Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:41])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[N:7]=[C:6]1[CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=2[C:34]2C=CC(F)=C[CH:35]=2)[CH2:23][CH2:22]1.[CH2:42]([O:44]/C=C/B1OC(C)(C)C(C)(C)O1)[CH3:43]>>[CH3:1][N:2]([CH3:41])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:19])([F:18])[F:20])[CH:11]=2)[N:7]=[C:6]1[CH:21]1[CH2:22][CH2:23][N:24]([C:27]2[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=2/[CH:34]=[CH:35]/[O:44][CH2:42][CH3:43])[CH2:25][CH2:26]1
Reactant: CCO/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: CCO/C=C/c1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN(C)C)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(4-fluorophenyl)pyrimidin-4-amine using (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of 4-fluorophenyl boronic acid. LC-MS: (M+1=548, obsd.=548).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[N:4]=[C:5](O)[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2)[CH:12]=[C:3]([N:2]([CH3:16])[CH3:1])[N:4]=1
Reactant: COc1ccc2c(O)nc(N(C)C)cc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(N(C)C)cc2c1
Yield: 52.6 %

Procedure:
A solution of 3-(dimethylamino)-6-methoxyisoquinolin-1-ol (700 mg, 3.21 mmol) in POCl3 (2 ml, 21.46 mmol) was refluxed for 4 h. The reaction mixture was concentrated. The residue was dissolved in DCM and the pH was adjusted to 7 with 4N NaOH. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum. The crude material was purified by silica gel chromatography using 50% DCM in hexanes as eluent. The product fractions were collected and the solvent was removed under vacuum to give 1-chloro-6-methoxy-N,N-dimethylisoquinolin-3-amine (400 mg, 53% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.96 (d, J=9.3 Hz, 1H), 6.87 (dd, J=9.2, 2.4 Hz, 1H), 6.80 (d, J=2.3 Hz, 1H), 6.43 (s, 1H), 3.91 (s, 3H), 3.14 (s, 6H); MS m/z 237.0 (M++1).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:25])[C:4](=[O:24])[CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[CH2:21][CH2:22][CH3:23].C1C=C(Cl)C=C(C(OO)=[O:34])C=1>>[CH3:1][O:2][N:3]([CH3:25])[C:4](=[O:24])[CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:13]([O-:34])=[CH:12][C:11]=2[N:10]=[C:9]1[CH2:21][CH2:22][CH3:23]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)N(C)OC
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCC(=O)N(C)OC

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate N-methoxy-N-methyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyramide (7.4 g, 21.7 mmol) by reaction with m-CPBA (9.50 g) to provide N-methoxy-N-methyl-4-(5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyramide followed by reaction with p-toluenesulfonyl chloride (7.20 g, 37.8 mmol) and ammonium hydroxide solution (200 mL) to provide 4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-methoxy-N-methyl-butyramide as white crystals after recrystallization from aqueous methanol, mp 163-165° C.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].O[C:23]1[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]2[C:24]=1[CH2:25][CH2:26][C:27](=[O:34])[NH:28]2>ClCCl>[CH3:33][C:30]1[CH:31]=[CH:32][C:23]([O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])=[C:24]2[C:29]=1[NH:28][C:27](=[O:34])[CH2:26][CH2:25]2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1ccc(O)c2c1NC(=O)CC2
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(OS(=O)(=O)C(F)(F)F)c2c1NC(=O)CC2
Reaction time: 1 h
Yield: 97 %

