Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3](=[O:7])[CH2:4][C:5]#[N:6].C(N(CC)CC)C.[N+:16]([C:19]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22])([O-:18])=[O:17]>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:1][N:2]([CH3:8])[C:3](=[O:7])[C:4]([C:5]#[N:6])=[C:21]([OH:22])[C:20]1[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[CH:27][C:19]=1[N+:16]([O-:18])=[O:17]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CN(C)C(=O)CC#N
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)C(C#N)=C(O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a well stirred solution of 5.0 g of N,N-dimethylcyanoacetamide, 8 ml of triethylamine, and 0.05 g of p-dimethylaminopyridine dissolved in 8 ml of dry THF was added 10 g of 2-nitro-4-trifluoromethylbenzoyl chloride dissolved in a min. amount of THF at such a rate that the reaction temperature did not exceed 45° C. The reaction was stirred overnight, at which time TLC analysis indicated that the reaction was complete. The reaction was worked up by removing the solvents under reduced pressure, diluting the residue with 15% NaOH, and extracting well with ether. The aqueous phase was acidified and extracted with 2×100 ml of CH2Cl2. The combined CH2Cl2 extracts were washed once with saturated brine, dried over molecular sieves, filtered, and then passed through a short column of silica gel. The eluate was concentrated under reduced pressure to yield 9.8 g of an orange oil that solidified upon standing. The impure solid was crystallized from ether/hexane to yield 4.24 g of the product, m.p. 104°-6° C.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:34](=[O:35])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:16]([CH3:20])([CH3:19])[S:17](=[O:18])[C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:36]N(C)S(C1C=CC(C)=CC=1)(=O)=O>>[CH3:19][C:16](=[CH2:20])[CH:15]([N:14]1[C:34](=[O:35])[CH:12]([NH:11][C:9](=[O:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]1[S:17]([Cl:36])=[O:18])[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22]
Reactant: CC1(C)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2S1=O
Reactant: Cc1ccc(S(=O)(=O)N(C)Cl)cc1
Product: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1S(=O)Cl
Temperature: 25 °C

Procedure:
To 150 ml. of distilled and molecular sieve-dried toluene were added 3.0 g. (6 mmol.) of p-nitrobenzyl 6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide and 1.3 g. (6 mmol.) of N-chloro-N-methyl-p-toluenesulfonamide. The mixture was heated at reflux for 60 minutes. The resulting reaction mixture then was cooled to room temperature. An aliquot (15 ml.) was separated, washed with water, and brine, dried over magnesium sulfate, and evaporated to dryness in vacuo. The nmr spectrum of the residue was consistent for the title compound contaminated with some N-methyl-p-toluenesulfonamide.
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1S(O)(=O)=[O:10].[C:14]1([S:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[NH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CO.I([O-])(=O)(=O)=O.[Na+]>O>[C:14]1([S:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[NH:21])=[O:10])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cc(C)c(S(=O)(=O)O)c(C)c1
Reactant: N=S(c1ccccc1)c1cccs1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: N=S(=O)(c1ccccc1)c1cccs1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10 g. Phenyl-(2-thienyl)-sulphimide mesitylene-sulphonate are dissolved in 200 ml. methanol. A solution of 7 g. sodium periodate in 150 ml. water are added dropwise thereto, whereafter the reaction mixture is stirred for 24 hours at ambient temperature. The reaction mixture is then rendered alkaline and evaporated on a rotary evaporator. The residue obtained is partitioned between water and dichloromethane and the organic phase is evaporated. There are obtained 3.7 g. phenyl-(2-thienyl)-sulphoximide which, after recrystallisation from ethyl acetate/isopropanol, melts at 133° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:17][CH:16]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([NH2:22])(=[O:23])=[O:24])=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCCCCCCOc1ccc(S(N)(=O)=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCCCCOc1ccc(S(N)(=O)=O)cc1
Yield: 193.3 %

