Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:10][C:11]1[C:16](=[O:17])[CH:15]=[C:14]([CH3:18])O[C:12]=1[C:19]([OH:21])=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH3:1][NH2:2].[CH2:3]([O:10][C:11]1[C:16](=[O:17])[CH:15]=[C:14]([CH3:18])[N:2]([CH3:1])[C:12]=1[C:19]([OH:21])=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1
Agent: CN
Solvent: CO
Product: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)O)n1C
Temperature: 70 °C
Yield: 87 %

Procedure:
As described previously, a 2 M methylamine solution in methanol (5.8 ml, 11.6 mmol) was added to a suspension of the 3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carboxylic acid (1.0 g, 3.84 mmol) in methanol (3 ml) at room temperature. The resulting solution was sealed, and then heated at 70° C. for overnight. A clear yellow solution was observed. The titled compound was obtained as a light yellow solid after solvent was removed by reducing pressure (1.02 g, 87% yield). 1H NMR (DMSO-D6) δ(ppm): 7.8 (br, 2H), 7.49 (m, 2H), 7.3 (m, 3H), 6.03 (s, 1H), 4.91 (s, 2H), 3.47 (s, 3H), 2.35 (s, 3H), 2.24 (s, 3H); MS (m/z): 274 (C15H16NO4+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:18])[NH:15][CH2:16][CH2:17][C:12]=3[C:11]([C:19]([F:22])([F:21])[F:20])=[N:10]2)=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:26][C:27]([O:29][CH3:30])=[O:28]>CN(C)C=O>[CH3:30][O:29][C:27](=[O:28])[CH2:26][N:15]1[CH2:16][CH2:17][C:12]2[C:11]([C:19]([F:22])([F:20])[F:21])=[N:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:13]=2[C:14]1=[O:18]
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)NCC3)cc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1CCc2c(C(F)(F)F)nn(-c3ccc(OC)cc3)c2C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
Part D: 1-(4-Methoxy-phenyl)-3-trifluoromethyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one (1.0 g, 3.213 mmol) was dissolved in N,N-dimethylformamide (20 mL) and cooled to 0° C. Sodium hydride (60%, 0.321 g, 8.032 mmol) was added followed by methyl bromoacetate (0.608 mL, 6.425 mmol). The reaction was stirred at rt overnight. The reaction was quenched with 1N hydrochloric acid (100 mL), extracted with ethyl acetate (3×100 mL), washed with water (2×100 mL), washed with brine (1×100 mL), dried over MgSO4, concentrated, and purified by flash chromatography using 0–100% ethyl acetate/hexanes gradient as the eluent to afford the title compound (0.91 g, 74%): 1H NMR (CDCl3) δ 7.45 (d, j=8.8 Hz, 2H), 6.96 (d, j=9.2 Hz, 2H), 4.25 (s, 2H), 3.84 (s, 3H), 3.78 (t, j=7.0 Hz, 2H), 3.75 (m, 3H), 3.02 (t, j=6.8 Hz, 2H) ppm.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)#[N:14].N12CCCN=C1CCCCC2.O>CN(C=O)C>[O:12]=[C:5]1[N:6]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([C:13]#[N:14])=[CH:16][CH:17]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=2[C:2](=[O:3])[O:4]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Cn2c(=O)oc(=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 48.4 %

Procedure:
To a stirred mixture of isatoic anhydride (2.0 g) and 4-cyano-benzyl bromide (2.40 g) in DMF (20 ml) was added drop-wise 1,8-diazabicyclo[5,4,0]-undec-7-ene (2.20 ml). The reaction mixture was stirred at room temperature for 22 hours, cooled in an ice-bath and water (75 ml) was added. The resulting precipitated material was isolated by filtration and re-crystallised from hot toluene and gave the title compound (1.65 g) as an off-white solid. 13C-NMR (DMSO-d6) δ 158.7, 148.2, 141.2, 141.1, 136.9, 132.4, 129.5, 128.8, 128.1, 127.5, 123.7, 118.6, 114.8, 112.2, 110.2, 47.3.
Reaction SMILES: [Si]([O:8][C@H:9]([CH3:42])[CH2:10][CH2:11][CH2:12][C@H:13]([OH:41])/[CH:14]=[CH:15]/[C@H:16]1[C@H:20]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:19][C@@H:18]([Cl:28])[C@@H:17]1[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH:39]=[CH2:40])=[O:36])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>>[Cl:28][C@H:18]1[C@H:17]([CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH:39]=[CH2:40])=[O:36])[C@@H:16](/[CH:15]=[CH:14]/[C@@H:13]([OH:41])[CH2:12][CH2:11][CH2:10][C@H:9]([OH:8])[CH3:42])[C@H:20]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:19]1
Reactant: C=CCOC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCC[C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H](OC2CCCCO2)C[C@H]1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCOC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCC[C@@H](C)O)[C@H](OC2CCCCO2)C[C@H]1Cl
Yield: 79.3 %

