Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][C:13](=[CH:16][C:17]#[CH:18])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:19][C:20]([F:30])([F:29])[O:21][C:22]1[CH:23]=[C:24](I)[CH:25]=[CH:26][CH:27]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][C:13](=[CH:16][C:17]#[C:18][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:19])([F:29])[F:30])[CH:23]=3)[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C#CC=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Reactant: FC(F)(F)Oc1cccc(I)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=[N+]([O-])c1cccnc1N1CCC(=CC#Cc2cccc(OC(F)(F)F)c2)CC1
Temperature: 80 °C
Yield: 56.5 %

Procedure:
A mixture of Compound 1c (60 mg, 0.25 mmol), 3-(trifluoromethoxy)iodobenzene (41.6 μL, 0.26 mmol), bis(triphenylphosphine)palladium(II)dichloride (8.65 mg, 0.01 mmol), CuI (4.69 mg, 0.1 mmol) in anhydrous and degassed triethylamine (3 mL) was heated at 80° C. under a nitrogen atmosphere for 2 h in a sealed vessel. The reaction mixture was cooled, filtered on Celite, poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography (EtOAc—Petroleum Ether 5:95) affording the title product (57 mg).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH:7]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[NH:39][N:38]=[N:37][N:36]=2)[CH:30]=1)[C:8]1[CH:28]=[CH:27][C:11]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[C:16]([OH:23])[C:15]=2[CH2:24][CH2:25][CH3:26])=[CH:10][CH:9]=1>>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:11]2[CH:10]=[CH:9][C:8]([CH:7]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4[NH:39][N:38]=[N:37][N:36]=4)[CH:30]=3)[NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:28][CH:27]=2)=[C:15]([CH2:24][CH2:25][CH3:26])[C:16]=1[OH:23])(=[O:22])[CH3:21]
Reactant: CS(=O)(=O)Cl
Reactant: CCCc1c(OCc2ccc(C(N)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O
Product: CCCc1c(OCc2ccc(C(NS(C)(=O)=O)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O

Procedure:
The title compound is prepared essentially as described in Example 74 employing methane sulfonyl chloride and 1-[4-(4-{amino-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone to give 22 mg, 28%, as a white solid. 1H NMR (DMSO-d6) δ 12.86 (s, 1H), 8.49 (d, 1H), 8.17 (s, 1H), 7.91-7.94 (m, 1H), 7.80 (d, 1H), 7.60-7.62 (m, 2H), 7.44-7.51 (m, 4H), 6.72 (d, 1H), 5.81 (d, 1H), 5.25 (s, 2H), 2.75 (s, 3H), 2.57-2.62 (m, 5H), 1.46-1.53 (m, 2H), 0.87 (t, 3H). LCMS M+1 536.
Reaction SMILES: [Br-:1].[Na+].CN(C=O)C.S([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)([O-])(=O)=O>O>[Br:1][CH2:13][CH2:14][CH:15]([CH3:16])[CH2:17][CH2:18][CH2:12][CH2:17][CH2:18][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCC(C)CCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridine (20 ml) was added to a methylene chloride (50 ml) solution of the 3-methyldodecan-1-ol (4″) (12.8 g, 63.9 mols), and p-toluenesulfonyl chloride (12.8 g, 67.1 mmols) was further added under ice-cooling. The reaction mixture was stirred overnight at 4° C., then poured into diluted hydrochloric acid, and extracted with hexane. The organic layer was washed (water, a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of sodium chloride), dried (magnesium sulfate), and concentrated under reduced pressure to obtain 21.7 g of a tosylate. Sodium bromide (9.9 g, 96 mols) was added to a DMF solution (100 ml) of the resulting tosylate, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and extracted with hexane. The organic layer was washed (water and a saturated aqueous solution of sodium chloride), dried (magnesium sulfate), and concentrated under reduced pressure to obtain 1-bromo-3-methyldodecane (5″) (15.1 g, 90%). 1H-NMR (90 MHz, CDCl3) 0.8-1.0 (6H,m,Me), 1.0-2.0 (19H,m,2˜11-H), 3.43 (2H,br t,J=7,1-H).
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[CH2:10][C:11]1[N:12]([C@@H:17]2[CH2:26][C:25]3[C:20](=[C:21]([F:28])[CH:22]=[C:23]([F:27])[CH:24]=3)[O:19][CH2:18]2)[C:13](=[S:16])[NH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O1CCCC1.B(F)(F)F.Cl.[OH-].[Na+]>O1CCCC1>[CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[N:12]([C@@H:17]2[CH2:26][C:25]3[C:20](=[C:21]([F:28])[CH:22]=[C:23]([F:27])[CH:24]=3)[O:19][CH2:18]2)[C:13](=[S:16])[NH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1c[nH]c(=S)n1[C@H]1COc2c(F)cc(F)cc2C1)NCc1ccccc1
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: C1CCOC1
Product: Fc1cc(F)c2c(c1)C[C@@H](n1c(CCNCc3ccccc3)c[nH]c1=S)CO2
Temperature: 0 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
To a solution of (R)—N-benzyl-2-(3-(6,8-difluorochroman-3-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-yl)acetamide (16.62 g, 40 mmol) in tetrahydrofuran (133 ml) was added sodium borohydride (3.78 g, 100 mmol). The suspension was then cooled to 0° C. and a solution of boron trifluoride tetrahydrofuran (14.56 ml, 132 mmol) in tetrahydrofuran (85 ml). The mixture was warmed up to room temperature (20-25° C.) and stirred for 24 hours. After cooling to 0° C., 1N hydrochloric acid (64 ml, 64 mmol), pH to 1 with 6N hydrochloric acid (17.7 ml, 108 mmol), and the mixture was refluxed for 30 min. Tetrahydrofuran was removed under reduced pressure. The precipitate was collected, washed with water (50 mL). The wet solid was suspended in a mixture of methanol (250 ml) and water (38 ml). The suspension was heated to reflux until complete dissolution; 1N sodium hydroxide (45 ml, 48 mmol) was added (pH 8-9). The crystallization occurred at approx 50° C. The suspension was cooled to 15° C., aged for 3 hours. The precipitate was collected, washed with methanol (33 mL), dried in vacuum at 50° C. to give (R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione (12.5 g, 30.01 mmol, 76% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10].[C-]#N.[Na+].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].O>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[O:7])[CH2:16][CH2:15][C:14]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][C:3]=1[F:10]
Reactant: C=CC(=O)OCC
Reactant: O=Cc1ccc(Cl)c(F)c1
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCC(=O)c1ccc(Cl)c(F)c1
Reaction time: 3 h

