Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.C[N:30](C)C=O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[CH3:1][N:2]([S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([NH2:30])=[O:20])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CN(C)C=O
Reactant: CN(c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(c1cccc2cc(C3=NCC(CC(N)=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Yield: 82 %

Procedure:
To a mixture of (2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (100 mg), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (42 mg) and N,N-dimethylformamide (6 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (53 mg) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=9:1-ethyl acetate), and the obtained pale-yellow oil was crystallized from ethyl acetate-hexane to give the title compound (82 mg, yield: 82%) as pale-yellow prism crystals. MS: 435 (MH+). melting point 193-194° C.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[F:8][C:9]([F:36])([F:35])[C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:34]=[CH:33][C:24]([C:25]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:26])=[CH:23][CH:22]=3)=[CH:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][N:2]([CH3:7])[S:3]([N:30]1[CH2:31][CH2:32][N:27]([C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:14]3[C:13]4[C:18](=[CH:19][C:10]([C:9]([F:8])([F:35])[F:36])=[CH:11][CH:12]=4)[N:17]=[CH:16][CH:15]=3)=[CH:34][CH:33]=2)[CH2:28][CH2:29]1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)N1CCN(C(=O)c2ccc(Nc3ccnc4cc(C(F)(F)F)ccc34)cc2)CC1
Reaction time: 19 h
Yield: 88.3 %

Procedure:
Dimethylsulfamoyl chloride (0.72 g, 0.54 ml, 0.005 mol) is added dropwise to a solution of 2.00 g (0.005 mol) of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine and 2 ml of triethylamine in 20 ml of dimethylformamide. The reaction is stirred for 19 hours and then partitioned with chloroform-aqueous sodium carbonate. The organic phase is dried over anhydrous sodium sulfate, concentrated, and chromatographed with methylene chloride to 1% methanol/chloroform on silica gel to give 2.24 g of 1-[(dimethylamino)sulfonyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine. This is crystallized from methylene chloride-cyclohexane to give 1.60 g of 1-[(dimethylamino)sulfonyl]-4-[4-[[-7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine of melting point 223°-224.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[CH:26]=[N:27][CH:28]=[N:29][CH:30]=3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([C:25]5[CH:30]=[N:29][CH:28]=[N:27][CH:26]=5)=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccc(-c3cncnc3)cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cc(-c3cncnc3)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-pyrimidin-5-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([NH:6][NH:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:5].[C:22](Cl)(Cl)=[O:23]>Cl>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([NH:7][N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:1][C:22]2=[O:23])=[O:17])=[CH:10][CH:11]=1
Reactant: COc1ccc(C(=O)NNC(=O)c2ccccc2N)cc1
Reactant: O=C(Cl)Cl
Agent: Cl
Product: COc1ccc(C(=O)Nn2c(=O)[nH]c3ccccc3c2=O)cc1

Procedure:
28.5 g N-(2-amino-benzoyl)-N'-p-methoxy-benzoylhydrazine are dissolved in 800 cc 2N hydrochloric acid. A phosgene stream is passed through the solution, for a period of time of 1 hour. After purging the apparatus, the reaction product is suction filtered and washed with water. It is purified by recrystallization from isopropanol. M.P.=289° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[N:14]=2)=[CH:9][CH:8]=1.[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(Cl)Cl>[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]([N:36]1[CH2:37][CH2:38][N:39]([C:24]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:15]3[N:14]=[C:13]([C:10]4[CH:9]=[CH:8][C:7]([S:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:12][CH:11]=4)[CH:18]=[CH:17][N:16]=3)=[CH:28][CH:27]=2)=[O:25])[CH2:40][CH2:41]1)=[O:35]
Reactant: O=C(O)c1ccc(Nc2nccc(-c3ccc(SCCCCO)cc3)n2)cc1
Reactant: O=C(c1ccco1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(c1ccc(Nc2nccc(-c3ccc(SCCCCO)cc3)n2)cc1)N1CCN(C(=O)c2ccco2)CC1
Reaction time: 12 h
Yield: 8.8 %

