Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Mg]Br)([CH3:3])=[CH2:2].[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[N+:14]([O-])=O.[NH4+].[Cl-]>C1COCC1.CCOCC>[Cl:13][C:12]1[C:7]([Cl:6])=[C:8]2[C:9]([CH:2]=[C:1]([CH3:3])[NH:14]2)=[CH:10][CH:11]=1
Reactant: C=C(C)[Mg]Br
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc2ccc(Cl)c(Cl)c2[nH]1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
1600 ml of isopropenylmagnesium bromide at 0.5 M in THF are introduced under nitrogen and cooled to −20° C., 51.2 g of 2,3-dichloronitrobenzene in 250 ml of anhydrous THF are added and then the mixture is left with stirring at −20° C. for 1 hour. The reaction mixture is poured at −20° C. into 1 liter of saturated NH4Cl solution and diluted with Et2O and then the aqueous phase is washed twice with Et2O. The organic phases are combined and concentrated to dryness. The product is extracted with DCM and washed twice with water and then with saturated NaCl solution. It is dried and then evaporated and the residue is chromatographed on a hexane/AcOEt (95/5; v/v) mixture. This gives 24.27 g of the expected compound, m.p.=70–71° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[CH:11]1([NH2:14])[CH2:13][CH2:12]1>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:14][CH:11]1[CH2:13][CH2:12]1)[C:5]#[N:6]
Reactant: N#Cc1ccc(F)c(Br)c1
Reactant: NC1CC1
Solvent: CO
Product: N#Cc1ccc(NC2CC2)c(Br)c1
Yield: 118.9 %

Procedure:
A solution of 3-bromo-4-fluorobenzonitrile (9.33 mmol) and cyclopropylamine (7.90 g, 136 mmol) in methanol (60 mL) was heated to 60° C. for 20 hours and concentrated. The concentrate was purified by flash column chromatography with 96:4 hexane/ethyl acetate to provide 2.63 g of the desired product. MS (ESI(+)) m/z 239 (M+H)+;
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][NH:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH3:13][N:14]([C:8](=[O:10])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=1)[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a mixture of 4-nitrobenzoic acid (16.7 g), ethyl 3-(methylamino)propanoate (13.1 g), 1-hydroxybenzotriazole monohydrate (18.4 g), and N,N-dimethylformamide (200 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (23.0 g), and the mixture was stirred at room temperature for 8 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (28.0 g, 100%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1
Reactant: CCOC(=O)Cc1ccc(O)c(Cl)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Reaction time: 0.17 h
Yield: 46.8 %

Procedure:
To a solution of compound ethyl 2-(3-chloro-4-hydroxyphenyl)acetate (2.0 g, 0.009 mol) in DMF (10 mL) was added K2CO3 (3.8 g, 0.02 mol) at RT. The reaction mixture was stirred for 10 minutes and then 2-(chloromethyl)quinoline (1.2 g, 0.19 mol) was added. The reaction mixture was refluxed for 16 h, quenched with ice water and filtered. The residue that was obtained was extracted with DCM (2×100 mL). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated in vacuo to afford ethyl 2-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)acetate (1.5 g, 45%) as a solid.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]1[CH2:22][S:19](=[O:21])(=[O:20])[O:18][CH2:17]1>C1(C)C=CC=CC=1>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:17][CH2:16][CH2:22][S:19]([OH:21])(=[O:20])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S1(=O)CCCO1
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=S(=O)(O)CCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of dibenzylamine (9.8 mL, 50.8 mmol) in toluene (50 mL) was added 1,3-propane sultone (6.50 g, 53.3 mmol). The mixture was stirred at reflux for 3 h. A sticky paste was formed at the bottom of the flask. The reaction mixture was cooled to room temperature. The top layer was decanted; and the paste was partially dissolved in EtOAc with heating. The mixture was poured in a 10% EtOAc/Hexanes (200 mL). The mixture was heated and the paste was spread on the walls of the conical flask. The solvent was removed. This process was repeated twice. MeOH (75 mL) was added to the paste. The mixture was heated until a white solid appeared. The solid was collected by filtration, washed with cold MeOH, and dried in vacuo, affording compound AV, 7.03 g (43%).
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH2:4]([C:13]1(O)[CH2:18]CC[CH2:15][CH2:14]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl>O>[CH3:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:13]1[CH:14]=[CH:15][C:1]([OH:3])=[CH:2][CH:18]=1
Reactant: C1CO1
Reactant: CCCCCCCCCC1(O)CCCCC1
Agent: Cl
Solvent: O
Product: CCCCCCCCCc1ccc(O)cc1
Reaction time: 1 h

