Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]#[CH:36]>>[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]#[C:36][C:13]1[CH:12]=[C:11]2[C:16]([C:7](=[N:6][OH:5])[CH:8]=[C:9]([C:18]3[N:19]=[CH:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:10]2)=[CH:15][CH:14]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Reactant: C#Cc1ccccc1Cl
Product: ON=c1cc(-c2cc3ccccc3cn2)oc2cc(C#Cc3ccccc3Cl)ccc12

Procedure:
7-(2-chlorophenyl)ethynyl-2-isoquinolin-3-yl-chromen-4-one oxime was prepared in 10% overall yield using the method described in example 24, starting from 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 2B) and 2-chlorophenylacetylene. The title compound was isolated as an orange solid and as a 80/20 mixture of Z/E oxime isomers.
Reaction SMILES: [Si]([O:18][CH:19]([C:21]1[S:22][CH:23]=[C:24]([C:26]([NH:28][C@@H:29]([CH3:45])[CH2:30][N:31]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[C:38]([Cl:44])[CH:37]=3)=[N:32]2)=[O:27])[N:25]=1)[CH3:20])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:44][C:38]1[CH:37]=[C:36]([C:33]2[CH:34]=[CH:35][N:31]([CH2:30][C@@H:29]([NH:28][C:26]([C:24]3[N:25]=[C:21]([CH:19]([OH:18])[CH3:20])[S:22][CH:23]=3)=[O:27])[CH3:45])[N:32]=2)[CH:41]=[CH:40][C:39]=1[C:42]#[N:43]
Reactant: CC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1-(tert-butyldiphenylsilyloxy)ethyl)-N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide (264 mg, 0.403 mmol) dissolved in THF (20 ml) and tetrabutylammonium fluoride, 1.0 M solution in THF (0.41 ml, 0.410 mmol), were added into a flask and stirred at RT overnight. After reacting for an hour, more of tetrabutylammonium fluoride, 1.0 M solution in THF (0.41 ml, 0.410 mmol), was added. The crude product was dried by evaporating and extracted with DCM/water. The organic phase was isolated with phase separator and evaporated. The product was purified by flash chromatography and recrystallization from ethyl acetate/heptane, respectively. 1H-NMR (400 MHz; DMSO-d6): δ 1.10-1.15 (m, 3H), 1.46 (t, 3H), 4.29-4.52 (m, 3H), 4.93-5.01 (m, 1H), 6.24 (s, 1H), 6.94-6.98 (m, 1H), 7.83-7.87 (m, 1H), 7.92-8.00 (m, 2H), 8.08 (s, 1H), 8.10 (d, 1H), 8.33-8.39 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([O:17]C)=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2c1c(C)nn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nn(C(C)C)c2cc(Br)cc(C(=O)O)c12

Procedure:
To a stirred solution of methyl 6-bromo-1-isopropyl-3-methyl-1H-indazole-4-carboxylate (7.5 g, 24.11 mmol) in ethanol (400 mL) was added sodium hydroxide (1.45 g, 36.17 mmol) in water (60 mL) and the reaction mixture was stirred at reflux for 6 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (150 mL), and acidified with 2N HCl to pH˜2. The precipitated acid was collected by filtration, washed with ether (200 mL, and dried to afford 6-bromo-1-isopropyl-3-methyl-1H-indazole-4-carboxylic acid as an off white solid (6.85 g, 95.6%). LCMS (ES−): 294.9 [M−H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH:17](OC)OC)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8].[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:37]2[CH2:36][CH2:35][N:34]([C:31]3[CH:30]=[CH:29][C:28]([F:27])=[CH:33][CH:32]=3)[CH2:39][CH2:38]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: COC(CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O)OC
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCN(c3ccc(F)cc3)CC2)C1

