Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([N:12]1[C:16]2[N:17]=[C:18]([Cl:21])[N:19]=[CH:20][C:15]=2[C:14](I)=[CH:13]1)[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([CH:35]=1)[C:29](N(OC)C)=[O:30]>>[Br:23][C:24]1[CH:35]=[C:28]([C:29]([C:14]2[C:15]3[CH:20]=[N:19][C:18]([Cl:21])=[N:17][C:16]=3[N:12]([CH:10]([CH3:11])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:13]=2)=[O:30])[CH:27]=[N:26][CH:25]=1
Reactant: CC(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cnc(Cl)nc21
Reactant: CON(C)C(=O)c1cncc(Br)c1
Product: CC(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(Br)c2)c2cnc(Cl)nc21

Procedure:
The title compound was prepared according to the method described for Preparation 28 using 7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-2-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (see Preparation 55, enantiomer 2) and 5-bromo-N-methoxy-N-methylnicotinamide to afford the title compound as a yellow solid in 30% yield, 1.4 g. 1H NMR (400 MHz, DMSO-D6) δ: −0.14 (s, 6H), 0.61 (s, 9H), 1.52 (d, 3H), 3.91-3.96 (m, 2H), 5.00 (m, 1H), 8.37 (s, 1H), 8.58 (s, 1H), 8.95 (s, 1H), 9.00 (s, 1H), 9.33 (s, 1H).
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](N2CCNCC2)=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:22]2[CH2:21][CH2:20][N:19]([C:16]3[CH:15]=[CH:14][C:13]4[NH:12][CH:11]=[C:10]5[C:25](=[O:26])[N:7]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)[N:8]=[C:9]5[C:18]=4[N:17]=3)[CH2:24][CH2:23]2)=[CH:30][CH:29]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Product: O=c1c2c[nH]c3ccc(N4CCN(c5ccc(F)cc5)CC4)nc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described for 6a using 1-(4-fluorophenyl)-piperazine instead of piperazine. 1H-NMR (DMSO-d6) δ (ppm): 3.22 (4H, brm), 3.83 (4H, brm), 7.07 (5H, m), 7.32 (1H, d, J=9.34 Hz), 7.43 (2H, dd, J=8.24, 7.69 Hz), 7.85 (1H, d, J=9.34 Hz), 8.19 (2H, dd, J=8.24, 0.82 Hz), 8.57 (1H, s). m/z 441.5 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[N:15]=[C:14](Cl)[C:13]([CH:21]=[O:22])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:23].[Na+].Cl>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[N:15]=[C:14]([I:23])[C:13]([CH:21]=[O:22])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc2cc(OCc3ccccc3)c(F)cc2nc1Cl
Reactant: [I-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: O=Cc1cc2cc(OCc3ccccc3)c(F)cc2nc1I
Yield: 67.9 %

Procedure:
A suspension of 6-benzyloxy-2-chloro-7-fluoro-3-quinolinecarbaldehyde (obtained according to 1.d, 15 g, 47 mmol) and sodium iodide (18 g, 120 mmol) in anhydrous acetonitrile (500 ml) is treated with a catalytic quantity of concentrated hydrochloric acid (1.2 ml), then taken to reflux under argon for 8 hours. The reaction mixture is then concentrated to 20% of the initial volume, then treated with a 10% aqueous solution of sodium bicarbonate to a neutral pH, then filtered and washed successively with water, ethanol and ethyl ether in order to produce 13 g (68%) of a yellow solid, m.p. 210° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[NH:7][CH:8]=[CH:9][C:2]=12.[N+:10]([O-])([OH:12])=[O:11].C(=O)(O)[O-].[Na+]>O>[N+:10]([C:9]1[C:2]2[C:3](=[N:4][CH:5]=[CH:6][N:1]=2)[NH:7][CH:8]=1)([O-:12])=[O:11]
Reactant: c1cnc2[nH]ccc2n1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1c[nH]c2nccnc12
Temperature: 0 °C

