Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C@H](NC(=O)OC(C)(C)C)C)=[CH:15][CH:14]=2)[N:3]=1.NC1C=CC([CH2:34][OH:35])=CC=1>>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:34][OH:35])=[CH:15][CH:14]=2)[N:3]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reactant: Nc1ccc(CO)cc1
Product: OCc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1

Procedure:
C7 was prepared in a manner similar to that described in for making C3 in Step 3 of Example 1 except that 4-aminobenzyl alcohol (2.4 g, 19 mmol) was used instead of C2. When the reaction was complete the reaction mixture was concentrated and dissolved in EtOA. The resultant solution was washed with water, brine, dried over MgSO4, and concentrated. The resultant tan solid was triterated with ether and a small amount of EtOAc, filtered and concentrated to provide C7 as a tan solid. Yield: 2.98 g, 50%. MS+ 304.1. 1H NMR (500 MHz, d6-DMSO) δ: 10.61 (s, 1H), 8.76 (s, 1H), 7.59 (d, 2H), 7.26 (d, 2H), 5.10 (bs, 1H), 4.43 (s, 2H).
Reaction SMILES: [C:1](OC1C=CC=CC=1)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:17][C:18]1[C:19](Cl)=[N:20][CH:21]=[CH:22][CH:23]=1>ClC1C=CC(Cl)=CC=1Cl>[N:20]1[C:19]2[O:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:9])[NH:17][C:18]=2[CH:23]=[CH:22][CH:21]=1
Reactant: Nc1cccnc1Cl
Reactant: O=C(Oc1ccccc1)c1ccccc1O
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: O=C1Nc2cccnc2Oc2ccccc21
Yield: 28.3 %

Procedure:
A mixture of 21.4 g of phenyl salicylate, 25.71 g 3-amino-2-chloropyridine and 20 ml of 1,2,4-trichlorobenzene is refluxed for 1 hour under argon and the liberated phenol and HCl simultaneously distilled (from the refluxing mixture) and collected in a solution of 1N NaOH. The hot mixture is poured into 200 ml of ethanol and the precipitated solid collected by filtration. The solid is washed with ethanol and dried Recrystallization from methanol--DMF (6:1) gives 6.0 g of product, m.p. 268°-270° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])=[O:10])[CH:5]=[N:6][C:7]=1Cl.[OH-].[K+].[F:14][C:15]([F:19])([F:18])[CH2:16][OH:17].Cl>CS(C)=O.O>[Br:1][C:2]1[C:7]([O:17][CH2:16][C:15]([F:19])([F:18])[F:14])=[N:6][CH:5]=[C:4]([CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: OCC(F)(F)F
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93 %

