Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C[CH2:4][NH:5][C:6](=[O:32])[C@@H:7]([NH:12][C:13]([N:15]1[C:19]2[CH2:20][CH2:21][O:22][CH2:23][C:18]=2[C:17]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)=[N:16]1)=[O:14])[C:8]([CH3:11])([CH3:10])[CH3:9])#N.[N:33]1([C:39]2[S:40][CH:41]=[CH:42][N:43]=2)[CH2:38]CN[CH2:35][CH2:34]1>>[F:31][C:26]1[CH:25]=[C:24]([C:17]2[C:18]3[CH2:23][O:22][CH2:21][CH2:20][C:19]=3[N:15]([C:13]([NH:12][C@@H:7]([C:8]([CH3:9])([CH3:10])[CH3:11])[C:6](=[O:32])[N:5]3[CH2:4][CH2:38][N:33]([C:39]4[S:40][CH:41]=[CH:42][N:43]=4)[CH2:34][CH2:35]3)=[O:14])[N:16]=2)[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(=O)NCCC#N
Reactant: c1csc(N2CCNCC2)n1
Product: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(=O)N1CCN(c2nccs2)CC1

Procedure:
Compound 108 was prepared by the procedure described for the synthesis of compound 104 by replacing 2-cyanoethylamine with 2-(piperazin-1-yl)thiazole. LCMS (+ESI) m/z=545.3 [M+H]+. 1H NMR (CDCl3) δ 7.93 (d, J=9.6 Hz, 1H), 7.48-7.52 (m, 1H), 7.30-7.32 (m, 1H), 7.19-7.26 (m, 2H), 6.63 (d, J=3.7 Hz, 1H), 4.87 (d, J=9.6 Hz, 1H), 4.82 (s, 2H), 3.87-3.98 (m, 4H), 3.64-3.81 (m, 3H), 3.45-3.58 (m, 3H), 3.18 (br, 2H), 1.11 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:44]=[C:35]5[CH2:36][N:37]([CH2:40][CH:41]([F:43])[F:42])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:45])[N:27]([CH3:46])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.ClCCl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:44]=[C:35]5[CH2:36][N:37]([CH2:40][CH:41]([F:43])[F:42])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:45])[N:27]([CH3:46])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2C=O)cc(Nc2cc3n(n2)CCN(CC(F)F)C3)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2cc3n(n2)CCN(CC(F)F)C3)c1=O
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a solution of 135e (100 mg, 0.158 mmol) in methanol/dichloromethane(4/4 mL) was added NaBH4 (18 mg, 0.475 mmol) at room temperature. After the reaction was stirred for 1 h, LCMS indicated the reaction was complete. The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 135 (60 mg, 60%) as a white solid. MS-ESI: [M+H]+ 635.3. 1H NMR (500 MHz, CDCl3) δ 8.66 (d, J=5.0 Hz, 1H), 8.35 (d, J=2.5 Hz, 1H), 8.00 (d, J=2.5 Hz, 1H), 7.59-7.58 (m, 1H), 7.56-7.55 (m, 1H), 7.53-7.52 (m, 2H), 7.45 (s, 1H), 6.07-5.83 (m, 1H), 5.72 (s, 1H), 4.51-4.49 (m, 2H), 4.11-4.08 (m, 2H), 4.05-4.03 (m, 1H), 3.94 (s, 2H), 3.73 (s, 3H), 3.13-3.10 (m, 2H), 3.00-2.94 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[OH-].[NH4+:15].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:10]([NH2:15])(=[O:12])=[O:11]
Reactant: [NH4+]
Reactant: COc1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cl)c(S(N)(=O)=O)c1
Reaction time: 0.25 h
Yield: 95.4 %

