Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]1[CH:12]=[C:13]([C@H:24]([OH:27])[CH2:25][OH:26])[C:14]2[S:18][C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[N:16][C:15]=2[CH:23]=1)([CH3:9])([CH3:8])[CH3:7]>N1C=CC=CC=1>[C:6]([O:10][C:11]1[CH:12]=[C:13]([C@H:24]([OH:27])[CH2:25][O:26][S:2]([CH3:1])(=[O:4])=[O:3])[C:14]2[S:18][C:17]([O:19][CH:20]([CH3:21])[CH3:22])=[N:16][C:15]=2[CH:23]=1)([CH3:7])([CH3:8])[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Oc1nc2cc(OC(C)(C)C)cc([C@H](O)CO)c2s1
Solvent: c1ccncc1
Product: CC(C)Oc1nc2cc(OC(C)(C)C)cc([C@H](O)COS(C)(=O)=O)c2s1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Methane sulfonylchloride (112 mg) is added to (S)-1-(5-tert-Butoxy-2-isopropoxy-benzothiazol-7-yl)-ethane-1,2-diol (289 mg) in pyridine (2 ml) at 0° C. The reaction mixture is then stirred at 0° C. for 3 hours. The solvent is removed in vacuo, The resulting residue is partitioned between HCl(aq) (2M) and ether. The organics is washed with water (2×), brine (1×), dried over MgSO4, filtered and the solvent removed in vacuo to give the title compound. 1H nmr (CDCl3, 400 MHz); 7.20 (d, 1H), 6.80 (d, 1H), 5.30 (sept, 1H), 5.10 (t, 1H), 4.30 (d, 2H), 3.00 (s, 3H), 1.40 (d, 6H), 1.30 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=1)[O:10][CH:11]([CH3:17])[C:12]([O:14]CC)=[O:13])([O-:3])=[O:2].[OH-].[Na+]>C(O)C.O>[N+:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=1)[O:10][CH:11]([CH3:17])[C:12]([OH:14])=[O:13])([O-:3])=[O:2]
Reactant: CCOC(=O)C(C)Oc1cccc(Oc2ccccc2[N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(Oc1cccc(Oc2ccccc2[N+](=O)[O-])c1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
In 100 ml of ethanol was dissolved 6.7 g of ethyl 2-[3-(2-nitrophenoxy)phenoxy]propionate followed by addition of a solution of 1.6 g of sodium hydroxide in 10 ml of water, and the mixture was stirred at room temperature for 1 hour. The ethanol was then distilled off and the residue was diluted with water, acidified with hydrochloric acid and extracted with chloroform. The chloroform layer was dried and concentrated to give 6.2 g of the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH3:11])=[CH:8][C:9]=1[Br:10])=[O:4].C1C(=O)N([Br:19])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11][Br:19])=[CH:8][C:9]=1[Br:10])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1sc(C)cc1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1sc(CBr)cc1Br
Yield: 44.7 %

Procedure:
A mixture of 3-Bromo-5-methyl-thiophene-2-carboxylic acid methyl ester (1.66 g, 7.06 mmol), NBS (1.63 g, 9.18 mmol), and Benzoyl peroxide (0.085 g, 0.35 mmol) in CCl4 (15 ml) was refluxed in a pressure tube 15 h. The reaction mixture was cooled and evaporated. The residue was purified by column (0-15% EtOAc in hexane) to give 0.99 g (45%) yellow oil product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:23])[C:9]2[CH:22]=[CH:21][C:12]3[N:13]([CH3:20])[C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:35])=[C:29]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:30]=1>>[Cl:35][C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:2]2[N:7]=[C:6]([N:8]([C:9]3[CH:22]=[CH:21][C:12]4[N:13]([CH3:20])[C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:15][C:11]=4[CH:10]=3)[CH3:23])[CH:5]=[CH:4][N:3]=2)=[CH:30][C:29]=1[S:31]([NH2:34])(=[O:33])=[O:32]
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: CC(C)Nc1nc2cc(N(C)c3ccnc(Cl)n3)ccc2n1C
Product: CC(C)Nc1nc2cc(N(C)c3ccnc(Nc4ccc(Cl)c(S(N)(=O)=O)c4)n3)ccc2n1C

