Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.OC1C=CC=CC=1C=O.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH2:33])[N:28]=1.[OH-].[Na+]>N1C=CC=CC=1.C(OCC)(=O)C>[OH:5][C:6]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH3:25])[N:28]=1)=[O:10]
Reactant: COc1cccc(N)n1
Reactant: Cc1cccc(C(=O)O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O=Cc1ccccc1O
Solvent: O=S(Cl)Cl
Product: COc1cccc(NC(=O)c2cccc(C)c2O)n1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
10 ml of thionyl chloride are added to 1.47 g (16.11 mmol) of 2-hydroxy-3-methylbenzoic acid and the reaction mixture is heated at 90° C. for 2 h. The reaction medium is concentrated to dryness by azeotroping with toluene. The residue is then put into solution in 10 ml of pyridine, to which 600 mg (4.83 mmol, 1 eq) of 2 methoxypyridin-6-amine are added dropwise, and the reaction medium is left stirring at room temperature for 1 h 30 mins. 30 ml of 1M sodium hydroxide (19.34 mmol, 4 eq) are added and the reaction medium is heated at 60° C. for 16 h. The reaction medium is diluted with 100 ml of ethyl acetate, the aqueous phase is extracted and washed with 50 ml of ethyl acetate. The aqueous phase is then acidified at 0° C. with 37% HCl dropwise to pH=4. The organic phases are extracted twice with 50 ml of ethyl acetate and then they are washed twice with 50 ml of water. The organic phases are concentrated to dryness and the residue is purified by chromatography over silica, eluting with a heptane/ethyl acetate (1/1) mixture. 2-Hydroxy-N-(6-methoxypyridin-2-yl)-3-methylbenzamide is obtained in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][N:19]1[C:25](=[O:26])[CH:24]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:23]2[CH:37]=[CH:38][CH:39]=[CH:40][C:22]=2[C:21]2[CH:41]=[CH:42][CH:43]=[CH:44][C:20]1=2>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][N:19]2[C:25](=[O:26])[CH:24]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:23]3[CH:37]=[CH:38][CH:39]=[CH:40][C:22]=3[C:21]3[CH:41]=[CH:42][CH:43]=[CH:44][C:20]2=3)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NN1C(=O)C(CCCCc2ccccc2)c2ccccc2-c2ccccc21
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NN1C(=O)C(CCCCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using N-(3,5-difluorophenylacetyl)-L-alanine (Ex. B) and 5-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-K), the title compound was prepared. The reaction was monitored by tlc (Rf=0.35, 3% MeOH/CHCl3) and product was purified by chromatography (silica, 3% MeOH/CHCl3).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([CH:12](C(OCC)=O)[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.C(O)(=O)C>O>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cccc2ccc(C)nc12
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2cccc(CC(=O)O)c2n1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A solution of diethyl 2-(2-methylquinolin-8-yl)malonate (2.34 g, 7.77 mmol), 6 N HCl (7.77 mL, 46.6 mmol) in water, and acetic acid (7.77 mL) was heated at 106° C. for 18 hours. After cooling to ambient temperature, the solvent was removed under reduced pressure to give 2-(2-methylquinolin-8-yl)acetic acid (1.56 g, 99.8%) as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].Br[C:23]1[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:26]=[CH:25][C:24]=1[F:33].[F-].[Cs+]>COCCOC.CO.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]>[F:33][C:24]1[CH:23]=[CH:28][C:27]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:26][C:25]=1[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:21])[N:2]([CH3:1])[CH:11]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Reactant: CS(=O)(=O)c1ccc(F)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: CO
Solvent: COCCOC
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2F)c2ccccc2c1=O
Temperature: 70 °C
Reaction time: 12 h
Yield: 74.4 %

