Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH:18]=[O:19])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][Mg]Br>C1COCC1.CCOCC>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[CH:18]([OH:19])[CH3:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CCc1ccc(Br)cc1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)[C@H](CCc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred, cooled solution of [(S)-3-(4-bromo-phenyl)-1-formyl-propyl]-carbamic acid tert-butyl ester (7.3 g) in THF (40 ml) and Et2O (30 ml) at 0° C. was added dropwise over 30 min a solution of methylmagnesium bromide (20.0 ml, 3 M solution in Et2O). The reaction mixture was then stirred at room temperature for 4 hours before being quenched by dropwise addition of water (gas formation!). The reaction mixture was then poured into EtOAc, the layers were separated and the organic layer was washed sequentially with diluted aq. HCl (pH 5) and saturated brine, then dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, gradient: 0% to 80% EtOAc in hexane) to afford {(1S,2RS)-1-[2-(4-bromo-phenyl)-ethyl]-2-hydroxy-propyl}-carbamic acid tert-butyl ester as a colourless amorphous solid comprising a mixture of epimers (5.1 g, 66%). MS (EI): 303 ([{81Br}M-C4H8]+), 301 ([{79Br} M-C4H8]+), 258([{81Br}M-C4H8—CO2H]+), 256 ([{79Br} M-C4H8—CO2H]+), 214, 212, 171, 169, 57 ([C4H9]+).
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].C(Cl)Cl.C(N(CC)CC)C.[CH3:16][C@H:17]1[O:22][C@@H:21]([CH3:23])[CH2:20][NH:19][CH2:18]1.O>>[CH3:23][C@H:21]1[O:22][C@@H:17]([CH3:16])[CH2:18][N:19]([S:1]([Cl:5])(=[O:3])=[O:2])[CH2:20]1
Reactant: O=S(=O)(Cl)Cl
Reactant: C[C@@H]1CNC[C@H](C)O1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(S(=O)(=O)Cl)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of sulfuryl chloride (0.773 mL, 0.00955 mol) in methylene chloride (2.39 mL, 0.0372 mol) at 0° C. was added a mixture of triethylamine (0.666 mL, 0.00478 mol) and cis-2,6-dimethylmorpholine (0.55 g, 0.0048 mol) at such a rate as to keep the temperature below 20° C. The reaction mixture was stirred at room temperature for 2 h, then poured into iced water (5 g, 0.3 mol) and extracted with dichloromethane. The combined organic layers were washed with 10% HCl, cold water, brine, dried over calcium chloride, evaporated to dryness. The crude sulfamoyl chloride was used directly in next step.
Reaction SMILES: Cl[C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:10][N:11]([CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2([CH3:29])[CH2:28][O:27]2)[CH2:21][CH2:20]1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].C([O-])(=O)C.[Na+]>C(O)CC>[CH3:10][N:11]([CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2([CH3:29])[O:27][C:2]3=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]3[CH2:28]2)[CH2:21][CH2:20]1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16]
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(CC2(C)CO2)CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCCO
Product: CN(C(=O)OC(C)(C)C)C1CCN(CC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Yield: 12 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (1.08 g, 7.31 mmol), tert-butyl N-methyl-[1-(2-methyloxiran-2-yl-methyl)piperidin-4-yl]carbamate (2.08 g, 7.31 mmol) and sodium acetate (660 mg, 8.04 mmol) in 1-propanol (15 ml) were stirred under reflux overnight. The reaction mixture was concentrated under reduced pressure. The residue was added water, and the mixture was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1), crystallized from methylene chloride-isopropyl ether to afford tert-butyl N-methyl-[1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperidin-4-yl]carbamate (348 mg, yield 12%) as a white powder.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]([C:17](=[O:28])[C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[C:15]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:14]=[C:13]2[C:8]=1[C:9](=[O:36])[CH2:10][C:11]([CH3:35])([CH3:34])[O:12]2)(=O)=O.[F:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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>[CH:29]1([C:15]2[CH:14]=[C:13]3[C:8]([C:9](=[O:36])[CH2:10][C:11]([CH3:34])([CH3:35])[O:12]3)=[C:7]([C:43]3[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=3)[C:16]=2[C:17](=[O:28])[C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=2)[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CC1(C)CC(=O)c2c(cc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c2OS(=O)(=O)C(F)(F)F)O1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC1(C)CC(=O)c2c(cc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c2-c2ccc(F)cc2)O1

Procedure:
In a flask which had been dried by heating, 250 mg (0.44 mmol) of 7-cyclopentyl-2,2-dimethyl-4-oxo-6-[4-(trifluoromethyl)benzoyl]-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate (Example 10A), 81 mg (0.58 mmol) of 4-fluorophenylboronic acid, 160 mg (0.75 mmol) of potassium phosphate and 56 mg (0.05 mmol) of tetrakis(triphenylphosphine)palladium(0) are initially charged, and the apparatus is flushed by repeated evacuation and venting with argon. 4 ml of dioxane are then added, the apparatus is closed and the reaction mixture is heated under reflux overnight. The mixture is cooled and filtered through a layer of silica gel, the filter cake is washed thoroughly with ethyl acetate and the filtrate is concentrated. The crude product is purified on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 10:1→5:1). This gives 194 mg (86% of theory) of the title compound.