Procedure:
A solution of silyl ether 7 (270 mg, 0.43 mmol) was stirred at 30° C. with 2 mL (2 mmol) of 1.0M TBAF/THF in a vial for 20 h. TLC indicated starting material was mostly desilylated and the reaction was concentrated in vacuo. The residual crude products were taken up in 50 mL of ethyl acetate and washed sequentially with saturated ammonium chloride (50 mL), brine (50 mL), and dried over 10 g of anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo. The residual products were purified by flash column chromatography on 20 g of silica gel eluted in 1:1 hexanes:EtOAc, then straight EtOAc. Combination of appropriate fractions and removal of the solvents yielded 175 mg (79%) of pure diol 8 as an oil; 1H NMR (CDCl3): 1.18 (d, J=6 Hz, 3H), 1.38-1.84 (m, 13H), 1.91 (m, 1H), 2.00-2.40 (m, 11H), 3.47 (m, 1H), 3.81 (m, 2H), 3.99 (m, 1H), 4.09 (m, 2H), 4.54-4.72 (m, 3H), 5.21-5.66 (m, 6H), 5.92 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]=[C:18]1[C:23]2=[CH:24][NH:25][C:26]([CH:27]=O)=[C:22]2[CH2:21][CH2:20][O:19]1>>[O:16]=[C:11]1[C:10](=[CH:27][C:26]2[NH:25][CH:24]=[C:23]3[C:18](=[O:17])[O:19][CH2:20][CH2:21][C:22]=23)[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=2)[NH:12]1
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: O=C1Nc2ccc(-c3ccccc3)cc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
5-Phenyl-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](O)([C:13]1[C:22]([OH:23])=[CH:21][C:16]3[O:17][CH2:18][CH2:19][O:20][C:15]=3[CH:14]=1)[C:5](=[O:12])[N:6]2[CH3:11].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:13]1[C:22]([OH:23])=[CH:21][C:16]3[O:17][CH2:18][CH2:19][O:20][C:15]=3[CH:14]=1)[C:5](=[O:12])[N:6]2[CH3:11]
Reactant: CN1C(=O)C(O)(c2cc3c(cc2O)OCCO3)c2c(Br)cccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)C(c2cc3c(cc2O)OCCO3)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.8 %

Procedure:
To a stirred solution of 4-bromo-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-methyl-1,3-dihydro-2H-indol-2-one (61.0 g; 155 mmol) and triethylsilane (75.0 mL, 456 mmol) in dichloromethane (300 mL) was added trifluoroacetic acid (48 mL, 623 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 20 h and concentrated in vacuo. The residue was triturated in methanol and washed with diethyl ether to afford 4-bromo-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-methyl-1,3-dihydro-2H-indol-2-one (57.0 g, 97%): 1H NMR (300 MHz, CDCl3) δ 7.31-7.17 (m, 3H), 6.87-6.83 (m, 1H), 6.62 (s, 1H), 6.17 (s, 1H), 4.97 (s, 1H), 4.22-4.08 (m, 4H), 3.18 (s, 3H); MS (ES+) m/z 376.1 (M+1), 378.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[P:9](OC)OC.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1>C(OCC)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([P:9]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[CH:17][CH:16]=1
Reactant: COc1ccccc1P(OC)OC
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: CCOCC
Product: COc1ccccc1P(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 58 %

