Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH:8]([C:10]1[C:11]2[CH2:12][C:13]3[N:18]4[CH:19]=[C:20]([C:22]([O:24]CC)=[O:23])[N:21]=[C:17]4[C:16](=[O:27])[NH:15][C:14]=3[C:28]=2[CH:29]=[CH:30][CH:31]=1)[CH3:9])=[O:7])C>O1CCOCC1>[C:6]([CH:8]([C:10]1[C:11]2[CH2:12][C:13]3[N:18]4[CH:19]=[C:20]([C:22]([OH:24])=[O:23])[N:21]=[C:17]4[C:16](=[O:27])[NH:15][C:14]=3[C:28]=2[CH:29]=[CH:30][CH:31]=1)[CH3:9])([OH:7])=[O:5]
Reactant: CCOC(=O)c1cn2c3c([nH]c(=O)c2n1)-c1cccc(C(C)C(=O)OCC)c1C3
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C(=O)O)c1cccc2c1Cc1c-2[nH]c(=O)c2nc(C(=O)O)cn12
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
19 ml of 1N sodium hydroxide solution are added dropwise, under a stream of nitrogen and at a temperature in the region of 20° C., to a suspension of 1.9 g of ethyl 9-(1-ethoxycarbonylethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylate in a mixture of dioxane (245 ml) and distilled water (65 ml). The reaction is continued for 4 hours and 30 minutes at the same temperature. The insoluble material, formed after partial evaporation of the solvents, is filtered, washed with water and then with a mixture of dimethylformamide (10 ml) and methanol (80 ml), and dried. The solid is dissolved in 20 ml of 1N sodium hydroxide solution and stirred for 4 hours at a temperature in the region of 20° C. The reaction mixture is then treated with 1N hydrochloric acid to pH 1 and the precipitate formed is filtered, washed with water and then with acetone and dried to result in 0.62 g of the hydrate of 9-(1-carboxyethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid in the form of a pink powder, the melting point of which is greater than 260° C. (Analysis C17H13N3O5.1.4H2O; % Calculated C: 60.18, H: 3.86, N: 12.38; % Found C: 60.1, H: 3.2, N: 12.5; 1H NMR spectrum in d6-DMSO, T=300K, δ in ppm (300 MHz): 1.5 (3H, CH3), 3.9 (1H, CH), 4.1 (2H, CH2), 7.3, 7.5, 7.9 (each 1H, 3 arom. CH), 8.6 (1H, imidazole CH), between 12 and 13.5 (3H, 2 COOH and NHCO)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[C:18]([C:20]1[CH:36]=[CH:35][C:23]([O:24][CH2:25][C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28](Cl)=O)=[C:22]([F:37])[CH:21]=1)#[N:19].C([O-])(=O)C.[Na+]>ClCCl.C(O)(=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[NH:9][C:28]([C:27]3[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=3[CH2:25][O:24][C:23]3[CH:35]=[CH:36][C:20]([C:18]#[N:19])=[CH:21][C:22]=3[F:37])=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: N#Cc1ccc(OCc2ccccc2C(=O)Cl)c(F)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#Cc1ccc(OCc2ccccc2-c2nc3cc(F)c(F)cc3[nH]2)c(F)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
To a mixture of 4,5-difluoro-benzene-1,2-diamine (501 mg, 3.47 mmol; CAS Reg. No. 76179-40-3) and triethylamine (0.64 ml, 4.74 mmol) in dichloromethane (10 ml) at 0° C. was added a solution of 2-(4-cyano-2-fluoro-phenoxymethyl)-benzoyl chloride (1.06 g, 3.65 mmol) in dichloromethane (15 ml) drop wise over 10 minutes. After stirring for 3 h at 0° C. the volatiles were removed in vacuo to give a yellow solid. The solid was dissolved in glacial acetic acid (15 ml), and sodium acetate was added to the solution, and the mixture was refluxed for 13 h. The reaction mixture was cooled to 25° C., evaporated in vacuo, and partitioned between dichloromethane and water. The biphasic mixture was cooled in an ice bath, and neutralized with solid potassium carbonate while maintaining vigorous stirring. The phases were separated, and the extraction was completed with additional portions of dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by flash chromatography over silica gel (15% ethyl acetate/n-hexane) to yield the desired compound as a brown solid (16%). MS (Turbo Spray): m/z=380.4 (M+H).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]([CH3:25])[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:26][CH2:27][CH2:28][S:29][CH3:30])(=[O:5])[CH2:2][CH2:3][CH3:4].C([O-])(O)=[O:32].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl.O>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]([CH3:24])[CH3:25])=[CH:13][CH:12]=[CH:11][C:10]=2[O:26][CH2:27][CH2:28][S:29]([CH3:30])=[O:32])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])O
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1C(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCC(=O)c1cnc2c(OCCS(C)=O)cccc2c1Nc1ccccc1C(C)C
Reaction time: 1 h
Yield: 57 %

