Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[NH2:23])C(O)=O.C1C[O:27][CH2:26]C1>>[N:8]1([C:1]([C:16]2[CH:20]=[CH:21][C:22]3[NH:23][C:26](=[O:27])[NH:13][C:14]=3[CH:15]=2)=[O:2])[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1CCOC1
Reactant: Nc1ccc(C(=O)O)cc1N
Product: O=C(c1ccc2[nH]c(=O)[nH]c2c1)n1ccnc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66 %

Procedure:
To a solution of 1,1′-carbonyl-diimidazole (11.7 g, 72.3 mmol) in THF (500 mL) was added 3,4-diaminobenzoic acid (5.00 g, 32.9 mmol) and stirred for 3 days at ambient temperature. The reaction mixture was concentrated and stirred for 30 min at 80° C. in water (100 mL). The resulting suspension was then cooled to ambient temperature and the mixture was filtered off and washed with water (2×50 mL) to afford the title compound (4.94 g, 66%) which was obtained as a white solid. MS: m/e=229.3 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=O)[CH2:2]1.Cl.[CH3:12][O:13][NH2:14].C([O-])(=O)C.[Na+]>CO>[CH3:12][O:13][N:14]=[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][CH2:2]1
Reactant: CON
Reactant: O=C1COc2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CON=C1COc2ccccc21
Yield: 89.1 %

Procedure:
6.7 g (0.05 mol) of benzofuran-3-one together with 4.2 g (0.05 mol) of O-methylhydroxylamine hydrochloride and 4.1 g (0.05 mol) of sodium acetate in 50 ml of methanol are heated under reflux for 3 hours. The solvent is distilled off under reduced pressure and the reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium carbonate solution. The organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. 7.27 g (89.2% of theory) of crude benzofuran-3-one O-methyl-oxime are obtained. For analysis, the crude product is distilled at 2 torr and 70° C. using a Kugelrohr. An oil is obtained which, both according to NMR analysis and according to HPLC analysis, comprises two stereoisomers (79% of isomer B and 21% of isomer A).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16]OS(C)(=O)=O)[CH2:10][C@H:9]1[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)=[O:7].[NH:42]1[CH2:47][CH2:46][S:45][CH2:44][CH2:43]1.C(N(CC)CC)C.[ClH:55]>CO.C(OCC)(=O)C>[ClH:55].[ClH:55].[F:40][C:2]([F:41])([F:1])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:37])([F:39])[F:38])[CH:35]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:42]2[CH2:47][CH2:46][S:45][CH2:44][CH2:43]2)[CH2:10][C@H:9]1[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)=[O:7]
Reactant: C1CSCCN1
Reactant: CS(=O)(=O)OCCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc3ccccc3c2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCCN2CCSCC2)C[C@H]1Cc1ccc2ccccc2c1

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (250 mg), thiomorpholine (43 mg) and triethylamine (46 mg) in dry methanol (5 ml) was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel using ethyl acetate as an eluent. The product obtained was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-(3-thiomorpholinopropyl)piperazine dihydrochloride (195 mg).
Reaction SMILES: [C:1]([CH2:8][C:9]([OH:11])=O)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(Cl)(=O)C([Cl:15])=O>CCCCCC>[C:1]([CH2:8][C:9]([Cl:15])=[O:11])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)CC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCCCCC
Product: CCCCCC(=O)CC(=O)Cl
Reaction time: 1 h
Yield: 96.8 %

Procedure:
8.7 g (0.05 m) of hexanoylacetic acid and 12.7 g (0.10 m) of oxalyl chloride were mixed together at room temperature. The reaction was heated gradually over one hour to 50°-60° C., then to 60°-70° C. under aspirator pressure for one hour. The reaction mixture was diluted with 125 ml hexane, washed with 3×100 ml ice water, dried over 20 g MgSO4, and roto-vapped at 50° C. to yield an oil (9.4 g, 98% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.[N:13]([CH2:16][CH2:17][CH2:18][CH3:19])=[C:14]=[O:15].[H-].[Na+].Cl>O.O1CCCC1>[CH2:16]([N:13]1[C:7](=[O:9])[C:6]2[CH:5]=[C:4]([CH2:11][CH3:12])[S:3][C:2]=2[NH:1][C:14]1=[O:15])[CH2:17][CH2:18][CH3:19]
Reactant: CCc1cc(C(=O)OC)c(N)s1
Reactant: CCCCN=C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCn1c(=O)[nH]c2sc(CC)cc2c1=O
Temperature: 60 °C
Yield: 54 %