Procedure:
The title compound was prepared following the procedure of example 1 with N5-(2-chloropyrimidin-4-yl)-N2-isopropyl-N5,1-dimethyl-1H-benzimidazole-2,5-diamine (83 mg, 0.25 mmol) and 5-amino-2-chloro-benzenesulfonamide (52 mg, 0.25 mmol) as a white solid (74 mg, 59%). 1H NMR (300 MHz, d6-DMSO) δ 9.58 (s, 1H), 8.78 (s, 1H), 7.83 (dd, J=8.7 and 2.1 Hz, 1H), 7.78 (d, J=5.7 Hz, 1H), 7.55 (br s, 1H), 7.40 (d, J=8.7 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.08 (s, 12H), 6.80 (d, J=8.1 Hz, 1H), 6.61 (d, J=7.5 Hz, 1H), 5.64 (d, J=6.0 Hz, 1H), 4.04 (m, 1H), 3.52 (s, 3H), 3.45 (s, 3H), 1.23 (d, J=6.3 Hz, 6H) ppm. MS (ESI) m/z=501 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[C:50]([O:54][C:55](=[O:76])[NH:56][C@H:57]([CH2:63][NH:64][C:65]([C:67]1[C:72]([NH2:73])=[N:71][C:70]([NH2:74])=[C:69]([Cl:75])[N:68]=1)=[O:66])[CH2:58][CH2:59][CH2:60][CH2:61][NH2:62])([CH3:53])([CH3:52])[CH3:51]>CN(C=O)C>[C:50]([O:54][C:55](=[O:76])[NH:56][C@H:57]([CH2:63][NH:64][C:65]([C:67]1[C:72]([NH2:73])=[N:71][C:70]([NH2:74])=[C:69]([Cl:75])[N:68]=1)=[O:66])[CH2:58][CH2:59][CH2:60][CH2:61][NH:62][C:16](=[O:18])[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)CNC(=O)c1nc(Cl)c(N)nc1N
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)Cc1ccc(OCc2ccccc2)cc1)CNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 4-benzyloxy-phenyl-acetic acid (39 mg, 0.16 mmol) and HATU (61 mg, 0.16 mmol) in DMF (3 mL) is added N-methylmorpholine (64 mg, 0.64 mmol) followed by a solution of ((S)-5-amino-1-{[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-methyl}-pentyl)-carbamic acid tert-butyl ester (Intermediate C) (64 mg, 0.16 mmol) in DMF (2 mL). The resulting mixture is stirred at RT for 17 h. The solvent is removed in vacuo to afford the title compound which is used in the next step without further purification. [M+H]+ 626.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](=[N:16][OH:17])[NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11](I)[CH:10]=2)=[N:4][O:5][N:6]=1.[CH2:18]([OH:21])[C:19]#[CH:20].C(NCC)C>CN(C)C=O.C(#N)C.O.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>[NH2:1][C:2]1[C:3]([C:7](=[N:16][OH:17])[NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:20]#[C:19][CH2:18][OH:21])[CH:10]=2)=[N:4][O:5][N:6]=1
Reactant: Nc1nonc1C(=NO)Nc1cccc(I)c1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nonc1C(=NO)Nc1cccc(C#CCO)c1
Temperature: 120 °C
Yield: 26.6 %

Procedure:
A solution of 4-amino-N′-hydroxy-N-(3-iodophenyl)-1,2,5-oxadiazole-3-carboximidamide (19 mg, 55 μmol), 2-propyn-1-ol (3.6 μL, 62 μmol), bis(triphenylphosphine)palladium(II) chloride (1 mg, 2 μmol), and copper (I) iodide (0.4 mg, 2 μmol) in N,N-dimethylformamide (0.5 mL) was treated with N,N-diethylamine (74 μl, 0.72 mmol) and heated in the microwave at 120° C. for 15 min. The reaction mixture was diluted with 1:1 acetonitrile/water (1.5 mL), filtered, and purified by preparative LCMS to give the desired product (4 mg, 28%). LCMS for C12H12N5O3 (M+H)+: m/z=274.0.
Reaction SMILES: [C:1]([CH2:3][C:4]1(O)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][C:5]1([CH3:17])[CH3:16])#[N:2].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][C:5]([CH3:17])([CH3:16])[C:4]2=[CH:3][C:1]#[N:2])=[CH:9][CH:10]=1
Reactant: COc1ccc2c(c1)C(O)(CC#N)C(C)(C)CC2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(=CC#N)C(C)(C)CC2

