Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].Cl[CH2:20][C:21]1[S:22][CH:23]=[CH:24][CH:25]=1.O>CS(C)=O>[CH2:20]([O:7][N:8]1[C:9](=[O:18])[C:10]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]2[C:12]1=[O:13])[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1
Reactant: ClCc1cccs1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OCc1cccs1
Reaction time: 16 h
Yield: 86 %

Procedure:
Anhydrous potassium carbonate (11.04 g.) was added to a stirred suspension of N-hydroxyphthalimide (17.12 g.) in dry dimethyl sulphoxide (200 ml.). A brown colour developed, 2-Chloromethylthiophene (28.5 g.) was added dropwise and the mixture was stirred for 16 hr., during which time the colour disappeared. The suspension was poured into water (800 ml.) and cooled to 5°. The white precipitate was filtered off, and recrystallised from ethanol to give colourless needles of N-(then-2-yloxy)phthalimide (23.4 g., 83%), m.p. 129.7° - 130.9° τ values (DMSO-d6) are 4.58 (CH2), 2.28, 2.68, 2.90 thienyl protons) 2.08 (phthalimide protons)
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:15][C:14]2[NH:13][C:12]3[CH2:11][C:10]([CH3:17])([CH3:16])[CH2:9][C:8](=[O:18])[C:7]=3[CH:6]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=3)[C:5]=2[C:4](=[O:28])[CH2:3]1.[H][H]>C(O)C.Cl.[Pd]>[CH3:16][C:10]1([CH3:17])[CH2:11][C:12]2[NH:13][C:14]3[CH2:15][C:2]([CH3:1])([CH3:29])[CH2:3][C:4](=[O:28])[C:5]=3[CH:6]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=3)[C:7]=2[C:8](=[O:18])[CH2:9]1
Reactant: [H][H]
Reactant: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc(N)c1
Yield: 97.4 %

Procedure:
A solution of 10 g of 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9-(3-nitrophenyl)-1,8(2H,5H)-acridinedione in 190 ml of ethanol and 100 ml of 1M hydrochloric acid was hydrogenated at atmospheric temperature and pressure in the presence of 0.5 g of 10% palladium on carbon catalyst. When hydrogen uptake had ceased, the catalyst was removed by filtration and the filtrate evaporated. The residue was dissolved in water (20 ml) and the solution made alkaline by addition of excess 1M sodium carbonate solution. The precipitated solid was filtered off, washed with water and dried giving 9.0 g of 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9-(3-aminophenyl)-1,8(2H,5H)-acridinedione as a pale brown solid; mass spectrum (ESP) m/e 365 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=1)(C)[C:6](OCC)=O)C.[OH-].[Na+]>CCO>[I:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:5]([CH3:6])[C:4]([OH:20])=[O:3])=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(I)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(Cc1ccc(I)cc1)C(=O)O

Procedure:
To 2.30 g (5.89 mmol) 2-(4-iodo-benzyl)-2-methyl-malonic acid diethyl ester (V.1) in 30 mL EtOH are added 30 mL 1N NaOH. The mixture is stirred at reflux for 2 h. The solvent is evaporated and 35 mL 4N HCl are added. The mixture is stirred at 60° C. for 12 h. The solid is filtered off to yield the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24](O)=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[F:27][CH2:28][C:29]([CH3:32])([NH2:31])[CH3:30]>>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([NH:31][C:29]([CH3:32])([CH3:30])[CH2:28][F:27])=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: CC(C)(N)CF
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NC(C)(C)CF)c2n1
Yield: 78 %

Procedure:
Prepared by the method described in Example 1 using (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation K) and 1-fluoro-2-methylpropan-2-amine. The combined organic extracts were concentrated and the residue was purified by reverse phase HPLC (0-90% acetonitrile/water) to provide the title compound (28 mg, 78% yield). MS (apci) m/z=431.0 (M+H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][C:13]([O:15]CC)=O)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([N:20]([CH2:25][CH3:26])[CH2:21][CH2:22][CH2:23][NH2:24])[CH3:19].O>CN(C=O)C>[CH2:18]([N:20]([CH2:25][CH3:26])[CH2:21][CH2:22][CH2:23][NH:24][C:13](=[O:15])[CH2:12][N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[N:9]1)[CH3:19]
Reactant: CCN(CC)CCCN
Reactant: CCOC(=O)Cn1cc(-c2ccccc2)cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCCNC(=O)Cn1cc(-c2ccccc2)cn1
Yield: 19.9 %