Procedure:
To a stirred solution of dimethyl 2-methoxyphenylphosphonite (1.0 g, 5.0 mmol) in diethyl ether (40 mL) at 0° C. is added dropwise over 30 minutes a solution (1 M) of (4-chlorophenyl)magnesium bromide in diethyl ether (10.5 mL, 10.5 mmol). After allowing to warm to room temperature, the mixture is filtered and stripped to give an oil that is triturated with MeOH to give a white solid (0.98 g, 58%) 1H NMR (C6D6): δ 7.09 (m, 5H), 7.03 (m, 4H), 6.78 (m, 1H), 6.74 (m, 1H), 6.47 (d of d, 1H, J=8.2, 4.7), 3.16 (s, 3H); 13C NMR (C6D6): δ 161.47 (d, 1C, JCP=15.1 Hz), 135.88 (d, 2C, JCP=13.8 Hz), 135.52 (d, 4C, JCP=21.4), 135.30 (s, 2C), 133.74 (d, 1C, JCP=2.6 Hz), 130.86 (s, 1C), 128.99 (d, 4C, JCP=6.6 Hz), 125.60 (d, 1C, JCP=14.2 Hz), 121.47 (s, 1C), 110.64 (s, 1C), 55.15 (s, 1C); 31P NMR (C6D6) δ-16.54. Elemental analysis calculated for C19H15Cl2OP: C, 63.18; H, 4.19; 0, 4.43; P, 8.58. Measured: C, 63.31; H, 4.40.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4](=[N:11][OH:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[K+].S(OC)(O[CH3:23])(=O)=O>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH3:23][O:12][N:11]=[C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[NH2:1]
Reactant: Nc1ccccc1C(=NO)c1ccccc1
Reactant: COS(=O)(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CON=C(c1ccccc1)c1ccccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.0 g (14.15 mmol) of 2-amino-benzophenone oxime in 120 ml of tetrahydrofuran is treated successively with 1.07 g of potassium hydroxide, 100 mg of tetrabutylammonium bromide, 1.81 ml of dimethyl sulphate and the mixture is stirred at room temperature overnight. The mixture is taken up in methylene chloride, washed with water, dried and evaporated. The residue is twice suspended in boiling ether and filtered off, there being obtained 2-amino-benzophenone O-methyl oxime of melting point 138°.
Reaction SMILES: N[C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1.[ClH:10].N([O-])=O.[Na+].O>O1CCOCC1.[Cu](Cl)Cl.C(OCC)(=O)C>[Cl:10][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: Nc1nc(C(=O)O)cs1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(O)c1csc(Cl)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a solution of 2.84 g (19.7 mmol) of 2-aminothiazole-4-carboxylic acid in 30 ml of 1,4-dioxane was added 50 ml of concentrated hydrochloric acid, followed by cooling to 0° C., and 10 ml of an aqueous solution of 2.04 g (29.6 mmol) of sodium nitrite was added charged dropwise thereto at 0° C. to 5° C. The reaction liquid was stirred at 0° C. for 2 hours, and then 2.93 g (29.6 mmol) of copper chloride was charged in separate portions thereto. The reaction liquid was returned to room temperature, followed by stirring for 8 hours. To the reaction liquid were added water and ethyl acetate, followed by extraction with ethyl acetate four times. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to prepare 1.77 g (yield 55%) of a target compound.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[CH:16]=[N:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:19]=2)O1.Br[C:29]1[CH:30]=[C:31]([NH2:35])[CH:32]=[N:33][CH:34]=1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O.O1CCCC1>[C:23]([O:22][C:20]([N:18]1[CH:19]=[C:15]([C:29]2[CH:34]=[N:33][CH:32]=[C:31]([NH2:35])[CH:30]=2)[CH:16]=[N:17]1)=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: Nc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)n1cc(-c2cncc(N)c2)cn1
Reaction time: 2.75 h
Yield: 34.6 %

Procedure:
Water (0.5 ml), sodium carbonate (92 mg), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-carboxylate (203 mg), and bis(tri-tert-butylphosphine)palladium (30 mg) were added to a tetrahydrofuran (4.5 ml) solution containing 5-bromopyridin-3-amine (100 mg) in a nitrogen atmosphere, followed by stirring for 2.75 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (chloroform:methanol=1:0 to 30:1), and a white solid of tert-butyl-4-(5-aminopyridin-3-yl)-1H-pyrazol-1-carboxylate (52 mg) was thus obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Br:24])[CH:23]=1)[C:5]([N:7]([CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:11][CH:12]=C)[CH3:8])=[O:6].FC1C=CC([C@H](CC=C)CN(C)C(=[O:50])C2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Br:24])[CH:23]=1)[C:5]([N:7]([CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:11][CH:12]=[O:50])[CH3:8])=[O:6]
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(F)cc1
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(Br)cc(Br)c1)c1ccc(F)cc1
Product: CN(C[C@@H](CC=O)c1ccc(F)cc1)C(=O)c1cc(Br)cc(Br)c1

Procedure:
The compound was synthesized in an analogous way to that of Method 20b but using 3,5-dibromo-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methylbenzamide rather than N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methyl-3,5-bis(trifluoromethyl)benzamide (yield, 96%). 1H NMR (400 MHz, CDCl3): 2.6-3.9 (cm, 8H), 6.8-8.2 (cm, 7H), 9.8 (s, 1H).
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:7][N:6]=[C:5]([CH2:8][C:9]([OH:11])=O)[CH:4]=1.[CH2:12]([C@H:19]1[CH2:23][NH:22][C@H:21]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[CH:29][CH:28]=2)=[O:25])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([C@H:19]1[CH2:23][N:22]([C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[C:3]([CH3:2])[NH:7][N:6]=2)[C@H:21]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)=[CH:29][CH:28]=2)=[O:25])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cc(CC(=O)O)n[nH]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: Cc1cc(CC(=O)N2C[C@H](Cc3ccccc3)C[C@H]2C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)n[nH]1
Yield: 45 %

