Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:15][C:16]1[CH:28]=[CH:27][C:19]([O:20][CH:21]([CH2:25][CH3:26])[C:22](Cl)=[O:23])=[CH:18][C:17]=1[C:29]([F:32])([F:31])[F:30]>C1(C)C=CC=CC=1>[CH2:1]([NH:8][C:22](=[O:23])[CH:21]([O:20][C:19]1[CH:27]=[CH:28][C:16]([Cl:15])=[C:17]([C:29]([F:31])([F:32])[F:30])[CH:18]=1)[CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Oc1ccc(Cl)c(C(F)(F)F)c1)C(=O)Cl
Reactant: NCc1ccccc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCC(Oc1ccc(Cl)c(C(F)(F)F)c1)C(=O)NCc1ccccc1
Yield: 43 %

Procedure:
In 50 ml of toluene were dissolved 1.6 g (0.015 mole) of benzylamine and 2.4 g (0.030 mole) of pyridine. Then, was added dropwise thereto a solution of 3.0 g (0.010 mole) of 2-(4-chloro-3-trifluoromethylphenoxy)-butyroyl chloride in 30 ml of toluene and the mixture was treated, according to the same procedure as in Synthesis Example 10. The resultant crude crystals were recrystallized from ethanol to give 1.6 g of N-benzyl-2-(4-chloro-3-trifluoromethylphenoxy)-butyramide melting at 93°-95° C. as colorless needless.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([CH3:13])[C:6]([CH3:14])=[C:5]2[OH:15].[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:18]([O:15][C:5]1[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=[C:2]([Br:1])[CH:3]=2)[N:8]=[C:7]([CH3:13])[C:6]=1[CH3:14])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nc2c(C)cc(Br)cc2c(O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2c(C)cc(Br)cc2c(OCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
26.6 Grams of 6-bromo-4-hydroxy-2,3,8-trimethylquinoline synthesized in the same way as that described in Example 1 was suspended in 70 ml of dimethylformamide, to which 4.4 g of 60% sodium hydride was added under cooling with ice and then the mixture was stirred at room temperature for 30 minutes. 19 Grams of benzyl bromide was added dropwise to the reaction mixture under cooling with ice and the mixture was allowed to react at room temperature overnight. After 50 ml of water was added, the reaction mixture was extracted with ethyl acetate and the organic layer was washed with a saturated brine and dried over anhydrous sodium sulfate overnight. After the solvent was evaporated under reduced pressure, the resultant crude product was purified by column chromatography on silica gel (WAKOGEL® C-200) eluting with n-hexane/ethyl acetate (6:1) to obtain 24.3 g of 4-benzyloxy-6-bromo-2,3,8-trimethylquinoline.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH2:70]([NH2:74])[CH:71]([CH3:73])[CH3:72]>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:74][CH2:70][CH:71]([CH3:73])[CH3:72])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CC(C)CN
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)NCC(C)C)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-2-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and isobutylamine (10.0 uL, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (12.6 mg, 44%). LC-MS m/z 577 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:28]([NH:30][CH2:31][CH2:32][OH:33])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.C(Cl)(Cl)=O>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([C:22](=[O:27])[C:23]([CH3:26])([CH3:24])[CH3:25])[CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:28]1[O:33][CH2:32][CH2:31][N:30]=1)([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CC1(C)CCC(N(C(=O)C(C)(C)C)[C@H]2C[C@@H](C(=O)NCCO)N(C(=O)OC(C)(C)C)C2)CC1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCC(N(C(=O)C(C)(C)C)[C@H]2C[C@@H](C3=NCCO3)N(C(=O)OC(C)(C)C)C2)CC1
Reaction time: 48 h
Yield: 61.4 %

Procedure:
The product of Step A, (2S,4S)-1-Boc-2-{[(2-hydroxyethyl)amino]carbonyl}-4-[dimethylpropanoyl(4,4-dimethylcyclohexyl)amino]pyrrolidine (410 mg, 0.58 mmol) together with DMAP (70.7 mg, 0.58 mmol) and DIPEA (0.39 ml, 2.32 mmol) were dissolved in toluene (3 ml), and phosgene (20% in toluene, 0.31 ml, 0.87 mmol) was added dropwise. After the reaction solution was stirred at 30˜40° C. for 48 h, the solution was concentrated in vacuo. The residue was diluted with EtOAc, and washed with a saturated NaHCO3 aqueous solution, water and 1N HCl. The organic solution was dried over MgSO4, concentrated in vacuo, and the residue was purified by column chromatography (eluent: EtOAc) to give the title compound (160 mg, 62%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:25]([O-])=[O:26].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:25]=[O:26])[C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CCCCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=CO
Product: CCCCCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h
Yield: 38.8 %

