Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][CH:3]([C:6]([CH3:20])([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[CH3:19])=[CH:10][CH:9]=1)Cl)[C:4]#[N:5].N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C>>[C:27]([O:2][C:3](=[C:6]([CH3:20])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[CH3:19])=[CH:10][CH:9]=1)[C:4]#[N:5])(=[O:29])[CH3:28]
Reactant: Cc1ccsc1-c1ccc(C(C)(Cl)C(O)C#N)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)OC(C#N)=C(C)c1ccc(-c2sccc2C)cc1
Yield: 92 %

Procedure:
A 30-ml portion of the toluene solution containing 3.7 g (0.0145 mole) of 3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]glycidonitrile obtained in (1) was saturated with dried hydrogen chloride and stirred for a further one hour so that 2-hydroxy-3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]-3-chloropropionitrile may be formed. To the reaction mixture, which had been freed from the remaining hydrogen chloride by introducing dried nitrogen, was added 1.43 g (0.0181 mole) of pyridine and 1.70 g (0.0167 mole) of acetic anhydride, followed by adding 2.1 g (0.0207 mole) of triethylamine. After refluxing for 15 hours, the reaction mixture was washed with diluted hydrochloric acid, dried over anhydrous sodium sulfate, and freed from the solvent by distillation under reduced pressure to obtain 4.2 g (92% yield) of oily 2-acetoxy-3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]acrylonitrile.
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].Cl[C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1.CN(C=O)C>O>[CH2:1]([S:3][C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)c1ncccc1Cl
Reactant: CC[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cccnc1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
0.91 g of sodium ethanethiolate was added to a mixture of 1.29 g of 3-chloro-N-(4-trifluoromethylphenyl)picolinamide and 3 mL of DMF, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture cooled to room temperature was poured to water, and the precipitated solid was taken by filtration. The resulting solid was dissolved in ethyl acetate, and the mixture was extracted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 1.37 g of 3-ethylsulfanyl-N-(4-trifluoromethylphenyl)picolinamide (hereinafter, referred to as Compound of Present Invention 9).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][N:14]([C:18](OC4C=CC([N+]([O-])=O)=CC=4)=[O:19])[CH2:15]3)=[CH:10][CH:9]=2)[CH:5]=[C:4]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)[N:3]=1.[C:37]1([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[CH3:36][N:33]1[CH2:34][CH2:35][N:30]([C:4]2[CH:5]=[C:6]([C:8]3[CH:17]=[C:12]4[C:11]([CH2:16][CH2:15][N:14]([C:18]([N:46]5[CH2:47][CH2:48][CH:43]([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=6)[CH2:44][CH2:45]5)=[O:19])[CH2:13]4)=[CH:10][CH:9]=3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:31][CH2:32]1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC4)nc(N)n2)CC1
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)N3CCC(c5ccccc5)CC3)CC4)nc(N)n2)CC1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
4-Nitrophenyl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (10 mg, 0.02 mmol) was added to a mixture of 4-phenylpiperidine (4.9 mg, 0.031 mmol) (Aldrich, Cat. #639869) and N,N-diisopropylethylamine (11 uL, 0.061 mmol) in N-methylpyrrolidinone (0.5 mL). The reaction mixture was stirred at 110° C. for 5 h. The mixture was purified by RP-LCMS (pH=10) to afford the desired product. Analytic LCMS (M+H)+: m/z=512.3.
Reaction SMILES: [CH3:1][CH:2]([CH2:17][CH3:18])[CH2:3][O:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([O:14][CH3:15])[NH:11]2)=[C:7]([NH2:16])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CN(C=O)C.CCOC(C)=O>[CH3:1][CH:2]([CH2:17][CH3:18])[CH2:3][O:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([O:14][CH3:15])[N:11]2[CH2:26][CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[C:7]([NH2:16])[N:6]=1
Reactant: BrCC1CCOCC1
Reactant: CCC(C)COc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(C)COc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 35.6 %