Procedure:
7-Nitro-5H-pyrrolo[2,3-b]pyrazine (5) is prepared by adding 5H-pyrrolo[2,3-b]pyrazine (3) to fuming nitric acid while cooling (e.g. 0° C.). After stirring for one to several hours, water is carefully added and the mixture neutralized with saturated sodium bicarbonate. The solids are collected by filtration and dried to provide 7-nitro-5H-pyrrolo[2,3-b]pyrazine 5.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([CH:28]=[CH:29][CH:30]=1)[CH2:9][NH:10][C:11]1[C:12]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26]O)=[CH:22][CH:21]=3)[NH:17][C:13]=2[N:14]=[CH:15][N:16]=1>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[C:8]([CH:28]=[CH:29][CH:30]=1)[CH2:9][NH:10][C:11]1[C:12]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][Cl:3])=[CH:22][CH:21]=3)[NH:17][C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: OCc1ccc(-c2cc3c(NCc4cccc(Cl)c4)ncnc3[nH]2)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: ClCc1ccc(-c2cc3c(NCc4cccc(Cl)c4)ncnc3[nH]2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 0.79 ml (10 mmol) thionylchloride in 5.5 ml of toluene is cooled to −10° C. Solid {4-[4-(3-chloro-benzylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol is added and the suspension stirred at 0° C. for 2 h and then at RT for 17 h. The solid is filtered off, washed with toluene and suspended in water (3 ml). The mixture is treated with saturated sodium bicarbonate solution (3 ml) and stirred for 10 min. The crystals are collected by filtration washed with water, a small amount of ethanol and ether and dried to give the title compound; m.p. decomposition ˜300° C.; Rf(dichloromethane/methanol/conc. ammonia 90:10:1)=0.61; MS-ES+: (M+H)+=383.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH3:18][C:19]([C:29]1[CH:33]=[C:32]([NH:34][C:35]([C@@H:37]2[CH2:40][CH2:39][N:38]2[C:41]2[C:46]([Cl:47])=[CH:45][C:44]([C:48]([F:51])([F:50])[F:49])=[CH:43][N:42]=2)=[O:36])[O:31][N:30]=1)([CH3:28])[CH2:20][O:21]C1CCCCO1>C(O)C>[OH:21][CH2:20][C:19]([C:29]1[CH:33]=[C:32]([NH:34][C:35]([C@@H:37]2[CH2:40][CH2:39][N:38]2[C:41]2[C:46]([Cl:47])=[CH:45][C:44]([C:48]([F:51])([F:50])[F:49])=[CH:43][N:42]=2)=[O:36])[O:31][N:30]=1)([CH3:28])[CH3:18]
Reactant: CC(C)(COC1CCCCO1)c1cc(NC(=O)[C@@H]2CCN2c2ncc(C(F)(F)F)cc2Cl)on1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CC(C)(CO)c1cc(NC(=O)[C@@H]2CCN2c2ncc(C(F)(F)F)cc2Cl)on1
Temperature: 55 °C
Reaction time: 5 h

Procedure:
Pyridinium p-toluenesulfonate (13.3 mg; 0.053 mmol) is added to a solution of (S)-1-(3-Chloro-5-trifluoromethyl-pyridin-2-yl)-azetidine-2-carboxylic acid {3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl}-amide (204 mg; 0.406 mmol) in ethanol (2 mL). The reaction mixture is stirred at 55° C. for 5 hours and more pyridinium p-toluenesulfonate (15 mg; 0.060 mmol) is added and the reaction mixture is stirred at 55° C. for 18 hours. After this time, the reaction mixture is concentrated and then diluted with ethyl acetate. It is washed with saturated NaHCO3 aqueous solution. The layers are separated and the aqueous layer is extracted with ethyl acetate once. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using ethyl acetate/hexanes provides the title compound, m/z 419 [M+H+]
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([F:20])[C@H:17]([F:21])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([C@:24]1([OH:32])[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1)#[CH:23].C(N(CC)CC)C.N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[CH2:1]([C:8]1[C:13]([C:23]#[C:22][C@:24]2([OH:32])[CH:29]3[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]3)[CH2:25]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([F:20])[C@H:17]([F:21])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: F[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1F
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CO
Solvent: CCN(CC)CC
Product: O[C@]1(C#Cc2ccc(N3C[C@@H](F)[C@H](F)C3)nc2Cc2ccccc2)CN2CCC1CC2
Temperature: 75 °C
Reaction time: 3 h
Yield: 40.4 %

