Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:27])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[C:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:12]=1)[CH2:5]O.B(Br)(Br)[Br:29]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:27])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:12]=1)[CH2:5][Br:29]
Reactant: BrB(Br)Br
Reactant: COc1ccc(Oc2c(Cl)cc(CO)cc2Cl)cc1Cc1ccc(F)cc1
Solvent: ClCCl
Product: Oc1ccc(Oc2c(Cl)cc(CBr)cc2Cl)cc1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
To a stirred solution of 3,5-dichloro-4-[3′-(4-fluorobenzyl)-4′-methoxyphenoxy]benzyl alcohol (0.53 g, 1.29 mmol) in CH2Cl2 (20 mL) at −78° C. was added BBr3 (0.82 g, 3.2 mmol). The reaction mixture was stirred at room temperature for 16 h, poured into ice water (100 mL) and extracted with CH2Cl2 (200 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (1:4) to afford 3,5-dichloro-4-[3′-(4-fluorobenzyl)-4′-hydroxyphenoxy]benzyl bromide as a colorless oil (0.4 g, 67%): 1H NMR (300 MHz, CDCl3): δ 7.39 (s, 2 H), 7.14 (dd, J=5.4, 8.7 Hz, 2 H), 6.95 (t, J=8.7 Hz, 2 H), 6.66 (d, J=9.0 Hz, 1 H), 6.62 (d, J=2.7 Hz, 1 H), 6.53 (dd, J=3.0, 8.7 Hz, 1 H), 4.04 (s, 2 H), 3.90 (s, 2 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:4); Rf=0.8.
Reaction SMILES: O[CH:2]([C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH3:3].N1C=CC=CC=1.P(Br)(Br)[Br:20]>CCOCC>[Br:20][CH:2]([C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH3:3]
Reactant: BrP(Br)Br
Reactant: CC(O)C#Cc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(Br)C#Cc1ccc(Cl)cc1
Temperature: 0 °C
Yield: 70 %

Procedure:
The product prepared in step (d) above (0.05 mol) and dry pyridine (1 ml) are dissolved in dry ether (20 ml) and cooled to 0° C. Phosphorous tribromide (0.025 mol) in 20 ml dry ether is added dropwise with stirring. The reaction mixture is then refluxed for 3 hours. After cooling the mixture to 0°, the excess PBr3 is destroyed by adding crushed ice. The ether layer is washed and dried. The ether is removed and the title product is obtained by distillation.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25]C(=O)C)[CH:18]=2)[CH2:10][CH2:9][CH:8]([C:11]([F:14])([F:13])[F:12])[CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[K+].[K+].CC(=O)OCC.Cl>CO>[CH3:1][O:2][C:3]([C:5]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([OH:25])[CH:18]=2)[CH2:6][CH2:7][CH:8]([C:11]([F:14])([F:13])[F:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(OC(C)=O)c2)CCC(C(F)(F)F)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(O)c2)CCC(C(F)(F)F)CC1
Reaction time: 2 h
Yield: 63.5 %

Procedure:
105 mg of 1-(3-Acetoxy-4-methoxy-benzoylamino)-4-trifluoromethyl-cyclohexanecarboxylic acid methyl ester and 7.0 mg of K2CO3 were stirred in 4 ml of anhydrous methanol for 1 h at room temperature. Then, 10.4 mg of K2CO3 were added and stirring was continued for 2 h at room temperature. 10 ml of EA and 10 ml of a 1N aqueous HCl-solution were then added. The layers were separated and the aqueous layer was extracted twice using 10 ml of EA each. The combined organic layers were washed twice using 10 ml of a saturated aqueous NaHCO3-solution, once using 10 ml of a 1N aqueous HCl-solution, and once using a 10 ml of a saturated aqueous NaCl-solution. The organic layer was then dried using MgSO4 and evaporated to yield 60 mg of the title compound that was used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)=[N:2]1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:24])[CH2:22][CH3:23])=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>[Cu]I.OC1C=CC=C2C=1N=CC=C2.CN(C=O)C.O>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=3)=[N:2]2)=[CH:16][CH:17]=1)(=[O:24])[CH2:22][CH3:23]
Reactant: CCC(=O)c1ccc(Br)cc1
Reactant: N#Cc1ccc(-c2cc[nH]n2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)c1ccc(-n2ccc(-c3ccc(C#N)cc3)n2)cc1
Yield: 86 %

