Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[Cl:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[Cl-].[Cl-].[Ca+2].[O:15]1[CH:17]([CH2:18][CH3:19])[CH2:16]1>>[OH:15][CH:17]([CH2:18][CH3:19])[CH2:16][N:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:3]1[Cl:2]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CCC1CO1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na]
Product: CCC(O)Cn1c(Cl)nc2ccccc21
Reaction time: 15 h

Procedure:
5 g of the sodium salt of 2-chlorobenzimidazole are suspended in 50 ml of epoxybutane in a flask provided with a reflux condenser and a CaCl2 plug. The mixture is boiled for 15 hours, the epoxybutane is then evaporated under vacuum and the residue is taken up with water and made alkaline with 10% sodium hydrate. After agitation for about 1 hour it is filtered and the residue obtained is crystallised twice from benzene. A white product is obtained which melts at 126°.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:52][C:53]1[CH:58]=[CH:57][C:56]([CH:59]([C:66]2[CH:71]=[CH:70][C:69]([F:72])=[CH:68][CH:67]=2)[N:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)=[CH:55][CH:54]=1>CN(C=O)C.C(OCC)C>[F:72][C:69]1[CH:68]=[CH:67][C:66]([CH:59]([C:56]2[CH:57]=[CH:58][C:53]([F:52])=[CH:54][CH:55]=2)[N:60]2[CH2:61][CH2:62][N:63]([C:12]([C@@H:11]([NH:10][C:8]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:64][CH2:65]2)=[CH:71][CH:70]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
(S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (0.56 g, 2.2 mmol) was dissolved in dry DMF (7 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.76 mL, 4.4 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.82 g, 2.2 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.63 g, 2.2 mmol, Acros Organics, Pittsburgh, Pa.) was then added. After sequentially 30 minutes stirring at 0° C. and 2 hours at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (60% EtOAc in hexane) to provide 1.1 g (96%) of the pure titled compound as a white foam: mp 78-86° C. APCI-MS m/z 527.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][NH2:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.[C:15](OCC)(OCC)(OCC)[CH3:16]>>[Cl:1][C:2]1[C:11]2[N:10]([C:15]([CH3:16])=[N:13][N:12]=2)[C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[C:7]([Cl:14])[CH:8]=2
Reactant: NNc1nc2cc(Cl)ccc2nc1Cl
Reactant: CCOC(C)(OCC)OCC
Product: Cc1nnc2c(Cl)nc3ccc(Cl)cc3n12
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture consisting of 20 g. (0.087 mole) of 2,6-dichloro-3-hydrazinoquinoxaline and 160 ml. (0.87 mole) of triethyl orthoacetate was heated with mechanical stirring under a dry nitrogen atmosphere in a preheated oil bath at 100° C. for a period of 20 hours to give a yellow suspension. The resulting mixture was cooled to room temperature and filtered, and the recovered solid product was subsequently washed with ethanol and air-dried to constant weight to ultimately afford 10.2 g. (46%) of pure 4,8-dichloro-1-methyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. >280° C. Mass Spectrum: m/e, 254/252 (P+).
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:11][C:12]1[C:21](N)=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1.O>CO>[CH2:1]([C:8]1[NH:9][C:21]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[CH:18]3)=[CH:13][C:12]=2[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1ccccc1
Reactant: Nc1cc2ccccc2cc1N
Agent: Cl
Solvent: CO
Solvent: O
Product: c1ccc(Cc2nc3cc4ccccc4cc3[nH]2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 1M solution of benzyl cyanide in anhydrous methanol is treated with hydrogen chloride gas at 0° C. for about thirty minutes. The mixture is stirred for two hours at 0° C. and then a 1M solution of 2,3-diaminonaphthalene is added and the resulting solution is stirred at 0° C. The progress of the reaction is monitored by thin layer chromatography. The reaction mixture is then poured into water. The unreacted nitrile is extracted with ethyl acetate. The aqueous layer is neutralized with 1N sodium hydroxide. The organic fraction is extracted with ethyl acetate and condensed. The desired title product is recrystallized from methanol/water.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Yield: 98.4 %

