Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>CN(C=O)C.O>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]([Br:18])=[C:12]([NH2:17])[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc2c1cnn2Cc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(Br)ccc2c1cnn2Cc1ccccc1
Reaction time: 4 h
Yield: 4.2 %

Procedure:
A solution of 1-benzyl-1H-indazol-4-amine (0.087 g, 0.39 mmol) in DMF (2 mL) was treated with N-bromosuccinimide (0.069 g, 0.39 mmol) at ambient temperature and stirred for 4 hours. The mixture was diluted with water, extracted with EtOAc, dried (phase separator silicone treated filter paper), concentrated and purified on silica gel (10-50% EtOAc in hexanes) to provide 1-benzyl-5-bromo-1H-indazol-4-amine (0.005 g, 4% yield).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5](=[O:13])[O:4][C:3]=1[CH:14]([OH:16])[CH3:15].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:13])[O:4][C:3]([CH:14]([OH:16])[CH3:15])=[C:2]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(O)c1oc(=O)c2ccc(F)cc2c1Br
Reactant: OB(O)c1ccccc1
Product: CC(O)c1oc(=O)c2ccc(F)cc2c1-c1ccccc1
Yield: 78.2 %

Procedure:
The title compound was made in a similar way of that of Intermediate B53 from 4-bromo-6-fluoro-3-(1-hydroxyethyl)-1H-isochromen-1-one (intermediate A7, 0.95 g, 3.31 mmol) and phenylboronic acid (0.605 g, 4.96 mmol) to afford title compound (0.736 g) which was used without any additional purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([F:10])[C:3]=1[F:11].[N+:12]([O-])([OH:14])=[O:13].O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([N+:12]([O-:14])=[O:13])[C:5]([O:8][CH3:9])=[C:4]([F:10])[C:3]=1[F:11]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(F)c(F)c1F
Solvent: CC(=O)O
Solvent: O
Product: COc1c([N+](=O)[O-])cc(F)c(F)c1F
Temperature: 60 °C

Procedure:
To a solution of 1,2,3-trifluoro-4-methoxybenzene (1.6 g, 10 mmol) in acetic acid (20 mL) was added nitric acid (5 mL) and the mixture was heated at 60° C. for 3 hours. After cooling to ambient temperature, water (100 mL) was added and the mixture was extracted with ethyl acetate (3×100 mL). The organic layers were concentrated to give the crude title compound, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].[Cl:32]C1C=CC(CCI)=CC=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[Cl:32][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][N:16]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][C:2]([CH3:1])([CH3:6])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)=[CH:20][CH:21]=1
Reactant: Clc1ccc(CCI)cc1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCc2ccc(Cl)cc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-Methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl -ureido]-thiazol-5-ylsulfanyl}-propionic acid using 1-chloro-4-(2-iodo-ethyl)-benzene (J. Med. Chem. 1998, 41,3, 358-378) and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [SH:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([CH3:29])=[CH:23][N:22]=1>>[CH3:28][O:27][C:25]1[C:24]([CH3:29])=[CH:23][N:22]=[C:21]([CH2:20][S:1][C:2]2[N:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:10](=[O:18])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:26]=1
Reactant: O=c1c2ccccc2nc(S)n1-c1ccccc1
Reactant: COc1cc(CCl)ncc1C
Product: COc1cc(CSc2nc3ccccc3c(=O)n2-c2ccccc2)ncc1C
Yield: 22.5 %

Procedure:
The title compound was prepared in a yield of 22.5%, using 2-mercapto-3-phenyl-4(3H)-quinazolinone in place of 2- mercapto-6-methyl-3-phenyl-4(3H)-quinazolinone and 2-chloromethyl-4-methoxy-5-methylpyridine in place of 2-chloromethylpyridine hydrochloride.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[CH3:24]>>[CH3:24][C:16]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=1[NH:14][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: Clc1nccc(-c2cccnc2)n1
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1

Procedure:
Thus, Imatinib is obtained by a synthetic route comprising reacting 2-chloro-4-(3-pyridyl)-pyrimidine with 2-amino-4-nitro-toluene to obtain N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine, which is subsequently reduced and reacted with 4-(4-methyl-piperazine-1-ylmethyl)-benzoyl chloride to yield the final product.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2].[CH3:23][O:24][CH2:25][CH2:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:30]3[CH:29]=[N:28][N:27]([CH2:26][CH2:25][O:24][CH3:23])[CH:31]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCCn1cc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cn1
Reaction time: 8 h

