Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:41])([CH3:40])[CH2:3][CH2:4][NH:5][C:6](=[O:39])[CH2:7][CH2:8][CH:9]([CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[C:10]([C:31]#[N:32])=[CH:11][C:12]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([O:25][CH2:26][CH3:27])=[CH:14][C:13]=1[N+:28]([O-])=O.[NH4+].[Cl-:43].Cl>CO.[Zn]>[ClH:43].[NH2:32][C:31]1[C:10]([CH:9]([CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH2:8][CH2:7][C:6]([NH:5][CH2:4][CH2:3][C:2]([CH3:41])([CH3:40])[CH3:1])=[O:39])=[CH:11][C:12]2[C:13](=[CH:14][C:15]([O:25][CH2:26][CH3:27])=[C:16]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)[N:28]=1
Reactant: CCOc1cc([N+](=O)[O-])c(C=C(C#N)C(CCC(=O)NCCC(C)(C)C)C2CCOCC2)cc1Oc1ccccc1
Reactant: [Cl-]
Agent: Cl
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CCOc1cc2nc(N)c(C(CCC(=O)NCCC(C)(C)C)C3CCOCC3)cc2cc1Oc1ccccc1

Procedure:
To a solution of 5-cyano-6-(4-ethoxy-2-nitro-5-phenoxy-phenyl)-4-(tetrahydro-pyran-4-yl)-hex-5-enoic acid (3,3-dimethyl-butyl)-amide (160 mg, 0.28 mmol) in methanol was added Zn (0.4 g) and NH4Cl (0.10 g). The resulting mixture was treated under μW at 95° C. for 20 min, filtered through Celite® and concentrated. The resulting crude product was purified by chromatography (silica gel, 0-2% methanol in methylene chloride) to yield a white solid that was converted to the HCl salt of the title compound by reacting with 1M HCl in diethyl ether.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][NH:13][CH3:14])=[CH:10][C:5]=2[S:4](=[O:15])[CH2:3]1.[Cl:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:13]([CH3:14])[CH2:18][CH2:17][Cl:16])=[CH:10][C:5]=2[S:4](=[O:15])[CH2:3]1
Reactant: ClCCBr
Reactant: CNCCc1ccc2c(c1)S(=O)CN2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CN(CCCl)CCc1ccc2c(c1)S(=O)CN2C
Temperature: 60 °C
Reaction time: 48 h

Procedure:
In a ground-necked flask, 6 mmol of 3-methyl-6-(2-(N-methylamino)ethyl]benzothiazolinone are dissolved in 50 ml of dioxane, 20 mmol of 1-chloro-2-bromoethane and 20 mmol of potassium carbonate. The mixture is stirred for 48 hours at a temperature of 60° C. After cooling, the mixture is evaporated and the reaction medium is extracted with chloroform after adding water. After washing, drying and evaporation of the organic phase, 3 -methyl-6-{2-[N-methyl-N-(2-chloroethyl) amino]ethyl}benzothiazolinone is obtained, which product is transferred to a ground-necked flask. A catalytic amount of potassium iodide, 25 cm3 of methanol and 10 cm3 of chloroform are added. A stream of gaseous ammonia is bubbled into the solution to the point of saturation and a reflux condenser is then fitted. The temperature is stabilized at 50° C. with an oil bath and the mixture is then left stirring magnetically for 72 hours. After cooling, the reaction mixture is evaporated on a water bath under vacuum. The residue is ground with distilled water acidified with 5% HCl solution, and then drained. The filtrate is recovered, washed with ethyl acetate and then alkalinized with 10% sodium hydroxide solution. It is extracted with chloroform, leaving the 2 phases agitating for 1/2 hour, and the organic phase is washed with distilled water and then dried over calcium chloride. The organic phase is evaporated on a water bath under vacuum, the residue is then taken up in absolute ethanol, a stream of gaseous HCl is bubbled through and the mixture is then evaporated to dryness on a water bath under vacuum. The product is dried and then recrystallized.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10](OC)[CH:9]=[CH:8][C:3]=1[C:4](OC)=O.[C:14]1([CH3:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N#N>CCN(CC)CC.CCOC(C)=O.[Cu]I.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>[C:3]1([C:4]#[C:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:2]=1
Reactant: Cc1ccccc1
Reactant: COC(=O)c1ccc(OC)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Compound 11 (106 mg, 0.43 mmol) and copper (I) iodide (1.6 mg, 2 mol %) were added to an oven-dried reaction flask containing toluene (2 mL) and Et3N (2 mL). The reaction mixture was stirred at room temperature for 5 min with N2 (g) bubbling. Bis(triphenylphosphine)palladium(II) dichloride (3 mg, 1 mol %) and a solution of compound 8 (63 mg, 0.43 mmol) in Et3N (1 mL) were added. The reaction mixture was stirred at 100° C. for 24 h. The reaction was cooled to room temperature, then diluted with EtOAc (50 mL) and washed with brine (3×20 mL). The organic layer was collected, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (20% EtOAc in hexanes) to afford compound 12 in 62.8% (84 mg) yield as a brown solid. 1H-NMR (CDCl3, 400 MHz) δ 8.00 (1H, d, J=8.4 Hz, Ar), 7.14 (1H, s, Ar), 6.93 (1H, d, J=1.6 Hz, Ar), 6.88 (1H, dd, J=8.4 Hz, 1.6 Hz, Ar), 6.81 (1H, dd, J=8.4 Hz, 1.6 Hz, Ar), 6.68 (1H, d, J=8.4 Hz, Ar), 4.79 (2H, s, NH2), 3.89 (6H, s, 2×OCH3), 3.76 (3H, s, OCH3); 13C-NMR (CDCl3, 100 MHz) δ 165.9, 162.3, 151.4, 144.5, 132.8, 126.6, 122.9, 118.5, 117.9, 115.8, 115.6, 114.4, 107.6, 93.9, 92.6, 56.0, 55.7, 52.2; MS (ESI) m/z Calcd for C18H17NO4 (M+): 311.1, Found: 312.0 (M+H+).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:11]([C:12](=[S:14])[NH2:13])[N:10]=[C:9]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[S:8]1)=[N+:2]=[N-:3].Br[CH:30]1[C:35](=O)[CH2:34][CH2:33][N:32]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:31]1.CCN(C(C)C)C(C)C>C(O)C>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:11]([C:12]2[S:14][C:30]3[CH2:31][N:32]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:34][C:35]=3[N:13]=2)[N:10]=[C:9]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[S:8]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(N)=S
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCCN=[N+]=[N-])c3ccccc3)sc2C1
Reaction time: 8 h