Procedure:
A solution of tert-butyl(6-(4-sulfamoylphenoxy)hexyl)carbamate (1.178 g, 3.16 mmol) in TFA (5.0 mL) and DCM (5.0 mL) was stirred at rt for overnight. After the solvent was evaporated under a steam of N2, the reaction mixture was dissolved in water (5.0 mL) and acetonitrile (5.0 mL) and lyophilized to afford 4-((6-aminohexyl)oxy)benzenesulfonamide (1.664 g) containing TFA. MS (ESI), 273.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[N:6][CH:5]=[CH:4][N:3]=1.[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C:15]1=[O:20].C(N(CC)CC)C>C(Cl)(Cl)Cl.C(O)(C)C>[N+:8]([C:7]1[C:2]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][OH:11])[C:15](=[O:20])[CH2:16]2)=[N:3][CH:4]=[CH:5][N:6]=1)([O-:10])=[O:9]
Reactant: O=C1CNCCN1CCO
Reactant: O=[N+]([O-])c1nccnc1Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: O=C1CN(c2nccnc2[N+](=O)[O-])CCN1CCO
Reaction time: 20 h
Yield: 33.7 %

Procedure:
A solution of 2-chloro-3-nitropyrazine (1.59 g, 10 mmol) in chloroform (20 ml) was added over 30 minutes to an icebath cooled solution of 4-(2-hydroxyethyl)piperazin-3-one (1.44 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) in isopropanol (30 ml). After addition was complete, the reaction mixture was allowed to warm to 20°-25° and was stirred at this temperature for 20 hours. Solvents were removed under reduced pressure and the residue was partitioned between a saturated aqueous solution of sodium chloride and ethyl acetate. The ethyl acetate extract was dried over anhydrous sodium sulfate, filtered and concentrated to an oil. Flash chromatography over silica gel and elution with 5% methanol-95% chloroform gave 0.90 g (48.6%) of 1-(3-nitro-2-pyrazinyl)-4-(2-hydroxyethyl)piperazin- 3-one. An analytical sample, m.p. 117°-120°, was obtained upon recrystallization from ethyl acetatehexane.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([C:14](=[O:17])[CH2:15]Br)[CH:11]=[CH:10][C:8]=2[N:9]=1)(=O)C.[CH2:18]([CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([C:14](=[O:17])[CH2:15][N:28]3[CH2:29][CH2:30][CH:25]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CC(=O)Nc1nc2ccc(C(=O)CBr)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc2ccc(C(=O)CN3CCC(Cc4ccccc4)CC3)cc2s1

Procedure:
A solution of 2 g of 1-(2-Acetylamino-benzothiazol-6-yl)-2-bromo-ethanone and 1.5 g of 4-benzylpiperidin and 2.5 g of K2CO3 in 20 ml of DMF was heated at 35° C. for 2 hours.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].C(N(CC)CC)C.[C:31]1([CH:37]([CH3:40])[CH:38]=O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(O)C>[C:31]1([CH:37]([C:40]2[NH:10][C:9]3=[N:8][C:7]([N:11]4[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]5[CH2:23][CH2:22][CH2:21][CH2:20]5)=[O:18])[CH2:12]4)=[CH:6][CH:5]=[C:4]3[N:3]=2)[CH3:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CC(C=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(c1ccccc1)c1nc2ccc(N3CCC[C@@H](C(=O)N4CCCC4)C3)nc2[nH]1
Yield: 9.5 %

Procedure:
To a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (Intermediate 1) (0.5 g, 1.7 mmol) in ethanol (20 mL) was added triethylamine (1 mL) and 2-phenylpropanal (0.25 g, 1.9 mmol). The reaction mixture was heated at reflux for 12 h. The mixture was then concentrated under reduced pressure, diluted with ice cold water and extracted with ethyl acetate. The organic layers were dried, filtered and concentrated, and the resulting residue was purified by preparative TLC to afford the title compound (65 mg, 9%). MS (ES+APCI) (M+H) 404.2; LCMS retention time 2.206 min (Method Y).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)Br)=[CH:4][CH:3]=1.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22]([NH2:24])=[S:23]>C(O)C.C(OCC)(=O)C>[C:21]([C:22]1[S:23][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:24]=1)([CH3:26])([CH3:25])[CH3:20]
Reactant: CC(C)(C)C(N)=S
