Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:29])([O: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]([C:23]#[C:24][C:25]([OH:28])([CH3:27])[CH3:26])[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].I[CH3:31]>C1(C)C=CC=CC=1.[Ag-]=O.[Ag+]>[C:1](=[O:29])([O: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]([C:23]#[C:24][C:25]([O:28][CH3:31])([CH3:27])[CH3:26])[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: CI
Reactant: COc1ccc(F)c(-c2ccc(OC(=O)OC(C)(C)C)cc2C#CC(C)(C)O)c1
Agent: O=[Ag-]
Agent: [Ag+]
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(-c2ccc(OC(=O)OC(C)(C)C)cc2C#CC(C)(C)OC)c1
Temperature: 40 °C
Reaction time: 20 h

Procedure:
To a solution of tert-butyl 2′-fluoro-2-(3-hydroxy-3-methylbut-1-yn-1-yl)-5′-methoxybiphenyl-4-yl carbonate (314 mg) and iodomethane (0.50 mL) in toluene (5 mL) was added silver(I) oxide (365 mg). After stirring at 40° C. for 20 hr, silver(I) (365 mg) was added to the reaction mixture. The mixture was stirred at 40° C. for 70 hr. The reaction mixture was filtered, the solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (244 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)(=[O:18])=[O:17])=[CH:11][CH:10]=3)[S:8][C:4]=2[CH:3]=1.[CH3:28][OH:29]>>[CH3:28][O:29][C:9]1([C:7]2[S:8][C:4]3[CH:3]=[C:2]([CH3:1])[CH:27]=[CH:26][C:5]=3[N:6]=2)[CH:10]=[CH:11][C:12](=[N:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:13]=[CH:14]1
Reactant: CO
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(-c3nc4ccc(C)cc4s3)cc2)cc1
Product: COC1(c2nc3ccc(C)cc3s2)C=CC(=NS(=O)(=O)c2ccc(C)cc2)C=C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67 %

Procedure:
To the sulfonamide (0.1 g) dissolved in methanol (2 mL) was added BTIB (1.1 eq.) in one portion as a solid. The resulting suspension was stirred at room temperature for 5 hours. The precipitate formed was collected on a filter, washed with ice cold methanol (2 mL) and dried under vacuum to give the title compound.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(S(NN)(=O)=[O:24])C=CC=CC=1.CN([CH:31]=[O:32])C>>[O:10]=[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][C:4]([C:31]([OH:32])=[O:24])=[CH:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: NNS(=O)(=O)c1ccccc1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Product: O=C(O)c1ccc(CCC(=O)c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 15 h
Yield: 31 %

Procedure:
To a stirred solution at room temperature of chalcone XXIIIa (1.29 g, 5.13 mmol) in DMF (20 ml) was added phenylsulfonylhydrazine (1.76 g, 10.26 mmol). The reaction mixture was stirred at 10° C. for 15 h, cooled and concentrated. The remained oily residue was partitioned between a saturated aqueous solution of NH4Cl and AcOEt. After separation, the organic layer was dried, partially evaporated and filtered. The filtrate was purified by flash chromatography on silica gel (AcOEt/hexane:50/50□75/25) to form a material which after a second column purification (MeOH/CH2Cl2:5/95) afford the title compound XXVIa (400 mg, 1.59 mmol, 31% yield).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1>>[BrH:8].[CH3:1][CH:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:7]1
Reactant: CC1CNCCN1
Reactant: Brc1ccccn1
Product: Br
Product: CC1CN(c2ccccn2)CCN1
Temperature: 25 °C
Yield: 17.8 %

Procedure:
A solution of 2-methylpiperazine (1.0 g, 0.01 mol, racemic mixture) and 2-bromopyridine (10 mL, 0.1 mol) was heated to 120° C. for 16 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The layers were separated, and the water layer was concentrated under reduced pressure. The residue was triturated with ethyl acetate, dichloromethane, and methanol to afford 460 mg (26% yield) of racemic 3-methyl-1-pyridin-2-yl-piperazine hydrobromide as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.27 (d, J=6.6 Hz, 3H), 2.90 (dd, J=10.5, 14.1 Hz, 1H), 3.10 (m, 2H), 3.40 (m, 2H), 4.32 (m, 2H), 6.77 (dd, J=4.8, 6.9 Hz, 1H), 6.98 (d, J=8.1 Hz, 1H), 7.64 (m, 1H), 8.15 (m, 1H), 8.63 (br s, 1H), 8.92 (br s, 1H); MS (APCI) m/e 178 (M+H) +.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.Cl.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19]N)=[CH:15][CH:14]=1.[CH3:21][N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1>C(N(CC)CC)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]2[N:19]([CH2:2][CH2:3][N:4]3[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]3)[C:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][C:24]=3[C:15]=2[CH:14]=1
Reactant: CN1CCN(CCBr)CC1
Reactant: NNc1ccc(Cl)cc1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCN(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)CC1