Procedure:
4-(1H-Pyrazol-3-yl)-benzonitrile (100 mg, 0.591 mmol), 1-(4-bromophenyl)-propan-1-one (126 mg, 0.591 mmol), Cs2CO3 (770 mg, 2.364 mmol), CuI (4 mg, 0.018 mmol), 8-hydroxyquinoline (3 mg, 0.018 mmol), and DMF/H2O (2 mL; 10:1 solution) were combined in a 10 mL CEM Microwave reaction vessel fitted with magnetic stir bar and subjected to microwave irradiation at 150° C. for 30 min. The contents were then filtered and concentrated to dryness affording the nitrile (158 mg, 0.508 mmol, 86%). Reduction of the nitrile to the corresponding aldehyde was accomplished following the DIBAL procedure described earlier.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:63]([NH2:67])[CH:64]([CH3:66])[CH3:65]>C(Cl)Cl>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:67][CH2:63][CH:64]([CH3:66])[CH3:65])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CC(C)CN
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NCC(C)C)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (40 mg, 0.074 mmol) in methylene chloride (2 mL) were added HBTU (30 mg, 0.079 mmol) and isobutylamine (0.038 mL, 0.37 mmol). The mixture was stirred at rt overnight. Solvent was removed by rotovap. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (19 mg, 43%). LC-MS m/z 577 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:16]2[NH:27][C:19]3=[N:20][CH:21]=[C:22]([C:24]([OH:26])=O)[CH:23]=[C:18]3[CH:17]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH:28]([NH2:31])([CH3:30])[CH3:29].CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C=O.C(OCC)(=O)C>[CH:28]([NH:31][C:24]([C:22]1[CH:23]=[C:18]2[CH:17]=[C:16]([CH:11]([C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=3)[CH2:12][CH:13]([CH3:14])[CH3:15])[NH:27][C:19]2=[N:20][CH:21]=1)=[O:26])([CH3:30])[CH3:29]
Reactant: CC(C)N
Reactant: CC(C)CC(c1ccc(S(C)(=O)=O)cc1)c1cc2cc(C(=O)O)cnc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CC(c1ccc(S(C)(=O)=O)cc1)c1cc2cc(C(=O)NC(C)C)cnc2[nH]1
Temperature: 25 °C
Reaction time: 14 h
Yield: 20.2 %

Procedure:
To a solution of 2-[1-(4-methanesulfonyl-phenyl)-3-methyl-butyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid (200 mg, 0.52 mmol) and isopropylamine (54 μL, 0.62 mmol) in dichloromethane (1 mL), N,N-dimethylformamide (500 μL) and N-methylmorpholine (200 μL, 1.56 mmol) was added 1-hydroxybenzotriazole hydrate (141 mg, 1.04 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (199 mg, 1.04 mmol) in one portion. The mixture was then stirred at 25° C. for 14 h. The mixture was diluted with ethyl acetate (100 mL), washed with a 1 N aqueous sodium bicarbonate solution, 1 N aqueous hydrochloric acid solution, brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[1-(4-methanesulfonyl-phenyl)-3-methyl-butyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid isopropylamide (45 mg, 20%) as a white solid: LC/MS m/e calcd for C23H29N3O3S [M+H]+ 428.57, observed 428.2; 1H NMR (400 MHz, CDCl3) δ ppm 0.94 (d, J=6.7 Hz, 3H), 0.97 (d, J=6.7 Hz, 3H), 1.29 (d, J=6.6 Hz, 6H), 1.49 (m, 1H), 1.96 (m, 1H), 2.08 (m, 1H), 3.03 (s, 3H), 4.24-4.37 (m, 2H), 6.17 (d, J=7.9 Hz, 1H), 6.38 (s, 1H), 7.43 (d, J=8.3 Hz, 2H), 7.84 (d, J=8.3 Hz, 2H), 8.24 (d, J=2.0 Hz, 1H), 8.55 (d, J=2.0 Hz, 1H), 10.31 (br, 0.3H).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH3:11])[CH3:10])[C:5](=[O:12])[N:4]2[CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:3]=12.[CH3:18][Si](C=[N+]=[N-])(C)C>CO.CCOCC>[CH:9]([N:6]1[C:7](=[O:8])[C:2]([O:1][CH3:18])=[C:3]2[C:16](=[O:17])[NH:15][CH2:14][CH2:13][N:4]2[C:5]1=[O:12])([CH3:10])[CH3:11]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)n1c(=O)c(O)c2n(c1=O)CCNC2=O
Solvent: CO
Solvent: CCOCC
Product: COc1c2n(c(=O)n(C(C)C)c1=O)CCNC2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 9-hydroxy-7-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,6,8(7H)-trione (1.0 g, 4.2 mmol) in MeOH (30 mL) was added trimethylsilyldiazomethane (7 mL of a 2.0 M solution in ether, 14 mmol). The mixture was stirred at ambient temperature for 24 h. The solvent was removed in vacuo and the residue was triturated in MeOH and the solid was collected by filtration to give the title compound as a solid. HPLC RT=2.07 min (Method A); ES MS (M+H)=254; 1H NMR (400 MHz, DMSO-d6) δ 8.64 (2, 1H), 5.03 (septet, J=7 Hz, 1H), 3.86 (m, 2H), 3.66 (s, 3H), 3.37 (m, 2H), 1.38 (d, J=7 Hz, 6H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13](C)C)=[CH:9][CH:8]=1)=[O:6].[Br:16]N1C(=O)CCC1=O>C(Cl)Cl>[Br:16][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]([CH:4]2[CH2:3][CH2:2]2)=[O:6])=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1ccc(C(=O)CCCCl)cc1
Solvent: ClCCl
Product: O=C(c1ccc(CBr)cc1)C1CC1
Temperature: 5 °C
Reaction time: 7.5 h
Yield: 165.6 %