Procedure:
Compound 748 was prepared from 1-(2,2-dimethoxy-ethyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide and 1-(4-fluoro-phenyl)-piperazine using the method described for compound 747. The title compound was isolated as an amber foam (0.009 g, 25% yield). HRMS (M+H) calcd for C24H28N4Cl2O3F: 521.15226. found: 521.1531.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[NH:10][S:11]([C:14]1[CH:15]=[C:16]([CH:23]=C)[C:17]2[O:21][CH:20]=[CH:19][C:18]=2[CH:22]=1)(=[O:13])=[O:12].N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:34].[Na+].Cl>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH:23]([C:16]1[C:17]2[O:21][CH:20]=[CH:19][C:18]=2[CH:22]=[C:14]([S:11]([NH:10][C:4]2[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])(=[O:12])=[O:13])[CH:15]=1)=[O:34]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(S(=O)(=O)Nc2cc(C)ccc2OC)cc2ccoc12
Agent: O=[Os](=O)(=O)=O
Agent: Cl
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C)cc1NS(=O)(=O)c1cc(C=O)c2occc2c1
Reaction time: 1.5 h
Yield: 98.3 %

Procedure:
Osmium tetroxide (84 mg, 0.33 mmol) was added to a solution of N-(2-methoxy-5-methylphenyl)-7-vinyl-1-benzofuran-5-sulfonamide (1.25 g, 3.3 mmol; Intermediate 61) and lutidine (0.71 g, 6.6 mmol) in dioxane (30 mL). A solution of sodium periodate (2.82 g, 13.2 mmol) in water (10 mL) was added under stirring. After 90 min, aqueous HCl (2 M; 40 mL) was added to give a clear solution. Addition of water (200 mL) gave a precipitate that was collected by filtration. This material was washed with water and dried to give 1.12 g (88%) of the title product. 1H NMR (400 MHz, CDCl3) δ 2.27 (s, 3H), 3.55 (s, 3H), 6.57 (d, 1H), 6.80-6.85 (m, 1H), 6.92 (d, 1H), 7.02 (br s, 1H), 7.38 (d, 1H), 7.85 (d, 1H), 8.22 (d, 1H), 8.28 (d, 1H), 10.38 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9](C(=O)C(F)(F)F)[CH2:8][CH:7]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH2:28][CH:29]([CH3:31])[CH3:30])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[C:6]=2[CH:5]=[C:4]([O:32][CH3:33])[C:3]=1[O:34][CH3:35].[OH-].[Na+].CO>O>[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([C:19]3[CH:20]=[CH:21][C:22]([S:25]([CH2:28][CH:29]([CH3:31])[CH3:30])(=[O:27])=[O:26])=[CH:23][CH:24]=3)[C:6]=2[CH:5]=[C:4]([O:32][CH3:33])[C:3]=1[O:34][CH3:35]
Reactant: COc1cc2c(c(Cl)c1OC)CCN(C(=O)C(F)(F)F)CC2c1ccc(S(=O)(=O)CC(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2c(c(Cl)c1OC)CCNCC2c1ccc(S(=O)(=O)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
A mixture of 8.9 g (0.015 m) of the amide, 1 g (0.025 m) of sodium hydroxide and 100 ml of methanol was stirred at room temperature for 2 hours, then, poured into water. The quench was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to give 4.4 g of 6-chloro-1-(4'-isobutylsulfonylphenyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:21])[C:7](=[O:20])[CH2:8][CH2:9][N:10]2[CH2:13][C:14]2[N:15]=[C:16]([CH3:19])[S:17][CH:18]=2)=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:39][CH3:40].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CC(C)CC(O)C.CO>[CH3:40][O:39][C:24]1[CH:25]=[C:26]([CH:37]=[CH:38][C:23]=1[NH:22][C:2]1[N:12]=[C:11]2[C:5](=[CH:4][N:3]=1)[N:6]([CH3:21])[C:7](=[O:20])[CH2:8][CH2:9][N:10]2[CH2:13][C:14]1[N:15]=[C:16]([CH3:19])[S:17][CH:18]=1)[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1)=[O:28]
Reactant: Cc1nc(CN2CCC(=O)N(C)c3cnc(Cl)nc32)cs1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(Cc1csc(C)n1)CCC(=O)N2C
Temperature: 160 °C