Procedure:
Pyridine (6.2 ml) and trifluoromethanesulfonic anhydride (10.3 ml) were added with stirring at 0° C. to an anhydrous dichloromethane solution (30 ml) of 5-hydroxy-8-methyl-3,4-dihydro-1H-quinolin-2-one (9.0 g), followed by stirring for 1 hour. The resulting mixture was concentrated under reduced pressure, water was added to the residue, and extraction with dichloromethane was performed. The extract was washed with water, an aqueous potassium hydrogensulfate solution and water in this order, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was recrystallized from an ethyl acetate-diisopropyl ether mixed solvent to thereby obtain 28 g (yield: 97%) of 8-methyl-5-trifluoromethanesulfonyloxy-3,4-dihydro-1H-quinolin-2-one as a light brown powder.
Reaction SMILES: C(OC(=O)[N:7]([CH2:17][CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>Cl.O1CCOCC1>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH:19]=[CH:18][CH2:17][NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N(CC=Cc1ccc(Cl)cc1)Cc1ccc(F)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Fc1ccc(CNCC=Cc2ccc(Cl)cc2)cc1F
Yield: 97.9 %

Procedure:
A solution of [3-(4-chloro-phenyl)-allyl]-(3,4-difluoro-benzyl)-carbamic acid tert-butyl ester (2.04 g) in 20 mL of 4N HCl in dioxane was stirred at room temperature for 1 hr. The solution was poured into 150 mL of aq. K2CO3, and extracted with 3×50 mL of ethyl acetate. The combined organic layer was washed with 50 mL brine, dried over Na2SO4, filtered and concentrated to provide 1.49 g of [3-(4-chloro-phenyl)-allyl]-(3,4-difluoro-benzyl)-amine.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:15]=O)=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:8]=1)([O-:3])=[O:2].[F:17][C:18]1[CH:19]=[C:20]([NH2:32])[C:21]([NH2:31])=[CH:22][C:23]=1[N:24]1[CH2:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CN(C=O)C>[F:17][C:18]1[C:23]([N:24]2[CH2:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:22][C:21]2[NH:31][C:15]([C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][N:7]([CH:9]4[CH2:14][CH2:13][CH2:12][CH2:11][O:10]4)[N:6]=3)=[N:32][C:20]=2[CH:19]=1
Reactant: O=Cc1nn(C2CCCCO2)cc1[N+](=O)[O-]
Reactant: Nc1cc(F)c(N2CCCOCC2)cc1N
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cn(C2CCCCO2)nc1-c1nc2cc(F)c(N3CCCOCC3)cc2[nH]1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
3 g of 4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazole-3-carbaldehyde and 43 mg of ferric chloride are added to a solution of 3 g of 4-fluoro-5-perhydro-1,4-oxazepin-4-ylbenzene-1,2-diamine in 60 mL of DMF. The reaction medium is stirred at 22° C. for 16 hours. After evaporation, the reaction crude is purified by flash chromatography. The elution is carried out in a 1/1 mixture of cyclohexane/ethyl acetate. 3 g of 5-fluoro-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-6-perhydro-1,4-oxazepin-4-yl-1H-benzimidazoleare isolated in the form of a red oil. 1H NMR (400 MHz, DMSO-d6, δ in ppm): from 1.40 to 2.25 (m, 8H); from 3.25 to 3.39 (m partially masked, 4H); 3.70 (m, 1H); 3.78 (m, 4H); 3.99 (m, 1H); 5.59 (dd, J=2.5 and 9.5 Hz, 1H); 7.16 (broad m, 1H); 7.39 (broad d, J=11.5 Hz, 1H); 9.17 (s, 1H); 12.75 (broad m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[O:12][C:11](=[O:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1.C(Cl)(Cl)Cl>CC(C)=O>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:16][CH:17]=2)[O:12][C:11](=[O:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)c2ccc(O)cc2o1
Reactant: Fc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: O=c1cc(OCc2ccccc2)c2ccc(OCCc3ccc(F)cc3)cc2o1

