Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8]2)[CH:2]=1.[Br:21]N1C(=O)CCC1=O.O>C(#N)C>[Br:21][C:6]1[N:1]=[CH:2][C:3]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8]2)=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccnc2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(Br)nc2)CC1
Temperature: 0 °C

Procedure:
1-(3-Pyridyl)-4-tert-butoxycarbonyl homopiperazine (25.0 g, 90.1 mmol) was solved in acetonitrile (400 ml) and cooled to 0° C. N-Bromosuccinimide (19.3 g, 108.2 mmol) was added during 10 min. Water (400 ml) was added and the mixture was extracted twice with diethyl ether (200 ml). Chromatography on silica gel with a mixture of petroleum:ethyl acetate (1:1) gave the title compound as free base. Yield 18.7 g, 58%.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Cl:1][C:2]1[S:3][C:4]2[C:10]([N+:12]([O-:14])=[O:13])=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(Cl)ccc2nc(Cl)sc12
Temperature: 17 °C

Procedure:
4.76 g (23 mmol) of 2,6-dichlorobenzothiazole, in solution in 10 ml of concentrated sulphuric acid, are introduced into a 100 ml round-bottomed flask. The mixture is cooled to 17° C. in order to add a solution of 1.62 g (26 mmol) of nitric acid in 10 ml of sulphuric acid and then the temperature is allowed to rise to ambient temperature.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[CH2:14](N)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(O)CCC.Cl>CO>[OH2:12].[ClH:1].[CH2:27]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCCCCCCCCCN
Reactant: Cc1cc(Cl)c2cc(O)ccc2n1
Agent: Cl
Solvent: CCCCO
Solvent: CO
Product: CCCCCCCCCCCCCCc1cc(C)nc2ccc(O)cc12
Product: O

Procedure:
A solution of 150 mg (0.78 mmol) of 4-chloro-2-methylquinolin-6-ol, 174 mg (0.81 mmol) of n-tetradecylamine, and 5 mL of n-butanol was heated under reflux for 24 hours. Excess butanol was removed by codistillation with cyclohexane. The residue was chromatographed on 30 g of silica gel (eluent 1:9 methanol-dichloromethane) to furnish crude product. This was taken up in methanol, and the solution was treated with dry hydrogen chloride gas. The solution was evaporated under reduced pressure to give the title compound as crystalline material: m.p. 180°-183° C.
Reaction SMILES: COC(OC)N(C)C.[Br:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([OH:15])=[O:14].[C:20]1([CH3:26])[CH:25]=CC=C[CH:21]=1>>[Br:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([O:15][C:20]([CH3:26])([CH3:25])[CH3:21])=[O:14]
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: Cc1ccccc1
Agent: COC(OC)N(C)C
Product: Cc1ccc(C(=O)OC(C)(C)C)cc1Br
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
Dimethylformamide dimethyl acetal (48 mL, 200 mmol) was added dropwise over 15 min to a suspension of 3-bromo-4-methylbenzoic acid (85%; 10.75 g, 42.5 mmol) in toluene (100 mL) at 70° C. The reaction was stirred at 70-80° C. for an additional 0.5 h, then was cooled, washed sequentially with water and 5% sodium bicarbonate, and dried (sodium sulfate). The mixture was filtered through a pad of silica gel, and the filter pad was washed with toluene. The filtrate was concentrated to afford the title compound (8.0 g, 69%) as a yellow oil. TLC (toluene) Rf 0.68.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10](=[O:13])[CH2:11][CH3:12].[CH2:14](Br)[CH2:15][C:16]([CH3:18])=[CH2:17]>[OH-].[K+]>[OH:1][C:2]1[C:7]([CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[C:6]([OH:8])[C:5]([CH2:7][CH:2]=[C:3]([CH3:10])[CH3:4])=[C:4]([OH:9])[C:3]=1[C:10](=[O:13])[CH2:11][CH3:12]
Reactant: CCC(=O)c1c(O)cc(O)cc1O
Reactant: C=C(C)CCBr
Agent: [K+]
Agent: [OH-]
Product: CCC(=O)c1c(O)c(CC=C(C)C)c(O)c(CC=C(C)C)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
1-(2,4,6-trihydroxyphenyl)propan-1-one (2.0 g, 11.0 mmol) was dissolved in a 5% potassium hydroxide aqueous solution (20 mL). After the mixture was cooled below 0° C., isopentenyl bromide (3.3 g, 22 mmol) was slowly added dropwise within 30 min. The reaction mixture was stirred at room temperature for 2 hours, then poured into an ice water and acidified to pH 2. The reaction mixture was extracted with ethyl acetate. The extract was collected and dried over anhydrous sodium sulfate. After removal of solvent, The residue was purified by silica gel column chromatography (dichloromethane as eluent) to give the desired compound (0.63 g, yield 18%).
Reaction SMILES: NC1C=C[C:5]([N:9]2[CH2:14][CH2:13][CH:12](O)[CH2:11][CH2:10]2)=[N:6][C:7]=1N.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(OCC)OCC.CO>C1(C)C=CC=CC=1>[N:9]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[NH:6][CH:5]=1
Reactant: Nc1ccc(N2CCC(O)CC2)nc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(OCC)OCC
Solvent: CO
Product: c1ccc2[nH]cnc2c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 127.9 %

