Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][OH:15])[CH2:9]1)C1C=CC=CC=1.Cl.C(O)C.[C:20](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OC(C)C)(C)C>C(O)C.C(Cl)Cl.[C].[Pd].C(N(CC)CC)C.CO>[C:20]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][OH:15])[CH2:9]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC[C@@H]1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Solvent: CO
Product: OC[C@@H]1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCO1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 44.6 %

Procedure:
3.5 g of (S)-4-benzyl-2-hydroxymethylmorpholine was dissolved in 5 ml of ethanol. To the solution was added 5 ml of a 5.9N dry hydrogen chloride-ethanol solution with ice cooling. The resulting mixture was stirred for 10 minutes at the same temperature. Thereto was added a mixture of 500 mg of 5% palladium-carbon and 10 ml of methanol. The resulting mixture was subjected to hydrogenation for 3 hours at 40° C. After the completion of the reaction, palladium-carbon was removed by filtration. The solvent was removed by distillation under reduced pressure to obtain a yellow oily product. To the oily product were added 20 ml of dry methylene chloride and 4.7 ml of triethylamine. The resulting mixture was stirred at room temperature for 30 minutes. Thereto was dropwise added a solution of 4.7 g of trityl chloride dissolved in 10 ml of methylene chloride in 20 minutes, with ice cooling. The mixture was stirred at room temperature for 3 hours and added to 50 ml of ice water. The organic layer was separated and 20 ml of water was added thereto. The resulting mixture was adjusted to pH 12 with a 1N aqueous sodium hydroxide solution. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain a yellow oily product. The oily product was mixed with 10 ml of diisopropyl ether. The resulting crystals were collected by filtration to obtain 2.7 g of (S)-4-trityl-2-hydroxymethylmorpholine.
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[N:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.[Sn](Cl)(Cl)(Cl)Cl>Cl>[ClH:5].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][NH2:1])=[CH:10][N:11]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)nc1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Product: NNc1ccc(Cl)nc1
Reaction time: 1 h
Yield: 269.9 %

Procedure:
An aqueous sodium nitrite solution (3.49 g of sodium nitrite in 12.5 mL of water) was dropwise added to a solution of 6-chloropyridine-3-amine (5.00 g) in hydrochloric acid (77.8 mL) over 10 minutes (such that the temperature does not exceed −20° C.) under dry ice-acetone cooling (−20 to −40° C.), followed by stirring under the same conditions for 1 hour. A solution of tin chloride (14.8 g) in hydrochloric acid (25 mL) was dropwise added thereto over 15 minutes, followed by stirring at approximately 0° C. for 2 hours. The precipitated solid was collected by filtration (washed with water and n-hexane) and was vacuum dried at 40° C. to yield the title compound (9.45 g, brown solid).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:25]([CH2:26][CH2:27][C@:6]12[CH3:7])[C@:19]1([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C:14]([CH2:15][C@@H:16]([OH:28])[CH2:17][CH2:18]1)=[CH:13][CH2:12]3)(=[O:3])[CH3:2].F[B-](F)(F)F.[CH2:34]([O+](CC)CC)[CH3:35].O>C(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:25]([CH2:26][CH2:27][C@:6]12[CH3:7])[C@:19]1([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C:14]([CH2:15][C@@H:16]([O:28][CH2:34][CH3:35])[CH2:17][CH2:18]1)=[CH:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCO[C@H]1CC[C@@]2(COC(C)=O)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Androstene-3β,17β,19-triol 17,19-diacetate is dissolved in methylenechloride and triethyloxonium fluoroborate added thereto. After stirring for a period of about two hours at room temperature, water is added to the reaction mixture. The methylenechloride layer is dried over magnesium sulfate and concentrated to dryness. The residue is crystallized from an acetone-hexane mixture to yield the desired 3β-ethoxy-5-androstene-17β,19-diol diacetate.
Reaction SMILES: Cl[C:2]([N:4]=[C:5]=[O:6])=[O:3].[OH:7][NH:8][C:9](=[O:20])[N:10]([CH:17]([CH3:19])[CH3:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C(Cl)Cl>[CH3:19][CH:17]([N:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:9]([N:8]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[O:7]1)=[O:20])[CH3:18]
Reactant: CC(C)N(C(=O)NO)c1ccccc1
Reactant: O=C=NC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)N(C(=O)n1oc(=O)[nH]c1=O)c1ccccc1
Reaction time: 2 h
Yield: 32.3 %