Procedure:
2,4-Dibenzyloxybenzaldehyde (20 g) was dissolved in methanol (700 ml) and then thereto was added sodium borohydride (3.6 g) and this was left to stand at room temperature (20° C.) for 1.5 hours. To the reaction mixture was added water (1.5 l) and the resulting precipitate was collected by filtration and recrystallized from ethanol to obtain 2,4-dibenzyloxybenzyl alcohol (19.8 g, yield 98%). Melting point; 84°-85° C.
Reaction SMILES: Cl[C:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)=[O:3].[CH2:13]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)=[O:3])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C([O-])c1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(CNCc2ccccc2)cc1
Product: COc1ccc(CN(Cc2ccccc2)C(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-27 from 4-(chlorocarbonyl)benzoate and N-benzyl-1-(4-methoxyphenyl)methanamine. 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.72(d, J=7.6 Hz, 3H), 4.26(s, 1H), 4.30(s, 1H), 4.50(s, 1H), 4.55(s, 1H), 6.89(m, 2H), 7.02(m, 1H), 7.10(m, 1H), 7.10(m, 1H), 7.20(m, 1H), 7.28(m, 4H), 7.55(m, 2H), 7.96(m, 2H), 13.13(s, 1H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CS([C:20]1[N:25]=[CH:24][C:23]2=[CH:26][CH:27]=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[N:22]2[N:21]=1)=O>>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([NH:16][C:20]3[N:25]=[CH:24][C:23]4=[CH:26][CH:27]=[C:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[N:22]4[N:21]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CS(=O)c1ncc2ccc(-c3ccccc3NS(C)(=O)=O)n2n1
Reactant: Nc1cccc(OCCN2CCOCC2)c1
Product: CS(=O)(=O)Nc1ccccc1-c1ccc2cnc(Nc3cccc(OCCN4CCOCC4)c3)nn12

Procedure:
Prepared by following a procedure analagous to Example 251c by using 3-(2-Morpholin-4-yl-ethoxy)-phenylamine and N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-methanesulfonamide. 1H-NMR (DMSO) δ 9.9 (br s, 1H), 9.6 (s, 1H), 9 (s, 1H), 8.8 (s, 1H), 7.7 (d, J=8.0 Hz, 1H), 7.6 (m, 2H), 7.5 (m, 1H), 7.4 (brs, 1H), 7.2 (m, 1H), 7.1 (t, J=8.0 Hz, 1H), 7 (s, 2H), 6.6 (d, J=7.2 Hz, 1H), 4.1-3 (m, 12H), 2.7 (s, 3H); LC/MS (ESI+): 509 (M+H).
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:17][CH2:18][CH3:19])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:20]([C:28]1[CH:36]=[C:35]([Br:37])[CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31])(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br:37][C:35]1[CH:36]=[C:28]2[C:29](=[CH:33][CH:34]=1)[C:30](=[O:31])[N:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH2:16])(=[O:14])=[O:15])=[CH:11][CH:12]=1)[C:4]([C:3](=[O:2])[CH2:17][CH2:18][CH3:19])=[C:20]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCCC(O)CNCc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)c1ccc(Br)cc1C(=O)c1ccccc1
Agent: Cl
Product: CCCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(N)(=O)=O)cc1