Procedure:
To a solution of 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothioamide (0.300 g, 0.717 mmol) in 10 mL of ethanol was added tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (0.239 g, 0.860 mmol) followed by DIEA (0.25 mL, 1.43 mmol). The mixture was allowed to stir overnight at reflux, then treated with tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (100 mg) and stirred at reflux for a further 3 hours. The cooled mixture was partitioned between a saturated NaHCO3 solution (30 mL) and EtOAc (30 mL), and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (5-10% ethyl acetate/hexanes) to afford the desired product as a bright yellow foam, 0.313 g, 73%.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:6][N:5]([C:7](=[N:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21]C(=O)C)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[NH:8][CH2:9][CH3:10])[N:4]=[CH:3]1.Cl.[OH-].[Na+]>CO>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([N:11]=[C:7]([N:5]2[CH2:6][C:2]([CH3:1])([CH3:25])[CH:3]=[N:4]2)[NH:8][CH2:9][CH3:10])(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: CCNC(=NS(=O)(=O)c1ccc(NC(C)=O)cc1)N1CC(C)(C)C=N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCNC(=NS(=O)(=O)c1ccc(N)cc1)N1CC(C)(C)C=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
900 mg N-(4-{[(4,4-Dimethyl-4,5-dihydro-pyrazol-1-yl)-ethylamino-methylene]-sulfamoyl}-phenyl) acetamide was dissolved in 5 mL MeOH, and 5 mL of concentrated HCl was added. The mixture was stirred overnight at room temperature. The mixture was basified with 2M NaOH, and extracted twice with DCM. The combined organic layers were dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (DCM/MeOH 99:1) to give 400 mg (50%) of 4-Amino-N-[(4,4-dimethyl-4,5-dihydro-pyrazol-1-yl)-ethylamino-methylene]-benzenesulfonamide as an amorphous solid. 1H NMR (400 MHz, CDCl3) δ 1.15 (t, J=7 Hz, 3H), 1.20 (s, 6H), 3.42-3.51 (m, 2H), 3.74 (br.s., 2H), 4.00 (br.s., 2H), 6.62-6.68 (m, 2H), 6.71 (s, 1H), 6.90 (br.s., 1H), 7.67-7.73 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH3:9].[CH3:41][NH:42][CH2:43]C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:41][N:42]([CH3:43])[CH2:2][CH2:9][CH2:8][N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:37])=[O:38])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11]
Reactant: CCNC
Reactant: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)CCCN(C)C)c4)cc23)CC1
Yield: 31.8 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting [3-(dimethylamino)propyl]methylamine (116 mg, 1.0 mmol) for N-methylethanamine to afford 21.0 mg of the title compound (31.8%).
Reaction SMILES: [CH:1]([C:3]([C:6]1[N:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1)=[CH:4]O)=O.[CH3:15][NH:16][NH2:17]>C(O)C>[CH3:15][N:16]1[CH:4]=[C:3]([C:6]2[N:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][CH:7]=2)[CH:1]=[N:17]1
Reactant: CNN
Reactant: O=CC(=CO)c1ccc(C(=O)O)cn1
Solvent: CCO
Product: Cn1cc(-c2ccc(C(=O)O)cn2)cn1
Yield: 64 %