Procedure:
5-Bromo-6-chloro-3-pyridinecarboxylic acid (68.0 g, 0.288 mol, CAN 29241-62-1) was dissolved in DMSO (1000 mL). To this solution was added with stirring potassium hydroxide (48.25 g, 0.86 mol) and after 10 minutes of stirring at room temperature 2,2,2-trifluoroethanol (26.9 mL, 0.374 mol) was added. The mixture was stirred at room temperature for 24 h. Water (1000 mL) and concentrated hydrochloric acid (107 mL, 1280 mmol, 37%) was added and the suspension was stirred vigorously for 4 hours. The precipitate was filtered, washed with water (4×100 mL) and vacuum dried over night to give the title compound (80.4 g) as an off white solid; MS (EI) 299, 301 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][O:16][CH2:17][CH2:18][OH:19])[CH:5]=[CH:4][C:3]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])=[O:21].[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>N1C=CC=CC=1>[CH3:39][C:29]1[CH:34]=[CH:33][C:32]([S:35]([O:19][CH2:18][CH2:17][O:16][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:6]2[CH:5]=[CH:4][C:3]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[O:21])=[C:2]([Cl:1])[CH:7]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2COCCO)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCc2ccccc2Nc2ccc(C(=O)c3ccccc3C)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound 156 (1.0 g, 2.55 mmol) was dissolved in pyridine (1.3 mL) under an argon atmosphere. The solution was cooled on an ice bath and p-toluenesulfonyl chloride (0.56 g, 2.9 mmol) was added. The suspension was stirred for 3 h at room temperature. The reaction was quenched with water and the water phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude product was purified by flash chromatography eluting with EtOAc/petroleum ether 1:2. This afforded the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:22]=[C:21]([OH:23])[C:20]([C:24]([CH3:26])=[O:25])=[CH:19][C:18]=1[Cl:27].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:27][C:18]1[C:17]([CH3:16])=[CH:22][C:21]([O:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:20]([C:24](=[O:25])[CH3:26])[CH:19]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC(=O)c1cc(Cl)c(C)cc1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc(C)c(Cl)cc3C(C)=O)c2cc1OC
Temperature: 150 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 5-chloro-2-hydroxy-4-methylacetophenone (248 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 150° C. for 2 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (71 mg, yield 45%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].Cl.[CH3:7][N:8]([CH3:16])[C:9]1[S:10][CH:11]=[C:12]([CH2:14]Cl)[N:13]=1>Cl>[CH3:7][N:8]([CH3:16])[C:9]1[S:10][CH:11]=[C:12]([CH2:14][S:5][CH2:4][CH2:3][NH2:2])[N:13]=1
Reactant: CN(C)c1nc(CCl)cs1
Reactant: NCCS
Agent: Cl
Product: CN(C)c1nc(CSCCN)cs1

Procedure:
Cysteamine hydrochloride (5.24 g; 45.9 mmoles) and 2-dimethylamino-4-chloromethylthiazole hydrochloride (9.8 g; 45.9 mmoles) [prepared from N,N-dimethylthiourea and 1,3-dichloro-2-propanone] were dissolved in 45 ml of concentrated hydrochloric acid and heated at an oil bath temperature of 100° for 96 hours. The mixture was evaporated under reduced pressure and the residue made basic with 40% aqueous NaOH. The aqueous phase was extracted with methyl acetate, dried and evaporated to give the title compound as an oil which was used without further purification in Step B.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:26])[CH:24]([NH2:25])[C@H:21]2[S:20][CH2:19][CH:18]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([CH2:29][CH2:30][C:31](Cl)=[S:32])#[N:28].C(N(CC)CC)C>C(Cl)Cl>[CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:26])[CH:24]([NH:25][C:31](=[S:32])[CH2:30][CH2:29][C:27]#[N:28])[C@H:21]2[S:20][CH2:19][CH:18]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCC(=S)Cl
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCCC(=S)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Reaction time: 4 h

Procedure:
7-Amino-3-cephem-4-carboxylic acid benzhydryl ester (366 mg.) (prepared by the method of Netherlands Patent no. 7,309,135) is dissolved in methylene chloride (5 ml.), cooled in an ice bath, and cyanomethylthioacetyl chloride (149 mg.) in methylene chloride (5 ml.) is added followed by triethylamine (101 mg.). The mixture is stirred for 4 hours at 0°-5° and, after diluting with methylene chloride the reaction mixture is washed with water then with pH 4 buffer, and dried (Na2SO4). The solvent is removed in vacuo yielding the product 7-cyanomethylthioacetamido-3-cephem-4-carboxylic acid benzhydryl ester as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])=[N:5][CH:6]=[CH:7][CH:8]=1.[C:16]([O:20][C:21]([NH:23][C:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=S)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:30]([O:29][C:27]([NH:26][C:24]([NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])=[N:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:10]=1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: COc1cccnc1-c1cccc(N)c1
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccnc1-c1cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Reaction time: 18 h
Yield: 68.1 %