Procedure:
4-{4-[4-(4-Hydroxybutylsulfanyl)phenyl]pyrimidin-2-ylamino}benzoic acid (0.34 g, 0.86 mmol) was dissolved in THF (5 mL). To this solution was added 1-furoylpiperazine (0.170 g), EDCI (0.180 g), and HOBt (0.127 g). The mixture was stirred 12 h. The mixture was then diluted with CH2Cl2 (20 mL) and washed with 2% NaOH (aq, 30 mL), water (30 mL), and then brine (30 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The crude solid was subjected to preparatory HPLC (30-80 acetonitrile/water gradient, 20 min). The desired fractions were concentrated to remove most of the acetonitrile, and then the aqueous mixture was extracted with CH2Cl2/2% NaOH (aq). The organic layer was dried (Na2SO4), filtered, and concentrated to afford [4-(Furan-2-carbonyl)-piperazin-1-yl]-(4-{4-[4-(4-hydroxybutylsulfanyl)phenyl]pyrimidin-2-ylamino}phenyl)methanone (0.042 g, 9%): HPLC Retention Time; 10.07 min. (Method B) M+H=558.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CC(=O)C[C@H]1C(O)=O)=O)(C)(C)C.NOC[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[CH2:10][C@H:9]1[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CON)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Product: COc1ccc(CON=C2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Yield: 85 %

Procedure:
The same method as employed in the preparation of Intermediate 7, but starting from (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (Intermediate 1) and 1-[(aminooxy)methyl]-4-methoxy-benzene (Intermediate 10) gave the title compound as a gum in a 85% yield.
Reaction SMILES: [CH:1]1([CH2:5][O:6][CH:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:8](=O)[CH3:9])[CH2:4][CH2:3][CH2:2]1.[BH3-]C#[N:21].[Na+]>C(Cl)Cl>[NH2:21][CH:8]([CH:7]([O:6][CH2:5][CH:1]1[CH2:4][CH2:3][CH2:2]1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH3:9]
Reactant: [BH3-]C#N
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)OCC1CCC1
Agent: [Na+]
Solvent: ClCCl
Product: CC(N)C(Cc1ccc(Cl)cc1)OCC1CCC1
Reaction time: 8 h

Procedure:
A solution of 3-cyclobutylmethoxy-4-(4-chlorophenyl)butan-2-one (247 mg, 0.925 mmol, obtained from Step C) in 0.5 mL CH2Cl2 was added to a stirred suspension of NH4OAc (715 mg, 9.25 mmol) and NaBH3CN (35 mg, 0.555 mmol) at room temperature and allowed to stir overnight. The reaction was quenched by the addition of 2.2 mL conc. HCl allowed to stir for 30 minutes. The solvents were evaporated under reduced pressure and the residue was partitioned between ether and water. The aqueous layer was washed two more times with ether. The combined organics were dried over Na2SO4. The crude product mixture obtained after filtration and removal of volatiles was purified by flash chromatography, eluting using mixtures of mixtures of CH2Cl2 and MeOH (100% CH2Cl2, to 5% MeOH in CH2Cl2) to provide the title compound as a yellow oil, homogeneous by TLC Rf0.12 (5% MeOH in CH2Cl2). 500 MHz 1H NMR (CDCl3): δ 1.16 (t, 3H); 1.67 (m, 2H); 1.85 (m, 3H); 2.01 (m, 2H); 2.48 (m, 1H); 2.74 (m, 2H); 2.90 (dd, 1H); 3.15 (d quint, 2H); 3.37 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[NH2:4][CH:5]1[N:10]=[C:9]([Cl:11])[N:8]=[C:7](F)[N:6]1[O:13][CH:14]([F:16])[F:15]>C(OCC)C>[NH2:4][CH:5]1[N:10]=[C:9]([Cl:11])[N:8]=[C:7]([N:2]([CH3:3])[CH3:1])[N:6]1[O:13][CH:14]([F:16])[F:15]
Reactant: CNC
Reactant: NC1N=C(Cl)N=C(F)N1OC(F)F
Solvent: CCOCC
Product: CN(C)C1=NC(Cl)=NC(N)N1OC(F)F
Temperature: 22 °C
Reaction time: 8 h