Procedure:
In the same manner as in Example 452, Step 2, the title compound was synthesized from 4-[(2-hydroxypentylamino)methyl]benzenesulfonamide hydrochloride and 2-benzoyl-4-bromobenzoic acid.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12])[CH2:3][CH2:4][CH3:5].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CS(C)=O.CO>[CH2:2]([N:6]1[C:10]([CH3:11])=[CH:9][S:8]/[C:7]/1=[CH:12]\[C:17]([C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[C:14]([F:13])([F:24])[F:25])=[O:18])[CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CCCC[n+]1c(C)csc1C
Agent: CN(C)c1ccncc1
Agent: [I-]
Solvent: CO
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCCN1C(C)=CS/C1=C\C(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of 3-butyl-2,4-dimethylthiazol-3-ium iodide (47.92 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL) was added, followed by the addition of DMAP (49.24 mg, 0.40 mmol) dissolved in CH2Cl2 (0.8 mL). Then, to the solution was added 2-(trifluoromethyl)benzoyl chloride (33.4 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL). The vial was capped and shaken overnight at room temperature. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a Waters Sunfire C8 column (30×75 mm) eluting with a gradient of acetonitrile and 0.1% trifluoroacetic acid in water at a flow rate of 50 mL/min. Fractions selected by mass spectrometry to provide the title compound. 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 0.90 (t, 3 H) 1.27-1.38 (m, 2 H) 1.57-1.67 (m, 2 H) 2.27-2.32 (m, 3 H) 3.90-3.97 (m, 2 H) 5.99-6.02 (m, 1 H) 6.56-6.60 (m, 1 H) 7.53-7.62 (m, 2 H) 7.66-7.77 (m, 2 H); MS (ESI) positive ion 342 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[Li]CCCC>C1COCC1>[Br:8][C:6]1[N:5]=[C:4]([CH3:9])[C:3]([OH:10])=[CH:2][CH:7]=1
Reactant: Cc1nc(Br)cc(Br)c1O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(Br)ccc1O
Temperature: -78 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
4,6-Dibromo-2-methylpyridin-3-ol (15.8 g, 59.4 mmol) was dissolved in THF (200 mL). The solution was cooled to −78° C. and n-BuLi (50 mL, 125 mmol, 2.5 M in hexane) was added drop-wise keeping the temperature below −78° C. The mixture was allowed to stir at that temperature for 2 h. The mixture was quenched with water (50 mL) and was neutralized with 2 N HCl. The aqueous mixture was extracted with dichloromethane (2×). The combined organic layers were dried (Na2SO4) and concentrated to give 6-bromo-2-methylpyridin-3-ol (10.5 g, 95%) as a yellow oil. 1H-NMR (300 MHz, DMSO-d6) 2.29 (s, 3H), 7.08 (d, 1H), 7.26 (d, 1H), 10.08 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.[Cl-].[NH4+].[Na].[OH-].[K+].[CH3:29]COCC>C1C=CC=CC=1.C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:23][O:22][C:10]1[CH:9]=[CH:8][C:7]2[CH2:19][C@H:18]3[N:2]([CH3:1])[CH2:3][CH2:4][C@@:5]4([C:6]=2[C:11]=1[OH:12])[C:17]3=[CH:16][C@@H:15]([CH3:29])[C:14]([O:20][CH3:21])=[CH:13]4
Reactant: CCOCC
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Solvent: ClCCl
Product: COC1=C[C@]23CCN(C)[C@H](Cc4ccc(OC)c(O)c42)C3=C[C@H]1C
Reaction time: 1 h
Yield: 75 %

Procedure:
Referring to Scheme I, thebaine (1) is reacted with lithium dimethyl cuprate to provide the 7-methyl-4,5α-epoxy cleaved product, 3,6-dimethoxy-7β,17-dimethyl-4-hydroxy-5,6,8,14-tetradehydromorphinane (2). This compound serves as a useful starting material for the preparation of 7-methyl-3-methoxy-4,5α-epoxy morphinan-6-ones. Thus, to a solution of 1.25 equivalents of lithium dimethyl cuprate, prepared in ether at 0° under inert atmosphere is added a solution of thebaine (1) in benzene or toluene (aromaic hydrocarbon) or methylene chloride (halogenated hydrocarbon) or other suitable inert solvent. The resulting yellow suspension is stirred in the cold for a period of one hour and then poured into a saturated solution of ammonium chloride to quench the reaction. The aqueous phase is adjusted to pH 10 to 13 by use of an inorganic base such as sodium or potassium hydroxide and the organic phase separated. After extraction of the aqueous phase with additional organic solvent, the combined extracts are backwashed, dried and evaporated to a foam. This foam is crystallized from chloroform with the addition of hexane to yield (2) as the monochloroform solvate, mp 98°-101.5°, in about 75% yield.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](O)([CH2:16][CH3:17])([CH3:15])[CH3:14].C([Li])CCC>S(Cl)(Cl)=O.CN(C)C=O.CCOCC>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([O:6][C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=[O:5]
Reactant: O=C(O)c1cc(Cl)c(Cl)nc1Cl
Reactant: CCC(C)(C)O
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: CCC(C)(C)OC(=O)c1cc(Cl)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 3117.6 %

