Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[CH:17]=[C:16]([I:18])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:19]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[C:1]([C@@H:5]1[CH2:6][CH2:7][C@H:8]([NH:11][C:12]2[C:17]([Cl:19])=[C:16]([I:18])[N:15]=[CH:14][N:13]=2)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)[C@H]1CC[C@@H](Nc2cc(I)ncn2)CC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[C@H]1CC[C@@H](Nc2ncnc(I)c2Cl)CC1
Temperature: 25 °C

Procedure:
3.6 g (10 mmol) of 4-(cis-4-tert-butylcyclohexylamino)-6-iodopyrimidine and 2.0 g of N-chlorosuccinimide were heated at reflux for 8 hours in 15 ml of chloroform. After cooling to room temperature, the mixture was extracted by stirring with dilute sodium hydroxide solution and water and the organic phase was dried and concentrated. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate 4:1) to give first of all 2.3 g (58.4% of theory) of product (a colorless oil which gradually crystallized, m.p. 89° to 90° C.) and, finally, 1.0 g of unreacted starting material.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:21][O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:5]([NH:7][CH:8]1[C:19](=[O:20])[N:10]2[C:11]([C:16]([OH:18])=[S:17])=[C:12]([CH3:15])[CH2:13][S:14][C@H:9]12)=[O:6].[CH3:29][NH:30][C:31]([NH2:33])=[S:32].C([O-])(=O)C.[Na+]>O.O1CCCC1>[CH3:29][NH:30][C:31]1[S:32][CH:2]=[C:3]([C:4](=[N:21][O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:5]([NH:7][CH:8]2[C:19](=[O:20])[N:10]3[C:11]([C:16]([OH:18])=[S:17])=[C:12]([CH3:15])[CH2:13][S:14][C@H:9]23)=[O:6])[N:33]=1
Reactant: COC(=O)CON=C(C(=O)CCl)C(=O)NC1C(=O)N2C(C(O)=S)=C(C)CS[C@H]12
Reactant: CNC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNc1nc(C(=NOCC(=O)OC)C(=O)NC2C(=O)N3C(C(O)=S)=C(C)CS[C@H]23)cs1
Reaction time: 2.5 h
Yield: 69 %

Procedure:
A mixture of 7-[4-chloro-2-(methoxycarbonylmethoxyimino)-3-oxobutyramido]-3-methylthio-3-cephem-4-carboxylic acid (syn isomer) (4.3 g), N-methylthiourea (1.8 g) and sodium acetate (4.1 g) in water (20 ml) and tetrahydrofuran (40 ml) was stirred at 38° to 42° C. for 2.5 hours. Water (50 ml) was added to the reaction mixture and the resultant solution was washed with ethyl acetate. The separated aqueous layer was acidified to pH 2.3 with 10% hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried over magnesium sulfate. The solution was evaporated and the residue was triturated with ether to give 7-[2-(2-methylaminothiazol-4-yl)-2-(methoxycarbonylmethoxyimino)acetamido]-3-methylthio-3-cephem-4-carboxylic acid (syn isomer) (3.2 g).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:19])=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH2:24]>C1(C)C=CC=CC=1>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:19])[N:3]=[C:2]([NH:24][CH2:23][CH2:22][N:21]([CH3:25])[CH3:20])[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:10]2
Reactant: CN(C)CCN
Reactant: Clc1cc2nc(Cl)c(-c3ccccn3)nc2cc1Cl
Solvent: Cc1ccccc1
Product: CN(C)CCNc1nc2cc(Cl)c(Cl)cc2nc1-c1ccccn1
Yield: 44.6 %

Procedure:
A solution of 2,6,7-trichloro-3-pyridin-2-yl-quinoxaline (0.50 g) and N,N-dimethyl-ethane-1,2-diamine (0.28 g) in toluene (20 mL) was refluxed under nitrogen atmosphere for 16 hours. After refluxing, the reaction mixture was cooled, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 1:9 methanol/dichloromethane) to give the product as a yellow solid (0.26 g); mp 95-97° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CC(C)N=C=NC(C)C.[C:19]([O:23][C:24]([N:26]1[CH2:39][CH2:38][C:37]2[C:36]3[CH:35]=[C:34]([Cl:40])[C:33]([Cl:41])=[CH:32][C:31]=3[N:30]([CH2:42][C:43](O)=[O:44])[C:29]=2[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C1C=CN=CC=1)C.C1COCC1.CCOC(C)=O>[Cl:41][C:33]1[C:34]([Cl:40])=[CH:35][C:36]2[C:37]3[CH2:38][CH2:39][N:26]([C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25])[CH2:27][CH2:28][C:29]=3[N:30]([CH2:42][C:43]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:44])[C:31]=2[CH:32]=1
Reactant: COc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3cc(Cl)c(Cl)cc23)CC1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)Cn2c3c(c4cc(Cl)c(Cl)cc42)CCN(C(=O)OC(C)(C)C)CC3)cc1
Reaction time: 18 h
Yield: 32.6 %