Procedure:
The title compound is prepared by following Method 8 by using 1-(2-bromoethyl)-4-methylpiperazine, 4-chlorophenylhydrazine hydrochloride, triethylamine and N-methyl-4-piperidone
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH2:6]([N:8](CC)[CH2:9]C)[CH3:7].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCC)C>[CH3:9][N:8]([CH2:6][CH2:7][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1)[C:1](=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: c1ccncc1
Reactant: CCN(CC)CC
Solvent: CCOCC
Product: C=CC(=O)N(C)CCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acryloyl chloride (4.52 g, 0.05 mole) was added dropwise to a stirring solution of triethylamine (30 ml) and 2-β-methylaminoethyl)pyridine (6.81 g, 0.05 mole) in ethyl ether (500 ml). After stirring overnight at room temperature, the white solid was removed by filtration and washed well with ethyl ether. The organic phases were combined, dried over sodium sulfate, filtered then concentrated to dryness to give an orange oil. The structure was confirmed by NMR.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH2:27][CH3:28])[CH2:25]O)[C:5]1=[O:29])[CH:2]=[CH2:3].C(C=P(CCCC)(CCCC)CCCC)#N.[C:47]1([SH:53])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C1(C)C=CC=CC=1>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][S:53][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: Sc1ccccc1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CC)CO)C1=O
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CSc2ccccc2)C1=O
Temperature: 110 °C

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (180 mg, 0.403 mmol; Example 91, Step B) in 2 mL of toluene was added cyanomethylenetributylphosphorane (324 uL, 1.21 mmol) and benzenethiol (121 μL 1.21 mmol) at RT. The mixture was heated to 110° C. for 2 h. The reaction was cooled down, quenched (sat. aq. NH4Cl solution), extracted (2×EtOAc), and washed with brine. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (4 g SiO2, 10, 20, 40% EtOAc/hexane) provided the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:16])[N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[N:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])=[CH:20][CH:19]=1.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]([CH:28]([CH3:30])[CH3:29])[C:25]([O:27][CH2:2][C:3]2[O:4][C:5](=[O:16])[N:6]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH3:15])[N:7]=2)=[O:26])=[CH:22][CH:23]=1
Reactant: Cc1ccccc1Cn1nc(CCl)oc1=O
Reactant: CC(C)C(C(=O)O)c1ccc(Cl)cc1
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: Cc1ccccc1Cn1nc(COC(=O)C(c2ccc(Cl)cc2)C(C)C)oc1=O
Temperature: 110 °C
Yield: 48.4 %

Procedure:
A solution of 2-chloromethyl-4-(2-methylbenzyl)-1,3,4-oxadiazolin-5-one (13.3 g) in xylene (35 cc) is added in the course of 20 minutes to a solution of 2-(4-chlorophenyl)-3-methyl-butyric acid (19 g) and triethylamine (11.7 cc) in xylene (175 cc) heated to 110° C. The reaction mixture is heated at the reflux temperature for 4 hours and, after cooling, is washed successively with water (100 cc), a 3.5% strength aqueous hydrochloric acid solution (100 cc), a 4% strength aqueous sodium carbonate solution (100 cc) and water (100 cc). After drying, decolorizing over animal charcoal and concentrating under reduced pressure, the residue obtained is purified by chromatography on a silica column and gives [4-(2-methylbenzyl)-1,3,4-oxadiazolin-5-on-2-yl]-methyl 2-(4-chlorophenyl)-3-methylbutyrate (11.2 g) in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28]C(=O)OC(C)(C)C)[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13]([Cl:16])=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:44]2[CH:45]=[C:46]([N:50]3[CH2:53][CH2:52][CH2:51]3)[CH:47]=[CH:48][CH:49]=2)O1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[ClH:16].[NH2:28][C:24]1([C:21]2[CH:20]=[CH:19][C:18]([N:17]3[C:11]4=[N:12][C:13]([C:44]5[CH:49]=[CH:48][CH:47]=[C:46]([N:50]6[CH2:53][CH2:52][CH2:51]6)[CH:45]=5)=[CH:14][CH:15]=[C:10]4[N:9]=[C:8]3[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[CH:23][CH:22]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: CC1(C)OB(c2cccc(N3CCC3)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(Cl)nc43)cc2)CCC1
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cl
Product: Nc1ncccc1-c1nc2ccc(-c3cccc(N4CCC4)c3)nc2n1-c1ccc(C2(N)CCC2)cc1
Temperature: 100 °C
Yield: 7.6 %