Procedure:
The resulting 292.4 grams of NCH-1.5 was then mixed with 1.9 grams CaO in an autoclave and reacted with 220 grams of ethylene oxide (EO) fed into the autoclave over a six-hour period at a temperature of 150° C. and a pressure of 50 psi. Pressure and temperature were controlled by EO charge rate and rate of flow of cooling water. After all the oxide was charged, the reaction was held for one hour and the autoclave was placed under a 50 mm vacuum for thirty minutes and the vacuum was broken with nitrogen. The resulting 5 mole ethoxylate of nonylcyclohexyl alcohol (NCH-5 pk) was then cooled to 50° C. and the catalyst was neutralized with HCl to a pH balance between 6 and 7, inclusive.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11](O)=[O:12])=[CH:5][CH:4]=1)#[N:2].[CH2:28]([O:30][C:31]([CH:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([CH:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:11](=[O:12])[C:10]2[CH:9]=[C:8]([O:7][C:6]3[CH:26]=[CH:27][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:14]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Reactant: CCOC(=O)C1CCC(N)CC1
Product: CCOC(=O)C1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 37.7 %

Procedure:
Following the procedure of Example 9(e) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 1.0 g (2.6 mmol) and 4-amino-cyclohexanecarboxylic acid ethyl ester (0.48 g, 2.6 mmol) were used to afford 0.5 g of the required product. 1H NMR (DMSO-d6): δ 1.34 (5H, m), 1.41 (5H, m), 1.92 (4H, m), 2.1 (1H, t), 3.81 (1H, m), 4.12 (2H, q), 7.04 (4H, dd), 7.51 (2H, s), 7.89 (3H, d), 8.41 (1H, d). Percentage purity (HPLC): 89.3%.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[Cl:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[C:19]([CH2:26][OH:27])=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1.Br[CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>O>[Cl:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[N:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[C:19]([CH2:26][O:27][CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: OCc1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Reactant: BrCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1nc(Nc2cccc(Cl)c2)ncc1COCC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 60% sodium hydride (26 mg) and N,N-dimethylformamide (4 mL) was added {2-[(3-chlorophenyl)amino]-4-(trifluoromethyl)pyrimidin-5-yl}methanol (200 mg), followed by stirring at room temperature for 30 minutes. Thereafter, bromomethyl cyclohexane (139 μL) was added thereto, followed by stirring at room temperature for 2 hours. 60% Sodium hydride (26 mg) and bromomethyl cyclohexane (139 μL) were added thereto again, followed by stirring at room temperature overnight. To the reaction mixture was added water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, then dried over anhydrous magnesium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain N-(3-chlorophenyl)-5-[(cyclohexylmethoxy)methyl]-4-(trifluoromethyl)pyrimidin-2-amine (100 mg) as a white solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:23])=[CH:4][CH:3]=1.[F:24][C:25]([F:40])([F:39])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1>>[F:24][C:25]([F:39])([F:40])[C:26]1[CH:27]=[C:28]([C:2]2[S:6][C:5]([CH2:7][N:8]3[C:16]4[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=4)[CH:10]=[C:9]3[CH3:23])=[CH:4][CH:3]=2)[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1ccc(Br)s1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)s1