Procedure:
A mixture of compound 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one (4.1 g, 14.5 mmol), 2-bromo-4-methylsulfonyl-1-fluorobenzene (3.5 g, 13.8 mmol) prepared in a similar manner to Example 79 steps 1-2, CsF (6.3 g, 41.3 mmol), and Pd(dppf)Cl2 (1.0 g, 1.38 mmol) in DME (70 mL) and MeOH (35 ml) was stirred at 70° C. for 12 h under N2. The mixture was concentrated and the residue was purified by column chromatography on silica gel (PE: EA=2:1-0:1) to give the title compound (3.4 g, 74.4%) as a red solid. LCMS (M+H)+=331.9 (M+1)+
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([Cl:35])[C:32]([Cl:34])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([Cl:35])[C:32]([Cl:34])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(Cl)c(Cl)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2cc(Cl)c(Cl)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5,6-dichloro-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [F:1][C:2]([F:10])([C:6]([F:9])([F:8])[F:7])[CH2:3][O:4][CH3:5].S(Cl)([Cl:14])(=O)=O>CCOCC>[F:1][C:2]([F:10])([C:6]([F:9])([F:8])[F:7])[CH2:3][O:4][CH2:5][Cl:14]
Reactant: COCC(F)(F)C(F)(F)F
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOCC
Product: FC(F)(F)C(F)(F)COCCl

Procedure:
The ether V can be prepared by a method analogous to that described by Weinmayr1, or from methyl 2,2,3,3,3-pentafluoropropyl ether and one molar equivalent of sulfuryl chloride at 0°-35°C with ultraviolet irradiation to give the chloromethyl 2,2,3,3,3-pentafluoropropyl ether XXVII,
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([C:21](=O)[NH2:22])=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O>C(N(CC)C=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([C:21]#[N:22])=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1noc2cccc(C(N)=O)c12
Agent: CCN(C=O)CC
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)NCCOc1noc2cccc(C#N)c12
Temperature: 5 °C
Yield: 91.8 %

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethoxy)-4-carbamoyl-1,2-benzisoxazole (0.15 g) in diethylformamide (1.5 ml) was added phosphorus oxychloride (0.09 g) with stirring at 5° C., and the mixture was then stirred at the same temperature for 15 minutes. The reaction mixture was poured into ice water (20 ml), extracted with ethyl acetate (twice each with 20 ml) and the combined extracts were dried over anhydrous magnesium sulphate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with cyclohexane/ethyl acetate (4/1) as an eluent, to give the title compound (0.13 g, 93%) as a colorless powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C@H:10]([CH2:13][O:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[O:9][C:8]=2[C:25]=1[CH:26]=[C:27]([N+]([O-])=O)[CH2:28][CH3:29])([O-])=O.[H][H]>C(OCC)(=O)C.[Pt]=O>[CH3:24][C:21]1[CH:20]=[CH:19][C:18]([S:15]([O:14][CH2:13][CH:10]2[O:9][C:8]3=[C:25]4[C:4](=[CH:5][CH:6]=[C:7]3[O:12][CH2:11]2)[NH:1][C:27]([CH2:28][CH3:29])=[CH:26]4)(=[O:17])=[O:16])=[CH:23][CH:22]=1
Reactant: CCC(=Cc1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2)[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCc1cc2c3c(ccc2[nH]1)OCC(COS(=O)(=O)c1ccc(C)cc1)O3

