Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[Br:12][C:13]1[C:14]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:15]2[CH:21]=[N:20][NH:19][C:16]2=[N:17][CH:18]=1.[C:28]([O:32][C:33]([NH:35][C@H:36]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1)[C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Br:12][C:13]1[C:14]([N:22]2[CH2:23][CH2:24][N:25]([C:37](=[O:38])[C@H:36]([NH:35][C:33](=[O:34])[O:32][C:28]([CH3:29])([CH3:30])[CH3:31])[CH2:40][C:41]3[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=3)[CH2:26][CH2:27]2)=[C:15]2[CH:21]=[N:20][NH:19][C:16]2=[N:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: Brc1cnc2[nH]ncc2c1N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(Br)cnc3[nH]ncc23)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
DIEA (0.0687 mL, 0.394 mmol) was added to a solution of 5-bromo-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.050 g, 0.0986 mmol, see Example 11), (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (0.0295 g, 0.099 mmol) and TBTU (0.0380 g, 0.118 mmol) in DCM (1 mL) and stirred at room temperature for 16 hours. The reaction was concentrated to dryness. The resulting residue was dissolved in THF/MeOH (2 mL, 1:1), and an aqueous LiOH solution (1 mL, 2M) was added. The solution was stirred for 30 minutes, and then ether (20 mL) was added. The organic layer was separated, washed with brine (10 mL), and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by column chromatography (hexane:ethyl acetate, 1:1) to give (R)-tert-butyl 1-(4-(5-bromo-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-(4-chlorophenyl)-1-oxopropan-2-ylcarbamate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The mixture was stirred at room temperature for 1 hour, and the reaction was concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (R)-2-amino-1-(4-(5-bromo-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-(4-chlorophenyl)propan-1-one dihydrochloride (0.015 g, 29%). MS APCI (+) m/z 463.1 detected.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:68]([SH:75])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1.C(N(C(C)C)CC)(C)C>C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].O1CCOCC1>[CH2:68]([S:75][C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1)[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1
Reactant: CN1CCC(OC(c2cccc(Br)c2)c2nc3ccccc3s2)CC1
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN1CCC(OC(c2cccc(SCc3ccccc3)c2)c2nc3ccccc3s2)CC1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
A screw-cap tube is charged with 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (208 mg), palladium bis(dibenzylideneacetone) (14 mg), Xantphos (14 mg), benzyl mercaptan (59 μL), diisopropylethylamine (174 μL) and 1,4-dioxane (2 mL). The tube is evacuated, filled with argon and sealed. After stirring at 120° C. for 15 h, the mixture is diluted with ethyl acetate and water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 100/0/0 to 95/5/0.5). The residual yellowish oil is re-crystallized from hot acetonitrile to give 2-[(3-benzylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole melting at 195° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[NH2:17])[CH3:2].C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:31](Cl)=[O:32]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[NH:17][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:28]([O:27][CH3:26])[CH:29]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(N2CCCCC2)ccc1N
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc(N2CCCCC2)ccc1NC(=O)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.5 %