Procedure:
To a solution of 2-chloro-5-methoxybenzenesulfonyl chloride (2.5 g, 10.4 mmol) (i.e. the product of Step A) in tetrahydrofuran (30 mL) was added 30% ammonium hydroxide (3.0 mL, 25.7 mmol) dropwise. The reaction mixture was stirred for 15 minutes, during which time a suspension formed. To this mixture water (10 mL) was added, and the tetrahydrofuran was evaporated under reduced pressure to leave an aqueous suspension of a tan solid. The solid was isolated by filtration and washed with water to afford 2.2 g of the title compound. 1H NMR (CDCl3) δ 7.63 (d, 1H), 7.43 (d, 1H), 7.03 (d, 1H), 5.13 (br s, 2H), 3.85 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C(O)(=[O:26])C>>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4=[CH:22][NH:23][C:2](=[O:26])[CH:3]=[C:4]4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(=O)O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1c[nH]c(=O)cc1OCC2
Temperature: 155 °C
Reaction time: 1 h

Procedure:
A solution of 2.64 g (8.00 mmol) of 9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine 317 in 250 ml of glacial acetic acid was placed into 350 ml glass pressure vessel. The vessel was closed and the mixture was heated for 64 hours at 155° C. The mixture was cooled down to room temperature. White precipitate appeared. The mixture was concentrated to 50 ml volume in vacuum, the solid material was filtered out, washed with acetic acid, ethyl ether and dried on air. Weight 1.68 g. The above product was stirred with 15 ml of sat NaHCO3 for 1 hour, filtered out, washed with 2×10 ml of water, dissolved in THF/water (10:1) mixture and concentrated. The residue was dried in high vacuum for 18 hours to give 2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9(10H)-one. Yield 1.12 g (45%). M/z 313.1, calc. 312.13. 1H NMR (400 MHz, DMSO) δ 11.79 (s, 1H), 8.41 (s, 1H), 7.89 (s, 1H), 7.82 (s, 1H), 5.84 (s, 1H), 5.78 (dt, J=13.2, 6.6, 1H), 4.57-4.51 (m, 2H), 4.50-4.45 (m, 2H), 1.45 (d, J=6.6, 6H)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.CN(C)C1C=CC=CC=1.[CH2:29]1[O:31][CH:30]1[CH2:32][OH:33]>O1CCCC1.O>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][CH2:29][CH:30]([OH:31])[CH2:32][OH:33])[CH:15]=1
Reactant: OCC1CO1
Reactant: Cc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: OCC(O)CCc1cccnc1
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
Under argon gas, a solution of diisopropylamine (5.57 g, 55 mmol) in tetrahydrofuran (5 mL) was added dropwise to n-butyllithium (1.53 M in hexane, 31.8 mL, 50 mmol) at 5° C. and the mixture was stirred for 30 minutes. To this was further added a solution of 3-methylpyridine (5.588 g, 60 mmol) in tetrahydrofuran (5 mL) dropwise ast 5° C., and the mixture was stirred for 30 minutes. Then, N,N-dimethylaniline (3.64 g, 30 mmol) was added and the mixture was further stirred at 5° C. for 30 minutes. To this was added a solution of glycidol (1.480 g, 20 mmol) in tetrahydrofuran (5 mL) at 5° C., and the reaction was carried out for 2 hours. This reaction mixture was diluted with 30 mL of water for hydrolysis and concentrated under reduced pressure. The residue was extracted with ethyl acetate twice (200 mL each). The organic layers were combined and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residual oil was purified by silica gel column chromatography (Merck's Kieselgel 60, MeOH/ethyl acetate=1/9) to give 2.505 g (isolation yield: 75%) of 4-(3-pyridyl)-1,2-butanediol (yellow oil).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][C:9]([Si:12]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[O:13][C:14]1[CH:32]=[CH:31][C:17]2[C:18](OS(C(F)(F)F)(=O)=O)=[CH:19][C:20](=[O:22])[O:21][C:16]=2[C:15]=1[CH3:33])([CH3:11])[CH3:10].C1COCC1.OP([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH3:10][C:9]([Si:12]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[O:13][C:14]1[CH:32]=[CH:31][C:17]2[C:18]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:19][C:20](=[O:22])[O:21][C:16]=2[C:15]=1[CH3:33])([CH3:8])[CH3:11]
Reactant: Cc1c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ccc2c(OS(=O)(=O)C(F)(F)F)cc(=O)oc12
Reactant: CN1CCNCC1
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ccc2c(N3CCN(C)CC3)cc(=O)oc12