Procedure:
10-chloro-6-methyl-2-[(2-methyl-1,3-thiazol-4-yl)methyl]-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 101; 58 mg, 0.18 mmol), 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220; 49 mg, 0.19 mmol) and p-toluene sulphonic acid (70 mg, 0.37 mmol) were taken up in 4-methyl-2-pentanol (2 mL) and heated to 160° C. in microwave by microwave irradiation for 1 hour. The reaction mixture was dissolved in methanol (5 mL) and water (˜5 mL) and poured directly onto an SCX-3 cartridge (2 g). The cartridge was washed through with methanol (˜30 mL), before elution of products with 2M ammonia in methanol (˜30 mL). Evaporation of the ammoniacal fraction gave an amber film which was purified by reverse phase HPLC to yield the title compound as an off white solid (43 mg, 26%)
Reaction SMILES: [CH2:1]([S:3][C:4]([CH3:14])([CH3:13])[C:5]([CH2:7][C:8]([O:10]CC)=O)=[O:6])[CH3:2].[Cl:15][C:16]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:45])[CH:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:38][CH3:39])([CH3:37])[CH3:36])=[CH:31][C:30]=2[C:40]([CH2:43][CH3:44])([CH3:42])[CH3:41])[CH2:26][CH3:27])=[CH:19][C:17]=1[NH2:18]>>[Cl:15][C:16]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:45])[CH:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:38][CH3:39])([CH3:37])[CH3:36])=[CH:31][C:30]=2[C:40]([CH2:43][CH3:44])([CH3:42])[CH3:41])[CH2:26][CH3:27])=[CH:19][C:17]=1[NH:18][C:8](=[O:10])[CH2:7][C:5](=[O:6])[C:4]([S:3][CH2:1][CH3:2])([CH3:13])[CH3:14]
Reactant: CCOC(=O)CC(=O)C(C)(C)SCC
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1ccc(Cl)c(N)c1
Product: CCSC(C)(C)C(=O)CC(=O)Nc1cc(NC(=O)C(CC)Oc2ccc(C(C)(C)CC)cc2C(C)(C)CC)ccc1Cl
Yield: 83 %

Procedure:
A mixture of 21.8 g of ethyl (2-ethylthio-2-methylpropionyl)acetate obtained in Step 1 above and 44.5 g of 2-chloro-5-[2-(2,4-di-tert-amylphenoxy)butyramido]aniline was stirred in an oil bath at 150° C for 3 hours under a reduced pressure of 50 to 100 mmHg. The reaction mixture was recrystallized from ligroin to yield 51 g (yield 83%) of Coupler (1) having a melting point of 65° to 68° C.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[N:4][N:3]=1.CN1CCOCC1.ClC(OCC)=O.Cl.[CH3:25][O:26][NH2:27]>O1CCCC1>[CH3:25][O:26][NH:27][C:8](=[O:10])[CH2:7][N:6]1[C:2]([SH:1])=[N:3][N:4]=[N:5]1
Reactant: O=C(O)Cn1nnnc1S
Reactant: CON
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CONC(=O)Cn1nnnc1S
Reaction time: 1 h

Procedure:
To a solution cooled at -28° C. to -35° C. of 5-mercapto-1H-tetrazole-1-acetic acid (0.8 g) in tetrahydrofuran (40 ml) are added N-methylmorpholine (1.26 ml) and ethyl chloroformate (0.62 ml). After stirring for 1 hour, a solution of methoxyamine hydrochloride (0.34 g) and N-methylmorpholine (0.71 ml) in tetrahydrofuran (11 ml) is added to the mixture at -50° C. After 2 hours' stirring at about -30° C., the mixture is concentrated under reduced pressure, and the resultant mixture is diluted with water (50 ml) and ethyl acetate (50 ml). The mixture is acidified to pH 2 with hydrochloric acid and extracted with ethyl acetate. The extract solution is dried over magnesium sulfate and concentrated to give 5-mercapto-1H-tetrazole-1-acetohydroxamic acid methyl ester. mp. 165°-167° C. (decomp.).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[O:9])=[C:6]([OH:22])[CH:5]=1)([O-])=O.[H][H]>[Pd].[Cr].[Co].O1CCOCC1>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[O:9])=[C:6]([OH:22])[CH:5]=1
Reactant: [H][H]
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1O
Agent: [Co]
Agent: [Cr]
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1ccc(NC(=O)c2ccc(N)cc2O)cc1