Procedure:
Subsequently, crude 2-amino-5-piperidin-1-yl-benzoic acid ethyl ester (compound A) (1.3 g) was dissolved in anhydrous methylene chloride (100 ml). Triethylamine (5.6 ml) and 3,4-dimethoxy-benzoyl chloride (compound B) (1.8 g) were added at 0° C., and the mixture was stirred at room temperature for 24 hr. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a hexane-chloroform system to give 2-(3,4-dimethoxy-benzoylamino)-5-piperidin-1-yl-benzoic acid ethyl ester (960 mg, yield 52%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])/[CH:10]=[CH:11]/[C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH2:26][N:27]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:28][Si](C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:33]([N:27]1[CH2:28][C@@H:11]([C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C@H:10]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:23])[CH2:26]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCOC(=O)c1ccccc1/C=C/C(=O)OCc1ccccc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccccc1[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
To a solution of (E)-ethyl 2-(3-(benzyloxy)-3-oxoprop-1-enyl)benzoate (1.44 g, 4.64 mmol)) in 20 mL of CH2Cl2 was added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (1.78 mL, 6.96 mmol) and trifluoroacetic acid (0.072 mL, 0.93 mmol). The solution was allowed to stir at ambient temperature for 18 h. Starting material still remained by TLC analysis and so additional N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (0.5 g, 2.1 mmol) and trifluoroacetic acid (2 drops) were added and the reaction was stirred at ambient temperature for 1 h. The reaction was evaporated and purified by ISCO (elution with 0-30% EtOAc/hexane) to afford 1.97 g (95%) of the title compound as an oil. LRMS (ES)+: 444.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(N(CC)C(C)C)(C)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][NH:5][S:16]([CH3:15])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: COCCN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a stirred solution of 2-methoxyethylamine (2.67 mL, 31.0 mmol) in anhydrous methylene chloride (100 mL) and N,N-diisopropylethyl amine (8.54 mL, 51.7 mmol) at 0° C. was slowly added methanesulfonyl chloride (2.0 mL, 25.8 mmol). The reaction mixture was slowly warmed to room temperature and stirred overnight. The mixture was concentrated and the residue was purified by silica gel column chromatography (0-100% ethyl acetate in hexanes) to afford the product as a colorless oil (2.8 g, 71%). 1H NMR (300 MHz, CDCl3) δ 4.66 (br s, 1H), 3.54 (t, 2H, J=4.8 Hz), 3.39 (s, 3H), 6.37-3.29 (m, 2H), 3.00 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:13][C:14]([Cl:16])=[CH2:15].O>C(Cl)Cl>[Cl:13][C:14]([Cl:16])=[CH:15][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: C=C(Cl)Cl
Reactant: O=C(Cl)CCCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(C=C(Cl)Cl)CCCCCl
Reaction time: 1 h

Procedure:
100 g (0.62 mol) 5-Chlorovaleroyl chloride was added dropwise to 78.53 g (0.589 mmol) aluminium chloride in 150 ml methylene chloride at room temperature. After stirring for 1 hour, 45 ml (0.558 mol) 1,1-dichloroethylene in 25 ml methylene chloride was added dropwise. Under ice-cooling 100 ml water was added dropwise and solid material suction filtered on Celite. The filtrate was washed with water and the organic phase dried and concentrated. The residue was distilled in a rotary evaporator.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[F:15][C:16]([F:36])([F:35])[C:17]1[CH:34]=[CH:33][C:20]2[C:21](=O)[NH:22][C:23]3[CH2:31][CH2:30][CH:29]=[CH:28][C:24]=3[S:25](=[O:27])(=[O:26])[C:19]=2[CH:18]=1.O>N1C=CC=CC=1>[F:15][C:16]([F:36])([F:35])[C:17]1[CH:34]=[CH:33][C:20]2[C:21](=[S:2])[NH:22][C:23]3[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=3[S:25](=[O:27])(=[O:26])[C:19]=2[CH:18]=1
Reactant: O=C1NC2=C(C=CCC2)S(=O)(=O)c2cc(C(F)(F)F)ccc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: c1ccncc1
Product: O=S1(=O)c2ccccc2NC(=S)c2ccc(C(F)(F)F)cc21
Yield: 84.2 %

Procedure:
Phosphorus pentasulphide (1 g) was added to a solution of 3-trifluoromethyl-9,10-dihydrodibenzo [b,f][1,4]thiazepin-11-one-5,5dioxide (1 g, 3 mmol) in pyridine (20 ml) and heated under reflux for 6.5 hr. A further 500 mg of phosphorus pentasulphide was added and the mixture heated for a further 6 hr before being allowed to cool overnight. The mixture was added to hot water (100 ml) with stirring. Filtration of the cooled mixture and recrystallisation from ethanol gave the title compound as a yellow solid (650 mg, m.p. 275°-278° C., Rf 0.4, hexane/EtOAc 2:1).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:22])[C:14]([C:15]3[S:19][C:18](Cl)=[N:17][C:16]=3[Cl:21])=[C:10]2[N:9]=[C:8]([CH3:23])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].CC(O)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>O>[CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:22])[C:14]([C:15]3[S:19][C:18]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[N:17][C:16]=3[Cl:21])=[C:10]2[N:9]=[C:8]([CH3:23])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(Cl)nc3Cl)c(C)nn12
Solvent: CC(C)O
Solvent: O
Product: CCC(CC)c1cc(C)nc2c(-c3sc(N4CCOCC4)nc3Cl)c(C)nn12
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 94.1 %