Procedure:
1.25 ml of N-methyl piperazine is added to a solution containing 2.53 g of 7-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-8-methyl-4-[[(trifluoromethyl)sulphony]oxy]-2H-1-benzopyran-2-one and 22 ml of THF. The reaction medium is maintained under agitation for 1 hour, poured into a 1M aqueous solution of sodium acid phosphate, and extraction is carried out with ethyl acetate. The organic phases are combined, washed, dried and concentrated under reduced pressure. Chromatography is carried out on silica eluting with a methanol-methylene chloride mixture (6-94). 2.31 g of sought product is isolated. rf=0.3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:56][O:57][C:58](=[O:68])[C:59]1[CH:64]=[C:63]([F:65])[C:62]([NH2:66])=[CH:61][C:60]=1[F:67].NC1C=CC=CC=1>C(Cl)Cl>[CH3:56][O:57][C:58](=[O:68])[C:59]1[CH:64]=[C:63]([F:65])[C:62]([NH:66][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:30])=[CH:61][C:60]=1[F:67]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1cc(F)c(N)cc1F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: Nc1ccccc1
Product: COC(=O)c1cc(F)c(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1F
Reaction time: 0.08 h

Procedure:
To a stirred solution of (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (300 mg, 0.64 mmol) in methylene chloride (5 mL), DIPEA (Aldrich, 2.57 mmol, 0.45 ml) was added followed by diphenylphosphinic chloride (Aldrich, 1.93 mmol, 0.37 ml). The mixture was stirred for 5 min. and 4-amino-2,5-difluoro-benzoic acid methyl ester (Prepared by methylation of the corresponding acid. 201 mg, 0.76 mmol) was added and the mixture was stirred overnight. The reaction was quenched with 10% sodium carbonate (6 mL) and the mixture was stirred for 15 min. The organic layer was separated and the solvent was reduced to about 3 ml. The solution was loaded onto a 40 g silica gel column and eluted with 2% EtOAc/CH2Cl2 to give a mixture of the desired product and aniline. The crude was again chromatographed on a reverse phase column and eluted with 50-95% acetonitrile/water to give a white solid. 82 mg. (ES+) m/z Calcd: [(M+H)+]: 636. found: 636.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:7]([CH3:8])[O:6][C:5](=[O:9])[C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16](Cl)(=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C1COCC1>[C:16]([O:1][CH2:2][C:3]1[CH:7]([CH3:8])[O:6][C:5](=[O:9])[C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CC1OC(=O)C(c2ccccc2)=C1CO
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)OCC1=C(c2ccccc2)C(=O)OC1C

Procedure:
4-Hydroxymethyl-5-methyl-3-phenyl-2(5H)-furanone (Compound 7), (73 mg, 0.36 mmol), lauroyl chloride (117 mg, 0.54 mmol), triethylamine (47 mg, 0.47 mmol) and dimethylaminopyridine (1 mg, 0.01 mmol) were stirred in anhydrous THF (2 mL) at ambient temperature under argon for 2 hours. The crude reaction mixture was concentrated, the organics were extracted into diethyl ether and solids were filtered off. The ether was removed by rotary evaporator and the resulting oil was purified by flash chromatography on silica to give the title compound.
Reaction SMILES: C1(C(=[N:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([C:25]([C:30]2[N:31]=[CH:32][N:33](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:34]=2)([OH:29])[CH:26]([CH3:28])[CH3:27])[CH:19]=[CH:18]3)C2C=CC=CC=2)C=CC=CC=1.[C:54]([O-:57])(=O)[CH3:55].[Na+].Cl.NO.[OH-].[Na+]>C1COCC1.CO>[OH:29][C:25]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([NH:14][C:54](=[O:57])[CH3:55])[CH:24]=[CH:23]2)([C:30]1[N:31]=[CH:32][NH:33][CH:34]=1)[CH:26]([CH3:27])[CH3:28]
Reactant: CC(C)C(O)(c1ccc2cc(N=C(c3ccccc3)c3ccccc3)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 164.5 %

