Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH2:14][C:15]#[C:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1C2N(CC#C)C3C(=CC=CC=3)C=2C=CC=1.BrC#CCCCCO.C(O)CCCC#C.Br[O-].[Na+].[CH3:58][N:59]=[C:60]=[O:61]>>[CH3:58][NH:59][C:60]([O:23][CH2:22][CH3:21])=[O:61].[CH:10]1[C:11]2[N:12]([CH2:14][C:15]#[C:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CN=C=O
Agent: C#CCCCCO
Agent: C#CCn1c2ccccc2c2ccccc21
Agent: OCCCCC#CBr
Product: CCOC(=O)NC

Procedure:
For example, 9-(N-carbazolyl)-5,7-nonadiyn-1-ol (5) is synthesized in about 80% yield by cross coupling of 3-(N-carbazolyl)-1-propyne (3) with 6-bromo-5-hexyn-1-ol (6), which, in turn, is synthesized from 5-hexyn-1-ol with sodium hypobromite. Reaction of (5) with methylisocyanate (7) gives 9-(N-carbazolyl)-5,7-nonadiyn-1-ol methylurethane (8) in almost quantitative yield. ##STR12##
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][N:11]=[C:5]2[N:4]2[C@H:19]3[CH2:24][CH2:23][CH2:22][C@H:20]3[N:21]=[C:3]12.I[CH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10][N:11]([CH2:26][CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:5]=2[N:4]2[C@H:19]3[CH2:24][CH2:23][CH2:22][C@H:20]3[N:21]=[C:3]12
Reactant: CN1C(=O)c2c(n[nH]c2Nc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Reactant: ICC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1C(=O)c2c(Nc3ccccc3)nn(CC3CCOCC3)c2N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 140 °C

Procedure:
A mixture of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (50 mg, 0.155 mmol), 4-(iodomethyl)-tetrahydro-2H-pyran (70 mg, 0.310 mmol), and Cs2CO3 (101 mg, 0.310 mmol) in DMF (1 mL) is heated in microwave at 140° C. for 30 min. After cooling, the mixture is filtered through a 0.45 μm microfilter, and the filtrate is purified by a semi-preparative HPLC to give pure product as white powder. MS (ESI) m/z 421.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:33][C:34]1[CH:35]=[C:36]([N:40]=[C:41]=[O:42])[CH:37]=[CH:38][CH:39]=1>ClCCl>[Cl:33][C:34]1[CH:35]=[C:36]([NH:40][C:41]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:42])[CH:37]=[CH:38][CH:39]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(Cl)c1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (20 mg, 0.19 mmol) (Aldrich), followed by the addition of 3-chloro-phenyl isocyanate (24 mg, 0.16 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (3-chloro-phenyl)-amide as a white solid. (Yield 32 mg, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][NH:11][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.B(O[O-])=[O:16].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][NH:11][CH:12]([CH3:14])[CH3:13])=[O:16])=[CH:6][CH:7]=1
Reactant: CC(C)NCCSc1ccc(Cl)cc1
Reactant: O=BO[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)NCCS(=O)c1ccc(Cl)cc1
Yield: 90.6 %

Procedure:
A solution of 15.05 g (0.066 mole) of N-[2-[(4-chlorophenyl)thio]ethyl]-1-methylethanamine and 12.0 g (0.0779 mole) of sodium perborate in 400 ml of 1M sulfuric acid was stirred at room temperature for about 18 hr. The solution was made basic with 50% sodium hydroxide and the basic solution was extracted with methylene chloride. The methylene chloride layer was dried with magnesium sulfate and the solvent removed in vacuo to give 14.7 g of solid. Nuclear magnetic resonance analysis showed a 9 to 1 ratio of sulfoxide to sulfide. The solid was recrystallized from ether-hexane to give 12.3 g (76.4%) of the free base title compound as crystalline solid, m.p. 52.5°-53.5° C.
Reaction SMILES: BrC1C=CC(O)=C(C=1)C(C1C=CC(C)=CC=1)=O.[Br:18][C:19]1[CH:20]=[CH:21][C:22]([O:34]C)=[C:23]([CH:33]=1)[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)=[O:25]>>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([OH:34])=[C:23]([CH:33]=1)[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)=[O:25]
Reactant: COc1ccc(Br)cc1C(=O)c1cccc(C)c1
Agent: Cc1ccc(C(=O)c2cc(Br)ccc2O)cc1
Product: Cc1cccc(C(=O)c2cc(Br)ccc2O)c1