Reaction SMILES: C(ON=O)CC(C)C.I[CH2:10][I:11].[NH2:12][C:13]1[N:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH:16]=[N:15][C:14]=1C#N>C(Cl)(Cl)Cl>[I:11][C:10]1[N:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH:16]=[N:15][C:14]=1[C:13]#[N:12]
Reactant: ICI
Reactant: CC(C)Cn1cnc(C#N)c1N
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: CC(C)Cn1cnc(C#N)c1I
Temperature: 80 °C
Yield: 90 %

Procedure:
A solution of isoamylnitrite (0.27 g, 2.3 mmol), diiodomethane (1 mL), and chloroform (5 mL) was heated at 85° C. under a nitrogen atmosphere. A mixture of 5-amino-1-(2-methylpropyl)-1H-imidazole-4-carbonitrile (0.1 g, 0.6 mmol) and chloroform (5 mL) was added over a period of 15 minutes followed by a rinse with chloroform (2 mL). The reaction was stirred and heated at 80° C. for an additional 10 minutes, allowed to cool to room temperature, and concentrated under reduced pressure. The residue was purified through a layer of silica gel (eluting sequentially with chloroform, 2% methanol in chloroform, 4% methanol in chloroform, and 8% methanol in chloroform) to provide 0.15 g (90%) of 5-iodo-1-(2-methylpropyl)-1H-imidazole-4-carbonitrile as an orange solid.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=S)[CH:9]([NH:19][C:20](=[O:31])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][O:33][CH:34]([O:37][CH3:38])[CH2:35][NH2:36]>C1COCC1>[CH3:32][O:33][CH:34]([O:37][CH3:38])[CH2:35][N:36]=[C:10]1[CH:9]([NH:19][C:20](=[O:31])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11]1
Reactant: COC(CN)OC
Reactant: O=C(CCc1ccc(Cl)cc1Cl)NC1N=C(c2ccccc2)c2ccccc2NC1=S
Solvent: C1CCOC1
Product: COC(CN=C1Nc2ccccc2C(c2ccccc2)=NC1NC(=O)CCc1ccc(Cl)cc1Cl)OC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of N-(2,3-dihydro-5-phenyl-2-thioxo-1H-1,4-benzodiazepin-3-yl)-3-(2,4-dichlorophenyl)propanamide (234 mg, 0.5 mmol) and 2,2-dimethoxyethylamine (210 mg, 2 mmol) in THF (6 mL) was stirred at room temperature for 17 h. Mercuric chloride (0.20 g, 0.75 mmol) was added and the mixture was stirred at 55° C. for 3 h. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (20 mL). The mixture was washed with aqueous citric acid (10%, 5 mL), brine (5 mL), saturated aqueous sodium carbonate (5 mL) and brine (5 mL), dried (Na2 SO4) and the solvent was evaporated under reduced pressure to give N-[2,3-dihydro-2-(2,2-dimethoxyethylimino)-5-phenyl-1H-1,4-benzodiazepin-3-yl)-3-(2,4-dichlorophenyl)propanamide as a solid. The residue was dissolved in aqueous sulfuric acid (50%, 1 mL) and mercuric chloride (0.20 g, 0.75 mmol) was added. The mixture was stirred at room temperature for 18 h., cooled to 0° C. and the pH was adjusted to 7.0 with aqueous sodium hydroxide (10%). The mixture was extracted with ethyl acetate and the combined organic fractions were washed with water and brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2 /MeOH (99.5:0.5) to give 3-(2,4-dichlorophenyI)-N-{6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl}propanamide as a solid, m.p. 183°-184° C.