Procedure:
To a solution of 1-{6-[(diphenylmethylene)amino]naphthalene-2-yl}-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (15.0 g) in THF (100 mL)-methanol (100 mL) were added sodium acetate (4.29 g) and hydroxylamine hydrochloride (2.73 g), and the mixture was stirred at room temperature for 20 min. After addition of 0.1N-NaOH solution, the mixture was extracted with ethyl acetate. The extract was washed with brine, dried and concentrated. The residue was dissolved in dichloromethane and pyridine (5.3 mL) and acetic anhydride (4.1 mL) were added. The mixture was stirred at room temperature for 40 min and then saturated sodium bicarbonate solution was added and was extracted with dichloromethane. The extract was dried and concentrated and the residue was crystallized from ethyl acetate to give the titled compound (11.6 g) as pale red crystals.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8](O)=[O:9])([CH3:3])[CH3:2].CN(C)C=O.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[CH:1]([S:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([Cl:23])=[O:9])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)cc1SC(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cl)cc1SC(C)C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A solution of 3-isopropylthio-4-methoxybenzoic acid (2.5 g; that is prepared as described in Reference Example 49) in toluene (25 mL), and dimethylformamide (0.2 mL) is treated with thionyl chloride (2.5 mL) and the solution is stirred at 60° C. for 3 hours. The solution is concentrated, treated with toluene (10 mL) and again evaporated to dryness, to give 3-isopropylthio-4-methoxybenzoyl chloride (2.7 g), in the form of a light brown oil.
Reaction SMILES: [CH3:1][C:2]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15](C3C=CC(CO)=CC=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9].OCC1C=CC(B(O)O)=CC=1.CC1(C)C(C)(C)OB([C:52]2[CH:53]=[C:54]([CH:64]=[CH:65][CH:66]=2)[CH2:55][NH:56][C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60])O1>>[CH3:1][C:2]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15]([C:52]3[CH:53]=[C:54]([CH:64]=[CH:65][CH:66]=3)[CH2:55][NH:56][C:57](=[O:63])[O:58][C:59]([CH3:60])([CH3:61])[CH3:62])[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: CC(C)(C)OC(=O)NCc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4ccc(CO)cc4)cccc32)c1C
Agent: OCc1ccc(B(O)O)cc1
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cccc(CNC(=O)OC(C)(C)C)c4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to 4-(2,3-dimethylphenoxy)-1-(5-(4-(hydroxymethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)butan-1-one except that 4-(hydroxymethyl)phenylboronic acid was replaced with tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate. LCMS, [M+Na]+=551.4.
Reaction SMILES: [C:1]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.NN.C(O)COCCO.[OH-].[K+]>O>[CH2:1]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)c1cccs1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCCCCCc1cccs1
Temperature: 110 °C
Yield: 82.8 %

