Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[CH3:21][S:18]([CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:3][C:2]([C:32]4[CH:33]=[CH:34][C:29]([NH2:28])=[N:30][CH:31]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CS(=O)(=O)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CS(=O)(=O)C1CCN(Cc2cc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in General Procedure A. Purification on silica yielded 129. NMR (MeOD): 1.72-1.90 (2H, m), 2.05-2.10 (2H, m), 2.60 (3H, s, Me), 2.85-2.88 (1H, m), 3.08-3.14 (2H, m), 3.30-3.33 (2H, m), 3.80 (2H, s, CH2), 3.83-3.87 (4H, m, CH2), 3.94-3.98 (4H, m, CH2), 6.53 (1H, d, J 8.5, Ar), 7.19 (1H, s, Ar), 8.32 (1H, dd, J 8.5 and 1.8, Ar) and 8.92 (1H, d, J 1.8, Ar). MS: (ESI+): MH+=489.27
Reaction SMILES: [C:1]([C:3]1([C:9](OC)=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].CO.[BH4-].[Li+]>O1CCCC1>[OH:10][CH2:9][C:3]1([C:1]#[N:2])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)C1(C#N)CCCCC1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: N#CC1(CO)CCCCC1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
To a solution of methyl 1-cyanocyclohexanecarboxylate (prepared according to Fleming et. al, J. Org. Chem. 2005, 70, 2200) (8.54 g, 51.10 mmol) in anhydrous tetrahydrofuran (300 mL) was added anhydrous methanol (3.1 mL, 78.00 mmol) and lithium borohydride (4.0 M solution in tetrahydrofuran 19 mL, 76 mmol). The reaction solution was heated to reflux under a nitrogen atmosphere for 4 hours, cooled to ambient temperature. The mixture was quenched by the slow addition of saturated aqueous ammonium chloride (5 mL). The mixture was diluted with ethyl acetate (400 mL), washed with a 2:1 mixture of saturated aqueous ammonium chloride and water (2×300 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as a colorless oil (6.30 g, 89%): 1H NMR (300 MHz, CDCl3) δ 3.55 (s, 2H), 2.78 (br s, 1H), 1.98-1.93 (m, 2H), 1.74-1.69 (m, 4H), 1.63-1.48 (m, 4H).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[N:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][CH:7]=1.[CH3:15]O>C(Cl)(Cl)Cl>[Cl:5][C:6]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)c1cccc(Cl)n1
Reactant: CO
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(Cl)n1
Yield: 100 %

Procedure:
Add thionyl chloride (3.7 mL, 50.8 mmol) to a solution of 6-chloropicolinic acid (4.0 g, 25.4 mmol) in methanol (85 mL) at 0° C. Stir the resultant solution for 15 minutes at 0° C., 0.5 hours at room temperature, and 6 hours at 50° C. Concentrate the reaction in vacuo and dilute with CHCl3 (150 mL). Wash the organic solution with saturated aqueous sodium bicarbonate (3×100 mL), and brine (1×100 mL) and dry with sodium sulfate. Filtration and concentration afford methyl 6-chloropicolinate 4.38 g (100%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16](OC1C=CC(C(C2C=CC=CC=2)=O)=CC=1)[CH:17]=[CH2:18]>>[CH2:18]([C:15]1[CH:14]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])[CH:17]=[CH2:16]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: C=CCOc1ccc(C(=O)c2ccccc2)cc1
Product: C=CCc1cc(C(=O)c2ccccc2)ccc1O
Yield: 46.2 %