Procedure:
Synthesized as described in Example 310D using 1-[(5-bromo-2-thienyl)methyl]-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 314B) and [3,5-bis(trifluoromethyl)phenyl]boronic acid: MS (ES) m/z 531 (M−1).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]#[C:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH3:29])[C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=1)(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]([CH3:29])[C:23](=[O:28])[C:24]([F:26])([F:25])[F:27])=[CH:20][CH:21]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCCCOCCC#Cc1ccc(N(C)C(=O)C(F)(F)F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)OCCCCCCOCCCCc1ccc(N(C)C(=O)C(F)(F)F)cc1
Yield: 99.1 %

Procedure:
A solution of Intermediate 54 (1.2 g, 2.9 mmol) in methanol was treated with palladium on carbon (10% w/w, 50 mg). Mixture was shaken under 50 psi of hydrogen gas for two hours and then filtered through a pad of Celite diatomaceous earth. The filtrate was concentrated under reduced pressure to provide the title compound as an oil (1.2 g, 100%). ES/MS calcd. for C21H31F3NO4+ 418.2. Found m/z=418.3 (M+H)+.
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][NH:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:20]=2)=[S:13])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>>[CH:1]1([NH:7][C:8]2[S:13][C:12]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[CH:20]=3)=[N:11][N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1)NC1CCCCC1
Solvent: O=P(Cl)(Cl)Cl
Product: c1cc(CN2CCCCC2)cc(OCCCNc2nnc(NC3CCCCC3)s2)c1

Procedure:
The compound is prepared by a method analogous to that of Example 40 from N-cyclohexyl-2-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]aminothioxomethyl]-hydrazine carboxamide and phosphorus oxychloride. The analytical values are summarized in Table III.
Reaction SMILES: [CH3:1]N(C)C=O.P(Cl)(Cl)(Cl)=O.[C:11]1([NH:17][C:18]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][C:20]([O:22][CH3:23])=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)CCl>[CH3:27][O:26][C:24]([C:18]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:1][C:12]2[C:11](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:17]=1)=[O:25]
Reactant: CN(C)C=O
Reactant: COC(=O)C=C(Nc1ccccc1)C(=O)OC
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc2ccccc2nc1C(=O)OC
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of dimethylformamide (DMF, 0.10 mol) in ethylene dichloride (EDC, 100 mL), cooled in an ice bath, is added dropwise with stirring phosphorous oxychloride (POCl3, 0.10 mol). The resulting solution is stirred for one and one-half hours at room temperature and then cooled in an ice bath. To the cooled solution is then added, in small increments, a solution of dimethyl 3-phenylaminobut-2-ene-dioate (0.10 mol) in ethylene dichloride. The resulting mixture is thereafter heated to reflux for three hours, cooled, and washed with half saturated brine. The organic phase is washed with half saturated brine. The organic phase is separated from the aqueous phase and dried. The solvent is removed under vacuum, and the residue recrystallized from methanol to afford 18.2 g (0.074 mol) of dimethyl-2,3-quinolinedicarboxylate, mp 105°-106.5° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]([CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])#[N:2].N.[H][H]>CO.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][CH:5]([CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CCCC(CCC#N)CCc1cccnc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: COC(=O)CCCC(CCCN)CCc1cccnc1

Procedure:
To a solution of 0.1 g (0.37 mmol) of methyl 7-cyano-5-[2-(3-pyridyl)ethyl]-heptanoate in 20 ml of methanol saturated with ammonia is added 0.15 ml Raney Nickel and the mixture is hydrogenated at 3 atmospheres (=3.04 bar) pressure of hydrogen and room temperature for 4 h. The catalyst is filtered off and washed with methanol (4×20 ml). The filtrate is evaporated to give methyl 8-amino-5-[2-(3-pyridyl)ethyl]-octanoate.
Reaction SMILES: [Mg].C[O-].[Mg+2].C[O-].[CH2:7]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:26](O)(=[O:28])C>CO.C1(C)C=CC=CC=1>[CH2:7]([C:19]1[CH:20]=[C:21]([CH:26]=[O:28])[C:22]([OH:25])=[CH:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCc1ccc(O)cc1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Mg+2]
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCCCCCCCCCc1ccc(O)c(C=O)c1
Temperature: 45 °C
Reaction time: 0.75 h
Yield: 65 %