Procedure:
0.70 g (1.5 mmole) of toluene-4-sulfonic acid (2R)-7-nitro-8-(2-nitro-but-1-enyl)-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester was dissolved in 100 mL of ethyl acetate and 0.10 g of platinum oxide added. The mixture was treated with 45 psi of hydrogen on a Parr hydrogenation apparatus for 5 hours. The mixture was then filtered through celite and concentrated in vacuum. The residue was column chromatographed on silica gel with 1:1 ethyl acetate/hexane to give 0.52 g of the (R)-enantiomer of the title compound as a yellow oil. 1H-NMR (CDCl3): doublet 7.8 δ (2H); doublet 7.3 δ (2H); doublet 6.76 δ (1H); doublet 6.64 δ (1H); singlet 6.16 δ (1H); multiplet 4.5 δ (1H); multiplet 4.3 δ (3H); quartet 4.1 δ (1H); quartet 2.75 δ (2H); singlet 2.5 δ (3H); triplet 1.3 δ (3H).
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([C:7]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:13]=[C:12]3[C:8]=2[CH2:9][CH2:10][N:11]3[C:22](=[O:35])[C@@H:23]([NH:31]C(=O)[O-])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:31][C@@H:23]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:22]([N:11]1[C:12]2[C:8](=[C:7]([C:5]3[O:6][C:2]([NH2:1])=[N:3][N:4]=3)[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:13]=2)[CH2:9][CH2:10]1)=[O:35]
Reactant: Nc1nnc(-c2cc(-c3ccncc3)cc3c2CCN3C(=O)[C@H](Cc2ccccc2)NC(=O)[O-])o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(-c2cc(-c3ccncc3)cc3c2CCN3C(=O)[C@@H](N)Cc2ccccc2)o1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
To a 100 ml flask containing (S)-1-(4-(5-amino-1,3,4-oxadiazol-2-yl)-6-(pyridin-4-yl)indolin-1-yl)-1-oxo-3-phenylpropan-2-ylcarbamate was added 20 ml of DCM and 10 ml of TFA. The reaction was stirred at room temperature for 6 hours at which time the solvent was removed with a stream of nitrogen to give (2S)-2-amino-1-(4-(5-amino-1,3,4-oxadiazol-2-yl)-6-(pyridin-4-yl)indolin-1-yl)-3-phenylpropan-1-one 59 (98 mg, 100% yield) as a white solid LCMS ESI (pos.) m/e: 427.1 (M+1): 1H NMR (400 MHz, DMSO-d6) δ ppm 8.76 (d, J=6.26 Hz, 2H), 8.58 (d, J=1.56 Hz, 1H), 8.36 (br. s., 3H), 7.71-7.81 (m, 3H), 7.22-7.41 (m, 7H), 4.55 (br. s., 1H), 4.31 (td, J=10.37, 6.65 Hz, 1H), 3.68 (td, J=10.27, 6.46 Hz, 1H), 3.33-3.50 (m, 1H), 3.08-3.28 (m, 3H).
Reaction SMILES: C1(C)C=CC=CC=1.Br/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[O:25])[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].C([Sn](CCCC)(CCCC)/[CH:31]=[CH:32]/[CH:33]([O:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][O:44]1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])CCC.C(OCC)C>CCCCCC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[O:25]=[C:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1/[CH:10]=[CH:9]/[CH:31]=[CH:32]/[CH:33]([O:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][O:44]1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: CCCCCCCCC(/C=C/[Sn](CCCC)(CCCC)CCCC)OC1CCCCO1
Reactant: COC(=O)CCCC(=O)c1ccccc1/C=C/Br
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCCCCCCCC(/C=C/C=C/c1ccccc1C(=O)CCCC(=O)OC)OC1CCCCO1
Temperature: 25 °C
Yield: 54.3 %

Procedure:
To 1 ml of toluene was added 0.1 g (0.35 mmol) of the product of Example 4, 0.11 g (0.38 mmol) of the product of Example 9, and 5.0 mg of tetrakis(triphenylphosphine)palladium(O). The solution was degassed with argon and then heated at reflux under argon for approximately 5 hours. The reaction mixture was then cooled to room temperature and flash chromatographed. Gradient elution with hexane, 1% diethyl ether in hexane, 5% diethyl ether in hexane, and 10% diethyl ether in hexane produced 0.90 mg (0.19 mmol) of the titled product.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[CH:28]1(O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([O:23][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:22])[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:25])[F:26])[CH:3]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Reactant: OC1CCCCC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)OC3CCCCC3)cs2)CC1

Procedure:
A solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-4, 6.00 g) is reacted analogously to Example I-811 with cyclohexanol (1.94 g). This gives, after chromatographic purification, cyclohexyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (5.00 g, 69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[CH2:7][CH2:8][N:9](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCN(S(=O)(=O)c1ccc(C)cc1)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(c1)CCNCC2