Procedure:
DMAP (60 mg, 0.49 mmol), p-anisidine (66 mg, 0.54 mmol) and DIC (0.084 mL, 0.54 mmol) were added to the solution of crude [3-(tert-butoxycarbonyl)-8,9-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid (0.20 g, 0.48 mmol) in dry THF (2.5 mL). After 18 h, the reaction was diluted with EtOAc and washed with 10% aqueous citric acid, saturated aqueous NaHCO3, and brine. The organic layer was then dried over Na2SO4, decanted, and concentrated. The crude product was first purified by column chromatography (Biotage, 40S, SIM) with CH2Cl2/EtOAc (gradient, 99:1 to 95:5) to give 81 mg of impure product. Then, crystallization from EtOAc/heptane gave 73 mg (29%) of a white solid: mp 151-151.5° C.; IR (diffuse reflectance) 3288, 1695, 1661, 1550, 1513, 1473, 1422, 1367, 1318, 1269, 1250, 1172, 1161, 1118, 831 cm−1; MS (CI) m/z 518 (M+H+), 222, 221, 220, 167, 166, 124, 59, 58, 52, 51; Anal. Calcd for C26H29Cl2N3O4: C, 60.24; H, 5.64; N, 8.10; found: C, 60.23; H, 5.73; N, 8.10.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[C:8](OCC)(=[O:13])[CH2:9][C:10]([CH3:12])=O.N1CCCCC1>C(O)C>[SH:7][C:4]1[S:3][C:2]2=[N:1][C:10]([CH3:12])=[CH:9][C:8](=[O:13])[N:6]2[N:5]=1
Reactant: Nc1nnc(S)s1
Reactant: CCOC(=O)CC(C)=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(=O)n2nc(S)sc2n1
Reaction time: 8 h
Yield: 63.5 %

