Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].N1C=CC=CC=1>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:25](=[O:27])[CH3:26])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(N)cc2)c1C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(NC(C)=O)cc2)c1C
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
To a solution of [4-(4-Amino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (115 mg, 0.34 mmol) and acetic anhydride (68.8 mg, 67 mmol) were mixed together under nitrogen and then pyridine (3 mL) was added to afford clear solution which was stirred for 10 minutes. The mixture was diluted with ethyl acetate (20 mL) and washed with 1.0 N HCl solution (10 mL), brine solution (20 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum gave [4-(4-acetylamino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (120 mg, 93.1%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.13 (s, 1 H), 7.94 (d, J=8.8 Hz, 1 H), 7.86 (s, 1 H), 7.76 (d, J=8.2 Hz, 2 H), 7.46 (dd, J=8.8, 1.8 Hz, 1 H), 7.11-7.19 (m, 3 H), 3.95 (s, 2 H), 3.65 (s, 3 H), 2.10 (s, 3 H), 2.07 (s, 3 H). HRMS calcd. for C22H19ClNO3 [(M−H)−.
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:16]C)[CH:3]=1.B(Br)(Br)Br.Cl>ClCCl>[OH:16][C:4]1[CH:3]=[C:2]([CH3:1])[C:11]([C:12]([F:13])([F:14])[F:15])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(C(F)(F)F)c(C)cc1OC
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1cc(C(F)(F)F)c(C)cc1O
Reaction time: 2 h

Procedure:
To a solution of methyl 4-methyl-2-(methyloxy)-5-(trifluoromethyl)benzoate (may be prepared as described in Description 44; 1.76 g, 7.09 mmol) in dichloromethane (70 ml) at 0° C. was added BBr3 (14.89 ml, 14.89 mmol). The solution was stirred for 2 hours, 2M HCl (30 ml) was added and the organic layer removed in vacuo. The residue was partitioned between water (10 ml) and ethyl acetate (20 ml). The organic layer was separated, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (SiO2, 3:1 cyclohexane/ethyl acetate) to give the title compound as an oil. 1.37 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([NH2:28])[CH:23]=[C:22]2[CH2:29][CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([NH:28][C:15]([C:11]1[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=1)=[O:17])[CH:23]=[C:22]2[CH2:29][CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1
Reactant: Nn1cc(CCc2cccnc2)c2cc(F)ccc21
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(CCc2cccnc2)c2cc(F)ccc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 1.3 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (232 mg, 1 mmol) and 5-fluoro-3-(2-pyridin-3-yl-ethyl)-indol-1-ylamine (255 mmol) in DMF (10 mL) is stirred at 50° C. for 10 min. The mixture is treated with DMTMM (276 mg, 1 mmol) and stirred at 50° C. for 0.5 h. The mixture is diluted with saturated aqueous Na2CO3 (50 mL), and extracted with EtOAc (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by triturating in MeOH:H2O (2:1) to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid [5-fluoro-3-(2-pyridin-3-yl-ethyl)-indol-1-yl]-amide (6 mg, 1%). MS: 470 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 9.21 (s, 1H), 8.51 (m, 1H), 8.40 (m, 1H), 8.33 (d, 1H), 8.19 (d, 1H), 7.74 (d, 1H), 7.63 (m, 1H), 7.45 (m, 4H), 7.33 (m, 1H), 7.06 (m, 1H), 3.29 (s, 2H), 3.01 (s, 2H), 2.77 (s, 3H).
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([N:11]([CH2:17][CH3:18])[CH2:12][CH2:13][CH2:14]2)[CH2:9]1)C1C=CC=CC=1.CO>[OH-].[OH-].[Pd+2].CCOC(C)=O>[CH2:17]([N:11]1[CH2:12][CH2:13][CH2:14][CH:15]2[CH2:16][NH:8][CH2:9][CH:10]12)[CH3:18]
Reactant: CCN1CCCC2CN(Cc3ccccc3)CC21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN1CCCC2CNCC21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-benzyl-1-ethyloctahydro-1H-pyrrolo[3,4-b]pyridine (2.58 g) in the mixture solvent of MeOH and EtOAc was added a catalytic amount of 20% Pd(OH)2/C. The mixture was stirred for 2 h at room temperature under H2 and filtered. The filtrate was concentrated in vacuo and the residue was used for the next step without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 155.2 (M+1).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:38][C:39](=[O:41])[CH3:40])([CH2:33][O:34][C:35](=[O:37])[CH3:36])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]3[C:19](=[C:20](OS(C(F)(F)F)(=O)=O)[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(=[O:3])[CH3:2].[C:42]1([SH:48])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(N(C(C)C)CC)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O>[C:35]([O:34][CH2:33][C:6]([NH:38][C:39](=[O:41])[CH3:40])([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]3[C:19](=[C:20]([S:48][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)NC(CCc1ccc(-c2cccc3c(OS(=O)(=O)C(F)(F)F)cccc23)cc1)(COC(C)=O)COC(C)=O
Reactant: Sc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)NC(CCc1ccc(-c2cccc3c(Sc4ccccc4)cccc23)cc1)(COC(C)=O)COC(C)=O
Temperature: 120 °C
Reaction time: 3 h