Reaction SMILES: C(OC(=O)[N:7]([C:14]1[C:15]2[N:16]([C:20](Br)=[CH:21][N:22]=2)[CH:17]=[CH:18][N:19]=1)[CH2:8][CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])(C)(C)C.CS[C:27]1[N:32]=[C:31]([Sn](CCCC)(CCCC)CCCC)[CH:30]=[CH:29][N:28]=1.[CH:46]([NH2:49])([CH3:48])[CH3:47]>>[CH:46]([NH:49][C:27]1[N:28]=[C:29]([C:20]2[N:16]3[CH:17]=[CH:18][N:19]=[C:14]([NH:7][CH2:8][CH2:9][S:10]([CH3:13])(=[O:11])=[O:12])[C:15]3=[N:22][CH:21]=2)[CH:30]=[CH:31][N:32]=1)([CH3:48])[CH3:47]
Reactant: CC(C)N
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Reactant: CC(C)(C)OC(=O)N(CCS(C)(=O)=O)c1nccn2c(Br)cnc12
Product: CC(C)Nc1nccc(-c2cnc3c(NCCS(C)(=O)=O)nccn23)n1

Procedure:
[3-(2-Isopropylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-methanesulfonyl-ethyl)-amine was prepared by a process analogous to that described in Example 12 starting from (3-bromo-imidazo[1,2-a]pyrazin-8-yl)-(2-methanesulfonyl-ethyl)-carbamic acid tert-butyl ester (from Example 5 supra), 2-methylsulfanyl-4-tributylstannanyl-pyrimidine, and isopropylamine. LC-MS: [M+H]+ 376.3.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.C(N(CC)CC)C.[CH3:31][C:32]1[CH:33]=[C:34]([N:39]=[C:40]=[O:41])[CH:35]=[CH:36][C:37]=1[CH3:38]>C1COCC1>[CH3:31][C:32]1[CH:33]=[C:34]([NH:39][C:40]([NH:2][CH2:3][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[C:6](=[O:23])[N:7]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]2=[O:22])[C:8]([CH3:14])=[N:9]3)=[O:41])[CH:35]=[CH:36][C:37]=1[CH3:38]
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: Cc1ccc(N=C=O)cc1C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)NCc2cccc3nc(C)n(C4CCC(=O)NC4=O)c(=O)c23)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a stirred suspension of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.53 g, 1.6 mmol) and triethylamine (0.31 mL, 2.2 mmol) in THF (15 mL) at 5˜10° C., was added 3,4-dimethyl phenyl isocyanate (0.29 mL, 2.1 mmol). Then the mixture was stirred at room temperature overnight. The mixture was quenched with methanol (˜1 mL), and the solvent was evaporated. The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 1-(3,4-dimethyl-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-urea as an off-white solid (520 mg, 73% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.14 min (96.6%); mp, 241-243° C.; 1HNMR (DMSO-d6)2.11-2.21 (m, 7H, CHH, 2ArCH3), 2.59-2.94 (m, 6H, CHCH2, CH3), 4.71 (d, J=5 Hz, 2H, CH2NH), 5.27 (dd, J=6, 11 Hz, 1H, CH), 6.56 (t, J=5 Hz, 1H, CH2NH), 6.92-7.78 (m, 6H, Ar), 8.58 (s, 1H, NH), 11.05 (s, 1H, NH); 13C NMR (DMSO-d6) δ 18.58, 19.59, 20.70, 23.24, 30.62, 42.26, 56.52, 115.18, 117.76, 118.99, 125.54, 126.28, 128.50, 129.46, 134.01, 136.03, 138.15, 141.69, 148.27, 154.87, 155.11, 160.94, 169.47, 172.65. LCMS MH=448; Anal Calcd For C24H25N5O4+2.0H2O: C, 59.62; H, 6.05; N, 14.48. Found: C, 59.36; H, 5.95; N, 14.24.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)C.[OH-].[Li+]>C1COCC1.O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([N:9]2[CH2:10][CH2:11][CH:6]([CH2:5][C:4]([OH:21])=[O:3])[CH2:7][CH2:8]2)=[CH:13][CH:14]=1)(=[O:20])[CH3:19]