Procedure:
To a solution of 2-[(2-methylbutyl)oxy]-8-methoxy-9H-purin-6-amine (109 mg) in dry DMF (1.86 mL) was added potassium carbonate (165 mg) and the mixture was stirred at 60° C. for 90 mins. The mixture was cooled to room temperature and 4-(bromomethyl)tetrahydro-2H-pyran (59 mg) was added. The reaction was stirred at 50° C. overnight and was cooled to room temperature. The mixture was taken up in EtOAc (15 mL) and washed with water (2×10 mL). The organics were separated, dried over MgSO4, filtered and concentrated in vacuo to give a yellow viscous oil. The material was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluent (20-60%) to afford the title compound as a yellow oil (41 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[S:12][CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.C([Li])CCC.[C:25](=[O:27])=[O:26]>C1COCC1>[CH3:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:25]([OH:27])=[O:26])=[CH:10][CH:9]=2)[C:5]([S:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:6]1
Reactant: CN1CCC(Sc2cn(C)c3ccc(Br)cc23)CC1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(Sc2cn(C)c3ccc(C(=O)O)cc23)CC1
Reaction time: 1 h

Procedure:
A solution of 5-bromo-1-methyl-3-[(1-methylpiperidin-4-yl)thio]-1H-indole (19 g, prepared in Example 58) in THF (100 ml) is treated at -78° C. with a solution of butyllithium (31.5 ml, 2.5M in hexane). After 1 hour at this temperature, carbon dioxide is passed into the solution until it is saturated. After one hour, the reaction mixture is left to return to room temperature. The solvent is evaporated off and the residue is taken up with ether to give 1-methyl-3-[(1-methylpiperidin-4-yl)thio]-1H-indole-5-carboxylic acid (22.8 g) in the form of a yellow solid, which is used for the next step without purification.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C@@H:15]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[NH:28][CH:29]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:34][CH:33]=3)[N:31]=2)=[CH:23][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:14][C@@H:15]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[NH:28][CH:29]=[C:30]([C:32]4[CH:33]=[CH:34][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:36][CH:37]=4)[N:31]=3)=[CH:25][CH:26]=2)[C:16]([O:18][CH3:19])=[O:17])=[O:11])=[CH:12][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: CCCCCCCOc1ccc(-c2c[nH]c(-c3ccc(C[C@H](N)C(=O)OC)cc3)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCOc1ccc(-c2c[nH]c(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)OC)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.1 %

Procedure:
To a solution of 4-(tert-butyl)benzoic acid (25 mg, 0.14 mmol), (S)-methyl 2-amino-3-(4-(4-(4-(heptyloxy)phenyl)-1H-imidazol-2-yl)phenyl)propanoate (55 mg, 0.13 mmol), and TEA (53 μl, 0.38 mmol) in DMF (1 mL) was added HATU (53 mg, 0.14 mmol). The reaction mixture was stirred at RT for 2 h, diluted in DCM, and washed aq. NaHCO3. The organic layer was dried, concentrated and purified by chromatography (EA/hexane) to provide 14 mg (17%) of methyl (S)-2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)-1H-imidazol-2-yl)phenyl)propanoate. LCMS-ESI (m/z) calculated for C37H45N3O4: 595.8. found 596.4 [M+H]+, tR=2.33 min. (Method 8).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:4][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][N:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH2:30])[CH2:25]2)=[N:4][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][N:7]=1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2cnc(Cl)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cnc(Cl)c(N3CCC[C@H](N)C3)n2)n1
Yield: 49.9 %

Procedure:
A solution of tert-butyl N-[(3S)-1-[3-chloro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-3-piperidyl]carbamate (30 mg, 0.057 mmol) in dichloromethane 4.0 ml and trifluoroacetic acid (0.80 ml, 10 mmol) was stirred at RT 3 h. The reaction was concentrated and diluted with water then extracted with EtOAc. The aqueous layer was basified with 1M NaOH to pH 10 then extracted with EtOAc. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuum. The crude product was submitted for reverse phase HPLC to give 226 (12 mg, 49% yield). MS (ESI) m/z: 422.1.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][C:9]1([CH3:23])[CH:14]=[C:13]([CH3:15])[CH2:12][C:11]([CH3:17])([CH3:16])[CH:10]1[C:18](=C)[CH2:19]CO.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:5]([O:4][CH2:1][CH2:2][C:18](=[CH2:19])[CH:10]1[C:11]([CH3:17])([CH3:16])[CH2:12][C:13]([CH3:15])=[CH:14][C:9]1([CH3:23])[CH3:8])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(CCO)C1C(C)(C)C=C(C)CC1(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(CCOC(C)=O)C1C(C)(C)C=C(C)CC1(C)C