Procedure:
4.2 g (0.093 mol) of dimethylamine were passed over the course of 20 minutes into a stirred solution of 10 g (0.047 mol) of 2-amino-4-chlorodifluoromethoxy-6-fluoro-1,3,5-triazine in 150 ml of diethyl ether at 0° C. The mixture was stirred at 0° C. for one hour and at 22° C. overnight. Washing with water, drying and concentration yielded 9.8 g (87.8% of theory) of the title compound of melting point 130°-133° C. (decomposition).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:28][C@H:29]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:30][C:31](O)=[O:32])(=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(Cl)CCl.CI>>[CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH:11][C:31](=[O:32])[CH2:30][C@H:29]([O:28][C:15](=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O
Reactant: N[C@@H](CO)C(=O)OCc1ccccc1
Solvent: CI
Solvent: ClCCCl
Product: CCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)N[C@@H](CO)C(=O)OCc1ccccc1
Yield: 89.4 %

Procedure:
In the same manner as described in Example 2-(5), L-serine benzyl ester (390 mg, 2.0 mmol) was acylated with (R)-3-dodecanoyloxytetradecanoic acid (935 mg, 2.2 mmol) in the presence of EDC·MeI (745 mg, 2.5 mmol) in CH2C2 to afford 1.08 g (90%) of N-[(R)-3-dodecanoyloxytetradecanoyl]-L-serine benzyl ester: mp 53-54° C. 1H NMR (CDCl3) δ 0.88 (t, 6H, J=6.5 Hz), 1.1-1.6 (m, 46H), 2.30 (t, 2H, J=7.7 Hz), 2.50 (d, 2H, 5.6 Hz), 2.62 (t, 1H, J=6.2 Hz), 3.97 (m, 2H), 4.65 (m, 1H), 5.19 (m, 3H), 6.63 (d, 1H, J=6.8 Hz), 7.35 (br s, 5H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][CH2:19][C:20]#[N:21]>CN(C=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:17][CH2:18][CH2:19][C:20]#[N:21])=[CH:3][CH:4]=1)=[O:7]
Reactant: N#CCCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCCCOc1ccc(C=O)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 109.7 %

Procedure:
Under argon, 2.44 g (20 mmol; 1 eq.) of 4-hydroxybenzaldehyde are dissolved in 20 mL DMF, and 5.53 g (40 mmol; 2 eq.) of K2CO3 are added. After 1 hour's stirring at 70° C., the medium becomes pink. Using a dropping funnel, a solution of 2.4 mL (24 mmol; 1.2 eq.) of 4-bromobutyronitrile in 6 mL DMF are added slowly. The reaction medium is stirred 1 hour at 70° C. then 2 hours at 90° C. After cooling, the medium is filtered through a sintered glass filter. The filtrate is diluted with dichloromethane until precipitation, then filtered again through a sintered glass filter. The new filtrate is concentrated to dryness then re-dissolved in dichloromethane. The organic phase is washed twice in water then with a saturated NaCl solution, dried over Na2SO4 and concentrated to dryness. 4.15 g of compound (11) are obtained and used without any additional purification (quantitative yield).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:20][CH:19]([O:21][CH3:22])[CH2:18]2)=[O:16])[CH:12]=[C:11]([Cl:23])[C:10]=1[F:24])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:18][CH:19]([O:21][CH3:22])[CH2:20]2)=[O:16])[CH:12]=[C:11]([Cl:23])[C:10]=1[F:24]
Reactant: COC1CN(C(=O)c2cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC1CN(C(=O)c2cc(Cl)c(F)c(CN)c2)C1

Procedure:
was prepared according to Scheme C3 (step B) from [3-chloro-2-fluoro-5-(3-methoxy-azetidine-1-carbonyl)-benzyl]-carbamic acid tert-butyl ester (99 mg, 0.3 mmol) and TFA (0.5 mL) in CH2Cl2. MS (LC-MS): 273.0 [M]+; tR (HPLC conditions c): 2.73 min.
Reaction SMILES: [O:1]=[C:2]1[NH:6][N:5]=[C:4]([CH2:7][N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])OC2=O)[NH:3]1.Cl.[CH3:21][C:22]1[S:23][CH:24]=[C:25]([CH2:27][O:28][NH2:29])[N:26]=1>>[CH3:21][C:22]1[S:23][CH:24]=[C:25]([CH2:27][O:28][NH:29][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:8][CH2:7][C:4]2[NH:3][C:2](=[O:1])[NH:6][N:5]=2)[N:26]=1
Reactant: Cc1nc(CON)cs1
Reactant: O=c1[nH]nc(Cn2c(=O)oc(=O)c3ccccc32)[nH]1
Agent: Cl
Product: Cc1nc(CONC(=O)c2ccccc2NCc2n[nH]c(=O)[nH]2)cs1