Procedure:
A mixture of 152 mg of 2-benzyl-6-[(3R,4R)-3,4-difluoropyrrolidine-1-yl]-3-iodopyridine, 60 mg of (3R)-3-ethynyl-3-quinuclidinol, 22 mg of tetrakis(triphenylphosphine)palladium(0), 7 mg of cuprous iodide, 106 μl of triethylamine and 1.5 ml of methanol was heated under stirring for 3 hours at 75° C. in a nitrogen atmosphere. The reaction solution was poured into an aqueous dilute ammonia and then extracted with ethyl acetate. The extract was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography, eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (15:1) and crystallized from hexane/ethyl acetate, to give 65 mg of the target compound.
Reaction SMILES: C(CC[C:6]1[CH:7]=[C:8](/[C:12](/[CH:37]=[CH:38]/[C:39]2[C:40]([CH3:57])([CH3:56])[C:41]3[C:42]([N:55]=2)=[N+:43]([CH2:48][CH2:49][CH2:50][S:51]([O-:54])(=[O:53])=[O:52])[CH:44]=[C:45]([Cl:47])[CH:46]=3)=[CH:13]\[CH:14]=[C:15]2\[N:16]([CH2:30][CH2:31][CH2:32][S:33]([O-:36])(=[O:35])=[O:34])[C:17]3[C:22]([C:23]\2([CH3:25])[CH3:24])=[CH:21][C:20]([S:26]([O-:29])(=[O:28])=[O:27])=[CH:19][CH:18]=3)[CH:9]=[CH:10][CH:11]=1)(O)=O.[Na+:58].[Na+].[C:60](C1C=CC(B(O)O)=CC=1)([OH:62])=[O:61]>>[C:60]([C:11]1[CH:6]=[CH:7][C:8](/[C:12](/[CH:37]=[CH:38]/[C:39]2[C:40]([CH3:57])([CH3:56])[C:41]3[C:42]([N:55]=2)=[N+:43]([CH2:48][CH2:49][CH2:50][S:51]([O-:54])(=[O:52])=[O:53])[CH:44]=[C:45]([Cl:47])[CH:46]=3)=[CH:13]\[CH:14]=[C:15]2\[N:16]([CH2:30][CH2:31][CH2:32][S:33]([O-:36])(=[O:34])=[O:35])[C:17]3[C:22]([C:23]\2([CH3:25])[CH3:24])=[CH:21][C:20]([S:26]([O-:29])(=[O:28])=[O:27])=[CH:19][CH:18]=3)=[CH:9][CH:10]=1)([OH:62])=[O:61].[Na+:58].[Na+:58]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2cccc(CCC(=O)O)c2)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]
Agent: [Na+]
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2ccc(C(=O)O)cc2)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]

Procedure:
Compound 15 is prepared analogously to compound 10 (Example 10), except that 4-carboxyphenylboronic acid is used as a starting material. λMeOH=680 nm.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](=[O:13])[N:7]([CH3:12])[CH:8]=[C:9]([Cl:11])[CH:10]=1)=[O:4].[OH-].[Na+]>CO>[Cl:11][C:9]1[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[C:6](=[O:13])[N:7]([CH3:12])[CH:8]=1
Reactant: COC(=O)c1cc(Cl)cn(C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(Cl)cc(C(=O)O)c1=O
Temperature: 80 °C

Procedure:
A mixture of methyl-5-chloro-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (0.36 g, 1.8 mmol) and 2.0 mL each MeOH and 1N NaOH was heated in a sealed vial to 80° C. for 1 h. The reaction was cooled to ambient temperature, and the methanol was removed by a stream of nitrogen. Water (2 ml) was added and the solution was adjusted to pH 1 with 6N HCl. A thick white precipitate formed which was partitioned between water and dichloromethane. The organic layer was removed and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried with Na2SO4, filtered, and concentrated to give an orange-yellow solid. The material was partitioned between 1N HCl and EtOAc. The organic layer was washed twice with 1N HCl, dried with Na2SO4, filtered, and concentrated to give the desired product as a light orange solid. MS (m/z): 188.0 (M+H)+. Calc'd for C7H6ClNO3: 187.58.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([NH:15][NH2:16])[C:9]([Cl:17])=[N:8]2)=[O:4].[CH3:18][O:19][C:20](OC)(OC)OC>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]1[C:18]([O:19][CH3:20])=[N:16][N:15]=[C:10]1[C:9]([Cl:17])=[N:8]2)=[O:4]
Reactant: COC(OC)(OC)OC
Reactant: COC(=O)c1ccc2nc(NN)c(Cl)nc2c1
Product: COC(=O)c1ccc2c(c1)nc(Cl)c1nnc(OC)n12
Temperature: 23 °C