Procedure:
A mixture of 4-benzyloxy-7-hydroxycoumarin (5.36; 0.02 mole) anhydrous potassium carbonate (4.0g) and 1-bromo-2-(4-fluorophenyl) ethane (4.06g) in acetone (100ml) was stirred at reflux for 20 hours and the inorganic material filtered off. Evaporation of the filtrate in vacuo gave an oil which rapidly set solid on scratching. Chloroform (200ml) was added and the mixture filtered to remove unchanged 4-benzyloxy-7-hydroxycoumarin. Reevaporation of the filtrate afforded a white solid, 3.34g (43%) of m.p. 120°,νmax (mull) 1715, 1675, 1620cm-1 ; τ(CDCl3); 6.93 (2H, t, J 6.7Hz); 5.80 (2H, t, J 6.7Hz); 4.87 (2H,S); 4.38 (1H,); 3.29-2.49 (6H, m) 2.32 (1H, d, J 10Hz); (Found C, 73.75 H,5.14 C24H19FO4 requires; C, 73.84; H, 4.91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23](/[CH:25]=[CH:26]/[C:27]#[N:28])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.C(O)(C)C.O.[N-:34]=[N+:35]=[N-:36].[Na+]>Cl.[Br-].[Zn+2].[Br-]>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:23](/[CH:25]=[CH:26]/[C:27]4[NH:36][N:35]=[N:34][N:28]=4)[N:24]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(Cc3cccc(/C=C/C#N)n3)c(-c3ccccc3)[nH]c2c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COc1ccc2c(Cc3cccc(/C=C/c4nnn[nH]4)n3)c(-c3ccccc3)[nH]c2c1
Reaction time: 0.08 h
Yield: 34.5 %

Procedure:
To a mixture of (E)-3-[6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridin-2-yl]acrylonitrile (67 mg), isopropyl alcohol (1.5 mL) and water (0.5 mL) were added sodium azide (59.6 mg) and zinc bromide (51.6 mg), and the mixture was heated under reflux for 32 hours. Then isopropyl alcohol (1.5 mL) and water (0.5 mL) were added thereto, followed by heating under reflux for 62 hours. The reaction mixture was left to be cooled, diluted with 1 mol/L hydrochloric acid, and then stirred for 5 minutes. To the mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (25.8 mg). 1H-NMR (DMSO-d6) δ ppm: 3.77 (3H, s), 4.34 (2H, s), 6.65 (1H, dd, J=2.3, 8.5 Hz), 6.87 (1H, d, J=2.3 Hz), 7.16-7.23 (1H, m), 7.32-7.43 (2H, m), 7.46-7.54 (3H, m), 7.65-7.85 (5H, m), 11.16 (1H, s). ESI-MS (m/z): 409 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=1)[C:6]([C:25]([O:27]CC)=[O:26])=[C:5]2[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36]([CH3:38])[CH3:37].[OH-].[Na+].Cl>O1CCCC1.CO>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=1)[C:6]([C:25]([OH:27])=[O:26])=[C:5]2[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36]([CH3:38])[CH3:37]
Reactant: CCOC(=O)c1c(-c2ccccc2C(C)C)c2cc(O)ccc2n1CCCOc1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1ccccc1-c1c(C(=O)O)n(CCCOc2cccc3ccccc23)c2ccc(O)cc12
Temperature: 70 °C

Procedure:
To a solution of EXAMPLE 149B (22 mg) in tetrahydrofuran (2 ml) and methanol (2 ml) was added 10% NaOH 0.3 ml. The reaction was heated at 70° C. for 24 hours, cooled, acidified with diluted aqueous HCl and concentrated. The residue was purified by RPHPLC to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 8.83 (s, 1H), 8.20-8.23 (m, 1H), 7.85-7.88 (m, 1H), 7.45-7.55 (m, 5H), 7.34-7.40 (m, 2H), 7.28-7.34 (m, 1H), 7.17 (td, J=7.36, 1.23 Hz, 1H), 7.04 (dd, J=7.52, 1.38 Hz, 1H), 6.85 (d, J=7.36 Hz, 1H), 6.75 (dd, J=8.90, 2.45 Hz, 1H), 6.37 (d, J=2.15 Hz, 1H), 4.84 (t, J=7.52 Hz, 2H), 4.15 (t, J=5.68 Hz, 2H), 2.63-2.87 (m, 1H), 2.25-2.41 (m, 2H), 1.02 (d, J=6.75 Hz, 3H), 0.96 (d, J=7.06 Hz, 3H).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:22]2[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:23]=2)[C:9]([NH:12][C:13]2[CH:14]=[N:15][C:16]([O:20][CH3:21])=[C:17]([F:19])[CH:18]=2)=[N:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].FC(F)(F)S(O)(=O)=O.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:22]2[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH2:29])[N:23]=2)[C:9]([NH:12][C:13]2[CH:14]=[N:15][C:16]([O:20][CH3:21])=[C:17]([F:19])[CH:18]=2)=[N:10][CH:11]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)c1cnc(Nc2cnc(OC)c(F)c2)c(-c2nc(C)nc(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)n2)c1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)c1cnc(Nc2cnc(OC)c(F)c2)c(-c2nc(C)nc(N)n2)c1
Temperature: 70 °C
Yield: 69 %

