Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:7][C:8]([NH:10][CH:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12]([O:14][C@@H:15]2[CH:20]3[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]3)[CH2:16]2)=[O:13])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:29][CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32]>CCOC(C)=O>[Br-:29].[CH:1]1([O:7][C:8]([NH:10][CH:11]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:12]([O:14][C@@H:15]2[CH:20]3[CH2:19][CH2:18][N+:17]([CH2:30][C:31](=[O:32])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([CH2:22][CH2:21]3)[CH2:16]2)=[O:13])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1)OC1CCCCC1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(NC(C(=O)O[C@H]1C[N+]2(CC(=O)c3ccccc3)CCC1CC2)c1ccccc1)OC1CCCCC1
Product: [Br-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 53 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-(cyclohexyloxycarbonylamino)-2-phenylacetate (C38) (105 mg, 0.27 mmol) in EtOAc (3 ml), was added 2-bromo-1-phenylethanone (59.5 mg, 0.30 mmol). The reaction was stirred at RT for 15 hours, and then the solvent was evaporated. The crude was purified by flash chromatography (DCM/MeOH=95/5 to 93/7) to obtain (3R)-3-(2-(cyclohexyloxycarbonylamino)-2-phenylacetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide (83.8 mg; 53% yield).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[Br:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25]>C1(C)C=CC=CC=1>[Br-:20].[CH3:25][O:24][CH2:23][CH2:22][CH2:21][P+:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COCCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
A solution of PPh3 (42.8 g, 163.2 mmol) and 1-bromo-3-methoxypropane (25 g, 163.3 mmol) in toluene (70 mL) is heated at 150° C. in an autoclave for 44 h. After completion of the reaction, the mixture is filtered and the precipitate washed with toluene and dried under high vacuum for 4 h affording the title compound as a white powder Rt (HPLC, Nucleosil C18, 10:90-100:0 CH3CN/H2O+0.1% TFA within 5 min then 100% CH3CN+0.1% TFA): 5.06 min.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.[C:9](=[S:11])=S.[OH-].[Na+].ClCC([O-])=O.[Na+].[NH2:20][NH2:21]>>[NH2:7][C:4]1[CH:5]=[CH:6][C:1]([NH:8][C:9](=[S:11])[NH:20][NH2:21])=[CH:2][CH:3]=1
Reactant: S=C=S
Reactant: Nc1ccc(N)cc1
Reactant: NN
Agent: O=C([O-])CCl
Agent: [Na+]
Agent: [OH-]
Product: NNC(=S)Nc1ccc(N)cc1
Yield: 37.6 %

Procedure:
As per general procedure (9) except with benzene-1,4-diamine (2.16 g, 20.00 mmol), CS2 (1.20 mL, 20.00 mmol), NaOH (0.80 g, 20.00 mmol), sodium chloroacetate (2.33 g, 20.00 mmol) and NH2NH2 (5.60 mL, 0.18 mol). The product was isolated as a cream solid (1.37 g, 38%). 1H NMR: δ 4.65 (2H, s, PhNH2); 4.95 (2H, s, NHNH2); 6.49 (2H, d, J 8.65, 3-ArH); 7.08 (2H, d, J 8.30, 2-ArH); 8.80 (1H, s, NH); 9.25 (1H, s, NHNH2).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH3:8][C:9]1([CH3:34])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19](O)=[O:20])[CH:16]=2)[NH:11][CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:8][C:9]1([CH3:34])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:20])[CH:16]=2)[NH:11][CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1
Reactant: CS(N)(=O)=O
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CCNCC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cccc(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
To a suspension of 60% sodium hydride (196 mg, 4.9 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (475 mg, 5 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-(3-piperazin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (180 mg, 0.5 mmol) and 1,1′-carbonyldiimidazole (162 mg, 1.0 mmol) in N,N-dimethylformamide (1.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[3,3-dimethyl-2-(3-piperazin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (66 mg, 30%) as a white solid: LC/MS m/e calcd for C23H30N4O3S (M+H)+: 443.58, observed: 442.9.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH:13]1([CH2:19][N:20]=[C:21]=[S:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH:12][C:21]([NH:20][CH2:19][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[S:22])(=[O:10])=[O:11]
Reactant: S=C=NCC1CCCCC1
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Agent: Cl
Product: Nc1cc(Cl)sc1S(=O)(=O)NC(=S)NCC1CCCCC1
Yield: 8 %

