Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14](O)(=[O:24])[C:15]1[CH:23]=[C:21]([OH:22])[C:19]([OH:20])=[C:17]([OH:18])[CH:16]=1>S(=O)(=O)(O)O>[C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:24])[C:15]1[CH:16]=[C:17]([OH:18])[C:19]([OH:20])=[C:21]([OH:22])[CH:23]=1
Reactant: O=C(O)c1cc(O)c(O)c(O)c1
Reactant: CCCCCCCCCCCCO
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCCCOC(=O)c1cc(O)c(O)c(O)c1
Temperature: 55 °C

Procedure:
Lauryl alcohol in the amount of 294.4 g was heated in a flask of 1 L to a temperature of 60° C. One hundred grams (100 g) of gallic acid was added (purity 90%) together with 1 ml of sulfuric acid (96%) as a catalyst. The mixture was submitted to reaction in a Rotavapor at a temperature of approximately 160° C. and a vacuum of −0.4 bar. While reacting, the azeotropic water/lauryl alcohol was distilled off. Approximately 5 to 6 hours were needed for completion. The percent of remaining gallic acid was controlled by HPLC. When the remaining gallic acid was less than 1%, the process can be taken to the next step. The distilled azeotropic water/lauryl alcohol mixture was separated by means of a separation funnel and the lauryl alcohol can be re-used after quality control by GC. The remaining reaction mixture was cooled down to approximately 55° C., while stirring. In another flask of 2 L with reflux cooler and stirrer, 1 L of petroleum ether (Bp. 40-60° C.) was heated to approximately 55° C. When both the petroleum ether and the reaction mixture had the same temperature (approximately 55° C.), the reaction mixture was slowly added to the petroleum ether while stirring. The mixture of the reactants and the petroleum ether was cooled down over a period of approximately 5 hours to room temperature (hour 0, temp. 55° C.; h. 0.5, temp. 60° C.; h. 1, temp. 55° C.; h.2, temp. 45° C.; h3, temp. 35° C.; h. 4, temp. 25° C.; h. 5, temp. 25° C.). The lauryl gallate crystallized and was filtered via a vacuum sucked glass filter. Solid impure lauryl gallate and filtrate A (lauryl gallate, lauryl alcohol, petroleum ether) were obtained. The solid impure lauryl gallate was mixed again with 0.5 L of petroleum ether (Bp. 40-60° C.), but this time at room temperature. Again, this mixture was filtered by a vacuum sucked glass filter. This time pure lauryl gallate and filtrate B (lauryl gallate, lauryl alcohol, petroleum ether) were obtained. Filtrate A and B were combined and the petroleum ether was recovered via vacuum distillation with a Rotavapor (temp. 60° C., −0.4 Bar). After quality control, the petroleum ether could be re-used. The residue was also checked for remaining lauryl gallate and lauryl alcohol by HPLC and GC, it can be re-used at the start of a next batch. Drying of the pure lauryl gallate for 24 hours at approximately 60° C. and at a vacuum of −0.4 Bar in a vacuum oven, yields crystalline lauryl gallate. Lauryl gallate was obtained as a crystalline silver white powder with a purity of 81.35%. The conversion rate was rather good as only 0.2% of gallic acid was found remaining in the reaction mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[S:28]([NH:19][C:4]1[CH:5]=[N:6][C:7]([O:8][C:9]2[N:10]=[CH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([Cl:1])[CH:3]=1)(=[O:30])=[O:29]
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Cl
Product: O=S(=O)(Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1)c1ccc(F)cc1Cl

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 2-chloro-4-fluorobenzene-1-sulfonyl chloride.
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([CH3:21])([CH3:20])[CH2:11][C:12]([C:16]([F:19])([F:18])[F:17])([OH:15])CO)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1>CO>[O:1]1[C:5]2[C:6]([C:10]([CH3:21])([CH3:20])[CH2:11][C:12](=[O:15])[C:16]([F:18])([F:19])[F:17])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CC(C)(CC(O)(CO)C(F)(F)F)c1cccc2c1OCC2
Solvent: CO
Product: CC(C)(CC(=O)C(F)(F)F)c1cccc2c1OCC2
Yield: 99.6 %