Procedure:
A solution of 13.5g (0.059 mol) of ethyl 4-phenyl-1H-pyrazole-1-acetate of example 3 and 12.6 mL (0.08 mol) of 3-(diethylamino)propanamine in 130 mL of DMF was stirred at 100° C. for 4hr. The reaction was poured into water, extracted into methlene chloride, and stripped. The residue was triturated in ether and the resulting solid was recrystallized from ether-hexane to yield 3.70g of product, mp 55°-57° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=O)[CH:6]=1)[CH3:2].[C:14]1([CH2:20][C:21]([OH:23])=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.O>C(OC(=O)C)(=O)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[C:20]([C:21]([OH:23])=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(C=O)c1
Reactant: O=C(O)Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(C=C(C(=O)O)c2ccccc2)c1
Yield: 438.7 %

Procedure:
17.8 g (0.01 mol) of 3-formyl-benzoic acid ethyl ester, 13.6 g (0.1 mol) of phenylacetic acid and 10 g of triethylamine were dissolved in 30 ml of acetic anhydride and the solution was heated to the reflux for 5 hours. After cooling, 300 ml of water were added to the reaction mixture and the mixture was then heated to the boil for 20 minutes. The solid residue was then decanted off hot, and this was recrystallised from methanol, to which a little water had been added. 13 g (43.9% of theory) of 3-(2-carboxy-2-phenylvinyl)-benzoic acid ethyl ester were obtained as light yellow crystals of melting point 139°-140° C. (isomer mixture with a cis proportion of about 90%). ##STR60##
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=3[F:50])[CH:34]=2)([O:31][CH3:32])[O:11][C@:10]1([CH2:53][OH:54])[CH:51]=[O:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=3[F:50])[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1([CH2:51][OH:52])[CH2:53][OH:54])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cc2cc([C@]3(OC)O[C@@](C=O)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(Cc2cc([C@]3(OC)OC(CO)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Reaction time: 0.33 h
Yield: 39.9 %

Procedure:
(2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 2m (1.29 g, 1.71 mmol) was dissolved in 15 mL of mixed solution (THF and MeOH, v:v=1:2), followed by addition of sodium borohydride (129 mg, 3.42 mmol). The reaction mixture was stirred for 20 minutes. Thereafter, the reaction mixture was concentrated under reduced pressure and partitioned after 30 mL ethyl acetate and 15 mL saturated sodium chloride solution were added. The aqueous phase was extracted with ethyl acetate (15 mL×2) and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound [(3S,4S,5R,6S)-3,4,5-tri-benzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 2n (520 mg, white solid), with yield: 40%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(OCC)(=O)C>[C:16]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:14])([CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)(=[O:18])[CH3:17]
Reactant: CCOC(=O)C(C)(C)c1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)c1ccc(NC(C)=O)cc1
Yield: 76 %

Procedure:
5.0 g of ethyl 2-(4-aminophenyl)-2-methylpropionate was dissolved in 50 ml of ethyl acetate, and 2.5 ml of acetic anhydride was added dropwise with stirring and the solution was still stirred in the same condition for 3 hours. The reaction mixture was washed with a saturated solution of sodium bicarbonate, and successively, with a saturated solution of sodium chloride, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure and the residue was recrystallized from ethyl acetate-n-hexane to give 4.61 g of ethyl 2-(4-acetylaminophenyl)-2-methylpropionate (Yield: 76%). M.P. 76.0°-76.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19](C(OCC)=O)[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:27]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:27]=1
Reactant: CCOC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Clc1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1
Yield: 93.3 %