Procedure:
To a mixture of methyl 2-amino-5-ethylthiophene-3-carboxylate (2.5 g), 1-isocyanatobutane (1.52 mL) and tetrahydrofuran (20 ml) was added sodium hydride (1.2 g), and the mixture was stirred at 60° C. for. 5 hr. The reaction mixture was diluted with water, and the mixture was adjusted to pH 4 with 1N hydrochloric acid, the precipitated solid was collected by filtration. The obtained solid was recrystallized from ethyl acetate to give the title compound as colorless crystals (1.85 g, 54%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)=[O:5].[C:13]([C:16]([CH2:23][Br:24])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])(O)=[O:14].CN1CCOCC1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C1COCC1>[Br:24][CH2:23][C:16]([O:17][CH2:18][CH3:19])([O:20][CH2:21][CH3:22])[C:13]([NH:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)=[O:5])=[O:14]
Reactant: NCC(=O)c1cccc(Br)c1
Reactant: CCOC(CBr)(OCC)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(CBr)(OCC)C(=O)NCC(=O)c1cccc(Br)c1
Reaction time: 18 h

Procedure:
The 2-amino-1-(3-bromophenyl)ethanone hydrochloride (4.6 g, 19 mmol), HO2CC(OEt)2CH2Br (5.0 g, 21 mmol), and NMM (12.5 mL, 113 mmol) were suspended in anhyd THF (270 mL) under N2 and PyBOP (10.8 g, 21 mmol) was added in one portion. The reaction mixture was stirred for 18 h and concentrated to ¼ vol and the precipitates were removed by filtration (HCl salt of NMM). The mother liquor was taken up in dichloromethane and washed with water. After concentration, the crude residue was subjected to flash chromatography (silica gel) eluting with 60% EtOAc/hexanes to give Intermediate J.1, 5.3 g (65%). 1H NMR (500 MHz, DMSO-d6): δ 8.27 (t, J=5.5 Hz, 1H), 8.14 (t, J=1.5 Hz, 1H), 8.00 (dt, J=7.9, 1.2 Hz, 1H), 7.87 (dd, J=8.8, 1.8 Hz, 1H), 7.51 (t, J=7.9 Hz, 1H), 4.65 (d, J=5.8 Hz, 2H), 3.67 (s, 2H) 3.58-3.46 (m, 4H), 1.18 (t, J=7.0 Hz, 6H). LCMS: 2.2 min; LRMS: Calcd. for C15H19Br2NO4: 435.98. Found: 435.98 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]([C:19]3[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[N:17]=[C:16]([CH:27]([F:29])[F:28])[CH:15]=2)=[CH:10][CH:9]=1)(=O)=O.[OH2:30].[CH3:31][N:32]([CH:34]=[O:35])C>>[F:29][CH:27]([F:28])[C:16]1[CH:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][N:32]3[C:31](=[O:30])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:34]3=[O:35])=[CH:9][CH:10]=2)[N:18]([C:19]2[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[N:17]=1
Reactant: COc1ccc(-n2nc(C(F)F)cc2-c2ccc(CCOS(C)(=O)=O)cc2)cn1
Reactant: CN(C)C=O
Reactant: O
Product: COc1ccc(-n2nc(C(F)F)cc2-c2ccc(CCN3C(=O)c4ccccc4C3=O)cc2)cn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenyl}ethyl methanesulfonate (7.4 g) and Ph(CO) 2NK (3.88 g) in DMF (50 ml) was stirred at 60° C. for 8 hours. Added water. The organic layer was extracted twice with EtOAc. Aqueous layer was washed with water (twice) and brine, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was triturated with IPE, filtered and dried to give 7.65 g of 2-(2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenyl}ethyl)-1H-isoindole-1,3 (2H)-dione as a solid.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C@H:10]3[CH2:14][CH2:15][CH2:16][C@@H:9]23)=[N:6][CH:7]=1.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)#[CH:18].C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:19]1([C:17]#[C:18][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:12](=[O:13])[CH2:11][C@H:10]4[CH2:14][CH2:15][CH2:16][C@@H:9]34)=[N:6][CH:7]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C#Cc1ccccc1
Reactant: O=C1C[C@H]2CCC[C@H]2N1c1ccc(I)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1C[C@H]2CCC[C@H]2N1c1ccc(C#Cc2ccccc2)cn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
In a 10 ml Pyrex tube were dissolved (3aR,6aR)-1-(5-iodopyridin-2-yl)hexahydro-cyclopenta[b]pyrrol-2(1H)-one (107 mg, 326 μmol) in 2 ml of THF. Argon was bubbled through the solution. Ethynylbenzene (59.9 mg, 64.5 μl, 587 μmol, 1.8 equiv.), triethylamine (99.0 mg, 136 μmol, 978 μmol, 3.0 equiv.), bis(triphenylphosphine)palladium(II) chloride (13.7 mg, 19.6 μmol, 0.06 equiv.), triphenylphosphine (1.71 mg, 6.52 μmol, 0.02 equiv.), and copper (I) iodide (1.86 mg, 9.78 μmol, 0.03 equiv.) were added. The dark brown solution was stirred at 50° C. for 2 h. The residue was taken up in ethyl acetate, the solids were filtered off and washed with ethyl acetate. The filtrate was concentrated in vaccuo and the residue was purified by flash chromatography (SiO2, 20 g) using a 0% to 60% ethyl acetate in heptane gradient. One obtained 95 mg (96%) of the title compound as a viscous yellow oil, MS: m/e=303.2 (M+H+).
Reaction SMILES: [CH3:1][C:2](=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3]Cl.[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]=2[N:22]=1>C(Cl)(Cl)Cl>[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][N:18]([CH2:3][C:2]([CH3:1])=[CH:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:19][CH2:20][C:21]=2[N:22]=1
Reactant: CC(=Cc1ccccc1)CCl
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: ClC(Cl)Cl
Product: CC(=Cc1ccccc1)CN1CCc2nc(N)sc2CC1
Yield: 8 %