Procedure:
3-Butyryl-4-(2-isopropylphenylamino)-8-(2-methylthioethoxy)quinoline (0.22 g, 0.52 mmol) was dissolved in methylene chloride (15 ml) and added to a mixture of 0.093 g NaHCO3 in 15 ml H2O. A solution of 71% m-CPBA (0.12 g, 0.50 mmol) in 7 ml methylene chloride was added dropwise at 4° C. The solution was stirred for one hour at this temperature. The reaction mixture was washed with a saturated sodium bicarbonate solution. The organic layer was dried over Na2SO4 and evaporated. Chromatography with methylene chloride:methanol 10:1 as eluent gave 0.130 g (57%) of the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[CH:7]2.[Li]C(C)(C)C.C(=O)=O.[C:27](OC)(=[O:32])[C:28]([O:30][CH3:31])=[O:29]>C1COCC1.CCOC(C)=O>[CH3:31][O:30][C:28](=[O:29])[C:27]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[CH:7]2)=[O:32]
Reactant: COC(=O)C(=O)OC
Reactant: C[Si](C)(C)CCOCn1ccc2cccc(Br)c21
Agent: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1cccc2ccn(COCC[Si](C)(C)C)c12
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 84.5 %

Procedure:
A solution of 7-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole (3.0 g, 9.19 mmol) in THF (100 mL) was cooled to −78° C. and a 1.7 M solution of tBuLi in pentanes (15 mL, 25.5 mmol) added dropwise over 15 min. After 15 min, the resultant bright yellow suspension was transferred over 15 min via a cannula cooled with dry ice to a solution of dimethyl oxalate (3.61 g, 30.6 mmol) in THF (40 mL) maintained at −78° C. After 15 min, the mixture was allowed to warm to room temperature and stirred 3 h. The cloudy yellow mixture was treated with pH 7.0 buffer, poured into-EtOAc and the EtOAc washed with pH 7.0 buffer (brine was added to clarify the layers), brine, dried (MgSO4) and concentrated to a cloudy oil. Flash chromatography (10% EtOAc/hexanes) afforded the title compound (2.59 g, 84%) as a bright yellow oil. 1H NMR (400 MHz, DMSO-d6) 7.97 (dd, J=8, 1 Hz, 1H), 7.64 (d, J=3 Hz, 1H), 7.57 (dd, J=8, 1 Hz, 1H), 7.24 (dd, J=8, 8 Hz, 1H), 6.68 (d, J=3 Hz, 1H), 5.59 (s, 2H), 3.91 (s, 3H), 3.04 (t, J=8 Hz, 2H), 0.62 (t, J=8 Hz, 2H), −0.17 (s, 9H). 13C NMR (75.5 MHz, DMSO-d6) 185.17, 163.31, 132.59, 131.60, 130.87, 127.19, 126.15, 120.09, 118.95, 102.40, 77.05, 63.92, 52.83, 16.74, −1.69. IR (CHCl3, cm−1) 1740, 1683. HRMS 334.1481 (M++1, calcd for C17H24NO4Si 334.1475).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[OH:17].[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20]>>[CH3:8][C:7]1[C:2]([CH3:1])=[C:3]([OH:17])[C:4]([C:9]([CH2:10][C:11]([CH3:12])([CH3:14])[CH3:13])([CH3:16])[CH3:15])=[CH:5][C:6]=1[CH2:20][CH2:19][C:18]([O:22][CH3:23])=[O:21]
Reactant: Cc1ccc(C(C)(C)CC(C)(C)C)c(O)c1C
Reactant: C=CC(=O)OC
Product: COC(=O)CCc1cc(C(C)(C)CC(C)(C)C)c(O)c(C)c1C