Reactant: CCOC(=O)CC1CCN(c2ccc(C(C)=O)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(N2CCC(CC(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [1-(4-acetyl-phenyl)-piperidin-4-yl]-acetic acid ethyl ester (20.5 mol) in THF (10 mL) and water (20 mL) is added lithium hydroxide (41 mmol). The resulting mixture is stirred at rt overnight. The organic solvent is evaporated, and the residue is acidified to pH=4-5. The solid is collected by filtration, washed with water and dried at 60° C. in vacuo to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.86 (2H, d), 6.86 (2H, d), 3.90 (2H, br, d), 2.90 (2H, dt), 2.52 (3H, s), 2.34 (2H, d), 2.04 (1H, m), 1.88 (2H, br, d), 1.39 (2H, ddd); LC-MS (M+1) 262.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[S:6][C:7]([CH3:9])=[CH:8][C:4]=2[CH:3]=1.[C:12](=[O:14])=[O:13]>>[CH3:9][C:7]1[S:6][C:5]2[CH:10]=[CH:11][C:2]([C:12]([OH:14])=[O:13])=[CH:3][C:4]=2[CH:8]=1
Reactant: O=C=O
Reactant: Cc1cc2cc(Br)ccc2s1
Product: Cc1cc2cc(C(=O)O)ccc2s1

Procedure:
Conversion of 5-bromo-2-methylbenzo[b]thiophene to the Grignard reagent followed by reaction with carbon dioxide by the method of Example 3(i) gave 2-methylbenzo[b]thiophene-5-carboxylic acid, m.p. 220°-222°.
Reaction SMILES: C(O[C:4](=[O:21])[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:8][N:9]([CH3:11])C)C.C(N)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[CH3:15][O:14][C:12]([C:6]1[CH:7]=[CH:8][N:9]([CH2:11][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:4](=[O:21])[C:5]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:13]
Reactant: CCOC(=O)C(C(=O)OCC)=C(C=CN(C)C)C(=O)OC
Reactant: NCc1ccccc1
Solvent: CO
Product: CCOC(=O)c1c(C(=O)OC)ccn(Cc2ccccc2)c1=O
Temperature: 25 °C
Yield: 77.9 %

Procedure:
A mixture of 5-dimethylamino-2-ethoxycarbonyl-3-methoxycarbonyl-penta-2,4-dienoic acid ethyl ester (5 g, 16.7 mmol) and benzylamine (1.9 mL, 17.6 mmol) in MeOH (30 mL) was refluxed for 5 h. The mixture was cooled to r.t., concentrated in vacuo, and taken up in ether. The solution was washed with 1 M HCl and water, and then dried over MgSO4. Evaporation of the solvent in vacuo afforded 4.1 g of the title compound as a dark brown oil. 1H NMR (CDCl3, 200 MHz): δ=7.20-7.40 (m, 6H), 6.56 (d, 1H, J=7.0 Hz), 5.15 (s, 2H), 4.42 (q, 2H, J=7.4 Hz), 3.88 (s, 3H), 1.40 (t, 3H, J=7.0 Hz).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[C:32]2[N:31]=[C:30]3[N:33]([C:37]4[C:38]([CH3:46])=[N:39][C:40]([O:44][CH3:45])=[N:41][C:42]=4[CH3:43])[CH2:34][CH2:35][CH2:36][N:29]3[C:28]=2[C:27]([CH:47]([OH:50])[CH2:48][CH3:49])=[CH:26][CH:25]=1>CS(C)=O.C(#N)C.C(=O)([O-])O.[Na+]>[Cl:23][C:24]1[C:32]2[N:31]=[C:30]3[N:33]([C:37]4[C:38]([CH3:46])=[N:39][C:40]([O:44][CH3:45])=[N:41][C:42]=4[CH3:43])[CH2:34][CH2:35][CH2:36][N:29]3[C:28]=2[C:27]([C:47](=[O:50])[CH2:48][CH3:49])=[CH:26][CH:25]=1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)nc(OC)nc1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CS(C)=O
Product: CCC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)nc(OC)nc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
Dess-Martin reagent (207 mg, 0.487 mmol) was added to a stirred solution of 1-[9-chloro-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (178 mg, 0.443 mmol) in dimethyl sulfoxide (1.0 mL) and acetonitrile (3.0 mL) at 0° C., and the mixture was stirred at 0° C. for 30 min. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow solid (172 mg, 0.430 mmol, 97%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([B:9]([OH:11])[OH:10])=[CH:5][CH:4]=1)#N.[OH-:12].[K+].N.[OH2:15]>CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([B:9]([OH:11])[OH:10])=[CH:5][CH:4]=1)([OH:15])=[O:12]