Procedure:
To a stirring suspension of 5′,6′-Diamino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ol (8.90 g, 39.7 mmol) and p-toluenesulfonic acid (1.63 g, 8.55 mmol, 0.2 eq) in toluene was added triethyl orthoformate (21.5 mL, 129 mmol, 3.0 eq) in two portions. The first (11 mL) was added in a fast dropwise addition manner the mixture stirred to 16 hr at 100° C. Methanol (10 mL) was added followed by the final portion of triethyl orthoformate (10.5 mL) and the reaction stirred an additional 1 hr at 110° C. The solution was cooled and concentrated to a dark solid. The resulting solid was triturated from Acetonitrile/Water (20:1) giving 6.0 g of benzimidazole as a brown powder. Benzimidazole (5.72 g, 26.2 mmol) was dissolved in DMF (100 mL) and imidazole (3.75 g, 55.1 mmol, 2.1 eq) followed by tert-butyl-diphenylsilylchloride (15.0 mL, 58.4 mmol, 2.2 eq) were added and the reaction stirred for 16 hr at 23° C. The reaction was quenched with sat'd NaHCO3 (20 mL) and then diluted (100 mL) with water. EtOAc (500 mL) was added and the layers partitioned. The organic was washed with brine, dried (Na2SO4), and concentrated. The crude product was purified by chromatography eluting with EtOAc/Heptane giving desired product as an oil, which was precipitated in Acetone to afford 5-[4-(tert-Butyl-diphenyl-silanyloxy)-piperidin-1-yl]-3H-imidazo[4,5-b]pyridine as an orange solid (4.75 g, 10.4 mmol, 40%). MS ESI m/z 457.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C@H:11]([CH3:15])[C@H:12]([OH:14])[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([I:24])=[CH:19][N:18]=1.[Cl-].[Na+]>C(OCC)C.CCCCCC.C(OCC)(=O)C>[CH2:3]([O:10][C@H:11]([CH3:15])[C@@H:12]([CH3:13])[O:14][C:19]1[C:20]([I:24])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: C[C@@H](O)[C@@H](C)OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C[C@@H](OCc1ccccc1)[C@@H](C)Oc1nc(Cl)ncc1I
Yield: 41 %

Procedure:
2.07 g sodium hydride (55%) was added in portions to 8.55 g (47.4 mmol) (2R,3R)-3-benzyloxy-butan-2-ol in 56 ml diethyl ether at 0° C. with stirring. After 10 minutes the ice bath was removed and it was stirred for a further 3 minutes at room temperature. The suspension formed was added at 0° C. to a solution of 6.52 g (23.7 mmol) of 2,4-dichloro-5-iodo-pyrimidine. The mixture was stirred for 4 hours at 40° C. and then dilute sodium chloride solution was added. It was then extracted with ethyl acetate (2×). The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. The residue obtained was chromatographically (hexane/ethyl acetate 4:1). 4.12 g (9.8 mmol; yield: 41%) of the product was obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[N:9][CH:8]=[CH:7]C=1C#N)[CH3:2].[OH-:11].[Na+].[CH2:13]([OH:15])[CH3:14]>O>[CH2:1]([C:3]1[CH:10]=[N:9][CH:8]=[CH:7][C:14]=1[C:13]([OH:11])=[O:15])[CH3:2]
Reactant: CCc1cnccc1C#N
Reactant: CCO
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CCc1cnccc1C(=O)O
Temperature: 25 °C