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CSc1ccc(-c2sc(C(C)(C)C)nc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylthiophenyl)ethanone (Example 1, Step 3) (0.196 g, 0.578 mmol) in ethanol (6 mL) in a 25 mL round bottom flask was added 2,2-dimethylthiopropionamide from Step 1 (0.071 g, 0.606 mmol) and the mixture heated to reflux overnight. The reaction was cooled to room temperature, diluted with ethyl acetate (50 mL) and this solution washed successively with Na2CO3 (10% solution) and brine, dried over Na2SO4, filtered and concentrated in vacuo yielding 2-(tert-butyl)-4-(4-fluorophenyl)-5-(4-methylthiophenyl)thiazole as a pale yellow oil (0.162 g, 78%): 1H NMR (CDCl3) 300 mHz δ7.56-7.51 (m, 2H), 7.24 (d, J=8.48 Hz, 2H), 7.20 (d, J=8.48 Hz, 2H), 6.98 (t, J=8.85 Hz, 2H), 2.49 (s, 3H), 1.52 (s, 9H). MS (EI): m/e 357 (M+). HRMS Δ=0.1 mmu.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1([CH3:9])[CH2:8][O:7][CH2:6]1.[H][H].Br[CH2:13][C:14]([CH2:19]Br)([CH2:17]Br)[CH2:15]Br>CN(C=O)C>[CH3:9][C:5]1([CH2:4][O:3][CH2:13][C:14]([CH2:19][O:3][CH2:4][C:5]2([CH3:9])[CH2:8][O:7][CH2:6]2)([CH2:17][O:3][CH2:4][C:5]2([CH3:9])[CH2:8][O:7][CH2:6]2)[CH2:15][O:3][CH2:4][C:5]2([CH3:9])[CH2:8][O:7][CH2:6]2)[CH2:8][O:7][CH2:6]1
Reactant: CC1(CO)COC1
Reactant: [H][H]
Reactant: BrCC(CBr)(CBr)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(COCC(COCC2(C)COC2)(COCC2(C)COC2)COCC2(C)COC2)COC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
Sodium hydride (50% dispersion in mineral oil, 16.10 g. 0.33 mol) was washed twice with hexanes and was suspended in 500 mL of DMF. Then, 3-hydroxymethyl-3-methyloxetane (34.2 g, 0.33 mol) was added dropwise over 45 min while hydrogen gas was evolved and a beige solid precipitated. The mixture was stirred for 30 min and a solution of tetrakis-(bromomethyl)methane (25.0 g, 0.0645 mol) in 250 mL of DMF was added. The mixture was heated to 100° C. for 64 h when 1H NMR analysis of an aliquot showed that the starting halide had been consumed. The mixture was poured into 500 mL of water and extracted with three portions of 200 mL of methylene chloride. The combined organic extracts were washed with 3 portions of 200 mL of water, dried over magnesium sulfate, and evaporated to give an oil. The oil was cooled to -15° C. for 24 h, and the solid that formed was triturated with ether, filtered, and recrystallized from ethanol to give 6.15 g (21.3%) of tetrakis-[(3-methyl-3-oxetanyl)methoxymethyl]methane, mp 108.5°-109.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[CH:17]=1.[Br:18]Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:18][C:17]1[N:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:11]2=[N:10][C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: BrBr
Reactant: Clc1ccc(-c2cn3c(n2)CCCC3)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1ccc(-c2nc3n(c2Br)CCCC3)c(Cl)c1
Reaction time: 2 h

Procedure:
To 0.8 g (3.0 mmol) of the above 2-(2,4-dichlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine stirring in 50 ml of methylene chloride at room temperature, 0.5 g (3.1 mmol) of bromine in 5 ml of methylene chloride was added dropwise. The solution was stirred for 2 h. Another 20 ml of methylene chloride and excess saturated aqueous sodium bicarbonate were added. After sufficient mixing, the methylene chloride layer was separated, washed with water and brine, and dried over magnesium sulfate. Evaporating the solvent in vacuo gave a yellow solid residue which was purified by silica gel column chromatography (5:1 followed by 3:1 followed in turn by 1:1 hexane/ethyl acetate) to yield a 0.55 g sample of the title compound (m.p. 112°-113° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=3)[NH:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[N:19]([O-])=[O:20].[Na+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=3)[N:10]([N:19]=[O:20])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Cc1ccc2c(c1)C(c1ccc(F)cc1)CN2
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)C(c1ccc(F)cc1)CN2N=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
3-(4-Fluorophenyl)-5-methylindoline (0.7 g, 0.00308 mol) was dissolved in ethanol (4.2 mL) and concentrated hydrochloric acid (4.2 mL) was added at 0° C. The reaction mixture was stirred for 5 min. at 0° C. A solution of sodium nitrite (0.425 g, 0.00616 mol) in water (4.2 mL) was added at 0° C., and the reaction mixture was stirred for 2 h at RT. After completion of reaction (monitored by TLC), solvent was removed under reduced pressure, the residue basified with 10% aq. sodium hydroxide solution and the mixture extracted with EtOAc (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give desired compound as a brown colored oil (0.6 g, 76% yield).
