Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:20]([CH3:21])[CH2:19][CH2:18][C@@:14]4([C:15]=2[C:16]=1[OH:17])[C@@:9]3([O:24][CH3:25])[C@H:10]([CH3:23])[CH2:11][C:12](=[O:22])[CH2:13]4.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:20]([CH3:21])[CH2:19][CH2:18][C@@:14]4([C:15]=2[C:16]=1[O:17][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@@:9]3([O:24][CH3:25])[C@H:10]([CH3:23])[CH2:11][C:12](=[O:22])[CH2:13]4
Reactant: COc1ccc2c(c1O)[C@]13CCN(C)[C@H](C2)[C@]1(OC)[C@H](C)CC(=O)C3
Reactant: Brc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: COc1ccc2c(c1Oc1ccccc1)[C@]13CCN(C)[C@H](C2)[C@]1(OC)[C@H](C)CC(=O)C3

Procedure:
To a solution of 3,14-dimethoxy-[α,17-dimethyl-4-hydroxymorphinan-6-one (21) (0.4 g, 1.159 mmol) in dry pyridine (1 ml) was added bromobenzene (0.205 g, 1.35 mmol) and 0.216 g (1.565 mmol) of K2CO3 (freshly dried at 110° C. for 2 hours in a vacuum oven and quickly ground and sieved to 200 mesh). More pyridine (0.5 ml) followed by copper powder (20 mg, 10 micron) was added and the mixture was refluxed (oil bath temperature 130°-140°) for 24 hours under a nitrogen atmosphere with stirring. The mixture was filtered while hot and the residue was washed with hot pyridine (2 ml). After adding 10 ml of toluene, the solution was concentrated under reduced pressure to give (22) as a foamy solid. Thin layer chromatography on a silica gel plate (solvent system: CHCl3 :MeOH, 80:20) showed a single spot. The compound was quickly chromatographed on a silica gel column and eluted with graded methanol/chloroform mixtures to give 0.45 g (92% theory) of 3,14-dimethoxy-8α,17-dimethyl-4-phenoxymorphinan-6-one (22) as a foamy solid.
Reaction SMILES: C([O:8][C:9](=O)[NH:10][C:11]1[CH:20]=[CH:19][C:14]2[O:15][CH2:16][CH2:17][O:18][C:13]=2[CH:12]=1)C1C=CC=CC=1.[C:22]([Si:26]([CH3:36])([CH3:35])[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]1[CH2:34][O:33]1)([CH3:25])([CH3:24])[CH3:23].C(O[Li])(C)(C)C.C1COCC1.Cl>CN(C=O)C>[C:22]([Si:26]([CH3:35])([CH3:36])[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]1[O:33][C:9](=[O:8])[N:10]([C:11]2[CH:20]=[CH:19][C:14]3[O:15][CH2:16][CH2:17][O:18][C:13]=3[CH:12]=2)[CH2:34]1)([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OCCCCC1CO1
Reactant: O=C(Nc1ccc2c(c1)OCCO2)OCc1ccccc1
Agent: Cl
Agent: [Li]OC(C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCC1CN(c2ccc3c(c2)OCCO3)C(=O)O1
Temperature: 25 °C
Reaction time: 22 h
Yield: 82.1 %

Procedure:
A solution of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-carbamic acid benzyl ester (0.75 g, 2.6 mmol) and rac-tert-butyl-dimethyl-(4-oxiranyl-butoxy)-silane (prepared according to Angew. Chem. (2007), 46, 5896; 0.91 g, 1.5 eq.) in DMF (8 mL) at 0° C. was treated with a 2.2M solution of t-BuOLi in THF (3.6 mL, 3 eq.). The mixture was stirred at rt for 22 h. HCl 1M (5.3 mL) was added and the mixture partitioned between EA and water. The org. phase was washed with water and brine, dried over MgSO4 and concentrated. The product was purified by FC (Hex/EA 1:1, 1:2) to give the title intermediate as a yellowish oil (0.87 g, 81% yield).
Reaction SMILES: [CH2:1]([O:3]C(=O)C=C(C)C=CCC(C)CCCC(C)(OCC#C)C)C.[CH3:24][CH:25]([CH2:33][CH:34]=[O:35])[CH2:26][CH2:27][CH2:28][C:29]([OH:32])([CH3:31])[CH3:30].[CH3:36]OC(O)O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(=O)C.[Na+]>CO>[CH3:36][O:35][CH:34]([O:3][CH3:1])[CH2:33][CH:25]([CH3:24])[CH2:26][CH2:27][CH2:28][C:29]([CH3:31])([OH:32])[CH3:30]
Reactant: C#CCOC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OCC
Reactant: COC(O)O
Reactant: CC(CC=O)CCCC(C)(C)O
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CO
Product: COC(CC(C)CCCC(C)(C)O)OC
Reaction time: 2 h