Procedure:
A mixture of 2.7 g of 3-ethyl isonicotinonitrile, 1.63 g of sodium hydroxide, 20 ml of ethanol and 20 ml of water was heated to reflux for five hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. 3 M hydrochloric acid was added so that pH of the resultant residue became about 3, which was concentrated under reduced pressure again. To the resultant solid, 50 ml of ethanol was added and heated to reflux for five minutes, followed by hot filtration. To the solid collected by filtration, the same operation was carried out by using 50 ml each of ethanol. Combined filtrates were concentrated to give 2.49 g of 3-ethyl isonicotinic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[N:9]=[CH:8][N:7]=[C:6]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]=2[C:4]=1[NH2:22].[C:23](N1C=CN=C1)(N1C=CN=C1)=[S:24]>ClCCCl>[CH3:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]3[C:6]([N:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:23](=[S:24])[NH:22][C:4]=3[C:3]=1[O:2][CH3:1])=[N:7][CH:8]=[N:9]2
Reactant: COc1cc2ncnc(Nc3ccccc3)c2c(N)c1OC
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: COc1cc2ncnc3c2c(c1OC)NC(=S)N3c1ccccc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 6,7-dimethoxy-N4-phenyl-quinazoline-4,5-diamine (80 mg, 0.27 mmol) (from Example 1, Step, C supra) in 1,2-dichloroethane (30 mL) was added 1,1′-thiocarbonyldiimidazole (0.58 g, 3.24 mmol) (Fluka). The reaction mixture was heated with stirring at 80° C. for 4 hours. The solvent was evaporated and the residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:1:0.04) as eluent to give the desired 8,9-dimethoxy-3-phenyl-1H,3H-1,3,4,6-tetraaza-phenalene-2-thione as a gray solid. (Yield 50 mg (55%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[CH3:24].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:24][C:23]1[CH:22]=[CH:21][C:20]([C:2]2[N:3]=[C:4]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]3[S:10][CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:19][C:18]=1[NH2:17]
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Reactant: Cc1ccc(B(O)O)cc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1ccc(-c2nc(N3CCOCC3)c3sccc3n2)cc1N
Yield: 94.4 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 4 (772 mg), 3-amino-4-methylbenzeneboronic acid (502 mg), DME (10 mL), water (5 mL), sodium carbonate (640 mg) and PdCl2(PPh3)2 (100 mg) was heated to reflux for 16 hours. The reaction mixture was then cooled, diluted with ethyl acetate, and reduced in vacuo. The residue was purified using flash chromatography to yield 2-methyl-5-(4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl)-phenylamine (930 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)C>[CH3:19][S:20]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)C(=O)CCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To a solution of 7-amino-1-tetralone in 30 ml CH2Cl2 was added 1.03 g (0.013 mole) pyridine and 1.33 g (0.0116 mole) methanesulfonyl chloride. The solution was stirred at room temperature for 3 hours, saturated NaHCO3 solution was added. The CH2Cl2 solution was separated and washed with H2O. The resulting solution was dried over Na2SO4 (anhydrous), filtered, concentrated in vacuo and recrystallized from abs. ethanol to give 1.45 g (58% yield) of 7-methanesulfonamido-1-tetralone.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4](=[O:29])[C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[C:7]([O:27][CH3:28])[CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[CH3:12][O:11][C:9]1[CH:10]=[C:5]([C:4](=[O:29])[C:3]([OH:30])=[O:2])[CH:6]=[C:7]([O:27][CH3:28])[C:8]=1[O:13][CH2:14][CH2:15][O:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1
Reactant: COC(=O)C(=O)c1cc(OC)c(OCCOc2ccc3ccccc3c2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)C(=O)O)cc(OC)c1OCCOc1ccc2ccccc2c1
Yield: 93.2 %