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and cyclohexylmethyl isothiocyanate by a procedure analogous to the procedure described in example 3-a; a syrup was obtained (yield 8%), 1H-NMR (DMSO-d6): δ0.95 (m, 2H), 1.25 (m, 3H), 1.70 (m, 6H), 3.45 (d, 2H, CH2), 4.45 (br, HDO+NH), 6.65 (s, 1H, H4).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[C:8]([Cl:16])[C:9]=1[O:10][CH2:11][C:12]([F:15])([F:14])[F:13].Br[CH2:24][CH2:25][CH2:26]Br>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([C:17]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:26][CH2:25][CH2:24]2)[CH:7]=[C:8]([Cl:16])[C:9]=1[O:10][CH2:11][C:12]([F:15])([F:13])[F:14]
Reactant: CCOC(=O)Cc1cc(Cl)c(OCC(F)(F)F)c(Br)c1
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(Br)c2)CCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To a suspension of NaH (0.65 g, 60% in paraffin oil) in DMF (100 mL), slowly added a mixture of ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (3.0 g, 6.8 mmol) and 1,3-dibromo propane (1.61 g, 8.0 mmol) dissolved in DMF (20 mL) at 0° C. for 15 min under an atmosphere of nitrogen. The reaction mixture was allowed stir at 0° C. for 15 min, upon which the reaction mixture was poured onto crushed ice and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by Flash column chromatography to give ethyl 1-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (2.12 g) as a thick syrup.
Reaction SMILES: C(OC([NH:11][C@@H:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:15])=O)=O)C1C=CC=CC=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.[Pd]>[NH2:11][C@@H:12]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:13]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:15]
Reactant: C1COCCN1
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[C@H](N)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a solution of (S)-2-(benzyloxycarbonylamino)-3,3-dimethylbutanoic acid (2.0 g, 7.54 mmol) in DMF (10 mL) were added morpholine (1.31 g, 15.1 mmol) and DIEA (3.95 mL, 22.62 mmol). TBTU (3.63 g, 11.31 mmol) was added in three portions 15 minutes apart. The reaction stirred at room temperature for 2 hours. DMF was removed under vacuum and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude material (2.11 g, 7.54 mmol) was combined with palladium on carbon, 10% dry basis, (0.29 g, 2.69 mmol) in MeOH (15 mL) and placed on a Parr Shaker under H2 atmosphere, 20 psi, for 3 hours. The reaction was filtered through a celite plug and concentrated under reduced pressure to provide 1.46 g (7.31 mmol) of intermediate 77D. LCMS (+ESI) m/z 201.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[CH2:11][NH:12][C@@H:13]([CH3:16])[CH2:14][OH:15])[CH:5]=[CH:4][N:3]=1.[C:20]([O:24][C:25]([N:27]([CH2:29][C:30](O)=[O:31])[CH3:28])=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25](=[O:26])[N:27]([CH2:29][C:30](=[O:31])[N:12]([CH2:11][C:10]1[CH:17]=[CH:18][CH:19]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:9]=1)[CH:13]([CH3:16])[CH2:14][OH:15])[CH3:28])([CH3:23])([CH3:21])[CH3:22]
Reactant: C[C@@H](CO)NCc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Product: CC(CO)N(Cc1cccc(-c2ccnc(Cl)n2)c1)C(=O)CN(C)C(=O)OC(C)(C)C