Procedure:
A 2-liter round-bottomed flask was charged with magnesium turnings (12.2 g, 0.50 mole), methanol (133 ml), toluene (60 ml), and magnesium methoxide solution (10 ml of an 8% w/w solution of magnesium methoxide in methanol). The reaction mixture was heated to 45° C. at which point the magnesium dissolution became vigorous. The temperature of the reaction mixture was maintained between 45 and 55° C. Para-dodecyl phenol (128.0 g, 0.50 mol) dissolved in toluene (125 ml) was added in one portion to the reaction mixture which was then maintained at 65° C. for one hour. Glacial acetic acid (30.1 g, 0.50 mol) was added over a 1 hour period, while maintaining the reaction mixture at reflux (65-66° C.). The reaction flask was then rigged for fractional distillation and the methanol/toluene azeotrope was distilled off until an internal temperature of 85° C. was reached. A total of 117 g of distillate, assaying 65% methanol and 35% toluene, was collected. Toluene (130 g) was added to the reaction mixture in one portion. Paraformaldehyde (45.0 g) slurried in toluene (90 g) was then added over a 90 minute period. During the addition, the reaction mixture was maintained at a temperature of 85-90° C. allowing a continuous distillation of the volatile reaction by-products. When the paraformaldehyde addition was complete, the reaction mixture was maintained at 90° C. for an additional 90 minutes. The reaction mass as then cooled to 35° C. and 500 ml of 20% v/v sulfuric acid was added. The hydrolysis mass was then stirred for an additional 45 minutes. After phase separation, the organic phase was washed twice with 200 ml portions of water. The washed organic phase was then separated, dried and rendered free of the solvent to yield crude 5-dodecyl salicylaldehyde. A 65% yield was obtained.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]2[NH:8][C:9](=[O:18])[N:10]([CH:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[C:26]([O:34][CH3:35])[CH:25]=1)([O-:23])=[O:22].O>C1COCC1>[Cl:3][C:4]1[CH:20]=[CH:19][C:7]2[N:8]([S:30]([C:27]3[CH:28]=[CH:29][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][C:26]=3[O:34][CH3:35])(=[O:31])=[O:32])[C:9](=[O:18])[N:10]([CH:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Reactant: O=c1[nH]c2ccc(Cl)cc2n1C1CCCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)n1c(=O)n(C2CCCCCC2)c2cc(Cl)ccc21
Reaction time: 18 h
Yield: 64.4 %

Procedure:
600 mg of sodium hydride as a 60% dispersion in oil were added in portions, with stirring, to a solution of 3 g of 5-chloro-3-cycloheptyl-1,3-dihydro-2H- benzimidazol-2-one in 30 ml of THF. 3 g of 4-nitro-2- methoxybenzenesulfonyl chloride were then added and the reaction mixture was stirred for 18 hours. The reaction mixture was then poured into a water+ ice mixture, extracted with ethyl acetate and washed with water and the organic phase was dried over sodium sulfate and concentrated to dryness. 3.5 g of the expected product were obtained by crystallization from an iso ether/AcOEt mixture (60/40; v/v). M.p.=193° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6]Cl.[N+:13]([C:16]1[O:20][C:19]([CH:21]=[CH:22][C:23]2[NH:24][CH:25]=[CH:26][N:27]=2)=[CH:18][CH:17]=1)([O-:15])=[O:14]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][N:27]1[CH:26]=[CH:25][N:24]=[C:23]1[CH:22]=[CH:21][C:19]1[O:20][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=1
Reactant: COc1ccc(CCl)cc1OC
Reactant: O=[N+]([O-])c1ccc(C=Cc2ncc[nH]2)o1
Product: COc1ccc(Cn2ccnc2C=Cc2ccc([N+](=O)[O-])o2)cc1OC