Procedure:
The product was obtained by reacting 2,3-dimethyl-6-(1,1,3,3-tetramethylbutyl)phenol with methyl acrylate in a similar manner as described in Example 1. The desired product was obtained as white crystals melting at 83° to 85° C (Compound 2).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:46]([O:50][C:51](=[O:60])[NH:52][C@H:53]([CH:55](O)[CH2:56][CH2:57][CH3:58])[CH3:54])([CH3:49])([CH3:48])[CH3:47]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH:55]([CH2:56][CH2:57][CH3:58])[C@@H:53]([NH:52][C:51]([O:50][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:60])[CH3:54])=[O:9])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: CCCC(O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: O=C([O-])c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(OC(=O)c1ccc([N+](=O)[O-])cc1)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 59.3 %

Procedure:
4-nitrobenzoate (16.3 g), triphenylphosphine (32 g), and diisopropyl azodicarboxylate (40% toluene solution) (64 ml) were added dropwise to a tetrahydrofuran (50 ml) solution containing tert-butyl((2S)-3-hydroxyhexan-2-yl)carbamate (17 g) for 30 minutes, followed by stirring at room temperature for 14 hours. The solvent was distilled away from the reaction solution under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=5.5:1), and a yellow solid of (2S)-2-((tert-butoxycarbonyl)amino)hexane-3-yl 4-nitrobenzoate (17 g) was thus obtained.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11]O)[N:10]=1)[CH3:4].S(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[ClH:15].[CH3:2][N:3]([CH2:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][Cl:1])[N:10]=1)[CH3:4]
Reactant: CN(C)Cc1nc(CO)cs1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN(C)Cc1nc(CCl)cs1

Procedure:
The methanols produced by the process of this example are readily converted to the corresponding thiazolemethyl chlorides according to the following procedure: A suspension was prepared from 1.05 grams of 2-dimethylaminomethyl-4-thiazolemethanol hydrochloride and 15 ml. of chloroform. Thionyl chloride (2.50 g) was added and the resulting mixture was stirred at reflux temperature for about 2.75 hours. Any volatile constituents including excess thionyl chloride were removed by evaporation. The residue was suspended in chloroform and the chloroform removed by evaporation. The residue was then recrystallized from a methanol-ethyl acetate solvent mixture to yield 2-dimethylaminomethyl-4-thiazolylmethylchloride hydrochloride melting at 136-8° C.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH3:13])(=[O:22])=[O:21]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: Brc1cccc2[nH]ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1S(=O)(=O)n1ccc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
Aq. 2.5 M NaOH (5 mL) was added to a stirring mixture of 4-bromo-1H-indole (1000 mg, 5.3 mmol), 2-methylbenzenesulfonyl chloride (1100 mg, 5.6 mmol) and tetrabutylammonium hydrogen sulfate (173 mg, 0.5 mmol) in DCM (10 mL). The reaction mixture was stirred at ambient temperature overnight. The mixture was diluted with DCM and water and the layers were separated. DCM was washed with water 2 times, dried (MgSO2) and concentrated to give 1.6 g of crude material that was purified using flash chromatography (SiO2, eluent EtOAc:hexane 9:1) giving the title product (1 g, 54%). MS (ESI+) for C15H12BrNO2S m/z 350 (M+H)+.
Reaction SMILES: C1(COC([NH:11][C@@H:12]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:13]([OH:34])[CH2:14][NH:15][C@H:16]([C:24]([O:26]CC2C=CC=CC=2)=[O:25])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=O)C=CC=CC=1.[ClH:42]>C(O)C.[Pd]>[ClH:42].[ClH:42].[NH2:11][C@@H:12]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH:13]([OH:34])[CH2:14][NH:15][C@H:16]([C:24]([OH:26])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(O)CN[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: N[C@@H](Cc1ccccc1)C(O)CN[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of N-[(3S)-3-[[(Phenylmethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]-L-phenylalanine, phenylmethyl ester (1.14 g, 2.06 mmol) in 30 ml of 95% ethanol was added 4.2 ml of 1N hydrogen chloride and 250 mg of 10% palladium on carbon catalyst. The reaction mixture was stirred at room temperature under an atmosphere of hydrogen. A white precipitate which separated upon addition of the aqueous hydrogen chloride redissolved as the reaction proceeded. After 17 hours, the catalyst was filtered and the solvent was evaporated. Trituration with methanol-ether afforded 531 mg of the title compound as a white solid, melting point 147°-163° C. The 1H-NMR showed an approximately 1:1 mixture of alcohol isomers. Evaporation of the filtrate from the trituration gave 0.21 g of material which was enriched in one of the diastereomers.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:21][C:22]([F:52])([C:48]([F:51])([F:50])[F:49])[C:23]([F:47])([F:46])[C:24]([F:45])([F:44])[O:25][C:26]([F:43])([F:42])[C:27]([F:41])([F:40])[O:28][C:29]([F:39])([F:38])[CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]Br>>[CH2:1]([O:7][C:8]1[CH:13]=[N:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][O:31][CH2:30][C:29]([O:28][C:27]([F:40])([F:41])[C:26]([F:42])([F:43])[O:25][C:24]([F:44])([F:45])[C:23]([F:46])([F:47])[C:22]([F:21])([F:52])[C:48]([F:51])([F:50])[F:49])([F:39])[F:38])=[CH:18][CH:19]=2)=[N:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: FC(F)(COCCCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Product: CCCCCCOc1cnc(-c2ccc(OCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-hexyloxy-2-(4-hydroxyphenyl)pyrimidine (8.0 g, 29.4 mmol) and 5-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-bromopentane (18.6 g, 32 mmol, Example 2). The resulting crude product was isolated and further purified essentially as described in Example 1 (b.p. 210°-25° C. at 0.3 torr).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][OH:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>[O-2].[Mn+4].[O-2].ClC(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccc2ncccc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.7 %