Procedure:
Proceeding as in Example 1, but substituting 2-(5-methyl-1H-pyrazol-3-yl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 177, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(5-methyl-1H-pyrazol-3-yl)acetyl)pyrrolidine-2-carboxamide (42 mg, 45%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 12.25 (s, 1H), 9.92 (s, 1H), 7.63-7.54 (m, 2H), 7.33-7.26 (m, 2H), 7.25-7.15 (m, 6H), 7.05-6.93 (m, 4H), 5.87 (s, 1H), 4.52-4.45 (m, 1H), 3.77-3.45 (m, 2H), 3.34-3.27 (m, 2H), 2.24-1.85 (m, 6H). MS (EI) for C30H29FN4O3. found 513.0 (MH+).
Reaction SMILES: CO[C:3]([C:5]1([CH2:8][S:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([C:25]3[S:26][C:27]4[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=4[N:29]=3)[O:17][CH:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:11]=2)[CH2:7][CH2:6]1)=O.[Li].[C:35](OCC)(=[O:37])C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[S:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[CH:16]([O:17][CH:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]1)[C:12]1[CH:11]=[C:10]([S:9][CH2:8][C:5]2([CH2:3][CH2:35][OH:37])[CH2:6][CH2:7]2)[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C1(CSc2cccc(C(OC3CCN(C)CC3)c3nc4ccccc4s3)c2)CC1
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [Li]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(OC(c2cccc(SCC3(CCO)CC3)c2)c2nc3ccccc3s2)CC1
Reaction time: 0.08 h

Procedure:
To a solution of 1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}cyclopropanecarboxylic acid methyl ester (56 mg) in tetrahydrofuran (5 mL) is added lithium aluminumhydride (25 mg) at 0° C. The reaction mixture is allowed to reach room temperature and ethyl acetate (2 mL) is added. After stirring for 5 minutes, a half-saturated aqueous solution of sodium carbonate (6 mL) is added. 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) to afford 2-(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}cyclopropyl)ethanol.
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]([CH3:14])([CH3:13])[CH:6]([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].CC(C)([O-])C.[K+]>O1CCCC1>[CH3:12][C:6]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]([CH3:14])([CH3:13])[CH:4]1[CH:3]=[CH2:2]
Reactant: CCOC(=O)C(C)C(C)(C)C=CCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC1C(C)(C)C1(C)C(=O)OCC
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A solution of 526 mg (2 mmoles) of ethyl 6-bromo-2,3,3-trimethyl-4-hexenoate in 2 ml of anhydrous tetrahydrofuran was added dropwise to a suspension of 224 mg (2 mmoles) of potassium t-butoxide in 10 ml of tetrahydrofuran. The mixture was heated under reflux for two hours and then allowed to cool to room temperature. An additional 116 mg (1 mmole) of potassium t-butoxide was added, and the mixture again heated under reflux for two hours. The reaction mixture was poured into ice water, and the aqueous mixture extracted with diethyl ether. The ether extract was dried over magnesium sulfate and distilled to give 200 mg (55% yield) of ethyl 1,3,3-trimethyl-2-vinylcyclopropanecarboxylate, b.p. 92°-95°/1.5 mm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([OH:13])=O)[NH:10][C:5]2=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:18]([NH:20][NH2:21])=[O:19].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([NH:21][NH:20][C:18](=[O:19])[C:17]3[CH:22]=[CH:23][C:24]([Cl:25])=[C:15]([Cl:14])[CH:16]=3)=[O:13])[NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2nc(Cl)ccc2[nH]1
Reactant: NNC(=O)c1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NNC(=O)c1cc2nc(Cl)ccc2[nH]1)c1ccc(Cl)c(Cl)c1
Reaction time: 0.08 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (Preparation 5, 20.0 mg, 0.10 mmol) in DMF (5 mL) was added 3,4-dichlorobenzoic acid hydrazide (23 mg, 0.11 mmol), DIPEA (19.5 μL, 0.11 mmol) and HOBt (14.0 mg, 0.10 mmol). The resulting solution was stirred for 5 min prior to the addition of EDCI (23 mg, 1.20 mmol). The reaction mixture was stirred for 16 hr at rt then partitioned between water (10 mL) and dichloromethane (20 mL) on a hydrophobic frit. The aqueous phase was extracted with a further portion of dichloromethane (30 mL) and the combined organics were concentrated in vacuo. Trituration of the resulting residue with ethyl acetate/dichloromethane gave the title compound. δH (d6 DMSO): 12.25 (1H, s), 10.83 (2H, d), 8.17 (1H, s), 7.55-7.97 (3H, m), 7.38 (1H, s), 7.26 (1H, d); m/z (ES+)=383 [M+H]+; RT=3.37 min.
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:6](=[C:7]3[C:12](=[C:13]([NH2:16])[N:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:23][CH:24]=O>CC(O)C>[Br:1][C:2]1[C:15]2[N:14]3[CH:23]=[CH:24][N:16]=[C:13]3[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCl
Reactant: Nc1nc2c(Br)cccc2c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Brc1cccc2c3ccccc3c3nccn3c12
Temperature: 75 °C
Yield: 62.6 %