Procedure:
4,4'-Dinitro-2-hydroxybenzanilide (20.0 g, 0.066 mol), dioxane (300 mL), and 10 percent Pd/C were placed in a 600 mL Hastelloy C Parr Reactor. The material was hydrogenated at 100° C. and 150 psi (1033 kPa) of hydrogen for 16 hours, after which the reactor was allowed to cool and hydrogen was vented off. The catalyst was filtered and the major portion of the solution was set aside for Step C, while dioxane was removed in vacuo from a small portion of the solution to give a product having a melting point of 235° C. to 238° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:30][NH2:31])[CH2:9][C:10]([CH3:29])([CH3:28])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C@@H:21]2[CH2:25][O:24]C(C)(C)[O:22]2)=[CH:15][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@H:8]([CH2:30][NH2:31])[CH2:9][C:10]([CH3:28])([CH3:29])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C@@H:21]([OH:22])[CH2:25][OH:24])=[CH:15][CH:14]=1
Reactant: CC(C)(CCc1ccc(OC[C@@H]2COC(C)(C)O2)cc1)C[C@@H](CN)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CCc1ccc(OC[C@@H](O)CO)cc1)C[C@H](N)CN

Procedure:
A solution of {(S)-1-Aminomethyl-5-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-3,3-dimethyl-pentyl}-carbamic acid tert-butyl ester (0.13 g, 0.28 mmol) and TFA (1 ml) in DCM (5 ml) is stirred at room temperature for 1 hour, then loaded onto an SCX-2 cartridge which has been pre-eluted with MeOH. The cartridge is eluted with MeOH (2×5 ml), followed by 7M NH3 in MeOH (2×5 ml) to yield (S)-3-[4-((S)-5,6-Diamino-3,3-dimethyl-hexyl)-phenoxy]-propane-1,2-diol in 80% purity as a colourless oil; [M+H]+ 311
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[N+:16]([O-:18])=O)[C:4](O)=[O:5].Cl.NC(CC1C=CC(Br)=CC=1[N+]([O-])=O)C(O)=O.C(NC(CC1C=C(Cl)C=C(C)C=1[N+]([O-])=O)(C(OCC)=O)C(OCC)=O)(=O)C>>[NH2:2][CH:3]1[CH2:7][C:8]2[C:9](=[C:10]([CH3:15])[CH:11]=[C:12]([Cl:14])[CH:13]=2)[N:16]([OH:18])[C:4]1=[O:5]
Reactant: Cc1cc(Cl)cc(CC(N)C(=O)O)c1[N+](=O)[O-]
Agent: CCOC(=O)C(Cc1cc(Cl)cc(C)c1[N+](=O)[O-])(NC(C)=O)C(=O)OCC
Agent: Cl
Agent: NC(Cc1ccc(Br)cc1[N+](=O)[O-])C(=O)O
Product: Cc1cc(Cl)cc2c1N(O)C(=O)C(N)C2