Procedure:
In a 10 liter-five-necked flask, 300 g (1.65 mol) of 2-hexanoylthiophene, 582.1 ml of 60% hydrazine hydrate and 5 liter of diethyleneglycol were placed and reacted for 2 hours at 180° C. with distilling-off of excessive water and hydrazine hydrate. The mixture was cooled to 110° C. and 313.7 g of KOH was added thereto, followed by heating again for 2 hours of reaction at 180° C. After the reaction, the reaction mixture was poured into 10 liter of water, extracted two times with 2 liter of isopropyl ether and washed four times with 2 liter of water, followed by drying with CaCl2 and distilling-off of the solvent to obtain 285 g of a crude product. The crude product was subjected to reduced-pressure distillation in an atmosphere of nitrogen to obtain 230 g of a pure product (yield: 83%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:10])=[N:6][CH:7]=1.C[Si](C)(C)[C:15]([F:18])([F:17])[F:16].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:12])([CH3:11])[CH:9]([OH:10])[C:15]([F:18])([F:17])[F:16])=[N:6][CH:7]=1
Reactant: CC(C)(C=O)c1ccc(Br)cn1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(c1ccc(Br)cn1)C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-(5-bromopyridin-2-yl)-2-methylpropanal (1.0 g, 4.4 mmol) and trimethyl(trifluoromethyl)silane (1.1 g, 7.5 mmol) in THF (10 mL) under nitrogen was added the solution of TBAF (230 mg, 0.88 mmol) in THF (5 mL) dropwise at −30° C. The resulting solution was stirred at −30° C. for 1 hour and at ambient temperature for additional 1 hour before the addition of the second batch of TBAF (1.1 g, 4.4 mmol) at ambient temperature. The resulting mixture was stirred at ambient temperature for 20 minutes, then the reaction solution was diluted with water (10 mL), and extracted with EtOAc (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by MPLC on Silica gel (eluting with 2-5% EtOAc/hexane) to afford the title compound as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.55 (s, 1H), 7.86 (d, J=8.7 Hz, 1H), 7.24 (d, J=8.7 Hz, 1H), 4.01 (q, J=7.8 Hz, 1H), 1.51 (s, 6H). MS ESI: [M+H]+ m/z 298, 300.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH3:9][C:10]([CH3:12])=[O:11]>C1(C)C=CC=CC=1>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([C:10]([OH:11])([CH3:12])[CH3:9])=[N:3][CH:4]=1
Reactant: Clc1cnc(Br)cn1
Reactant: CC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(O)c1cnc(Cl)cn1
Temperature: -78 °C
Yield: 56.1 %

Procedure:
2-Bromo-5-chloropyrazine (900 mg, 4.65 mmol) was dissolved in toluene (20 mL). The reaction vessel was flushed with nitrogen and cooled to −78° C. n-Butyllithium (2.5M solution in hexanes, 2.23 mL) was added slowly under stirring and allowed to stir for a further 10 minutes upon complete addition. Acetone (3.42 mL, 46.53 mmol) was added and the reaction mixture was stirred at −78° C. for 30 minutes. The reaction mixture was allowed to warm to room temperature and the solvent was removed in vacuo. The residue was taken up in EtOAc (50 mL) and washed using saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulphate, filtered and concentrated in vacuo. The crude brown oil was purified by chromatography on silica (Biotage, 25 g cartridge), eluting with 0 to 100% ethyl acetate in heptanes, to afford the title compound (450 mg, 56%) as a yellow oil. Method B HPLC-MS: MH+ m/z 173, RT 1.31 minutes.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[S:18])[S:12][CH2:13][C:14](=O)[CH2:15][Cl:16].[H][H]>>[Cl:16][CH2:15][C:14]1[N:10]([C:3]2[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=2[F:1])[C:11](=[S:18])[S:12][CH:13]=1
Reactant: [H][H]
Reactant: O=C(CCl)CSC(=S)Nc1ccc(F)c(F)c1F
Product: Fc1ccc(-n2c(CCl)csc2=S)c(F)c1F
Yield: 69 %

