Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]1)[CH:13]=[CH:12]3)(=[O:3])[CH3:2].[CH2:25]([Si](C)(C)C)[CH:26]=[CH2:27]>ClCCl.CCOCC.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]1)[CH2:13][C@H:12]3[CH2:27][CH:26]=[CH2:25])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C=CC[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C=CC[C@@H]1CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]12
Reaction time: 0.08 h

Procedure:
To a solution of 17β-acetoxy-4,6-androstadien-3-one 1 (2.0 g, 6.1 mmol) in dry dichloromethane (130 ml) was added titanium tetrachloride (5.36 g, 3.1 ml, 28 mmol) at -70° C. The reaction mixture was allowed to stir for 5 min. Then, a solution of allyltrimethylsilane (4.0 g, 5.6 ml, 35 mmol) in dry dichloromethane (10 ml) was added over a period of 10 min and the resulting solution stirred during 1 hour at -70° C. followed by 1 hour at -20° C. Afterwards, the solution was diluted with 150 ml of ether and was washed with water (6×100 ml), dried, filtrated and concentrated to yield the crude 17β-acetoxy-7α-allyl-4-androsten-3-one which was immediately hydrolyzed.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][C:11](=[N:16][OH:17])[CH2:10][C:9]2([CH3:19])[CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:16]([CH:11]1[CH2:12][C:13]([CH3:14])([CH3:15])[N:8]([O:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:9]([CH3:19])([CH3:18])[CH2:10]1)[OH:17])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)CC(=NO)CC(C)(C)N1OC1CCCCC1
Product: CC1(C)CC(N(O)Cc2ccccc2)CC(C)(C)N1OC1CCCCC1
Yield: 50 %

Procedure:
Following the procedure of Example 1, the title compound is prepared from 1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-one oxime (3.7 g, 13 mmol) and benzyl bromide (2.4 g, 14 mmol) in a 50% yield to give 2.3 g of product as white crystals melting at 133° C. after recrystalization from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[C:11]([C:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH:18]=2)[N:10]=[N:9]1.[C:26](C1CCN(C(OC(C)(C)C)=O)CC=1)#CC>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH3:26])=[C:11]([C:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH:18]=2)[N:10]=[N:9]1
Reactant: CC#CC1=CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cn(-c3ccccc3Cl)nn2)CC1
Product: Cc1c(C2=CCN(C(=O)OC(C)(C)C)CC2)nnn1-c1ccccc1Cl

Procedure:
The same operation as in Example 7 was carried out using the azide compound prepared in Example 1 and tert-butyl 4-(1-propynyl)-1,2,3,6-tetrahydropyridine-1-carboxylate prepared in 3) of Example 7 to give the title compound as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.O[N:22]1[CH:26]=[CH:25][CH:24]=[N:23]1>>[N:22]1([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:8][CH:9]=2)[CH:26]=[CH:25][CH:24]=[N:23]1
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Reactant: On1cccn1
Product: CN(C(=O)Oc1ccc(CCOn2cccn2)cc1)c1ccccc1
Yield: 62 %

Procedure:
The title compound was prepared in 62% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 1-hydroxypyrazole.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9](Cl)=[O:10])[CH:4]=1.[NH3:12]>>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH2:12])=[O:10])[CH:4]=1
Reactant: N
Reactant: O=C(Cl)c1cc(Cl)ccn1
Agent: Cl
Product: NC(=O)c1cc(Cl)ccn1

Procedure:
Entry 12: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 using DISC in place of DMF to give 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 3-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[O:11][C:12]3[N:13]=[C:14]([S:20][CH3:21])[N:15]=[C:16]([OH:19])[C:17]=3[N:18]=2)=[CH:5][C:4]=1[CH3:22].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH3:32].O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([CH3:22])=[CH:5][C:6]([C:10]2[O:11][C:12]3[N:13]=[C:14]([S:20][CH3:21])[N:15]=[C:16]([O:19][CH2:30][CH2:31][CH3:32])[C:17]=3[N:18]=2)=[CH:7][C:8]=1[CH3:9]
Reactant: CCCBr
Reactant: COc1c(C)cc(-c2nc3c(O)nc(SC)nc3o2)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1nc(SC)nc2oc(-c3cc(C)c(OC)c(C)c3)nc12
Temperature: 60 °C
Reaction time: 5 h
Yield: 37.4 %