Procedure:
A solution of acetic anhydride (0.23 mL) in dichloromethane (2 mL) was reacted with a mixture of 2,2,4,6,6-pentamethyl-γ-methylene-3-cyclohexene-1-propanol (0.56g, 0.0025 mol), triethylamine (0.41 mL), 4-dimethylaminopyridine (0.031g) and dichloromethane at 25° C. Work-up, chromatography and distillation gave 0.60g of 2,2,4,6,6-pentamethyl-γ-methylene-3-cyclohexene-1-propanol acetate bp (kugelrohr bath 110°-120° C.), 0.5 mm (GLC purity: 88%). 1H-NMR (60 MHz, CDCl3) δ0.93 (6H, s), 1.00 and 1.03 (6H, 2s), 1.60 (3H, s), 2.00 (3H, s), 0.9-2.6 (5H, m), 4.20 (lH, t, J =7 Hz), 4.86-5.07 (3H, m); IR (film) vmax 2960, 1735, 1635, 1440, 1370, 1350 cm-1 ; MS (m/e) 264, 249, 221, 204, 189, 108, 96.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[CH:20]=[CH:21]/[C:22](O)=[O:23])[CH:17]=[N:18][CH:19]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:22](=[O:23])/[CH:21]=[CH:20]/[C:16]1[CH:17]=[N:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=1)[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: COc1cncc(/C=C/C(=O)O)c1
Agent: Cl
Product: COc1cncc(/C=C/C(=O)N[C@H]2CN3CCC2CC3)c1

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(5-methoxy-3-pyridyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 288 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[O:15]=[CH:16][C:17]1[CH:25]=[CH:24][C:21]([O:22][CH3:23])=[C:19]([OH:20])[CH:18]=1>>[CH3:23][O:22][C:21]1[CH:24]=[CH:25][C:17]([CH:16]=[O:15])=[CH:18][C:19]=1[O:20][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8]
Reactant: COc1ccc(C=O)cc1O
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Product: COc1ccc(C=O)cc1OCc1nc(-c2ccccc2)oc1C

Procedure:
In substantially the same manner as in Reference Example 3, 4-chloromethyl-5-methyl-2-phenyloxazole was allowed to react with isovanilline to yield 4-methoxy-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde, which was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.121-122° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:12]=[C:11]([NH2:13])[NH:10][N:9]=1)=[O:7])[CH3:4].[CH2:14](I)[CH2:15][CH2:16][CH3:17]>C(#N)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:14][CH2:15][CH2:16][CH3:17])[N:10]=[C:11]([NH2:13])[CH:12]=1)=[O:7])[CH3:4]
Reactant: CCCCI
Reactant: CCOC(=O)c1cc(N)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCCCn1nc(N)cc1C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
Sodium hydride (920 mg, 21 mmol) was added to a solution of 5-aminopyrazol-3-carboxylic acid ethyl ester (3.10 g, 20 mmol) in acetonitrile (100 mL) under a nitrogen atmosphere, and the obtained mixture was then stirred at room temperature for 30 minutes. The reaction solution was cooled on ice, and butyl iodide (2.3 mL, 20 mmol) was then added thereto. The obtained mixture was stirred at room temperature for 1 hour, and then at 60° C. for 1 hour. The reaction solution was left at room temperature overnight. Thereafter, the solvent was distilled away, and water was then added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated saline, and it was dried over sodium sulfate and was then concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain the title compound (1.60 g, yield: 38%) in the form of a pale yellow oily substance.
Reaction SMILES: [K].[OH:2][C:3]1[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].Cl[CH2:19][O:20][CH2:21]Cl.Cl>O1CCCC1>[CH3:19][O:20][CH2:21][O:2][C:3]1[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: ClCOCCl
Reactant: CCCc1c(OC)ccc(C(=O)OC)c1O
Agent: Cl
Agent: [K]
Solvent: C1CCOC1
Product: CCCc1c(OC)ccc(C(=O)OC)c1OCOC
Reaction time: 0.33 h