Procedure:
Using the same general procedure as employed in Example 1, the captioned compound was prepared from 3,4-dimethoxybenzyl chloride (as prepared from the corresponding alcohol) in lieu of the 2,3-dimethoxybenzyl chloride intermediate of Example 1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[OH:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][N:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:3][C:4]2=[O:18])=[CH:11][CH:12]=1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Reactant: BrCc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1cc(OCc2ccncc2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 400 mg (1.63 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) in 20 mL DMF is added 0.45 g (1.79 mmol) 4-bromomethyl-pyridine and 0.68 g (4.89 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT, diluted with 60 mL of EtOAc and is washed twice with water. The organic phase is dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Waters symmetry C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH:14]=O)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[NH2:23][C:24]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28]([CH3:35])=[N:29]2.C([BH3-])#N.[Na+]>>[F:34][C:31]1[CH:32]=[CH:33][C:24]([NH:23][CH2:14][C:13]([OH:20])([C:16]([F:17])([F:19])[F:18])[CH2:12][C:11]([C:4]2[C:5]3[O:9][CH2:8][CH2:7][C:6]=3[CH:10]=[C:2]([F:1])[CH:3]=2)([CH3:21])[CH3:22])=[C:25]2[C:30]=1[N:29]=[C:28]([CH3:35])[CH:27]=[CH:26]2
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1cc(F)cc2c1OCC2
Reactant: Cc1ccc2c(N)ccc(F)c2n1
Agent: [BH3-]C#N
Agent: [Na+]
Product: Cc1ccc2c(NCC(O)(CC(C)(C)c3cc(F)cc4c3OCC4)C(F)(F)F)ccc(F)c2n1

Procedure:
Analogously to Example 1, the corresponding imine is produced starting from 45 mg of 4-(2,3-dihydro-5-fluoro-7-benzofuranyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal and 25 mg of 5-amino-8-fluoro-2-methylquinoline. After reaction with sodium cyanoborohydride, the title compound is obtained.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[CH3:32][Si:33]([CH3:40])([CH3:39])[CH2:34][CH2:35][O:36][CH2:37]Cl>C1COCC1.CCOC(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:37][O:36][CH2:35][CH2:34][Si:33]([CH3:40])([CH3:39])[CH3:32])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: COC(=O)c1csc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)n1
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1csc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.8 %

Procedure:
To a solution of methyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)thiazole-4-carboxylate (14 g, 31.1 mmol) in THF (150 mL) was added TEA (6.3 g, 62.1 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (7.77 g, 46.6 mmol). The mixture was stirred at r.t. for 4 h. The mixture was diluted with EtOAc (400 mL) and washed with 3% HCl, water and brine. Evaporation of solvent gave 18.2 g of product. LC/MS (APCI): m/z 580.9 (M+H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:50]([O:52][C:53]1[C:58]([C:59]2[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=2)=[CH:57][CH:56]=[CH:55][N:54]=1)[CH3:51]>CN(C=O)C>[CH2:50]([O:52][C:53]1[C:58]([C:59]2[CH:60]=[C:61]([NH:65][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:62]=[CH:63][CH:64]=2)=[CH:57][CH:56]=[CH:55][N:54]=1)[CH3:51]
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: CCOc1ncccc1-c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ncccc1-c1cccc(NC(=O)c2cc3cccc(OC)c3oc2=O)c1
Temperature: 25 °C
Yield: 85.8 %

Procedure:
DIEA (0.013 mL, 0.077 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.015 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2-Ethoxy-pyridin-3-yl)-phenylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.025 g of product in 86% yield: LCMS (ESI) m/z 417 (MH+).