Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:63]([CH3:66])([CH3:65])[CH3:64])[C:13]([N:15]1[C@H:19]([C:20](=[O:32])[NH:21][C@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24][CH2:23]2)[CH2:18][C@H:17]([C:33]2[CH:42]=[C:41]3[C:36]([CH2:37][C@@H:38]([C:50](=[O:62])[NH:51][C@H:52]4[C:61]5[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=5)[CH2:55][CH2:54][CH2:53]4)[N:39](C(OC(C)(C)C)=O)[CH2:40]3)=[CH:35][CH:34]=2)[CH2:16]1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCCl>[CH3:64][C:63]([CH3:66])([CH3:65])[C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:13](=[O:14])[N:15]1[CH2:16][C@@H:17]([C:33]2[CH:42]=[C:41]3[C:36]([CH2:37][C@@H:38]([C:50](=[O:62])[NH:51][C@H:52]4[C:61]5[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=5)[CH2:55][CH2:54][CH2:53]4)[NH:39][CH2:40]3)=[CH:35][CH:34]=2)[CH2:18][C@H:19]1[C:20](=[O:32])[NH:21][C@H:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc([C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)[C@@H](NC(=O)OCc4ccccc4)C(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1C[C@@H](c2ccc3c(c2)CN[C@H](C(=O)N[C@@H]2CCCc4ccccc42)C3)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of (S)-tert-butyl 7-((3R,5S)-1-((S)-2-(((benzyloxy)carbonyl)amino)-3,3-dimethylbutanoyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.44 g, 0.49 mmol) in DCE (5 mL) was added TFA (1.2 mL, 15.6 mmol). The reaction mixture was stirred at rt for 2 h and concentrated in vacuo. The residue was basified with sat. aq. NaHCO3 solution. The resulting mixture was extracted with EtOAc (2×) and the organic layer was separated, washed with brine and dried over MgSO4. The filtrate was concentrated in vacuo to give the title compound as a light yellow solid (0.35 g, 91%). MS (ESI+) m/z 796.5 (M+H)+.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:26][C:16]3=[C:17]4[C:21](=[C:22]([CH3:24])[CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:25])[CH2:18]4)(=O)=O)=CC=1.[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1.O>CS(C)=O>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:34][CH2:11][CH:12]2[O:26][C:16]3=[C:17]4[C:21](=[C:22]([CH3:24])[CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:25])[CH2:18]4)=[CH:31][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3cc(C)c4c(c3O2)CC(=O)N4)cc1
Reactant: NCc1ccc(F)cc1
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc2c(c3c1NC(=O)C3)OC(CNCc1ccc(F)cc1)CO2
Temperature: 90 °C

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-6-methyl-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (0.28 g, 0.72 mmole) and 4-fluorobenzylamine (0.45 g, 3.6 mmole) were combined in 10 ml of dry DMSO and heated to 90° C. for 4 hours under a nitrogen atmosphere. After cooling to room temperature, 150 ml of water was added and the mixture was extracted twice with 250 ml portions of 35% ethyl acetate in hexane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuum to yield an orange semisolid. Column chromatography on silica gel using 1% methanol/CH2Cl2 as eluant gave the free base of the title compound as a brown oil. This was crystallized from isopropanol with the addition of fumaric acid (0.20 g, 1.7 mmole) to give 0.06 g of the (S) enantiomer of the title compound as a beige solid fumarate, m.p. 233-234° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:7][N:6]=[C:5]([C:8](O)=O)[CH:4]=1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[NH2:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][C:50]=1[NH2:51])[N:47]([CH2:52][CH3:53])[C:46](=[O:54])[C:45]2([CH3:56])[CH3:55]>CN(C)C=O>[CH2:52]([N:47]1[C:48]2[CH:49]=[C:50]3[NH:51][C:8]([C:5]4[CH:4]=[C:3]([O:2][CH3:1])[NH:7][N:6]=4)=[N:41][C:42]3=[CH:43][C:44]=2[C:45]([CH3:56])([CH3:55])[C:46]1=[O:54])[CH3:53]
Reactant: CCN1C(=O)C(C)(C)c2cc(N)c(N)cc21
Reactant: COc1cc(C(=O)O)n[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN1C(=O)C(C)(C)c2cc3nc(-c4cc(OC)[nH]n4)[nH]c3cc21
Temperature: 25 °C
Yield: 28 %

