Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:29])[C:5]([CH3:21])([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Reaction time: 20 h
Yield: 94.9 %

Procedure:
2-Phenoxy-3-(4-benzyloxyphenyl)-2-methyl-propionic acid ethyl ester (24.1 g, 59.3 mmol) was dissolved in ethanol (200 mL) and treated with 10% palladium on carbon (2.41 g), and then stirred under an atmosphere of hydrogen for 20 h. The suspension was filtered through celite and concentrated in vacuo to produce 3-(4-hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester colorless oil (16.9 g, 95%).
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:21])([CH3:20])[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[CH:9][C:8]=1[F:22])([CH3:4])([CH3:3])[CH3:2].[Li]C(CC)C.B(OC)(OC)[O:31]C.C(O)(=O)C.OO>C1COCC1>[C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[C:8]([F:22])=[C:9]([OH:31])[CH:10]=[C:11]([C:13]([CH3:21])([CH3:20])[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: COB(OC)OC
Agent: OO
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a solution of 2-(tert-butyl-dimethyl-silanyloxy)-4-(tert-butyl-dimethyl-silanyloxymethyl)-1-fluoro-benzene (23.70 g, 63.9 mmol, 1.0 eq.) in anhydrous THF (130 mL) was added at −78° C. under Ar a solution of sec-BuLi (54.5 mL, 71.6 mmol, 1.1 eq., 1.3 M solution in hexane) within 30 min. Then a solution of trimethyl borate (7.13 mL, 6.64 g, 63.9 mmol, 1.0 eq.) in anhydrous THF (30 mL) was added slowly within 30 min and the cooling bath removed. A solution of conc. acetic acid (5.49 mL, 5.76 g, 95.9 mmol, 1.5 eq.) was slowly added followed by addition of 35% hydrogen peroxide (6.28 mL, 2.39 g, 70.3 mmol, 1.1 eq.) and the reaction mixture kept at 0° C. for 30 min. After stirring at rt for an additional 4 h, the reaction was extracted with diethyl ether (2×100 mL) and the combined organic phases washed with a solution of 10% sodium hydroxide (2×100 mL) and a sat. solution of sodium chloride (2×100 mL). The organic phase was dried over Na2SO4, concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with hexane/ethyl acetate (19:1) providing 15.80 g (64%) of the title compound. 1H NMR (400 MHz, CDCl3): δ0.00 (s, 6H), 0.10 (s, 6H), 0.85 (s, 9H), 0.91 (s, 9H), 4.50 (s, 2H), 4.93 (br s, 1H), 6.37 (d, J=5.6 Hz, 1H), 6.47 (d, J=5.6 Hz, 1H). MS: 329.2 [M-tert-Bu]+.
Reaction SMILES: S([O-])(O)(=O)=O.[CH3:6][S+:7]([CH3:9])[CH3:8].[S:10]([O:15]C)([O:13][CH3:14])(=[O:12])=[O:11].CSC>>[CH3:14][O:13][S:10]([O-:15])(=[O:12])=[O:11].[CH3:6][S+:7]([CH3:9])[CH3:8]
Reactant: COS(=O)(=O)OC
Agent: C[S+](C)C
Agent: O=S(=O)([O-])O
Solvent: CSC
Product: COS(=O)(=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Synthesis of trimethysulfonium hydrogen sulfate: To dimethyl sulfate (10.0 mL, 1.05×10−1 mol) at 0° C. was added dimethyl sulfide (10.4 mL, 1.42×10−1 mol). After rapidly stirring at 0° C. for 30 minutes, the reaction was slowly warmed to room temperature yielding a crystalline solid, trimethylsulfonium methyl sulfate. After 3 hours, distilled water (20 mL) was added to form a clear solution of trimethylsulfonium sulfate.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH:26]1([CH2:29][NH2:30])[CH2:28][CH2:27]1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:30][CH2:29][CH:26]4[CH2:28][CH2:27]4)=[O:2])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[CH:23][CH:22]=1
Reactant: NCC1CC1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2C)nc1
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)NCC2CC2)cn1
Yield: 70 %