Procedure:
7-(1-ethyl-propyl)-3-(2,4-dichloro-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (11.64 mmoles) is charged into a 100 mL 3-necked round bottomed flask followed by addition of 2-propanol (16 mL, 3.72 volumes). The yellowish brown slurry is stirred at about 20° C. for 5 min. Then morpholine (3.3 g, 37.84 mmoles) is added over 2-5 minutes. Contents are refluxed for 6 hr. The slurry is cooled to 25° C. 2-Propanol (32 mL, 7.44 volumes) and water (8.6 mL, 2.0 volumes) are added and the mixture warmed to 70-75° C., filtered and concentrated to ˜9 volumes at atmospheric pressure. The clear solution is gradually cooled to 55° C., seeded with 0.06 g of crystalline 7-(1-ethyl-propyl)-3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine slurried in 0.5 mL 2-propanol, rinsed with additional 0.5 mL 2-propanol and added to crystallization flask. The slurry is cooled to 0-5° C., maintained for 1 hr., filtered and the product rinsed with 2-propanol (9 mL, 2.1 volumes). Suctioned dried under vacuum at 60° C. to afford 4.6 g of dry 7-(1-ethyl-propyl)-3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (88.8% yield, purity by HPLC assay is 99.88%). MS (ES)=420 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[F:33][C:34]([F:44])([F:43])[C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Br)=[CH:37][CH:36]=1>O>[C:16]([O:15][C:13]([N:10]1[CH2:9][CH2:8][CH:7]([CH2:6][C:5]2[CH:20]=[CH:21][C:2]([O:1][CH2:39][C:38]3[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:43])[F:44])=[CH:42][CH:41]=3)=[CH:3][CH:4]=2)[CH2:12][CH2:11]1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
tert-Butyl 4-(4-hydroxybenzyl)piperidine-1-carboxylate (1.78 g, 6.1 mmol), potassium carbonate (1.27 g, 9.2 mmol), N,N-dimethylformamide (18 ml) and 4-(trifluoromethyl)benzylbromide (1.75 g, 7.3 mmol) were mixed and stirred at room temperature overnight. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→60:40) to afford the title compound as a colorless powder (2.64 g, 96%).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:15]=1[CH2:16][NH:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>O1CCCC1>[CH2:24]([N:21]1[CH2:22][CH2:23][CH:18]([N:17]2[CH2:16][C:15]3[C:14](=[CH:34][C:33]([F:35])=[CH:32][CH:31]=3)[NH:13][C:1]2=[O:2])[CH2:19][CH2:20]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1cc(F)ccc1CNC1CCN(Cc2ccccc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1Nc2cc(F)ccc2CN1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.3 %