Procedure:
To a solution of 1-cyanomethyl-1-hydroxy-7-methoxy-2,2-dimethyl-1,2,3,4-tetrahydronaphthalene (5.27 g, 21.5-mmol) in toluene (50 ml) was added camphor sulfonic acid (0.5 g, 2.15 mmol). The mixture was heated for one hour under reflux. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate, and the organic layer was subjected to extraction with chloroform. The extract solution was washed with brine and water, which was dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (ethyl acetate:hexane=2:8) to give the above-titled compound (a mixture of isomers) (4.88 g, quantitative).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:12][C:13]([S@@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14]>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[Si:1]([O:8][CH2:9]/[CH:10]=[N:18]/[S@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
To a solution of 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (Aldrich, 15 g, 86.05 mmol) in DCM (200 mL) at room temperature was added copper(II) sulfate (41.2 g, 258.16 mmol) and (S)-2-methylpropane-2-sulfinamide (Aldrich, 15.64 g, 129.08 mmol). The reaction mixture was stirred overnight at room temperature, then filtered through celite, washed with DCM and concentrated to afford an oil. Silica gel chromatography (0%-25% ethyl acetate/hexanes) afforded the title compound (14.73 g, 61.7%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:17][CH3:18])[CH2:9][CH2:8][N:7](CC2C=CC=CC=2)[CH2:6]1)=[O:4].CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.ClC(C)C(Cl)=O>ClC(Cl)C>[CH3:1][O:2][C:3]([C:5]1([S:17][CH3:18])[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(SC)CCN(Cc2ccccc2)C1
Agent: CC(Cl)C(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: CC(Cl)Cl
Product: COC(=O)C1(SC)CCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-benzyl-3-methylsulfanyl-pyrrolidine-3-carboxylic acid methyl ester 8BP (131 g, 493.7 mmol) dissolved in dichloroethane (2.6 L) at 0° C. was added N,N,N′,N′-Tetramethyl-naphthalene-1,8-diamine 9BP (31.8 g, 0.144 mmol) and then 2-Chloropropionyl chloride 10BP (64 mL, 593.1 mmol) sequentially. The reaction mixture was stirred for one overnight at ambient temperature and then concentrated to dryness. The residue was dissolved in 2.8 L of methanol and refluxed at 65° C. for 3.5 h. The reaction mixture was then concentrated to dryness and the residue was purified by column chromatography on silica gel eluting with a solution of methanol in dichloromethane (1:9) to give 3-Methylsulfanyl-pyrrolidine-3-carboxylic acid methyl ester 4BP (75 g, 86%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10]C)=[CH:6][CH:5]=1)=[O:3].C1(C)C(S([O-])(=O)=[O:19])=CC=CC=1.C([N+](CC)(CC)CC)C>[Pt].CO>[OH:10][C:7]1[CH:6]=[CH:5][C:4]([C:2]([CH:1]=[O:19])=[O:3])=[CH:9][CH:8]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: Cc1ccccc1S(=O)(=O)[O-]
Agent: [Pt]
Agent: CC[N+](CC)(CC)CC
Solvent: CO
Product: O=CC(=O)c1ccc(O)cc1