Reactant: [OH-]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O
Agent: N
Agent: [K+]
Solvent: CO
Product: O=C(O)c1ccc(B(O)O)cc1
Yield: 90 %

Procedure:
14.5 g (100 mmol) of 4-cyanophenylboronic acid were dissolved in a mixture of 11 g (200 mmol) of potassium hydroxide and 10 g of water in 100 ml of methanol, and the mixture was refluxed until the evolution of ammonia gas was complete, giving 14.9 g (90 mmol) of 4-carboxyphenylboronic acid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([CH3:13])=[C:11]([O:14][CH3:15])[C:10]([CH3:16])=[C:9]([CH3:17])[C:8]=1[O:18][CH3:19].[CH2:20]([N:27]1[CH2:32][CH2:31][CH:30]([C:33](=[O:43])[C:34]2[CH:39]=[CH:38][C:37]([CH:40]([CH3:42])[CH3:41])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>O1CCCC1>[CH2:20]([N:27]1[CH2:28][CH2:29][CH:30]([C:33]([C:7]2[C:12]([CH3:13])=[C:11]([O:14][CH3:15])[C:10]([CH3:16])=[C:9]([CH3:17])[C:8]=2[O:18][CH3:19])([C:34]2[CH:35]=[CH:36][C:37]([CH:40]([CH3:42])[CH3:41])=[CH:38][CH:39]=2)[OH:43])[CH2:31][CH2:32]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)c1ccc(C(=O)C2CCN(Cc3ccccc3)CC2)cc1
Reactant: COc1c(C)c(C)c(OC)c(Br)c1C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)c(C)c(OC)c(C(O)(c2ccc(C(C)C)cc2)C2CCN(Cc3ccccc3)CC2)c1C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
n-Butyllithium (1.6 M, 12.0 mL, 19.2 mmol) was added to a solution of 1-bromo-2,5-dimethoxy-3,4,6-trimethylbenzene (4.89 g, 18.87 mmol) in tetrahydrofuran (100 mL) at −78° C., and the mixture was stirred for 30 minutes at the same temperature. To the reaction mixture was added 1-benzyl-4-(4-isopropylbenzoyl)piperidine (5.02 g, 15.6 mmol). The mixture was stirred for 30 minutes at the same temperature, then poured into the water, and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain the title compound (6.54 g, yield 83%).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[N:11]=[N:10][C:9]([CH:12]([OH:14])[CH3:13])=[N:8]2)[CH:2]=1.[H-].[Na+].CS([C:22]1[N:23]([CH3:33])[C:24]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[N:25][N:26]=1)(=O)=O>>[CH3:33][N:23]1[C:22]([O:14][CH:12]([C:9]2[N:10]=[N:11][N:7]([C:3]3[CH:2]=[C:1]([CH3:15])[CH:6]=[CH:5][CH:4]=3)[N:8]=2)[CH3:13])=[N:26][N:25]=[C:24]1[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1
Reactant: Cn1c(-c2ccncc2)nnc1S(C)(=O)=O
Reactant: Cc1cccc(-n2nnc(C(C)O)n2)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1cccc(-n2nnc(C(C)Oc3nnc(-c4ccncc4)n3C)n2)c1
Yield: 80.5 %

Procedure:
The title compound (70 mg, 79%, off-white solid) was prepared from 1-(2-m-tolyl-2H-tetrazol-5-yl)-ethanol (50.3 mg, 0.24 mmol), sodium hydride (16 mg, 0.4 mmol) and 4-(5-methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine (70.2 mg, 0.30 mmol). The product was purified by chromatography using a silica SPE tube (2.5-4% methanol in dichloromethane). 1H NMR (CDCl3) δ (ppm): 8.76 (br.d, 2H), 7.95 (s, 1H), 7.94 (d, 1H), 7.62 (d, 2H), 7.44 (t, 1H), 7.32 (d, 1H), 6.61 (q, 1H), 3.63 (s, 3H), 2.28 (s, 3H), 2.04 (d, 3H).