Procedure:
As described for example 117, 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (144 mg, 0.4 mmol) was converted, using cyclopropanemethylamine instead of 2,2,2-trifluoroethylamine, to the title compound (111 mg, 70%) which was obtained as a white solid. MS: m/e=398.4 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([O:24]C)=[O:23])=[CH:12][CH:11]=2)[C:7]2[C:26]([C:30]([O:32]C)=[O:31])=[CH:27][CH:28]=[CH:29][C:6]=2[N:5]=1)[CH3:2]>CO>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([OH:24])=[O:23])=[CH:14][CH:15]=2)[C:7]2[C:26]([C:30]([OH:32])=[O:31])=[CH:27][CH:28]=[CH:29][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Solvent: CO
Product: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
To a solution of methyl 2-ethoxy-1-[(2'-methoxycarbonylbiphenyl-4-yl)methyl]benzimidazole-7-carboxylate (0.7 g) in methanol (10 ml) was added 1N NAOH (5 ml) and the mixture was stirred at 80° C. for 3 hours. After evaporation of the methanol, the aqueous residue was neutralized with 1N hydrochloric acid to give crystals. The crystals were recrystallized from methanol--chloroform to afford colorless crystals (0.54 g, 83%), m.p. 213-215° C.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][C:10]#[N:11])[CH:4]=1.Cl[CH2:13][CH2:14][N:15]([CH2:23][CH2:24]Cl)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>CN(C)C=O>[C:10]([C:9]1([C:5]2[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=2)[CH2:24][CH2:23][N:15]([C:16]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:22])[CH2:14][CH2:13]1)#[N:11]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: N#CCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccnc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 61.7 %

Procedure:
A flask was charged with sodium hydride (5.08 g, 127 mmol) and dimethylformamide (100 ml) at 0° C. under nitrogen. 2-(Pyridin-3-yl)acetonitrile (5 g, 42.3 mmol) was added in 25 mL of dimethylformamide via addition funnel over 20 min. After 20 min, tert-butyl bis(2-chloroethyl)carbamate (12.81 g, 52.9 mmol) was added in 20 mL of dimethylformamide via addition funnel over 20 min. The reaction was allowed to stir at 0° C. for 2 h and then at 60° C. for 12 h. The reaction was quenched with 10% sodium bicarbonate (100 mL) and extracted with ethyl acetate (5×100 mL). The organics were collected, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified via column chromatography (10% 2M ammonia in methanol, 90% dichloromethane) to yield 7.5 g (49%) of desired product. Mass Spec.: 288.20 (MH)+. LC tr=1.380 min (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA Gradient Time=2 min, Flow rate=4 mL/min)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[CH:9]=O)=[CH:4][CH:3]=1.[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>O1CCOCC1.C(OCC)(=O)C.CCCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[CH:9]=[CH:17][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: CC(C=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: C1COCCO1
Product: CCOC(=O)C=CC(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3.9 g (0.023 mole) of 2-(4-chlorophenyl)propionaldehyde in 25 mL of 1,4-dioxane is added in one portion 9.0 g (0.026 mole) of (carbethoxymethylene)triphenylphosphorane. The reaction mixture is stirred for approximately 16 hours at ambient temperature after which the solvent is evaporated under reduced pressure, leaving a residue which is then dissolved in ethyl acetate. Approximately 10 g of silica gel is mixed with the resulting solution. The solvent is evaporated from this mixture, and the residue is placed in a sintered glass filter. The silica gel is then eluted with 100 mL of heptane/ethyl acetate (3:1). These solvents are evaporated under reduced pressure, leaving a residue. This residue is dissolved in 30 mL of heptane/ethyl acetate (9:1), treated with 5 g of silica gel, and filtered. The filtrate is evaporated under reduced pressure, leaving ethyl 4-(4-chlorophenyl)-2-pentenoate as a residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([S:12]([CH3:14])=[O:13])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[OH:19][C:20]1[N:21]([CH3:25])[N:22]=[CH:23][CH:24]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>C(OCC)(=O)C.CCCCCCC.O>[OH:19][C:20]1[N:21]([CH3:25])[N:22]=[CH:23][C:24]=1[C:5]([C:4]1[CH:8]=[CH:9][C:10]([C:15]([F:18])([F:17])[F:16])=[C:11]([S:12]([CH3:14])=[O:13])[C:3]=1[O:2][CH3:1])=[O:7]
Reactant: Cn1nccc1O
Reactant: COc1c(C(=O)O)ccc(C(F)(F)F)c1S(C)=O
Solvent: c1ccncc1
Solvent: O
Solvent: CCCCCCC
Product: COc1c(C(=O)c2cnn(C)c2O)ccc(C(F)(F)F)c1S(C)=O
Temperature: -10 °C
Yield: 88.1 %