Procedure:
A solution of 4-(2,3-dihydrobenzofuran-7-yl)-4-methyl-2-trifluoromethylpentane-1,2-diol (24.0 g, 78.9 mmol) and NaIO4 (84.3 g, 394 mmol) in 360 mL of methanol was stirred at room temperature overnight. The resulting mixture was filtered through pad of CELITE® filter aid and the filter cake was washed with three 100 mL portions of methanol. The filtrate was concentrated in vacuo, taken up in hexanes, filtered again, and concentrated in vacuo to give 21.4 g of 4-(2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methylpentan-2-one as colorless oil (quantitative yield), which was used without purification.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[CH2:12]([C:16]1[CH:23]=[CH:22][C:19](C#N)=[CH:18][CH:17]=1)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([C:16]1[CH:23]=[CH:22][C:19]([C:1]2[NH:2][C:3](=[O:11])[C:4]3[C:5]([CH:10]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:18][CH:17]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CNC(=O)c1ccccc1C
Reactant: CCCCc1ccc(C#N)cc1
Product: CCCCc1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Yield: 31.5 %

Procedure:
According to the method of Example 10-1, N-methyl-2-methylbenzamide (4.28 g) and 4-(n-butyl)benzonitrile (4.57 g) were reacted, to give 3-[4-(n-butyl)phenyl]isoquinolin-1-one (2.51 g).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4]C1C([N+]([O-])=O)=CC=CC=1S([O-])(=O)=O.[OH:18][C:19]1[CH:28]=[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:24][O:23][C:21](=[O:22])[C:20]1[CH:25]=[CH:26][C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)=[CH:28][C:19]=1[O:18][CH2:4][C@@H:2]1[CH2:3][O:1]1
Reactant: COC(=O)c1ccc(OCc2ccc(OC)cc2)cc1O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1C[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccc(OC)cc2)cc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
A mixture of 2(S)-oxiran-2-ylmethyl3-nitrobenzenesulfonate (518 mg, 2.0 mmol), methyl 2-hydroxy-4-[(4-methoxybenzyl)oxy]benzoate (576.6 mg, 2.0 mmol) and cesium carbonate (Cs2CO3) (812.5 mg, 2.5 mmol) in dimethylformamide (10 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate, Na2SO4, filtered, concentrated in vacuo and the residue was purified by silica gel flash chromatography (0-30% ethyl acetate in petroleum ether) to give the subtitled compound (600 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([NH:33][CH2:34][C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:11][CH:10]=1)=O.[CH3:41][NH2:42]>>[CH3:41][NH:42][CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([NH:33][CH2:34][C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:13][CH:14]=1
Reactant: O=Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Reactant: CN
Product: CNCc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1

Procedure:
The title compound was prepared from 10-[(2′-formyl-1,1′-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 56, Step B, and methylamine (8 M solution in ethanol) in the manner of Example 42, m.p. 149-150° C.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH2:7][CH:8]([NH2:12])[C:9]([OH:11])=[O:10])[C:4]([OH:13])=[CH:3][CH:2]=1.O=O>>[CH:1]1[CH:6]=[C:5]([CH2:7][C@@H:8]([NH2:12])[C:9]([OH:11])=[O:10])[C:4]([OH:13])=[CH:3][CH:2]=1
Reactant: NC(Cc1ccccc1O)C(=O)O
Agent: O=O
Product: N[C@H](Cc1ccccc1O)C(=O)O