Reaction SMILES: [CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH:15]=1)[C:10](O)=[O:11])=[O:6])[CH2:2][CH3:3].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:59][C@@H:60]([CH2:75][C:76]1[CH:81]=[C:80]([F:82])[CH:79]=[C:78]([F:83])[CH:77]=1)[C@H:61]([OH:74])[CH2:62][NH:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([CH:71]([CH3:73])[CH3:72])[CH:66]=1>CN(C=O)C>[F:82][C:80]1[CH:81]=[C:76]([CH:77]=[C:78]([F:83])[CH:79]=1)[CH2:75][C@H:60]([NH:59][C:10](=[O:11])[C:9]1[CH:13]=[C:14]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH:15]=[C:7]([C:5]([N:4]([CH2:21][CH2:22][CH3:23])[CH2:1][CH2:2][CH3:3])=[O:6])[CH:8]=1)[C@H:61]([OH:74])[CH2:62][NH:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([CH:71]([CH3:73])[CH3:72])[CH:66]=1
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2nccs2)c1
Reactant: CC(C)c1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CCC)C(=O)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(C(C)C)c2)cc(-c2nccs2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[(Dipropylamino)carbonyl]-5-(1,3-thiazol-2-yl)benzoic acid is dissolved in DMF (8 mL), and diisopropylethylamine (456 μL, 2.6 mmol), HATU (342 mg, 0.9 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-isopropylbenzyl)amino]butan-2-ol dihydrochloride (350 mg, 0.83 mmol) are added. The reaction stirred at room temperature 1 h. The reaction is partitioned between ethyl acetate and water. The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/chloroform) provides the title compound as the free base. The residue is dissolved in diethyl ether (5 mL) and 1N hydrochloric acid in diethyl ether (2 mL) is added. The mixture is concentrated under reduced pressure to yield the title compound. ESI MS m/z 663.3 [M+H]+.
Reaction SMILES: COC1C=CC([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[C:17](OC)[C:11]=3[CH:10]=2)=CC=1.FC1C=C(C=C(F)C=1F)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl.CCOC(C)=O>[S:13]1[CH:9]=[CH:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]1=2
Reactant: COc1ccc(-c2cc3c(OC)cccc3s2)cc1
Agent: O=C(Cl)c1cc(F)c(F)c(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: c1ccc2sccc2c1
Reaction time: 18 h
Yield: 10.8 %

Procedure:
To a well stirred solution of 2-(4′-methoxyphenyl)-4-methoxybenzo[b]thiophene (0.201 g, 0.74 mmol) and 3,4,5-trifluorobenzoyl chloride (0.288 g, 1.48 mmol) in CH2Cl2 (7 mL) was added AlCl3 (0.304 g, 2.22 mmol) portion-wise over a 15 minute period. After 18 h, water was added, and the product was isolated initially with CH2Cl2 and subsequently by extraction with EtOAc. The organic layers were separately washed sequentially with NaHCO3 and brine and then dried over MgSO4. Purification by flash chromatography (silica gel, 80:20 hexane/EtOAc) afforded benzo[b]thiophene (0.032 g, 0.08 mmol, 10%) as a white solid. Recrystallization (Ethanol/hexane/CH2Cl2) yielded a highly pure crystalline sample. 1H-NMR(CDCl3, 360 MHz) δ7.74 (d, J=8.9 Hz, 2H, ArH), 7.70 (d, J=9.3 Hz, 1H, ArH), 7.68 (s, 1H, ArH), 7.43 (dd, J=7.5, 6.6 Hz, 2H, ArH), 7.00 (d, J=8.9 Hz, 2H, ArH), 6.83 (d, J=8.4 Hz, 1H, ArH), 4.09 (s, 3H, —OCH3), 3.87 (S, 3H, —OCH3). 13C-NMR (CDCl3, 90 MHz) 190.5, 160.1, 159.1, 152.3, 150.0, 146.6, 141.3, 134.4, 132.9, 132.1, 127.9, 126.9, 122.4, 114.5, 114.1, 114.1, 114.0, 113.9, 113.8, 56.0, 55.4. HRMS (EI) M+ calcd for C23H15F3O3S 428.0694 found 428.0620. Compound 12A shows an inhibition of tubulin polymerization >40 μM. Biological activity of compound 12A is shown in Table 18.