Procedure:
To a solution of ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate (383 mg, 1 mmol) in ethanol, a 30% sodium hydroxide aqueous solution was added. The mixture was refluxed overnight. The solvent was distilled off, and the resulting residue was dissolved in water and neutralized with concentrated hydrochloric acid. The extraction with ethyl acetate was performed 3 times, and the combined organic layer was dried over magnesium sulfate. The solvent was distilled off, and thus the title compound (290 mg, 93.3%) was obtained as a yellowish white solid.
Reaction SMILES: FC(F)(F)C([O-])=[O:4].FC1C=CC(C2C(C[P+](CCCC)(CCCC)CCCC)=C(C(C)C)N=C(N(C)S(C)(=O)=O)N=2)=CC=1.C[Si](C)(C)N[Si](C)(C)C.[Na].[Si:54]([O:61][C@H:62]1[CH2:67][C:66](=[O:68])[O:65][C@H:64]([CH:69]=[O:70])[CH2:63]1)([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55]>C1(C)C=CC=CC=1>[Si:54]([O:61][C@@H:62]1[CH2:63][C@@H:64]([CH:69]([OH:4])[OH:70])[O:65][C:66](=[O:68])[CH2:67]1)([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55]
Reactant: O=C([O-])C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)O[C@H](C=O)C1
Agent: CCCC[P+](CCCC)(CCCC)Cc1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)O[C@H](C(O)O)C1
Reaction time: 1 h

Procedure:
To a stirred suspension of ((4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethyl-sulfonamido)pyrimidin-5-yl)methyl)tributylphosphonium 2,2,2-trifluoro-acetate (VI′) (504 mg, 0.77 mmol) at room temperature in dry toluene (8 mL), sodium hexamethyldisilazane in toluene (1.3 mL of 0.6 M, 0.77 mmol) is added portionwise in 10 minutes. The reaction mixture is stirred for 60 min and treated at room temperature with a solution of (2S,4R)-4-(tert-butyldimethylsilyl oxy)-6-oxo-tetrahydro-2H-pyran-2-carbaldehyde (IV′) (200 mg, 0.77 mmol) in 25 mL of dry toluene obtained by dissolution of (4R,6S)-4-(tert-butyldimethylsilyloxy)-6-(dihydroxymethyl)-tetrahydropyran-2-one (V′) (214 mg, 0.77 mmol) in toluene and removal of released water. After 24 hours of stirring at room temperature the solution is treated with saturated ammonium chloride solution or water. The aqueous phase is extracted with tBuMeO (2×20 mL), and the combined organic layers dried and concentrated. The residue is purified by silica gel chromatography (elution with tBuMeO/hexane mixture) to give 273 mg (61%) of N-(5-((E)-2-((2S,4R)-4-(tert-butyldimethylsilyloxy)-6-oxo-tetrahydro-2H-pyran-2-yl)vinyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide as a white solid.
Reaction SMILES: CON(C)[C:4](=[O:12])[C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH2:7].[F:14][C:15]([F:28])([F:27])[C:16]1[CH:17]=[C:18](Br)[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1.C([Li])CCC>O1CCCC1>[F:14][C:15]([F:27])([F:28])[C:16]1[CH:17]=[C:18]([C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[NH2:7])[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=1
Reactant: CON(C)C(=O)c1ccccc1N
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1ccccc1C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -78 °C
Yield: 97.1 %

Procedure:
Then, in a nitrogen atmosphere, N-methoxy-N-methyl-anthranilamide (0.62 g, 3.4 mmol), and 3,5-bis(trifluoromethyl)-1-bromobenzene (1.00 g, 3.4 mmol) were dissolved in tetrahydrofuran (20 mL), followed by stirring at −78° C. To the solution, 1.66 mol/L n-butyl lithium (4.11 mL, 6.8 mmol) was gradually added dropwise, followed by stirring for 30 minutes. The reaction was terminated by adding 1 mol/L hydrochloric acid. The reaction solution was extracted with ethyl acetate. The organic layer was washed with a sodium chloride solution and then dried with magnesium sulfate, followed by filtration. The filtrate was concentrated using a rotary evaporator. The residue was purified by recrystallization (hexane). Thus, 3′,5′-bis(trifluoromethyl)-2-aminobenzophenone (1.1 g, 3.3 mmol) was obtained in a yield of 96%.
Reaction SMILES: CN1CCOCC1.ClC(OCC(C)C)=O.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=O.[CH3:27][NH:28][CH2:29][CH2:30][CH2:31][CH3:32].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([N:28]([CH2:29][CH2:30][CH2:31][CH3:32])[CH3:27])=[O:26]
Reactant: CCCCNC
Reactant: O=C(O)CCCCCCCBr
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCN(C)C(=O)CCCCCCCBr
Reaction time: 0.5 h