Procedure:
Under argon atmosphere, to a solution of 4-chloro-3-fluoro-benzaldehyde (10 g) in N,N-dimethylformamide (50 ml) was added sodium cyanide (620 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hours. Then, to the mixture was added dropwise a solution of ethyl acrylate (5.2 ml) in N,N-dimethylformamide (25 ml), and the resulting mixture was stirred at the room temperature for 3 hours. The reaction mixture was poured into water and extracted with diethyl ether. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane:ethyl acetate=20:1) to obtain ethyl 4-(4-chloro-3-fluorophenyl)-4-oxobutyrate (9.4 g) as pale yellowish powder.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][OH:11].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[OH-].[Na+]>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[S:2][CH3:1]
Reactant: CSc1ccccc1CCO
Reactant: BrCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: CSc1ccccc1CCOCCCCCCBr

Procedure:
2-(Methylthio)benzeneethanol (2.0 g) and 1,6-dibromohexane (9.31 g) were stirred rapidly at room temperature with tetrabutylammonium bisulphate (0.34 g) and 12.5 M aqueous sodium hydroxide (11 ml) for 16 h. The mixture was diluted with water (45 ml), extracted with ER (3×55 ml) and the combined organic extracts were washed consecutively with water (45 ml) and brine (45 ml), dried and evaporated. The residual oil (8.84 g) was purified by [FCS] using ER-cyclohexane (0:100→2:98) as eluent to give the title compound. T.l.c. (Cyclohexane--ER, 79:1) Rf 0.17.
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[O:3][CH:4]([C:7]([CH3:13])([CH3:12])[CH2:8][CH2:9][CH2:10][CH3:11])[C:5]#[CH:6].OC(C(C)(C)CCCC)C#C.C([Si](CC)(CC)OC(CCCCC)C#C)C.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:55]([SnH:59]([CH2:64][CH2:65][CH2:66][CH3:67])[CH2:60][CH2:61][CH2:62][CH3:63])[CH2:56][CH2:57][CH3:58]>>[CH2:64]([Sn:59]([CH2:55][CH2:56][CH2:57][CH3:58])([CH2:60][CH2:61][CH2:62][CH3:63])/[CH:6]=[CH:5]\[CH:4]([O:3][Si:2]([CH3:14])([CH3:15])[CH3:1])[C:7]([CH3:13])([CH3:12])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:65][CH2:66][CH3:67]
Reactant: C#CC(O[Si](C)(C)C)C(C)(C)CCCC
Reactant: CCCC[SnH](CCCC)CCCC
Agent: C#CC(CCCCC)O[Si](CC)(CC)CC
Agent: C#CC(O)C(C)(C)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCC(C)(C)C(/C=C\[Sn](CCCC)(CCCC)CCCC)O[Si](C)(C)C
Temperature: 130 °C
Reaction time: 2 h