Procedure:
Dissolve 4-chloro-1-(4-isopropyl-phenyl)-butan-1-one (20 g, 124 mmol) and 2,2′-Azolons (2-methylpropionitrile) (0.5 g) in methylene chloride (100 mL) and cool to 5° C. Add a suspension of N-bromosuccinimide (12 g) in methylene chloride (50 mL) and irradiate with light (150 Watt lamp), maintaining the temperature at 5° C. After 2, 3 and 7 hour time periods, add additional N-bromosuccinimide (6 g, 6 g, 2.8 g) and continue stirring. After 7.5 hours, wash with water (200 mL) and with 0.4M sodium hydrogen carbonate (2×200 mL). Dry (Na2SO4), evaporate the solvent in vacuo and recrystallize (hexane) to give the title compound as a crystalline solid (26.7 g).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:26][CH3:27])[CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:13][C:12]=3[N+:23]([O-])=O)=[N:6][CH2:5]1.O.NN.C(OCC)(=O)C.CCCCCC>C(O)C.[C].[Pd]>[CH3:27][O:26][CH:3]([O:2][CH3:1])[CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:13][C:12]=3[NH2:23])=[N:6][CH2:5]1
Reactant: COCCOc1cc([N+](=O)[O-])c2[nH]c(C3=NCC(C(OC)OC)S3)cc2c1
Agent: [Pd]
Agent: NN
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCCOc1cc(N)c2[nH]c(C3=NCC(C(OC)OC)S3)cc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
2-[5-(Dimethoxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]-5-(2-methoxyethoxy)-7-nitro-1H-indole (100 mg) was suspended in ethanol, and 10% palladium-carbon (50% containing water, 50 mg) was added under nitrogen atmosphere. Hydrazine monohydrate (0.07 mL) was added to the mixture, and the mixture was stirred at 90° C. for 2 hr. Hydrazine monohydrate (0.07 mL) was added again, and the mixture was further stirred at 90° C. for 1 hr. The reaction solution was allowed to cool to room temperature, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=30:70-80:20) to give the title compound (27 mg, yield 29%) as a orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Br:9])=[CH:4][C:3]=1[CH2:10]O.[CH3:12][C:13]1[CH:18]=[C:17]([C:19]([CH3:21])=O)[CH:16]=[C:15]([CH3:22])[CH:14]=1.[OH-].[K+]>C1(C)C=CC=CC=1>[Br:9][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[Cl:8])[N:1]=[C:19]([C:17]1[CH:18]=[C:13]([CH3:12])[CH:14]=[C:15]([CH3:22])[CH:16]=1)[CH:21]=[CH:10]2
Reactant: CC(=O)c1cc(C)cc(C)c1
Reactant: Nc1cc(Cl)c(Br)cc1CO
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(-c2ccc3cc(Br)c(Cl)cc3n2)c1
Temperature: 25 °C
Yield: 43.2 %