Procedure:
To a solution of tert-butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (75 mg, 0.15 mmol) in toluene/ethanol (3 ml each), were added 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]azetidine (79 mg, 0.31 mmol), Pd(PPh3)4 (9 mg), and saturated sodium bicarbonate in water (300 ul). The reaction was degassed and heated to 100° C. for 18 hr under nitrogen gas. The mixture was poured to water, extracted with ethyl acetate (15 mL×3). The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate: methanol=9:1:0.1 to 1:1:0.1) and again purified with HPLC (acetonitrile/water (0.05% formic acid), gradient, 25 ml/min) to give the product (6 mg, 8%). LCMS: 488 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH2:16])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:25][C:26]1[NH:30][N:29]=[N:28][N:27]=1)[CH2:19][CH2:20][S:21](=[O:24])(=[O:23])[NH2:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C=C(C(C)(C)C)C=1O)[CH:38]=[O:39])(C)(C)C.C1C=CC=CC=1.[Pb](=O)=O>ClCCCl.O>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[C@:15]([NH2:16])([O:39][CH3:38])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:25][C:26]1[NH:30][N:29]=[N:28][N:27]=1)[CH2:19][CH2:20][S:21](=[O:24])(=[O:23])[NH2:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1=C(C(CCS(N)(=O)=O)Sc2nnn[nH]2)CS[C@@H]2C(N)C(=O)N12
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: O=[Pb]=O
Solvent: ClCCCl
Solvent: O
Solvent: c1ccccc1
Product: CO[C@@]1(N)C(=O)N2C(C(=O)OC(C)(C)C)=C(C(CCS(N)(=O)=O)Sc3nnn[nH]3)CS[C@@H]21
Reaction time: 0.5 h

Procedure:
A solution of 1.91 g. (4 mmol.) of 7-amino-3-[1-(2-sulfamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester and 0.94 g. (4 mmol.) of 3,5-di-t-butyl-4-hydroxybenzaldehyde in 150 ml. of dry benzene is refluxed for ca. 4 hours under a Dean-Stark trap until no more water separates. The solution is evaporated under reduced pressure to give a residue which is dissolved in 150 ml. of 1,2-dichloroethane and cooled to 0°-5° in an ice bath. Freshly prepared lead dioxide (5 g.) is added in 1 g. portions over 30 minutes and the reaction is stirred in the cold until complete consumption of the starting material is indicated by thin layer chromatography. The mixture is then filtered through Celite and the filter cake is washed with two 30 ml. portions of cold 1,2 -dichloroethane. The filtrate is treated with 30 ml. of dry methanol (distilled from magnesium) and the reaction is stirred at ambient temperature for 3 hours until complete consumption of the intermediate and formation of a new product is shown by thin layer chromatography. The reaction mixture is evaporated to dryness and the residue is taken up in 50 ml. of methanol and treated with 4.0 g. of Girard reagent T (trimethylaminoacetohydrazide chloride). This solution is stirred at ambient temperature for 3 hours and evaporated under vacuum to give a solid residue which is partitioned between 150 ml. of ethyl acetate and 100 ml. of 20% aqueous sodium chloride solution. The organic phase is washed with three 100 ml. portions of 10% aqueous sodium chloride, two 100 ml. portions of water and 100 ml. of a saturated sodium chloride solution. The organic phase is dried (MgSO4), filtered and evaporated to dryness to give 7β-amino-7α-methoxy-3-[1-(2-sulfamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]1[CH2:34][O:33][C:15]2([C:24]3[C:19](=[C:20]([O:27][CH3:28])[CH:21]=[CH:22][C:23]=3[O:25][CH3:26])[CH2:18][CH:17]([C:29]([O:31][CH3:32])=[O:30])[CH2:16]2)[O:14]1.[OH2:35]>O1CCCC1.CCCCCC>[CH2:34]1[CH2:13][O:14][C:15]2([C:24]3[C:19](=[C:20]([O:27][CH3:28])[CH:21]=[CH:22][C:23]=3[O:25][CH3:26])[CH2:18][C:17]([OH:35])([C:29]([O:31][CH3:32])=[O:30])[CH2:16]2)[O:33]1
Reactant: O
Reactant: COC(=O)C1Cc2c(OC)ccc(OC)c2C2(C1)OCCO2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(O)Cc2c(OC)ccc(OC)c2C2(C1)OCCO2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
(a) To a solution of 84 ml of diisopropylamine in 250 ml of dry tetrahydrofuran at -78° C. under argon was added a solution of n-butyl lithium (39 ml, 1.6 mol) in hexane. The mixture was stirred for 10 minutes and then a solution of 12.32 g of methyl 4,4-ethylenedioxy-1,2,3,4-tetrahydro-5,8-dimethoxynaphthalene-2-carboxylate in 75 ml of dry tetrahydrofuran was added rapidly. The mixture was held at -78° C. while stirring for 50 minutes and then 27.8 g of finely ground diperoxo-oxohexamethylphosphoramidomolybdenum (VI) pyridine were added. After a further 80 minutes, the mixture was warmed to 0° C. and stirred for 20 minutes before the addition of 400 ml of water. After 10 minutes, most of the tetrahydrofuran was evaporated in vacuo and the aqueous residue was extracted with five 200 ml portions of ethyl acetate. The combined ethyl acetate extracts were dried over magnesium sulphate, filtered and evaporated to give an oil which was purified by chromatography on silica gel using ethyl acetate/hexane (1:1, vol/vol) for the elution. After the elution of 1.57 g of starting material, there were obtained 7.51 g (58%) of methyl rac-4,4-ethylenedioxy-1,2,3,4-tetrahydro-2-hydroxy-5,8-dimethoxynaphthalene-2-carboxylate in the form of colourless crystals of melting point 74°-75° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](=O)([O-])[O-].[K+].[K+].CI.O>CS(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cccnc1Cl
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Solvent: O
Product: COc1cccnc1Cl
Temperature: 50 °C