Procedure:
The compound (200 mg) of Example (1-3) was dissolved in 1,4-dioxane (700 μL), and benzenethiol (40 μL), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (9 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (10 mg) and diisopropylethylamine (120 μL) were added. The mixture was stirred at 120° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was crudely purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give a mixture (170 mg) as a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[C:33](Cl)(=[O:37])[CH2:34][CH2:35][CH3:36]>>[NH2:8][C:9]1[C:14]([C:15](=[O:16])[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([C:33](=[O:37])[CH2:34][CH2:35][CH3:36])[CH2:31][CH2:32]2)[N:10]=1
Reactant: CCCC(=O)Cl
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: O=C(O)C(F)(F)F
Product: CCCC(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 60 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and butyryl chloride (Aldrich) to give 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-butan-1-one. MS (M+H)+, 416.
Reaction SMILES: [Na:1].[CH3:2][C:3]1[C:4]([CH2:22][S:23]([C:25]2[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[N:26]=2)=[O:24])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10]C1(C)OCC2(OCCO2)CO1.ClC1C=C[N+]([O-])=C(C)C=1C.[CH3:44][O:45][CH2:46][C:47]1([CH2:52]CO)[O:51][CH2:50][CH2:49][O:48]1>>[Na:1].[CH3:44][O:45][CH2:46][C:47]1([CH2:52][CH2:10][O:9][C:8]2[CH:7]=[CH:6][N:5]=[C:4]([CH2:22][S:23]([C:25]3[NH:29][C:28]4[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=4[N:26]=3)=[O:24])[C:3]=2[CH3:2])[O:51][CH2:50][CH2:49][O:48]1
Reactant: Cc1c(OCC2(C)OCC3(CO2)OCCO3)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: COCC1(CCO)OCCO1
Agent: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [Na]
Product: COCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCCO1
Yield: 3.9 %

Procedure:
The same procedure as in the steps (5d) to (5h) of Example 5 was repeated using 4-chloro-2,3-dimethylpyridine 1-oxide and 2-(2-(methoxymethyl)-1,3-dioxolan-2-yl)ethanol to obtain the title compound (312 mg, 5 steps 3.9%) as a light yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:22])[S:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:28][C:17](=[O:19])[C:16]2[CH:15]=[CH:14][C:13]([S:10](=[O:11])(=[O:12])[N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH3:22])=[CH:21][CH:20]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: COc1cccc(N)c1
Reactant: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Product: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)Nc3cccc(OC)c3)cc2)cc1

Procedure:
4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (7) (100 mg, 0.31 mmol) was treated with 3-methoxyaniline (32 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with 0-30% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give N-(3-methoxyphenyl)-4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzamide as a white solid. Yield: 70 mg (63%). 1H-NMR: 10.44 (s, 1H), 8.10 (d, J=8.5 Hz, 2H), 7.66 (d, J=8.5 Hz, 2H), 7.45 (t, J=2.0 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.27 (t, J=7.5 Hz, 1H), 7.00 (d, J=9.0 Hz, 2H), 6.90 (d, J=8.5 Hz, 2H), 6.72 (ddd, J=8.0, 2.5, 1.0 Hz, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 3.15 (s, 3H).
Reaction SMILES: CC1(C)C(C)(C)OB(C2C=NNC=2)O1.Cl[C:16]1[CH:21]=[CH:20][C:19]([C:22]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[CH3:34][C:35]1[C:39](B2OC(C)(C)C(C)(C)O2)=[C:38]([CH3:49])[NH:37][N:36]=1>>[CH3:34][C:35]1[C:39]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[C:38]([CH3:49])[NH:37][N:36]=1
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Clc1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Cc1n[nH]c(C)c1-c1ccc(C2(c3ccccc3)CCNCC2)cc1