Procedure:
2-Amino-3-(5-chloro-3-methyl-2-nitrophenyl)propanoic acid, hydrochloride salt (40) Following the procedure for the preparation of 2-amino-3-(4-bromo-2-nitrophenyl)propanoic acid, hydrochloride salt (25) in Example 5, diethyl acetamido(5-chloro-3-methyl-2-nitrobenzyl)malonate (39) was converted to the title product, which was obtained as a solid (assumed quantitative); LCMS m/z 259.0 (M+1).
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])=[CH:9][C:8]=1[C:18]1[C:19]2[CH:28]=[C:27]([C:29](O)=[O:30])[NH:26][C:20]=2[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=1.C(Cl)(=O)C(Cl)=O.[F:39][C:40]([F:44])([F:43])[CH2:41][NH2:42]>ClCCl.CN(C)C=O>[F:1][C:2]1([F:32])[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][CH3:17])(=[O:14])=[O:15])=[CH:9][C:8]=1[C:18]1[C:19]2[CH:28]=[C:27]([C:29]([NH:42][CH2:41][C:40]([F:44])([F:43])[F:39])=[O:30])[NH:26][C:20]=2[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=1
Reactant: NCC(F)(F)F
Reactant: CCS(=O)(=O)c1ccc(OCC2CC2(F)F)c(-c2cn(C)c(=O)c3[nH]c(C(=O)O)cc23)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(OCC2CC2(F)F)c(-c2cn(C)c(=O)c3[nH]c(C(=O)NCC(F)(F)F)cc23)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a solution of Example 327d (0.070 g, 0.15 mmol) in anhydrous dichloromethane (5 mL) were added oxalyl chloride (0.026 mL, 0.300 mmol) and dimethylformamide (0.581 μl, 7.50 μmol). The reaction mixture was stirred at ambient temperature for 2 hours and then evaporated. The residue was dissolved in dichloromethane (5 mL) and treated with 2,2,2-trifluoroethylamine (0.048 mL, 0.600 mmol) and the mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between water (15 mL) and ethyl acetate (25 mL). The aqueous layer was extracted with additional ethyl acetate (15 mL) twice. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase HPLC (C18, mobile phase A:water (10 mM NH4HCO3); B: acetonitrile, Gradient 25-60% B in A) to give the title compound (70 mg, 85%). 1H NMR (400 MHz, CD3OD) δ ppm 7.96-7.90 (m, 2H), 7.66-7.25 (m, 2H), 6.92 (s, 1H), 4.29 (t, J=7.5 Hz, 1H), 4.16 (t, J=9.2 Hz, 1H), 4.05 (tt, J=9.2, 4.5 Hz, 2H), 3.72 (s, 3H), 3.22 (q, J=7.4 Hz, 2H), 2.00 (td, J=12.0, 7.3 Hz, 1H), 1.58-1.46 (m, 1H), 1.32-1.25 (m, 4H). MS (ESI+) m/z 548.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:10][O:11][C:12]=2[CH2:13]Br)[CH:5]=[CH:4][N:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:10][O:11][C:12]=2[CH2:13][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:5]=[CH:4][N:3]=1
Reactant: C1COCCN1
Reactant: BrCc1onc(-c2ccccc2)c1-c1ccnc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cc(-c2c(-c3ccccc3)noc2CN2CCOCC2)ccn1
Yield: 94.3 %

Procedure:
A stirred solution of the above Compound 18a (484 mg, 1.22 mmol), morpholine (0.45 mL, 5.1 mmol) and K2CO3 (340 mg, 2.45 mmol) in anhydrous DMF (2 mL) was warmed to 40° C. for 18 h. The solution was poured into brine (10 ml), extracted with CH2Cl2 (3×15 mL), dried (MgSO4), and filtered. Flash chromatography (SiO2, 50% EtOAc-hexanes) provided the title compound (461 mg, 1.15 mmol, 94%).
Reaction SMILES: C([O:4][CH:5]1[CH:6]([CH3:53])[CH2:7][CH2:8][CH:9]([O:47][CH:48]([O:50][CH2:51][CH3:52])[CH3:49])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:46])=[CH:20]/[CH:21]=[CH:22]/[C:23]([O:40][CH:41]([O:43][CH2:44][CH3:45])[CH3:42])([CH3:39])[CH2:24][CH:25]2[O:38][CH:26]2[CH:27]([CH3:37])[CH:28]([O:31][CH:32]([O:34][CH2:35][CH3:36])[CH3:33])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[CH2:51]([O:50][CH:48]([O:47][CH:9]1[CH2:8][CH2:7][CH:6]([CH3:53])[CH:5]([OH:4])[CH:17]=[CH:16][CH:15]([CH3:18])[CH:14](/[C:19](/[CH3:46])=[CH:20]/[CH:21]=[CH:22]/[C:23]([O:40][CH:41]([O:43][CH2:44][CH3:45])[CH3:42])([CH3:39])[CH2:24][CH:25]2[O:38][CH:26]2[CH:27]([CH3:37])[CH:28]([O:31][CH:32]([O:34][CH2:35][CH3:36])[CH3:33])[CH2:29][CH3:30])[O:13][C:11](=[O:12])[CH2:10]1)[CH3:49])[CH3:52]
Reactant: CCOC(C)OC1CCC(C)C(OC(C)=O)C=CC(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Agent: CCOC(C)OC1CCC(C)C(O)/C=C/C(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Agent: CCOC(C)OC1CCC(C)C(OC(C)=O)/C=C/C(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(C)OC1CCC(C)C(O)C=CC(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(8E,12E,14E)-7-acetoxy-3,16,21-tris(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (186 mg) as the crude product was dissolved in methanol (2 mL). Potassium carbonate (75.0 mg, 543 μmol) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for three hours. This reaction solution was diluted with ethyl acetate (50 mL), and the organic layer was washed with brine (10 mL) twice. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The resulting concentrate was purified by silica gel column chromatography (Merck Silica gel 60, 63 to 200 μm; hexane:ethyl acetate=3:1->2:1) to obtain the title compound (131 mg, 185 μmol, 78.6%, 2 steps) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][C:10](=O)[CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.Cl.[Cl:15][C:16]1[CH:17]=[C:18]([NH:22]N)[CH:19]=[CH:20][CH:21]=1>>[Br:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[C:19]3[C:18](=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=3)[NH:22][C:10]=2[CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CCC(=O)CSc1cccc(Br)c1
Agent: Cl
Product: CCc1[nH]c2cc(Cl)ccc2c1Sc1cccc(Br)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 1-(3-bromo-phenylsulfanyl)-butan-2-one and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.B(Br)(Br)Br>O1CCCC1.C(OCC)(=O)C.O>[NH:9]1[C:6]2=[N:7][CH:8]=[C:3]([OH:2])[CH:4]=[C:5]2[CH:11]=[CH:10]1
Reactant: COc1cnc2[nH]ccc2c1
Agent: BrB(Br)Br
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Oc1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.7 %

