2cccc(C(F)(F)F)c2)c(=O)c1Cl
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(N)c1cnn(-c2cccc(C(F)(F)F)c2)c(=O)c1
Reaction time: 1 h

Procedure:
To a solution consisting of 15.9 grams of 4-chloro-2-(3-trifluoromethylphenyl)-5-(1-methylhydrazino)-pyridazin-3 (2H)-one prepared as in example 2, 120 grams of ethanol and 5 grams of 50 percent sodium hydroxide in a pressure reactor, 1 gram of 5 percent Palladium on carbon is added and the mixture is hydrogenated at a pressure of about 15 pounds per square inch for one hour at room temperature. The resulting product is then filtered and washed with 30 grams of warm ethanol, after which the filtrate is concentrated under reduced 3 pressure. The resulting product is dissolved in 250 grams of chloroform and washed several times with water. The chloroform layer is concentrated under reduced pressure, and the resulting solid is crystallized from benzene to yield 2-(3-trifluoromethylphenyl)-5-(1-methylhydrazino)-pyridazin-3(2H)-one, (m.p. 125° to 127° C).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1(=O)[NH:11][C:10](=O)[C@H:9]2[CH2:13][CH2:14][CH2:15][CH2:16][C@@H:8]12.O>C(OCC)C.O1CCCC1>[C@@H:8]12[CH2:7][NH:11][CH2:10][C@@H:9]1[CH2:13][CH2:14][CH2:15][CH2:16]2
Reactant: O=C1NC(=O)[C@@H]2CCCC[C@H]12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C1CC[C@H]2CNC[C@H]2C1

Procedure:
To a slurry of lithium aluminium hydride (17.1 g) in dry diethyl ether (375 ml) under a nitrogen atmosphere, cis-hexahydrophthalimide (23.0 g) in dry tetrahydrofuran (300 ml) was added over a two-hour period. The mixture was refluxed for 2.5 hours, cooled and treated very slowly with excess of water. The precipitate was filtered off and the filtrate was evaporated to yield the title compound as a viscous oil, which was used in the next step without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[N:17]([CH3:18])[CH:16]=[N:15][N:14]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[CH3:2]>CCOC(C)=O.CCO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[N:17]([CH3:18])[CH:16]=[N:15][N:14]=2)[CH:7]=[CH:8][C:9]=1[NH2:10])[CH3:2]
Reactant: CCOc1cc(-c2nncn2C)ccc1[N+](=O)[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1cc(-c2nncn2C)ccc1N

Procedure:
The title compound was prepared according to the method described for Preparation 158 using 3-(3-Ethoxy-4-nitrophenyl)-4-methyl-4H-1,2,4-triazole (Preparation 217) in EtOAc and EtOH (1:8 v:v).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][NH:13]C(=O)OC(C)(C)C)=[CH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][NH2:13])=[CH:3]1
Reactant: Cn1cc(CCNC(=O)OC(C)(C)C)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(CCN)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a solution of tert-butyl (2-(1-methyl-1H-indol-3-yl)ethyl)carbamate (4 g, 14.6 mmol) in DCM (30 mL) was added TFA (15 mL) at ˜0° C. to 5° C. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to give a crude title compound (2.5 g, crude) as yellow oil. MS (ESI) m/z 175.1 [M+H]+.
Reaction SMILES: B(Br)(Br)Br.[CH3:5][C:6]1([CH3:24])[O:11][C:10]2[C:12]3[CH:13]=[CH:14][C:15]([O:22]C)=[CH:16][C:17]=3[C:18]([C:20](=[O:21])[C:9]=2[CH2:8][CH2:7]1)=[O:19]>C(Cl)Cl>[CH3:5][C:6]1([CH3:24])[O:11][C:10]2[C:12]3[CH:13]=[CH:14][C:15]([OH:22])=[CH:16][C:17]=3[C:18]([C:20](=[O:21])[C:9]=2[CH2:8][CH2:7]1)=[O:19]
Reactant: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC(C)(C)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CCC2=C(O1)c1ccc(O)cc1C(=O)C2=O
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 27.1 %