Procedure:
Employing the same general procedure as for the preparation 5-bromo-2-hydroxy-4′-methylbenzophenone (Compound K), 533 mg (1.7 mmol) of 5-bromo-2-methoxy-3′-methylbenzophenone (Compound J) was converted into the title compound using 2.6 mL (2.6 mmol) of boron tribromide (1M in dichloromethane) and 15 mL of dichloromethane. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) gave the title compound as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)([CH3:23])[CH3:22]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([CH:21]([CH3:22])[CH3:23])=[CH:25][CH:26]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: CC(C)c1ccc(C(=O)O)cc1
Agent: Cl
Product: CC(C)c1ccc(C(=O)NCC(=O)NC(c2ccccc2)c2ccc(Cl)cc2)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-isopropylbenzoic acid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:50])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[C:39]([CH2:41][O:42]C3CCCCO3)[N:38]=[C:37]([CH3:49])[CH:36]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:42][CH2:41][C:39]1[CH:40]=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:50])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:22])([F:21])[F:23])[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[CH:36]=[C:37]([CH3:49])[N:38]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cc(COC2CCCCO2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(CO)n1

Procedure:
The title compound was prepared from (RS)-[2-(3-{3-[2-methyl-6-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-3-oxo-propionylamino)-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M300) (0.49 g, 0.67 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (230 mg, 65%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=O)[CH2:8]2.Cl>O1CCCC1>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[C:2]1[CH:3]3[CH2:9][CH:7]4[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]4)[CH2:4]3)[CH2:8]2
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: Cl
Solvent: C1CCOC1
Product: C1C2CC3CC1CC(C2)C3=C1C2CC3CC(C2)CC1C3
Yield: 85.7 %

Procedure:
A slurry of titanium trichloride (3.10 gm, 20.0 mmol) in 40 ml dry tetrahydrofuran was prepared under a nitrogen atmosphere, and powdered lighium aluminum hydride (380 mg, 10.0 mmol) was cautiously added. The resulting solution was stirred for one hour at room temperature to form the Ti(II) reagent, and a solution of adamantanone (1.50 gm, 10.0 mmol) in 10 ml dry Tetrahydrofuran was added. The reaction was refluxed for twelve hours, then poured into 50 ml 2 N aqueous hydrochloric acid. The solution was extracted several times with ether, and the ether extracts were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated by solvent removal at the rotary evaporator. The resulting residue was further pruified by chromatography over silica gel. Elution with haxane gave 1.15 gm (85% yield) adamantylideneadamantane, identified by its spectral properties (infra-red, mass spectrum, and nuclear magnetic resonance), and by its melting point: mp 185°-186°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(-c2cccc(F)c2)nc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-c2cccc(F)c2)nc1
Reaction time: 4 h

Procedure:
To a round-bottom flask was added 2-(3-fluorophenyl)-5-nitropyridine (3.8 g, 17 mmol), Pd/C (0.5 g) and methanol (100 mL). The reaction was stirred for 4 hours under hydrogen atmosphere by attaching a hydrogen balloon. The reaction was flushed with nitrogen and the solid was removed by filtration. The solvent was removed by rotary evaporation to give 6-(3-fluorophenyl)pyridin-3-amine 219-1 as brown solid. MS m/z 189.1 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:21])=[C:9]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)[N:10]=1.O1CCCC1.CO.[BH4-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:21])=[C:9]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=2)[N:10]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccco2)nc1COc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a mixture of 4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]benzaldehyde (37.8 g), tetrahydrofuran (140 ml) and methanol (60 mL) was added sodium borohydride (2.53 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into iced water, and the precipitated solid was collected by filtration, and dried with air to give crystals (34.6 g, 91%) of [4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]phenyl]methanol. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 91-92° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34]([NH:37][C@@H](C3C=CC=CC=3)CO)(=[O:36])=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].S(=O)(=O)(O)O.C(Cl)(Cl)Cl>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1c(-c2c(S(=O)(=O)N[C@H](CO)c3ccccc3)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1c(-c2c(S(N)(=O)=O)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 61.2 %

Procedure:
To (S)-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrazole-4-sulfonamide (prepared in Example 212) (813 mg) was added in water bath (at 20° C.) concentrated sulfuric acid (30 ml) and the resulting mixture was stirred for fifteen minutes. The mixture was cooled to 0° C. and to the reaction solution was then added water (60 ml) dropwise followed by an addition of chloroform (50 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (50 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford the same product as Example 209, (+)-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide (406 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][C:12]([CH3:14])=[C:11]([CH:15]=[O:16])[CH:10]=1.[CH:17]1([Mg]Br)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.O1CCCC1>>[CH:17]1([CH:15]([C:11]2[CH:10]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[O:13][C:12]=2[CH3:14])[OH:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Br[Mg]C1CCCCC1
Reactant: Cc1oc(-c2ccc(F)cc2F)cc1C=O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(F)cc2F)cc1C(O)C1CCCCC1
Yield: 76 %