Procedure:
5-Methoxy-1H-pyrazole-3-carboxylic acid (86 mg, 0.61 mmol), 1-hydroxybenzotriazole hydrate (111 mg, 0.73 mmol) and triethylamine (253 μl, 184 mg, 1.82 mmol) were dissolved in N,N-dimethylformamide (DMF) (2 ml) and after the addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (139 mg, 0.73 mmol) dissolved in DMF (2 ml) the reaction mixture was stirred at room temperature. After 1 hour a solution of 5,6-diamino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one in DMF (2 ml) was added and the reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, the residue was quenched with water (20 ml) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (15 ml), dried over sodium sulfate and evaporated. The residue was dissolved in ethanol (5 ml) and after the addition of hydrochloric acid (10 M, 2 ml) it was stirred under reflux for 2 hours. The ethanol was evaporated and the residue was adjusted to pH 9-10 with ammonium hydroxide. After the addition of water (20 ml) the aqueous phase was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate and evaporated. The crude product was purified by column chromatography on silica gel. Elution with ethyl acetate/n-heptane (9:1) yielded 56 mg (28%) of an off-white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][CH:6]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[CH2:5][C:4]([CH3:20])([CH3:19])[NH:3]1.[C:22](Cl)(=[O:26])[O:23][CH2:24][CH3:25].[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:24]([O:23][C:22]([N:8]([CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]1)[CH:6]1[CH2:7][C:2]([CH3:21])([CH3:1])[NH:3][C:4]([CH3:20])([CH3:19])[CH2:5]1)=[O:26])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: CC1(C)CC(NC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N(C1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1

Procedure:
The N-ethoxycarbonyl-bis(2,2,6,6-tetramethyl-4-piperidyl)-amine is prepared by reacting bis(2,2,6,6-tetramethyl-4-piperidyl)-amine with ethyl chlorocarbonate in chloroform at 10°-20° C. in the presence of aqueous NaOH. The product obtained, which has a purity of 99.2% and melts at 117° C., can be used directly.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[Cl:9][C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:13]=[C:12](Cl)[N:11]=1.CCN(C(C)C)C(C)C>CN(C)C=O.CCOC(C)=O>[Cl:9][C:10]1[N:11]=[C:12]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH:13]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:15]=1
Reactant: Clc1cc(N2CCOCC2)nc(Cl)n1
Reactant: NCCCCC(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CCCCNc1cc(N2CCOCC2)nc(Cl)n1
Temperature: 40 °C
Reaction time: 40 h
Yield: 60.4 %

Procedure:
5-Aminopentanoic acid (140 mg, 1.19 mmol), 4-(2,6-dichloropyrimidin-4-yl)morpholine (prepared as in Method 22; 234 mg, 1.0 mmol) and DIEA (0.530 mL, 3.0 mmol) were dissolved in N,N-dimethylformamide (6 mL). The reaction solution was stirred at 40° C. for 40 hours. The reaction was diluted with EtOAc (100 mL) and washed with 0.5 M HCl (40 mL), water (40 mL), brine (40 mL), dried with Na2SO4, filtered and evaporated to give a solid. The crude product was chromatographed on a silica gel column by eluting with 80% EtOAc in hexane to give 5-(2-chloro-6-morpholinopyrimidin-4-ylamino)pentanoic acid as a white solid (190 mg, 60%). LC/MS (m/z): 315.0 (MH+), Rf 1.79 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=C(N)[C:5]=1[Cl:11].[CH3:13][N:14]([CH:16]=O)[CH3:15].C(=O)([O-])[O-].[K+].[K+].CI>O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:16]([N:14]([CH3:13])[CH3:15])[C:5]=1[Cl:11]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cccc(N)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)c1cccc(N(C)C)c1Cl
Temperature: 60 °C
Yield: 75 %