Procedure:
A mixture of 34 parts of 6-quinolinemethanol, 70 parts of manganese(IV)oxide and 300 parts of trichloromethane was stirred for 24 hours at room temperature. The reaction mixture was filtered over diatomaceous earth and the filtrate was evaporated, yielding 27.7 parts (82.7%) of 6-quinolinecarboxaldehyde; mp. 72° C. (interm. 16).
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9]1.C([SiH](CC)CC)C>>[S:8]1[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=2
Reactant: c1ccc2sccc2c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c(c1)CCS2
Temperature: 50 °C
Yield: 40.9 %

Procedure:
Trifluoroacetic acid (5.2 mL) was slowly added to the mixture of benzothiophene (1 g, 7.45 mmol) and triethylsilane (3.6 mL, 22.35 mmol) with heating under reflux at 50° C. for 125 hours. After cooling to 0° C., the reaction was quenched by addition of aq. saturated NH4Cl solution. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography to provide the intermediate 112 (415 mg, 41%).
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:7]=[CH:6][C:5]=2[N:4]1[S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH3:2].C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:7]=[CH:6][C:5]=2[N:4]1[S:24]([C:27]1[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=1)(=[O:26])=[O:25])[CH3:2]
Reactant: CCC1c2cc(F)ccc2-c2cc(-c3ccccc3)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CCC1c2cc(F)ccc2-c2cc(-c3ccccc3)ccc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.3 %

Procedure:
A stirred suspension of 6-ethyl-8-fluoro-5-[(4-methoxyphenyl)sulfonyl]-2-phenyl-5,6-dihydrophenanthridine (0.13 g, 0.26 mmol) and cyclohexene (0.48 mL, 4.8 mmol) was treated drop-wise at room temperature under nitrogen with a solution of 1 M boron tribromide in dichloromethane (1.6 mL, 1.6 mmol). After stirring for 20 hours at room temperature, the reaction was quenched by the drop-wise addition of a saturated, aqueous, sodium bicarbonate solution (300 mL), followed by extraction with dichloromethane (6×20 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a crude product. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:4 to 3:7 gradient), followed by re-crystallization from a mixture of ethyl acetate-hexane, to yield 4-[(6-ethyl-8-fluoro-2-phenylphenanthridin-5(6H)-yl)sulfonyl]phenol as a homogeneous solid (0.09 g, 71%), m.p. 207° C.;
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCl.CO>[C:14]([O:13][C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(OC1CCN(Cc2ccccc2)C1)c1ccccc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(O[C@H]1CCNC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a crude mixture of N-benzyl-3-benzoyloxypyrrolidine (114 mg, 0.41 mmol) in dichloromethane (1 mL) is added α-chloroethyl chloroformate (57 μL, 0.49 mmol) at 0° C., and the mixture is stirred for 1 hour while warming to room temperature. After removing dichloromethane, resulting mixture is diluted with MeOH. The reaction mixture is heated to 80° C. for 0.5 hour. After cooling to room temperature, solvent is evaporated under reduced pressure to obtain (S)-(−)-3-benzoyloxypyrrolidine which is used for next reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]([OH:30])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)C.[CH3:32]I>>[CH3:1][O:3][C:4](=[O:31])[CH:5]([O:30][CH3:32])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:12]=1
Reactant: CCCCCCCN(CCc1ccc(CC(O)C(=O)OCC)cc1)C(=O)OC(C)(C)C
Reactant: CI
Product: CCCCCCCN(CCc1ccc(CC(OC)C(=O)OC)cc1)C(=O)OC(C)(C)C