Procedure:
An operation similar to that in Example 3 (2) was performed using 5-(2,4-difluorophenyl)-2-methyl-3-furaldehyde (2.4 g) and 1N cyclohexylmagnesium bromide-tetrahydrofuran solution (16.5 mL) to give the title compound (2.6 g, 76%) as a white crystal.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:3]=1[C:17]([OH:19])=O.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:42]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[OH:54])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[OH:54][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[N:42]1[CH2:47][CH2:46][N:45]([C:17]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[O:19])[CH2:44][CH2:43]1
Reactant: Oc1ccccc1N1CCNCC1
Reactant: Cc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Cc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)N1CCN(c2ccccc2O)CC1
Yield: 58.7 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-methyl-3-(3-(trifluoromethyl)phenyl)isoxazol-4-carboxylic acid (500 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 2-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (466 mg, 1.08 mmol, 59%) was obtained.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]([F:27])([F:26])[C:7]([N:9]1[CH2:16][CH2:15][C@:14]2([CH3:20])[C:17]([CH3:19])([CH3:18])[C@H:10]1[CH2:11][C:12]1[C:24]([OH:25])=[CH:23][CH:22]=[CH:21][C:13]=12)=[O:8]>C(O)(=O)C>[F:27][C:6]([F:5])([F:26])[C:7]([N:9]1[CH2:16][CH2:15][C@:14]2([CH3:20])[C:17]([CH3:19])([CH3:18])[C@H:10]1[CH2:11][C:12]1[C:24]([OH:25])=[C:23]([N+:1]([O-:4])=[O:2])[CH:22]=[CH:21][C:13]=12)=[O:8]
Reactant: CC1(C)[C@H]2Cc3c(O)cccc3[C@]1(C)CCN2C(=O)C(F)(F)F
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC1(C)[C@H]2Cc3c(ccc([N+](=O)[O-])c3O)[C@]1(C)CCN2C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Nitric acid (0.4 mL) is slowly added to a solution of 2,2,2-trifluoro-1-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone (2.9 g) in acetic acid (5 mL) chilled in an ice bath. The ice bath is removed and the solution is stirred at ambient temperature overnight. The solution is poured into ice-cold water and the resulting mixture is extracted with ethyl acetate. The combined extracts are washed with brine and dried (Na2SO4). After removal of the solvent under reduced pressure, the residue is purified by chromatography on silica gel (ethyl acetate/cyclohexane 1:9->1:3).
Reaction SMILES: F[C@H:2]([C@H:4]1[O:12][C@H:11]2[C@H:7]([N:8]=[C:9]([N:13]([CH3:15])[CH3:14])[S:10]2)[C@@H:6]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C@@H:5]1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH3:3].C(O)(C(F)(F)F)=[O:37]>ClCCl>[CH3:14][N:13]([CH3:15])[C:9]1[S:10][C@H:11]2[O:12][C@H:4]([C:2](=[O:37])[CH3:3])[C@@H:5]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C@H:6]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C@H:7]2[N:8]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(CO[C@H]2[C@H](OCc3ccc(OC)cc3)[C@H]3N=C(N(C)C)S[C@H]3O[C@@H]2[C@H](C)F)cc1
Solvent: ClCCl
Product: COc1ccc(CO[C@@H]2[C@H]3N=C(N(C)C)S[C@H]3O[C@H](C(C)=O)[C@H]2OCc2ccc(OC)cc2)cc1
Reaction time: 0.17 h
Yield: 24 %

Procedure:
A solution of (3aR,5S,6S,7R,7aR)-5-((S)-1-fluoroethyl)-6,7-bis(4-methoxybenzyloxy)-N,N-dimethyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-amine (240 mg, 0.48 mmol) in dichloromethane (20 mL) was treated with TFA (2 mL) for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by Prep-HPLC under the following conditions [(Agilent 1200 prep HPLC): Column, SunFire Prep C18, 19*50 mm 5 um; mobile phase, water with 0.03% NH4OH and CH3CN (10% CH3CN up to 45% in 10 min); Detector, UV 220 nm] to afford compound 51 (Example 9) as a white solid (30 mg, 24%). (ES, m/z): [M+H]+ 265.0; 1H NMR (300 MHz, D2O) δ 6.23-6.25 (d, J=6.0 Hz, 1H), 4.93-4.99 (m, 0.5H), 4.77-4.84 (m, 0.5H), 4.17 (t, J=6.0 Hz, 1H), 4.00 (t, J=6.0 Hz, 1H), 3.71-3.74 (m, 1H), 3.36-3.49 (m, 1H), 2.94 (s, 1H), 1.25-1.35 (dd, J=6.6 Hz, 6.3 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:26][NH:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1)=[O:29].ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:33]4[CH:34]=[CH:35][C:30]([C:28]([NH:27][CH3:26])=[O:29])=[N:31][CH:32]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)CC3)cn1
Temperature: 25 °C