Procedure:
In a standard undivided cell having a platinum anode and a glossy carbon cathode (33 cm2 each) there is charged 200 g methanol (65° C.), 11.3 g of 4-methoxyacetophenone (4-MAP), and 11.5 g tetraethylammonium toluene sulfonate. This electrolysis is conducted at a current density of about 30 mA/cm2 until a current passage of 50.9 Ah is charged (633% of theoretical value). According to an iodometrical determination, a current efficiency of 50% is obtained. About 150 g methanol is distilled off and the remaining solution is neutralized with aqueous NaHCO3 and extracted with ethyl acetate. The extract is dried and the solvent is removed by evaporation. The remaining oil is separated by column chromatography (silica gel, MTBE/cyclohexane =1/4). The acetal product is 6.4 g of 2,2-dimethoxy-1-[4-methoxyphenyl]-ethanale (41% based on 4-MAP). Subsequent hydrolysis at 62° C. yields 4hydroxyphenyl glyoxal (HPGO).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[NH2:39][CH2:40][CH2:41][S:42]([CH2:45]CN)(=[O:44])=[O:43].C(N(C(C)C)CC)(C)C>CN(C)C(=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:39][CH2:40][CH2:41][S:42]([CH3:45])(=[O:44])=[O:43])=[O:15])[CH:3]=1
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Reactant: NCCS(=O)(=O)CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1nc(C(=O)NCCS(C)(=O)=O)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of Example 104A (32.5 mg, 0.16 mmol) dissolved in N,N-dimethylacetamide (0.8 mL) was added, followed by the addition of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (50.4 mg, 0.16 mmol) dissolved in N,N-dimethylacetamide (0.8 mL). Then, 2-aminoethylsulfone hydrocloride (30.3 mg, 0.19 mmol) dissolved in N,N-dimethylacetamide (0.6 mL) was added followed by the addition of diisopropyl ethyl amine (57.9 uL, 0.31 mmol) dissolved in N,N-dimethylacetamide (0.8 mL). The mixture was shaken at room temperature overnight. The reaction was checked by LC/MS and concentrated to dryness. The residue was dissolved in 1:1 dimethyl sulfoxide/methanol and purified by reverse phase (0-70% CH3CN in 10 mM aq. ammonium acetate) to give the titled compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.26-1.38 (m, 3H) 2.93-3.08 (m, 3H) 3.29-3.47 (m, 2H) 3.72-3.80 (m, 2H) 4.30-4.61 (m, 2H) 7.05-7.09 (m, 1H); MS (ESI) positive ion 313 (M+H).
Reaction SMILES: [NH2:1][CH:2]([C:6]([NH2:8])=[O:7])[C:3]([NH2:5])=[O:4].[C:9](O)(=O)C(O)=[O:11].C(OCC)(OCC)OCC.[ClH:25]>O.CC(O)C>[OH2:4].[OH2:11].[ClH:25].[OH:4][C:3]1[NH:5][CH:9]=[N:1][C:2]=1[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)C(N)C(N)=O
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: CCOC(OCC)OCC
Solvent: CC(C)O
Solvent: O
Product: NC(=O)c1nc[nH]c1O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Under the nitrogen atmosphere, 10 g of 2-aminomalonamide and 38.4 mg of oxalic acid were added to 200 mL of 2-propanol. After heating to 80° C., 35.4 mL of triethyl orthoformate was added dropwise to the mixture over 5 minutes. Subsequently, the reaction mixture was stirred for 8 hours at 80° C. Color of the reaction liquid was pale yellow when the reaction was completed. Subsequently, after cooling to 53° C., the reaction mixture was added with 10 mL of water followed by 8 mL of conc. hydrochloric acid. After cooling with water, the crystal was collected by filtration and then washed with 40 mL of acetone to give 16 g of 5-hydroxy-1H-imidazole-4-carboxamide hydrochloric acid salt dihydrate as a pale yellow crystal.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]4[CH:31]=[CH:32][C:33]5[O:37][C:36]([CH2:38][CH3:39])=[N:35][C:34]=5[CH:40]=4)[N:24]=3)=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[CH2:41](O)[CH3:42]>[Pd]>[CH2:38]([C:36]1[O:37][C:33]2[CH:32]=[CH:31][C:30]([NH:29][C:25]3[N:24]=[C:23]([C:20]4[CH:21]=[CH:22][C:17]([N:14]5[CH2:13][CH2:12][N:11]([CH2:41][CH3:42])[CH2:16][CH2:15]5)=[N:18][CH:19]=4)[CH:28]=[CH:27][N:26]=3)=[CH:40][C:34]=2[N:35]=1)[CH3:39]
Reactant: CCc1nc2cc(Nc3nccc(-c4ccc(N5CCN(C(=O)OCc6ccccc6)CC5)nc4)n3)ccc2o1
Reactant: CCO
Agent: [Pd]
Product: CCc1nc2cc(Nc3nccc(-c4ccc(N5CCN(CC)CC5)nc4)n3)ccc2o1
Reaction time: 2 h