Procedure:
Commercially available DL-o-tyrosine 1 (Fluka) is treated with L-aminoacid oxidase and oxygen according to the procedure of Sun et al. (J. Med. Chem. 1998, 41, 1034-1041) to afford the D-o-tyrosine 2. Reaction with di-t-butyl-dicarbonate in the presence of base affords the boc protected amino acid 3 (J. Med. Chem. 1998, 41, 1034-1041). The boc protected acid 3 is then treated with benzyl bromide in the presence of potassium carbonate to afford the benzyl ether 4 (J. Med. Chem. 1998, 41, 1034-1041). The four step sequence reported for the preparation of the corresponding epoxide of phenylalanine (see J. Med. Chem. 1994, 37, 1758-1768) is used to prepare the desired epoxides. Thus, the acid 4 is treated with isobutylchloroformate in the presence of N-methylmorpholine to afford the mixed anhydride which is then treated with diazomethane to afford the α-diazoketone 5 (see scheme 1). The ketone 5 is treated with HCl to form the α-chloroketone 6 which is then reduced with sodium borohydride to form the chloro alcohol 7. The 2S, 3R diastereoisomer is separated by chromatography and treated with base (e.g. potassium hydroxide) to afford the epoxide 8.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[C:22]([N:24]1[CH2:28][CH2:27][S:26][CH2:25]1)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH2:35]([N:13]([C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([C:22]([N:24]2[CH2:28][CH2:27][S:26][CH2:25]2)=[O:23])[CH2:10]1)[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][N:15]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Nc2ccc(C#N)cn2)C[C@H]1C(=O)N1CCSC1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](N(Cc2ccccc2)c2ccc(C#N)cn2)C[C@H]1C(=O)N1CCSC1
Reaction time: 0.17 h

Procedure:
3-[(2S,4S)-1-tert-Butoxycarbonyl-4-(5-cyano-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine [product of Example 58(1)] (305 mg) was dissolved in DMF (10 mL), and potassium tert-butoxide (93 mg) was added under ice cooling. After stirring the mixture for 10 min, benzyl bromide (94 μl) was added, and the mixture was stirred at room temperature for 3 days. 10% citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogencarbonate solution and brine, and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography to give 3-{(2S,4S)-4-[N-benzyl-N-(5-cyano-2-pyridyl)amino]-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (202 mg) as a pale-yellow solid.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][O:3][CH2:2]1.[CH2:9]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:11][CH2:12][NH2:13]>CN(C)C=O>[C:5]([CH2:4][O:3][CH2:2][C:1]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:14][CH2:15][NH:16][C:5]([CH2:4][O:3][CH2:2][C:1]([OH:7])=[O:8])=[O:6])=[O:8])([OH:7])=[O:6]
Reactant: NCCCCCCN
Reactant: O=C1COCC(=O)O1
Solvent: CN(C)C=O
Product: O=C(O)COCC(=O)NCCCCCCNC(=O)COCC(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 25.9 %