Procedure:
4.3 g of 1-(2-chloroethyl)-3-n-hexyl-3-D-glucopyranosylurea are dissolved in 15 ml of formic acid, and 2.4 g of sodium nitrite are added gradually thereto at 0° to 5° C. for one hour under stirring. The mixture is further stirred at the same temperature for 1.5 hours. After the reaction, the mixture is treated in the same manner as described in Example 5-(2). 1.8 g of 1-(2-chloroethyl)-1-nitroso-3-n-hexyl-3-D-glucopyranosylurea are thereby obtained as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH3:13])[CH:6]=[CH:5]2.C([Li])(C)(C)C.[C:19](=[O:21])=[O:20]>C1COCC1>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:19]([OH:21])=[O:20])[CH:11]=[CH:10]2
Reactant: O=C=O
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc2cc(C(=O)O)ccc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
A solution of 8.00 g (33.8 mmol, Aldrich) of 6-bromo-2-methoxynaphthalene in 75 ml of dry THF was cooled to -78° C. and 36 ml (1.8M in pentane, 65 mmol, Aldrich) of t-butyllithium was added over 30 minutes. The reaction mixture was stirred for 30 minutes at -78° C. then warmed to -20° C. for 30 minutes. The mixture was recooled to -78° C. and b 8.00 g (180 mmol) of crushed dry ice was added to the slurry, and then this was allowed to warm to room temperature over 2 hours. The mixture was concentrated in vacuo, 100 ml of 1N HCl was added to the residue and this was extracted with 100 ml of hot EtOAc. The organic layer was washed with water, dried (MgSO4) and concentrated in vacuo to give a solid. Purification via recrystallization (EtOAc/petroleum ether) afforded 5.80 g (85%) of the title compound as small white needles: m.p. 198°-200° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[C:4](I)[CH:3]=1.N#N.[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19]>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[C:4](/[CH:19]=[CH:18]/[C:17]([O:21][CH3:22])=[O:20])[CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Fc1cc(-n2cnnn2)c(I)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: CC#N
Product: COC(=O)/C=C/c1cc(Cl)c(F)cc1-n1cnnn1
Temperature: 85 °C

Procedure:
A solution of Intermediate 5B (100 g, 324.4 mmol) in ACN (1000 mL) was degassed with N2. TEA (64 mL) and methyl acrylate (60 mL) were added and the reaction was further degassed. Pd(OAc)2 (8 g, 11.8 mmol) was added and the reaction was heated to 85° C. for 18 h. The reaction was concentrated and the residue was diluted with H2O. The aqueous layer was extracted with EtOAc and the combined organics were washed with brine. Purification by silica gel chromatography gave 25 g of Intermediate 5C. MS (ESI) m/z: 283.0 (M+H)+.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([CH:15]=[C:16]([Br:18])[Br:17])[CH2:11][CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:17][C:16]([Br:18])=[CH:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([NH:7][CH3:6])[CH2:10][CH2:11]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C=C(Br)Br)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H]1CC[C@H](C=C(Br)Br)CC1
Reaction time: 2 h

Procedure:
A solution of 975 mg (3.28 mmol) of trans-[4-(2,2-Dibromo-vinyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 20 ml CH2Cl2 was treated at 0° C. with 10 ml TFA (for 20 min). After 2 h at RT, the reaction was evaporated, treated with aqueous saturated NaHCO3(+Na2CO3)/Et2O (3×), dried over Na2SO4 and evaporated to yield 981 mg (87%) of trans-[4-(2,2-Dibromo-vinyl)-cyclohexyl]-methyl-amine, MS: 295 (M, 2Br).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[N:18]1([C:24]2[C:32]3[N:31]=[C:30]([C:33]([F:36])([F:35])[F:34])[NH:29][C:28]=3[CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C(OCC)(=O)C>[F:36][C:33]([F:34])([F:35])[C:30]1[NH:31][C:32]2[C:24]([N:18]3[CH2:19][CH2:20][N:21]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]4[N:9]=[C:10]5[C:5]([CH2:4][CH2:3][C:2](=[O:1])[NH:11]5)=[CH:6][CH:7]=4)[CH2:22][CH2:23]3)=[CH:25][CH:26]=[CH:27][C:28]=2[N:29]=1
Reactant: FC(F)(F)c1nc2c(N3CCNCC3)cccc2[nH]1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5nc(C(F)(F)F)[nH]c45)CC3)nc2N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.7 %