Procedure:
A solution of 3,5-dimethoxy-4- [2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2 mL) and after 10 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from diethyl ether-hexane provided 0.45 g of purified 3,5-dimethoxy-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid as a yellow solid, mp 114°-116° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[S:16]([O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:18])(=[O:17])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: COCCOCCOCCOCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCCOCCOCCOS(C)(=O)=O
Reaction time: 0.33 h

Procedure:
A solution of 8.16 g (0.040M) of tetraethylene glycol monomethyl ether and 5.0 g (0.044M) of methanesulfonyl chloride in 100 ml of methylene chloride was stirred at 0° C. while 5.7 g (0.044M) of diisopropylethylamine was added dropwise so the temperature remained below 5° C. Stirring was continued at 0° C. for 20 minutes and the temperature was allowed to rise to room temperature over 2 hours. The solution was washed twice with an equal volume of water. It was then dried and concentrated to an oil, yielding 11 g (96%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:12].[C:13]([NH:17][C:18](=[O:32])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:20]=1)([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([C:6]([N:29]2[CH2:28][CH2:27][N:26]([CH2:25][C:21]3[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=3)[C:18]([NH:17][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:32])[CH2:31][CH2:30]2)=[O:8])=[CH:9][C:10]=1[F:11]
Reactant: Nc1c(F)cc(C(=O)O)cc1F
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3cc(F)c(N)c(F)c3)CC2)c1
Reaction time: 2 h
Yield: 90 %

Procedure:
To a stirred solution of 4-ammo-3,5-difluorobenzoic acid (1 g, 5.78 mmoles), N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (1.59 g, 5.78 mmoles) and triethylamine (4 mL) in dichloromethane (30 mL) was added 1-propanephosphonic acid cyclic anhydride (8 mL, 50% solution in ethyl acetate). After 2 hours stirring, the reaction mixture was diluted with ethyl acetate and washed with sodium carbonate (aqueous) (3×), dried (magnesium sulfate) and concentrated under reduced pressure to give the title compound (2.24 g) as an off-white foam.
Reaction SMILES: [C:1]([C:3]1[C:20]([F:21])=[CH:19][C:6]([O:7][CH2:8][C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[CH:5][C:4]=1[F:22])#[CH:2].Br[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)=[CH:26][N:25]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.[Cu](I)I.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:32]1([CH2:31][O:30][C:27]2[CH:28]=[CH:29][C:24]([C:2]#[C:1][C:3]3[C:4]([F:22])=[CH:5][C:6]([O:7][CH2:8][C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:17])[CH3:15])[CH3:10])=[CH:19][C:20]=3[F:21])=[N:25][CH:26]=2)[CH2:33][CH2:34]1
Reactant: C#Cc1c(F)cc(OC[C@H](C)NC(=O)OC(C)(C)C)cc1F
Reactant: Brc1ccc(OCC2CC2)cn1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[C@@H](COc1cc(F)c(C#Cc2ccc(OCC3CC3)cn2)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 35.9 %

Procedure:
A mixture of tert-butyl [(1S)-2-(4-ethynyl-3,5-difluorophenoxy)-1-methylethyl]carbamate (2.5 g), 2-bromo-5-(cyclopropylmethoxy)pyridine (1.8 g), copper iodide (I) (0.15 g), dichloropalladium-triphenylphosphine (1:2) (0.56 g) and triethylamine (2.2 mL) in toluene (20 mL) was stirred at 100° C. overnight under argon atmosphere. After cooling to room temperature, the mixture was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford the title compound (1.3 g).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].N1C=CC=CC=1.[C:19]1([O:29][CH3:30])[C:20](=[CH:22][CH:23]=[C:24]([CH:28]=1)[CH2:25][CH:26]=[CH2:27])[OH:21].Cl[C:32]([O-])=[O:33].Cl>ClCCl>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][O:1][C:32](=[O:33])[O:21][C:20]2[CH:22]=[CH:23][C:24]([CH2:25][CH:26]=[CH2:27])=[CH:28][C:19]=2[O:29][CH3:30])=[CH:6][CH:7]=1
Reactant: O=C([O-])Cl
Reactant: COc1ccc(C(=O)CO)cc1
Reactant: C=CCc1ccc(O)c(OC)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCc1ccc(OC(=O)OCC(=O)c2ccc(OC)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.8 %