Procedure:
A solution of chlorocarbonyl isocyanate (5.0 g, 0.047 mol) was added dropwise to a slurry of the title compound of Step A (9.2 g, 0.047 mol) and triethylamine (5.3 g, 0.052 mol) in 200 mL of THF while maintaining the reaction temperature below 30° C. using an ice bath. After 2 hours, TLC showed the presence of starting material. Another 0.5 g of chlorocarbonyl isocyanate was added, and the reaction mixture was stirred for another hour. At that point, TLC showed still the presence of starting material. The reaction mixture was filtered to, remove solids, and the filtrate was stripped to dryness and then extracted with 1N HCl and ether. Upon evaporation of volatiles, a gummy product was obtained which was taken into methylene chloride and potassium carbonate solution. Solids were collected by a filtration, washed with methylene chloride and air dried. The solids (5.3 g) were found to be the potassium salt of the title compound. The basic aqueous filtrate was acidified with concentrated HCl and extracted with methylene chloride to afford 4 g of the title compound, an intermediate useful for the preparation of the compounds of the present invention, melting at 116-7° C. From the methylene chloride used to wash the solids, 2.6 g of the title compound of Step A was recovered. This represented a 71.7% conversion. The combined yield was therefore 96% based on the 71.7% conversion.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[C:3]=1[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5]>CO>[NH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:2]([CH3:1])[C:3]=1[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5]
Reactant: C=CCOC(=O)c1c(C)cccc1[N+](=O)[O-]
Solvent: CO
Product: C=CCOC(=O)c1c(C)cccc1N
Yield: 74.8 %

Procedure:
Stannous chloride dihydrate (15.3 g, 67.8 mM) was suspended in methanol (25 ml), and a solution of allyl 2-methyl-6-nitrobenzoate (3.0 g, 13.6 mM) in methanol (5 ml) was added. The mixture was heated at reflux for 1 hour, cooled, and solvent removed. The residue was treated with ethyl acetate (100 ml), made basic with 880 ammonia and diluted with water (50 ml). The organic layer was decanted from the slurry of tin salts, which was extracted with two further portions of ethyl acetate. The combined organic extracts were washed with dilute ammonia, water, brine, and dried over MgSO4, to give allyl 2-amino-6-methylbenzoate as an oil (1.94 g, 75%).
Reaction SMILES: [N+]([O-])([O-])=O.[Ag+:5].N.[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[N:8]1>>[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[N:8]1.[Ag:5]
Reactant: [Ag+]
Agent: N
Agent: O=[N+]([O-])[O-]
Agent: c1ccc2[nH]nnc2c1
Product: [Ag]

Procedure:
Prepared by mixing simultaneously an ammoniacal silver nitrate aqueous solution and bendotriazole (containing 0.2 mol % of aqueous ammonia per mol benzotriazole) into a 10%-aqueous solution of phenylcarbamoyl gelatin of 50° C. After completing the addition, the pH was reduced and then flocculation and desalting were carried out to obtain needle crystals (width: 0.1 to 0.2 μm, length: 0.5 to 2 μm). ##STR9##
Reaction SMILES: [CH:1]1([C:4]2[C:5]3[CH:12]=[CH:11][NH:10][C:6]=3[N:7]=[CH:8][N:9]=2)[CH2:3][CH2:2]1.[F:13][C:14]1[C:19]([CH:20]=[O:21])=[C:18]([F:22])[CH:17]=[CH:16][C:15]=1[NH:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>>[CH:1]1([C:4]2[C:5]3[C:12]([CH:20]([OH:21])[C:19]4[C:14]([F:13])=[C:15]([NH:23][S:24]([C:27]5[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=5)(=[O:26])=[O:25])[CH:16]=[CH:17][C:18]=4[F:22])=[CH:11][NH:10][C:6]=3[N:7]=[CH:8][N:9]=2)[CH2:3][CH2:2]1
Reactant: c1nc(C2CC2)c2cc[nH]c2n1
Reactant: O=Cc1c(F)ccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F
Product: O=S(=O)(Nc1ccc(F)c(C(O)c2c[nH]c3ncnc(C4CC4)c23)c1F)c1ccc(C(F)(F)F)cc1

Procedure:
4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine (44) was reacted with N-(2,4-difluoro-3-formyl-phenyl)-4-trifluoromethyl-benzenesulfonamide (10) similarly to the protocol of Example 4, Scheme 2, Step 1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Cl[CH2:10][C:11]([NH:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][N:15]=1)=[O:12].C([O-])([O-])=O.[Cs+].[Cs+].CC#N>C(Cl)Cl>[CH3:21][O:20][C:18]1[C:17]([O:22][CH3:23])=[CH:16][N:15]=[C:14]([NH:13][C:11](=[O:12])[CH2:10][N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)[N:19]=1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: COc1cnc(NC(=O)CCl)nc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: COc1cnc(NC(=O)Cn2cc([N+](=O)[O-])cn2)nc1OC
Temperature: 80 °C