Procedure:
4-hydroxybenzophenone (25 g) was converted to 4-allyloxybenzophenone (29.2 g, yellow solid) by the procedure of Example 23. Claisen rearrangement using that procedure gave 13.5 g (47%) of desired 3allyl-4-hydroxybenzophenone, the balance being recovered. Finally, acylation of 3-allyl-4-hydroxybenzophenone (5.9 G) according to general procedure of Example 1 produced 6.9 g (86%) of product as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:18]([O-])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C@@H:13]([CH3:17])[C:14]([NH2:16])=[O:15])[CH:6]=[CH:5]2.C(O)C.[Cl-].[NH4+].O>[Fe]>[NH2:18][C:3]1[C:2]([Cl:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]([C@@H:13]([CH3:17])[C:14]([NH2:16])=[O:15])[C:8]2=[O:12]
Reactant: C[C@@H](C(N)=O)n1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: C[C@@H](C(N)=O)n1ccc2c(N)c(Cl)ccc2c1=O
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-2-(6-chloro-5-nitro-1-oxoisoquinolin-2(1H)-yl)propanamide (201 mg, 0.000679 mol), ethanol (10 mL, 0.2 mol), ammonium chloride (363.03 mg, 0.0067868 mol) and water (10 mL, 0.6 mol) was heated at 85° C. Iron (152 mg, 0.00271 mol) was added in three portions, 2 minutes apart and the reaction was stirred at that temperature for 1 hour. The mixture was poured onto dichloromethane (150 mL) and the layers were separated. The organic layer was washed with brine, dried, and the solvent was removed under reduced pressure to afford the product as a light yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][Si:5](Cl)([CH3:7])[CH3:6].C(=O)([O-])[O-].[Na+].[Na+].[OH2:15]>>[Cl:1][CH2:2][CH2:3][CH2:4][Si:5]([CH3:7])([CH3:6])[O:15][Si:5]([CH2:4][CH2:3][CH2:2][Cl:1])([CH3:7])[CH3:6]
Reactant: C[Si](C)(Cl)CCCCl
Reactant: O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[Si](C)(CCCCl)O[Si](C)(C)CCCCl
Temperature: 25 °C
Yield: 89 %

Procedure:
To a triangular flask of 2 l containing 1200 ml of water was added dropwise 342 g of 3-chloropropylchlorodimethylsilane (hereinafter referred to as "CPCDMSi") in an hour while stirring with a magnetic stirrer at a room temperature. After completion of the addition, the reaction mixture was neutralized with sodium carbonate and then extracted three times with each 500 ml of n-hexane. After drying the n-hexane layer with anhydrous magnesium sulfate, n-hexane was removed under reduced pressure. The obtained residue was distilled under reduced pressure, and then the distillate obtained at 103° C./1.5 mmHg was collected to give 255 g (Yield 89%) of 1,3-bis(3-chloropropyl)-1,1,3,3-tetramethyldisiloxane (hereinafter referred to as "BCPSi").
Reaction SMILES: [N:1]#[C:2]Cl.[CH3:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1>[OH-].[Na+]>[N:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][C:2]#[N:1])[CH:6]=1
Reactant: N#CCl
Reactant: Cc1cccnc1
Agent: [Na+]
Agent: [OH-]
Product: N#CCc1cccnc1

Procedure:
As the reactor there was used a quartz tube 1 meter long and 20 mm wide which was heated from the outside. There were fed into the tube separately from each other in homogeneous flow hourly 7.1 grams (0.12 mole) of cyanogen chloride and 42.8 grams (0.46 mole) of 3-methylpyridine) both of which were preheated to 550° C. The reaction temperature was 680° C. The reaction mixture was treated hourly with 1.2 liters of 5 percent aqueous sodium hydroxide solution in a gas washer directly post-connected to the reactor. The aqueous mixture which discharged from the gas washer was extracted hourly with 2 liters of dichloromethane. By distillation of the organic phase there were recovered the dichloromethane and the unreacted 3-methylpyridine. The pyridine-3-acetonitrile obtained had a boiling point of 101° to 109° C. at 1, 5 mbar. Its purity was 98 to 99%. The yield amounted to 10.4 grams, corresponding to 75% based on the cyanogen chloride added.
Reaction SMILES: [Mg].O(CC)CC.Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH:24]=[O:25])[CH:22]=2)[CH:17]=[CH:16][CH:15]=1>O1CCCC1>[C:8]1([CH:24]([C:21]2[CH:22]=[C:23]3[C:18]([CH:17]=[CH:16][CH:15]=[N:14]3)=[CH:19][CH:20]=2)[OH:25])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccc2cccnc2c1
Reactant: Brc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1ccccc1)c1ccc2cccnc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 26.6 %