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([N:12]3[CH2:17][CH2:16][N:15](C4CC5C(=CC=CC=5)C4)[CH2:14][CH2:13]3)[C:6]=2[O:5][CH:4]=[CH:3][CH2:2]1.S(C1C=CC(C)=CC=1)(OC1CC2C(=CC=CC=2)C1)(=O)=O>>[O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([N:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[C:6]=2[O:5][CH:4]=[CH:3][CH2:2]1
Reactant: C1=COc2c(cccc2N2CCN(C3Cc4ccccc4C3)CC2)OC1
Agent: Cc1ccc(S(=O)(=O)OC2Cc3ccccc3C2)cc1
Product: C1=COc2c(cccc2N2CCNCC2)OC1
Yield: 20 %

Procedure:
4-[benzo(1,5)dioxepin-6-yl]-1-(indan-2-yl)-piperazine, m.p. (M.K): 138°-140° C., from indan-2-yl tosylate and N-[benzo(1,5)dioxepin-6-yl]-piperazine [cf. J. Med. Chem. (1988), p. 1935] (yield: 20%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[N+:15]([O-])([OH:17])=[O:16]>OS(O)(=O)=O.O>[F:1][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]([C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Fc1cc(F)cc(-c2ncccn2)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1c(F)cc(F)cc1-c1ncccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
To a room temperature solution of 2-(3,5-difluoro-phenyl)-pyrimidine (1.2 g, 6.24 mmole) in H2SO4 (3 mL) was added 90% HNO3 (0.375 mL, 9.37 mmoles) over 10 seconds via syringe. The resulting mixture was stirred at room temperature for 1 hour then poured into ice. The resulting heterogeneous mixture was then diluted with water, warmed to room temperature, and filtered. The solids were washed with water and dried in vacuo to afford the title compound (1.53 g, 100%) as a tan solid. 1H NMR (dmso-d6, 500 MHz): 8.92 (d, 2H); 8.67 (m, 1H); 7.94 (m, 1H); 7.65 (dd, 1H).
Reaction SMILES: [OH-].[K+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:12]=[CH:13][C:14](I)=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17]>O.[Cu]>[Br:10][C:11]1[CH:19]=[C:15]([C:14]([S:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:13][CH:12]=1)[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1cc(Br)ccc1I
Reactant: Sc1ccccc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(Br)ccc1Sc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 400 g of potassium hydroxide in 3 litres of water is treated at 45° C under a nitrogen atmosphere with 179 ml of thiophenol and the mixture is stirred for 15 minutes. After the addition of 7.1 g of copper powder and 564 g of 5-bromo-2-iodo-benzoic acid, the resulting mixture is heated under reflux for 5 hours and subsequently filtered while hot, acidified while cooling with 420 ml of concentrated hydrochloric acid and extracted with ethyl acetate. The organic solution is washed with water, dried over magnesium sulphate and evaporated under reduced pressure. There is obtained 3-bromo-6-(phenylthio)-benzoic acid of melting point 171°-173° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)[CH:7]=1.[N-:15]=[N+:16]=[N-:17].[Na+].O.CCOC(C)=O>CN(C=O)C>[N:15]([CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)[CH:7]=1)=[N+:16]=[N-:17]
Reactant: ClCc1cn(-c2ccc(I)cc2)cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1cn(-c2ccc(I)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
The compound 4-chloromethyl 1-(4-iodophenyl)imidazole 1-3 (0.780 g, 2.45 mmol) was dissolved in DMF (10 mL). To the solution, NaN3 (0.520 g, 8.00 mmol) was added. After being stirred at room temperature overnight, water and EtOAc were added. The organic layer was separated, dried over Na2SO4, concentrated in vacuo to give 4-azidomethyl 1-(4-iodophenyl)imidazole 1-4 as a solid (0.725 g). MS 326.0 (M+H)
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:28]=[CH:27][C:8]([CH2:9][N:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[Cl:29][C:30]1[C:35](Cl)=[N:34][CH:33]=[CH:32][N:31]=1>CN(C=O)C.O>[Cl:29][C:30]1[C:35]([O:17][C@H:14]2[CH2:15][CH2:16][C@H:11]([N:10]([CH2:9][C:8]3[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:28][CH:27]=3)[CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[CH2:12][CH2:13]2)=[N:34][CH:33]=[CH:32][N:31]=1