Procedure:
2-Chloro-3-amino-benzoic acid methyl ester (1.20 g, 6.47 mmol) was placed in a round bottomed flask with DMF (5 mL), Potassium carbonate (1.97 g, 14.2 mmol) and methyl iodide (0.89 mL, 14.22 mmol) were added. A reflux condenser was fitted and the reaction was heated to 60° C. for 12 h. The reaction was cooled to rt, diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The organics were dried (MgSO4), concentrated, then purified by column chromatography using hexanes/ethyl acetate (1:1) to afford 2-chloro-3-dimethylamino-benzoic acid methyl ester (1.04 g, 75%)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:4][N:3]=1.[CH3:19]I.[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:19])[C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:4][N:3]=1
Reactant: CI
Reactant: Clc1nccc(Nc2cnc3ccccc3c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cnc2ccccc2c1)c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-chloro-pyrimidin-4-yl)-quinolin-3-yl-amine (0.400 g, 1.64 mmol) in DMF (7 mL) at 0° C. was added MeI (0.133 mL, 2.13 mmol) and NaH (60% dispersion in mineral oil, 0.079 g, 1.97 mmol). The reaction mixture was warmed to RT, accompanied by the appearance of a yellow color and solid precipitate. After stirring for 1 h at RT, H2O (25 mL) was added and the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried with MgSO4, filtered and concentrated under reduced pressure. Chromatography on silica gel (1:1 EtOAc:Hexanes) provided the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:27]=1[C:28]([OH:30])=O.CCN(C(C)C)C(C)C.[Cl:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[CH2:53][N:54]1[CH:58]=[C:57]([NH2:59])[CH:56]=[N:55]1>CN(C=O)C>[Cl:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:26]([Cl:25])[C:27]=1[C:28]([NH:59][C:57]1[CH:56]=[N:55][N:54]([CH2:53][C:47]2[CH:48]=[CH:49][C:50]([Cl:52])=[CH:51][C:46]=2[Cl:45])[CH:58]=1)=[O:30]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: Nc1cnn(Cc2ccc(Cl)cc2Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cnn(Cc2ccc(Cl)cc2Cl)c1)c1c(Cl)cccc1Cl
Reaction time: 0.08 h
Yield: 76.7 %

Procedure:
A solution of HATU (46 mg, 0.12 mmol) in DMF (200 μl) was added to 2,6-dichlorobenzoic acid (22 mg, 0.11 mmol, Avocado) followed by DIPEA (50 μl, 0.286 mmol) and left to stand for 5 min at ambient temperature. A solution of 1-[(2,4-dichlorophenyl)methyl]-1H-pyrazol-4-amine (Art Chem GmbH; 53 mg, 0.22 mmol) in DMF (200 μl) was then added and the solution left to stand for 16 h at ambient temperature. The solvent was removed using a Genevac. The sample was dissolved in 1:1 MeOH:DMSO (0.6 ml) and purified by MDAP on a standard C18 column (method D) using acetonitrile-water with a TFA modifier. The solvent was evaporated in vacuo using a Genevac to give the title compound (35 mg); LCMS (System 3): MH+=414, tRET=1.18 min.
Reaction SMILES: [CH2:1]([OH:10])[C@H:2]1[O:7][C:5](=[O:6])[C@H:4]([OH:8])[C@@H:3]1[OH:9].CO.[OH:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[OH:23])[CH2:17][CH2:18][NH2:19].C(N(CC)CC)C>CC(C)=O>[O:6]=[C:5]([NH2:19])[C@@H:4]([C@@H:3]([C@@H:2]([CH2:1][OH:10])[OH:7])[OH:9])[OH:8].[NH2:19][CH2:18][CH2:17][C:16]1[CH:20]=[CH:21][C:22]([OH:23])=[C:14]([OH:13])[CH:15]=1
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: NCCc1ccc(O)c(O)c1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: NC(=O)[C@H](O)[C@H](O)[C@H](O)CO
Yield: 188.1 %