Procedure:
3-Chloro-2-oxopropyl N-(2,3,4-trifluorophenyl)dithiocarbamate (4.0 g) is added to 30% hydrogen chloridemethanol solution (15 ml), and the mixture is refluxed for 3 hours. The solvent is distilled off under reduced pressure, and cold water is added to the residue and the mixture is extracted with chloroform. The extract is washed with saline solution, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue is recrystallized from cyclohexane to give the title compound (2.6 g) as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:11](=O)[CH2:10][CH:9]([C:13]([O:15][CH3:16])=[O:14])[C:7](=O)[CH2:6]1)=[O:4].[CH3:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.Cl>CO>[CH3:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:7]2[CH2:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:11]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([CH3:17])=[CH:19][CH:20]=3)[CH2:10][C:9]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:20][CH:19]=1
Reactant: COC(=O)C1CC(=O)C(C(=O)OC)CC1=O
Reactant: Cc1ccc(N)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)C1=C(Nc2ccc(C)cc2)CC(C(=O)OC)=C(Nc2ccc(C)cc2)C1
Yield: 97.4 %

Procedure:
Dimethyl 1,4-cyclohexanedione-2,5-dicarboxylate (4.56 gm; 20 mmol) and methanol (100 ml) were heated to boiling; then 4-methylaniline (4.5 gm; 42 mmol) was added followed by conc. hydrochloric acid (200 μl). The mixture was refluxed for 5 hours under a nitrogen atmosphere. On cooling a cream solid precipitated out which was collected by filtration, washed with methanol and dried under vacuum to give 7.92 gm (97%) of dimethyl 2,5-bis{(4-methylphenyl)amino}cyclohexa-1,4-diene-1,4-dicarboxylate.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].[CH2:19]([C:21]1[N:31]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH:40][C:41](=O)[O:42]C3C=CC=CC=3)=[CH:34][CH:33]=2)[C:24]2=[N:25][C:26]([CH3:30])=[CH:27][C:28]([CH3:29])=[C:23]2[N:22]=1)[CH3:20].O>CN(C=O)C>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:41]([NH:40][CH2:39][CH2:38][C:35]2[CH:36]=[CH:37][C:32]([N:31]3[C:24]4=[N:25][C:26]([CH3:30])=[CH:27][C:28]([CH3:29])=[C:23]4[N:22]=[C:21]3[CH2:19][CH3:20])=[CH:33][CH:34]=2)=[O:42])(=[O:8])=[O:9])=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(-c3ccccc3)cc2)cc1
Reaction time: 0.08 h
Yield: 49.7 %

Procedure:
To a stirred solution of 4-biphenylsulfonamide (Greenlee, W. J.; Walsh, T. F.; et al. Eur. Pat. Appl., EP 617001 (1994)., 56 mg, 0.24 mmol) in DMF (3 mL) was added NaH (60% oil dispersion, 20 mg, 0.5 mmol) at room temperature. After 5 min, phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1, 100 mg, 0.24 mmol) was added, and the mixture was stirred for an additional 1 h. The mixture was poured into water (50 mL) and extracted with diethyl ether (2×50 mL). The combined extracts were washed with water (50 mL), brine (50 mL) and dried (MgSO4). Removal of solvent gave white oily solids. Purification by preparative TLC (ethyl acetate) gave 66 mg (50%) of the title compound as a colorless oil: MS (ESI) m/z 554 (M+H)+; 1H-NMR (CDCl3) δ 8.06 (2H, d, J=8.6 Hz), 7.13 (2H, d, J=8.6 Hz), 7.60–7.53 (2H, m), 7.48–7.36 (3H, m), 7.21 (2H, d, J=8.4 Hz), 7.12 (2H, d, J=8.3 Hz), 6.92 (1H, s), 6.11 (1H, br.t, J=5.5 Hz), 3.54 (2H, dt, J=5.9, 6.0 Hz), 2.89 (2H, J=6.0 Hz), 2.64 (2H, q, J=7.5 Hz), 2.66 (3H, s), 2.40 (3H, s), 1.18 (3H, t, J=7.5 Hz).