Procedure:
A flask was charged with 4-nitro-1H-pyrazole (A) (317 mg, 2.8 mmol), 2-chloro-N-(4,5-dimethoxypyrimidin-2-yl)acetamide (2.26 mmol), Cs2CO3 (1.0 g, 3.09 mmol) and MeCN (9.0 mL). The resulting reaction mixture was stirred at reflux (80° C.) for 1 h, then allowed to reach rt. The mixture was diluted with DCM, filtered, the filter cake was washed with DCM. The filtercake was redisolved in DCM and water, the org. layer was separated and the aq. layer was extracted with DCM (2×). The combined org. layers were washed with brine, dried (MgSO4), filtered and concentrated to yield N-(4,5-dimethoxypyrimidin-2-yl)-2-(4-nitro-1H-pyrazol-1-yl)acetamide as a crude which was used in the next step without further purification. LC-MS conditions B: tR=0.46 min, [M+H]+=309.10.
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].Br[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O>CN(C)C=O>[N+:1]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH3:6])([O-:3])=[O:2]
Reactant: O=N[O-]
Reactant: CCCCCCCCCCCCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCC[N+](=O)[O-]
Reaction time: 6 h

Procedure:
To a stirred, room temperature suspension of sodium nitrite (227 g, 3.29 mol) in dimethylformamide (3.8 L) was added 1-bromotridecane (514.51 g, 1.95435 mol), and the mixture was stirred for 6 hours. The mixture was poured into cold water (8 L) and extracted with petroleum ether (2×2 L). The organic layer was washed with water (2 L), saturated sodium chloride, dried (MgSO4), and rotoevaporated to a yellow oil. The oil was distilled in vacuo to give another oil; yield 171.9 g, bp 101°-120° C. (0.2 mm Hg). The oil was chromatographed on silica gel (3.0 kg, 230-400 mesh) using ether/ethyl acetate (100:1, 4×2 L; 80:1, 4×2 L; 50:1, 7×2 L) to give a clear colorless oil; yield 109.8 g (24.5%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=O)[CH2:4][CH2:3]1.Cl.[OH-].[Na+]>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=3)[CH2:14][CH2:13][CH2:12]2)[CH2:4][CH2:3]1
Reactant: CN1CCN(CC(=O)N2CCCc3ccc([N+](=O)[O-])cc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCN(CCN2CCCc3ccc([N+](=O)[O-])cc32)CC1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Under a nitrogen atmosphere, 6 g (18 mmol) of 2-(4-methylpiperazin-1-yl)-1-(7-nitro-3,4-dihydroquinolin-1(2H)-yl)ethanone are dissolved in 20 ml of anhydrous THF. With stirring, at 0° C., a solution of 100 ml of 1.0M BH3 in THF (5.5 eq) is added. The temperature was allowed to return to ambient temperature and stirring was carried out for 24 h, before acidifying (drop by drop) with 1N HCl (considerable foaming and release of gas), and the medium was then brought to reflux for 0.5 h. After a return to ambient temperature, a 4.0N aqueous solution of NaOH was added. The medium was extracted several times with ethyl acetate. The combined organic phases were dried over Na2SO4, and then filtered. After removal of the solvent, a residue was obtained, which was purified on a silica column (dichloromethane-methanol). 1-(2-(4-Methylpiperazin-1-yl)ethyl)-7-nitro-1,2,3,4-tetrahydroquinoline was thus obtained in the form of an orange powder (Mp 58-60° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[CH:13]1([CH2:18][C:19]2[O:23][N:22]=[C:21]([NH:24][C:25](=[O:31])[C@@H:26]([NH2:30])[CH2:27][CH2:28][CH3:29])[CH:20]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH:13]1([CH2:18][C:19]2[O:23][N:22]=[C:21]([NH:24][C:25](=[O:31])[C@@H:26]([NH:30][CH:7]3[CH2:6][CH2:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=4)[CH2:8]3)[CH2:27][CH2:28][CH3:29])[CH:20]=2)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCC[C@H](N)C(=O)Nc1cc(CC2CCCC2)on1
Reactant: O=C1CCc2cc(F)ccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC[C@H](NC1CCc2cc(F)ccc2C1)C(=O)Nc1cc(CC2CCCC2)on1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-Fluoro-3,4-dihydro-1H-naphthalen-2-one (0.2 mmol) was combined with 2-(S)-Amino-pentanoic acid (5-Cyclopentylmethyl-isoxazol-3-yl)-amide (0.2 mmol) in 2 mL of anhydrous dichloromethane under N2. Sodium triacetoxyborohydride (0.3 mmol) and two drops acetic acid were added and the reaction was stirred at rt for 16 h. The crude solution was then concentrated under reduced pressure and purified through flash chromatography on silica gel to give 2-(S)-(6-Fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (5-cyclopentylmethyl-isoxazol-3-yl)-amide, LC-MS: retention time 2.0 min, M+1: 414.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[S:11]1.[Br:22][CH2:23][CH2:24][CH2:25]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Br:22][CH2:23][CH2:24][CH2:25][O:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[S:11]1
Reactant: COc1ccc(O)c(C2Sc3ccccc3N(C)C2=O)c1
Reactant: OCCCBr
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(OCCCBr)c(C2Sc3ccccc3N(C)C2=O)c1
Reaction time: 2 h
Yield: 51 %