Procedure:
The product of Example 11 (2.5 g, 11 mmol) was slurried in thionyl chloride (30 mL) containing 2 drops of dry dimethylformamide (DMF). The slurry was heated to reflux at which time all components fully dissolved into solution. Reflux was continued for an additional three hours. After cooling to ambient temperature, the excess thionyl chloride was removed in vacuo and the resulting oily residue was taken up in diethyl ether (Et2O) (20 mL) and cooled to 0° C. in an ice bath. A solution of t-amyl alcohol (0.88 g, 10 mmol) in Et2O (15 mL) was cooled to -10° C. in a dry ice bath and n-butyllithium (1.6 M solution in hexanes, 6.5 mL, 1 eq) was added dropwise over 10 minutes, keeping the temperature below 0° C. The solution was warmed to ambient temperature, charged to an addition funnel under nitrogen and added dropwise to the nitrogen-purged ethereal solution of the acyl chloride prepared above. After complete addition, the solution was warmed to ambient temperature with stirring overnight. The solution was washed with saturated brine (3×200 mL) and the organics were dried over Na2SO4, filtered, and the solvent removed in vacuo to give t-amyl 2,5,6-trichloronicotinate (92.46 g) as an orange oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[O:4][C:3]1=[O:10].I.NC(N)=[S:14].[OH-].[Na+]>O>[SH:14][CH:5]([CH3:9])[CH2:6][CH2:7][CH2:8][CH:2]([CH3:1])[C:3]([OH:4])=[O:10]
Reactant: NC(N)=S
Reactant: CC1CCCC(C)C(=O)O1
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(S)CCCC(C)C(=O)O
Temperature: 25 °C
Yield: 91 %

Procedure:
A 10 mL round bottom flask equipped with a stir bar was charged with 3,7-dimethyloxepan-2-one (61, 0.729 g, 5.13 mmol), hydroiodic acid (2.029 ml, 15.38 mmol) and thiourea (2.73 g, 35.91 mmol). The flask was equipped with a water cooled water condenser, placed under a nitrogen atmosphere and heated to reflux. The reaction proceeded at reflux overnight. A sodium hydroxide (3.69 g, 92 mmol) solution in water (5 mL) was then added to the reaction flask. The reaction was refluxed overnight. The reaction mixture was removed from heat, cooled to room temperature and the flask contents were transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate and the extract was set to the side. The aqueous layer was acidified with HCl to pH 2 and extracted with ethyl acetate (2×100 mL) and methylene chloride (1×100 mL). The organic extracts were combined, washed with 30 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 823 mg of crude 6-mercapto-2-methylheptanoic acid (62, 92% yield) as a light brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:17]=[CH:18][C:11]=12)[NH2:5].[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:29](=[O:31])[CH3:30])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:17]=[CH:18][C:11]=12
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Oc4ccc(N)cc4F)ccnc32)cc1
Product: CC(=O)Nc1ccc(Oc2ccnc3c2ccn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
3.02 g (7.60 mmol) of 3-fluoro-4-({1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}oxy)aniline are dissolved in 30 ml of acetic anhydride and stirred at 50° C. for one hour. Volatile components are then removed under reduced pressure and excess reagent is repeatedly removed azeotropically using toluene. The crude product is purified on a silica gel column (mobile phase: cyclohexane/ethyl acetate 1:1).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Cl:10][CH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[CH2:11][Cl:10])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccccc1CCl
Reactant: Cc1c(N)cccc1Br
Solvent: ClCCl
Product: Cc1c(Br)cccc1NC(=O)c1ccccc1CCl
Yield: 44 %