Procedure:
9.1 ml of N-methylmorpholine and then 10.4 ml of isobutyl chloroformate were added dropwise at -10° C. to -15° C. to a solution of 5 g of 8-bromo octanoic acid in 200 ml of methylene chloride. The mixture was stirred for 30 minutes at -10° C. to -15° C. and then at this temperature, 13 ml of N-methylbutylamine were added. The mixture was allowed to rise ambient temperature and stood for 40 minutes. Then, 150 ml of a saturated solution of sodium bicarbonate were added and the mixture was stirred for 10 minutes. After decanting, extraction was done with methylene chloride and the extracts were washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The residue was chromatographed on silica (eluant: methylene chloride-acetone 95-5) to obtain 6.14 g of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH2:21][NH:22][CH2:23][CH2:24][CH3:25].Br[CH2:27][C:28]1C2C(=CC=C(C3C=CC=CC=3OC)C=2)NC(C)(C)[CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>C(N)CC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH2:21][NH:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:25][CH:24]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Reactant: CCCNCC1=CC(C)(C)Nc2ccc(-c3ccccc3OC)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCN
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]propylamine 44 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46 mg of potassium carbonate, and 30 μL of 1-propylamine reacted to give 4.6 mg of the title compound as a foam.
Reaction SMILES: COC1[CH:12]=[CH:11][C:6]2[CH:7]=[C:8]([CH3:10])[O:9][C:5]=2C=1.B(Br)(Br)Br.C(N(CC)CC)C.[C:24]([O:27][C:28](=O)[CH3:29])(=[O:26])[CH3:25]>ClCCl>[CH3:10][C:8]1[O:9][C:5]2[CH:29]=[C:28]([O:27][C:24](=[O:26])[CH3:25])[CH:12]=[CH:11][C:6]=2[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2cc(C)oc2c1
Agent: BrB(Br)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc2cc(C)oc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
A solution of 6-methoxy-2-methyl-benzofuran (17.4 g, 107 mmol) in dichloromethane (200 mL) at 0° C. is treated with boron tribromide (1.0 M, 107 mL). The mixture is stirred at 0° C. for 60 minutes and quenched with water (50 mL). The organic layer is dried over Na2SO4, filtered, and concentrated. The crude product is purified by flash chromatography eluted with 25% EtOAc/Hexanes, and the appropriate fractions are concentrated. The material is dissolved in dichloromethane (150 mL) and triethylamine (17.0 mL, 122 mmol) at 0° C. is treated with acetic acid anhydride (7.22 mL, 76.35 mmol). The reaction is stirred for 16 hours and allowed to warm to room temperature. The reaction is quenched with MeOH (10 mL) and concentrated. The residue is purified by silica gel chromatography with 25% EtOAc/Hexanes to provide acetic acid 2-methyl-benzofuran-6-yl ester (9.50 g, 82%). 1H NMR (400 MHz, CDCl3): δ 7.40-7.38 (d, 1H), 7.15 (s, 1H), 6.91-6.88 (d, 1H), 6.32 (s, 1H), 2.41 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=2)[NH2:10])[CH:4]=[N:3][CH:2]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([NH:10][C:9]1[CH:11]=[CH:12][CH:13]=[C:7]([C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)[CH:8]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(-c2cncnc2)c1
Product: CC(=O)Nc1cccc(-c2cncnc2)c1
Yield: 82 %