Procedure:
A mixture of 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (15 mg, 0.037 mmol, Example 1), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (15 mg, 0.056 mmol, Frontier, Cat. No. M10074), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (1.8 mg, 0.0022 mmol, Aldrich Cat. No. 379670), and potassium phosphate (24 mg, 0.11 mmol) in 1,4-dioxane (1 mL) and water (0.2 mL) was heated at 120° C. for 2 hours. The reaction mixture was cooled to r.t., and then concentrated. The residue was dissolved in MeOH, and purified by RP-HPLC (pH=10) to afford the desired compound. LCMS (M+H)±: m/z=459.4.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[C:18]([O:21][CH2:22][C:23](Cl)=[O:24])(=[O:20])[CH3:19].O>C(Cl)(Cl)Cl>[C:18]([O:21][CH2:22][C:23]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5])=[O:24])(=[O:20])[CH3:19]
Reactant: CC(=O)OCC(=O)Cl
Reactant: N#Cc1c(N)cccc1Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)OCC(=O)Nc1cccc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-chlorobenzonitrile (4.6 g) in chloroform (100 ml) is added triethylamine (4.8 ml), and thereto is added dropwise acetoxyacetyl chloride (3.8 ml). The mixture is stirred at room temperature for 1 hour, and thereafter, water is added thereto, and the mixture is extracted with chloroform. The organic layer is washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting crude crystals are recrystallized from ethanol-water to give the title compound (3.8 g) having the following physical properties.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:18]1([C:24]2[CH:59]=[CH:58][C:27]([C:28]([O:30][C@@H:31]3[CH2:39][C@@H:34]4[O:35][C:36](=[O:38])[CH2:37][C@@H:33]4[C@H:32]3/[CH:40]=[CH:41]/[C@@H:42]([O:51]C3CCCCO3)[CH2:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:29])=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[OH:51][C@@H:42]([CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)/[CH:41]=[CH:40]/[C@@H:32]1[C@@H:33]2[C@@H:34]([O:35][C:36](=[O:38])[CH2:37]2)[CH2:39][C@H:31]1[O:30][C:28](=[O:29])[C:27]1[CH:58]=[CH:59][C:24]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:25][CH:26]=1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: O=C1C[C@@H]2[C@@H](/C=C/[C@@H](O)CCc3ccccc3)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Temperature: 45 °C
Reaction time: 3.5 h
Yield: 81 %

Procedure:
Pyridinium p-toluenesulfonate (50 mg) was added to a stirred solution of the compound [7a] (1.00 g) in methanol (50 mL) at room temperature. The mixture was stirred at 40-50° C. for 3-4 hours (TLC monitoring) and evaporated under reduced pressure. The residue was diluted with dichloromethane (75 mL). The solution was washed with saturated aqueous solution of sodium bicarbonate (25 mL) and brine(25 mL), dried over sodium sulfate, filtered and evaporated to give 0.69 g (81.0%) of oily residue. The residue was crystallized from a mixture of ethyl acetate and isopropyl ether to give compound [5a] as white crystals with mp 126-128° C. 1H NMR (CDCl3) is in agreement with the structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH3:10])[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)ccc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: Cc1cc(Br)ccc1C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of (4-bromo-2-methylphenyl)methanol (1.8 g, 8.1 mmol) in CH2Cl2 (20 mL) was added Dess-Martin Periodinane (5.1 g, 12.1 mmol) at 0° C. The mixture was stirred at RT for 1 h, then diluted with water, and the solid was removed by filtration. The filtrate was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by normal phase silica gel column provided 4-bromo-2-methylbenzaldehyde as a yellow oil.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[CH2:24][O:23][CH:22]3[C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=2)[O:7][C@@H:6]1[CH2:36][O:37]C(=O)C)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[CH2:34]([C:31]1[CH:32]=[CH:33][C:28]([CH:22]2[C:21]3[C:25](=[CH:26][CH:27]=[C:19]([C@H:8]4[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:36][OH:37])[O:7]4)[CH:20]=3)[CH2:24][O:23]2)=[CH:29][CH:30]=1)[CH3:35]
Reactant: CCc1ccc(C2OCc3ccc([C@@H]4O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)cc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCc1ccc(C2OCc3ccc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)cc32)cc1
Reaction time: 1.5 h
Yield: 55.2 %

Procedure:
To a suspension of 151 (380 mg, 0.68 mmol) in CH3OH (5.0 mL) was added K2CO3 (65 mg, 0.47 mmol) at room temperature. After 1.5 h, the resulting mixture was filtered, and then purified by preparative HPLC (reverse phase) to provide the title compound (145 mg, 55%) as an off-white solid.