Procedure:
To a solution of 7-methoxy-3-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo-[d]azepine (6.62 g, 20 mmol) in anhydrous THF (150 ml) is added a solution of LiAlH4 in THF (1.0 M, 40 ml, 2.0 eq.). The resulting mixture is refluxed under N2 for 24 hr. To the solution at 0° C. is added water (1.52 g) very carefully with stirring, followed by the addition of sodium hydroxide solution (10.0 N, 1.52 ml) and then water (3.04 g). The mixture is stirred at rt for an additional 1 hr, then diluted with EtOAc (300 ml), and dried with magnesium sulfate (40.0 g). After filtration, and washing the filtering cake with EtOAc (100 ml×3), the combined organic phase is evaporated to dryness under reduced pressure to give the title compound. MS (+VE) m/z 178.1 (M++1).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][NH2:8].[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][N:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=3)[C:21]=2[OH:22])=[C:13]([CH3:32])[CH:12]=1)#[N:10]>>[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][N:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH:8][CH2:7][CH2:6][CH:2]4[CH2:3][CH2:4][CH2:5][O:1]4)=[O:28])=[CH:25][N:24]=3)[C:21]=2[OH:22])=[C:13]([CH3:32])[CH:12]=1)#[N:10]
Reactant: NCCC1CCCO1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCCC3CCCO3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 227 using 2-(tetrahydrofuran-2-yl)ethanamine and 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid. 1H NMR (400 MHz, DMSO-d6) δ 1.21-1.29 (m, 1H) 1.37-1.51 (m, 1H) 1.68-1.89 (m, 4H) 1.99 (dddd, J=11.8, 8.2, 6.6, 5.2 Hz, 1H) 2.44 (s, 3H) 3.26-3.47 (m, 3H) 3.61 (td, J=7.9, 6.4 Hz, 1H) 3.70-3.88 (m, 2H) 7.63-7.68 (m, 1H) 7.71-7.81 (m, 2H) 8.18 (br. s., 1H) 8.41 (d, J=6.3 Hz, 1H) 8.72 (t, J=5.4 Hz, 1H) 8.88-8.95 (m, 1H). MS m/z [M+H]+ 418.4.
Reaction SMILES: O[CH:2]([C:4]1[O:5][C:6](=[O:26])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].[F:27][C:28]1[CH:29]=[C:30]([C:36]2[C:44]3[C:39](=[N:40][CH:41]=[N:42][C:43]=3[NH2:45])[NH:38][N:37]=2)[CH:31]=[C:32]([O:34][CH3:35])[CH:33]=1>>[NH2:45][C:43]1[N:42]=[CH:41][N:40]=[C:39]2[N:38]([CH:2]([C:4]3[O:5][C:6](=[O:26])[C:7]4[C:12]([C:13]=3[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]5[CH2:22][CH2:23][CH2:24][CH2:25]5)=[CH:16][CH:15]=3)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH3:3])[N:37]=[C:36]([C:30]3[CH:31]=[C:32]([O:34][CH3:35])[CH:33]=[C:28]([F:27])[CH:29]=3)[C:44]=12
Reactant: COc1cc(F)cc(-c2n[nH]c3ncnc(N)c23)c1
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(CN2CCCC2)cc1
Product: COc1cc(F)cc(-c2nn(C(C)c3oc(=O)c4ccccc4c3-c3ccc(CN4CCCC4)cc3)c3ncnc(N)c23)c1
Yield: 26.5 %

Procedure:
The title compound was made in a similar way as that of the example 134, step a, from 3-(1-hydroxyethyl)-4-(4-(pyrrolidin-1-ylmethyl)phenyl)-1H-isochromen-1-one (Intermediate B47, 380 mg, 1.088 mmol) and 3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate G1, 310 mg, 1.197 mmol) to give 3-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(4-(pyrrolidin-1-ylmethyl)phenyl)-1H-isochromen-1-one (170 mg, 0.288 mmol, 26.5% yield) as a brown solid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:14])[CH2:12][OH:13])(=[O:3])[CH3:2].[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1.C(=O)(O)[O-].[Na+]>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:14])[CH2:12][O:13][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][O:16]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC=C(C)CCC=C(C)CO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OCC=C(C)CCC=C(C)COC1CCCCO1
Yield: 95.8 %

Procedure:
A mixture of 8-acetoxy-2,6-dimethyl-2,6-octadien-1-ol (1.81 g, 8.52 mmol) and dihydropyran (1.17 ml, 12.8 mmol) in dichloromethane (6 ml) was stirred, and p-toluenesulfonic acid (40 mg) was added thereto, and the mixture was stirred at room temperature for 30 minutes. After addition of saturated aqueous sodium bicarbonate (30 ml), the product was extracted with hexane/ether (5:1.2) (30 ml). The extract was dried over Na2SO4 and evaporated in vacuo to remove the solvent to give a residue, which was purified with silica gel column chromatography to give 1-acetoxy-8-(2-tetrahydropyranyl)oxy-3,7-dimethyl-2,6-octadiene (2.42 g, 96%).
Reaction SMILES: C[N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.CN(C)C=O.[N:31]12[CH2:39][C:35]([CH2:40][NH2:41])([CH2:36][CH2:37][CH2:38]1)[CH2:34][CH2:33][CH2:32]2>O1CCCC1.CO.C(Cl)Cl>[N:31]12[CH2:39][C:35]([CH2:40][NH:41][C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[NH:2][CH:3]=3)=[O:13])([CH2:36][CH2:37][CH2:38]1)[CH2:34][CH2:33][CH2:32]2
Reactant: Cn1cc(C(=O)O)c2ccccc21
Reactant: NCC12CCCN(CCC1)C2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCC12CCCN(CCC1)C2)c1c[nH]c2ccccc12
Reaction time: 0.17 h
Yield: 79.6 %