Procedure:
A mixture of 2 g (8.83 mmole) of 3-trimethylsilyloxy-4,4-dimethyl-1-octyne [prepared from 3-hydroxy-4,4-dimethyl-1-octyne U.S. Pat. No. 4,007,210 and chlorotrimethylsilane (Method of Example 1)], 10 mg of azobisisobutyronitrile and 2.09 ml (7.9 mM) of tri-n-butylstannane is stirred in an oil bath under argon atmosphere at ambient temperature and then the temperature is gradually raised to 130° C. The resulting solution is stirred at 130°-135° C. for 2 hours, then cooled to furnish Z-1-tri-n-butylstannyl-3-trimethylsilyloxy-4,4-dimethyl-1-octene. Vapor phase chromatography on a 6'5% SE 30 column at an oven temperature of 230° C. shows a peak at retention time of 5.2 minutes. Further treatment of this solution containing the Z isomer with additional tri-n-butylstannane (3-4 mmole) and azobisisobutyronitrile (20 mg) at 130°-135° C. for 4-hour furnishes E-1-tri-n-butylstannyl-3-trimethylsilyloxy-4,4-dimethyl-1-octene. Vapor phase chromatography shows a peak at retention time of 4.7 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([O:14][CH2:15]C)=[O:13].[H-].[Na+].[Cl:19][C:20]1[N:25]=[C:24]2[N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:27]=[CH:28][C:23]2=[C:22]([N+]([O-])=O)[CH:21]=1>CN(C=O)C>[Cl:19][C:20]1[N:25]=[C:24]2[N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:27]=[CH:28][C:23]2=[C:22]([CH:11]([C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[F:1])[C:12]([O:14][CH3:15])=[O:13])[CH:21]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c([N+](=O)[O-])cc(Cl)nc21
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc([N+](=O)[O-])cc1F)c1cc(Cl)nc2c1ccn2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
908 mg (4.26 mmol) of ethyl (2-fluoro-4-nitrophenyl)acetate are dissolved in 10 ml of DMF, and 170 mg (4.26 mmol) of sodium hydride (60% in mineral oil) are added. The mixture is stirred at RT for 30 min, and 698 mg (2.13 mmol) of 6-chloro-4-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine are then added. The mixture is heated at 70° C. for 2 hours and then stirred into ice-water and extracted with ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The product is purified by chromatography on silica gel (mobile phase: dichloromethane/pentane 2:1).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[CH:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19](O)=[O:20])([CH3:15])[CH3:14]>>[CH:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:10]1)=[O:20])([CH3:15])[CH3:14]
Reactant: N#Cc1ccc2c(c1)CNCC2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2ccc(C#N)cc2C1

Procedure:
Prepared in analogy to example 1.1 from 7-cyano-1,2,3,4-tetrahydro-isoquinoline (CA [149355-52-2]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([O:8][C:9]1[CH:10]=[N:11][C:12]([NH2:15])=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2].Br[C:18]1[C:19](=[O:26])[N:20]([CH3:25])[N:21]=[C:22]([Cl:24])[CH:23]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4](=[O:16])[C:5]([O:8][C:9]1[CH:10]=[N:11][C:12]([NH:15][C:18]2[C:19](=[O:26])[N:20]([CH3:25])[N:21]=[C:22]([Cl:24])[CH:23]=2)=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: CCOC(=O)C(C)(C)Oc1ccc(N)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)C(C)(C)Oc1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 91.1 %