Procedure:
3.0 g of 2-methoxy-3-methylsulfinyl-4-trifluoromethylbenzoic acid and 1.02 g of 3-hydroxy-2-methylpyrazole are suspended in 30 ml of ethyl acetate and 4.21 ml of pyridine under an inert atmosphere and cooled to −20° C. with stirring. 1.24 g of thionyl chloride are then slowly added dropwise such that the temperature always remains below −15° C. Following the complete addition of the thionyl chloride, the mixture is stirred for a further 20 minutes and warmed to −10° C. 10 ml of cold water are then added, and the mixture is warmed to 0° C. After adding 40 ml of heptane, the suspension is filtered and washed with 20 ml of heptane, 10 ml of water and again with 20 ml of heptane. Drying gives 3.32 g of (5-hydroxy-1-methyl-1H-pyrazol-4-yl)[2-methoxy-3-(methylsulfinyl)-4-(trifluoromethyl)phenyl]methanone (84% yield).
Reaction SMILES: [Li].O(CC)CC.[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22](OCC)=O)[CH2:18][CH2:17]1>O>[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][CH:16]1[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]1
Reactant: CCOC(=O)N1CCC(Nc2c(C)cccc2C)CC1
Agent: [Li]
Solvent: O
Solvent: CCOCC
Product: Cc1cccc(C)c1NC1CCN(C)CC1
Temperature: 5 °C
Reaction time: 20 h

Procedure:
To a stirred and refluxing suspension of 2 parts of lithium aluminumhydride in 120 parts of 1,1'-oxybisethane is added dropwise a solution of 13 parts of ethyl 4-[N-(2,6-dimethylphenyl)amino]-1-piperidinecarboxylate in 40 parts of 1,1'-oxybisethane. After the addition is complete, stirring and refluxing is continued for 20 hours. The reaction mixture is cooled to 5° C. and 7 parts of water are added. The formed precipitate is filtered off, washed on the filter with 1,1'-oxybisethane and the filtrate is evaporated. The oily residue is distilled, yielding 5.8 parts of N-(2,6-dimethylphenyl)-1-methyl-4-piperidinamine; bp. 90°-93° C. at 0.003 mm. pressure. On standing the distillate solidifies, to yield solid N-(2,6-dimethylphenyl)-1-methyl-4-piperidinamine with a melting point of 45° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.CCOCC.[C:18]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].CCN(CC)CC>[Cl-].[Cl-].[Zn+2].ClCCCl.CC(O)(C)C>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:37][C:34]2[CH:35]=[CH:36][C:31]([CH:28]3[CH2:27][CH2:26][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:30][CH2:29]3)=[CH:32][CH:33]=2)[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,4-Dichloro-5-(trifluoromethyl)pyrimidine (4.12 g, 19.0 mmol) was stirred in a 1:1 t-BuOH:DCE mixture (400 mL) at room temperature. A 1.0 M ZnCl2 solution in Et2O (21.7 mL, 21.7 mmol) was added cautiously and after addition the reaction was stirred at room temperature for 10 minutes. 1-Boc-4-(4-aminophenyl)piperidine (5.00 g, 18.1 mmol) was then added followed by Et3N (6.05 mL, 43.4 mmol) and the resulting mixture was stirred at room temperature overnight. The organic solvents were evaporated and the resulting solid was suspended in water (500 mL). The suspension was sonicated for 30 minutes and then filtered. The filter cake was washed with water (2×100 mL) and dried under high vacuum to give the title compound K5 as a tan solid (8.11 g, 98%); 1H NMR (400 MHz, d6-DMSO) δ 10.61 (s, 1H), 8.78 (s, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 4.07 (d, J=11.1 Hz, 2H), 2.80 (s, 2H), 2.65 (t, J=12.0 Hz, 1H), 1.74 (d, J=12.3 Hz, 2H), 1.42 (s, 11H). LCMS-A: rt 6.834 min; m/z 457 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:10](Cl)(=[O:12])[CH3:11].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)(=[O:12])[CH3:11]
Reactant: c1ccc2c(c1)CCO2
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCO2
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2,3-dihydrobenzofuran (5.0 g) in dichloromethane (30 ml) at -10° C. was slowly added a solution of acetyl chloride (5.9 ml) and anhydrous aluminum chloride (5.5 g) in dichloromethane (30 ml) while keeping the temperature below -6° C. After addition of the 2,3-dihydrobenzofuran was completed, the reaction mixture was stirred for 10 minutes at -10° C. The reaction mixture was then added to an ice/hydrochloric acid mixture which was extracted with dichloromethane. The combined dichloromethane extracts were washed with water and dilute sodium hydroxide, the organic layer dried over sodium sulfate and evaporated. The resulting residue was recrystallized from hexane to give 5-acetyl-2,3-dihydrobenzofuran, m.p.--56°-57° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[F:22][C:23]([F:27])([F:26])[CH2:24]I.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[O:8][CH2:24][C:23]([F:27])([F:26])[F:22]
Reactant: CCOC(=O)Cc1cc(Cl)c(O)c(Br)c1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cc(Cl)c(OCC(F)(F)F)c(Br)c1
Temperature: 60 °C
Yield: 78.7 %