Procedure:
A suspension of 4-(2-(4-benzyloxycarbonylpiperazin-1-yl)pyrid-5-yl)-N-(2-ethylbenzoxazol-5-yl)-2-pyrimidineamine (100 mg, 0.19 mmol) and 10% palladium on charcoal (30 mg) in ethanol (25 ml) was stirred under an atmosphere of hydrogen at 50° for 2 h, then filtered through Celite® and evaporated. The residue was subjected to column chromatography (silica, 0.88 ammonia solution-methanol-dichloromethane, 1:5:94) to afford the title compound (25 mg) as a white solid m.p. 174-176°. δH (CDCl3) 1.15 (3H, t, J 7.2 Hz), 1.45 (3H, t, J 7.6 Hz), 2.49 (2H, q, J 7.2 Hz), 2.58 (4H, m), 2.96 (2H, q, J 7.6 Hz), 3.71 (4H, m), 6.71 (1H, d, J 9.0 Hz), 7.04 (1H, d, J 5.3 Hz), 7.40 (1H, br s), 7.41 (1H, d, J 8.7 Hz), 7.49 (1H, dd, J 2.1, 8.7 Hz), 8.09 (1H, d, J 2.1 Hz), 8.20 (1H, dd, J 2.4, 9.0 Hz), 8.36 (1H, d, J 5.3 Hz) and 8.87 (1H, d, J 2.1 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Cl)[CH:17]=2)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].BrC1(OC)C=CC(CSC2C=CC([F:44])=CC=2)=C(C(OC)=O)C1>>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:44])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CS(=O)(=O)c2cccc(Cl)c2)ccc(Br)c1OC
Reactant: COC(=O)C1=C(CSc2ccc(F)cc2)C=CC(Br)(OC)C1
Product: COC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a manner similar to Intermediate 68, starting from methyl 3-bromo-6-(4-fluorophenylthiomethyl)-3-methoxybenzoate (Intermediate 118).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[CH2:14][CH2:13][NH:12][C:11](=[O:17])[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.I[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[CH3:25].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>[Cu](I)I.O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:16][C:15]3[CH2:14][CH2:13][N:12]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][C:24]=4[CH3:25])[C:11](=[O:17])[C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1NCCc2sc(-c3ccc(F)cc3)cc21
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2sc(-c3ccc(F)cc3)cc2C1=O
Yield: 14.5 %

Procedure:
Using analogous reaction conditions as described in Example 1, 2-(4-fluoro-phenyl)-6,7-dihydro-5H-thieno[3,2-c]pyridin-4-one (I-14e: 150 mg, 0.61 mmol) was reacted with 3-iodo-4-methyl-pyridine (133 mg, 0.61 mmol), 1,4-dioxane (10 mL), copper iodide (11.6 mg, 0.061 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (25.98 mg, 0.183 mmol) and potassium phosphate (323.3 mg, 1.525 mmol) to afford the crude product which was treated with 6N HCl and filtered. The residue was washed with ethylacetate, neutralized with NaHCO3 solution and extracted with ethylacetate. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford 30 mg of the product (14.56% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[CH:8]1([O:13][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[O:24][C:25]([F:28])([F:27])[F:26])[C:17]([O:19]C)=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1>CO>[CH:8]1([O:13][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[O:24][C:25]([F:26])([F:27])[F:28])[C:17]([OH:19])=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)c1ccc(OC(F)(F)F)c(OC2CCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(OC(F)(F)F)c(OC2CCCC2)c1
Yield: 71.2 %

Procedure:
Potassium carbonate (0.43 g) and water (2 mL) are added to a solution of methyl 3-cyclopentyloxy-4-trifluoromethoxybenzoate (0.78 g) in methanol (10 mL) and the mixture is heated under reflux for 2 hours. Methanol is evaporated off under reduced pressure, and the crude material is partitioned between water (75 mL) and ethyl acetate (75 mL). The organic layer is separated, and the aqueous layer is acidified with hydrochloric acid (2N) and extracted with ethyl acetate (2×75 mL). The combined organic extracts are dried over magnesium sulfate and evaporated under reduced pressure, to give 3-cyclopentyloxy-4-trifluoromethoxybenzoic acid (0.53 g), in the form of a white solid, m.p. 116-118° C. [NMR (CDCl3): 7.72(d,1H,J=2 Hz); 7.7(dd,1H,J=8 Hz, 2 Hz); 7.3(d,1H,J=8 Hz);4.9(m,1H,);2.0-1.6(m,8H)].
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[Br-].[CH:10]1([Zn+])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCCC1>[CH3:8][S:7][C:4]1[N:3]=[C:2]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[S:6][N:5]=1
Reactant: CSc1nsc(Cl)n1
Reactant: [Zn+]C1CCCCC1
Agent: [Br-]
Solvent: C1CCOC1
Product: CSc1nsc(C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
500 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole and 122 mg of {1,1′-bis(diphenylphosphino)ferrocene} dichloro palladium(II) dichloromethane complex were dissolved in 6 ml of tetrahydrofuran under nitrogen atmosphere, 6.58 ml of solution of cyclohexyl zinc bromide in tetrahydrofuran (0.5 mol/l) was added thereto under ice-cooling taking for about 5 minutes, and the reaction mixture was stirred for 16 hours at room temperature. Then, the reaction mixture was concentrated, and the residue subjected to silica gel column chromatography to give 370 mg of 3-methylthio-5-cyclohexyl-1,2,4-thiadiazole.
Reaction SMILES: [C:1]([C:4]([C@@H:6]([C@:8]([C:22](=[O:24])[CH3:23])([C@@:10]([C:19](=[O:21])[CH3:20])([C@@H:12]([CH:14]([C:16](=[O:18])[CH3:17])[OH:15])[OH:13])[OH:11])[OH:9])[OH:7])=[O:5])(=[O:3])[CH3:2].N1C=CC=CC=1.[N:31]([CH2:34][CH2:35][CH2:36][C:37](Cl)=[O:38])=[N+:32]=[N-:33].C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:31]([CH2:34][CH2:35][CH2:36][C:37]([C@:12]([C@:10]([C:19](=[O:21])[CH3:20])([C@@:8]([C:22](=[O:24])[CH3:23])([C@@H:6]([CH:4]([C:1](=[O:3])[CH3:2])[OH:5])[OH:7])[OH:9])[OH:11])([OH:13])[C:14]([C:16](=[O:18])[CH3:17])=[O:15])=[O:38])=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=NCCCC(=O)Cl
Reactant: CC(=O)C(=O)[C@H](O)[C@](O)(C(C)=O)[C@@](O)(C(C)=O)[C@H](O)C(O)C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)C(=O)[C@@](O)(C(=O)CCCN=[N+]=[N-])[C@](O)(C(C)=O)[C@@](O)(C(C)=O)[C@H](O)C(O)C(C)=O