Procedure:
A suspension of 6-(1-formyl-2-hydroxyvinyl)pyridine-3-carboxylic acid (1.93 g) Eastman Chemicals) in absolute ethanol (50 ml) and methylhydrazine (0.50 g) was stirred for 18 hours at room temperature. The reaction mixture was filtered to give the product (1.30 g). The filtrate was evaporated to give a solid which was recrystallized from ethyl acetate to give an analytical sample of the title compound (0.55 g), m.p. 262-264° C.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([S:15][CH3:16])[C:5]=1[O:17][CH3:18]>O.C(O)C>[Br:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([OH:10])=[O:9])=[C:6]([S:15][CH3:16])[C:5]=1[O:17][CH3:18]
Reactant: CCOC(=O)c1ccc(Br)c(OC)c1SC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1c(Br)ccc(C(=O)O)c1SC

Procedure:
A solution of potassium hydroxide (2.0 g) in water was added to a solution of ethyl 4-bromo-3-methoxy-2-(methylsulphenyl)-benzoate (4.5 g) in ethanol. The resulting solution was stirred and heated at reflux for 3 hours. After cooling, the mixture was evaporated to dryness and the residue was dissolved in water and washed with ethyl acetate. The aqueous solution was acidified to pH 1 and extracted with ethyl acetate, dried (anhydrous MgSO4) and filtered. The filtrate was evaporated to dryness to give 4-bromo-3-methoxy-2-(methylsulphenyl)benzoic acid as a white solid, NMR (CDCl3) 2.5(s,3H), 3.9(s,3H), 7.4(s,2H), 10.9(bs, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[O:15][N:14]=[C:13]([CH2:16][S:17][C:18]3[NH:19][C:20]4[C:21]([N:26]=3)=[N:22][CH:23]=[CH:24][CH:25]=4)[N:12]=2)[CH:8]=[CH:9][CH:10]=1.[CH3:27]I>C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[O:15][N:14]=[C:13]([CH2:16][S:17][C:18]3[N:19]([CH3:27])[C:20]4[C:21]([N:26]=3)=[N:22][CH:23]=[CH:24][CH:25]=4)[N:12]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc(-c2nc(CSc3nc4ncccc4[nH]3)no2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(-c2nc(CSc3nc4ncccc4n3C)no2)c1
Temperature: 1 °C
Reaction time: 0.25 h