Procedure:
Boron tribromide (15.0 mL, 1.0 M in CH2Cl2) was added to a solution of 54 (1.05 g, mmol) in anhydrous CH2Cl2 (40 mL) at 0° C. After stirring for 15 min, the mixture was allowed to warm to 20° C. and kept stirring for 2 h. Ice water (500 mL) was added, the mixture was extracted with CHCl3 (3×100 mL), the combined extracts were dried, and concentrated in vacuo. The residue was treated with concentrated H2SO4 (20 mL) at 20° C. The mixture was diluted with ice water (500 mL) and extracted with CHCl3 (3×100 mL). The combined extracts were reextracted with aqueous 5% NaHSO3 (3×150 mL). The aqueous extracts were acidified with concentrated HCl (100 mL), and extracted with CHCl3 (3×150 mL). The extracts were dried and concentrated to afford 55 (270 mg, 27%): 1H NMR (CDCl3) δ9.81 (OH, s), 7.64 (1H, d, J=8.5 Hz), 7.49 (1H, d, J=2.6 Hz), 7.06 (1H, dd, J=8.5, 2.6 Hz), 2.51 (2H, t, J=6.6 Hz), 1.84 (2H, t, J=6.6 Hz), 1.45 (6H, s); HRMS (m/z) calcd for C15H14O4 258.0892, found 258.0885.
Reaction SMILES: [O:1]([CH2:8][C@H:9]1[CH2:11][O:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@H:13]([C@@H:16]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C@@H:17]([N:27]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)[CH2:14][OH:15]>C(O)C>[CH2:43]([O:42][C@@H:16]([C@@H:17]([N:27]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:18][C:19]1[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=1)[C@H:13]([NH:12][CH2:11][C@@H:9]([OH:10])[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:14][OH:15])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: c1ccc(OC[C@H]2CO2)cc1
Reactant: N[C@H](CO)[C@@H](OCc1ccccc1)[C@H](Cc1cc(F)cc(F)c1)N(Cc1ccccc1)Cc1ccccc1
Solvent: CCO
Product: OC[C@@H](NC[C@@H](O)COc1ccccc1)[C@@H](OCc1ccccc1)[C@H](Cc1cc(F)cc(F)c1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 80 °C
Yield: 57 %

Procedure:
Add (R)-2-phenoxymethyl-oxirane (0.189 g, 1.258 mmol) to a solution of (2R,3R,4S)-2-amino-3-benzyloxy-4-dibenzylamino-5-(3,5-difluorophenyl)-pentan-1-ol (0.205 g, 0.434 mmol) in ethanol (2.1 mL). Heat in a sealed vessel at 80° C. overnight. Concentrate and purify (silica gel chromatography, eluting with 1-1.5% 2 M ammonia in methanol/dichloromethane) to give the desired compound as a clear semi-solid (0.165 g, 56.9%).
Reaction SMILES: F[C:2]1([F:9])[CH:7]=[CH:6][C:5](=[O:8])[CH:4]=[CH:3]1.[C-:10]#[N:11].[K+]>CN(C)C=O>[C:10]([C:7]1[CH:6]=[C:5]([OH:8])[CH:4]=[CH:3][C:2]=1[F:9])#[N:11]
Reactant: [C-]#N
Reactant: O=C1C=CC(F)(F)C=C1
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(O)ccc1F
Yield: 90 %

Procedure:
When 2 mmol of 4,4-difluorocyclohexadienone and 4 mmol of potassium cyanide in 0.5 ml of dimethylformamide were mixed for 10 minutes at room temperature, 3-cyano-4-fluorophenol was formed in 90% yield. The spectral data of this new compound are as follows: Mass spectrum: m/e 137 (M+); 109 (M-CO, H); 82; 57.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH:16]([CH:17]([CH3:19])[CH3:18])[CH2:15][C:14](=[O:20])[CH2:13][CH:12]3[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[NH2:28]O.Cl.[OH-].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>CCO.O.ClCCl.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@:6]3([C@H:16]([CH:17]([CH3:18])[CH3:19])[CH2:15][C:14](=[O:20])[NH:28][CH2:13][C@@H:12]3[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)C1CC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: NO
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)[C@@H]1CC(=O)NC[C@H](c2cccc(Cl)c2)[C@@]12C(=O)Nc1cc(Cl)ccc12
Temperature: 100 °C
Yield: 4.5 %