Procedure:
To a stirred mixture of 1.25 parts of magnesium, 14 parts of 1,1'-oxybisethane and 8 parts of bromobenzene was added a solution of 8 parts of intermediate 1, namely 7-quinolinecarboxaldehyde, in 72 parts of tetrahydrofuran, keeping the temperature between 0° C. and 5° C. After stirring for 12 hours at room temperature, the reaction mixture was poured into 300 parts of ice-water. The product was extracted with 1,1'-oxybisethane (3×70 parts). The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 98:2). The eluent of the desired fraction was evaporated, yielding 3.2 parts (26.6%) of α-phenyl-7-quinolinemethanol; mp. 118° C. (interm. 2). In a similar manner there were also prepared the intermediates listed in Table 1.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>CS(C)=O>[CH3:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:3][CH:4]=1
Reactant: CNC(=O)c1ccc(F)cc1
Reactant: C1CNCCN1
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(N2CCNCC2)cc1
Temperature: 120 °C
Reaction time: 68 h
Yield: 65.6 %

Procedure:
To a solution of 4-fluoro-N-methylbenzamide (6 g, 39.2 mmol) in DMSO (Volume: 24.0 mL) was added piperazine (16.87 g, 196 mmol) at 23° C. The reaction was stirred at 120° C. for 68 hr. The reaction mixture was poured into ice (261 g) and the reaction vessel was rinsed with H2O (˜50 mL). Next, celite (30 g) was added to aid the filtration. The resulting suspension was warmed to 100° C., cooled to ˜40° C., filtered, and rinsed with warm H20 (4×50 mL). The resulting solid was dried in vacuo. The filtrate was stirred at room temperature overnight affording a suspension. The suspension was filtered, rinsed with H2O (3×25 mL), and the resulting solid was dried in vacuo. The cloudy filtrate was filtered once again through a medium fitted funnel and rinsed with H2O (3×10 mL). Added NaCl (200.1 g) to the filtrate, cooled on ice, filtered, rinsed with cold H2O (3×25 mL), and dried the resulting solid in vacuo. Re-suspended the purified product in H2O (30 mL), stirred for 30 min at 23° C., filtered, rinsed with H2O (3×5 mL), and dried the resulting solid in vacuo. The purified product was re-suspended in ACN (25 mL), agitated for 10 min, and dried in vacuo. This procedure was repeated three times to provide N-methyl-4-(piperazin-1-yl)benzamide (5.64 g, 25.7 mmol, 65.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (br. s., 1H) 2.74 (d, J=4.55 Hz, 3H) 2.77-2.86 (m, 4H) 3.08-3.18 (m, 4H) 6.91 (m, 2H) 7.69 (m, 2H) 8.13 (q, J=4.04 Hz, 1H). ESI-MS: m/z 220.2 (M+H)+. mp=153.9-156.5° C.
Reaction SMILES: CO[C:3]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6].Cl.[CH:18]([NH:21][NH2:22])([CH3:20])[CH3:19].C(N(CC)CC)C>C(O)C>[NH2:6][C:5]1[N:21]([CH:18]([CH3:20])[CH3:19])[N:22]=[C:3]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=2)[C:4]=1[C:7]#[N:8]
Reactant: CC(C)NN
Reactant: COC(Cc1cccc(Br)c1)=C(C#N)C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)n1nc(Cc2cccc(Br)c2)c(C#N)c1N
Yield: 87.3 %