Procedure:
1-Methylethyl [(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for preparation see Intermediate 1) (185 mg), 1-[2-(methyloxy)ethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (for a preparation see Journal of Heterocyclic Chemistry, 41(6), 931-939; 2004) (151 mg), potassium carbonate (90 mg) and tetrakis(triphenylphosphine)palladium(0) (28.9 mg) were combined in ethanol and toluene under nitrogen and heated to 80° C. for 18 h. The reaction was concentrated, the residue partioned between ethyl acetate (10 ml) and water (10 ml) and the aqueous layer was extracted with ethyl acetate (10 ml). The combined organics were washed with brine (25 ml), dried with sodium sulphate, filtered and concentrated. The residue was purified by MDAP (formate ×2) and the collected product dissolved in 1,4-dioxane (0.5 ml) and cooled in a CO2 bath then left on a freeze dryer overnight. The resulting white solid was dried at 40° C. under vacuum overnight to give 1-methylethyl ((2S,4R)-1-acetyl-2-methyl-6-{1-[2-(methyloxy)ethyl]-1H-pyrazol-4-yl}-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (84.7 mg). LCMS (formate), Rt 0.84 min, MH+ 415
Reaction SMILES: [C:1]([C:4]1[CH:16]=[C:15]2[C:7]([C:8]3[CH:9]=[CH:10][C:11]([O:18][CH2:19][C@H:20]4[N:24]([CH2:25][CH2:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:23](=[O:34])[C@H:22]([CH2:35][C:36]([OH:38])=[O:37])[CH2:21]4)=[CH:12][C:13]=3[C:14]2=O)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[H][H]>C(O)(=O)C.[Pd]>[C:1]([C:4]1[CH:16]=[C:15]2[C:7]([C:8]3[CH:9]=[CH:10][C:11]([O:18][CH2:19][C@H:20]4[N:24]([CH2:25][CH2:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:23](=[O:34])[C@H:22]([CH2:35][C:36]([OH:38])=[O:37])[CH2:21]4)=[CH:12][C:13]=3[CH2:14]2)=[CH:6][CH:5]=1)(=[NH:2])[NH2:3]
Reactant: [H][H]
Reactant: N=C(N)c1ccc2c(c1)C(=O)c1cc(OC[C@@H]3C[C@@H](CC(=O)O)C(=O)N3CCCc3ccccc3)ccc1-2
Agent: [Pd]
Solvent: CC(=O)O
Product: N=C(N)c1ccc2c(c1)Cc1cc(OC[C@@H]3C[C@@H](CC(=O)O)C(=O)N3CCCc3ccccc3)ccc1-2

Procedure:
0.3 g of (3S,5S)-5-[(7-amidino-9-keto-2-fluorenyl)oxymethyl]-3-carboxymethyl-1-(3-phenylpropyl)-2-pyrrolidinone are dissolved in 7 ml of glacial acetic acid, 0.05 g of 10% palladium charcoal are added and the mixture is hydrogenated for 6 hours at 70° C. under 3 bar of hydrogen pressure. The catalyst is filtered off, the filtrate is evaporated down and the product is purified by chromatography on silica gel (eluent: tetrahydrofuran/2N acetic acid=10:1)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:20][C:21]1[C:26]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[CH:25][CH:24]=[CH:23][N:22]=1.[F:34][C:35]1[CH:36]=[C:37]([CH2:41]O)[CH:38]=[CH:39][CH:40]=1>C1COCC1>[F:34][C:35]1[CH:36]=[C:37]([CH:38]=[CH:39][CH:40]=1)[CH2:41][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:26]2[C:21]([NH2:20])=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:28][CH:29]=1
Reactant: OCc1cccc(F)c1
Reactant: Nc1ncccc1-c1ccc(O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncccc1-c1ccc(OCc2cccc(F)c2)cc1
Reaction time: 8 h

Procedure:
Diisopropylazadicarboxylate (1.19 mL) was added dropwise to a solution of triphenylphosphine (1585 mg), 4-(2-aminopyridin-3-yl)phenol (750 mg) and (3-fluorophenyl)methanol (0.434 mL) in THF (dry) (15 mL) at room temperature and the mixture was stirred overnight and concentrated in vacuo. The residue was purified by column chromatography (1st; NH-silica gel, eluted with EtOAc in hexane, 2nd; silica gel, eluted with EtOAc in hexane) to give the title compound (210 mg) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[NH:12][C:13]([NH:15][C:16]1[N:21]=[C:20]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:18][CH:17]=1)=[O:14].[BH4-].[Na+].Cl.C(Cl)Cl.CO.[CH3:36][C:37]([CH3:39])=O>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[NH:12][C:13]([NH:15][C:16]1[N:21]=[C:20]([CH:22]2[CH2:23][CH2:24][N:25]([CH:37]([CH3:39])[CH3:36])[CH2:26][CH2:27]2)[CH:19]=[CH:18][CH:17]=1)=[O:14]
Reactant: O=C(Nc1cccc(C2CCNCC2)n1)Nc1ccnc2c(F)cccc12
Reactant: CC(C)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)N1CCC(c2cccc(NC(=O)Nc3ccnc4c(F)cccc34)n2)CC1