Procedure:
In a manner similar to the method described in example 2 (method B), rac-(1R,2S,6R)-6′-chloro-2-(3-chlorophenyl)-6-(1-methylethyl)-spiro[cyclohexane-1,3′-[3H]indole]-2′,4(1′H)-dione (402.3 mg, 1.00 mmole) was reacted with NH2OH—HCl (347.5 mg, 5.00 mmol), NaOH (200.0 mg, 5.00 mmole) in EtOH-water (3/2, 15 mL) at refluxing for 3 hrs, followed by reacting with p-toluenesulfonyl chloride (762.8 mg, 4.00 mmol) in dichloromethane (20 mL) at room temperature for 2 hrs, and heating under microwave irradiation at 100° C. for 20 min. After diluted with AcOEt the mixture was washed with water, dried over Na2SO4 and concentrated. The residue was purified by chiral column chromatography to give (3R,4S,5S)-6′-chloro-3-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-5-(1-methylethyl)-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (18.9 mg): HRMS (ES+) m/z Calcd for C22H22Cl2N2O2+H [(M+H)+]: 417.1131. Found: 417.1132; (3R,4S,5R)-6′-chloro-5-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-3-(1-methylethyl)-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (18.2 mg): HRMS (ES+) m/z Calcd for C22H22Cl2N2O2+H [(M+H)+]: 417.1131. Found: 417.1132; (3S,4R,5R)-6′-chloro-3-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-5-(1-methylethyl)-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (17.6 mg): HRMS (ES+) m/z Calcd for C22H22Cl2N2O2+H [(M+H)+]: 417.1131. Found: 417.1132; and (3S,4R,5S)-6′-chloro-5-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-3-(1-methylethyl)-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (15.1 mg): HRMS (ES+) m/z Calcd for C22H22Cl2N2O2+H [(M+H)+]: 417.1131, Found: 417.1132.
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)=[O:11].O>ClCCl>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:2][CH3:1])=[O:11]
Reactant: O=S(Cl)c1ccccc1Br
Reactant: CN
Solvent: ClCCl
Solvent: O
Product: CNS(=O)c1ccccc1Br
Temperature: -10 °C
Yield: 82.7 %

Procedure:
Liquified methylamine (36.3 mL, 0.817 mol) was added slowly to a stirred solution of 2-bromobenzenesulfinyl chloride (48.9 g, 0.204 mol) in dichloromethane (489 mL) cooled below -70° C. The reaction mixture was allowed to warm to -10° C. and was then shaken with water (489 mL). The layers were separated, and the dichloromethane layer was washed with water (2×245 mL), dried (Na2SO4), and filtered. Evaporation of the solvent left a pale yellow oil (44.4 g) that mostly crystallized on standing. This was dissolved in dichloromethane and chromatographed on a column of silica gel using 2:1 dichloromethane-ether as eluant. Fractions containing product (Rf =0.52, UV) were evaporated to leave 2-bromo-N-methylbenzenesulfinamide as a white crystalline solid (39.5 g) melting at 66°-70° C.
Reaction SMILES: C(O[C:4](=[O:19])[C:5](=[CH:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[OH:19][C:4]1[C:14]2[C:13](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=CNc1ccccc1)C(=O)OCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccccc2c1O
Temperature: 80 °C

Procedure:
The 2-phenylaminomethylene-malonic acid diethyl ester was refluxed in Dowtherm® for 15 min to 2 h. The reaction mixture was cooled to 80° C. and solid was collected by filtration and washed with hexane to yield crude ethyl 4-hydroxy-quinoline-3-carboxylate 2a which was used in next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C@H:6]1[CH2:10][C@H:9]([F:11])[CH2:8][NH:7]1.Cl[C:17]1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[NH:19][CH:20]=[N:21]2.C(N(C(C)C)C(C)C)C>C(O)CCC>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C@H:6]1[CH2:10][C@H:9]([F:11])[CH2:8][N:7]1[C:17]1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[N:19]=[CH:20][NH:21]2
Reactant: F[C@@H]1CN[C@@H](COc2ccccc2Cl)C1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: F[C@H]1C[C@H](COc2ccccc2Cl)N(c2ncnc3[nH]cnc23)C1

Procedure:
7.8 780 mg of (2R,4S)-2-(2-chlorophenoxymethyl)-4-fluoropyrrolidine and 525 mg of 6-chloropurine are irradiated at 120° C. in the microwave for 6 h together with 1.2 ml of N-ethyldiisoproylamine and 40 ml of 1-butanol, during which a pressure of 10 bar arises. After conventional aqueous work-up, the residue obtained is crystallised from ether, giving 350 mg of 6-[(2R,4S)-2-(2-chlorophenoxymethyl)-4-fluoropyrrolidin-1-yl]-9H-purine (“A7”) as beige crystals; Rt.: 1.790 min; [M+H]+348.2; m.p. 143-144°;
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[C:4](Cl)[N:3]=1.[CH3:12][O:13][C:14]([C:16]1([OH:19])[CH2:18][CH2:17]1)=[O:15].[H-].[Na+]>C1COCC1>[CH3:12][O:13][C:14]([C:16]1([O:19][C:4]2[C:5]([O:9][CH3:10])=[C:6]([Cl:8])[N:7]=[C:2]([Cl:1])[N:3]=2)[CH2:18][CH2:17]1)=[O:15]
Reactant: COc1c(Cl)nc(Cl)nc1Cl
Reactant: COC(=O)C1(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(Oc2nc(Cl)nc(Cl)c2OC)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,4,6-trichloro-5-methoxy-pyrimidine (213 mg, 1.00 mmol) and 1-hydroxy-cyclopropanecarboxylic acid methyl ester (139 mg, 1.20 mmol) in THF (4 mL) was added sodium hydride (48 mg, 1.20 mmol, 60% dispersion in mineral oil) at −78° C. The resulting mixture was allowed to warm to RT and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo affording 1-(2,6-Dichloro-5-methoxy-pyrimidin-4-yloxy)-cyclopropanecarboxylic acid methyl ester as a white solid (300 mg, quantitative). LCMS: RT=3.49 min, [M+H]+=341/343/345.
Reaction SMILES: C[O:2][C:3]1[C:10]([O:11]C)=[C:9]([F:13])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].B(Br)(Br)Br>ClCCl>[F:13][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[C:3]([OH:2])[C:10]=1[OH:11]
Reactant: COc1c(F)ccc(C=O)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1ccc(F)c(O)c1O
Temperature: -78 °C
Reaction time: 18 h
Yield: 87.7 %