Procedure:
Synthesized from 3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-2-hydroxy-propionic acid ethyl ester using a procedure analogous to that used for Example 47 and substituting methyl iodide as the electrophile to give 3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-2-methoxy-propionic acid methyl ester as a clear oil containing a mixture of methyl and ethyl ester (48 mg, 18%).
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[CH2:6][C:7]([OH:9])=O.[CH2:10]([C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]([CH3:34])[CH3:33])[CH:24]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:18][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]([CH3:34])[CH3:33])[CH:24]=2)[CH2:20][CH2:21][N:22]1[C:7](=[O:9])[CH2:6][C:5]1[N:4]=[N:3][NH:2][N:1]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC(C)C
Reactant: O=C(O)Cc1nn[nH]n1
Product: COc1ccc(N2CCN(C(=O)Cc3nn[nH]n3)[C@@H](Cc3ccccc3)C2)cc1OC(C)C

Procedure:
Prepared by the method outlined for Example 189 using (2H-tetrazol-5-yl)-acetic acid and 3(S)-benzyl-1-(3-(1-methylethoxy)-4-methoxy-phenyl)-piperazine (Example 9, Compound 97) as starting materials. Product as an oil. LC/MS (Method B) 2.50 min, [M+1]+ 450. Potency class B.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:11](=O)[CH2:12][CH2:13][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].C([O-])(=O)C.[NH4+:34].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:10]([C:11]2[NH:34][C:14]([C:16]3[CH:21]=[N:20][CH:19]=[CH:18][N:17]=3)=[CH:13][CH:12]=2)[CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: CSc1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2cnccn2)cc1F
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CSc1ccc(C(CC2CCOCC2)c2ccc(-c3cnccn3)[nH]2)cc1F
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 87.8 %

Procedure:
To a solution of 5-[3-fluoro-4-(methylsulfanyl)phenyl]-1-(pyrazin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (438 mg) in acetic acid (5 mL) was added ammonium acetate (1.29 g), and the mixture was stirred at 110° C. for 2.5 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (367 mg, yield 88%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 398 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25](=[O:37])[CH2:26]C(NC2C=CC(F)=CC=2)=O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15]CCN2CCOCC2)C=1.[CH2:38]([O:45][C:46]1[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.COCCOCCOC>O>[CH2:38]([O:45][C:46]1[CH:47]=[CH:48][C:49]([NH:50][C:13]2[N:12]=[CH:11][N:15]=[C:9]([O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:24][C:25](=[O:37])[CH3:26])=[CH:3][C:2]=3[F:1])[CH:14]=2)=[CH:51][CH:52]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(CC(=O)Nc1ccc(Oc2ccnc(NCCN3CCOCC3)c2)c(F)c1)Nc1ccc(F)cc1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Solvent: O
Solvent: COCCOCCOC
Product: CC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1
Temperature: 160 °C
Yield: 45 %

Procedure:
A mixture of N-(4-(6-chloropyrimidin-4-yloxy)-3-fluorophenyl)acetamide (Compound B of Example 13, 281 mg, 1.00 mmol), 4-benzyloxyaniline (Aldrich, 398 mg, 2.00 mmol), and 2-methoxyethyl ether (2 mL) was heated at 160° C. for 45 min. The cooled mixture was treated with H2O (50 mL) and extracted with EtOAc (100 mL). The EtOAc extract was washed with brine (3×25 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (200 mg, 22%) as a purple solid. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.43 (s, 1H), 8.23 (s, 1H), 7.72 (dd, 1H, J=12.5, 2.0 Hz), 7.44-7.42 (m, 4H), 7.38 (dd, 2H, J=8.0, 6.9 Hz), 7.33-7.23 (m, 3H), 6.98 (d, 2H, J=9.0 Hz), 6.07 (s, 1H), 5.07 (s, 2H), 2.05 (s, 3H); MS(ESI+) m/z 445.13 (M+H)+.