Procedure:
Compound 33 (3.124 g, 11.3 mmol), isopropylhydrazine hydrochloride (1.27 g, 11.5 mmol) (purchased from Ryan Scientific) and triethylamine (6.40 mL, 46.0 mmol) were allowed to react in ethanol (75 mL) at room temperature for 1 hr. After concentrating the reaction mixture, it was purified by silica chromatography using a chloroform/methanol solvent system (methanol gradient increased with time from 0-10%). The relevant fractions were concentrated in vacuo to yield a yellow powder (3.15 g, 87% yield): 1H NMR (400 MHz, DMSO) δ 7.41 (m, 2H), 7.26 (td, J=7.7, 1.2, 1H), 7.21 (dt, J=7.7, 1.3, 1H), 6.50 (s, 2H), 4.38 (hept, J=6.5, 1H), 3.81 (s, 2H), 1.27 (d, J=6.5, 6H); 13C NMR (100 MHz, DMSO) δ 151.01, 150.15, 141.24, 131.05, 130.53, 129.16, 127.45, 121.55, 115.16, 71.77, 47.24, 32.88, 21.35; [M+H]+ calculated for C14H15BrN4 319.0, 321.0 found 318.9: 321.0.
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([NH2:19])=[O:18])=[O:14])[CH2:11][CH3:12])=[O:8].[H][H]>C(O)(=O)C.[Pd]>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([NH2:19])=[O:18])=[O:14])[CH2:11][CH3:12])=[O:8]
Reactant: [H][H]
Reactant: CC[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(N)=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N1CCC[C@H]1C(N)=O
Yield: 91.3 %

Procedure:
2.67 g (6 mmoles) of Z-Glp-Abu-Pro-NH2 are dissolved in 100 ml of acetic acid. 0.5 g of a 10% palladium-on-carbon catalyst are added to the solution, and hydrogen is bubbled through the mixture for one hour. The catalyst is filtered off, the filtrate is evaporated, and the residue is triturated with ether. The resulting 1.82 g of amorphous crude product are dissolved in water, the solution is decolourized, filtered, and the clear filtrate is freeze-dried. 1.70 g (91%) of Glp-Abu-Pro-NH2 are obtained; Rf4 =0.24, [α]D25 =-102.5° (c=1%, in acetic acid).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8]Cl)=[CH:3][CH:2]=1.[SH:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]>>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][S:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:3][CH:2]=1
Reactant: ClCCc1ccncc1
Reactant: COC(=O)CS
Product: COC(=O)CSCCc1ccncc1

Procedure:
Using the above procedure 2-(4-pyridyl)ethyl chloride is reacted with methyl 2-mercaptoacetate to yield methyl 2-[2-(4-pyridyl)ethylthio]acetate.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]([CH3:21])([CH2:19][SH:20])[C:10]([NH:12][C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][SH:15])=[O:11].II>C(Cl)Cl>[CH3:8][C:9]1([CH3:21])[CH2:19][S:20][S:15][CH2:14][C@@H:13]([C:16]([OH:18])=[O:17])[NH:12][C:10]1=[O:11]
Reactant: CC(C)(CS)C(=O)N[C@@H](CS)C(=O)O
Agent: II
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CSSC[C@@H](C(=O)O)NC1=O
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of triethylamine (13.3 g) in methylene chloride (0.5 l), N-(2,2-dimethyl-3-mercaptopropionyl)-L-cysteine (15.6 g) dissolved in methylene chloride (0.5 l) and iodine (18.3 g) dissolved in methylene chloride (0.5 l) were added dropwise simultaneously under ice-salt cooling. After the addition, the reaction mixture was stirred for 1 hr at the same temperature. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Separated crystals were collected by filtration to give 8.5 g (55%) of the titled compound.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:34])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:35])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:35][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:36])=[O:2])[C:14]([CH3:15])=[C:13]2[CH:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:34])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[CH:25]=2)[CH2:18][CH2:17]1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)Nc3cccc(C(F)(F)F)c3)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(C(=O)Nc2cccc(C(F)(F)F)c2)CC1
Reaction time: 4 h
Yield: 69.8 %