Procedure:
Starting materials: 1-(5-Oxo-4,5-dihydro-1H-[1,2,4]triazol-3-ylmethyl)-1H-benzo[d][1,3]oxazine-2,4-dione (see preparation 7E) and O-(2-methyl-thiazol-4-ylmethyl)-hydroxylamine hydrochloride (see preparation 12).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC#N>[C:12]1([NH:11][C:2]2[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cnccc1Cl
Solvent: CC#N
Product: O=C(O)c1cnccc1Nc1ccccc1
Temperature: 80 °C
Yield: 99 %

Procedure:
A mixture of 4-chloronicotinic acid (150 mg, 0.952 mmol) and aniline (177 mg, 1.90 mmol) in MeCN (2 mL) was stirred and heated in the microwave (80° C., 300 W) for 1 h. The solid material was filtered off and the solvent was removed in vacuo. The crude 4-(phenylamino)nicotinic acid (202 mg) obtained was dissolved in THF (25 mL). After dropwise addition of LiAlH4 (1 M solution in THF, 3.77 mL, 3.77 mmol) at 0° C., the reaction mixture was stirred for 30 min, allowed to warm to room temperature and stirred overnight. The reaction was quenched with water (0.4 mL) at 0° C. and excess EtOAc was added. All solid material was filtered off and the solvent was removed in vacuo. Trituration with Et2O provided (4-(phenylamino)pyridin-3-yl)methanol (115 mg, 60% over 2 steps). ESI-MS [M+H]+=201.1.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][C:9]([CH3:37])=[CH:10][C:11]=3[CH:13]([O:15][CH2:16][C:17]3([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[CH2:22][CH2:21][N:20]([C:23](OC(C)(C)C)=O)[CH2:19][CH2:18]3)[CH3:14])[CH:6]=[N:5]2)[CH2:3][CH2:2]1.C([BH3-])#N.[Na+].C=O>FC(F)(F)C(O)=O.C(O)(=O)C>[CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][C:9]([CH3:37])=[CH:10][C:11]=3[CH:13]([O:15][CH2:16][C:17]3([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)[CH3:14])[CH:6]=[N:5]2)[CH2:2][CH2:3]1
Reactant: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C(=O)OC(C)(C)C)CC2)c2c(cnn2C2CC2)c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C)CC2)c2c(cnn2C2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-tert-Butyl 4-((1-(1-cyclopropyl-5-methyl-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (10 mg, 0.02 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 1 mL) and stirred at room temperature for 1 h. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2 M ammonia in methanol and concentrated. The resulting residue was dissolved in acetonitrile (1 mL), cooled to 0° C., and treated with sodium cyanoborohydride (6.2 mg, 0.1 mmol) and formalin (54 μL). After 5 min, the reaction was treated with a few drops of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was concentrated and purified by flash chromatography on silica gel (10% methanolic ammonia/methylene chloride) to afford 3 mg (36%) as a clear oil. LC/MS (HPLC method 1): tR=2.46 min, 422.37(MH)+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]#[C:12][C:13]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[N:6]2[CH3:19].[NH3:27]>C(COC)OC.C(OCC)(=O)C>[NH2:27][C:2]1[N:10]=[C:9]([C:11]#[C:12][C:13]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[N:6]2[CH3:19]
Reactant: Cn1c(-c2cccc(F)c2)nc2c(Cl)nc(C#CC3(O)CCCC3)nc21
Reactant: N
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cn1c(-c2cccc(F)c2)nc2c(N)nc(C#CC3(O)CCCC3)nc21
Temperature: 70 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
1-{2-[6-Chloro-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl)-1-ethynyl}-1-cyclopentanol (732 g) was dissolved in 16 liters of dimethoxyethane, 8 liters of a concentrated aqueous ammonia were added and the mixture was stirred at 70° C. for 5 hours using a sealed tube reactor. After the reaction solution was cooled in room temperature, it was diluted with 20 liters of ethyl acetate and washed with water twice (8 liters and 4 liters). The organic layer was concentrated to about 15 liters and the resulting residue was diluted with 15 liters of hexane, filtered and washed with hexane twice. Then it was dried at 50° C. for 2.5 hours to give 620 g of the product. The yield was 89%.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:42][CH2:43][CH2:44][OH:45]>C(Cl)Cl>[OH:45][CH2:44][CH2:43][NH:42][C:23]([C:22]1[CH:26]=[CH:27][C:19]([C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:12][CH2:13]2)=[O:18])=[CH:20][CH:21]=1)=[O:24]
Reactant: NCCO
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCO)cc2)CC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
4-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid (1.5 g) was dissolved in methylene chloride (50 ml) and then, triethylamine (0.7 ml) was added and cooled. Pivaloyl chloride(0.58 ml) was added slowly to the solution at 0~5° C. and the mixture was stirred at 5° C. for 2 hours. And then, triethylamine (0.7 ml) and 2-aminoethanol(1.27 g) were added in order, the solution was stirred at 0~5° C. for 2 hours and heated slowly to 20~25° C. and stirred for 30 minutes. The reaction mixture was washed with water twice and the solvent was concentrated under reduced pressure. The concentrated residue was crystallized by treatment with ether and further recrystallized using isopropanol and ether. The recrystallized product was filtered and dried to give 1.34 g (yield: 80%) of the desired compound as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][NH:5][C:4](=[O:8])[CH2:3]1.F[B-](F)(F)F.[CH3:15][O+](C)C>>[CH3:1][C:2]1([CH3:9])[CH2:3][C:4]([O:8][CH3:15])=[N:5][CH2:6][CH2:7]1
Reactant: C[O+](C)C
Reactant: CC1(C)CCNC(=O)C1
Agent: F[B-](F)(F)F
Product: COC1=NCCC(C)(C)C1