Procedure:
To a suspension of 3-(3-methoxypyridin-2-yl)aniline (0.34 g), N,N′-bis(tert-butoxycarbonyl)thiourea (563 mg) and diisopropylethyl-amine (0.681 ml) in dichloromethane (15 ml) was added 1-methyl-2-chloropyridinium iodide (565 mg), and the mixture was stirred for 18 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from methanol. The precipitate was collected by filtration, washed with methanol and dried to give N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-methoxypyridin-2-yl)phenyl)guanidine (512 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[C:8]=1[F:16])(=O)=O.[C:19]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[F:36])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.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>[C:22]([O:21][C:19](=[O:20])[NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[C:8]=2[F:16])=[CH:29][C:28]=1[F:36])([CH3:25])([CH3:23])[CH3:24]
Reactant: N#Cc1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1F
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)c(F)c2F)cc1F
Yield: 16.5 %

Procedure:
A solution of 3.75 g of 4-cyano-2,3-difluorophenyl trifluoromethanesulfonate in 220 mL of dioxane is admixed at ambient temperature with 5 g of N-Boc-4-amino-3-fluorophenylboronic acid, 3.87 g of sodium carbonate in solution with 56 mL of distilled water and then 1.81 g of tetrakistriphenylphosphinepalladium. The reaction mixture is heated for 3 h at reflux and then poured, after cooling, into the distilled water. This mixture is extracted with ethyl acetate, the organic phase is decanted, washed a number of times with distilled water, then with saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated to dryness under reduced pressure. The solid obtained is chromatographed on a silica column (eluent: cyclohexane/ethyl acetate, 90/10 by volume). Evaporation to dryness under reduced pressure of the fractions containing the expected product gives 0.75 g of tert-butyl(4′-cyano-3,2′,3′-trifluorobiphenyl-4-yl)carbamate in the form of a pale pink solid, whose characteristics are as follows:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[CH:3]=1.[C:16]([O:20][C:21]([NH:23][C:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=S)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:30]([O:29][C:27]([NH:26][C:24]([NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])=[N:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([O:8][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=2)[CH:10]=1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: Cc1ccnc(Oc2cccc(N)c2)c1
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccnc(Oc2cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Reaction time: 16 h
Yield: 77.5 %

Procedure:
To a suspension of 3-(4-methylpyridin-2-yloxy)aniline (264 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (474 mg) and diisopropylethyl-amine (0.529 ml) in dichloromethane (13.2 ml) was added 1-methyl-2-chloropyridinium iodide (438 mg), and the mixture was stirred for 16 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 25 g, n-hexane:ethyl acetate 4:1) to give N,N′-bis(tert-butoxycarbonyl)-N″-(3-(4-methylpyridin-2-yloxy)phenyl)-guanidine (452 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])[O:12][C:13]=2[CH2:14][CH2:15][C:16](OC)=[O:17])[CH:5]=[CH:6][C:7]=1[Cl:8].O.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].O.O.[Na+].[K+].C(C(C(C([O-])=O)O)O)([O-])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])[O:12][C:13]=2[CH2:14][CH2:15][CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nccn1-c1nc(-c2ccc(Cl)c(Cl)c2)c(CCCO)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
Methyl 4-(3,4-dichlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionate (0.67 g) was dissolved in toluene (5 ml). To the obtained solution was added dropwise a mixture of a 70% toluene solution (0.81 g) of sodium dihydrobis(2-methoxyethoxy)aluminate, and toluene (5 ml) at 0° C., which was stirred at 0° C. for 1 hour. To the reaction mixture was carefully added a 10% aqueous solution of (+)-sodium potassium tartrate sesquihydrate (50 ml), which was stirred at room temperature for 1 hour. The precipitated crystals were filtered, washed in sequence with a 10% aqueous solution of (+)-sodium potassium tartrate sesquihydrate, pure water, and isopropyl ether, and air-dried to give crystals of 4-(3,4-dichlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol (0.46 g, 74%). Recrystallization from acetone-hexane gave pale yellow prisms. Melting point 140-141° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[Br:12]N1C(=O)CCC1=O.O>CC#N>[Br:12][C:6]1[CH:7]=[CH:2][CH:3]=[C:4]([NH2:9])[C:5]=1[NH2:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CC#N
Solvent: O
Product: Nc1cccc(Br)c1N
Temperature: 70 °C
Reaction time: 14 h
Yield: 119.9 %