Procedure:
Prepared from 2-methyl-3-phenyl-allyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform for 2 hours at ambient temperature. Yield: 8% of theory, Melting point: 112°-115° C.
Reaction SMILES: F[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[C:16](=O)[CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13][C:12]3=[O:20])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[NH2:21][C:22]1C=CC(OC)=C[C:23]=1C(O)=O.[C:33](O)(=[O:41])C1C(=CC=CC=1)N>>[CH3:33][O:41][C:3]1[CH:2]=[CH:10][C:9]2[NH:8][C:7]3[C:22]([CH3:23])=[N:21][C:16]4[CH2:15][C:14]([CH3:18])([CH3:19])[CH2:13][C:12](=[O:20])[C:11]=4[C:6]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc(N)c(C(=O)O)c1
Reactant: CC1(C)CC(=O)C(c2c[nH]c3cc(F)ccc23)C(=O)C1
Reactant: Nc1ccccc1C(=O)O
Product: COc1ccc2[nH]c3c(C)nc4c(c3c2c1)C(=O)CC(C)(C)C4

Procedure:
Utilizing the procedures described in Example 3 a-c except substituting 2-(5-methoxy-1H-indol-3-yl)-5,5-dimethylcyclohexane-1,3-dione for 2-(6-fluoro-1H-indol-3-yl)-5,5-dimethylcyclohexane-1,3-dione in step 3a, and 2-amino-5-methoxybenzoic acid for anthranilic acid in step 1a of Example 1, the title compound was prepared and crystallized from toluene; m.p. 241-243° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.[N:13]([O-])=O.[Na+].[Sn](Cl)[Cl:18]>Cl.O>[ClH:18].[CH3:12][O:11][C:4]1[CH:3]=[C:2]([NH:1][NH2:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COc1cc(N)ccc1C(=O)O
Reactant: Cl[Sn]Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(NN)ccc1C(=O)O
Temperature: 0 °C