Procedure:
To a solution of 5-methoxy-1H-pyrrolo[2,3-b]pyridine (81, 0.5 g, 3 mmol) in tetrahydrofuran (20 mL) was added boron tribromide (1.5 g, 6.0 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature, then stirred at room temperature for 3 hours. The reaction mixture was quenched by methanol. After repeated addition of methanol and removal of solvent, the concentrated reaction mixture was dissolved in ethyl acetate and water. The organic layer was collected, washed with brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as an off-white solid (82, 0.18 g, 40%).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]1[CH2:16][C:17]1[C:18]([C:23](O)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:4].[OH-].[K+]>>[ClH:1].[CH3:2][N:3]([CH2:5][CH:6]1[CH:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][C:9]=3[C:23](=[O:24])[C:18]3[C:17]([CH2:16]2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:15]1)[CH3:4]
Reactant: CN(C)CC1CCc2ccccc2C1Cc1ccccc1C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CN(C)CC1CCc2cccc3c2C1Cc1ccccc1C3=O

Procedure:
A mixture of 17.85 g (0.05 mole) of α-(2-dimethylaminomethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-o-toluic acid hydrochloride and 150 g. polyphosphoric acid is heated at 110° for 5 hours allowed to cool and poured onto crushed ice with stirring. The resulting solution is cooled on ice and made basic by the addition of solid potassium hydroxide, and extracted with methylene chloride. The methylene chloride is washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue is dissolved in isopropanol and treated with gaseous hydrogen chloride. The resulting precipitate is filtered and recrystallized from isopropanol to give the intermediate 1,2,3,12a-tetrahydro-1-(dimethylaminomethyl)-7(12H)-pleiadenone hydrochloride m.p. 262.5°-263.0°C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[NH:11][C:12]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:27])[CH3:26])[CH2:21][CH2:20]3)[CH:16]=[C:15]([CH3:28])[C:13]=2[N:14]=1.O.[ClH:30]>O1CCOCC1>[C:25]([N:22]1[CH2:23][CH2:24][N:19]([C:17]2[CH:16]=[C:15]([CH3:28])[C:13]3[N:14]=[C:10]([C:3]4[C:4](=[O:8])[NH:5][CH:6]=[CH:7][C:2]=4[Cl:30])[NH:11][C:12]=3[CH:18]=2)[CH2:20][CH2:21]1)(=[O:27])[CH3:26]
Reactant: COc1nccc(I)c1-c1nc2c(C)cc(N3CCN(C(C)=O)CC3)cc2[nH]1
Reactant: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2cc(C)c3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
To a solution of 1-{4-[2-(4-Iodo-2-methoxy-pyridin-3-yl)-7-methyl-3H-benzimidazol-5-yl]-piperazin-1-yl}-ethanone (5.2 g, 10.6 mmol) in 4 M HCl in dioxane (60 mL) was added water (5 mL). The reaction mixture was stirred at room temperature for 14 h. Concentration of the reaction mixture gave the title compound (4.02 g, 100%) which was used for the next step without purification. LCMS (M+H)+ m/z 486 (t=1.55 min.).