Procedure:
5.9 g of 2-(4-methoxy-3,5-dimethylphenyl)-5-methylsulfanyloxazolo[5,4-d]pyrimidin-7-ol were dissolved in 150 ml of N,N-dimethylformamide, and 7.7 g of potassium carbonate and then 2.7 g of 1-bromopropane were added. The solution was stirred at 60° C. for 5 h and then, after cooling, poured into 150 ml of water. The precipitate was filtered off with suction. The regioisomer mixture obtained was purified by silica gel chromatography (50 g silicon dioxide solute cartridge, heptane/ethyl acetate 9/1). In addition to 1.4 g of 2-(4-methoxy-3,5-dimethylphenyl)-5-methylsulfanyl-6-propyl-6H-oxazolo[5,4-d]pyrimidin-7-one (LC/MS (Method LC1): Rt=1.43 min; m/z=360.13 [M+H]+), 2.5 g of the title compound were obtained.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[CH:32]=[C:14]4[C:15]5[C:20]([CH2:21][CH2:22][N:13]4[C:12](=[O:33])[CH2:11][N:10]=3)=[C:19](B3OC(C)(C)C(C)(C)O3)[CH:18]=[CH:17][CH:16]=5)[CH:8]=2)[CH2:3][CH2:2]1.Br[C:35]1[CH:40]=[N:39][C:38]([F:41])=[CH:37][N:36]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[CH:32]=[C:14]4[C:15]5[C:20]([CH2:21][CH2:22][N:13]4[C:12](=[O:33])[CH2:11][N:10]=3)=[C:19]([C:35]3[CH:40]=[N:39][C:38]([F:41])=[CH:37][N:36]=3)[CH:18]=[CH:17][CH:16]=5)[CH:8]=2)[CH2:2][CH2:3]1
Reactant: Fc1cnc(Br)cn1
Reactant: CC1(C)OB(c2cccc3c2CCN2C(=O)CN=C(n4cnc(C5CC5)c4)C=C32)OC1(C)C
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: [Na+]
Solvent: COCCOC
Product: O=C1CN=C(n2cnc(C3CC3)c2)C=C2c3cccc(-c4cnc(F)cn4)c3CCN12
Temperature: 90 °C
Reaction time: 0.03 h
Yield: 61.1 %

Procedure:
Example 137. A suspension of 2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (100 mg, 0.225 mmol), 2-bromo-5-fluoropyrazine (90 mg, 0.51 mmol) and Pd(PPh3)4 (39 mg, 0.034 mmol) in DME (2.8 mL) was treated with a 2M aq. solution of Na2CO3 (0.6 mL, 1.12 mmol). The mixture was heated to 90° C. for 2 h, allowed to cool to RT and poured onto H2O. The mixture was extracted with DCM and the combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent: 25% EtOAc in heptane for 2 min, then from 25% EtOAc in heptane to 100% EtOAc in heptane in 10 min, 100% EtOAc in heptane for 5 min) to yield a solid which was crystallized from diethyl ether and afforded the title compound (57 mg). UPLC-MS: MS 415.2 (M-FH+); UPLC rt 0.92 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.59-0.69 (m, 2 H), 0.72-0.82 (m, 2 H), 1.75-1.86 (m, 1 H), 2.97 (t, J=5.62 Hz, 2 H), 3.70 (t, J=6.11 Hz, 2 H), 4.24 (br. s., 2 H), 7.15 (s, 1 H), 7.43 (s, 1 H), 7.54 (t, J=7.82 Hz, 1 H), 7.69 (d, J=7.58 Hz, 1 H), 8.01-8.16 (m, 2 H), 8.58 (s, 1 H), 8.83 (d, J=8.31 Hz, 1 H).
Reaction SMILES: [OH-].[Na+].[CH2:3](Br)[CH2:4][CH2:5][CH3:6].[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@:16]([OH:25])([CH2:23][SH:24])[CH2:17][N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.[ClH:26]>CO.C(OCC)C>[CH2:3]([S:24][CH2:23][C@:16]([C:10]1[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=1[Cl:8])([OH:25])[CH2:17][N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1)[CH2:4][CH2:5][CH3:6].[ClH:26]
Reactant: O[C@@](CS)(Cn1ccnc1)c1ccc(Cl)cc1Cl
Reactant: CCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: CCCCSC[C@](O)(Cn1ccnc1)c1ccc(Cl)cc1Cl
Reaction time: 5 h