Procedure:
To a suspension of 4-amino-2-methoxybenzoic acid (3.00 g, 18.0 mmol) in hydrochoric acid (1.0 M, 30 mL) at 0° C. was added a solution of sodium nitrite (1.28 g, 18.5 mmol) in water (5.0 mL) over 5 min. The reaction mixture was maintained at 0° C. for 5 hr and was then treated with tin(II) chloride (9.53 g, 50.3 mmol) in hydrochloric acid (1M, 60 mL) and warmed to RT for 64 hr. A thick precipitate formed which was isolated by filtration, washed with water (50 mL) and ether (15 mL) and dried in vacuo to afford 2-methoxy-4-hydrazinylbenzoic acid hydrochloride as a beige solid (1.05 g, 90% purity, 24%); Rt 0.17 min (Method 2); m/z 181 (M+H)+, (ES+). This material was used in the subsequent step without further purification.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:44])[CH2:14][O:15][C:16]1[CH:21]=[C:20]([C:22]2[NH:26][C:25](=[O:27])[O:24][N:23]=2)[CH:19]=[C:18]([O:28][CH2:29][C:30]([N:32]2[CH2:36][CH2:35][CH2:34][C@@H:33]2[C:37]([O:39]C(C)(C)C)=[O:38])=[O:31])[CH:17]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:37]([C@H:33]1[CH2:34][CH2:35][CH2:36][N:32]1[C:30](=[O:31])[CH2:29][O:28][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([C:22]2[NH:26][C:25](=[O:27])[O:24][N:23]=2)[CH:19]=1)[O:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:44])([OH:39])=[O:38]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1cc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)cc(-c2noc(=O)[nH]2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1C(=O)COc1cc(OCC(=O)N2CCC[C@@H]2C(=O)O)cc(-c2noc(=O)[nH]2)c1
Reaction time: 8 h
Yield: 74.3 %

Procedure:
A solution of 220 mg (0.36 mmol) (R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl) -phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 1.5 ml trifluoroacetic acid was stirred for 4 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 135 mg (74%) of the title compound as a light brown powder. MS m/e (%): 527 (M+Na+, 73), 522 (M+NH4+, 75), 505 (M+H+, 100).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@:3]1([OH:11])[C:7]([O:9][CH3:10])=[O:8].Cl.[CH3:13][C:14]1[CH:23]=[C:22]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1>C(Cl)Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[OH:11][C@:3]1([C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:5][CH2:6][C@H:2]1[NH:1][S:32]([C:29]1[CH:30]=[CH:31][C:26]([O:25][CH2:24][C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH3:13])[CH:23]=2)=[CH:27][CH:28]=1)(=[O:33])=[O:34]
Reactant: COC(=O)[C@@]1(O)CCC[C@H]1N
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)[C@@]1(O)CCC[C@H]1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.2 %

Procedure:
To a solution of methyl (1R,2R)-2-amino-1-hydroxycyclopentanecarboxylate (2.1 mmol) in CH2Cl2 (8 mL) and saturated sodium bicarbonate (8 mL) was added 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride (0.88 g, 1.1 eq). The reaction was allowed to stir for 18 h at room temperature, and then taken up in ethyl acetate, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified using ilica chromatography eluting with a gradient of 50% -70% ethyl acetate/hexanes afforded methyl (1R,2R)-1-hydroxy-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylate (0.2 g, 20%). MS: 470.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](O)=[S:12])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:24][O:23][N:22]([CH3:21])[C:11]([C:6]1[NH:7][C:8]2[C:4]([C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[S:12]
Reactant: CNOC
Reactant: OC(=S)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=S)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared from 5-chloro-3-phenylthioindole-2-carboxylic acid (1.0 g, 3.30 mmol)) N,O-dimethylhydroxylamine hydrochloride (0.64 g, 6.6 mmol), triethylamine (1.0 mL, 7 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorphosphate (1.64 g, 3.6 mmol) in dimethylformamide according to the general procedure described in Example 1 for the preparation of N-(3-pyridylmethyl)-5-chloro-3-phenylthio-2-carboxamide.
Reaction SMILES: Br[CH2:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CS(C)=O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:23]=[CH:24][C:3]([CH2:2][N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[CH:4][CH:5]=2)=[CH:11][C:12]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CN1CCNCC1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)cc1
Solvent: CS(C)=O
Product: CN1CCN(Cc2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)CC1

Procedure:
4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide (85 mg) was dissolved in DMSO (1 mL) and stirred for 1 h with methylpiperazine. The reaction mixture was concentrated, and the crude residue was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4-methylpiperazin-1-yl)methyl) benzamide. MS (Q1) 421.3 (M)+.
Reaction SMILES: [C:1]1([C:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+:10].[C:11](=[O:13])=[O:12]>>[C:11]([O-:13])(=[O:12])[C:4]1[CH:5]=[CH:6][C:1]([C:7]([O-:9])=[O:8])=[CH:2][CH:3]=1.[K+:10].[K+:10]
Reactant: O=C=O
Reactant: O=C([O-])c1ccccc1
Agent: [K+]
Product: O=C([O-])c1ccc(C(=O)[O-])cc1