Procedure:
To a solution of 2-amino-5-mercapto-l,3,4-thiadiazole (4.0 g) and ethyl acetoacetate (4.3 g) in 50 ml ethanol, piperidine (2.55 g) was slowly added. The mixture was refluxed for seven hours and then allowed to stand overnight at room temperature. The formed crystals were collected by filtration and dissolved in 100 ml of water. The pH was adjusted to 2.0, and the formed crystals were collected and washed with 20 ml of water, affording 3.8 g of the objective compound as colorless crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([NH2:25])=[CH:20][C:19]=2[O:26][CH3:27])=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.C(OCC)C>[NH2:25][C:21]1[C:22]([Cl:24])=[CH:23][C:18]([C:16]([NH:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:17])=[C:19]([O:26][CH3:27])[CH:20]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a solution of N-tert-butyloxycarbonyl-4-(4-amino-5-chloro-2-methoxyphenyl-carbonylaminomethyl)piperidine (500 mg, 1.26 mmol) in methanol solution (30 ml) was added an ethereal 1N hydrogen chloride solution (12.6 ml, 12.6 mmol). The solution was heated at 50° C. The reaction mixture became heterogeneous within 5 min. After 1.5 h, the reaction mixture was concentrated to give a white solid which was suspended in diethylether and filtered to give 4-(4-amino-5-chloro-2-methoxyphenylcarbonylaminomethyl)piperidine as a bis-hydrochloride salt (433 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[C:27]2[C:22](=[CH:23][C:24]([NH2:28])=[CH:25][CH:26]=2)[NH:21][N:20]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:28][C:24]2[CH:23]=[C:22]3[C:27]([C:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[Cl:12])=[N:20][NH:21]3)=[CH:26][CH:25]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: Nc1ccc2c(-c3ccccc3Cl)n[nH]c2c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc2c(-c3ccccc3Cl)n[nH]c2c1)c1cccc(Cl)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To 3-chlorobenzenesulfonyl chloride (43.4 mg, 0.205 mmol) in 1.0 mL pyridine was added 3-(2-chloro-phenyl)-1H-indazol-6-ylamine (50.0 mg, 0.205 mmol). The solution was heated to 120° C. and stirred for one hour, then cooled and concentrated under reduced pressure. The residue was chromatographed through silica gel (hexanes/EtOAc 0-30%) to give 51.0 mg of 3-Chloro-N-[3-(2-chloro-phenyl)-1H-indazol-6-yl]-benzenesulfonamide, MP=187-189° C., MS (M+H)=419.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[C:10](=[O:23])[N:11]([CH3:22])[C:12]3[C:17]([CH:18]=2)=[CH:16][N:15]=[C:14]([NH:19][CH2:20][CH3:21])[CH:13]=3)[C:5]([F:24])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH2:32]([S:35](Cl)(=[O:37])=[O:36])[CH2:33][CH3:34].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:20]([NH:19][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:9]([C:6]3[C:5]([F:24])=[CH:4][N:3]=[C:2]([NH:1][S:35]([CH2:32][CH2:33][CH3:34])(=[O:37])=[O:36])[C:7]=3[F:8])[C:10](=[O:23])[N:11]2[CH3:22])=[CH:16][N:15]=1)[CH3:21]
Reactant: CCNc1cc2c(cn1)cc(-c1c(F)cnc(N)c1F)c(=O)n2C
Reactant: CCCS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1ncc(F)c(-c2cc3cnc(NCC)cc3n(C)c2=O)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution 3-(2-Amino-3,5-difluoropyridin-4-yl)-7-(ethylamino)-1-methyl-1,6-naphthyridin-2(1H)-one (15 mg, 0.05 mmol), triethylamine (3 ml), and DCM (10 mL) was treated with n-propanesulfonyl chloride (0.05 ml, 0.4 mmol) at 0° C. The mixture was allowed to warm to rt and was stirred for 16 h. Aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in methanol (10 mL) and potassium carbonate (2 g) was added. The mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ethyl acetate, then the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (2% to 3% methanol in DCM eluant) to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1
Reactant: FC(F)(F)CCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)CCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of 4-bromophenol (2.2 g, 12.7 mmol) and 4-bromo-1,1,1-trifluorobutane (2.4 g, 12.7 mmol) in anhydrous DMF (15 mL) was added K2CO3 (3.5 g, 25.4 mmol). The mixture was stirred at rt overnight. The mixture was diluted with EtOAc (120 mL) and the solids were removed by filtration. The filtrate was washed with water and sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (40 g silica gel, eluted with EtOAc in hexanes) to provide Intermediate 11A (3.05 g, 85%) as a colorless oil.
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:10]=[C:9]([N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:20])[C:14]=3[CH:13]=[N:12]2)[CH:8]=[CH:7][N:6]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][CH2:29][S:30][CH3:31].CN1C(=O)CCC1>O>[CH3:31][S:30][CH2:29][CH2:28][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[CH:13]=[N:12][N:11]2[C:9]1[CH:8]=[CH:7][N:6]=[C:5]([S:4][CH2:1][CH2:2][CH3:3])[N:10]=1
Reactant: CSCCCl
Reactant: CCCSc1nccc(-n2ncc3c(O)cccc32)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCSc1nccc(-n2ncc3c(OCCSC)cccc32)n1
Temperature: 80 °C
Yield: 93.3 %

Procedure:
1-(2-Propylsulfanyl-pyrimidin-4-yl)-1H-indazol-4-ol (600 mg), potassium carbonate (1.104 g) and 1-chloro-2-methylsulfanyl-ethane 401.9 mg) were added to NMP (6 mL), and the mixture was heated to 80° C. for three hours. The mixture was cooled, diluted with water and filtered. The collected solid was washed with water and dried under reduced pressure to give 705 mg of 4-(2-Methylsulfanyl-ethoxy)-1-(2-propylsulfanyl-pyrimidin-4-yl)-1H-indazole.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26]>CN(C=O)C>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCC(C)C
Temperature: 50 °C