Procedure:
D-(+)-Ribonic acid gamma-lactone (2.0 gm, 13.5 mmol) was added to methanol (25 mL) in a 100 mL round bottom flask with stirring until dissolved, and then an additional 5 min. 3-Hydroxytyramine (2.6 gm, 13.5 mmol) was added slowly, allowing it to dissolve, with stirring, over the course of about 10 minutes. Triethylamine (1.4 gm, 13.5 mmol) was then added and the reaction mixture refluxed for 4 hr. in the dark, during which time the solution acquired a slight yellow color. Solvents were removed by rotary evaporation using anhydrous ethanol as an azeotrope to remove any residual water. The resultant dried product constituted a thick syrup which solidified upon standing (1 hr.) to give a white solid. The white solid product was stirred (1 hr.) with acetone (40 mL), again resulting in a white solid as a product. The resultant solid was collected by filtration and dried in vacuo for 6 hrs. yielding dopamine ribonamide (3.83 gm, 12.7 mmol, 94.1% yield.) 1H and 13C-NMR results and CHN analyses were consistent with structure. Melting point was 90-91° C. Predicted C13H19N1: (301.30): C, 51.82; H, 6.36; N, 4.65; Analysis results of synthesis product: C, 51.67; H, 6.40; N, 4.69.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)[CH3:2].[CH:11](OCC)=O.[C:16]([CH2:18][C:19]([NH2:21])=[O:20])#[N:17].[H-].[Na+]>>[C:16]([C:18]1[C:19]([OH:20])=[N:21][C:6]2[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:9][CH2:8][C:7]=2[CH:11]=1)#[N:17]
Reactant: CCN1CCCC(=O)CC1
Reactant: N#CCC(N)=O
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Product: CCN1CCc2cc(C#N)c(O)nc2CC1

Procedure:
Prepared from 1-ethylhexahydro-4-azepinone by reaction with ethyl formate and cyanoacetamide in the presence of sodium hydride.
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)C=1.[CH3:12][C:13]([NH:21][C:22]([C:24]1[N:25]=[C:26](SC)[S:27][C:28]=1[C:29]([O:31][CH3:32])=[O:30])=[O:23])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14].[S:35](=[O:38])(O)[O-:36].[Na+]>C(Cl)Cl>[CH3:14][C:13]([NH:21][C:22]([C:24]1[N:25]=[C:26]([S:35]([CH3:2])(=[O:38])=[O:36])[S:27][C:28]=1[C:29]([O:31][CH3:32])=[O:30])=[O:23])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:12]
Reactant: O=S([O-])O
Reactant: COC(=O)c1sc(SC)nc1C(=O)NC(C)(C)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1sc(S(C)(=O)=O)nc1C(=O)NC(C)(C)c1ccccc1
Reaction time: 8 h