Procedure:
isomerizing said dried potassium benzene carboxylic acid salt mixture by heating under an atmosphere comprising carbon dioxide to produce a dipotassium terephthalic acid salt;
Reaction SMILES: NC1[C:3]([O:12][CH3:13])=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.IC.C(=O)([O-])[O-].[K+].[K+].[CH3:22][N:23]([CH3:26])[CH:24]=O>C(OCC)(=O)C.O>[Br:8][C:6]1[CH:7]=[C:24]([N:23]([CH3:26])[CH3:22])[C:3]([O:12][CH3:13])=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=1
Reactant: CN(C)C=O
Reactant: COc1c(N)cc(Br)cc1C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: O
Product: COc1c(C(C)=O)cc(Br)cc1N(C)C
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(3-amino-5-bromo-2-methoxyphenyl)-1-ethanone (12.8 g), iodomethane (60 mL), potassium carbonate (14.4 g) and N,N-dimethylformamide (200 mL) was stirred at 60 to 70° C. for 2 hours. Water was added to the mixture, extraction was performed with ethyl acetate, and the organic layer was washed with brine and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (9.6 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[C:8]([O:17][C@@H:18]([C@@H:20]2[CH2:24][O:23]C(C)(C)[O:21]2)[CH3:19])[N:7]=1.C(O)(C(F)(F)F)=O>CO>[F:1][C:2]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[C:8]([O:17][C@H:18]([CH3:19])[C@@H:20]([OH:21])[CH2:24][OH:23])[N:7]=1
Reactant: C[C@@H](Oc1cc(NS(C)(=O)=O)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: C[C@@H](Oc1cc(NS(C)(=O)=O)nc(SCc2cccc(F)c2F)n1)[C@@H](O)CO
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of N-(2-[(2,3-difluorobenzyl)thio]-6-{(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy}pyrimidin-4-yl)methanesulfonamide (0.23 g) in MeOH (2 ml) was added TFA (0.4 ml) and the reaction was stirred at room temperature for 20 h. The mixture was evaporated, suspended in saturated sodium carbonate solution and then re-acidified to pH5 with glacial acetic acid with stirring. The resulting solid was collected, washed with H2O and dried to give the title compound as a cream solid. Yield 0.17 g.
Reaction SMILES: O=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH2:11]([NH2:17])[C:12]1[O:16][CH:15]=[CH:14][CH:13]=1.[Cl:18][CH2:19][CH2:20][N:21]=[C:22]=[O:23]>>[Cl:18][CH2:19][CH2:20][NH:21][C:22]([N:17]([CH2:11][C:12]1[O:16][CH:15]=[CH:14][CH:13]=1)[CH:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@H:3]1[OH:4])=[O:23]
Reactant: NCc1ccco1
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C=NCCCl
Product: O=C(NCCCl)N(Cc1ccco1)C1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 64.3 %

Procedure:
3.0 g of D-ribose, 2.8 g of furfurylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 31-(1). 4.3 g of 1-(2-chloroethyl)-3-furfuryl-3-(D-ribofuranosyl)urea are thereby obtained as colorless caramel.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20]C)=[O:19].Cl>CN(C)C=O.O>[C:18]([CH2:17][N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3])([OH:20])=[O:19]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: COC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of thymine (0.317 mol) and potassium carbonate (0.634 mol) in dimethylformamide (900 ml) is added methyl bromoacetate (0.634 mol) and the mixture is stirred vigorously overnight under nitrogen. The mixture is filtered, washed with ether and evaporated to dryness, in vacuo, to afford a solid residue. The solid residue is treated with water (300 ml) and 4N hydrochloric acid (12 ml), stirred for 20 minutes at 0° C., filtered and washed with water (2×100 ml). The precipitate is treated with water and 2 N sodium hydroxide (60 ml), and is boiled for 10 minutes. The mixture is cooled at 0° C., filtered, and precipitated by the addition of 4N hydrochloric acid (70 ml) to afford the the pure title compound.