Procedure:
To a solution of sodium hydroxide (2 g) in methanol (100 ml) were added n-butylbromide (2 g) and (R)-2-(2,4-dichlorophenyl)-1-(imidazol-1-yl)-3-mercapto-2-propanol (II) obtained in Example 2 at a temperature of 20°-25° C. in nitrogen atmosphere. The mixture was stirred at 25°-30° C. for 5 hours and then concentrated under reduced pressure. The residue was treated with water (50 ml) and extracted with dichloromethane (50 ml). The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to give an oil. The oil was dissolved in diethyl ether (20 ml), and hydrogen chloride gas was introduced thereto. Precipitated crystals were collected by filtration and dried to give (R)-3-(n-butylthio)-2-(2,4-dichlorophenyl)-1-(imidazol-1-yl)-2-propanol (I: n=3) hydrochloride (3.4 g). Yield, 86.8%. M.P., 168°-169° C. [α]D20 -89.7° (c=1, methanol). The optical purity of the product was not less than 99% determined by high performance liquid chromatography.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)C.Cl.[OH:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[OH:33])[CH2:27][CH2:28][NH2:29].C(O)CCC.Cl>O>[ClH:13].[CH2:17]([O:16][C:14]([N:6]([CH2:5][CH:4]1[C:30]2[C:26](=[CH:25][C:24]([OH:23])=[C:32]([OH:33])[CH:31]=2)[CH2:27][CH2:28][NH:29]1)[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)=[O:15])[CH3:18]
Reactant: CCOC(=O)N(CC(OCC)OCC)c1ccc(Cl)cc1
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: CCOC(=O)N(CC1NCCc2cc(O)c(O)cc21)c1ccc(Cl)cc1

Procedure:
N-ethoxycarbonyl-p-chloroanilinoacetaldehyde diethyl acetal (3.0 g) and 3,4-dihydroxyphenethylamine hydrochloride (1.5 g) were added to a mixture of n-butyl alcohol (30 ml), water (5 ml) and 10% hydrochloric acid (0.5 ml), and then the mixture was refluxed for 4 hours in a stream of nitrogen. Above mentioned acetal (0.8 g) was further added to the mixture and the resultant mixture was refluxed for 4 hours. The solvent was distilled off from the reaction mixture and the residue was washed with ethyl acetate and then recrystallized from water to give 1-(N-ethoxycarbonyl-p-chloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, mp 208° to 210° C. and mp 214° to 215° C. Analysis: Calcd. for C19H21N2O4Cl.HCl.3/10H2O: C 54.50, H 5.44, N 6.69, Cl 16.93. Measured: C 54.29, H 5.57, N 6.70, Cl 16.69.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)=[CH:22][CH:21]=1
Reactant: COc1ccc(S)cc1
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Product: COc1ccc(SCCCCOc2ccc3c(c2)CCC(=O)N3)cc1

Procedure:
Prepared analogous to Example 1 from 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril (m.p. 142°-147° C.) and 4-methoxy-thiophenol.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:22]([C:24]1[CH:37]=[CH:36][C:27]([CH2:28][N:29]2[C:33]([CH:34]=O)=[CH:32][N:31]=[CH:30]2)=[CH:26][CH:25]=1)#[N:23].CCOC(C)=O>ClCCCl>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:29]2[C:33]([CH2:34][NH:6][CH2:5][C:4]([O:3][CH3:2])=[O:7])=[CH:32][N:31]=[CH:30]2)=[CH:36][CH:37]=1)#[N:23]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Reactant: COC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)CNCc1cncn1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of glycine methyl ester hydrochloride (595 mg, 4.74 mmol) in 1,2-dichloroethane at 0° C. was added 4 Å powdered molecular sieves (3 g), followed by sodium triacetoxyborohydride (1.51 g, 7.1 mmol). The 1-(4-cyanobenzyl)-5-imidazolecarboxaldehyde from Step E of Example 1 (1.00 g, 4.74 mmol) was added, and the reaction was stirred overnight, allowing it to warm to room temperature. The reaction was poured into EtOAc, washed with sat. aq. NaHCO3, and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting product was taken up in CH2Cl2, and propylamine (20 vol %) was added. The reaction was stirred for one hour, then concentrated in vacuo, and purified by silica gel chromatography (95:5; CHCl3:MeOH) to provide the titled amine product.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5](O)=[CH:4][CH:3]=1.[C:11](=O)([O-])[O-:12].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[C:3]([O:12][CH3:11])=[CH:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1ccc(C=O)cc1Br