Procedure:
Intermediate 73 was coupled with (tert-butoxycarbonyl-methyl-amino)-acetic acid following procedure K. LC-MS showed the product had the expected M+H+ of 449. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.6 (m, 1H) 8.1 (m, 1H) 8.0 (m, 1H) 7.7 (m, 1H) 7.5 (m, 2H) 4.6 (m, 2H) 4.3 (m, 2H) 4.0 (m, 1H) 3.7 (s, 1H) 3.5 (s, 1H) 3.0 (m, 4H) 1.4 (m, 9H) 1.2 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22][CH2:23][CH2:24][N:25]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29].O>CS(C)=O>[CH2:30]([N:25]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24][CH2:23][CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCN(CCCC)CCCCl
Reactant: Oc1ccc(Sc2ccncc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCN(CCCC)CCCOc1ccc(Sc2ccncc2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 0.014 mol of 4-(4-hydroxy-phenylthio) pyridine and 3 g of finely crushed anhydrous potassium carbonate in 50 ml of dimethylsulphoxide was placed under stirring for 30 min. To this medium 0.016 mol of 1-chloro-3-(di-n-butylamino) propane was added and the stirring was maintained at room-temperature for 24 hours. The reaction medium was poured into water and extracted with ethyl ether. The organic phase was washed with water, dried no sodium sulphate and filtered. After the solvent was evaporated off, an oil was provided which was purified by chromatography on a silica column (eluent: methanol). The required compound in free base form so obtained was then transformed into an oxalate by adding an ethereal solution of oxalic acid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].[C:12]1([S:22](Cl)(=[O:24])=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][S:22]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)(=[O:24])=[O:23]
Reactant: COC(=O)CCCCCN
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCNS(=O)(=O)c1cccc2ccccc12
Reaction time: 12 h
Yield: 54.9 %

Procedure:
Then, 5.43 g of 6-aminocaproic acid methyl ester hydrochloride, 6.78 g of 1-naphthalenesulfonyl chloride and 3.03 g of triethylamine were dissolved in 50 mL of dichloromethane and stirred for 12 hours. The reaction mixture was washed with 10% aqueous citric acid and then with saturated aqueous sodium hydrogencarbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=7/3) to obtain 5.50 g of 6(1-naphthalenesulfonyl)aminocaproic acid methyl ester. The resulting 6-(1-naphthalenesulfonyl)aminocaproic acid methyl ester (3.35 g) was dissolved in methanol, and the solution was added with 20 mL of 1 N sodium hydroxide, and stirred for 3 hours. Then, the methanol was evaporated under reduced pressure, and the residue was made acidic with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 3.02 g of 6-(1-naphthalenesulfonyl)aminocaproic acid.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[CH:17][N:16]=[C:15](Cl)[C:14]=2[N+:20]([O-])=O)[CH2:9][CH2:8]1)=[O:6])[CH3:3].C(N(CC)CC)C.[H][H]>[Pd].C(O)C>[CH3:3][C:2]([CH3:23])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[N:18]=[CH:17][N:16]=[CH:15][C:14]=2[NH2:20])[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)c2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ncncc2N)CC1

Procedure:
A mixture of 1-[1,1-dimethylethoxycarbonyl]-4-[4-chloro-5-nitro-6-pyrimidyl]piperazine (PREPARATION 23, 0.56 g) and triethylamine (0.3 ml) and palladium on carbon (5%, 0.13 g) in ethanol (100 ml) is charged with hydrogen gas (30 psi). After the theoretical amount of hydrogen gas is consumed, the catalyst is removed under reduced pressure. The filtrate is concentrated under reduced pressure to a foam which is diluted with an aqueous saturated solution of potassium carbonate and dichloromethane. The phases are separated and the organic phase is dried over sodium sulfate and concentrated to give to give the title compound, NMR (CDCl3) 1.49, 3.49, 3.29, 3.56, 7.98, and 8.39δ.
Reaction SMILES: [C:1](=[S:4])([S-:3])[NH2:2].[NH4+].[Br-].[Br:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][N+:14]([CH3:17])=[CH:13][CH:12]=1)=O>CO>[Br-:7].[CH3:17][N+:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:2]=[C:1]([SH:3])[S:4][CH:8]=2)=[CH:12][CH:13]=1
Reactant: C[n+]1ccc(C(=O)CBr)cc1
Reactant: NC(=S)[S-]
Agent: [Br-]
Agent: [NH4+]
Solvent: CO
Product: C[n+]1ccc(-c2csc(S)n2)cc1
Temperature: 25 °C

Procedure:
0.69 g Ammonium dithiocarbamate were dissolved in 10 ml MeOH and 1.47 g 4-(2-bromoacetyl)-1-methylpyridinium bromide were added. After 2 h at ambient temperature the mixture was refluxed. After cooling the precipitate was filtered, washed with MeOH and dried.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[F:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14].[OH-].[Na+].Cl>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:11]([F:10])[CH:12]=2)[N:7]=1
Reactant: Nc1cccc(F)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Fc1cccc(Nc2nc(Cl)nc(Cl)n2)c1
Temperature: 2.5 °C