Procedure:
A solution of 1-methyl-1H-indole-3-carboxylic acid (1.53 g, 8.7 mmol) in anhydrous tetrahydrofuran (8 mL) under nitrogen was treated with 1.49 g (9.2 mmol) of 1,1'-carbonyldiimidazole (CDI) and stirred for 10 minutes. At this point a thick suspension formed, and anhydrous N,N-dimethylformamide (8 mL) was added. After an additional 45 minutes the solution was degassed under a stream of nitrogen over 10 minutes, then treated with a solution of 1-azabicyclo[3.3.1]nonane-5-methanamine (1.47 g, 9.5 mmol). After 18 hours at room temperature and six hours at 55°-60° C., no acid-CDI adduct was detected by TLC (5% methanol/methylene chloride on alumina), and the mixture was concentrated in vacuo. The residue was partitioned between 3N sodium hydroxide (50 mL) and toluene (100 mL) containing a little 2-propanol. The organic layer as separated and the aqueous solution was extracted with toluene (50 mL) containing some 2 -propanol. The combined organic solution was dried (Na2SO4), concentrated in vacuo, and the residue filtered through alumina (eluted with 20% methanol/tetrahydrofuran). The filtrate was concentrated in vacuo and the residue triturated from ether/petroleum ethers (30°-60° ) to give a solid, which was recrystallized from tetrahydrofuran/hexane to afford 2.06 g (76%) of colorless crystals; mp 145°-147° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([N:15]1C(=O)C2=CC=CC=C2C1=O)[CH2:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CCO>[NH2:15][C@@H:10]([CH2:11][CH2:12][CH:13]=[CH2:14])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCC[C@@H](COCc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: C=CCC[C@H](N)COCc1ccccc1
Yield: 0.1 %

Procedure:
To a stirred solution of 1-benzyloxy-2-(S)-phthalimido-5-hexene (2.95 g, 8.80 mmol) in EtOH (30 ml) was added hydrazine hydrate (80% in water, 460 ml, 11.4 mmol) at rt, and the resulting mixture was heated under reflux for 7.5 h with stirring. The solution was filtered, and the filtrate was concentrated in vacuo. The residue was poured into aq.NaHCO3 and extracted with CHCl3. The organic layer was dried over anhydrous Na2SO4, then concentrated in vacuo to give 2-(S)-amino-1benzyloxy-5-hexene (1.90 mg, quant.) as a colorless oil. 1H-NMR (CDCl3) δ 1.37–1.55 (series of m, 4 H), 2.08–2.19 (m, 2 H), 2.99–3.03 (m, 1 H), 3.25 (dd, J=9.2, 7.6 Hz, 1 H), 3.45 (dd, J=9.2, 4.0 Hz, 1 H), 4.53 (s, 2 H), 4.94–5.06 (series of m, 2 H), 5.76–5.85 (m, 1 H), 7.27–7.37 (m, 5 H); MS (ESI) m/z, 206 (M++H), 247 (M++H+CH3CN).
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].C(=O)([O-])O.[Na+].Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>O1CCCC1>[CH3:2][C:1]1[S:3][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:4]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1csc(C)n1
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a solution of thioacetamide (11.9 g) in tetrahydrofuran (600 ml) was added sodium hydrogen carbonate (66.4 g), followed by addition of 80% ethyl bromopyruvate (50.0 g) at 0° C. The mixture was stirred overnight, the insolubles were filtered using Celite and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (170 ml), and to the solution was added dropwise trifluoroacetic anhydride (170 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. To the mixture was added dropwise pyridine (200 ml) at 0° C., and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, to the mixture was added ethyl acetate, and the mixture was washed with saturated sodium hydrogen carbonate solution and further with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=2:1) to give ethyl 2-methylthiazole-4-carboxylate (13.0 g) as brown crystals.