Procedure:
A solution of 3-chloro-2-hydrazino-quinoxaline-6-carboxylic acid methyl ester (890 mg) in tetramethylorthocarbonate (10 mL) was heated at 100° C. for three hrs. After cooling to 23° C., the precipitated solid was isolated by filtration and rinsed with EtOAc, providing 4-chloro-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid methyl ester as an orange solid. MS (M+H)+=293.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.CO.O1C[CH2:17][CH2:16][CH2:15]1>[Ni]>[CH2:16]([C:17]1[NH:1][C:2]2=[N:3][CH:4]=[CH:5][C:6]([CH3:11])=[C:7]2[N:8]=1)[CH3:15]
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Reactant: C1CCOC1
Agent: [Ni]
Solvent: CO
Product: CCc1nc2c(C)ccnc2[nH]1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
10 g (65.3 mmol) of 2-amino-4-methyl-3-nitropyridine are hydrogenated in 40 ml of tetrahydrofuran and 40 ml of methanol in the presence of Raney nickel. The catalyst is filtered off, the solvent is removed, the residue is treated with ethanolic HCl solution and the precipitated 2,3-diamino-4-methylpyridine hydrochloride is filtered off with suction. 7 g of this hydrochloride are dissolved in 57 g of polyphosphoric acid (from 28.5 g of P2O5 and 28.5 g of H3PO 4 (85% strength)) and treated with 1.26 ml of propionic acid, and the solution is stirred at 100° C. for 2h. After cooling, it is poured into ice-water, rendered alkaline by addition of Na2CO3 and extracted several times with EA. The combined EA phases are washed with saturated NaCl solution, dried over Na2SO4 and concentrated and the residue is chromatographed on SiO2 (EA/MeOH 5:1). 4.2 g of the title compound result.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([O:11][CH3:12])=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)C>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: COc1c(Cl)cc(F)cc1C(C)O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: CC(C)=O
Product: COc1c(Cl)cc(F)cc1C(C)=O
Reaction time: 3 h
Yield: 92.8 %

Procedure:
To a solution of 1-(5-Fluoro-2-methoxy-3-chlorophenyl)ethanol (2.1 g 10.1 mmol) in acetone (30 mL) at room temperature was added pyridinium chlorochromate (5.5 g, 26.2 mmol). The reaction was stirred for 3 hours, diethyl ether was added (50 mL). The resultant sludge was filtered through celite. The organic phase was dried over Na2SO4, filtered over silica gel, and concentrated to the crude compound which was purified by silica gel column (20% ethyl acetate in hexanes) to afford 1-(5-fluoro-2-methoxy-3-chlorophenyl)ethanone (1.9 g, 97%): 1H NMR (400 MHz, CDCl3): δ 7.24 (m, 2H), 3.84 (s, 3H), 2.63 (s, 3H).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1>CC#N.C([O-])([O-])=O.[Na+].[Na+]>[N:4]1[CH:3]=[C:2]([C:16]2[CH:17]=[C:12]([NH2:11])[CH:13]=[CH:14][CH:15]=2)[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: Nc1cccc(B(O)O)c1
Reactant: Brc1cnc2ccccn12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Nc1cccc(-c2cnc3ccccn23)c1
Temperature: 80 °C
Yield: 66.3 %