Procedure:
To a solution at −78° C. of 2,3-dimethoxy-4-fluorobenzaldehyde (7.0 g, 38.0 mmol) in dry dichloromethane (150 mL) was added dropwise BBr3 (23.8 g, 95.0 mmol) in dichloromethane (30 mL). Reaction mixture was allowed to attain room temperature and stirred for 18 h. Then reaction mixture was cooled to −78° C., and quenched with a mixture of methanol (10 mL) and water (50 mL) and stirred at room temperature for 30 min. Precipitated solid was separated by filtration and washed with cold dichloromethane. Dichloromethane layer was concentrated to yield the title compound as a solid (5.2 g, 88%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 11.38 (s, 1H), 9.84 (s, 1H), 7.15 (dd, J=8.6, 5.5 Hz, 1H), 6.81 (t, J=9.4 Hz, 1H), 5.47 (s, 1H); MS (ESI) m/z=155 (M−1, negative).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][S:6][CH:7]=1)#[N:2].Cl.[C:9]1(N)[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15]>>[CH:13]1[CH:14]=[CH:9][C:10]2[N:15]=[C:1]([C:3]3[N:4]=[CH:5][S:6][CH:7]=3)[NH:2][C:11]=2[CH:12]=1
Reactant: N#Cc1cscn1
Reactant: Nc1ccccc1N
Agent: Cl
Product: c1ccc2[nH]c(-c3cscn3)nc2c1
Temperature: 201 °C
Reaction time: 5 h
Yield: 75.5 %

Procedure:
The mixture was heated and when the pot temperature reached 164° C., distillation commenced. The temperature gradually increased to 201° C. and a total of 44 ml of water plus ethylene glycol distillate were removed. The mixture was allowed to cool to 100° C. before 27.5 g (0.25 moles) of 4-cyanothiazole were added to the solution containing o-phenylenediamine monohydrochloride. The reaction mixture was heated to 125° C. and held within a temperature range of 125°-130° C. for a period of 5 hours. Thiabendazole formed as a precipitte during the 5 hours of heating. The reaction was monitored by gas chromatography and determined to be complete when the peaks corresponding to o-phenylenediamine and 4-cyanothiazole were negligible. Next, the reaction mass was cooled to 50° C. and filtered to collect the precipitate using a Buchner funnel and #4 Whatman filter paper. The wet cake was washed with 1.5 L of deionized water. The washed precipitate was dried overnight in a vacuum oven under 15-20" Hg and at a temperature of 90° C. The weight of dry thiabendazole crystals was 38.0 g, which corresponds to a yield of 75.5%. The purity was determined to be 99.67% (based on area %) using HPLC analysis.
Reaction SMILES: [C:1](OC)(=[O:3])C.[C:6](#[N:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[ClH:15].CC1CCCCC1>CO>[ClH:15].[C:6](=[NH:14])([O:3][CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: COC(C)=O
Reactant: CCCCCCCC#N
Agent: Cl
Solvent: CO
Solvent: CC1CCCCC1
Product: CCCCCCCC(=N)OC
Temperature: 0 °C
Reaction time: 25 h
Yield: 93.4 %

Procedure:
Methanol (2.81 g) and methyl acetate (30 ml) were added to octanenitrile (10.00 g), and the mixture was cooled to 0° C. Hydrogen chloride (7.50 g) was added and the mixture was stirred for 25 hours at the same temperature. Methylcyclohexane (60 ml) was added to the reaction solution, and then the solvent was distilled off under reduced pressure. Methylcyclohexane (20 ml) was added to the residue, the mixture was stirred for 1.5 hours at room temperature, and then crystals were filtered. The crystals were washed with methylcyclohexane and dried under reduced pressure to give the title compound as a white solid (14.45 g, 93.4% yield).