Procedure:
A sample of the title compound of EXAMPLE 168 (636 mg, 5 mmol) was reacted with trimethyloxonium tetrafluoroborate (890 mg, 6 mmol) by the method of EXAMPLE 26 to yield, after chromatography, 550 mg (78%) of the title material.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[NH:26]1[CH2:36][CH2:35][CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:27]1.CC(=O)CC>C(OCC)(=O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:26]3[CH2:27][CH2:28][CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:35][CH2:36]3)[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(c2nc(-c3ccc(Cl)cc3)c(CCCOc3ccccc3OC)o2)CC1
Yield: 69.2 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (378 mg), ethyl isonipecotate (1.57 g) and 2-butanone (10 ml) was stirred with heating under reflux for 6 hours. The reaction mixture was diluted with ethyl acetate (100 ml), and the organic layer was washed with a 10% aqueous solution of citric acid (50 ml) and dried over anhydrous magnesium sulfate. After the organic layer was concentrated, the residue was recrystallized from ethyl acetate-hexane to give ethyl N-[4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]-2-oxazolyl]isonipecotate as pale yellow prisms (345 mg, 69%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3]/[CH:4]=[CH:5]/[C:6]([O:8][CH2:9][CH3:10])=[O:7].C(O)(C(F)(F)F)=O.[CH2:20]([N:27]([CH2:33]O)[CH2:28][Si](C)(C)C)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH2:20]([N:27]1[CH2:33][C@@H:4]([CH2:3][C:2]([F:11])([F:12])[F:1])[C@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[Si](C)(C)CN(CO)Cc1ccccc1
Reactant: CCOC(=O)/C=C/CC(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1CC(F)(F)F
Yield: 98 %

Procedure:
To a stirred solution of ethyl (2E)-5,5,5-trifluoropent-2-enoate (3.0 g, 16.5 mmol) and TFA (0.38 g, 3.3 mmol) in DCM (40 mL) was added dropwise {benzyl[(trimethylsilyl)methyl]amino}methanol (7.8 g, 33 mmol) at 0° C. over a period of 30 min. After the addition, the mixture was refluxed overnight. TLC (petroleum ether:EtOAc 10:1) indicated ethyl (2E)-5,5,5-trifluoropent-2-enoate was consumed. The reaction mixture was washed with sat. NaHCO3 (40 mL), brine (40 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether:EtOAc=100:1 to 10:1) to give the title compound (5.1 g, 98% yield) as a yellow oil.