Procedure:
A mixture of 4-chloro-2-nitrobenzenamine (2.0 g, 11.59 mmol) and 1-bromopyrrolidine-2,5-dione (2.3 g, 12.75 mmol) in MeCN (30 mL) was stirred at 70° C. for 14 h. The reaction mixture was poured into water (100 mL) and stirred at RT for 1 h. The precipitate was filtered and washed with water. The solid was dried under vacuum to afford 3-bromobenzene-1,2-diamine as a yellow solid (2.6 g, 86.7%).
Reaction SMILES: [CH3:1][N:2]1[C:11](/[CH:12]=[CH:13]/[C:14](O)=[O:15])=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:23].S(Cl)([Cl:26])=O>>[CH3:1][N:2]1[C:11](/[CH:12]=[CH:13]/[C:14]([Cl:26])=[O:15])=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:23]
Reactant: Cn1c(/C=C/C(=O)O)c(-c2ccccc2)c2ccccc2c1=O
Reactant: O=S(Cl)Cl
Product: Cn1c(/C=C/C(=O)Cl)c(-c2ccccc2)c2ccccc2c1=O

Procedure:
A solution of (E)-3-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)propenoic acid (0.92 g) in thionyl chloride (15 ml) was heated at reflux for 4 hours. The excess thionyl chloride was then removed by distillation and the residual yellow solid was washed with petroleum ether (b.p. 40°-60° C.), to give (E)-3-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)propenoyl chloride (1.0 g) in the form of a yellow solid, m.p.213°-215° C.
Reaction SMILES: [CH2:1]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].Cl.[CH2:16](O)[CH3:17]>>[CH2:16]([O:13][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7])[CH3:17]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CCCCCCCCCCBr
Temperature: 25 °C

Procedure:
Compound 1, 11-Bromoundecanoic acid (41.38 g, 156 mmol), was placed in a 250 ml round-bottomed flask equipped with a reflux condenser. After absolute ethanol (60 ml) and concentrated HCl (1/2 ml) were added, the reaction mixture was refluxed overnight. The reaction mixture was allowed to cool to room temperature before the solvent was removed under reduced pressure The resulting yellow oil was dissolved in ether. The ether solution was extracted with saturated sodium carbonate (NaHCO3) and H2O, and dried over magnesium sulfate (MgSO4). The solvent was removed under reduced pressure. Purification of the crude product was obtained by vacuum distillation which yielded a colorless oil, ethyl-11-bromoundecanoate, compound 2 (37.32 g, 82.5% yield)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H][H].CC(C)=O>C(O)C.[C].[Pd]>[NH2:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([Cl:1])[CH:10]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)=O
Solvent: CCO
Product: Nc1ccc(C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In ethanol (250 mL) was dissolved 100 g (F.W. 201.57, 496 mmol) of 2-chloro-4-nitrobenzoic acid (1) and after replacing with argon, a 10% palladium carbon catalyst (4.0+1.5 g) was added thereto. After replacing with hydrogen, the mixture was stirred at room temperature for 72 hours. The formed crystal was dissolved with acetone and filtered to remove the catalyst. The solvent was distilled under reduced pressure to quantitatively obtain 88 g of the target 4-amino-2-chlorobenzoic acid (2).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][C@@H:11]([CH2:13][OH:14])[O:10][N:9]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:21][C:22]1[CH:23]=[C:24]([N:37]2[CH2:41][C@H:40]([CH2:42][NH:43][C:44](=[O:46])[CH3:45])[O:39][C:38]2=[O:47])[CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1>CN(C=O)C.O.C1(P([Pd-4](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)C=CC=CC=1>[F:21][C:22]1[CH:23]=[C:24]([N:37]2[CH2:41][C@H:40]([CH2:42][NH:43][C:44](=[O:46])[CH3:45])[O:39][C:38]2=[O:47])[CH:25]=[CH:26][C:27]=1[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH2:12][C@@H:11]([CH2:13][OH:14])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: OC[C@@H]1CC(c2ccc(Br)cn2)=NO1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)C(=O)O1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NO[C@H](CO)C4)nc3)c(F)c2)C(=O)O1
Temperature: 75 °C
Yield: 48.7 %