Procedure:
A solution of 4-(5-(ethylsulfonyl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.066 g, 0.100 mmol) in trifluoromethanesulfonic acid (0.089 mL, 1.000 mmol) and 1.5 mL TFA was sealed and heated to 70° C. for 30 min, cooled, and treated with ice and 10 N NaOH until basic. The reaction was partitioned between water and DCM. The aqueous layer was extracted with DCM 5 times, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting yellow solid was suspended in 1 mL EtOAc, filtered, rinsing 2× diethyl ether, and dried in vacuo to give 4-(5-(ethylsulfonyl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.029 g, 0.069 mmol, 69% yield) as a yellow solid. m/z (ESI, +ve ion) 420 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.87 (s, 1H), 8.73 (d, J=2.7 Hz, 1H), 8.52 (d, J=2.7 Hz, 1H), 8.41 (d, J=2.5 Hz, 1H), 8.33 (d, J=2.7 Hz, 1H), 7.98 (br. s., 1H), 7.83 (br. s., 1H), 3.95 (s, 3H), 3.06-3.21 (m, 1H), 2.73-2.89 (m, 1H), 2.44 (s, 3H), 1.09 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:17])[C:15]#[CH:16])=[CH:4][CH:3]=1.[N:18]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N+:19]=[N-:20]>>[CH2:21]([N:18]1[CH:16]=[C:15]([CH:14]([C:9]2[C:10]([CH3:13])=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[OH:17])[N:20]=[N:19]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C#CC(O)c1c(C)noc1-c1ccc(Br)cc1
Reactant: [N-]=[N+]=NCc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2ccccc2)nn1

Procedure:
Prepared according to the procedure described in Example 9, Step 2, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-prop-2-yn-1-ol and azidomethyl-benzene.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:18]([Cl:21])=[CH:19][CH:20]=1)[NH2:17]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[C:18]([Cl:21])=[CH:19][CH:20]=1
Reactant: O=C(O)Cc1ccccc1Br
Reactant: COc1ccc(Cl)c(N)c1
Product: COc1ccc(Cl)c(Nc2ccccc2CC(=O)O)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-methoxy-6-chloroaniline to yield 2-[(3-methoxy-6-chlorophenyl)amino]phenylacetic acid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[C:15]3[CH:16]=[C:17]([C:20]4[O:21][C:22]([CH3:25])=[N:23][N:24]=4)[CH:18]=[CH:19][C:14]=3[O:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[C:15]3[CH:16]=[C:17]([C:20]4[O:21][C:22]([CH3:25])=[N:23][N:24]=4)[CH:18]=[CH:19][C:14]=3[O:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:5]
Reactant: C1CCNC1
Reactant: Cc1nnc(-c2ccc3occ(-c4ccc(C(=O)O)c(F)c4)c3c2)o1
Product: Cc1nnc(-c2ccc3occ(-c4ccc(C(=O)N5CCCC5)c(F)c4)c3c2)o1
Yield: 53 %