Procedure:
To a solution of (-)-3,4-dihydro-2-(2-hydroxy-5-methoxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (6.3 g), which was prepared by the process (ii), in anhydrous tetrahydrofuran (70 ml), 3-bromo-1-propanol (8.8 g), triphenylphosphine (16.6 g) and then diethyl azodicarboxylate (10.0 ml) were added. The mixture was stirred for 2 hours under nitrogen atmosphere and concentrated in vacuo. The residue was purified by the silica gel column chromatography to give 4.5 g (51%) of (-)-3,4-dihydro-2-[2-(3-bromopropoxy)-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine.
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27](Cl)=[CH:28][C:29]=2[C:30]2[CH:34]=[CH:33][O:32][CH:31]=2)=[CH:18][C:17]=1[F:36])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.[F:38][C:39]1[C:44](B(O)O)=[CH:43][CH:42]=[CH:41][N:40]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Cl:22][C:20]1[C:19]([O:23][C:24]2[C:29]([C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)=[CH:28][C:27]([C:44]3[C:39]([F:38])=[N:40][CH:41]=[CH:42][CH:43]=3)=[N:26][CH:25]=2)=[CH:18][C:17]([F:36])=[C:16]([S:13]([NH:7][C:8]2[N:9]=[CH:10][S:11][CH:12]=2)(=[O:15])=[O:14])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(Oc2cnc(Cl)cc2-c2ccoc2)cc1F
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2cnc(-c3cccnc3F)cc2-c2ccoc2)cc1F
Reaction time: 0.08 h
Yield: 71.8 %

Procedure:
10 mg of tert-butyl((5-chloro-4-((6-chloro-4-(furan-3-yl)pyridin-3-yl)oxy)-2-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate was dissolved in 1,4-dioxane/H2O=1:1 (0.38 mL), and 3.5 mg of (2-fluoropyridin-3-yl)boronic acid, 0.65 mg (3 mol %) of Pd(PPh3)4 and 5.96 mg of Na2CO3 were added thereto. After reacting with microwave reactor at 120° C. for 5 minutes, 1,4-dioxane was removed by concentrating under reduced pressure. After extracting with ethyl acetate, the extract was treated with MgSO4, and concentrated under reduced pressure. The residue was separated by PLC (developing solvent, EA:n-Hex=1:1) to obtain 6.7 mg (72% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19](O)=[O:20])[CH:15]=2)[C:10]1=[O:22].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:44][C:45]1[CH:46]=[C:47]([CH:49]=[CH:50][C:51]=1[CH3:52])[NH2:48]>CN(C=O)C.O>[CH3:44][C:45]1[CH:46]=[C:47]([NH:48][C:19]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[C:10](=[O:22])[N:9]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])[C:17]3=[O:18])=[O:20])[CH:49]=[CH:50][C:51]=1[CH3:52]
Reactant: Cc1cccc(C)c1N1C(=O)c2ccc(C(=O)O)cc2C1=O
Reactant: Cc1ccc(N)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)c2ccc3c(c2)C(=O)N(c2c(C)cccc2C)C3=O)cc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 2-(2,6-dimethylphenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid (130 mg), EDCI (85 mg) and HOBt (60 mg) in DMF (3 mL) was added 3,4-dimethylaniline (53 mg) and the mixture was stirred at room temperature for 24 h. The mixture was poured into water and was extracted with EtOAc. The organic phase was washed with water (3×) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography using CH2Cl2 as eluent to give 2-(2,6-dimethylphenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid (3,4-dimethylphenyl)-amide as a pale-yellow solid, mp=223-225° C.; MS (m/z) 397 (M−1); 1H NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 8.09 (d, J=8.34 Hz, 1H), 7.81 (s, 1H), 7.45 (s, 1H), 7.37-7.15 (m, 5H), 2.30 (s, 3H), 2.27 (s, 3H), 1.54 (s, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[C:10]([O:14][C:15](ON=C(C1C=CC=CC=1)C#N)=[O:16])([CH3:13])([CH3:12])[CH3:11]>O1CCOCC1.O>[C:10]([O:14][C:15]([NH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCCN1CCNCC1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NCCN1CCNCC1