Procedure:
(2-amino-5-bromo-4-chlorophenyl)methanol (8.2 g, 34.7 mmol), 3,5-dimethylacetophenone (8.22 g, 55.5 mmol), RuCl2(PPh3)3 (0.15 g, 0.173 mmol), and KOH (1.31 g, 23.4 mmol) was refluxed in 90 mL of toluene for 18 hours. Water was collected from the reaction using a Dean-Stark trap. The reaction mixture was allowed to cool to room temperature and filtered through a silica gel plug and eluted with DCM and purified by column chromatography, eluting with 2:1 (v/v) hexanes:DCM, to give 6-bromo-7-chloro-2-(3,5-dimethylphenyl)quinoline (5.2 g, 43.3%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:36]=1)[O:7][CH2:8][C:9]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH:21]2[OH:27])=[C:15]([N+:28]([O-])=O)[CH:14]=1.C(N(CC)CC)C.N1C=CC=CC=1.C1C=CC(O[C:57](OC2C=CC=CC=2)=[N:58][C:59]#[N:60])=CC=1>O1CCCC1.[Pt]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:36]=1)[O:7][CH2:8][C:9]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]2[N:19]([C@H:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][C@@H:21]3[OH:27])/[C:57](=[N:58]/[C:59]#[N:60])/[NH:28][C:15]=2[CH:14]=1
Reactant: CN1CCC(Nc2ccc(/C=C3/c4ccc(F)cc4OCc4c(F)cccc43)cc2[N+](=O)[O-])C(O)C1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Agent: [Pt]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CC[C@H](n2/c(=N/C#N)[nH]c3cc(/C=C4/c5ccc(F)cc5OCc5c(F)cccc54)ccc32)[C@@H](O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.6 %

Procedure:
Dissolve 4-[4-((E)-3,7-difluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-2-nitro-phenylamino]-1-methyl-piperidin-3-ol (0.012 mol, 5.97 g) in tetrahydrofuran (50 mL). Add triethylamine (0.024 mol, 2.44 g) and 10% platinum on carbon (2.9 g) and hydrogenate in a Parr shaker at 50 psi (H2) at room temperature for 4 h. Filter off the catalyst through diatomaceous earth. Add pyridine (50 mL) and diphenyl N-cyanocarbonimidate (0.012 mol, 2.88 g) to the filtrate. Stir at room temperature for 16 h and then heat at 60-70° C. for 8 h. Remove the solvent under reduced pressure, dissolve the residue in dichloromethane and wash with water and saturated sodium bicarbonate solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue on a silica gel column using 5% methanol in dichloromethane as eluent to obtain the title compound (1.7 g, 27%) as an off-white solid. LC-MS m/z 514.4 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]3[C:25](=[O:26])[C:24]4=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]4[C:22]3=[O:31])[C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br.[OH-].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[OH:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]3[C:22](=[O:31])[C:23]4=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]4[C:25]3=[O:26])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCCN1C(=O)c2ccccc2C1=O
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCCCCN1CC[C@@H]2c3cccc(O)c3CC[C@@H]21
Reaction time: 2 h
Yield: 21.3 %

Procedure:
A solution of 15.0 g (0.036 mol) of rac-N-[5-(cis-1,2,3a, 4,5,9b-hexahydro-6-methoxy-3H-benzo[e]indol-3-yl)pentyl]phthalimide in 120 ml of methylene chloride was treated dropwise with a solution of 17.3 ml (0.179 mol) of boron tribromide in 60 ml of methylene chloride, whereupon the mixture was stirred at 0° for 2 hours. A solution of 20.4 g (0.51 mol) of sodium hydroxide in 70 ml of water was added dropwise while cooling with an ice bath. The mixture was poured into water, whereupon aqueous sodium hydrogen carbonate solution was added until a pH of 8 had been reached. The mixture was extracted with methylene chloride, the extracts were dried over sodium sulphate and the solvent was distilled off in a vacuum. Chromatography over silica gel with ethyl acetate yielded 3.1 g (21%) of rac-N-[5-(cis-1,2,3a,4,5,9b-hexahydro-6-hydroxy-3H-benzo[e]indol-3-yl)pentyl]phthalimide as a brown oil. A small sample was converted with ethanolic HCl into the hydrochloride, m.p. 246°-248°.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[CH3:38][O:39]C1C=C(B(O)O)C=CC=1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:5]4[CH:6]=[CH:7][CH:2]=[C:3]([O:39][CH3:38])[CH:4]=4)[CH2:15][CH2:16]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:33])([F:34])[F:35]
Reactant: COc1cccc(B(O)O)c1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: COc1cccc(-c2c(N)ncnc2N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3C)CC2)c1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 3-methoxyphenylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=527, obsd.=527).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[C:29]([Cl:31])[CH:30]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:27]2[CH:26]=[C:25]([Cl:24])[CH:30]=[C:29]([Cl:31])[CH:28]=2)=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Reactant: Oc1cc(Cl)cc(Cl)c1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cc(Cl)cc(Cl)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3,5-dichlorophenol: 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.6 Hz), 8.16 (1H, d, J=2.8 Hz), 8.02 (2H, dd, J=6.6, 1.8 Hz), 7.84 (1H, d, J=7.3 Hz), 7.42 (2H, d, J=8.6 Hz), 7.31 (1H, t, J=1.8 Hz), 7.08 (2H, d, J=1.8 Hz), 5.41–5.31 (1H, m), 3.91 (3H, s), 1.60 (3H, d, J=6.9 Hz).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][O:19]C(=O)C)[C:13]=1[CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+]>O>[CH2:1]([O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][OH:19])[C:13]=1[CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccnc(COC(C)=O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCOc1ccnc(CO)c1C
Yield: 127.1 %