Procedure:
5-Bromosalicylaldehyde (25 g, 124 mmol) was dissolved in acetone (300 ml) and anhydrous potassium carbonate (17.2 g, 124 mmol) was added. The mixture was heated and dimethyl sulfate (15.7 g, 124 mmol) was dropwise added over 45 min with gentle reflux. After the dropwise addition, the mixture was refluxed for 1 hr and cooled. Acetone was evaporated under reduced pressure. Toluene and water were added to the residue and the toluene layer was separated. The aqueous layer was extracted with toluene. The combined organic layer was washed with water and dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to give the objective compound (27.3 g, quantitative) as colorless crystals.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[O:12])=[N:9][CH:10]=1)[CH3:3].[CH3:13][Mg]Br.Cl>O1CCCC1>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([OH:12])[CH3:13])=[N:9][CH:10]=1)[CH3:1]
Reactant: C[Mg]Br
Reactant: CC(C)Oc1ccc(C=O)nc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C(C)O)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.7 %

Procedure:
5-(1-Methylethoxy)picolinaldehyde (24 mg, 0.145 mmol) was dissolved in tetrahydrofuran (1.5 mL). The resultant mixture was added with methylmagnesium bromide (230 μL, 0.218 mmol) under ice-cold conditions, stirred at 0° C. for 30 minutes, and further stirred at room temperature for 30 minutes. The reaction solution was added with 1N aqueous solution of hydrochloric acid, an aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and 1-[5-(1-methylethoxy)pyridin-2-yl]ethanol (27 mg, yield 98%) was obtained as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH2:13])[CH2:10]2)=[CH:5][CH:4]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:13][C:14](=[O:16])[CH3:15])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)CC(N)CC2
Reactant: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)CC(NC(C)=O)CC2
Yield: 51 %

Procedure:
Using a procedure similar to that described in Example 1, 0.40 g of 7-methoxy-2-amino-tetralin yielded 0.21 g (51%) of 7-methoxy-2-acetamido-tetralin following treatment with acetic anhydride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:21])=[C:4]([NH:12][C:13](=O)[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[N:17]1[CH:16]=[CH:15][C:14]([C:13]2[O:21][C:3]3[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:5][C:4]=3[N:12]=2)=[CH:19][CH:18]=1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(Cl)c1O)c1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc(Cl)c2oc(-c3ccncc3)nc2c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 0.42 g of N-[3-chloro-5-(trifluoromethyl)-2-hydroxyphenyl]isonicotinamide, 5 ml of tetrahydrofuran and 0.38 g of triphenylphosphine, 0.64 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. The reaction mixture was stirred while heating at room temperature for one hour and then at 50° C. for 2.5 hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2-(pyridin-4-yl)-7-chloro-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 64”).
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[NH:12]CC(O)COC1C=CC=C2C=1CC=C2>C(O)C>[NH2:12][CH:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1
Reactant: OC(CNC1CCc2ccccc2C1)COc1cccc2c1CC=C2
Agent: Cl
Solvent: CCO
Product: NC1CCc2ccccc2C1

Procedure:
Following the procedure of Example 27, but starting from 7-(2,3-epoxypropoxy)indene (18.8 g), obtained from 7-hydroxyindene and epichlorohydrin by the method described in DE 1,955,229, and 2-aminotetralin (14.85 g) in absolute ethanol (120 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-inden-7-yloxypropanamine hydrochloride is obtained ((i): R=H, Ar=radical 43, and the chain is attached to position 2 of the tetralin moiety).
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][NH:5][CH2:4][CH:3]1[OH:7].[OH-].[Na+].[C:11](Cl)(=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl.O>[OH:7][CH:3]1[CH2:4][N:5]([C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:20])[CH2:6][C:2]1([CH3:8])[CH3:1]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1(C)CNCC1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)CN(C(=O)OCc2ccccc2)CC1O
Reaction time: 18 h
Yield: 72.9 %