Procedure:
A solution of 8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.5 g, 6.6 mmol) in DMF (40 ml) was treated with sodium carbonate (0.9 g, 8.5 mmol) and 1-bromo-3-methylbutane (1.04 g, 6.9 mmol). The stirred mixture was heated at 50° C. for 18 hours then cooled and evaporated to dryness. The residue was treated with water (60 ml) and extracted with ethyl acetate (3×80 ml). The organic fractions were combined, dried over magnesium sulfate, filtered and evaporated. The residue was triturated with a mixture of diethyl ether and cyclohexane to reveal the product as a white solid which was filtered off and dried. This gave the title compound as a white solid m/z 297 [MH+].
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[Cu](C#N)[C:13]#[N:14]>CN(C=O)C.C(OCC)(=O)C>[O:9]=[C:7]1[NH:6][C:5]2[CH:10]=[CH:11][C:2]([C:13]#[N:14])=[CH:3][C:4]=2[O:8]1
Reactant: N#C[Cu]C#N
Reactant: O=c1[nH]c2ccc(Br)cc2o1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2[nH]c(=O)oc2c1

Procedure:
A mixture of 6-bromo-3H-benzooxazol-2-one (47) (400 mg, 1.87 mmol, 1 eq), copper cyanide (3.3 g, 37 mmol, 20 eq), in DMF (10 ml) was stirred at 175° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, filtered to remove the precipitated solid material, and the organic phase was washed with water, purified by flash chromatography to give 2-oxo-2,3-dihydro-benzooxazole-6-carbonitrile (48).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][OH:19])[CH:16]=2)[NH:11][N:10]=1.O>CS(C)=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=[O:19])[CH:16]=2)[NH:11][N:10]=1
Reactant: OCc1ccc2[nH]nc(COC3CCCCO3)c2c1
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc2[nH]nc(COC3CCCCO3)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [3-(tetrahydro-pyran-2-yloxymethyl)-1H-indazol-5-yl]-methanol (0.40 g, 1.50 mmol) in DMSO (3 mL), IBX (0.42 g, 1.50 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours under nitrogen. Water (50 mL) was added; the separated solid was filtered, and the solid was washed with ethyl acetate (100 mL). The filtrate was collected and the organic phase was separated, washed with brine (100 mL), and dried over anhydrous Na2SO4. Removal of solvent gave 3-(tetrahydro-pyran-2-yloxymethyl)-1H-indazole-5-carbaldehyde as an off-white solid. Yield: 0.33 g (84%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)=[C:13]=[S:14]>CCO>[Br:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[NH:1][C:13](=[S:14])[N:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:4]2=[O:6]
Reactant: Nc1c(Br)cccc1C(=O)O
Reactant: S=C=Nc1ccccn1
Solvent: CCO
Product: O=c1c2cccc(Br)c2[nH]c(=S)n1-c1ccccn1
Temperature: 25 °C
Yield: 28.5 %

Procedure:
A mixture of 2-amino-3-bromobenzoic acid (705 mg, 3.26 mmol, Sigma Aldrich) and 2-isothiocyanatopyridine (800 mg, 5.87 mmol, 415a) in EtOH (19.6 mL) was set stirring at RT, and TEA (0.68 mL, 4.90 mmol) was added dropwise. It was sealed and heated to 100° C. for 16 h. The mixture was concentrated under reduced pressure to a residue that was taken up in DCM. Silica was added, and the crude reaction was adsorbed. It was purified on 24 g SiO2 (eluent: 0-100% EtOAc/hexanes over 30 min, RediSep Gold). The product fractions were combined and concentrated under reduced pressure to give a yellow-orange solid (311 mg, 29%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.18 (1H, br. s.) 8.60 (1H, d, J=4.69 Hz) 8.39 (1H, d, J=4.11 Hz) 8.11 (1H, d, J=6.85 Hz) 7.83-7.93 (1H, m) 7.78 (1H, dd, J=7.82, 1.37 Hz) 7.44-7.53 (2H, m). m/z (ESI, +ve) 333.8 (M+H)+.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[NH2:24][C:25]1[S:26][CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[N:29]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([NH:24][C:25]4[S:26][CH:27]=[C:28]([C:30]5[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=5)[N:29]=4)=[O:3])([CH2:5][CH2:6]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1nc(-c2ccncc2)cs1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3nc(-c4ccncc4)cs3)(CC1)CC2
Yield: 20.4 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-amino-4-(4-pyridyl)thiazole (60.3 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-[4-(4-pyridyl)thiazol-2-yl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (15.2 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C@H:9]2[CH2:22][N:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([O:31]C)=O)[C:24]2=[O:33])=[CH:4][C:3]=1[F:34].O.[NH2:36][NH2:37].O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:10][C@H:9]2[CH2:22][N:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:36][NH2:37])=[O:31])[C:24]2=[O:33])=[CH:4][C:3]=1[F:34]
Reactant: COC(=O)c1cccn(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO[C@H]2c2ccc(Cl)c(F)c2)c1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](Cn2cccc(C(=O)NN)c2=O)C1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
To a solution of tert-butyl (6R,7R)-7-(4-chloro-3-fluorophenyl)-6-{[3-(methoxycarbonyl)-2-oxopyridin-1(2H)-yl]methyl}-1,4-oxazepane-4-carboxylate (155.7 mg) in ethanol (1.5 mL) was added hydrazine monohydrate (79 mg) at room temperature, and the mixture was heated under reflux for 2 days. The reaction mixture was allowed to cool to room temperature, and poured into water, and the mixture was partitioned with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (138 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH2:30][CH3:31])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1>C(OCC)(=O)C>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH2:30][CH3:31])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH:16]=3)=[CH:13][CH:14]=2)[S:3]1
Reactant: CCN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: CCN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)OC(C)(C)C
Yield: 19.7 %