Procedure:
3-Chloroperbenzoic acid (0.89 g) was added to a solution of methyl 4-{[(1-methyl-1-phenylethyl)amino]carbonyl}-2-(methylthio)-1,3-thiazole-5-carboxylate (Intermediate 15; 0.63 g) in DCM (25 ml). After stirring overnight the reaction was complete. Aqueous sodium bisulfite was added to quench any unreacted peroxides and the solution was washed with sat. NaHCO3. The organic portion was dried with MgSO4 and concentrated to a yellow solid (0.6 g). NMR: 1.63-1.68 (m, 6H), 3.58 (s, 3H), 3.89 (s, 3H), 7.23 (d, J=7.16 Hz, 1H), 7.34 (t, J=7.63 Hz, 2H), 7.47 (d, J=7.54 Hz, 2H), 8.91 (s, 1H).
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[S:14]1[C:18](B(O)O)=[CH:17][C:16]2[CH:22]=[CH:23][CH:24]=[CH:25][C:15]1=2>C1COCC1>[S:14]1[C:18]([C:2]2[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=2)[CH:7]=[O:8])=[CH:17][C:16]2[CH:22]=[CH:23][CH:24]=[CH:25][C:15]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: COc1cc(OC)c(C=O)cc1Br
Solvent: C1CCOC1
Product: COc1cc(OC)c(-c2cc3ccccc3s2)cc1C=O
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
An alternative procedure: 5-bromo-2,4-dimethoxybenzaldehyde (20 g), benzo[b]thiophene-2-boronic acid (16 g) and THF (200 mL) were sequentially charged into a clean reaction vessel fitted with a reflux condenser, mechanical stirrer and nitrogen inlet adapter. Nitrogen was bubbled into the resulting solution for 20 min followed by the sequential addition of KF (10 g), and Pd(tBu3P)2 (0.417 g). The solution was immediately heated to 60° C. and aged for 1.5 h. (Note: The HPLC assay at this point routinely indicated complete consumption of 5-bromo-2,4-dimethoxybenzaldehyde, <0.5 area % of benzo[b]thiophene-2-boronic acid along with 0.5 area % of an unknown (0.55 RRT). These impurities are removed during crystallization.) Upon completion, as determined by HPLC, the reaction was diluted with H2O (200 mL) and transferred to a separatory funnel containing EtOAc (200 mL) and H2O (200 mL). The layers were cut and the aqueous layer was extracted with EtOAc (100 mL). The combined organic cuts were filtered through a pre-washed pad of solka floc (5 g). The pad of solka floc and spent catalyst were washed with fresh EtOAc (200 mL) and this wash combined with the batch. The resultant filtrate was batch concentrated and solvent switched to 33 wt % 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde in THF in preparation for crystallization. (Note: The internal temperature during batch concentration should be kept above 45° C. to prevent premature crystallization.) The resulting THF solution of 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde was then charged with heptane (20 mL) and slowly cooled to ambient temperature. Crystallization was then completed with the slow addition of heptane (175 mL) and cooling to 4° C. After aging for 1 h, the batch was filtered and then dried on the filter funnel under a stream of N2. The semi-wet cake was then transferred to clean trays and dried to a constant weight in the vacuum oven (40° C., 20 inHg) affording 23.74 g (97% yield) of desired 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde as a light orange crystalline solid, m.p. 134–136° C. HPLC assay of this solid indicated >99.9 LCAP. 1H-NMR identical as above.
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([NH2:19])[C:13]=1[OH:20])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([NH:8][S:9]([C:12]1[C:13]([OH:20])=[C:14]([NH:19][C:29]([NH:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[Br:21])=[O:30])[CH:15]=[CH:16][C:17]=1[Cl:18])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)c(S(=O)(=O)NCc2ccccc2)c1O
Reactant: O=C=Nc1ccccc1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1Br)Nc1ccc(Cl)c(S(=O)(=O)NCc2ccccc2)c1O
Yield: 60.2 %

Procedure:
A solution of N-benzyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (80 mg, 0.26 mmol) and 2-bromophenylisocyanate (47 μL, 0.38 mmol) in 2 mL of N,N-dimethylformamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (30/70 to 70/30, v/v), gave the desired product (80 mg, 61%). EI-MS (m/z) 508.1, 510.2, 512.2 (M−).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]2([CH3:16])[CH3:15].[C:17]1([P:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl.C(OCC)C>[Br-:1].[CH3:13][C:9]1([CH3:14])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]2[CH:4]=[C:3]([CH2:2][P+:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(CBr)ccc21
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)ccc21
Product: [Br-]
Yield: 86 %