Procedure:
To a suspension of 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yloxy)-butyraldehyde (0.297 g, 1.266 mmol, 1.32 eq) and 4-piperazin-1-yl-2-trifluoromethyl-1H-benzoimidazole (0.258 g, 0.953 mmol, 1 eq) in dichloroethane (5 mL) was added NaBH(OAc)3 (0.723 g, 3.413 mmol, 3.58 eq). The slurry was allowed to stir overnight at room temperature (18 h). Analysis by HPLC showed reaction mostly complete. The mixture was diluted with Ethyl Acetate and quenched with saturated NaHCO3. The organic phase was then washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. Purification by silica gel chromatography (2% MeOH/CH2Cl2) followed by formation of the HCl salt using 1N HCl in ether provided the title compound (0.166 g, 35%). MS: APCI: M+1: 489.2 (Exact Mass: 488.21).
Reaction SMILES: Br.Br.[CH:3]1([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(=O)(O)[O-].[K+].O.[C:27]([O:30][CH2:31]C)(=[O:29])[CH3:28]>CN(C)C=O>[CH:3]1([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:16][CH2:17][N:18]([CH2:10][CH2:9][C:3]4[CH:8]=[CH:7][C:28]([C:27]([O:30][CH3:31])=[O:29])=[CH:5][CH:4]=4)[CH2:19][CH2:20]3)=[CH:11][CH:10]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: c1cc(N2CCNCC2)ccc1C1CCCCC1
Reactant: CCOC(C)=O
Agent: Br
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCN2CCN(c3ccc(C4CCCCC4)cc3)CC2)cc1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
To a suspension of 1-(4-cyclohexylphenyl)piperazine dihydrobromide (2.5 g) and potassium bicarbonate (2.125 g) in N,N-dimethylformamide (6 ml) was added methyl 4-(2-chloroethylphenyl) benzoate (1.22 g) and stirred for 24 hours at 120° C. The reaction mixture was added to a mixture of water and ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give methyl 4-[2-[4-(4-cyclohexylphenyl)-piperazin-1-yl]ethyl]benzoate (1.247 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].I[C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1/[C:16](=[CH:24]/[C:25]1[NH:26][CH:27]=[CH:28][C:29]=1[O:30][CH3:31])/[C:17](=[O:23])[NH:18]2.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:31][O:30][C:29]1[CH:28]=[CH:27][NH:26][C:25]=1/[CH:24]=[C:16]1\[C:17](=[O:23])[NH:18][C:19]2[C:15]\1=[C:14]([C:7]1[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1)[CH:22]=[CH:21][CH:20]=2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(-c3ccc(C(=O)O)cc3)c21
Yield: 30.4 %

Procedure:
Using Method S above, 4-carboxy-phenyl boronic acid (27.2 mg, 0.164 mmol) (Lancaster) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.137 mmol) (Starting Material 3) using (Ph3P)4Pd (4.8 mg) (Aldrich) as catalyst in DME (5 mL) and solid Na2CO3 (51 mg, 0.48 mmol) at reflux for 18 h to give (Z)-4-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-benzoic acid (yield: 15 mg, 31%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[C:12](NC1C=CC(C(O)=O)=CC=1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[C:12]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)cc1
Reactant: Cc1cc(C(=O)O)ccc1N
Product: Cc1cc(C(=O)O)ccc1NC(=O)OC(C)(C)C