Procedure:
To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (6.5 g, 22 mmol), in DMF (100 mL), K2CO3 (7.67 g, 55.6 mmol) was added. Trifluoroethyl iodide (13.16 mL, 133 mmol) was added in a drop wise manner to the reaction mixture at RT. The mixture was then heated at 60° C. for 4 h. After completion of reaction, the mixture was poured into water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography to give compound ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (6.5 g) as a white solid.
Reaction SMILES: [C:1]1(=[N:13]O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:15]>>[C:1]1(=[O:15])[NH:13][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O
Reactant: ON=C1CCCCCCCCCCC1
Product: O=C1CCCCCCCCCCCN1

Procedure:
For example, after the reaction of cyclododecanone oxime, the reaction can be worked up by adding water, extracting a product with an organic solvent and then evaporating the solvent to give laurolactam, which can be further separated and purified by, for example, distillation or crystallization.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[C:17]([N:19]=[C:20](OCC)[CH2:21][CH3:22])#[N:18]>C(O)C>[C:17]([N:19]=[C:20]([NH:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:14])([CH3:15])[C@H:3]1[OH:16])[CH2:21][CH3:22])#[N:18]
Reactant: CCOC(CC)=NC#N
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Solvent: CCO
Product: CCC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Yield: 47 %

Procedure:
A mixture of trans-4-amino-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile (4.37 g) and ethyl N-cyanopropionimidate (2.65 g) in ethanol (22 ml) was refluxed for 10 hours. The mixture was cooled and concentrated under reduced pressure. The residue was pulverized with ethanol and recrystallized from ethanol to give trans-4-[N-[1-(cyanoimino)propyl]amino]-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile (2.81 g).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[OH:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:18][C:11]1[C:10]([CH3:9])=[CH:15][C:14]([Br:16])=[CH:13][C:12]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(Br)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(Br)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.7 mL (96.5 mmol) benzylbromide were added dropwise to 20 g (96.5 mmol) 2,6-dimethyl-4-bromophenol and 16.5 g (118 mmol) potassium carbonate in 300 mL acetone and stirred overnight at RT. The precipitate formed was suction filtered, washed with acetone and the filtrate was evaporated down. The residue was dissolved in DCM, filtered through Alox and washed with DCM. The filtrate was evaporated down.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:16][CH2:17]O>>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:16][CH3:17])=[O:5]
Reactant: O=C(O)c1ccccc1O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccccc1O
Yield: 97.25 %

Procedure:
To a solution of 2-hydroxybenzoic acid (63) (5.0 g, 36.2 mmol) in anhydrous EtOH (150 ml) was added 98% H2SO4 (4 ml). The mixture was refluxed for 4 h and concentrated. The residue was extracted with CH2Cl2 dried over MgSO4 and evaporated. The crude was purified by distillation to give 68 as colorless liquid. (5.85 g, 35.21 mmol). Yield: 97.25%; MS (EI, 70 eV): m/z 166.2 (M+); 1H-NMR (CDCl3, 200 MHz): δ 1.39 (t, J=7.2 Hz, 3H), 4.37 (q, J=7.2, 7.0 Hz, 2H), 6.81 (t, J=6.6 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 7.42 (t, J=7.2 Hz, 1H), 7.82 (dd, J1=8.0, 1.8 Hz, 1H), 10.83 (s, 1H); 13C-NMR (CDCl3, 50 MHz) δ: 170.20, 161.64, 135.56, 129.89, 119.06, 117.53, 61.40, 14.18; Anal. Calcd for C9H10O3: C, 65.05; H, 6.07.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.Cl.[CH3:11][NH:12][O:13][CH3:14].O>C(Cl)Cl>[CH3:14][O:13][N:12]([CH3:11])[C:7](=[O:9])[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: O=C(O)c1ccncc1
Reactant: CNOC
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)c1ccncc1
Reaction time: 0.67 h