Procedure:
To a solution of {6-fluoro-3-methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (97 mg, 0.193 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (92.4 mg, 2.2 mmol) in water (2.0 mL) at room temperature. The resulting solution was stirred for four hours under a nitrogen atmosphere. The solvent was evaporated. Water (˜25 mL) was added and the mixture was acidified with 1.0 N aqueous HCl (3.9 mL). The resulting white precipitate was collected by filtration, washed with water and hexanes, and dried under high vacuum to provide {6-fluoro-3-methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid (65.8 mg, 70%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.50 (br. s, 1H), 8.97 (br. s, 1H), 8.00-8.22 (m, 1H), 7.97 (s, 1H), 7.90 (dd, J=9.10, 6.50 Hz, 1H), 7.78 (d, J=8.50 Hz, 1H), 7.66-7.73 (m, 1H), 7.49 (t, J=8.30 Hz, 1H), 7.30-7.38 (m, 1H), 7.28 (d, J=8.30 Hz, 1H), 4.28-4.36 (m, 2H), 3.71-3.85 (m, 3H), 3.01-3.18 (m, 2H), 2.43 (s, 3H), 2.17-2.34 (m, 1H), 1.64-1.73 (m, 2H). MS cald. for C26H25F4N2O3 [(M+H)+]: 489, obsd. 489.2.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.C(OCC)(=O)C.[H][H]>CO.[Rh]>[O:1]1[CH2:5][CH:4]([C:6]([O:8][CH3:9])=[O:7])[CH:3]([C:10]([O:12][CH3:13])=[O:11])[CH2:2]1
Reactant: [H][H]
Reactant: COC(=O)c1cocc1C(=O)OC
Agent: [Rh]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C1COCC1C(=O)OC
Reaction time: 8.5 h
Yield: 98.7 %

Procedure:
Dimethyl 3,4-furandicarboxylate (5.20 g, 28.0 mmol) was combined with 5% Rhodium/C in methanol (30 mL) and ethyl acetate (10 mL) in a Parr shaker bottle. The reaction was charged to 50 psi hydrogen and was shaken for 8.5 h. The reaction was filtered over celite, concentrated in vacuo to give the dimethyl 3,4-tetrahydrofuran dicarboxylate (5.2 g, 100%) as an oil MS (M−CH3OH)+=156.
Reaction SMILES: [CH2:1]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3].[H-].[Na+].[Na].[CH3:17][CH:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25]>CN(C)C=O>[CH2:1]([N:4]([CH:18]([CH3:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3]
Reactant: CC(Cl)c1ccccc1Cl
Reactant: C=CCNS(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: C=CCN(C(C)c1ccccc1Cl)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.97 g (0.01 mole) of N-allylbenzenesulfonamide was added to 0.58 g (0.012 mole) of 50% sodium hydride in 15 ml of dry N,N-dimethylformamide. The mixture was stirred at room temperature for 30 minutes to react them. To the resulting sodium salt was added 2.10 g (0.012 mole) of α-methyl-2-chlorobenzyl chloride. The mixture was stirred at room temperature for 1 hour. The N,N-dimethyl formamide was distilled off under reduced pressure, and cold water was added. The resulting oil layer was extracted with benzene. The benzene layer was dried over anhydrous magnesium sulfate, concentrated, and purified by silica gel chromatography to afford the final product. The final product is designated as compound No. 89 in Table 2, and its melting point and elemental analysis values are shown in Table 2.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7](=[O:23])[C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH:19]=O)[CH2:15][C:16](=O)[CH3:17])=[C:10]([O:21][CH3:22])[CH:9]=1.C([O-])(=O)C.[NH4+:28]>C(OCC)(=O)C>[CH3:5][O:6][C:7](=[O:23])[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:15]=[C:16]([CH3:17])[N:28]=[CH:19]2)=[C:10]([O:21][CH3:22])[CH:9]=1
Reactant: COC(=O)c1ccc(N(C=O)CC(C)=O)c(OC)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-n2cnc(C)c2)c(OC)c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
An acetic acid (255 mL) solution of 4-(formyl-(2-oxopropyl)amino)-3-methoxybenzoic acid methyl ester (118 g) and ammonium acetate (172 g) was heated under stirring at 140° C. for 1 hour. The reaction solution was neutralized with an ammoniac solution under ice-cooling after the reaction completed. Ethyl acetate was added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was filtered with a silica gel pad after dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. Tert-butylmethyl ether and heptane were added to the residue and the deposited solids were separated by filtering and washed with a 50% heptane solution of tert-butylmethyl ether. 68.4 g of the title compound was obtained by air-drying the obtained solids overnight. Furthermore, crystallization mother liquid was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system), and 22.3 g of the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3.[CH3:14][N:15]=[C:16]=[S:17]>C(#N)C>[CH3:14][NH:15][C:16](=[S:17])[NH:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3
Reactant: CN=C=S
Reactant: Nc1ccc2c(c1)C(=O)C1(CC1)O2
Solvent: CC#N
Product: CNC(=S)Nc1ccc2c(c1)C(=O)C1(CC1)O2
Yield: 65.3 %