Procedure:
[(5S)-3-(5-Bromopyridin-2-yl)-4,5-dihydroisoxazol-5-yl]methanol (Intermediate 11, 0.5 g, 1.95 mmol), potassium carbonate (0.622 g, 4.5 mmol), N-({(5S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (Intermediate 13, 0.736 g, 1.95 mmol) and tetrakis(triphenylphosphino)palladium(0) (0.225 g, 0.195 mmol) were combined and suspended in DMF (7 ml) and water (1 ml). The mixture was heated at 75° C. for 2 hours, then was poured into cold water (30 ml). The solids formed were collected, rinsed with water and washed with dichloromethane, dried under vaccuum and collected to give the title compound (0.407 g).
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]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(Cl)cc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, light grey solid (78 mg, 93%), MS (ISP) m/z=336.5 [(M+H)+], mp 298° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][C@H:34]([OH:50])[CH2:35][O:36][CH2:37][CH2:38][S:39][CH2:40][CH2:41][CH2:42][C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45])=[CH:28][CH:27]=3)[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22]COC)=[CH:18][CH:17]=3)([CH3:15])[CH2:11][O:12]2)=[CH:7][CH:6]=1.Cl.O>CO>[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH2:33][C@H:34]([OH:50])[CH2:35][O:36][CH2:37][CH2:38][S:39][CH2:40][CH2:41][CH2:42][C:43]([F:49])([F:48])[C:44]([F:45])([F:46])[F:47])=[CH:30][CH:31]=3)[C:10]([C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)([CH3:15])[CH2:11][O:12]2)=[CH:7][CH:6]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2ccc(OC[C@H](O)COCCSCCCC(F)(F)C(F)(F)F)cc2)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1c1ccc(OC[C@H](O)COCCSCCCC(F)(F)C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 68.3 %

Procedure:
To a solution of 7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methyl-4-(4-(3-(2-(4,4,5,5,5-pentafluoropentylthio)ethoxy)-(R)-2-hydroxypropyloxy)phenyl)chroman (440 mg, 0.613 mmol) in methanol (9 ml) was added 6N HCl (3 ml) at room temperature, which was stirred for 40 minutes at 70° C. Water was added thereto, and the resulting solution was extracted with ethyl acetate. Then, the organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel (n-hexane:ethyl acetate=3:2) to give the title compound (269 mg, yield 68%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:11](Br)([CH3:14])([CH3:13])[CH3:12]>C(=O)([O-])[O-].[Ag+2]>[C:11]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: CC(C)(C)Br
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Product: CC(C)(C)OC(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a mixture of 3-bromo benzoic acid (10 g, 0.5 mol), silver carbonate (276 g, 1 mol) and dry molecular sieves (100 g) taken in dry CH2Cl2 (2 L), tert-butylbromide (115 mL, 1 mol) was added dropwise at 0° C. and the reaction mixture was stirred overnight at RT. The solid was filtered and washed with dichloromethane. Organic layer was washed with 10% aqueous solution of NaHCO3 (2×500 mL), water (2×500 mL), brine and dried. The solvent was removed under vacuum to give tert-butyl-3-bromobenzoate (70 g, 57%).