Procedure:
1-(2-aminoethyl)piperazine (1.29 g, 10 mmol) is dissolved in 20 mL of dioxane:water (1:1) mixture and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (2.46 g, 10 mmol) is added. The mixture is then stirred until no starting material is detected on thin layer chromatography. The obtained mixture is fractionally separated by silica gel chromatography, followed by RP-HPLC to obtain 1-[2-tert-butoxycarbonylaminoethyl]piperazine. Following the procedure of Example 6, but replacing 1-benzylpiperazine with 1-[2-tert-butoxycarbonylaminoethyl]piperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 1-[2-tert-butoxycarbonylaminoethyl]piperazine (1.396 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48%-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5, followed by a carefully deprotection of N-tert-butoxycarbonyl group with 10% trifluoroacetic acid to obtain the pure title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]([C@H:12]2[CH2:17][CH2:16][C@H:15](C3C=CC(CNC)=CC=3)[CH2:14][CH2:13]2)[CH2:9][C:10]#[CH:11])=[O:7])=[CH:4][CH:3]=1.Br[CH2:30][CH2:31][CH2:32][OH:33]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:4]3[CH:3]=[CH:2][C:28]([CH2:30][CH2:31][CH2:32][OH:33])=[CH:27][C:5]=3[CH2:6][NH:8][CH3:9])[CH2:14][CH2:13]2)[CH2:9][C:10]#[CH:11])=[O:7])=[CH:4][CH:3]=1
Reactant: C#CCN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccc(CNC)cc2)CC1
Reactant: OCCCBr
Solvent: ClCCl
Solvent: CO
Product: C#CCN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccc(CCCO)cc2CNC)CC1

Procedure:
from trans-N-(4-chlorobenzoyl)-N-propargyl-4-(4-methylaminomethylphenyl)cyclohexylamine and 3-bromo-1-propanol. Oil. Rf value: 0.53 (alumina, methylene chloride/methanol=50:1, v:v).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([CH3:30])[CH:29]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:32][CH2:33]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: COc1cc2ccccc2cc1NC(=O)Oc1ccccc1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cc2ccccc2cc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
Phenyl N-(2-methoxynaphth-3-yl)carbamate (375 mg, 1.28 mmol) and 1-(3,5-dimethylphenyl)piperazine (208 mg, 1.28 mmol) were dissolved in anhydrous tetrahydrofuran (25 ml) and thereto DBU (195 mg, 1.28 mmol) was added, and then stirred at room temperature for 2 hours, concentrated under the reduced pressure to remove the solvent and purified by column chromatography to obtain the titled compound.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]1[CH:15]=[C:14]([O:16][CH2:17][O:18][CH3:19])[CH:13]=[C:12]([C:20]([CH3:28])([CH3:27])[O:21][SiH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:11]=1[O:29][CH2:30][O:31][CH3:32])=[O:4].Cl.[CH3:34][NH:35][O:36][CH3:37].C([Mg]Cl)(C)C>>[CH3:37][O:36][N:35]([CH3:34])[C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]1[CH:15]=[C:14]([O:16][CH2:17][O:18][CH3:19])[CH:13]=[C:12]([C:20]([CH3:28])([CH3:27])[O:21][SiH2:22][C:23]([CH3:25])([CH3:26])[CH3:24])[C:11]=1[O:29][CH2:30][O:31][CH3:32])=[O:4]
Reactant: CNOC
Reactant: COCOc1cc(C2CCCC2C(=O)OC)c(OCOC)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Product: COCOc1cc(C2CCCC2C(=O)N(C)OC)c(OCOC)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Yield: 96.9 %

Procedure:
Use conditions analogous to those described in Step D of Examples 1A and 1B to react (±)-2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-2,5-bis-methoxymethoxy-phenyl]-cyclopentanecarboxylic acid methyl ester (0.605 g, 1.29 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.189 g, 1.94 mmol) in the presence of isopropylmagnesium chloride (2.13 mL, 4.26 mmol) to afford the subtitled product (0.622 g, 97%) as an oil that may be used without further purification.