Procedure:
THF (3 ml) was added to a mixture of sodium hydride (60%, 8 mg, 0.2 mmol) and 2-[5-(3-methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-imidazo[4,5-b]pyridine (24.6 mg, 0.072 mmol) and the resulting mixture was stirred at 1° C. for about 15 min. Methyl iodide (20 μL, 0.32 mmol) was added the resulting mixture was stirred at 0° C. for 2 h. The reaction was quenched by the addition of dichloromethane (10 ml) and water (2 ml). After vigorous stirring, the organic extracts (10 ml, plus 3×5 ml) were eluted through a Chem Elut Extraction Column (Varian, cat #1219-8002). Purification using SPE chromatography (5 g silica) using 25/25/50 to 50/25/25 ethyl acetate/dichloromethane/hexane yielded two products. The first product to elute was 2-{1-[5-(3-methoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-1-methyl-1H-imidazo[4,5-b]pyridine (6 mg, 23%). 1H NMR (CDCl3), δ (ppm): 8.46 (d, 1H), 7.72 (d, 1H), 7.62 (d, 1H), 7.55 (d, 1H), 7.42 (t, 1H), (m, 2H), 5.67 (q, 1H), 3.88 (s, 3H), 3.71 (s, 3H), 2.01 (d, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.Cl[C:13]1[CH:23]=[C:17]2[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=1>>[CH3:22][N:18]1[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=[C:13]([O:1][CH2:2][CH2:3][C:4]3[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=3)[CH:23]=[C:17]12
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: N#Cc1ccc(CCO)cc1
Product: CN1CCCn2c1cc(OCCc1ccc(C#N)cc1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E11 starting from of 4-(2-hydroxyethyl)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [F:1][C:2]([F:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.C1C(=O)[N:21](Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]([F:16])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][NH2:21])=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(F)(F)c2ccccc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: NCc1ccc(C(F)(F)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
Combine 4-(difluoro-phenyl-methyl)-toluene (0.29 g, 1.35 mmol, prepared by following the procedure described in Tetrahedron 1996, 52, 9), NBS (0.26 g, 1.48 mmol), and AIBN (6 mg, 0.03 mmol) in carbon tetrachloride (8 mL) and heat at 80° C. for 16 h. Evaporate the mixture and pass the residue through a pad of silica gel washing with hexane and evaporate the filtrate. Dissolve the residue in methanol and add dropwise to 7M ammonia in methanol (100 mL) at 0° C. After 4.5 h, evaporate the mixture and isolate the amine by SCX chromatography (0.1 g, 32%). MS (ES+) m/z: 234 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16]CO)=[CH:9][CH:8]=1)[CH3:6])=[O:4].[C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31]CCC#C)(=[O:23])[CH3:22]>>[C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][CH2:16][CH2:15][C:14]#[C:13][C:10]1[CH:9]=[CH:8][C:7]([N:5]([CH3:6])[C:3](=[O:4])[C:2]([F:1])([F:19])[F:20])=[CH:12][CH:11]=1)(=[O:23])[CH3:22]
Reactant: CN(C(=O)C(F)(F)F)c1ccc(C#CCCCO)cc1
Reactant: C#CCCOCCCCCCOC(C)=O
Product: CC(=O)OCCCCCCOCCC#Cc1ccc(N(C)C(=O)C(F)(F)F)cc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 36, using Intermediate 26 in place of Intermediate 33. ES/MS calcd. for C21H27F3NO4+ 414.2. Found m/z=414.3 (M+H)+.
Reaction SMILES: [C:1]1(=[O:17])[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Br:18]Br>C(Cl)(Cl)Cl>[Br:18][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=2)[C:1]1=[O:17]
Reactant: COC(=O)COc1ccc2c(c1)CCCC2=O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COC(=O)COc1ccc2c(c1)CCC(Br)C2=O
Reaction time: 4 h

Procedure:
To a solution of the product from step (ii) (1.3 g) in chloroform (15 ml) was added dropwise a solution of bromine (0.29 ml) in chloroform (1 ml) and the resulting mixture was stirred for 4 hours. The solvent was evaporated to give an oil. Purification by flash column chromatography on silica, eluting with ethyl acetate/hexane (30:70 v/v) gave methyl 2-bromotetralone-6-oxyacetate (1.55 g) as an oil: NMR (d6DMSO) δ 2.3-2.6(m,2H), 2.9-3.1(m,2H), 3.7(s,3H), 4.9(s,2H), 4.9-5.0(m,1H), 6.9-7.0(m,2H), 7.9(d,1H); m/e 313/315(M+H)+ Br pattern.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH:29]([CH3:31])[CH3:30])=[O:24])[C:5]1=[O:32].C(N(C(C)C)CC)(C)C.Cl[C:43]([O:45][CH3:46])=[O:44]>CN(C=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH:29]([CH3:30])[CH3:31])=[O:24])[C:5](=[O:32])[N:4]3[CH2:3][CH2:2][NH:1][C:43](=[O:44])[O:45][CH3:46])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)Cl
Reactant: CC(C)OCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN)c1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NCCn1c(=O)c(C(=O)NCCOC(C)C)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-{2-[(1-methylethyl)oxy]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.020 g, 0.045 mmol) and diisopropyl ethylamine (0.04 mL, 0.23 mmol) in DMF (5 mL) under nitrogen was treated with methyl chloroformate (0.0036 mL, 0.047 mmol) at ambient temperature. The reaction was concentrated in vacuo and the resulting residue was treated with 1N NaHSO4. The resulting suspension was filtered, washed with EtOH and Et2O, and dried in vacuo to provide the title compound as an beige solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.12 (d, J=6.18 Hz, 6 H), 3.22-3.31 (m, 2 H), 3.45 (s, 3 H), 3.49-3.56 (m, 4 H), 3.61 (dt, J=12.07, 6.04 Hz, 1 H), 4.14 (s, 2 H), 4.29 (t, J=6.32 Hz, 2 H), 7.11-7.19 (m, 2 H), 7.26 (t, J=5.62 Hz, 1 H), 7.39 (dd, J=8.56, 5.48 Hz, 2 H), 8.12 (s, 1 H), 8.53 (s, 1 H), 10.38 (t, J=5.48 Hz, 1 H), 17.12 (s, 1 H); ES+ MS: 501 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9]2)=[CH:4][CH:3]=1.O=[C:24]([CH3:38])[CH2:25][CH2:26][N:27]1C(=O)C2C(=CC=CC=2)C1=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:17]3[CH2:22][CH2:21][N:20]([CH:24]([CH3:38])[CH2:25][CH2:26][NH2:27])[CH2:19][CH2:18]3)[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: Brc1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Product: CC(CCN)N1CCC(C2(c3ccc(Br)cc3)Oc3ccccc3O2)CC1
Yield: 59.3 %