Procedure:
By following the procedure described in Example 1 but substituting 2-(4-chlorophenyl)-2-phenylethylamine hydrochloride and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 4-(4-chloro-phenyl)-4-phenyl-piperidine and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole, the title compound was obtained. LC/MS: (PS-A2) Rt 2.95 [M+H]+ 315. 1H NMR (Me-d3-OD) δ 2.22 (6H, s), 2.66-2.76 (4H, m), 3.16-3.28 (4H, m), 7.19-7.44 (9H, m).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.CN(C=O)C.S(Cl)([Cl:20])=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:20])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(Br)ccc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1cc(Br)ccc1C(=O)Cl
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-bromo-2-methoxybenzoic acid (2.5 g, 11.04 mmol) in CHCl3 (20 mL) was added DMF (catalytic) and thionyl chloride (1.6 mL, 22.08 mmol). The reaction was stirred at 55° C. for 1 hour and then concentrated to dryness to give the title compound.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH:27]([CH3:29])[CH3:28])[C:24](O)=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:15]([O:19][C:20](=[O:21])[NH:22][C@H:23]([C:24](=[O:25])[NH:14][C:13]1[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:9][CH:10]=[CH:11][CH:12]=1)[CH:27]([CH3:28])[CH3:29])([CH3:16])([CH3:18])[CH3:17]
Reactant: Nc1cccnc1Nc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccnc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of N2-phenylpyridine-2,3-diamine (556 mg, 3.0 mmol), (S)-2-tertbutoxycarbonylamino-3-methylbutyric acid (0.72 g, 3.3 mmol), HOAt (0.450 g, 3.3 mmol), 4-methylmorpholine (0.73 mL, 6.6 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.63 g, 3.3 mmol) in DCM (15 mL) was stirred at RT for 18 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was washed with brine, dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) to afford [(S)-2-methyl-1-(2-phenylaminopyridin-3-ylcarbamoyl)propyl]carbamic acid tert-butyl ester as a white solid (1.13 g, quantitative).
Reaction SMILES: ClC1C=CC=CC=1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=O.[C:19]([O:25][CH3:26])(=[O:24])[CH2:20][C:21]([CH3:23])=[O:22]>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:9]1[O:22][C:21]([CH3:23])=[C:20]([C:19]([O:25][CH3:26])=[O:24])[CH:8]=1
Reactant: O=C(Cc1ccccc1Cl)c1ccc(F)cc1F
Reactant: COC(=O)CC(C)=O
Product: COC(=O)c1cc(-c2ccc(F)cc2F)oc1C
Yield: 57.3 %

Procedure:
An operation similar to that in Example 1 (1) was performed using 2-chloro-2′,4′-difluorophenylacetophenone (19 g) and methyl acetoacetate (11 g) to give the title compound (10.3 g, 41%) as a yellow crystal.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([OH:11])=[O:10])[CH2:3][CH:4]=[CH2:5].[C:16](=O)(O)[O-].[Na+].CI>CN(C)C=O>[OH:1][CH:2]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([O:11][CH3:16])=[O:10])[CH2:3][CH:4]=[CH2:5]
Reactant: O=C([O-])O
Reactant: C=CCC(O)c1cc(C(=O)O)ccc1C
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCC(O)c1cc(C(=O)OC)ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
Into a 100-mL round-bottom flask, was added a solution of 3-(1-hydroxybut-3-en-1-yl)-4-methylbenzoic acid (compound 4.2, 1.4 g, 6.79 mmol) in N,N-dimethylformamide (20 mL). Sodium bicarbonate (1.14 g, 13.6 mmol) and methyl iodide (0.847 mL, 13.6 mmol) were added and the resulting mixture was stirred overnight at 25° C. The reaction was quenched with saturated aqueous Na2S2O3 (50 mL) and diluted with EtOAc (150 mL). The organic layer was washed with brine (3×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:3) as the eluent to yield the title compound as a light yellow oil (800 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[CH3:21][NH2:22]>C1COCC1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:22][CH3:21])=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: O=C(Cl)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Yield: 49.8 %