Procedure:
4-Amino-3-methylbenzoic acid (5 g, 33.1 mmol) was reacted according to the same procedure as that used in the process for preparing N-BOC-4-aminobenzoic acid. The resulting orange-brown solid was recrystallized from ethyl acetate and hexanes to provide the desired product (4.99 g) as tan prismatic crystals: m.p. 180-182° C.; 1H NMR (CD3OD) δ 1.51 (9h, s), 2.27 (3H, s), 7.66 (1H, d, J=8.1 Hz), 7.79-7.82 (2H, m), 8.32 (1H, s); 13C NMR (CD3OD) δ 17.98, 28.62, 81.47, 123.12, 127.05, 129.14, 130.65, 132.99, 142.45, 155.33, 168.70; Anal. Calc. for C13H17NO4, C: 62.15, H: 6.82, N: 5.58; Found C: 62.07, H: 6.86, N: 5.46; m/z (EI) 251; HRMS Calc. for C13H17NO4, 251.1158; Found, 251.1153.
Reaction SMILES: [CH3:1][C:2]([CH3:46])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:45])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:44])=[CH:11]/[CH2:12][CH2:13]/[C:14](/[CH3:43])=[CH:15]/[CH2:16][CH2:17]/[C:18](/[CH3:42])=[CH:19]/[CH2:20][CH2:21]/[C:22](/[CH3:41])=[CH:23]/[CH2:24][CH2:25]/[C:26](/[CH3:40])=[CH:27]/[CH2:28][CH2:29]/[C:30](/[CH3:39])=[CH:31]/[CH2:32][CH2:33]/[C:34](/[CH3:38])=[CH:35]/[CH2:36][OH:37].[CH:47]1([C:53](Cl)=[O:54])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>N1C=CC=CC=1.CCCCCC>[CH:47]1([C:53]([O:37][CH2:36][CH:35]=[C:34]([CH3:38])[CH2:33][CH2:32][CH:31]=[C:30]([CH3:39])[CH2:29][CH2:28][CH:27]=[C:26]([CH3:40])[CH2:25][CH2:24][CH:23]=[C:22]([CH3:41])[CH2:21][CH2:20][CH:19]=[C:18]([CH3:42])[CH2:17][CH2:16][CH:15]=[C:14]([CH3:43])[CH2:13][CH2:12][CH:11]=[C:10]([CH3:44])[CH2:9][CH2:8][CH:7]=[C:6]([CH3:45])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:46])[CH2:1][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[O:54])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO
Reactant: O=C(Cl)C1CCCCC1
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCCCCCCCCCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCOC(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 Grams of solanesol were dissolved in 50 ml of pyridine and the solution was added dropwise with of 15% solution of 4.6 g of cyclohexylcarboxylic acid chloride in pyridine over 30 minutes. After completion of the addition, the mixture was stirred at room temperature for two hours to complete the reaction. Then, the reaction product was diluted with n-hexane, washed with water and concentrated. The concentrate was purified by chromatography with 80 g of silica gel in n-hexane/benzene solvent mixture as elution solvent to obtain the final product as a white solid (m.p. 34.0°-35.0° C.). Yield: 6.2 g.
Reaction SMILES: [C:1]([C:4]1[C:8]([Cl:9])=[C:7]([C:10]([OH:12])=O)[NH:6][N:5]=1)(=[O:3])[CH3:2].[NH2:13][C@@H:14]([CH3:30])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=2)=[N:17]1>>[C:1]([C:4]1[C:8]([Cl:9])=[C:7]([C:10]([NH:13][C@@H:14]([CH3:30])[CH2:15][N:16]2[CH:20]=[CH:19][C:18]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=3)=[N:17]2)=[O:12])[NH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(=O)c1n[nH]c(C(=O)O)c1Cl
Product: CC(=O)c1n[nH]c(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c1Cl
Yield: 30.8 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 3-acetyl-4-chloro-1H-pyrazole-5-carboxylic acid (0.527 g, 2.79 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.56 g, 2.148 mmol). The product was purified by reverse phase flash chromatography. Yield 30.8%. 1H-NMR (400 MHz; DMSO-d6): δ 1.16 (d, 3H), 2.54 (s, 3H), 4.31 (dd, 1H), 4.37 (dd, 1H), 4.42-4.51 (m, 1H), 6.95 (d, 1H), 7.84 (d, 1H), 7.94 (dd, 1H), 7.98 (d, 1H), 8.06 (d, 1H), 8.27 (bs, 1H), 14.45 (s, 1H).
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][C:18]=2[Cl:26])=[CH:13][S:12][C:11]=1[N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37])=[O:9])C.Cl>O>[Cl:26][C:18]1[CH:19]=[C:20]([CH:23]([CH3:25])[CH3:24])[CH:21]=[CH:22][C:17]=1[CH:16]=[CH:15][C:14]1[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:27]2[C:35](=[O:36])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]2=[O:37])[S:12][CH:13]=1
Reactant: CCOC(=O)c1c(C=Cc2ccc(C(C)C)cc2Cl)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)c1ccc(C=Cc2csc(N3C(=O)c4ccccc4C3=O)c2C(=O)O)c(Cl)c1