Procedure:
In the same manner as in Example 117 and using 2-fluoro-4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]benzoic acid instead of 3-[5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazol-2-yl]propionic acid and using pyrrolidine instead of N,O-dimethylhydroxyamine hydrochloride, the title compound (yield 53%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[CH3:20][N:21]([CH3:23])/[CH:22]=[CH:1]/[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc([N+](=O)[O-])c(/C=C/N(C)C)c([N+](=O)[O-])c1
Temperature: 110 °C
Yield: 99.5 %

Procedure:
To a mixture of methyl 4-methyl-3,5-dinitrobenzoate (5.6 g) in toluene (20 mL) was added dimethylformamide dimethyl acetal (4.17 g) and 5-sulfo salycylic acid hydrate (0.1 g). The mixture was heated to 110° C. for 19 h, removed from heat and cooled to room temperature. The solvents were removed under reduced pressure at which time hexanes was added to the residue and the residue was filtered to give 6.85 g of the title compound: 1H NMR (CDCl3) δ 2.97, 3.96, 5.54, 6.74, 8.33.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:5][C:6]([C:8]1[CH:9]=[C:10]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[CH:11]=[CH:12][CH:13]=1)=[O:7])[CH3:4].Cl.[CH3:23][NH2:24]>>[CH3:23][NH:24][C:19]([CH2:18][CH2:17][CH2:16][C:15]#[C:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[C:6]([NH:5][CH:3]([CH3:4])[CH2:2][OH:1])=[O:7])=[O:21]
Reactant: CC(CO)NC(=O)c1cccc(C#CCCCC(=O)O)c1
Reactant: CN
Agent: Cl
Product: CNC(=O)CCCC#Cc1cccc(C(=O)NC(C)CO)c1
Yield: 52.8 %

Procedure:
6-[3-(2-Hydroxy-1-methyl-ethylcarbamoyl)phenyl]-hex-5-ynoic acid (4) (0.400 g, 1.37 mmol) was reacted using method C with methylamine hydrochloride (0.609 g) to give 3-(5-methylcarbamoyl-pent-1-ynyl)-N-(2-hydroxy-1-methyl-ethyl)benzamide (22) (0.221 g, 0.724 mmol; 53% yield).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[Cl:17][C:4]1[CH:3]=[C:2]([C:25]2[CH:26]=[CH:27][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:23][CH:24]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(S(C)(=O)=O)cc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (23 mg, 24%), MS (ISP) m/z=389.6 [(M+H)+], mp 321.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-methanesulfonyl-phenylboronic acid (65.0 mg, 0.325 mmol).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)C=O.OO.[OH:14]S([O-])=O.[Na+]>[OH-].[Na+].O>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[C:4]([OH:14])[C:3]=1[OH:11]
Reactant: O=Cc1c(F)ccc(Br)c1O
Reactant: O=S([O-])O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1c(F)ccc(Br)c1O
Reaction time: 2 h