Procedure:
1,3,4,6 tetraacetyl D-glucose (W. E. Dick, Carbohyd. Res., 21, 255-268 (1972)) is dissolved in CH2Cl2 to make a 0.1M solution. 6 eqivalents of pyridine and 3 equivalents of 4-azidobutyryl chloride (S. Kusumoto et. al., Bull. Chem. Soc. Jpn., 59, 1289-1298 (1986)) are added. After several hours, the reaction is poured into saturated NaHCO3, extracted with CH2Cl2, dried over Na2SO4, and concentrated. The residue is purified by flash chromatography to give the title compound.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][CH:16]3[CH:23]4[CH2:24][CH:19]5[CH2:20][CH:21]([CH2:25][CH:17]3[CH2:18]5)[CH2:22]4)=[O:14])[CH2:9][CH2:8]2)[CH2:6]1.[CH3:33][NH2:34]>>[CH3:33][NH:34][C:3](=[O:2])[CH2:4][CH:5]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][CH:16]3[CH:23]4[CH2:22][CH:21]5[CH2:20][CH:19]([CH2:18][CH:17]3[CH2:25]5)[CH2:24]4)=[O:14])[CH2:9][CH2:8]2)[CH2:6]1
Reactant: COC(=O)CC1CC2(CCN(C(=O)OC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Reactant: CN
Product: CNC(=O)CC1CC2(CCN(C(=O)OC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Yield: 37 %

Procedure:
(±)-2-Adamantyl 3-(2-methoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (33 mg, 0.075 mmol) was added to a solution of methylamine in alcohol (2 mL) at 0° C. The above mixture was heated under reflux overnight. LC-MS showed that the starting material was consumed completely. The mixture was evaporated to give a residue, which was purified by preparative HPLC to obtain (±)-2-adamantyl 3-(2-(methylamino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (12 mg, 37%). 1H-NMR (400 MHz, CD3OD): 8=-1.52-1.67 (m, 6H), 1.84 (m, 6H), 1.93 (m, 2H), 2.07 (M, 5H), 2.28 (m, 1H), 2.56 (m, 1H), 2.77 (m, 4H), 3.12 (br, 2H), 3.62 (m, 1H), 4.19 (br, 2H), 7.18 (m, 4H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH3:16][O:17]C1C=C(C=CC=1)CBr.[Mg].C(OCC)(=O)C(OCC)=O>>[CH3:16][O:17][C:7]1[CH:2]=[C:3]([CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(=O)Cc1ccccc1F
Reactant: COc1cccc(CBr)c1
Agent: [Mg]
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)Cc1cccc(OC)c1
Yield: 74 %

Procedure:
The title compound was prepared as described for B4 using 3-methoxybenzyl bromide (1.5 g, 7.46 mmol), magnesium (0.199 g, 8.21 mmol) and diethyl oxalate (2.18 g, 14.92 mmol). The product was isolated in the form of colorless oil in 74% yield and used instantly in next step.