Procedure:
To cyanuric chloride (1.6614 g, 9 mmol) dissolved in acetone (20 mL) stirring at 0-5° C., was added a solution of 3-fluoroaniline (0.9 mL, 9 mmol) in acetone (5 mL) followed by the addition of 2.5 N NaOH (3.6 mL, 9 mmol). The reaction mixture was allowed to stir at 0-5° C. for 1 hour under nitrogen. The reaction mixture was poured over crushed ice and neutralized with 10% HCl and 10% NaOH. The solid that formed was collected by vacuum filtration and the resulting solid was dried overnight under vacuum. Flash column chromatography (SiO2, 70:30 hexanes:ethyl acetate) yielded a faint yellow solid (159a, 1.67 g, 72%), mp 143° C.; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4 (0.01M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt 23.5 min, 87.0% purity.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[N:16]1[CH2:21][CH2:20][CH2:19][NH:18][C:17]=1[SH:22]>CC(C)=O>[BrH:1].[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2([C:3](=[O:4])[CH2:2][S:22][C:17]3[NH:18][CH2:19][CH2:20][CH2:21][N:16]=3)[CH2:8][CH2:7][CH2:6]2)=[CH:10][CH:11]=1
Reactant: O=C(CBr)C1(c2ccc(Cl)cc2)CCC1
Reactant: SC1=NCCCN1
Solvent: CC(C)=O
Product: Br
Product: O=C(CSC1=NCCCN1)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Yield: 86 %

Procedure:
A solution of 2-bromo-1-[1-(4-chlorophenyl)cyclobutyl]ethanone (2.9 g) in acetone (25 ml) was added to a solution of 3,4,5,6-tetrahydropyrimidine-2-thiol (1.2 g) in acetone (150 ml), then the mixture was heated under reflux for 1 hour, and allowed to cool to ambient temperature. The resulting solid was collected by filtration and dried in vacuo at ambient temperature to give 1-[1-(4-chlorophenyl)cyclobutyl]-2-(3,4,5,6-tetrahydropyrimidin-2-ylthio)ethanone hydrobromide as a white solid (3.5 g), m.p. 205° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11]2)=[CH:2]1.[H-].[Na+].[F:18][C:19]1[CH:38]=[CH:37][C:22]([CH2:23][NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[O:26])=[CH:21][CH:20]=1>CN(C=O)C>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][NH:24][C:25](=[O:26])[C:27]2[CH:32]=[CH:31][C:30]([S:33]([N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]([CH:10]4[CH2:14][CH2:13][C:12](=[O:15])[CH2:11]4)=[CH:2]3)(=[O:34])=[O:35])=[CH:29][CH:28]=2)=[CH:37][CH:38]=1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCC(c2c[nH]c3ccccc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCC(c2cn(S(=O)(=O)c3ccc(C(=O)NCc4ccc(F)cc4)cc3)c3ccccc23)C1
Yield: 29.7 %

Procedure:
Add a 3 nm DMF solution of 3-(1H-Indol-3-yl)-cyclopentanone (500 mg, 2.57 mmol, 1 eq) to a 3 ml DMF solution of NaH (155 mg, 60% by weight, 3.86 mmol, 1.1 eq) under N2 atmosphere. Stir reaction for 15 minutes and then add a 5 ml DMF solution of 4-(4-Fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (1.27 g, 3.86 mmol, 1.1 eq). Stir reaction for 48 hours, remove solvent on rotovap, and purify by silica gel chromatography to give N-(4-Fluoro-benzyl)-4-[3-(3-oxo-cyclopentyl)-indole-1-sulfonyl]-benzamide (375 mg, 22% yield). Mass Spectrum (m/e): 490.53 (MH+).
Reaction SMILES: [H][H].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([OH:13])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10].[I:14]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([I:14])[C:7]([OH:13])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: [H][H]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: O=C(O)c1cc(Cl)cc(I)c1O
Reaction time: 1 h