Procedure:
To a mixture of 4-bromo-6-aminophenanthridine (19.11 g, 69.91 mmole), sodium bicarbonate (12.3 g, 146 mmole) in 2-propanol (200 ml) was added chloroacetaldehyde (50% aqueous soln. 17.35 g). After the reaction mixture was heated at 75° C. for 5 hrs., the solvent was removed. The residue was redissolved in methylene chloride and washed with water. The organic fractions were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude mixture was purified by chromography on silica gel using hexane/ethyl acetate (80/20) to obtain the title compound (13 g, 62%).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.[H][H]>C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C.[OH-].[Pd+2].[OH-]>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:17][CH3:18])[N:8]=[CH:7][CH:6]=[C:5]2[O:4][C:3]1[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:2]=1[CH3:1]
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3C)c2cc1OC
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(N)cc3C)c2cc1OC
Yield: 105.6 %

Procedure:
4-Chloro-6,7-dimethoxyquinazoline (5.00 g) and 4-nitro-2-methylphenol (6.85 g) were suspended in monochlorobenzene (25 ml) to prepare a suspension which was then heated under reflux overnight. The solvent was removed by distillation under the reduced pressure. The residue was washed with ethyl acetate, was filtered, and was dried. Next, the resultant crystal was suspended in an aqueous sodium hydroxide solution to prepare a suspension. The suspension was then filtered, followed by drying to give 6.89 g of 4-(2-methyl-4-nitrophenoxy)-6,7-dimethoxyquinoline. 4-(2-Methyl-4-nitrophenoxy)-6,7-dimethoxyquinoline (1.36 g) was dissolved in ethyl acetate/N,N-dimethylformamide/triethylamine (25 ml/25 ml/5 ml). Palladium hydroxide (0.4 g) was added to the solution, and the mixture was stirred in a hydrogen atmosphere at room temperature overnight. After filtration through Celite, the solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure to give the title compound (1.31 g, yield 91%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH3:18])[CH:16]=2)[C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(C(Cl)=O)=O.[NH2:25][C:26]1[C:27]([CH3:34])=[C:28]([OH:33])[CH:29]=[CH:30][C:31]=1[F:32].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C1COCC1.O.CN(C=O)C>[F:32][C:31]1[C:26]([NH:25][C:11](=[O:13])[C:10]2[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH:9]=2)=[C:27]([CH3:34])[C:28]([OH:33])=[CH:29][CH:30]=1
Reactant: COc1cc(C(=O)O)cc(-c2cccc(F)c2)c1
Reactant: Cc1c(O)ccc(F)c1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(=O)Nc2c(F)ccc(O)c2C)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.5 %

Procedure:
To a solution of 3-(3-fluorophenyl)-5-methoxy-benzoic acid (524 mg, 2.1 mmol, 1.0 eq) in CH2Cl2 (10 mL) was added dropwise (COCl)2 (810 mg, 6.4 mmol, 3 eq) at 0° C. DMF (0.1 mL) was added and the reaction mixture stirred at room temperature for 3 h. The solvent was removed under reduced pressure and the residue obtained was dissolved in THF (20 mL) and added dropwise to a mixture of 3-amino-4-fluoro-2-methyl-phenol (300 mg, 2.1 mmol, 1 eq) and K2CO3 (1.47 g, 10.6 mmol, 5 eq.) in THF (20 mL) at 0° C. After the addition, the reaction mixture was stirred at room temperature for 3 h. The resulting mixture was poured into water and extracted with EtOAc. The organic extract was washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 20:1) to give the title compound as yellow solid (500 mg, 63%).