Procedure:
18.6 g (0.058 mol, 1.0 eq.) of 4-decyloxy-2-acetoxymethyl-3-methylpyridine was added dropwise to a 20% aqueous solution of sodium hydroxide (23 g) at 11 to 22° C., and the mixture was allowed to react for one hour at room temperature. Subsequently, water (93 mL) was added, and then the mixture was extracted with toluene (130 mL). The extract was washed with water, dried over anhydrous magnesium sulfate, and then concentrated to dryness, to obtain 20.6 g of 4-decyloxy-2-hydroxymethyl-3-methylpyridine as a brown oily matter.
Reaction SMILES: [Cl:1][C:2]([Cl:9])=[CH:3][CH2:4][CH2:5][C:6](O)=[O:7].S(Cl)([Cl:12])=O>>[Cl:1][C:2]([Cl:9])=[CH:3][CH2:4][CH2:5][C:6]([Cl:12])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCC=C(Cl)Cl
Product: O=C(Cl)CCC=C(Cl)Cl
Yield: 90.3 %

Procedure:
152 g of the 4,4-dichlorobut-3-ene-1-carboxylic acid is stirred with 140 g of thionyl chloride for 2 hours. The subsequent distillation yields 152.3 g of 4,4-dichlorobut-3-ene-1-carboxylic acid chloride; b.p. 62° C./15 Torr [b.p. 64°-65° C./11 Torr according to J. Ray and R. Vessiere, Bull. Soc. Chim. France, 269 (1967)].
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.S[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=2[N:12]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=3[N:12]=2)[CH2:23][CH2:22]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc2oc(S)nc2c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CN1CCN(c2nc3cc([N+](=O)[O-])ccc3o2)CC1
Temperature: 100 °C

Procedure:
Phosphorus pentachloride (1.37 g) was dissolved in anhydrous toluene (18 ml), the resulting solution was mixed with 2-mercapto-5-nitrobenzoxazole (900 mg) which has been obtained in the same manner as described in Reference Example 1, and the mixture was then stirred with heating at 100° C. for 3 hours. With cooling in an ice bath, to this was added dropwise N-methylpiperazine (6.09 ml). After 20 minutes of stirring, the thus obtained mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine in that order. After drying with magnesium sulfate, the solvent was evaporated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography (methylene chloride:methanol=10:1) to obtain 2-(4-methyl-1-piperazinyl)-5-nitrobenzoxazole (56.1 mg) in the form of yellow crystalline powder.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]3[C:11]([C:12]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.C([Li])CCC.C[O:34][B:35](OC)[O:36]C>C1COCC1>[C:16]1([C:12]2[C:11]3[C:6]([C:5]([C:4]4[CH:13]=[CH:14][CH:15]=[CH:2][CH:3]=4)=[C:22]4[C:23]=2[CH:24]=[C:25]([B:35]([OH:36])[OH:34])[CH:26]=[CH:27]4)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
In an argon atmosphere, 50 mL of dehydrated THF were added to 3.5 g (8.6 mmol) of 2-bromo-9,10-diphenylanthracene, and the temperature of the mixture was cooled to −78° C. Then, 6.0 mL of n-butyllithium (in hexane, 1.6 mol/L) were dropped. After the mixture had been stirred at −78° C. for 1 hour, the temperature of the mixture was increased to 0° C. The temperature of the mixture was cooled to −78° C. again, and 2.9 mL (26 mmol) of trimethoxyborane were dropped. The mixture was stirred at −78° C. for 1 hour, and was then stirred at room temperature for 2 hours. 50 mL of 10-mass % hydrochloric were added, and the whole was stirred for 1 hour, followed by filtration. The resultant solid was washed with toluene to obtain 2.6 g of 9,10-diphenylanthracene-2-boronic acid (80% yield).