Procedure:
To a solution of Diglycolic anhydride (30 g) in Dimethylformamide (85 ml) at 60° C. was added dropwise a solution of 1,6-Hexamethylene diamine (11.6 g) in Dimethylformamide (50 ml). The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was cooled to 0° C. and maintained for 3 hours. The solid was filtered and washed with chloroform and dried to get pure {[6-(2-Carboxy methoxy-acetylamino)-hexylcarbamoyl]-methoxy}-acetic acid (9 g) as white powder with a melting point of 178-180° C. The compound was characterized by 1H NMR (DMSO-d6) δ1.25 (m, 2H, CH2), 1.55 (m, 2H, CH2), 2.80 (m, 2H, CH2), 3.90 (s, 4H, 2×CH2), 7.90 (bs, 1H, NH).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[C:32]([O:36][C:37]([NH:39][C@@H:40]([CH2:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)[C:41]([OH:43])=O)=[O:38])([CH3:35])([CH3:34])[CH3:33].[C@:51]12([CH3:61])[C:57]([CH3:59])([CH3:58])[CH:54]([CH2:55][CH2:56]1)[CH2:53][CH:52]2[NH2:60]>CN(C=O)C>[C:32]([O:36][C:37](=[O:38])[NH:39][C@H:40]([C:41](=[O:43])[NH:60][C@H:52]1[CH2:53][C@@H:54]2[C:57]([CH3:59])([CH3:58])[C@@:51]1([CH3:61])[CH2:56][CH2:55]2)[CH2:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)([CH3:33])([CH3:34])[CH3:35]
Reactant: CC1(C)C2CC[C@@]1(C)C(N)C2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)N[C@H]1C[C@H]2CC[C@]1(C)C2(C)C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
3.53 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (18.4 mmol, 1.0 equiv.), 1.25 g of 1-hydroxybenzotriazole (9.2 mmol, 0.5 equiv.) and 7.3 ml of Hünig's base were added to a solution of 5.0 g of (S)-2-tert-butoxycarbonylamino-3-cyclohexylpropionic acid (Boc-Cha-OH, 18.4 mmol, 1.0 equiv.) in DMF (60 ml) at 0° C. under argon, and the mixture was stirred for 30 min. Then 2.83 g of (R)-(+)-bornylamine (18.4 mmol, 1.0 equiv.) and 3.7 ml of Hünig's base were added, and the mixture was stirred at RT for 16 h. The reaction mixture was quenched with NaHCO3 (saturated, aq.) and extracted three times with ethyl acetate. The combined organic phases were washed twice with water and dried over Na2SO4 and concentrated. Purification by flash chromatography on silica gel with heptane/ethyl acetate mixtures as eluent afforded 6.58 g (88% yield) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18](=[O:26])[C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[C:6]=2[C:5](=[O:27])[NH:4][C:3]1=[O:28].C(=O)([O-])[O-].[K+].[K+].[CH:35](I)([CH3:37])[CH3:36]>CN(C=O)C.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][N:7]3[C:6]4[C:5](=[O:27])[N:4]([CH:35]([CH3:37])[CH3:36])[C:3](=[O:28])[N:2]([CH3:1])[C:10]=4[N:9]=[CH:8]3)=[CH:17][CH:16]=2)=[O:26])=[CH:20][CH:21]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)n(C)c1=O
Yield: 6.3 %

Procedure:
A solution of 3-methyl-7-[4-(4-chlorobenzoyl)-benzyl]xanthine (544 mg), potassium carbonate (202 mg) and isopropyl iodide (356 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate =1:1) and recrystallized from acetone-hexane to provide the title compound as colorless solid (38 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Reactant: BrCCC1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCC1CCOCC1

Procedure:
Prepared similarly to Intermediate 215 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(2-bromoethyl)tetrahydro-2H-pyran.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1>CN(C=O)C>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc2cccnc12
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNc2cccc3cccnc23)cc1
Reaction time: 20 h
Yield: 172.4 %

Procedure:
8-Aminoquinoline (1.26 g) was dissolved in DMF (20 ml), and potassium carbonate (1.2 g) and methyl 4-bromomethylbenzoate (1.0 g) were added. After stirring for 20 hours, the reaction solution was concentrated. The resulting residue was diluted with chloroform and water was added. The mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (2.20 g) as a yellow syrup.
Reaction SMILES: [CH2:1]([N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1)[CH:2]=[CH2:3].[CH3:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=1)=[O:24]>>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[CH2:1][CH2:2][CH2:3][C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:23](=[O:24])[CH3:22])=[CH:27][CH:28]=2)=[CH:6][C:7]=1[C:13]([F:14])([F:15])[F:16])#[N:10]
Reactant: C=CCN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: CC(=O)Nc1ccc(Br)cc1
Product: CC(=O)Nc1ccc(CCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized according to Example 84B from 4-[2-propen-1-yl(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-bromoacetanilide: MS (APCI) m/z 444 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH:7]=[C:8]([C:12]3[N:13]=[CH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:9]2)=[CH:4][CH:3]=1.Cl.[C:24]([O:28][NH2:29])([CH3:27])([CH3:26])[CH3:25]>CO>[C:24]([O:28][N:29]=[C:6]1[C:5]2[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=2)[O:9][C:8]([C:12]2[N:13]=[CH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)ON
Reactant: O=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Agent: Cl
Solvent: CO
Product: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Yield: 76.6 %