Procedure:
1,1′-Carbonyldiimidazole (6.92 g, 42.7 mmol) was added to a solution of N-(2-amino-4-fluorobenzyl)-1-benzylpiperidin-4-amine (8.64 g, 30.2 mmol) in dry tetrahydrofuran (150 mL) at 0° C. in one portion. After 5 min, the mixture was allowed to warm to room temperature and stirred for 3 h. The reaction was partitioned between water/diethyl ether (200 mL/200 mL). After separation, the aqueous solution was extracted with diethyl ether (200 mL). The combined organic solution was washed with brine (100 mL), dried over magnesium sulfate, and concentrated in vacuo to afford a light yellow solid which was triturated with diethyl ether (3×10 mL) to give the title compound as a white solid (3.41 g, 36% yield). 1H-NMR (CDCl3, 400 MHz) δ 7.40-7.18 (m, 5H), 6.92-6.82 (m, 1H), 6.75 (dd, J=8.2, 2.6, 1H), 6.66 (dd, J=8.8, 4.8, 1H), 4.48-4.34 (m, 1H), 4.03 (s, 2H), 3.53 (s, 2H), 2.98 (d, J=11.2, 2H), 2.37-2.12 (m, 2H), 1.99-1.82 (m, 2H), 1.67 (d, J=11.2, 2H); Mass spec.: 340.03 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:23][CH3:24])[C:11]=1[O:12][CH2:13]/[CH:14]=[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])\[CH3:16])[C:6]([OH:8])=O.[NH2:25][CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:32][CH3:33]>>[CH2:32]([N:28]1[CH2:29][CH2:30][CH2:31][CH:27]1[CH2:26][NH:25][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:23][CH3:24])[C:11]([O:12][CH2:13]/[CH:14]=[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])\[CH3:16])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:33]
Reactant: CCN1CCCC1CN
Reactant: COc1cc(C(=O)O)cc(OC)c1OC/C=C(\C)CCC=C(C)C
Product: CCN1CCCC1CNC(=O)c1cc(OC)c(OC/C=C(\C)CCC=C(C)C)c(OC)c1
Yield: 95.9 %

Procedure:
In a manner identical to Example 15, 3,5-dimethoxy-4-geranyloxy benzoic acid (0.80 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.31 g), thereby yielding 1.02 g(95%) of the aimed compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH:22]3[CH2:24][CH2:25][CH:19]2[C:20](=[O:26])[O:21]3)(=[O:17])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C.CO>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH:22]3[CH2:24][CH2:25][CH:19]2[C:20](=[O:26])[O:21]3)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=C1OC2CCC1N(S(=O)(=O)c1ccc(OCc3ccccc3)cc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1OC2CCC1N(S(=O)(=O)c1ccc(O)cc1)C2
Yield: 104.6 %

Procedure:
A mixture of 5-(4-benzyloxy-benzenesulfonyl)-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one (1.0 g, 2.7 mmol), ethyl acetate-methanol (1:1, 100 mL) and 10% Pd on charcoal (0.22 g) was shaken under 50 psi of hydrogen for 1.5 h. Filtration through a pad of Celite and concentration of the filtrate in vacuo afforded 0.80 g of 5-(4-hydroxy-benzenesulfonyl)-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one as a colorless solid.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:22]([O-])([OH:24])=[O:23]>C(O)(=O)C>[C:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(Oc1ccc(-c2ccccc2)cc1)c1ccccc1
Solvent: CC(=O)O
Product: O=C(Oc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)c1ccccc1
Temperature: 85 °C

Procedure:
4-Benzoyloxybiphenyl (40 g) is mixed with 310 ml of glacial acetic acid and heated to 85° C. Fuming nitric acid (100 ml) is added slowly while maintaining the reaction medium temperature between 85°-90° C. After complete addition, the reaction is cooled to room temperature.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][C:21]1[O:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]=1[NH2:32]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:32][C:22]4[N:23]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:24][O:25][C:21]=4[CH3:20])[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: CC1=C(N)N(c2ccccc2)CO1
Product: CC1=C(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)N(c2ccccc2)CO1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with 5-methyl-3-phenyl-4-oxazolylamine gave N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(5-methyl-3-phenyl-4-oxazolyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.80-7.65 (m, 2H), 7.45 (bd, 1H), 7.20 (m, 1H), 7.00 (m, 1H), 6.65 (bd, 1H), 4.20 (s, 4H), 2.35 (s, 3H); LCMS: ret. time: 20.61 min.; purity: 78%; MS (m/e): 420 (MH+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][CH:6]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][C:8](Cl)=[O:9].[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:5][CH:6]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:9]
Reactant: c1ccccc1
Reactant: CC(CC(=O)Cl)CC(C)(C)C
Agent: [Al+3]
Agent: [Cl-]
Product: CC(CC(=O)c1ccccc1)CC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 143.3 grams of aluminum chloride and 400 mL of benzene was added 100 grams of 3,5,5-trimethylhexanoyl chloride over a 50 minute period at a rate such that the temperature did not exceed 35° C. When the addition was complete, the mixture was stirred at room temperature for three hours. The mixture was poured over 500 grams of ice and extracted with 400 mL of ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and the solvent was removed in vacuo to give 3,5,5-trimethylhexanoylbenzene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[S:14][CH:15]=[C:16]([CH2:18]Cl)[N:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:20]1([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[CH:24]=[N:23][N:22]=[N:21]1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[S:14][CH:15]=[C:16]([CH2:18][O:31][C:28]3[CH:29]=[CH:30][C:25]([N:20]4[CH:24]=[N:23][N:22]=[N:21]4)=[CH:26][CH:27]=3)[N:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(CCl)cs2)C1
Reactant: Oc1ccc(-n2cnnn2)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)C1