Procedure:
3-Bromo-6-fluoro-2-hydroxybenzaldehyde (9.0 g, 41 mmol, prepared according to Castro, Alfred C.; Depew, Kristopher M.; Grogan, Michael J.; Holson, Edward B.; Hopkins, Brian T.; Johannes, Charles W.; Keaney, Gregg F.; Koney, Nii O.; Liu, Tao; Mann, David A.; Nevalainen, Marta; Peluso, Stephane; Perez, Lawrence Blas; Snyder, Daniel A.; Tibbitts, Thomas T., WO 2008024337 A2) was stirred in 1.0 M NaOH (47 mL) and treated with hydrogen peroxide (6%; 49 g, 86 mmol). External cooling was applied to keep the temperature controlled below 50° C. After 2 h total stirring, the mixture was stirred with a solution of NaHSO3 in 50 mL water and extracted with ethyl acetate (2×75 mL). The combined extracts were washed with saturated NaCl (20 mL), dried (Na2SO4) and evaporated. The catechol derivative, as a dark orange liquid, was carried to the next step without further purification (8.9 g, qt): EIMS m/z 206.
Reaction SMILES: C[C:2]1[C:3]([O:33][CH3:34])=[C:4]([O:31][CH3:32])[C:5]([O:28][CH2:29][CH3:30])=[C:6]([C:14]2[C:19]([C:20]([O-:22])=[O:21])=[CH:18][C:17]([O:23][CH3:24])=[C:16]3[O:25][CH2:26][O:27][C:15]=23)[C:7]=1[C:8]([O:10]CCC)=[O:9].[OH-].[K+].Cl>O1CCOCC1>[CH2:29]([O:28][C:5]1[C:4]([O:31][CH3:32])=[C:3]([O:33][CH3:34])[CH:2]=[C:7]([C:8]([OH:10])=[O:9])[C:6]=1[C:14]1[C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]([O:23][CH3:24])=[C:16]2[O:25][CH2:26][O:27][C:15]=12)[CH3:30]
Reactant: CCCOC(=O)c1c(C)c(OC)c(OC)c(OCC)c1-c1c(C(=O)[O-])cc(OC)c2c1OCO2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOc1c(OC)c(OC)cc(C(=O)O)c1-c1c(C(=O)O)cc(OC)c2c1OCO2
Temperature: 70 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
In 4 ml of dioxane was dissolved 48 mg of methyl -ethoxy-2',3'-methylenedioxy-6-propoxycarbonyl-3,4,4'-trimethoxy-1,1'-biphenyl-6'-carboxylate obtained in Example 9, and 1 ml of a 5% aqueous solution of potassium hydroxide was added to the solution. The mixture was heated at 70° C. and stirred overnight, the pH value was adjusted to 1 by 3N hydrochloric acid, and the mixture was extracted with chloroform. The solvent was removed from the extract to obtain 36 mg of 2-ethoxy-2',3'-methylenedioxy-3,4,4'-trimethoxy-1,1'-biphenyl-6,6'-dicarboxylic acid having the following physical properties (the yield was 86%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[CH3:10][C:11]1([CH3:17])[CH2:15][O:14][NH:13][C:12]1=[O:16].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C.C(OCC)(=O)C>[CH3:10][C:11]1([CH3:17])[CH2:15][O:14][N:13]([CH2:8][C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)[C:12]1=[O:16]
Reactant: CC1(C)CONC1=O
Reactant: ClCc1ccncc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(C)CON(Cc2ccncc2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-picolyl chloride hydrochloride (1.4 g, 0.0084 mol), 4,4-dimethyl-3-isoxazolidinone (1.0 g, 0.0084 mol), potassium carbonate (3.6 g, 0.0261 mol), and 18-Crown-6 (0.10 g, 0.0004 mol) in acetonitrile (50 mL) is stirred at room temperature overnight. The reaction mixture is poured into ethyl acetate (50 mL) and the mixture washed with water (3×30 mL). The organic layer is dried (magnesium sulfate) and concentrated under reduced pressure to yield an oil. This oil is passed through a silica gel pad eluting with 4:1 chloroform:methanol. The filtrate is concentrated and converted to 1.4 g of the maleate salt of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.[H-].[Na+].Br[CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38]>O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: COCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
Treat a solution of 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepan (preparation 9, 0.50 g, 1.58 mmol) and dimethylformamide (10 mL) with sodium hydride (0.083 g, 2.08 mmol, 60% dispersion in oil) at room temperature. After 30 minutes, add 1-bromo-2-(2-methoxyethoxy)ethane (0.34 g, 1.88 mmol, Aldrich Chemical Company) and heat two hours at 70° C. Cool the reaction, add water (10 mL) and extract with dichloromethane (100 mL). Wash the organic phase with water, dry (Na2SO4), filter and concentrate the filtrate to afford 4-{1-[2-(2-methoxy-ethoxy)-ethyl]-1H-benzoimidazol-2-yl}-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.62 g).