Procedure:
The product from Example 126c (225 mg, 0.72 mmol) was reacted with methylamine (1.0 mL, 2.0 mmol) in THF (20 mL) at room temperature. The THF was removed under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/ethyl acetate (30:70) to give the title compound (110 mg, 50%).
Reaction SMILES: [CH:1]12[CH2:11][CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[CH:2]2[C:3](=[O:13])[CH2:4][C:5]1=[O:12].C>>[CH:7]12[CH2:8][CH2:9][CH:1]([CH2:11][CH2:10]1)[CH:2]1[CH:6]2[C:5](=[O:12])[CH2:4][C:3]1=[O:13]
Reactant: O=C1CC(=O)C2C3C=CC(CC3)C12
Product: O=C1CC(=O)C2C3CCC(CC3)C12

Procedure:
Reduction of tricyclo [5,2,2,02,6 ] undec-8-ene-3,5-dione over 10% palladinised charcoal as described in example 2a gave the title compound; m.p. (MeOH) 254°- 5° C.
Reaction SMILES: [CH2:1]([NH:3][C@@H:4]([C:12]([OH:14])=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2].O1CCOCC1.[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>[OH-].[Na+].O>[CH2:21]([O:28][C:29]([N:3]([CH2:1][CH3:2])[C@@H:4]([C:12]([OH:14])=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCN[C@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCN(C(=O)OCc1ccccc1)[C@H](Cc1ccccc1)C(=O)O
Reaction time: 3 h

Procedure:
2.9 g (0.015 mole) of N-ethyl-D-phenylalanine (Example 3, Step A) are dissolved in 22.5 ml of 2N sodium hydroxide, 10 ml of dioxane are added, the mixture is cooled to 5° to 10° C., then 2.5 ml (about 0.017 mole) of benzyloxycarbonyl chloride are added and the reaction mixture is stirred for 3 hours at cooling. Subsequently it is diluted with 40 ml of water and extracted with 30 ml of a mixture of diethyl ether-petroleum ether-1:1, when a three-phase system is formed. The two lower phases are again extracted with 30 ml of diethyl ether, then the combined diethyl ether layers are washed with 20 ml of water. The aqueous layers are combined and acidified with N sulfuric acid to pH 2. The separated product is extracted three times with 30 ml of ethyl acetate. The ethyl acetate layers are combined, washed twice with 20 ml of water, dried over anhydrous sodium sulfate and evaporated on a water bath having a temperature of max. 40° C. at 15 to 20 millibars. Yield 2.7 g (55%) of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:21])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[C:5]([F:9])=[CH:6][C:7]=1[Cl:8].[Br:22][CH2:23]/[CH:24]=[CH:25]/[C:26](Cl)=[O:27]>>[Br:22][CH2:23][CH:24]=[CH:25][C:26]([NH:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][N:12]=[C:11]2[NH:10][C:4]1[C:5]([F:9])=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:27]
Reactant: O=C(Cl)/C=C/CBr
Reactant: Nc1ccc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2c1
Product: O=C(C=CCBr)Nc1ccc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2c1