Procedure:
A mixture of 3-bromo-imidazo[1,2-a]pyridine (2.7 g, 13.7 mmol) and 3-aminobenzeneboronic acid (2.4 g, 17.5 mmol) in CH3CN (20 ml) and 2N aqueous Na2CO3 (20 ml) was deoxygenated by evacuation then refill with N2 (×3). PdCl2dppf (500 mg, 0.68 mmol) was added and the mixture was deoxygenated again (×3). The reaction was stirred and heated at 80° C. for 8 hours. After cooling to RT the mixture was partitioned between EtOAc/H2O and then filtered through Celite®. The Celite® was washed with CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2 (×2). The combined extracts were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica (100% CH2Cl2→2% 2M NH3-MeOH/CH2Cl2) to give the title compound (1.9 g, solid). MS: [M+H]+ 210
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CS(O[CH2:11][CH:12]([CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])(=O)=O>CN(C)C=O>[CH:21]1([CH:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH2:11][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OCC(c1ccc(Cl)cc1Cl)C1CCCC1
Solvent: CN(C)C=O
Product: Clc1ccc(C(Cn2ccnc2)C2CCCC2)c(Cl)c1

Procedure:
A mixture of 18 parts of 1H-imidazole, 18 parts of 2,4-dichloro-β-cyclopentylbenzeneethanol methanesulfonate and 225 parts of N,N-dimethylformamide is stirred and refluxed overnight. The reaction mixture is cooled and poured onto water. The product is extracted three times with trichloromethane. The combined extracts are washed three times with water and stirred with silicagel. The latter is filtered off and the filtrate is evaporated. The residue is crystallized from petroleumether. The product is filtered off and recrystallized from a mixture of 2,2'-oxybispropane and petroleum-ether, yielding 6.8 parts of 1-[2-cyclopentyl-2-(2,4-dichlorophenyl)-ethyl]-1H-imidazole; mp. 97.6° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.B([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)(O)O>>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)[CH:11]=[CH:10]2
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Oc1ccc2cc(Br)ccc2c1
Product: O=C(O)c1ccc(-c2ccc3cc(O)ccc3c2)cc1
Temperature: 85 °C
Yield: 7 %

Procedure:
Followed the coupling procedure described in Example 3, starting from 6-bromonaphthalen-2-ol and 4-boronobenzoic acid, where the reaction was heated at 85° C. for 8 h. After the prep-HPLC purification, a further purification by silica gel column (PE:EA=7:1 to 4:1) gave the compound as a yellow solid (26 mg, 7%). 1H NMR (DMSO-d6 500 MHz TMS): δ 12.97 (brs, 1H), 9.91 (brs, 1H), 8.19 (s, 1H), 8.04 (d, J=8.0 Hz, 2H), 7.87-7.92 (m, 3H), 7.80 (m, 2H), 7.13-7.16 (m, 2H); MS (ESI): m/z 265.1 [M+1]+.
Reaction SMILES: B.C1COCC1.[OH:7][CH2:8][CH:9]([C:14]([N+:21]([O-:23])=[O:22])([N+:18]([O-:20])=[O:19])[N+:15]([O-:17])=[O:16])[CH2:10][C:11](O)=[O:12]>O>[N+:15]([C:14]([N+:18]([O-:20])=[O:19])([N+:21]([O-:23])=[O:22])[CH:9]([CH2:10][CH2:11][OH:12])[CH2:8][OH:7])([O-:17])=[O:16]
Reactant: O=C(O)CC(CO)C([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])C(C(CO)CCO)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
A 1M solution of borane-THF (10 ML, 10 mmole) was stirred under a nitrogen atmosphere in a cold water bath (15° C.) while 2.1 g (8.94 mmole) of 4-hydroxy-3-(trinitromethyl)butyric acid, gamma-lactone was added. The solution was stirred at 25° C. for 1 hr. and then at 35°-37° C. for 3 days before it was cooled to room temperature and 1 ml of water was slowly added dropwise. Most of the THF was removed and the residue was stirred with ether. The insoluble material (boric acid) was removed by filtration and the ether filtrate was extracted twice with water to remove remaining boric acid. The ether was removed to give 2.10 g (98%) of an oil which was essentially pure by TLC. An analytical sample was obtained by chromatography on silica gel 60 with methylene chloride-acetone (80/20) as eluent: 1H NMR (CD2Cl2) 1.90-2.12 (m, 2H), 2.44 (broad OH), 3.60 (broad m, 1H), 3.93 (t, 2H), 4.23 (d, 2H); IR (film) 3700-3050 (OH), 1600 (NO2) cm-1.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[Cl:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>CCO>[Cl:21][C:6]1[CH:7]=[C:8]([S:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:22]=[C:23]([NH2:25])[S:24][CH:2]=1
Reactant: COc1ccc(Sc2cc(C)c(C(=O)CBr)c(Cl)c2)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: COc1ccc(Sc2cc(C)c(-c3csc(N)n3)c(Cl)c2)cc1
Yield: 57.7 %