Procedure:
To a solution of 50 mg of 1-(8-fluoro-quinolin-4-yl)-3-(1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-6-yl)-urea (example 62) (0.137 mmol) in 50 ml of acetone were added 26 mg of sodium borohydride (0.684 mmol) in small portions. The reaction was slightly exotherm. After stirring the reaction mixture over night a small amount of 2M HCl was added to the reaction mixture up to a pH of 3 to destroy the excess of sodium borohydride. After neutralization with sodium bicarbonate, acetone was evaporated under reduced pressure, water added to the residue, the reaction mixture extracted three times with DCM, the organic phases combined and dried over sodium sulfate and the solvent evaporated under reduced pressure. 45 mg of the desired product were obtained as off white powder (yield: 81%) after column chromatography (silica gel, DCM/MeOH 98/2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[C:6]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=1.[C:27](=[O:30])([O-])[O-:28].[Na+].[Na+]>COCCOC.O.C1OC2C=CC(B(O)O)=CC=2O1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:5]=[C:6]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[C:8]([C:4]2[CH:9]=[CH:8][C:7]3[O:28][CH2:27][O:30][C:6]=3[CH:5]=2)[CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OB(O)c1ccc2c(c1)OCO2
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(OCc2ccccc2)cc(-c2ccc3c(c2)OCO3)c1
Yield: 198.6 %

Procedure:
3-Benzyloxy-5-trifluoromethanesulfonyloxy-benzoic acid methyl ester (15.4 g) was dissolved in 1,2-dimethoxyethane (250 mL), followed by addition of Pd(PPh3)4 (2.5 g), solution of sodium carbonate (12 g) in water (120 mL) and 3,4-methylenedioxyphenylboronic acid (8.4 g). The resulting reaction mixture was refluxed under the flow of nitrogen for 5 h. After cooling the organic layer was separated and washed with water and then dried over magnesium sulfate. The crude material was purified on a silica gel column using ethyl acetate and hexanes to yield 14.2 g (99% yield) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[C:14](=[O:26])[NH:15][C:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:28]1[C:37]2[C:32](=[C:33]([CH3:40])[C:34]([O:38][CH3:39])=[CH:35][CH:36]=2)[N:31]=[C:30]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[N:42]=2)[CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([CH:8]1[CH2:12][CH:11]([O:13][C:28]2[C:37]3[C:32](=[C:33]([CH3:40])[C:34]([O:38][CH3:39])=[CH:35][CH:36]=3)[N:31]=[C:30]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[N:42]=3)[CH:29]=2)[CH2:10][CH:9]1[C:14](=[O:26])[NH:15][C:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(O)cc(-c3cccc(C)n3)nc2c1C
Reactant: C=CC1CC1(NC(=O)C1CC(O)CC1C(=O)OC(C)(C)C)C(=O)OCC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3cccc(C)n3)nc3c(C)c(OC)ccc23)CC1C(=O)OC(C)(C)C)C(=O)OCC
Reaction time: 8 h
Yield: 116.4 %

Procedure:
A solution of 2-(1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl)-4-hydroxycyclopentanecarboxylic acid tert-butyl ester (500 mg, 1.5 mmol), prepared as described in WO2005/073195, 4-hydroxy-2-(6-methyl-2-pyridyl)-7-methoxy-8-methylquinoline (97, 504 mg, 1.8 mmol) and triphenylphosphine (990 mg, 3.75 mmol) were stirred in dry THF (40 mL) at 0° C. for 10 min. Then, DIAD (0.74 mL, 3.75 mmol) was added drop wise. The resulting reaction mixture was stirred at a temperature from 0° C. to 22° C. overnight. Then, volatiles were evaporated and the residue was purified by column chromatography on silica gel (gradient CH2Cl2/AcOEt, 1:0 to 95:5) to give 1.1 g (88%) of the title compound 98: m/z=630 (M+H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15].[OH-].[Na+]>>[C:1]([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[F:8])(=[O:3])[CH3:2]
Reactant: Oc1ccccc1F
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Oc1ccccc1F
Reaction time: 0.5 h
Yield: 103 %