Procedure:
To a solution of 2-chloro-pyridin-3-ol (100 g) in DMSO (1 L) was added potassium carbonate (320 g). Methyliodide was added dropwise. The reaction mixture was heated to 50° C. overnight. The reaction mixture poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give the desired compound.
Reaction SMILES: [CH:1]1([C:5]([OH:7])=O)[CH2:4][CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[N:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=1>C(#N)C>[Cl:19][C:13]1[N:12]=[C:11]2[C:16]([CH:17]=[CH:18][C:9]([NH:8][C:5]([CH:1]3[CH2:2][CH2:3][CH2:4]3)=[O:7])=[N:10]2)=[CH:15][CH:14]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)C1CCC1
Solvent: CC#N
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)C1CCC1
Temperature: 20 °C
Yield: 61.8 %

Procedure:
The procedure is similar to that described in Example 1, but starting with cyclobutanecarboxylic acid (5 g), N,N'-carbonyldiimidazole (10.5 g) and 2-amino-7chloro-1,8-naphthyridine (7 g). The product produced by filtration (9 g; m.p. 192° C.) is dissolved in boiling acetonitrile (150 cc). After 3 hours' cooling at 20° C., the crystallised solid is separated by filtration, washed with ethyl ether (3×25 cc) and dried at 35° C. under reduced pressure (0.066 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)cyclobutanecarboxamide (6.3 g) is produced, m.p. 192°-194° C. EXAMPLE 6
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:21][CH:20]=[C:19]([CH3:22])[N:9]2[C:10](=[O:18])[C:11]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[CH3:5])=[N+]=[N-].CP(C)C.C(OCC)(=O)C>O1CCCC1.O>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:21][CH:20]=[C:19]([CH3:22])[N:9]2[C:10](=[O:18])[C:11]=1[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)[CH3:5]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3ccncc3)c(=O)n12
Agent: CP(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1csc2nc(C(C)N)c(-c3ccncc3)c(=O)n12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(1-azidoethyl)-3-methyl-6-pyridin-4-yl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.050 g, 0.16 mmol) in tetrahydrofuran (0.5 mL) and water (0.12 mL) was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.19 mL, 0.19 mmol) at room temperature and the mixture was stirred at room temperature for 1 hour. To the mixture was added ethyl acetate (EtOAc) and the mixture was extracted with 1N HCl two times. The combined extracts were neutralized with solid sodium bicarbonate, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue, shown two peaks with same desired mass, was used directly in next step. LCMS calculated for C14H15N4OS (M+H)+: m/z=287.1. Found: 287.0.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=2)[O:25][C:26]=1[CH3:27]>>[Cl:34][C:32]1[CH:33]=[C:28]([C:24]2[O:25][C:26]([CH3:27])=[C:22]([CH2:21][N:12]3[C:13]4[C:9](=[CH:8][C:7]([CH2:6][CH:5]([O:16][CH2:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:15][CH:14]=4)[CH:10]=[CH:11]3)[N:23]=2)[CH:29]=[C:30]([Cl:35])[CH:31]=1
Reactant: Cc1oc(-c2cc(Cl)cc(Cl)c2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3cc(Cl)cc(Cl)c3)oc2C)c1)C(=O)O
Yield: 4 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-2-(3,5-dichloro-phenyl)-5-methyl-oxazole, the title compound was obtained in 4% yield as a pale yellow solid. MS: (M+H)+ 473.1 and 475.2.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[F:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](B(O)O)[CH:20]=1.[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]1>>[F:14][C:15]1[CH:20]=[C:19]([C:5]2[CH:4]=[N:3][C:2]([NH:30][C:27]3[CH:28]=[CH:29][N:25]([CH3:24])[N:26]=3)=[C:11]3[C:6]=2[CH:7]=[CH:8][C:9]([CH3:12])=[N:10]3)[CH:18]=[N:17][CH:16]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: Cn1ccc(N)n1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Product: Cc1ccc2c(-c3cncc(F)c3)cnc(Nc3ccn(C)n3)c2n1