Procedure:
A mixture of 2-bromo-1-(2-chloro-4-(4-methoxyphenylsulfanyl)-6-methylphenyl)ethanone (3-3, 0.127 g) and thiourea (30 mg, 0.33 mmol) in 95% EtOH (3.0 mL) was heated at reflux for 60 min. The solution was concentrated under reduced pressure and the residue was re-dissolved in ethyl acetate. The solution was washed with saturated aqueous NaHCO3, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 4-(2-chloro-4-(4-methoxyphenylsulfanyl)-6-methylphenyl)thiazol-2-ylamine (3-4, 70 mg, 0.19 mmol) as yellow solids in 58% yield: 1H NMR (500 MHz, CDCl3) δ 7.44 (m, 2 H), 6.97 (d, J=1.45 Hz, 1 H), 6.93 (m, 3 H), 6.34 (s, 1 H), 3.84 (s, 3 H), 2.13 (s, 3 H); ESI-MS m/z 363.1 (M+H)+.
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([CH:23]([C:25]2([CH3:28])[CH2:27][CH2:26]2)[OH:24])[CH:9]=1)(C)C.CO.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CCOC(C)=O>[F:22][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]([CH2:7][OH:6])=[CH:9][C:10]=1[CH:23]([C:25]1([CH3:28])[CH2:27][CH2:26]1)[OH:24]
Reactant: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C(O)C2(C)CC2)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(F)c(-c2ccc(CO)cc2C(O)C2(C)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A 200 mL round bottom flask was charged with 83.18E (0.80 g, 1.9 mmol), MeOH (10 mL), and PPTS (0.047 g, 0.19 mmol). The solution was stirred overnight at room temperature and diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel flash chromatography (20-55% EtOAc/hexane) to afford 83.18F (0.52 g, 88%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:35]=[C:36]([NH2:45])[CH2:37][C:38](=[O:44])[N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>ClCCl>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]2[O:11][N:45]=[C:36]([CH2:37][C:38](=[O:44])[N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[N:35]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Reactant: NC(CC(=O)N1CCCC1)=NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CC(=O)N2CCCC2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
A solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (500 mg, 1.70 mmol) in dichloromethane (30 ml) was treated with 1,1′-carbonyldiimidazole (272 mg, 1.70 mmol) and the solution was stirred at room temperature for 1 hour. N′-hydroxy-3-oxo-3-(1-pyrrolidinyl)propanimidamide (Patent FR 73-36858 731016) (291 mg, 1.70 mmol) was then added and the mixture was stirred for 17 hours. The solvent was removed under reduced pressure and the residue was heated neat at 110° C. under a nitrogen atmosphere for 2 hours. The crude product was then purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:1) to afford the title compound as a colourless oil (309 mg).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:12])=[O:11])=[CH:6][CH:5]=1)[CH3:3].[Br:13]Br>C(OCC)(=O)C>[Br:13][CH2:12][C:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:2]([CH3:1])[CH3:3])=[CH:9][CH:8]=1)=[O:11]
Reactant: BrBr
Reactant: CC(=O)c1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(C(=O)CBr)cc1
Reaction time: 5 h
Yield: 66.2 %

Procedure:
A solution of 4-isopropylacetophenone (65 g) in ethyl acetate (250 mL) is cooled to 0° C. and treated with bromine (65 g) dropwise. The mixture is stirred for 5 h, then quenched by the addition of water (250 mL). The phases are separated, and the aqueous layer is extracted with ethyl acetate. The organic phases are washed with satd. aq. NaHCO3 and brine, combined, dried over Na2SO4, filtered and evaporated to afford the product, 2-bromo-4′-isopropylacetophenone (64 g, 66%).