Procedure:
A mixture of 3-(4-Chloromethyl-thiazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (From Step 1) (775 mg, 2.56 mmol), 4-tetrazol-1-yl-phenol (415 mg, 2.56 mmol), CsCO3 (1.25 mg, 3.84 mmol) and KI (44 mg, 0.26 mmol) in acetonitrile (20 mL) was heated under reflux overnight. After cooling, the solid was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified on silica gel (EtOAc-hexanes, 1:1) to afford the desired product. 1H NMR (CDCl3): δ 8.92 (1H, s), 7.63 (2H, d), 7.27 (1H, s), 7.17 (2H, d), 5.24 (2H, s), 3.87 (1H, m), 3.79 (1H, m), 3.65 (2H, m), 3.45 (1H, m), 2.40 (1H, m), 2.23 (1H, m), 1.47 (9H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:13][C:12]2[C:11]([NH2:14])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH:5]=1)[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][C:17]=1[C:25]([F:28])([F:27])[F:26].O>O1CCCC1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:14][C:11]2[C:12]3[CH2:13][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH2:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)=[O:24])=[CH:18][C:17]=1[C:25]([F:26])([F:27])[F:28]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCOC1=CCc2cccc(N)c2C1
Solvent: O
Solvent: C1CCOC1
Product: CCOC1=CCc2cccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.8 %

Procedure:
To a stirred solution of 7-ethoxy-5,8-dihydronaphthalen-1-ylamine (0.16 g, 0.84mmol) in tetrahydrofuran (15 mL) was added 4-chloro-3-trifluoromethyl-phenylisocyanate (0.22 g, 1.0 mmol). The mixture was stirred at room temperature for 1.5 hours and was poured into water. The product was extracted with ethylacetate, and the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford N-(4-chloro-3-trifluoromethyl-phenyl)-N′-(7-ethoxy-5,8-dihydro-naphthalen-1-yl)urea (0.31 g, 89% yield). Next, to a solution of N-(4-chloro-3-trifluoromethyl-phenyl)-N′-(7-ethoxy-5,8-dihydro-naphthalen 1-yl)-urea (0.21 g, 0.51 mmol) in tetrahydrofuran (20 mL) was added a solution of aqueous 1N hydrochloric acid (5 mL), and the mixture was stirred at 40° C. for 45 minutes. The mixture was neutralized with addition of 10% aqueous sodium bicarbonate solution, and extracted with ethylacetate. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford N(4-chloro-3-tri-fluoromethyl-phenyl)-N′-(7-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)urea (0.16 g, 85% yield). Next, to N-(4-chloro-3-trifluoromethyl-phenyl)-N′-7-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)urea (0.07 g, 0.18 mmol) in methanol (10 mL) was added sodium borohydride (0.04 g, 0.09 mmol) at 0° C., and the mixture was stirred for 30 minutes. The mixture was poured into water, and the product was extracted with ethylacetate. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure, and the obtained product was recrystalized from a mixture of ethylacetate/hexane (1/2) solution to give N-[4chloro-3-(trifluoromethyl)phenyl]-N′-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)urea (41 mg, 59% yield)