Procedure:
A suspension of 4-picolinic acid (3.00 g, 24.4 mmol) and 1,1-carbonyldiimidazole (4.74 g, 29.2 mmol) in CH2Cl2 (35 mL) was stirred for ˜40 min and became a clear solution. After the addition of N,O-dimethylhydroxylamine hydrochloride (2.85 g, 29.2 mmol), the mixture was stirred at room temperature for 22 hours. Water was added, the organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water once, and the aqueous layer was back extracted with CH2Cl2. The organic phase was dried (Na2SO4), filtered, concentrated, and purified by flash column chromatography (80 g silica gel column, 100% EtOAc) to give the title compound as a clear oil.
Reaction SMILES: CNCC[N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].C(=O)C1C=CC=NC=1.[Na].C(O)(=O)C>ClCCl>[C:6]1(=[O:15])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13](=[O:14])[NH:5]1
Reactant: CNCCN1C(=O)c2ccccc2C1=O
Agent: O=Cc1cccnc1
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of 2-(2-methylamino-ethyl)-isoindole-1,3-dione (1 eq) in dichloromethane was added nicotinaldehyde (1.5 eq), sodium acetoborohydride (4.5 eq) and acetic acid (1.5 eq). After stirring at room temperature for 1 hour, NaHCO3(sat) was added to the reaction mixture followed by an extraction with dichloromethane. The organic phase was washed with H2O, NaCl(sat) (50 mL), dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography using a solvent gradient of 97% DCM, 3% MeOH and 0.1% TEA (2L) to yield 2-[2-methyl-pyridin-3-ylmethyl-amino)-ethyl]-isoindole-1,3-dione (57%). MH+(296).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11]O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:16]>C(OC(C)C)(C)C.C(Cl)(Cl)Cl.O>[C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][Br:16])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccc(-c2ccccc2)cc1
Reactant: BrP(Br)Br
Solvent: CC(C)OC(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: BrCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.8 %

Procedure:
To a solution of 4-phenylbenzyl alcohol (1.00 g, 5.43 mmol) in a mixture of diisopropyl ether (10 mL) and chloroform (20 mL) was added phosphorus tribromide (0.98 g, 3.62 mmol) with ice-cooling and the mixture was stirred at room temperature for 1 hour. This reaction mixture was diluted with water and extracted with diisopropyl ether. The organic layer was washed with water and saturated aqueous sodium hydrogen carbonate solution, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was recrystallized from ethanol-hexane to provide 1.00 g of the title compound. Yield 75%.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[Cl:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11].C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:6][O:5][C:3](=[O:4])[CH2:2][NH:11][C:10]1[CH:12]=[CH:13][CH:14]=[C:8]([Cl:7])[CH:9]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COC(=O)CBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNc1cccc(Cl)c1
Temperature: 60 °C

Procedure:
Methyl bromoacetate (8.3 g, 54.3 mmol), 3-chloroaniline (8.31 g, 65.1 mmol) and diisopropylethylamine (7.01 g, 54.3 mmol) were dissolved in N,N-dimethylformamide (20 mL) to give a light yellow solution and the reaction mixture heated at 60° C. overnight. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give (3-chloro-phenylamino)-acetic acid methyl ester as a solid which was washed with hexanes, filtered and dried (10.2 g, 96%).
Reaction SMILES: [CH3:1][C:2]1[N+:7]([CH3:8])=[C:6]([NH2:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[C:15]([C:17]([CH3:19])=[O:18])[CH:14]=[CH:13][CH:12]=2)[CH:3]=1.C(C1C=C(NC2C=C(C)N=C(N)N=2)C=CC=1)(=O)C.C[I:39]>CC(C)=O>[I-:39].[C:17]([C:15]1[CH:16]=[C:11]([NH:10][C:4]2[CH:3]=[C:2]([CH3:1])[N+:7]([CH3:8])=[C:6]([NH2:9])[N:5]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:18])[CH3:19]
Reactant: CI
Agent: CC(=O)c1cccc(Nc2cc(C)[n+](C)c(N)n2)c1
Agent: CC(=O)c1cccc(Nc2cc(C)nc(N)n2)c1
Solvent: CC(C)=O
Product: [I-]

Procedure:
Compound No. 14 (CNI-H1494): 4-(3-acetylphenyl)amino-2-amino-6-methylpyrimidine, Compound No. 15, (0.968 g) was suspended in acetone (5 mL) containing methyl iodide (2 mL) was heated at reflux for 48 hr. Filtration after cooling gave 0.657 g of 4-(3-acetylphenyl)amino-2-amino-1,6-dimethylpyrimidinium iodide as a white powder, mp 238-40° C.