Procedure:
Acetic anhydride (81 cm3, 856 mmol) was added dropwise to a stirred mixture of 2-fluorophenol (60.0 g, 535 mmol) and aqueous sodium hydroxide (4 N, 214 cm3, 856 mmol) at 0° C. After the reaction had been stirred for 30 min the aqueous layer was separated from the organic portion and washed with dichloromethane (150 cm3). The combined organic extracts were washed with aqueous sodium hydroxide solution (4 N, 150 cm3) and then brine (100 cm3). The organic phase was dried (Na2SO4) and the solvent was evaporated in vacuo to afford the title compound (84.9 g, >100%).
Reaction SMILES: [N:1]1([C:6]2[CH:18]=[CH:17][C:9]([O:10][CH:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.CO.[CH3:21][O:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH:33]=O)=[CH:25][CH:24]=1>C(Cl)Cl>[N:1]1([C:6]2[CH:18]=[CH:17][C:9]([O:10][CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([CH2:33][C:26]4[C:27]5[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)[CH2:12]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(C=O)c2ccccc12
Reactant: c1cn(-c2ccc(OC3CCCNC3)cc2)cn1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CN2CCCC(Oc3ccc(-n4ccnc4)cc3)C2)c2ccccc12
Reaction time: 8 h
Yield: 10.4 %

Procedure:
To a mixture of 3-[4-(imidazol-1-yl)phenoxy]piperidine (308 mg, 1.26 mmol), methanol (6.0 mL) was added 4-methoxy-1-naphthaldehyde (1.25 eq, 298 mg), followed by borane pyridine complex (0.196 mL, 1.25 eq.). The resulting mixture was stirred overnight. The methanol was evaporated, and the residue diluted with ethyl acetate, washed with water and brine. Evaporation of the solvent in vacuo gave a crude product. Flash column chromatography on silical gel with 1–2% methanol in methylene chloride afforded 3-[4-(imidazol-1-yl)phenoxy]-1-[(4-methoxynaphth-1-yl)methyl]piperidine (54 mg), 1H NMR(CDCl3) 8.30 (m, 2), 7.70 (s, 1), 7.50 (m, 2), 7.30 (s, 1), 7.20 (m, 4), 6.90 (m, 2), 6.70 (d, 2), 4.30 (m, 1), 4.00 (s, 3), 3.90 (AB q , 2), 3.10 (m, 1), 2.80 (m, 1), 2.10–2.30 (m, 3), 1.80 (m, 1), 1.40–1.70 (m, 2) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)=[O:4].[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[CH2:17]I>[Ag]=O.O1CCOCC1>[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[CH2:17][C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=2)[NH:10][CH:9]=1
Reactant: Clc1ccc(CI)c(Cl)c1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: O=[Ag]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2[nH]cc(Cc3ccc(Cl)cc3Cl)c2c1
Yield: 16.4 %

Procedure:
Silver oxide (28.09 g) is added to a dioxane (200 ml) solution of 5-methoxycarbonylindole (17.52 g) and 2,4-dichlorobenzyl iodide (34.49 g), and stirred under reflux for 6.5 hours. The insoluble is removed through filtration, and the filtrate is concentrated under reduced pressure. The resulting oily residue is purified through silica gel column chromatography (eluent: hexane/ethyl acetate=4/1), and recrystallized from hexane/ethyl acetate to obtain 3-(2,4-dichlorobenzyl)-5-methoxycarbonylindole (46) (5.49 g).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O.ClCCl>[C:22]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(OCc1ccccc1)c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1ccc2c(ccn2C(=O)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 117.8 %

Procedure:
Sodium hydride (58 mg) was added to a solution of benzyl 1H-indole-5-carboxylate (300 mg) in N,N-dimethylformamide (2 ml) with ice cooling, and then stirred for 30 minutes. Benzoyl chloride (202 mg) was added thereto, and the mixture was stirred for 2 hours. The reaction mixture was diluted with dichloromethane, and the organic phase was washed with 2 N hydrochloric acid, a saturated sodium bicarbonate solution and a saturated saline solution. The organic phase was dried over sodium sulfate anhydrous. The product was concentrated under reduced pressure to give benzyl 1-benzoyl-1H-indole-5-carboxylate (500 mg, Y.:quant.) as pale orange crystals.
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C[N:28](C)[CH:29]=[O:30].[NH4+].[Cl-]>C1COCC1>[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH:26]=[CH:25][N:24]=[C:23]2[C:29]([NH2:28])=[O:30])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(CCCCn2ccnc2)cc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: NC(=O)c1nccn1CCCCc1ccccc1
Temperature: -78 °C