Procedure:
To a solution of 17.62 g of 2-hydroxy-4′-methoxyacetophenone (Kovach et al., J. Amer. Chem. Soc., Vol. 115, No. 23, (1993) p. 10476) and 12.96 g of pyridine in 240 ml of dichloromethane, a solution of 26.32 g of eugenol-chloroformate in 60 ml of dichloromethane was dropped in at 5-10° C. Then, the mixture was stirred for 6 hours at room temperature. The reaction mixture was then acidified with 2N HCl and extracted with ether. The combined organic phases were washed with 2N HCl, saturated sodium bicarbonate and brine, and then dried, filtered, and evaporated to dryness. The resulting solid was purified by recrystallization to yield 29.79 g of yellow crystals.
Reaction SMILES: CS(C)=O.[C-:5]#[N:6].[Na+].[CH3:8][C:9]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:10]=1[O:11][CH2:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15](Cl)=[N:16][O:17][CH3:18]>CCOCC>[CH3:8][C:9]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:10]=1[O:11][CH2:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15](=[N:16][O:17][CH3:18])[C:5]#[N:6]
Reactant: CON=C(Cl)c1ccccc1COc1cc(C)ccc1C
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CON=C(C#N)c1ccccc1COc1cc(C)ccc1C
Temperature: 110 °C
Reaction time: 2 h
Yield: 38.2 %

Procedure:
Dimethyl sulfoxide (2 ml) and 95% sodium cyanide (0.21 g, 0.004 mol) were added to 2-(2,5-dimethylphenoxy-methyl)-α-methoxyiminobenzyl chloride (0.60 g, 0.02 mol), and the mixture was stirred at 110° C. for 2 hours. After completion of the reaction, ether (100 ml) was added, and the mixture was washed with water twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetonitrile (0.45 g, 76.4%) as colorless crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:14]2[N:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:11]([CH2:24][CH2:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][NH:48]1>CN(C)C=O>[CH3:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][N:48]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:14]2[N:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:11]([CH2:24][CH2:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CC1CCCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCCCBr)cccc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CCCCN1CCCOc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 4-[3-bromopropoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole (77 mg, 0.124 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 ml) was treated with potassium carbonate (51.3 mg, 0.37 mmol, 2 eq) and (RS) 2-(methyl)piperidine (0.19 mmol, 1.5 eq). The resulting mixture was stirred at 80° C. for six hours. The reaction was quenched by the addition of water (10 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (3×10 ml), brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo to yield an oily crude product which was purified by flash chromatography to provide the title product.
Reaction SMILES: [NH2:1][C:2]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[S:13]([N:16]([CH3:21])CC(O)=O)(=[O:15])=[O:14])=[CH:10][C:9]([Cl:22])=[CH:8][CH:7]=2)=[O:3].[C:23](Cl)(=[O:27])[C:24](Cl)=O.C[N:30](C=O)C.[NH4+].[OH-].CC(C)=O>ClCCl.CC(C)=O>[NH2:1][C:2]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[S:13]([N:16]([CH3:21])[C:23](=[O:27])[CH2:24][NH2:30])(=[O:14])=[O:15])=[CH:10][C:9]([Cl:22])=[CH:8][CH:7]=2)=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(CC(=O)O)S(=O)(=O)c1c(C(N)=O)[nH]c2ccc(Cl)cc12
Reactant: CN(C)C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CN(C(=O)CN)S(=O)(=O)c1c(C(N)=O)[nH]c2ccc(Cl)cc12
Reaction time: 0.33 h

Procedure:
To a suspension of N-{[2-(Aminocarbonyl)-5-chloro-1H-indol-3-yl]sulfonyl}-N-methylglycine from Example 56 (10 mg, 0.029 mmol) in 1 mL of dichloromethane at room temperature was added oxalyl chloride (0.3 mL), followed by DMF (ca. 0.020 mL). After 20 minutes, the homogeneous mixture was concentrated in vacuo to give a yellow solid. This was taken up in 1 mL of acetone, and a solution of 10% NH4OH/acetone (2 mL) was added, whereupon a white precipitate formed. After two minutes, the solvent was decanted off, and the resulting solid was maintained in vac o until dry. Purification by preparative reversed phase HPLC provided the titled compound as a white solid. ESI+ MS: 345.2 [M+H]+.