Procedure:
In a manner similar to that of Example 1(g), starting with 500 mg (1.15 mmol) of tert-butyl [4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-ylmethyl]ethylcarbamate in 5 ml of ethyl acetate, 100 mg (20%) of the desired product with a melting point of 103° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C@H:17]([CH3:20])[CH2:18][OH:19]>CC(CC)=O>[Br:1][C:2]1[C:7]([O:8][CH2:16][C@H:17]([CH3:20])[CH2:18][OH:19])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[C@H](CO)CBr
Reactant: Oc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C[C@H](CO)COc1cccnc1Br
Temperature: 100 °C
Yield: 80 %

Procedure:
2-bromo-3-pyridinol (230 mg) and potassium carbonate (216 mg) was dissolved in methylethylketone (10 ml) and reacted for 30 minutes. Then, (R)-3-bromo-2-methyl-1-propanol (0.21 ml) was added to the solution and refluxed for 3 hours at 100° C. Potassium carbonate was filtered out and separated by flash chromatography under a silica gel phase (ethyl acetate:normal hexane=1:1). As a result, (R)-3-(2-bromopyridine-3-yloxy)-2-methyl-1-propanol (260 mg, yield: 80%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:30]1[CH2:31][CH2:32][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[CH:22]=3)[CH2:28][CH2:29]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Reactant: Cc1cccc(N2CCNCC2)c1
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2cccc(C)c2)CC1
Yield: 97 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(3-methylphenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 97%). 1H NMR (300 MHz, CDCl3): δ 3.27-3.30 (m, 4H), 3.74-3.77 (m, 4H), 4.15 (s, 3H), 6.75-6.78 (m, 3H), 7.11-7.45 (m, 3H), 7.74-7.76 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]([C:7]([O:22][CH2:23][C@:24]23[C@H:30]([OH:31])[C@H:27]([O:28][CH2:29]2)[C@H:26]([N:32]2[CH:39]=[CH:38][C:36](=[O:37])[NH:35][C:33]2=[O:34])[O:25]3)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.N1C=CN=C1.[Si:47](Cl)([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]>CN(C=O)C.CCOC(C)=O>[Si:47]([O:31][C@@H:30]1[C@@H:27]2[O:28][CH2:29][C@@:24]1([CH2:23][O:22][C:7]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:6]1[CH:40]=[CH:41][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[O:25][C@H:26]2[N:32]1[CH:39]=[CH:38][C:36](=[O:37])[NH:35][C:33]1=[O:34])([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]
Reactant: COc1ccc(C(OC[C@]23CO[C@H]([C@H](n4ccc(=O)[nH]c4=O)O2)[C@H]3O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(OC[C@]23CO[C@H]([C@H](n4ccc(=O)[nH]c4=O)O2)[C@H]3O[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 94 %

Procedure:
A solution of compound 112 (1.5 g) in anhydrous DMF (10 mL) was stirred with imidazole (0.913 g), trethylamine (375 μL) and t-butyldimethylsilylchloride (0.81 g) for 15 h. The reaction mixture was diluted with EtOAc (40 mL) and washed with aqueous sodium bicarbonate solution (2×20 mL). The organic layer was separated and dried over anhydrous Na2SO4. The solvent was removed and the product purified on silica gel using 10% acetone in CH2Cl2. The appropriate fractions were concentrated and dried to give Compound 114 in 94% yield.