Procedure:
2b is acetylated with acetic anhydride to afford 2c (15.4g, 82%). Mp 157-158° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-])=O)=[CH:6][N:5]=1>C(O)(=O)C>[NH2:11][C:7]1[C:8]([CH3:10])=[CH:9][C:4]([O:3][CH3:2])=[N:5][CH:6]=1
Reactant: COc1cc(C)c([N+](=O)[O-])cn1
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc(C)c(N)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
A mixture of stannous chloride dihydrate (41 g) and concentrated hydrochloric acid (40 ml) was added slowly to a solution of 2-methoxy-4-methyl-5-nitropyridine (5.1 g) in acetic acid (40 ml), maintaining the temperature below 35° C. The resulting mixture was stirred at room temperature for 2 hours, and then allowed to stand overnight in the refrigerator. The solid was collected and both solid and supernatant were separately basified with a 20% sodium hydroxide solution. The product was extracted with chloroform, combined, dried (anhydrous magnesium sulfate) and concentrated to give 3.9 g of the title compound as a solid, suitable for use in the next reaction.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=[C:21]([C:22]([OH:24])=O)[C:4]=2[N:3]=1.C(Cl)CCl.[CH3:35][S:36]([NH2:39])(=[O:38])=[O:37]>CN(C)C=O.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=[C:21]([C:22]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])=[O:24])[C:4]=2[N:3]=1
Reactant: Cc1nc2c(C(=O)O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1nc2c(C(=O)NS(C)(=O)=O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 60 °C
Yield: 39 %

Procedure:
To the mixture of 2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole-4-carboxylic acid, prepared as described in Example 20 (100 mg, 0.249 mmol) in N,N-Dimethylformamide (DMF) (2 mL) in a 20 mL vial was added EDC (57.3 mg, 0.299 mmol), methane sulfonamide (47.4 mg, 0.498 mmol) and DMAP (21.30 mg, 0.174 mmol). The mixture was stirred at 60° C. and monitored by LC/MS. After stirring for 5 days the DMF was removed in-vacuo and the remaining residue was dissolved in 2 mL of DMSO and purified by reverse phase chromatography with 2 injections eluting with a 27% to 57% AcCN/H2O gradient over 12 minutes. The fractions containing the desired compound, as determined by LC/MS, were combined and concentrated in-vacuo to provide the desired compound (47 mg, 0.097 mmol, 39.0% yield) as bright yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.52 (s, 3H), 3.12 (t, 4H), 3.50 (s, 3H), 3.73 (t, 4H), 6.15 (s, 2H), 6.38 (d, 1H), 7.35 (t, aH), 7.50 (s. 1H), 7.51-7.75 (m, 2H), 7.88 (d, 1H), 8.05 (d, 1H), 8.25 (2, 1H), 8.35 (s, 1H), 12.8 (br. s, 1H); LC-MS: m/e=480 [M+1]+
Reaction SMILES: CC([O-])=O.CC([O-])=O.[Pd+2:9].[CH:10]1([P:16]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[C:28]([CH:29]([CH3:31])[CH3:30])=[CH:27][C:26]([CH:32]([CH3:34])[CH3:33])=[CH:25][C:24]=2[CH:35]([CH3:37])[CH3:36])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[CH:10]1([P:16]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[C:28]([CH:29]([CH3:30])[CH3:31])=[CH:27][C:26]([CH:32]([CH3:33])[CH3:34])=[CH:25][C:24]=2[CH:35]([CH3:36])[CH3:37])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[Pd:9]
Reactant: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: [Pd]
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A solution of the catalyst was prepared as follows: A 20 mL Wheaton vial equipped with a magnetic stir bar was charged with Pd(OAc)2 (5.60 mg, 0.025 mmol, 1.0 eq.) and 2-dicyclohexylphosphino-2′.4′,6′-tri-iso-propyl-1,1′-biphenyl (4c) (24.5 mg, 0.050 mmol, 2.0 eq.). Toluene (3.0 mL) was added and the vial was sealed with a PTFE-lined plastic cap. The resulting mixture was stirred at 23° C. for 1 h to yield a reddish Pd/4c catalyst solution (0.00833 N Pd in toluene).