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 4-[2-(2-chloro-4-isopropylphenyl)vinyl]-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 31, Part C). The mixture is heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C(N(CC)CC)C.[CH2:19]([OH:22])[C:20]#[CH:21]>CN(C=O)C.[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:22][CH2:19][C:20]#[C:21][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: C#CCO
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCc2cc(C#CCO)ccc21
Yield: 71.2 %

Procedure:
5-Bromo-2,3-dihydro-1H-inden-1-one (1.68 g, 7.99 mmol) was dissolved in DMF and treated with triethylamine (1.61 g, 15.98 mmol), copper iodide (152 mg, 0.79 mmol) and prop-2-yn-1-ol (2.24 g, 39.96 mmol) in the presence of Pd(PPh3)4 (462 mg, 0.39 mmol) at ambient temperature. After being refluxed for 16 h, the reaction mixture was extracted with ethyl acetate (100 mL×3) and washed with brine. The combined organic layers were dried over MgSO4. Solvent removal under vacuum gave crude tan oil. Purification by preparative thin-layer chromatography afforded 5-(hydroxyprop-1-yn-1-yl)-2,3-dihydro-1H-indene-1-one (1.06 g, 72% yield): 1H NMR (400 MHz, CD3OD): δ 7.63 (d, 1H), 7.59 (s, 1H), 7.42 (d, 1H), 4.45 (s, 2H), 3.18 (m, 2H), 2.69 (m, 2H); MS (EI) for C12H10O2: 187.20 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH3:11])[C:6]=2[C:5]([F:12])=[C:4]([F:13])[CH:3]=1.BrN1[C:19](=[O:20])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][O:20][CH3:19])[C:6]=2[C:5]([F:12])=[C:4]([F:13])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1coc2c(Br)cc(F)c(F)c12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COCc1coc2c(Br)cc(F)c(F)c12
Yield: 41 %

Procedure:
To the compound (49.4 mg, 0.200 mmol) of Step 1 of Example 21, N-bromosuccinimide (hereinafter, NBS) (39.2 mg, 0.220 mmol), and a catalytic amount of benzoyl peroxide (hereinafter, BPO), carbon tetrachloride (2 mL) was added, and heated under reflux overnight. After the resultant was returned to room temperature, the insoluble material was filtered off. The solvent was distilled away under reduced pressure. The resulting residue was dissolved in methanol (2 mL), and a 25% sodium methoxide methanol solution (0.2 mL) was added thereto and heated under reflux for 3 hours. The resultant was returned to room temperature, and the solvent was distilled away under reduced pressure. To the resulting residue, 1 N hydrochloric acid (1 mL) and a saturated aqueous ammonium chloride solution were added, and extraction was performed with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The resulting residue was purified by silica gel chromatography to thus obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12]2[CH:13]=[C:14]([C:18](=O)[CH3:19])[CH:15]=[CH:16][CH:17]=2)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:21].[NH:22]1[CH2:25][CH:24]([C:26]([OH:28])=[O:27])[CH2:23]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:18]([N:22]3[CH2:25][CH:24]([C:26]([OH:28])=[O:27])[CH2:23]3)[CH3:19])[CH:15]=[CH:16][CH:17]=2)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:21]
Reactant: O=C(O)C1CNC1
Reactant: CC[C@@H](Nc1cccc(C(C)=O)c1)c1ccc(Cl)c(C)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@@H](Nc1cccc(C(C)N2CC(C(=O)O)C2)c1)c1ccc(Cl)c(C)c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of INT 11 (213 mg, 0.71 mmol) and azetidine-3-carboxylic acid (75 mg, 0.74 mmol) in MeOH (7 mL) was added HOAc (0.040 mL, 0.71 mmol) followed by NaCNBH3 (44 mg, 0.71 mmol). The reaction mixture was stirred at room temperature for 40 hours. More azetidine-3-carboxylic acid (10 mg, 0.099 mol) and NaCNBH3 (10 mg, 0.16 mmol) were added and the mixture was stirred at room temperature for an additional 4 hours. The mixture was concentrated. The residue was taken up in CH2Cl2 and washed with brine. The aqueous layer was extracted with CH2Cl2 and EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by preparative HPLC (H2O/CH3CN) to afford the title compound Example 6.