Procedure:
The 6-bromomethyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (9.0 g, 32.0 mmol) prepared in the previous step is mixed with triphenylphosphine (10.1 g, 38.4 mmol) in solution in 50 ml of dichloromethane for 24 hours, and then diluted with ethyl ether (200 ml). The (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)methyl-triphenyl-phosphonium bromide precipitates, is filtered and washed with ether. The white crystals obtained (15.0 g, yield 86%) are dried in a desiccator.
Reaction SMILES: [Li+].[OH-].[Br:3][C:4]1[CH:40]=[CH:39][C:7]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:30][C:31]([CH3:38])([CH3:37])[C:32]([O:34]CC)=[O:33])=[CH:6][CH:5]=1.C1COCC1.CO>O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:30][C:31]([CH3:37])([CH3:38])[C:32]([OH:34])=[O:33])=[CH:39][CH:40]=1
Reactant: CCOC(=O)C(C)(C)Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Br)cc1)C(=O)O
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
A solution of LiOH (39 mg, 0.9 mmol) in water (2 mL) was added to a 20 mL round-bottomed flask containing ethyl 3-(1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylpropanoate (106 mg, 0.19 mmol), THF (3 mL), MeOH (3 mL), and water (3 mL). The resulting solution was heated to 80° C. After 2 h, the solution was concentrated to dryness and the residue was treated with sat. ammonium chloride (20 mL) and EtOAc (20 mL). The organic layer was separated and the aqueous layer was further extracted with EtOAc (2×20 mL). The combined organic layers were dried with sodium sulfate, filtered, and concentrated to dryness. The residue was subjected to FCC to give the title compound (84 mg, 83%). MS (ESI): mass calcd. for C29H26BrN3O3, 543.12; m/z found, 544.2 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 9.00 (d, J=8.7, 1H), 8.32 (d, J=8.5, 1H), 8.26 (d, J=8.4, 1H), 8.15-8.08 (m, 2H), 7.94-7.88 (m, 1H), 7.59 (d, J=8.8, 1H), 7.57-7.51 (m, 3H), 7.41 (dd, J=9.1, 2.4, 1H), 7.19 (d, J=8.6, 2H), 5.82 (s, 2H), 5.76 (s, 2H), 3.53 (s, 2H), 1.42 (s, 6H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:20][CH3:21].[C:22]([Cu])#[N:23].CN(C=O)C>C(OCC)(=O)C>[CH3:21][O:20][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:7]=2)[C:2]=1[C:22]#[N:23]
Reactant: COc1ccc(-c2ccc3c(Br)c(OC)ccc3c2)cc1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc3c(C#N)c(OC)ccc3c2)cc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 29.7 %

Procedure:
A mixture of 1-bromo-2-methoxy-6-(4-methoxyphenyl)naphthalene (0.76 g, 2.21 g), CuCN (0.24 g, 2.66 mmol) and DMF (10 mL) was stirred at 120° C. for 4 hr. The reaction mixture was cooled to room temperature, slurried with ethyl acetate, filtered through silica, and evaporation of the solvent, and purification by silica column chromatography (20% ethyl acetate-hexanes) yielded 0.19 g (30%) of the title compound as a pale yellow solid: mp 182–185° C.; 1H NMR (CDCl3): δ 3.88 (3H, s), 4.09 (3H, s), 7.03 (2H, d, J=8.73 Hz), 7.29 (1H, d, J=9.12 Hz), 7.63 (2H, d, J=8.73 Hz), 7.88 (1H, dd, J=1.98 Hz, J=8.73 Hz), 7.97 (1H, d, J=1.98 Hz), 8.09 (1H, d, J=9.12 Hz), 8.14 (1H, d, J=8.73 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[N+:5]([O-:18])=[CH:4][CH:3]=1.[OH-:19].[K+]>>[OH:19][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[N+:5]([O-:18])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: [O-][n+]1ccc(Cl)c2ccc(-c3ccccc3)cc21
Agent: [K+]
Product: [O-][n+]1ccc(O)c2ccc(-c3ccccc3)cc21

Procedure:
A solution of 4-chloro-7-phenylquinoline-1-oxide (1.9 g) and potassium hydroxide (4.2 g) in industrial methylated spirit (70 ml) was heated under reflux for 3 hours. The solvent was removed by distillation and water (200 ml) was added. The mixture was filtered and the filtrate neutralised with glacial acetic acid (5 ml). The precipitate was collected by filtration and purified by crystallisation from industrial methylated spirit (100 ml) to give the novel compound '4-hydroxy-7-phenylquinoline-1-oxide, m.p. 244°-250° decomp.