Procedure:
Reaction under N2 atmosphere. A mixture of DIPA (0.455 mol) in THF (500 ml) was stirred at −78° C. Butyllithium, 2.5M/hexane (0.390 mol) was added dropwise at −40° C. The mixture was stirred for 15 min, then re-cooled to −78° C. A solution of 1-(4-phenylbutyl)-1H-imidazole, prepared according to the procedure described in J. Chem. Soc., Perkin Trans., 1 (1975), 17, 1670-1671, (0.325 mol) in THF (350 ml) was added dropwise at −60° C. The mixture was stirred for one hour, then re-cooled to −78° C. This mixture was added dropwise to a mixture of N,N-dimethylformamide (0.390 mol, dry, p.a.) in THF (500 ml), stirred at −78° C. The reaction mixture was stirred for one hour at −78° C., then allowed to warm to room temperature while stirring overnight. A saturated aqueous NH4Cl solution (400 ml) was added and this mixture was extracted with THF. The separated organic layer was dried, filtered and the solvent evaporated, yielding 74.2 g of 1-(4-phenylbutyl)-1H-imidazole-2-carboxamide (interm. 18).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][C:20]1[CH:21]=[C:22]([NH:30][C:31]2[N:40]=[CH:39][C:38]3[N:37]([CH3:41])[C:36](=[O:42])[CH2:35][N:34]([CH:43]([CH3:45])[CH3:44])[C:33]=3[N:32]=2)[CH:23]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:25]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10](=[O:12])[NH:19][C:20]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:27])=[O:28])[CH:23]=[C:22]([NH:30][C:31]2[N:40]=[CH:39][C:38]3[N:37]([CH3:41])[C:36](=[O:42])[CH2:35][N:34]([CH:43]([CH3:45])[CH3:44])[C:33]=3[N:32]=2)[CH:21]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CCCCC1
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(N)cc(S(C)(=O)=O)c3)nc21
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(NC(=O)[C@H](NC(=O)OC(C)(C)C)C4CCCCC4)cc(S(C)(=O)=O)c3)nc21
Yield: 17.5 %

Procedure:
Starting from (R)-tert-butoxycarbonylamino-cyclohexyl-acetic acid (31.6 mg; 0.123 mmol) and 2-(3-amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (40 mg; 0.102), 11.3 mg (0.018 mmol; 17.5% yield) of the desired compound were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[C:23]([F:26])([F:25])[F:24]>CC(N(C)C)=O.O>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:10][C:17]1[CH:18]=[CH:13][C:14]([C:23]([F:26])([F:24])[F:25])=[CH:15][C:16]=1[C:19]([F:20])([F:21])[F:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1ccc(Br)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NCCO
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)NCCOc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 18 h

Procedure:
(2-Hydroxy-ethyl)-carbamic acid tert-butyl ester (0.2 mL, 1.29 mmol) is dissolved in 3 mL dry dimethyl-acetamide. 2-Potassium-1,1,1,3,3,3-hexamethyl-disilazane (0.52 g, 2.6 mmol, 2 equiv.) is added, followed by 1-bromo-2,4-bis-trifluoromethyl-benzene 31 (0.26 mL, 1.5 mmol, 1.2 equiv.). The mixture is stirred at 60° C. under nitrogen for 18 hours. The mixture is cooled, diluted with 50 mL water and extracted with dichloromethane (3×50 mL). The combined organic extracts are washed with water and 10% aqueous citric acid, dried over Na2SO4 and concentration. Silica gel chromatography (5% to 25% ethyl acetate in hexanes) yielded [2-(2,4-Bis-trifluoromethyl-phenoxy)-ethyl]-carbamic acid tert-butyl ester 32 as a colorless, mobile oil: 1H-NMR (400 MHz, CDCl3) δ=7.61 (s, 1H), 7.00 (d, J=8 Hz, 1H), 6.76 (d, J=8 Hz, 1H), 5.10 (s, 1H), 4.26 (t, J=4 Hz, 2H), 3.65 (m, 2H), 1.45 (s, 9H). 19F-NMR (376 MHz, CDCl3) δ=−61.5, −62.0. No molecular ion could be obtained; a loss of tert-butyl group is observed: MS calculated for C11H10F6NO3 (M+H+—C4H8) 318.1, found 318.3.