Procedure:
The starting material of Example 1 can be prepared as follows: 172.2 g. of hydroxycitronellal and 106.1 g. of orthoformic acid methyl ester are treated dropwise, while cooling with ice, with a solution of 0.5 g. of p-toluenesulphonic acid in 800 ml. of absolute methanol. After 2 hours, 5 g. of sodium acetate are added and the mixture is concentrated on a rotary evaporator at 50°C. Upon distillation, the residue yields pure 1,1-dimethoxy-3,7-dimethyl-7-octanol; boiling point = 102°C/0.4 mmHg; nD22 = 1.4400.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:31]=[CH:30][C:10]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][C:19]([C:25]([O:27]C)=[O:26])=[CH:18][C:17]=3[CH:29]=2)=[CH:9][CH:8]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][C:19]([C:25]([OH:27])=[O:26])=[CH:18][C:17]=3[CH:29]=2)=[CH:30][CH:31]=1)[CH3:2]
Reactant: CCOCCOc1ccc(COc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOCCOc1ccc(COc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 37.6 %

Procedure:
Into a solution of methyl 7-[[4-(2-ethoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.59 g) in THF-methanol (10-5 ml) was added at room temperature a 1 M aqueous solution of potassium carbonate (2.6 ml), and the resulting mixture was stirred at 65° C. for 24 hours. Into this reaction mixture was added further a 1 M aqueous solution of potassium carbonate (1.3 ml), and the resulting mixture was stirred at 65° C. for 16 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. To the aqueous layer was added 1 N hydrochloric acid (10 ml), and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-[[4-(2-ethoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (215 mg) as light yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[N:4][C:5]([S:8][CH2:9][CH3:10])=[CH:6][CH:7]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:12][S:13]([O:11][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[C:5]([S:8][CH2:9][CH3:10])[N:4]=1)(=[O:15])=[O:14]
Reactant: CCSc1ccc(Cl)c(O)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCSc1ccc(Cl)c(OS(C)(=O)=O)n1
Temperature: 40 °C
Yield: 93.5 %

Procedure:
5 g of 3-chloro-6-ethylthio-2-pyridinol and 3.7 g of methanesulfonyl chloride were dissolved in 50 ml of methylene chloride, followed by stirring. 4 g of triethylamine was added dropwise to the solution at 10° C. or below and the obtained mixture was allowed to stand to lower the temperature to room temperature. The mixture was heated to 40° C. and stirred for 2 hours. 50 ml of chilled water was poured into the reaction mixture to separate the methylene chloride layer. The water layer was further extracted with 50 ml of methylene chloride. The obtained methylene chloride layer was combined with the above methylene chloride layer. The combined layer was washed with water and distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography (with toluene and n-hexane) to obtain 6.6 g of objective 3-chloro-6-ethylthio-2-pyridyl methanesulfonate as a colorless crystal (yield: 93.4%). m.p. 40° to 41° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Cl[C:21]1[N:26]=[C:25]([CH3:27])[N:24]([CH2:28][CH3:29])[C:23](=[O:30])[C:22]=1[CH3:31].O>O1CCOCC1>[CH3:27][C:25]1[N:24]([CH2:28][CH3:29])[C:23](=[O:30])[C:22]([CH3:31])=[C:21]([O:15][CH2:14][C:13]2[CH:16]=[CH:17][C:10]([O:9][CH2:8][C:7]3[CH:18]=[CH:19][C:4]([F:3])=[CH:5][CH:6]=3)=[CH:11][CH:12]=2)[N:26]=1
Reactant: CCn1c(C)nc(Cl)c(C)c1=O
Reactant: OCc1ccc(OCc2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCn1c(C)nc(OCc2ccc(OCc3ccc(F)cc3)cc2)c(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
Sodium hydride (55% in mineral oil) (0.23 g) was suspended in 10 ml of dioxane, and then 1.24 g of 4-(4'-fluorobenzyloxy)benzyl alcohol was added thereto. The resulting mixture was stirred for one hour at room temperature, then incorporated with 1.00 g of 6-chloro-2,5-dimethyl-3-ethyl-4(3H)-pyrimidinone and stirred for 15 hours. The resulting solution was poured into water, and the resulting crystals were filtered off and recrystallized from a benzene-hexane mixture to give 1.83 g of the intended product.
Reaction SMILES: OC[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.[C:12]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[OH:38].C(OC(N=NC(OCC)=O)=O)C>O1CCCC1>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:12])[NH:7]2
Reactant: OCc1cccc2[nH]ccc12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Oc1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: Cc1cc2c(Oc3ccccc3Cl)cccc2[nH]1