Procedure:
Using general procedure B with the above amine (400 mg, 1.11 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (482 mg, 2.22 mmol) and then using general procedure D gave 3-{4-[2-(4-bromophenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine (284 mg, 59% over 2 steps) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH:16]3[CH2:18][O:17]3)[O:14][CH2:13][CH2:12][N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:26][S-:27].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH:16]([OH:17])[CH2:18][S:27][CH3:26])[O:14][CH2:13][CH2:12][N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[S-]
Reactant: CC(C)(C)OC(=O)N1CCOC(C2CO2)C(c2ccc(Cl)c(Cl)c2)C1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCC(O)C1OCCN(C(=O)OC(C)(C)C)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.5 %

Procedure:
To a solution of a mixture (420 mg) of tert-butyl (6RS,7RS)-6-(3,4-dichlorophenyl)-7-[(2RS)-oxiran-2-yl]-1,4-oxazepane-4-carboxylate and tert-butyl (6SR,7SR)-6-(3,4-dichlorophenyl)-7-[(2RS)-oxiran-2-yl]-1,4-oxazepane-4-carboxylate in DMF (2 mL) was added sodium thiomethoxide (114 mg), and the mixture was stirred at room temperature for 10 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous potassium carbonate and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (0%-50%)) to give the title compound (130 mg) in a less polar fraction as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.[NH2:30]C1C=C2C(=CC=1)C(O)=CC=C2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[NH2:30][C:26]1[CH:25]=[C:24]2[C:29](=[CH:28][CH:27]=1)[C:20]([O:19][CH2:18][CH2:17][CH2:16][C:7]1[C:6]3[C:10](=[C:2]([Br:1])[CH:3]=[CH:4][CH:5]=3)[NH:9][C:8]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:21][CH:22]=[CH:23]2
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCOc1cccc2ccccc12
Reactant: Nc1ccc2c(O)cccc2c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCOc1cccc2cc(N)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of ethyl 7-bromo-3-(3-hydroxypropyl)-1H-indole-2-carboxylate (EXAMPLE 1C) (100 mg), 6-aminonaphthalen-1-ol (98 mg) and triphenylphosphine, polymer supported (204 mg 0.613 mmol) in tetrahydrofuran (4 ml) was added di-tert-butyl diazene-1,2-dicarboxylate (141 mg). The reaction mixture was stirred at room temperature for 3 hours. The insoluble material was filtered off and the filtrate was concentrated. The residue was purified by flash chromatography (ethyl acetate in hexanes) to provide the title compound.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]([C:11]1[N:12](S(C)(=O)=O)[C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([C:20]#[N:21])=[C:15]([C:22]([F:25])([F:24])[F:23])[CH:14]=2)([OH:10])[CH3:9])(C)(C)C.[OH-].[Na+].Cl>CO.O>[OH:10][C:8]([C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([C:20]#[N:21])=[C:15]([C:22]([F:25])([F:23])[F:24])[CH:14]=2)([CH3:9])[CH2:7][OH:6]
Reactant: CC(O)(CO[Si](C)(C)C(C)(C)C)c1cc2cc(C#N)c(C(F)(F)F)cc2n1S(C)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(O)(CO)c1cc2cc(C#N)c(C(F)(F)F)cc2[nH]1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-[2-(tert-butyl-dimethyl-silanyloxy)-1-hydroxy-1-methyl-ethyl]-1-methanesulfonyl-6-trifluoromethyl-1H-indole-5-carbonitrile (9.22 g, 0.01935 mole) in methanol (150 mL), a solution of NaOH (4.64 g 0.1161 mole) in water (25 mL) was added. The resulting mixture was heated in an oil-bath at 50° C. for 4 hr and then stirred at room temperature overnight. To the reaction mixture was then added 1 N HCl until the pH was 3. The aqueous mixture was extracted with EtOAc, the organic layer was washed with water, brine, then dried over MgSO4. The solvent was stripped off, the residue was triturated with DCM, and the resulting solid collected by filtration to yield the title compound as a light grey solid.