Reactant: Clc1nccnc1Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)[C@H]2CC[C@H](O)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)[C@H]2CC[C@H](Oc3nccnc3Cl)CC2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Sodium hydride (0.58 g, 14.5 mmol, 60% dispersion in mineral oil) was added to a solution of trans-4-(bis(4-methoxybenzyl)amino)cyclohexanol (4.30 g, 12.1 mmol) in DMF (50 mL). The mixture was stirred for 30 min at RT before 2,3-dichloropyrazine (1.89 mL, 12.7 mmol) was added dropwise via syringe. The reaction mixture was warmed to 60° C. and stirred overnight. The mixture was diluted with water and extracted with EtOAc (3×). The extracts were combined, washed with water (3×), washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The resulting crude oil was purified by silica gel chromatography to give trans-4-(3-chloropyrazin-2-yloxy)-N,N-bis(4-methoxybenzyl)cyclohexanamine as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8]C)=[O:6].BrC1C(OC)=C(C(CBr)=CC=1)C(OC)=O.[F:38]C1C=C(S)C=CC=1>>[Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:38])[CH:16]=2)=[CH:11][CH:12]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: Fc1cccc(S)c1
Reactant: CCOC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC
Agent: COC(=O)c1c(CBr)ccc(Br)c1OC
Product: COC(=O)c1c(CSc2cccc(F)c2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 73, starting from methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 89) and 3-fluorothiophenol.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:14]=[CH:13][C:7]([CH2:8][NH:9][C:10](=O)[CH3:11])=[CH:6][CH:5]=1.B>C1COCC1.C(OCC)C>[CH2:10]([NH:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:15])[F:16])=[CH:14][CH:13]=1)[CH3:11]
Reactant: CC(=O)NCc1ccc(OC(F)(F)F)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCNCc1ccc(OC(F)(F)F)cc1
Temperature: -10 °C
Reaction time: 8 h
Yield: 19.4 %

Procedure:
N-[4-(Trifluoromethoxy)benzyl]acetamide (10.4 g, 44.6 mmol) was dissolved in THF (100 mL) and cooled to −10° C. Borane (56 mL of a 2 M solution of the dimethylsulfide complex in diethyl ether) was added and the reaction mixture was stirrred at −10° C. for 15 minuters and was then allowed to warm to room temperature. The reaction mixture was refluxed overnight and was then allowed to cool to room temperature. The reaction was quenched by careful addition of 10% HCl (30 mL) at 0° C. and the mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was taken up in water (200 mL) and diethyl ether (200 mL) and the phases were separated. Concentration in vacuo of the diethyl ether phase afforded 1.9 g (21%) of the title compound as a colourless oil.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([OH:23])=O)=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:47][CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:51]2[CH2:52][CH2:53][CH:48]([CH3:47])[CH2:49][CH2:50]2)=[O:23])=[CH:15]3)=[O:11])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC1CCNCC1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-methyl piperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:21]([I:22])=[CH:20][C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12][C:6]=2[CH:5]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O.O.C(OCC)(=O)C>[I:22][C:21]1[C:4]([O:3][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)c(I)cc2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2cc(I)c(OCc3ccccc3)cc2CC1
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% disp. in mineral oil, 576 mg, 14.4 mmol) was added to a stirred solution of 1,1-dimethylethyl 7-hydroxy-8-iodo-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (D41) (4.67 g, 12 mmol) in dimethylformamide (30 ml). After 15 minutes, benzyl bromide (2.04 g, 1.4 ml, 12 mmol) was added and the mixture stirred for 2 hours. The mixture was diluted with water and ethyl acetate, the organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a mixture of ethyl acetate:hexanes (1:10) to afford the title product (D44).