Procedure:
7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime was prepared using the method D (step 1) illustrated in example 1B. 7-bromo-2-isoquinolin-3-yl-chromen-4-one (682 mg, 1.94 mmol) was treated with O-tert-butyl-hydroxylamine hydrochloride (486 mg, 3.87 mmol) in methanol (9 ml) under microwave irradiation to yield 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (629 mg, 77%) as a yellow solid after purification by flash chromatography over silica gel (cyclohexane/ethyl acetate: 50/50).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[CH:6][S:7][C:8]=1[CH2:9]O)[CH3:3].[Br:11]P(Br)Br>ClCCl>[Br:11][CH2:9][C:8]1[S:7][CH:6]=[N:5][C:4]=1[CH:2]([CH3:3])[CH3:1]
Reactant: CC(C)c1ncsc1CO
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CC(C)c1ncsc1CBr
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of [4-(propan-2-yl)-1,3-thiazol-5-yl]methanol (800 mg, 5.1 mmol) in anhydrous dichloromethane (35 mL) was added tribromophosphane (520 μL, 5.5 mmol). The mixture was stirred at room temperature for 1.5 hours. Dichloromethane was evaporated. The residue was dried in vacuo, affording 5-(bromomethyl)-4-(propan-2-yl)-1,3-thiazole. The crude product was used without further purification.
Reaction SMILES: C(C1[CH:9]([C:10]2C=CC(Cl)=CC=2)[NH:8][C:7]([C:17]2[CH:22]=[CH:21]C(OC)=CC=2OCC)=N1)CCC.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[N:39]([C:40]([N:42]3[CH2:47]CN(C)[CH2:44][CH2:43]3)=[O:41])[C:38]([C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=3[O:57][CH2:58][CH3:59])=[N:37][CH:36]2[CH2:60][CH:61]2[CH2:65][CH2:64]CC2)=[CH:31][CH:30]=1>>[CH2:60]([CH:36]1[CH:35]([C:32]2[CH:31]=[CH:30][C:29]([Cl:28])=[CH:34][CH:33]=2)[N:39]([C:40]([N:42]2[CH2:47][CH2:10][CH:9]([N:8]3[CH2:7][CH2:17][CH2:22][CH2:21]3)[CH2:44][CH2:43]2)=[O:41])[C:38]([C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=2[O:57][CH2:58][CH3:59])=[N:37]1)[CH2:61][CH2:65][CH3:64]
Reactant: CCCCC1N=C(c2ccc(OC)cc2OCC)NC1c1ccc(Cl)cc1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Product: CCCCC1N=C(c2ccc(OC)cc2OCC)N(C(=O)N2CCC(N3CCCC3)CC2)C1c1ccc(Cl)cc1

Procedure:
[4-Butyl-5-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone was prepared from 4-butyl-5-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (Example 13) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 567.3106, calculated for C32H44N4O3Cl [(M+H)+]567.3097.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[N:7][C:6]=1Cl)[CH3:2].[F:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[N:7][C:6]=1[O:29][C:26]1[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Oc2ccc(C#N)cc2)nc1Cl
Reactant: Oc1ccc(F)cc1
Product: CCOC(=O)c1ccc(Oc2ccc(C#N)cc2)nc1Oc1ccc(F)cc1
Yield: 75 %

Procedure:
2-Chloro-6-(4-cyano phenoxy)nicotinic acid ethyl ester (0.25 g, 0.81 mmol) and 4-fluorophenol (0.09 g, 0.81 mmol) were coupled using the procedure of Example 17(b) to afford 0.23 g of the required product. Percentage purity (LCMS): 61.86%.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:22]=[C:19]([CH:20]=O)[C:18]([OH:23])=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([OH:23])=[C:19]([CH:22]=1)[CH2:20][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3cc(Br)ccc3O)CC2)nc[nH]1

Procedure:
6-[4-(5-Bromo-2-hydroxy-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 5-bromosalicylaldehyde. Mass spectrum (ES) MH+=365.