Procedure:
A solution of 4-hydroxymethylindole (1.0 g) in tetrahydrofuran (10 ml) is instilled in a solution of triphenylphosphine (2.92 g), 2-chlorophenol (1.43 g) and azodicarboxylic acid diethyl ester (1.49 g) in tetrahydrofuran (50 ml). After a three-hour stirring of the reaction mixture, it is worked up in the usual way and the crude product is chromatographed, melting point 138°-140° C. (cyclohexane).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>CN(C)C(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:5]#[N:6]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: C1CNCCN1
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1ccc(N2CCNCC2)c(F)c1
Temperature: 120 °C
Yield: 95.4 %

Procedure:
3,4-Difluorobenzonitrile (2.0 g, 14.3 mmol) and piperazine (6.19 g, 71.8 mmol) were dissolved in N,N-dimethylacetamide (10 mL) and the solution was heated to 120° C. for 1.5 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined extracts were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to get 3-fluoro-4-(piperazin-1-yl)benzonitrile (2.8 g, yield 95%), which was carried through without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.69-7.65 (dd, J=13.6 Hz, 2.0 Hz, 1H), 7.56-7.53 (dd, J=8.5 Hz, 1.8 Hz, 1H), 7.12-7.07 (d, J=8.7 Hz, 1H), 3.08-3.05 (m, 4H), 2.83-2.80 (m, 4H). MS (ESI) m/z: Calculated for C11H12FN3: 205.10. found: 205.9 (M+H)+
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].F[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[CH2:26][CH2:25][CH2:24][N:16]3[C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:9][CH:8]=1>CN(C)C=O>[CH2:3]([S:5][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[CH2:26][CH2:25][CH2:24][N:16]3[C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)[CH3:4]
Reactant: CCS
Reactant: Fc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60%) (0.75 g, 19 mmol) was added to a solution of ethanethiol (2.1 ml, 1.7 g, 28 mmol) in N,N-dimethylformamide (15 ml) at 0° C. under an argon atmosphere. After stirring for 0.5 hours, 2-(4-fluorophenyl)-3-(4-pyridyl) 6,7-dihydro-[5H]-pyrrolo[1,2-a]-imidazole (3.5 g, 12.5 mmol) of Example 2 was added and the resulting solution heated to 95° C. for 6 hours. The cooled reaction mixture was evaporated under reduced pressure and the residue partitioned between IN aqueous sodium hydroxide and dichloromethane. The organic layer was washed successively with water and brine, dried (magnesium sulfate) and concentrated. The residue was chromatographed on silica gel eluting with 25:1 chloroform/methanol. Fractions containing product were combined, the solvent evaporated and the residue recrystallized from ethyl acetate to afford the titled compound; mp. 124-125° C. Anal. Calcd. for C19H19N3S: C,70 99; H, 5.96; N, 13.08; S, 9.97: Found: C, 70.99; H, 5.92; N, 13.07; S, 9.81.
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:20]2[C:21]3=[C:22]4[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][CH:14]=[C:13]4[CH:12]=[CH:11][C:10]3=[CH:9][CH:8]=1.C1COCC1.[Si:28](Cl)([Cl:31])([Cl:30])[Cl:29]>C1COCC1.CCOCC>[Cl:29][Si:28]([Cl:31])([Cl:30])[C:7]1[C:20]2[C:21]3=[C:22]4[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][CH:14]=[C:13]4[CH:12]=[CH:11][C:10]3=[CH:9][CH:8]=1
Reactant: Brc1ccc2ccc3cccc4ccc1c2c34
Reactant: Cl[Si](Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cl[Si](Cl)(Cl)c1ccc2ccc3cccc4ccc1c2c34
Temperature: -60 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
Under a dry nitrogen atmosphere, n-BuLi (10.6 mL, 1.6 M) in hexanes was added drop-wise to a cooled (−60° C.) solution of 1-bromopyrene (5.01 g, 0.018 mol) in THF/Et2O (1:1) (80 mL) and stirred for 2 hours at −60° C. The solution was cooled to −90° C. and a THF solution of SiCl4 (8.66 g, 0.051 mol) (10 mL) was added slowly and stirred for 24 hours at room temperature. The reaction mixture was evaporated to dryness, washed in Et2O (100 mL), and filtered to remove any unreacted 1-bromopyrene and LiBr. The filtrate was collected and evaporated to dryness to give a 48% yield of 1-trichlorosilylpyrene, a yellow powder. 1HNMR (CDCl3, ppm) 8.66 (d, J=9.3 Hz, 1H), 8.59 (d, J=8.1 Hz, 1H), 8.30 (m, 5H), 8.11 (m, 2H). 13C{1H} NMR (CDCl3, ppm) 136.18 (C), 135.85 (C), 133.13 (CH), 132.06 (C), 131.30 (C), 131.22 (CH), 130.31 (CH), 127.96 (CH), 127.67 (CH), 127.61 (CH), 126.65 (CH), 125.61 (C), 125.01 (CH), and 124.39 (C). 29Si{1H} (CDCl3, ppm) −1.64 (s).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)([C:11]3[CH:15]=[CH:14][S:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:21]1([O:27][CH2:28][CH2:29][Br:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[Br-:30].[OH:10][C:9]([C:11]1[CH:15]=[CH:14][S:13][CH:12]=1)([C:16]1[CH:20]=[CH:19][S:18][CH:17]=1)[C:4]12[CH2:7][CH2:8][N+:1]([CH2:29][CH2:28][O:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: BrCCOc1ccccc1
Reactant: OC(c1ccsc1)(c1ccsc1)C12CCN(CC1)CC2
Solvent: CO
Product: OC(c1ccsc1)(c1ccsc1)C12CC[N+](CCOc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 54.3 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct-4-yl(di-3-thienyl)methanol (0.0787 g, 0.258 mmol) and 2-bromoethyl phenyl ether (0.0839 g, 0.417 mmol) in 2 MeOH/3 CHCl3/2 CH3CN (5.0 mL) were reacted to give the desired product (0.0709 g, 54.5%). EI-MS m/z 426(M+) Rt (1.85 min).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][NH:35][CH3:36]>C1COCC1.CCOC(C)=O>[CH3:34][N:35]([CH3:36])[S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:21])=[O:22]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N(C)C)c3)n2)n1
Yield: 54.1 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available dimethylamine (40% in water, 0.52 ml, 4.1 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.110 g, 54%) as a white foam. MS (ISP) 498.3 [(M+H)+]; mp 155° C.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].[Sn](Cl)[Cl:17]>O.Cl>[ClH:17].[Br:15][C:13]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:5][NH2:1])[CH:14]=1
Reactant: Cl[Sn]Cl
Reactant: Nc1cc(Br)ccc1C(=O)O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(Br)ccc1C(=O)O
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 86.2 %