Procedure:
A solution of 4,4-dimethylpyrrolidin-3-ol (2.58 g, 22.4 mmol) in dichloromethane (90 mL), was added 1N sodium hydroxide (90 mL, 90 mmol), then benzyl carbonochloridate (4.16 mL, 24.6 mmol) at rt. The mixture was vigorously stirred for 18 h. The reaction was diluted with dichloromethane and water. The organic phase was separated, dried and concentrated. The crude was purified by silica gel chromatography, eluting with 20-50% ethyl acetate in hexanes to afford benzyl 4-hydroxy-3,3-dimethylpyrrolidine-1-carboxylate (4.07 g, 73% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.52-7.28 (m, 5H), 5.14 (s, 2H), 3.97-3.80 (m, 1H), 3.74 (td, J=11.3, 5.2 Hz, 1H), 3.49 (d, J=5.5 Hz, 1H), 3.43-3.18 (m, 2H), 1.74 (br. s., 1H), 1.09 (d, J=3.3 Hz, 3H), 1.03 (d, J=4.6 Hz, 3H). MS (ES+) m/z: 250.1 (M+H); LC retention time: 2.84 min (analytical HPLC Method I).
Reaction SMILES: [Br:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].[CH3:10]O>>[CH3:10][O:8][C:7]([C:6]1[CH:5]=[CH:4][O:3][C:2]=1[Br:1])=[O:9]
Reactant: O=C(O)c1ccoc1Br
Reactant: CO
Product: COC(=O)c1ccoc1Br
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Bromofuran-3-carboxylic acid (5.0 g, 26 mmol, 1 eq.) was dissolved in MeOH (100 mL) and the mixture was degassed and purged with nitrogen (2×). SO2Cl2 (15 mL, 0.2 mol, 7.7 eq.) was added dropwise and the resulting mixture was stirred for two days at room temperature. The mixture was then concentrated and DCM (150 mL) was added. Saturated NaHCO3 (20 mL) was added, and the resulting mixture was stirred at room temperature for 15 minutes. The organic layer was washed with saturated NaHCO3 (20 mL), water (20 mL), and saturated aqueous NaCl (20 mL), then dried over Na2SO4, filtered and concentrated to yield 2-bromofuran-3-carboxylic acid methyl ester (5.0 g) as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:19]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33]1>>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:35]2[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=2)=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCS(=O)(=O)c1cccc(C#Cc2cc(Br)ccc2OCC(=O)OC(C)(C)C)c1
Reactant: Cn1cc(B(O)O)cn1
Product: CCCS(=O)(=O)c1cccc(C#Cc2cc(-c3cnn(C)c3)ccc2OCC(=O)OC(C)(C)C)c1
Yield: 79 %

Procedure:
Following the general method as outlined in Intermediate 192, starting from tert-butyl(4-bromo-2-{[3-(propylsulfonyl)phenyl]ethynyl}phenoxy)acetate (Intermediate 191) and 1-methyl-1H-pyrazole-4-boronic acid, pinacol ester, the title compound was obtained as a yellow sticky solid in 79% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[CH:17]=[C:16]([CH:18]=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[C:9]1=[O:21])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH:28]1([NH:31][C:32](=[O:50])[C:33]2[CH:38]=[C:37](B3OC(C)(C)C(C)(C)O3)[C:36]([CH3:48])=[C:35]([F:49])[CH:34]=2)[CH2:30][CH2:29]1>CN(C=O)C.O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[CH:17]=[C:16]([CH:18]=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:37]3[CH:38]=[C:33]([C:32](=[O:50])[NH:31][CH:28]4[CH2:29][CH2:30]4)[CH:34]=[C:35]([F:49])[C:36]=3[CH3:48])[CH:14]=2)[C:9]1=[O:21])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCn1cc(C=O)c2cc(Br)ccc2c1=O
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCCn1cc(C=O)c2cc(-c3cc(C(=O)NC4CC4)cc(F)c3C)ccc2c1=O

Procedure:
3-(6-Bromo-4-formyl-1-oxoisoquinolin-2(1H)-yl)propyl acetate (Example 10c, 0.90 g), potassium carbonate (1.06 g), N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.82 g) and Pd-118 (0.050 g) in DMF (10 ml) were heated under nitrogen at 70° C. for 12 h. The cooled reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified (SiO2 chromatography, elution with ethyl acetate) to afford the subtitle compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:12](O)[CH3:13]>OS(O)(=O)=O>[OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)Cc1cccc(O)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cccc(O)c1

Procedure:
A solution of 55 g of 3-hydroxyphenylacetic acid in 400 ml of 100° ethanol is refluxed overnight in the presence of a few drops of concentrated H2SO4. It is evaporated to dryness and the residue is taken up in ethyl ether and washed with water and then with a saturated aqueous solution of NaHCO3. After drying over MgSO4 followed by evaporation, 58 g of an oil are obtained.