Procedure:
A solution of 3-bromo-2-methylaniline (10 g, 53.7 mmol) in DCM (200 mL) at 0° C. was treated with TEA (14.98 mL, 107 mmol), followed by dropwise addition of 2-(chloromethyl)benzoyl chloride (10.16 g, 53.7 mmol) in DCM (50 mL) over 1 h. The mixture was diluted with DCM (ca. 1 L), washed with NaHCO3 (aq) and water, and concentrated to remove most of the solvent. The precipitate was collected by filtration and washed with DCM (2×10 mL) to provide N-(3-bromo-2-methylphenyl)-2-(chloromethyl)benzamide as a white solid (8.0 g). The filtrate was concentrated further, resulting in additional precipitate which was collected by filtration and washed with DCM (2×10 mL) to provide additional N-(3-bromo-2-methylphenyl)-2-(chloromethyl)benzamide as a white solid (3.06 g), for a combined yield of 61%. Mass spectrum 338, 340, 342 The filtrate was concentrated and purified by column chromatography (hexane-EtOAc) to provide 2-(3-bromo-2-methylphenyl)isoindolin-1-one as a yellow solid (2.0 g, 12%). A solution of the N-(3-bromo-2-methylphenyl)-2-(chloromethyl)benzamide (11.06 g, 32.7 mmol) in DMF (50 mL) was cooled to 0° C. and treated with a mixture of sodium hydride (60% oil dispersion, pre-washed with hexane, 1.70 g, 42.5 mmol) and DMF (10 mL). The mixture was stirred at 0° C. for 1.5 h, then was treated with water. The precipitate was collected by filtration, dried and combined with the material purified by column chromatography (see above) to provide 2-(3-bromo-2-methylphenyl)isoindolin-1-one as a yellow solid (9.41 g, 95%). 1H NMR (400 MHz, chloroform-d) δ 7.96 (1 H, d, J=7.5 Hz), 7.58-7.67 (2 H, m), 7.49-7.57 (2 H, m), 7.20-7.25 (1 H, m), 7.15 (1 H, t, J=7.9 Hz), 4.72 (2 H, s), 2.31 (3 H, s). Mass spectrum m/z 302, 304 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[N:32]=[C:31]([C:33]([O:35]C)=[O:34])[C:30]([O:37][CH3:38])=[CH:29][CH:28]=4)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.O[Li].O>O1CCOCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[N:32]=[C:31]([C:33]([OH:35])=[O:34])[C:30]([O:37][CH3:38])=[CH:29][CH:28]=4)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OC)c(C(=O)OC)n3)cc12
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OC)c(C(=O)O)n3)cc12
Temperature: 70 °C
Reaction time: 3 h
Yield: 76.9 %

Procedure:
To a stirring solution of methyl 6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-3-methoxypicolinate (400 mg, 0.74 mmol) in dioxane/H2O (10 mL/1 mL) was added LiOH.H2O (93 mg, 2.22 mmol) under N2 protection. The mixture was stirred at 70° C. for 3 h. The mixture was concentrated in vacuo and then extracted with EtOAc. After the organic layer was washed with HCl (a.q.), brine, dried over Na2SO4, filtered and evaporated, the crude product was purified by prep-TLC (PE:EtOAc=1:3) to give the product of 6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-3-methoxypicolinic acid (300 mg, yield: 77%). 1H-NMR (Methanol-d4, 400 MHz) δ 7.86˜7.90 (m, 2H), 7.80 (s, 1H), 7.69 (s, 1H), 7.65 (s, 1H), 7.55˜7.57 (m, 1H), 7.14 (t, J=8.8 Hz, 2H), 3.83 (s, 3H), 3.04 (s, 3H), 2.86 (s, 3H), 2.82 (s, 3H). MS (M+H)+: 528.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:13][C:14]([F:38])([F:37])[CH2:15][NH:16][C:17]([C:19]1([CH2:32][CH2:33][CH2:34][CH2:35]Br)[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:18]>>[F:13][C:14]([F:37])([F:38])[CH2:15][NH:16][C:17]([C:19]1([CH2:32][CH2:33][CH2:34][CH2:35][N:10]2[CH2:9][CH2:8][N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:18]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccccn3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-pyridin-2-yl-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH:12]([NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:11]3)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:34][CH2:35][CH2:36][S:37](Cl)(=[O:39])=[O:38].[H-].[Na+]>CN(C)C=O>[O:38]=[S:37]1(=[O:39])[CH2:36][CH2:35][CH2:34][N:1]1[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH:12]([NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:11]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(N)c3)cc2C1
Reactant: O=S(=O)(Cl)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(N4CCCS4(=O)=O)c3)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.2 %

Procedure:
A mixture of N-[5-(3-aminophenyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (100 mg, 0.30 mmol), and diisopropylethylamine (79 mg, 0.61 mmol), in dry dimethylformamide (2 ml) was treated with 3-chloropropanesulfonyl chloride (54 mg, 0.30 mmol) and stirred at room temperature for 1 h. Sodium hydride (60% dispersion in oil, 15 mg, 0.38 mmol) was added and the mixture stirred at 60° C. for 0.5 h. The reaction mix was cooled then partitioned between dichloromethane and 0.5M hydrochloric acid, and the organic layer was evaporated under reduced pressure to give a brown oil which was purified by column chromatography on a 5 g isolute silica sep-pak column eluting from 0-50% ethyl acetate in 40-60° C. petroleum ether to give the title compound as a yellow oil (12 mg, 9%).