Procedure:
In one particular, 3,4-dichloro-6-fluoroaniline is reacted with 4-chloro-6-nitroquinazoline, so as to produce 4-[(3,4-dichloro-6-fluorophenyl)amino]-6-nitroquinazoline, which is reduced, by means of an ethanolic solution of hydrazine hydrate and Raney®Nickel, so as to produce 4-[(3,4-dichloro-6-fluorophenyl)amino]-6-aminoquinazoline. Then, the 4-[(3,4-dichloro-6-fluorophenyl)amino]-6-aminoquinazoline is reacted with 4-bromocrotonyl chloride, so as to produce 4-bromo-N-{4-[(3,4-dichloro-6-fluorophenyl)amino]quinazoline-6-yl}-2-butenamide, which is then reacted with methylamine, so as to produce N-{4-[(3,4-dichloro-6-fluorophenyl)amino]quinazoline-6-yl}-4-(methylamino)-2-butenamide. The obtained methylamino derivative of the butenamide is reacted with a carbon-11 labeled methyliodide, so as to produce a carbon-11 labeled N-{4-[(3,4-dichloro-6-fluorophenyl)amino]quinazoline-6-yl}-4-(dimethylamino)-2-butenamide (carbon-11 labeled Compound 4).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH:6]1[C:10]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[NH2:1][CH2:4][CH2:5][CH:6]1[C:10]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7]1
Reactant: N#Cc1ccc2c(c1)C(CCN=[N+]=[N-])CO2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)C(CCN)CO2
Reaction time: 7 h

Procedure:
To a solution of 3-(2-azido-ethyl)-5-cyano-2,3-dihydro-benzofuran (434 mg, 2 mmol) (reference example 7) in THF (10 mL) was added Ph3P (576 mg, 2.2 mmol). The resulting solution was stirred for 7 hr then H2O added (72 ml, 4 mmol). This solution was stirred for 18 hr then concentrated. The residue was azeotroped with toluene then used without further purification. 1H NMR (CDCl3) d 1.81 (m, 1H), 1.93 (m, 1H) 2.5 (bs, 2H), 2.81 (m, 2H), 3.60 (m, 1H), 4.32 (dd, J=8, 6 Hz, 1H), 4.73 (t, J=8 Hz, 1H) 6.83 (d, J=8 Hz, 1H), 7.46 (m, 2H).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5].[Li][CH3:17].[NH4+].[Cl-].O>C1COCC1>[NH:11]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:4](=[O:5])[CH3:17])[C:14]=2[N:13]=[CH:12]1
Reactant: [Li]C
Reactant: CON(C)C(=O)c1cccc2[nH]cnc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cccc2[nH]cnc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a stirred solution of 1H-benzoimidazole-4-carboxylic acid methoxy-methyl-amide (742 mg, 3.62 mmol) in THF (36 mL) at −78° C. was added MeLi (1.6M; 2.49 mL, 3.98 mmol) dropwise. The mixture was stirred at −78° C. for 2 hours before an additional 1.0 mol. eq. MeLi (2.3 mL) was added dropwise. The mixture was stirred at −78° C. for a further 2 hours before saturated aqueous NH4Cl solution was added and the mixture warmed to room temperature. Enough water was added to dissolve all solids and the phases were separated. The aqueous phase was extracted into CHCl3 (×3), dried and concentrated in vacuo to give a white solid. Trituration with EtOAc (5 mL) followed by collection by filtration and washing with 4:1 Et2O/EtOAc (5 mL) provided 1-(1H-benzoimidazol-4-yl)-ethanone (487 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:16](=[O:17])[NH:15][CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][NH:30][C:29](=[O:33])[CH:28]=2)=[N:23][CH:24]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][N:30]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[C:16](=[O:17])[NH:15][CH2:14][CH2:13][CH2:12][C:7]=5[N:8]([CH3:11])[C:9]=4[CH:10]=3)[C:29](=[O:33])[CH:28]=2)=[N:23][CH:24]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)C(=O)NCCC2
Reactant: O=c1cc(OCc2ccc(F)cn2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)cc31)C(=O)NCCC2
Yield: 21.8 %

Procedure:
8-Bromo-6-methyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (100 mg, 0.340 mmol) and 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (102 mg, 0.510 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (32 mg, 21%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.53 (d, J=8.6 Hz, 1H), 8.48 (s, 1H), 7.51-7.46 (m, 2H), 7.37-7.31 (m, 2H), 7.13-7.17 (dd, J=8.5, 1.8 Hz, 1H), 6.12-6.03 (m, 2H), 5.93-5.86 (m, 1H), 5.17 (s, 2H), 3.66 (s, 3H), 3.42-3.34 (m, 2H), 3.09 (t, J=6.8 Hz, 2H), 2.28-2.19 (m, 2H); ESI MS m/z 433 [M+H]+; HPLC (Method B) 98.7% (AUC), tR=13.8 min.