Procedure:
5-Aminospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (1.75 g.) and methyl isothiocyanate (1.1 g.) were stirred in acetonitrile (60 ml.) at room temperature for 15 hours, and then the mixture was refluxed under heating for 3 hours. The solvent was evaporated off under reduced pressure, and the residue was recrystallized from methanol to give yellow prisms of 5-methylthioureidospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (1.62 g.). m.p. 191°-194° C.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]#[CH:22].CN(C)C=O>O>[CH3:1][O:2][N:3]=[C:4]([O:13][CH2:22][C:21]#[CH:20])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12]
Reactant: C#CCBr
Reactant: CONC(=O)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOC(=NOC)c1ccc(Cl)cc1Cl
Reaction time: 3 h
Yield: 29.8 %

Procedure:
1.0 g of N-methoxy-2,4-dichlorobenzamide, 0.75 g of potassium carbonate and 0.65 g of propargyl bromide were added to 10 ml of N,N-dimethylformamide, and the mixture was stirred for 3 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried, concentrated and purified by silica gel column chromatography to obtain 0.35 g of propargyl N-methoxy-2,4-dichlorobenzimidate.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:8][CH2:9][C:10]([CH3:13])([CH3:12])[N:11]=1.C([Li])CCC.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[N:24]=[CH:23][N:22]=1>CCOCC.CCCCCC>[CH3:13][C:10]1([CH3:12])[CH2:9][O:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH2:14][C:23]2[N:24]=[C:25]([Cl:27])[CH:26]=[C:21]([Cl:20])[N:22]=2)=[N:11]1
Reactant: Cc1ccccc1C1=NC(C)(C)CO1
Reactant: Clc1cc(Cl)ncn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1(C)COC(c2ccccc2Cc2nc(Cl)cc(Cl)n2)=N1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 1.25 g of 2-o-tolyl-4,4-dimethyl-oxazoline in 20 ml of ether under N2 atmosphere at -30° C. is added by syringe 4.2 ml of 1.6M n-butyllithium in hexane with stirring which is continued for 1 hr at -10° C. 0.98 g of 4,6-dichloropyrimidine in 20 ml of ether are added slowly to the reaction mixture which is then stirred at -45° to -30° C. for 30 min and at 0° C. for a further 30 min. The reaction mixture is quenched with acetic acid (0.4 ml) and water (0.1 ml) in THF (1.3 ml) and then treated with 1.5 g of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in 6 ml of THF. The temperature is brought to RT and the mixture stirred for 5 min after cooling to 0° C. 7.6 ml of 1N NaOH (cooled) are added and the mixture stirred for 5 min. The organic phase is separated and dried over Na2SO4 filtered and the solvent removed. Following chromatography (10/90 ether/hexane) the title product is obtained.