Procedure:
Step 1 A solution of sodium nitrite (2.448 g, 35.5 mmol) in water (12 mL) was added dropwise to a suspension of 2-amino-4-bromobenzoic acid (7.30 g, 33.8 mmol) in concentrated hydrochloric acid (34 mL) at −5° C., at such rate that the temperature did not exceed 0° C. The resulting suspension was stirred at −5° C. for 10 min and was then added dropwise to a rapidly stirred solution of tin (II) chloride (13.46 g, 71.0 mmol) in concentrated hydrochloric acid (10 mL) at −5° C., at such a rate that the temperature did not exceed 0° C. The resulting suspension was warmed to rt and stirred for 1 h. The precipitate was collected by filtration, washed with water, and dried to provide 4-bromo-2-hydrazinylbenzoic acid hydrochloric acid salt as a pale tan solid (7.79 g, 86%). 1H NMR (400 MHz, DMSO-d6) δ 9.14 (br. s., 1H) 7.79 (d, J=8.35 Hz, 1H) 7.34 (d, J=1.76 Hz, 1H) 7.13 (dd, J=8.35, 1.76 Hz, 1H). Mass spectrum m/z 231, 233 (M+H)+.
Reaction SMILES: N#N.[OH:3][CH2:4][C:5]1[O:6][CH:7]=[C:8]([C:10](=[O:12])[CH3:11])[N:9]=1.CCN(CC)CC.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:10]([C:8]1[N:9]=[C:5]([CH2:4][O:3][S:20]([CH3:23])(=[O:22])=[O:21])[O:6][CH:7]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1coc(CO)n1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1coc(COS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(2-hydroxymethyl-oxazol-4-yl)-ethanone (75 mg, 0.53 mmol) in dry CH2Cl2 (5.0 mL) was treated at 0° C. with Et3N (0.10 mL, 0.71 mmol) followed by DMAP (6 mg, 0.05 mmol) and Ms-Cl (0.05 mL, 0.66 mmol). After stirring at 0° C. for 30 min, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. TLC: rf (EA)=0.63. LC-MS-conditions 02: tR=0.64 min; [M+H]+=220.22.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][CH2:18][CH3:19])=[O:5])[CH3:2].[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][CH2:18][CH3:19])=[O:5])[CH3:2]
Reactant: CCCc1cccc2c(Cl)c(C(=O)OCC)cnc12
Reactant: NC1CCCC1
Product: CCCc1cccc2c(NC3CCCC3)c(C(=O)OCC)cnc12