Procedure:
In argon atmosphere, a solution of potassium t-buthoxide (18.7 g) in tetrahydrofuran (200 ml) was cooled to 0° C., and to this solution was added dropwise a solution of methyl 2-hydroxy-3-n-propyl-4-methoxybenzoate (28 g) in tetrahydrofuran (100 ml) in 10 minutes, and the mixture was agitated for another 20 minutes. Chloromethyl ether (19.0 ml) was added thereto, and the mixture was agitated at 0° C. for 50 minutes. The reaction mixture was poured into 1N aqueous hydrochloric acid, and extracted twice with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, and then concentrated in evacuated atomosphere. The residue was subjected to column chromatography using silica gel, and there was obtained methyl 2-methoxymethoxy-3-n-propyl-4-methoxybenzoate (29.9 g) from fractions eluted with n-hexane-ethyl acetate (10:1 to 5:1).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([Br:12])[CH:5]=1)(=O)[CH3:2].[CH3:13][C:14]([S@@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>C1COCC1.CCOC(C)=O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:12][C:6]1[CH:5]=[C:4](/[C:1](=[N:19]/[S:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])/[CH3:2])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: CC(=O)c1ccc(C#N)c(Br)c1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C/C(=N\S(=O)C(C)(C)C)c1ccc(C#N)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-acetyl-2-bromobenzonitrile (4.0 g, 18 mmol) and (S)-2-methylpropane-2-sulfinamide (2.4 g, 20 mmol) in THF (35 mL) was added titanium(IV) isopropoxide (8.1 mL, 36 mmol) and the reaction mixture was heated to 40 C under an atmosphere of nitrogen. After 2 hours, the reaction was cooled to room temperature, diluted in EtOAc, washed with saturated sodium bicarbonate, rochelle's salt, brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography gave desired product. MS (M+H)+: observed=327.0/329.0, calculated=327.2/327.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[C:20]3[C:11](=[C:12]4[C:17](=[CH:18][CH:19]=3)[NH:16][C:15]([CH3:22])([CH3:21])[CH:14]=[C:13]4[CH3:23])[CH:10]([OH:24])[O:9][C:5]=2[CH:6]=[CH:7][CH:8]=1.[CH2:25]([Si](C)(C)C)[CH:26]=[CH2:27]>C(Cl)Cl>[CH2:27]([O:24][CH:10]1[C:11]2=[C:12]3[C:17](=[CH:18][CH:19]=[C:20]2[C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=2[O:9]1)[NH:16][C:15]([CH3:21])([CH3:22])[CH:14]=[C:13]3[CH3:23])[CH:26]=[CH2:25]
Reactant: COc1cccc2c1-c1ccc3c(c1C(O)O2)C(C)=CC(C)(C)N3
Reactant: C=CC[Si](C)(C)C
Solvent: ClCCl
Product: C=CCOC1Oc2cccc(OC)c2-c2ccc3c(c21)C(C)=CC(C)(C)N3
Temperature: 0 °C
Yield: 90.9 %