Procedure:
For example, a mixture of a compound of formula 40 wherein R3 and R4 are hydrogen and R5 is chloro, i.e., 5-chloro-2-hydroxy benzoic acid, (5.0 g, 29 mmol) and N-iodosuccinimide (7.17 g, 32 mmol) in acetic acid (30 mL) was heated to 95° C. for 2 h. Additional N-iodosuccinimide (0.70 g, 3.1 mmol) was added and heating was continued for 1 h. The mixture was cooled and poured over ice. The precipitate was isolated by filtration and the crude material was purified by recrystallization from methanol/water. The solid was isolated by filtration, rinsed with water and dried. 5-Chloro-2-hydroxy-3-iodo-benzoic acid 41 was obtained as a tan crystalline solid (6.14 g, 71% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([OH:25])=[C:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:7]2=[O:12].[O:27]1CC[CH2:29][CH2:28]1.[H-].[Na+].C(Cl)(=O)C>C(Cl)Cl>[C:28]([O:25][C:5]1[C:4](=[O:26])[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[C:7](=[O:12])[C:6]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:27])[CH3:29]
Reactant: CCCCCCCCCCCCC1=C(O)C(=O)c2c(Cl)cccc2C1=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCC1=C(OC(C)=O)C(=O)c2c(Cl)cccc2C1=O
Temperature: 25 °C

Procedure:
A solution of 0.95 parts of 5-chloro-2-dodecyl-3-hydroxy-1,4-naphthoquinone in 20 parts of anhydrous tetrahydrofuran was added under nitrogen to a mixture of 0.0635 parts of dispersed sodium hydride in 40 parts of tetrahydrofuran with stirring at room temperature. After 45 minutes of stirring, a solution of 0.275 parts of acetyl chloride in 30 parts of tetrahydrofuran was added and the mixture stirred for 5 hours. The tetrahydrofuran was stripped under reduced pressure and the residue taken up in methylene chloride and then washed with water, 10% hydrochloric acid, four more times with water, dried over sodium sulfate and stripped. The resulting yellow solid was purified by column chromatography on silica gel using 1-chlorobutane as eluent. Solvent removal gave 0.9 parts of 3-acetoxy-5-chloro-2-dodecyl-1,4-naphthoquinone, m.p. 57°-59° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][C:9]1[C:14]([OH:15])=[C:13]([CH2:16][SH:17])[C:12]([CH:18]=[CH2:19])=[CH:11][N:10]=1.[O:20]1CC[CH2:22][CH2:21]1>>[CH3:8][C:9]1[C:14]([O:15][C:1](=[O:3])[CH3:2])=[C:13]([CH2:16][S:17][C:21](=[O:20])[CH3:22])[C:12]([CH:18]=[CH2:19])=[CH:11][N:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: C1CCOC1
Reactant: C=Cc1cnc(C)c(O)c1CS
Product: C=Cc1cnc(C)c(OC(C)=O)c1CSC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 680 mg. of acetic anhydride and 10 ml. of tetrahydrofuran was added slowly to 653 mg. of 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine in 20 ml. of tetrahydrofuran at 10° C. After stirring for one hour at room temperature, the mixture was evaporated to dryness. The residue was triturated with a mixture of 20 ml. of ethyl acetate and 20 ml. of water. The ethyl acetate was separated, dried over magnesium sulfate, and evaporated to dryness. The residue was recrystallized from cyclohexane to give 2-methyl-3-acetoxy-4-acetylthiomethyl-5-vinylpyridine, m.p. 72°-73° C. The same product is obtained by starting with the S-acetate product of Example 5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[NH:19][C:18](=[O:28])[N:17]([CH3:29])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][O:39]C1CCCCO1>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[N:19]([CH2:37][CH2:38][OH:39])[C:18](=[O:28])[N:17]([CH3:29])[C:16]=3[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCCOC1CCCCO1
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(CCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[3-Methyl-7-(2-butynyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (0.30 g) and potassium carbonate (0.21 g) were dissolved in N,N-dimethylformamide (10 ml), and 2-(2-bromoethoxy)tetrahydro-2H-pyran (0.23 ml) was added thereto. After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. After removing the solvent by distillation, ethanol (10 ml) and pyridinium p-toluenesulfonate (60 mg) were added to the resulting residue, and the reaction mixture was stirred at 60° C. for 3 hours. The reaction solution was distilled. The residue was purified by silica gel column chromatography to obtain 0.14 g of the title compound from a fraction eluted with hexane-ethyl acetate (1:5).