Procedure:
4-Chloro-8-propyl-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.9 mmol) was treated with cyclopentylamine following general procedure B to afford 4-cyclopentylamino-8-propyl-quinoline-3-carboxylic acid ethyl ester (260 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (170 mg) following general procedure E.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:22][CH2:23][CH2:24][SH:25]>FC(F)(F)C(O)=O>[C:7]([S:25][CH2:24][CH2:23][NH2:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCS
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 85 %

Procedure:
Triphenylmethanol (22.9 g, 88 mmol) was added to a solution of 2-aminoethanethiol hydrochloride in trifluroacetic acid (TFA, 40 mL). The resulting solution was stirred at room temperature for about 40 min. The TFA was then removed under reduced pressure and the residue was triturated with diethyl ether. The white precipitate that formed was filtered, partitioned with aqueous NaOH (40 mL, 1N), and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4. The product was obtained as a white solid after solvent evaporation (23.8 g, yield 85%). ESI-MS(m/z): 320 (M+H+). 1H NMR δD (CDCl3): 7.21˜7.43 (m, 15H, phenyl), 2.58 (t, 2H, SCH2), 2.32 (t, 2H, CH2N).
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])[CH:5]([CH3:7])[CH3:6]>CCOCC.O1CCCC1>[CH2:4]([C:8]1[CH:9]=[C:10]([CH:11]([OH:12])[CH3:1])[CH:13]=[CH:14][CH:15]=1)[CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)Cc1cccc(C=O)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)Cc1cccc(C(C)O)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of methylmagnesium bromide in ether (4 ml) was added to a solution of 3-isobutylbenzaldehyde (1.0 g) in tetrahydrofuran (10 ml) at 0° C. After stirred at 0° C. for 30 minutes, the mixture was partitioned between ether and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (30 g) eluting with a mixture of ethyl acetate and hexane (1:10) to give 1-(3-isobutylphenyl)ethanol (1.12 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>>[C:25]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:23])([F:24])[F:22])=[CH:17][CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][CH:3]=1)(=[O:28])[CH2:26][CH3:27]
Reactant: CC(NC(=O)c1cccc(N)n1)c1ccc(OCC(F)(F)F)nc1
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1cccc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)n1
Yield: 18 %

Procedure:
The title compound is prepared in 18% yield (5.1 mg) from 6-amino-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)picolinamide (25 mg, 0.073 mmol, Step-1, single enantiomer) and propionyl chloride (24 mg, 0.26 mmol) by the similar manner in Step-2 of Example-8.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]Br)[C:5]([Br:10])=[CH:4][C:3]=1[CH2:11]Br.[P:13]([O:20][CH2:21][CH3:22])([O:17]CC)[O:14][CH2:15][CH3:16]>>[Br:10][C:5]1([P:13]([O:14][CH2:15][CH3:16])(=[O:17])[O:20][CH2:21][CH3:22])[C:4]([P:13]([O:20][CH2:21][CH3:22])(=[O:17])[O:14][CH2:15][CH3:16])=[C:3]([CH3:11])[C:2]([Br:1])=[CH:7][CH:6]1[CH3:8]
Reactant: CCOP(OCC)OCC
Reactant: BrCc1cc(Br)c(CBr)cc1Br
Product: CCOP(=O)(OCC)C1=C(C)C(Br)=CC(C)C1(Br)P(=O)(OCC)OCC
Temperature: 180 °C
Yield: 82.2 %

Procedure:
The mixture of 2, 5-dibromo-α,α′-dibromo-p-xylene (67) (7.58 g, 0.018 mol) and triethyl phosphite (60 ml) was refluxed at 180° C. overnight. The excess triethyl phosphite was removed under reduced pressure, 60 ml of hexanes was added, and white solid was formed. The solid was collected by filtration, washed three times with 20 ml of hexanes and gave 7.93 g (82.2%) of product.1H NMR (CDCl3, 500 MHz) δppm: 7.62 (s, 2H, Ar—H), 4.06 (m, 8H, CH2), 3.32 (d, J=20.5 Hz, 4H, CH2), 1.28 (t, J=7.0 Hz, 12H, CH3)13C NMR (CDCl3, 125.7 MHz) δppm: 135.2, 132.5, 123.6, 62.35, 62.32, 33.4, 32.2, 16.31, 16.28GC-MS (relative intensity %): 491 (M+, <5%).