Procedure:
A flask containing 2-(6-amino-pyridin-3-yloxy)-2-methyl-propionic acid ethyl ester (1.365 g, 6.09 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (1.77 g, 7.91 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (528 mg, 0.913 mmol) and cesium carbonate (6.94 g, 21.3 mmol) in dry dioxane (60 ml) was evacuated under vacuum and back filled with argon (repeat 3 times). Tris(dibenzylideneacetone)dipalladium (0) (418 mg, 0.457 mmol) was added and the flask evacuated under vacuum and back filled with argon (repeat 3 times). The flask was place in an oil bath heated to 90° C. and stirred for 16 hours under argon atmosphere. The flask was cooled to ambient and the material was filtered through a plug of celite, rinsing well with dioxane. The volatiles were concentrated in vacuo. and the residue was purified by silica gel chromatography, eluting with 5% to 25% ethyl acetate/hexane to provide the desired product as a light yellow-brown powder (2.035 g). (M+H)+=367 m/e.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([C:11]([O:13]C)=O)[CH2:7][C:6]=2[CH:15]=1.[CH2:16]([NH2:19])[CH:17]=[CH2:18]>C(Cl)Cl.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([C:11]([NH:19][CH2:16][CH:17]=[CH2:18])=[O:13])[CH2:7][C:6]=2[CH:15]=1
Reactant: COC(=O)C1COc2ccc(Cl)cc2C1
Reactant: C=CCN
Solvent: ClCCl
Solvent: CCO
Product: C=CCNC(=O)C1COc2ccc(Cl)cc2C1

Procedure:
A mixture of 500 mg of 6C, 5 ml of 2-propenamine and 25 ml of ethanol was refluxed for 18 hours. The sovlent was then stripped off and the residue was taken up in methylene chloride, triturated with hexane and cooled to give a solid. The solid was redissolved in ethanol, the solution was passed through a short silica gel column and the eluent was stripped of solvent. The residue was recrystallized from methylene chloride/hexane to give 6, as white needles, mp: 171°-171.5° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([C:12]1[C:13]([N+:26]([O-:28])=[O:27])=[C:14]2[C:19](=[C:20]([NH:22]C(=O)C)[CH:21]=1)[N:18]=[CH:17][CH:16]=[CH:15]2)(=[O:11])=[O:10])[CH3:2].O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([C:12]1[C:13]([N+:26]([O-:28])=[O:27])=[C:14]2[C:19](=[C:20]([NH2:22])[CH:21]=1)[N:18]=[CH:17][CH:16]=[CH:15]2)(=[O:10])=[O:11])[CH3:2]
Reactant: CCc1ccccc1S(=O)(=O)c1cc(NC(C)=O)c2ncccc2c1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCc1ccccc1S(=O)(=O)c1cc(N)c2ncccc2c1[N+](=O)[O-]

Procedure:
N-[6-(2-Ethyl-benzenesulfonyl)-5-nitro-quinolin-8-yl]-acetamide (0.5 g) is stirred at reflux in 2N hydrochloric acid (50 mL) and 1,4-dioxane (50 mL) for 2 hours. The mixture is added to 2N sodium carbonate (200 mL) and extracted with ethyl acetate (3×100 mL). The extracts are washed with saturated brine (150 mL), dried over magnesium sulfate, filtered, and evaporated to leave an orange solid. This solid is crystallized from hot ethyl acetate to give the title compound as orange crystals; mp 213°-216° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:16])[C:5]([CH3:15])=[C:6]2[C:10]=1[C:9](=O)[C:8]([CH3:13])([CH3:12])[C:7]2=O.C1C=CC=CC=1>Cl.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:16])[C:5]([CH3:15])=[C:6]2[C:10]=1[CH2:9][C:8]([CH3:12])([CH3:13])[CH2:7]2
Reactant: Cc1cc(Cl)c2c(c1C)C(=O)C(C)(C)C2=O
Agent: Cl
Solvent: c1ccccc1
Solvent: CCO
Product: Cc1cc(Cl)c2c(c1C)CC(C)(C)C2
Temperature: 25 °C
Yield: 50.2 %

Procedure:
To a mixture of 100 g of 7% Zn/Hg in 200 ml of 20% hydrochloric acid and 70 ml of ethanol was added 38.42 g of the 7-chloro-2,2,4,5-tetramethylindan-1,3-dione with stirring. After refluxing for 6 hours, the reaction mixture was added 100 ml of benzene and refluxed for 1 hour. The reaction mixture was cooled to room temperature and extracted with diethyl ether. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 17.0 g of the title compound as yellow oil.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH2:21])=[CH:17][CH:16]=1>O>[F:13][C:14]([F:24])([F:25])[C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH:21][C:2]2[N:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: NOCc1ccc(C(F)(F)F)cc1
Solvent: O
Product: CCOC(=O)c1cccnc1NOCc1ccc(C(F)(F)F)cc1
Temperature: 120 °C
Yield: 41 %