Procedure:
The title compound, MS: m/e=335.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 3-fluoropyridine-5-boronic acid and 1-methyl-1H-pyrazol-3-ylamine.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O:15]1[C:19]2[CH:20]=[CH:21][C:22](B(O)O)=[CH:23][C:18]=2[CH:17]=[CH:16]1>>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:2]3[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:23][C:18]=2[CH:17]=[CH:16]1
Reactant: OB(O)c1ccc2occc2c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(-c2ccc3occc3c2)c(-c2ccccc2)n1
Yield: 39.2 %

Procedure:
6-(1-benzofuran-5-yl)-5-phenyl-1,2,4-triazin-3-amine (225 mg, 47%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol) and benzofuran-5 boronic acid (0.32 g, 1.99 mmol) according to the general procedure of Example 1.
Reaction SMILES: [C:1]1([O:11][CH2:12][C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([CH:33]=[O:34])[CH2:25][C:26](=NNC(N)=O)[OH:27])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(O)(=[O:37])C.CO>C=O.O>[C:1]1([O:11][CH2:12][C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([CH:33]=[O:34])[CH2:25][C:26]([OH:27])=[O:37])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)O
Reactant: CC(C)C[C@H](NC(=O)COc1cccc2ccccc12)C(=O)N[C@H](C=O)CC(O)=NNC(N)=O
Agent: C=O
Solvent: CO
Solvent: O
Product: CC(C)C[C@H](NC(=O)COc1cccc2ccccc12)C(=O)N[C@H](C=O)CC(=O)O
Yield: 79 %

Procedure:
A solution of (3S)-3-[N-((1-naphthyloxy)acetyl)leucinyl]amino-4-oxobutanoic acid semicarbazone (0.320 g, 0.68 mmol) in 37% aqueous formaldehyde(1.0 mL)-acetic acid(1.0 mL)-methanol(3.0 mL) was stirred at room temperature under nitrogen for 3.5 hrs. The resulting solution was diluted with water and extracted with EtOAc. The extract was washed with water and saturated NaCl solution, dried over anhydrous Na2SO4 and evaporated to dryness. The residue was taken up in EtOAc, filtered through Celite and evaporated to dryness. The product was taken up in a small amount of dioxane, diluted with water, frozen and lyophilized to give the title compound (0.222 g, 79%) as a fluffy white solid. TLC(EtOAc-pyridine-AcOH—H2O; 60:20:5:10) Rf=0.65.
Reaction SMILES: [BrH:1].[N+]([C:5]1[NH:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[N:9]=1)([O-])=O.C(=O)([O-])O.[Na+]>CC1C=CC(C)=CC=1>[Br:1][C:5]1[NH:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[N:9]=1
Reactant: Br
Reactant: O=[N+]([O-])c1c[nH]c([N+](=O)[O-])n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccc(C)cc1
Product: O=[N+]([O-])c1c[nH]c(Br)n1
Yield: 47.6 %

Procedure:
2033.5 g of 49 mass % hydrobromic acid was added dropwise to 145.6 g of 2,4-dinitroimidazole wetted with p-xylene (wetted with 12 mass % of p-xylene). The temperature of the reaction liquid was elevated to 100° C. and reacted for 5 hours. After the reaction ended, the reaction liquid was gradually neutralized with 2000 mL of a saturated sodium hydrogen carbonate aqueous solution while the solution was cooled to deposit crystals. After the crystals were filtered, the crystals were heated and dissolved in 3000 mL of water at 95° C. and 75.0 g of 2-bromo-4-nitroimidazole (yield 47.6%) (HPLC purity 100%) was obtained by cooling, filtration and drying. This was identified to be 2-bromo-4-nitroimidazole by