Procedure:
A three-necked round bottom flask was charged with the product from Example 6 (59.0 g, 0.182 mol) followed by CH2Cl2 (1.18 L). The resulting suspension was stirred briefly before adding allyltrimethylsilane (58 ml, 0.364 mol) all at once at room temperature. The suspension was cooled to 0° C. under nitrogen and was treated with BF3OEt2 (46.3 ml, 0.364 mol) dropwise keeping the reaction temperature below 2° C. After complete addition, the mixture was stirred at 0° C. for ˜1 hour. The completion of the reaction was monitored with HPLC until the starting material was consumed. The reaction mixture was poured into saturated NaHCO3 solution and stirred for 30 minutes. The organic layer was separated, washed with brine, dried over Na2SO4, treated with charcoal, filtered and concentrated to an oil. EtOH (200 ml) was added and the solution was concentrated to give a crystalline solid which was suspended with heptane at 0° C. for 2 hours before filtration to give a solid which was dried under reduced pressure at 45° C. to provide the title compound as a light yellow crystalline solid (60.1 g, 95.1%). Anal. Calcd for C23H25NO2: C, 79.51; H, 7.25; N, 4.03; Found: C, 79.26; H, 7.12; N, 3.80, 1H NMR [(CD3)2SO] δ1.16 (3H, s) 1.17 (3H, s), 2.18 (3H, s), 2.22 (1H, m), 2.46 (1H, m), 3.85 (3H, s), 5.01 (2H, m), 5.44 (1H, br s), 5.77 (1H, dd), 5.82 (1H, m), 6.10 (1H, br s), 6.52 (1H, d), 6.60 (1H, d), 6.70 (1H, d), 7.06 (1H, t,), 7.96 (1H, d); 13C NMR [(CD3)2SO] δ23.8, 28.8, 28.9, 36.5, 49.7, 55.6, 73.4, 105.6, 110.5, 113.4, 113.4, 116.1, 116.4, 127.3, 117.3, 127.3, 127.7, 132.2, 133.8, 134.5, 145.8, 151.1, 156.4. MS (APCI) m/z: 348 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:24][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Solvent: CS(C)=O
Product: CCn1ncc2c(NCc3ccccc3)c3ccccc3nc21
Temperature: 80 °C
Yield: 91.6 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (15.0 g, 0.065 mol), benzylamine (15.6 ml, 0.14 mol) and DMSO (100 ml) is heated at 80° C. overnight. The reaction mixture is poured into ice/water and the gummy solid which formed is collected by filtration. The solid is dissolved in ethyl acetate, dried over MgSO4, filtered and concentrated. The residual oil is crystallized from ethyl acetate to afford 18 g (92%) of 1-ethyl-N-(phenyl methyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 130°-132° C.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:40]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:41])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)C4CCCCC4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.62 g, 4.08 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.60 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, cyclohexanecarbonyl chloride (0.33 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2C2 solution was washed with 1N HCL (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 6:4) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}cyclohexylcarboxamide (0.53 g, 72%) as a white solid: mp 142–144° C.; 1H NMR (DMSO-d6) δ 11.13 (s, 1H), 8.36 (t, J=5.8 Hz, 1H), 7.86–7.77 (m, 2H), 7.64–7.61 (m, 1H), 5.18–5.11 (dd, J=5.3 and 12.5 Hz, 1H), 4.70 (d, J=5.8 Hz, 2H), 2.97–2.83 (m, 1H), 2.63–2.47 (m, 2H), 2.26–2.17 (m, 1H), 2.08–2.0 (m, 1H), 1.79–1.61 (m, 5H), 1.43–1.12 (m, 5H); 13C NMR (DMSO-d6) δ 175.58, 172.75, 169.82, 167.49, 166.96, 139.68, 134.75, 132.76, 131.49, 126.99, 121.73, 48.83, 43.90, 37.43, 30.92, 29.20, 25.43, 25.24, 21.96; Anal. Calcd. For C21H23N3O5: C, 63.47; H, 5.83; N, 10.57. Found: C, 63.12; H, 5.68; N, 10.41.
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:8][CH2:9][C:10](=O)[CH2:11]Cl.[OH-].[Na+]>>[C:2]([C:1]1[O:6][CH:11]=[C:10]([CH2:9][Cl:8])[N:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(N)=O
Reactant: O=C(CCl)CCl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)c1nc(CCl)co1
Temperature: 135 °C
Yield: 51.2 %

Procedure:
25 g of pivalic acid amide and 25 g of 1,3-dichloro-2-propanone were mixed and heated on an oil bath at 135° C. for 2.5 hours. After having been cooled with ice, the mixture was made alkaline with an aqueous solution of sodium hydroxide added thereto. Then, the resulting product was extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was purified through column chromatography (silica gel; ethyl acetate:n-hexane=1:8) to obtain 17.5 g of 2-tert-butyl-4-chloromethyloxazole.
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)=[O:15])[CH2:10][C@H:9]1[CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)=[O:7].O.NN>C(O)C>[NH2:17][CH2:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]2[CH:4]=[C:3]([C:2]([F:46])([F:1])[F:45])[CH:40]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:38]=2)[C@H:9]([CH2:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][CH:30]=2)[CH2:10]1)=[O:15]
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCC(=O)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Yield: 55.2 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)-4-(phthalimidomethylcarbonyl)piperazine (250 mg), hydrazine hydrate (50 mg) in ethanol (5 ml) was heated under reflux for 2 hours. The resulting precipitate was removed by filtration and the filtrate was evaporated under reduced pressure. The residue was washed with aqueous 1N sodium hydroxide solution and then purified by column chromatography on a silica gel eluting with a mixture of ethyl acetate and methanol (4:1) to afford (2R)-4-(2-aminoacetyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (110 mg).