Procedure:
The mixture of ethyl 2-chloronicotinate (1.4 g, 7.54 mmol) and O-(4-(trifluoromethyl)benzyl)hydroxylamine (2.163 g, 11.31 mmol) was heated at 120° C. for 6 h. Reaction mixture was diluted with water and extracted with EtOAC. The organic layer was separated and distilled out to get crude product which was column purified using 15-20% EtOAc in hexane to get the titled compound in 41% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[CH2:10]([O:12][C:13](=[O:21])[C:14]#[C:15][C:16](OCC)=[O:17])[CH3:11]>CO>[CH2:10]([O:12][C:13]([C:14]1[CH:15]=[C:16]([OH:17])[C:7]2[C:5](=[CH:4][C:3]([CH3:9])=[C:2]([Cl:1])[CH:8]=2)[N:6]=1)=[O:21])[CH3:11]
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: Cc1cc(N)ccc1Cl
Solvent: CO
Product: CCOC(=O)c1cc(O)c2cc(Cl)c(C)cc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.5 g of 4-chloro-3-methylaniline in 30 ml of methanol, 4.2 g of but-2-ynedioic acid diethyl ester were added dropwise over 30 min at 0° C. and stirred for 3 h at RT. Then, the solvents were removed under reduced pressure and the residue was dissolved in 70 ml of Dowtherm® and heated to 250° C. for 2 h. Then, the reaction mixture was allowed to cool to RT and 300 ml of n-heptane were added to precipitate the crude product, which was collected by filtration. The title compound was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.1 g.
Reaction SMILES: C(OC(=O)[N:7]([C:14]1[S:18][C:17]([Cl:19])=[N:16][C:15]=1[Cl:20])[C:8](=[O:13])[CH2:9][CH2:10][S:11][CH3:12])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:19][C:17]1[S:18][C:14]([NH:7][C:8](=[O:13])[CH2:9][CH2:10][S:11][CH3:12])=[C:15]([Cl:20])[N:16]=1
Reactant: CSCCC(=O)N(C(=O)OC(C)(C)C)c1sc(Cl)nc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCCC(=O)Nc1sc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
To a solution of (2,4-dichloro-thiazol-5-yl)-(3-methylsulfanyl-propionyl)-carbamic acid tert-butyl ester (1.10 g, 2.97 mmol) in DCM (10 mL) was added trifluoroacetic acid (3.4 g, 2.2 mL, 30 mmol). The solution was stirred at room temperature for 15 minutes, before it was quenched slowly with saturated NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with 20 mL DCM. The combined organic layer was dried over Na2SO4 and purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give product as a white solid (612 mg, 76%): 1H NMR (300 MHz, CDCl3) δ 8.79 (s, 1H), 2.90 (t, J=7.2 Hz, 2H), 2.79 (t, J=7.2 Hz, 2H), 2.29 (s, 3H); ESIMS m/z 271.0 (M+1).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20].C(O)(=O)C.[BH3-]C#N.[Na+]>CO.O>[CH3:15][C:16]1[CH:17]=[C:18]([CH2:19][NH:20][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1cccc(CN)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cccc(CNC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of commercially available tert-butyl 4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 3-methylbenzylamine (0.125 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl ether (20 ml), extracted with HCl (0.1 N, 1×15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-((3-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 136 mg. To a solution of tert-butyl 4-((3-methylphenyl)methyl)amino-piperidine carboxylate (50 mg, 0.16 mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and water (10 ml), dried (Na2SO4), filtered and concentrated to give N-((3-methylphenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide. The crude product was used without any further purification. N-((3-Methylphenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2×15 ml), dried (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 48 mg; 13C-NMR (CD3OD, rotamers): δ 20.4, 26.8, 28.3, 40.2, 43.9, 44.1, 44.5, 51.8, 54.2, 54.57, 54.61, 114.0, 114.1, 123.2, 123.7, 126.7, 127.0, 127.1, 127.3, 128.0, 128.1, 128.7, 129.8, 129.9, 137.9, 138.6, 138.9, 159.0, 159.1, 173.1, 173.7.