Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:13])([F:12])[C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.Cl[C:15]1[CH:16]=[C:17]([CH3:25])[C:18]([N+:22]([O-:24])=[O:23])=[CH:19][C:20]=1[CH3:21].O>CN1CCCC1=O>[N+:22]([C:18]1[CH:19]=[C:20]([CH3:21])[C:15]([O:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([F:12])([F:13])[F:3])[CH:6]=2)=[CH:16][C:17]=1[CH3:25])([O-:24])=[O:23]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Cl
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Oc1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a suspension of sodium hydride (0.4 g of 60% in oil) in dry N-methylpyrroli-dinone (10 ml) was slowly added 3-trifluoromethylphenol (1.62 g). When effervescence had ceased, 3-chloro-6-nitro-p-xylene (1.85 g) was added and the mixture stirred at 120-40° C. for 5 hours. On cooling, the mixture was poured into water and the mixture extracted with diethyl ether (x3). The combined ether extracts were dried (MgSO4), filtered and evaporated to give the title compound as a solid, m.p. 68-71° C.
Reaction SMILES: [Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C@@H:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][CH2:14]Cl)[CH:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+]>>[N:22]([CH2:14][CH2:13][C@@H:12]([O:11][C:4]1[CH:3]=[C:2]([Br:1])[C:9]([F:10])=[CH:8][C:5]=1[C:6]#[N:7])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(F)c(Br)cc1O[C@H](CCCl)c1ccccc1
Agent: [Na+]
Product: N#Cc1cc(F)c(Br)cc1O[C@H](CCN=[N+]=[N-])c1ccccc1

Procedure:
This was prepared by the method of Example 68(b) using 4-bromo-2-[[(1R)-3-chloro-1-phenylpropyl]oxy]-5-fluorobenzonitrile and sodium azide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:19][CH2:20][C@H:21]2[CH2:23][O:22]2)=[C:13]([O:15]C(=O)C)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:19][CH2:20][C@H:21]([CH2:23][OH:22])[O:15][C:13]=2[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Oc1cc(OCc2ccccc2)ccc1OC[C@H]1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OC[C@H]1COc2ccc(OCc3ccccc3)cc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of acetic acid 5-benzyloxy-2-((R)-1-oxiranylmethoxy)phenyl ester (0.5 g, 1.59 mmol) in THF (10 ml) was added aq 2 M NaOH (1.04 ml). After stirring overnight at RT, THF was removed under reduced pressure and water (20 ml) was added. The water solution was then extracted two times with EtOAc. The combined organic layers washed with water and brine, dried (Na2SO4), and evaporated in vacuo. The crude product (0.45 g) was used without purification.
Reaction SMILES: O([C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]=1[N+:19]([O-:21])=[O:20])S(C(F)(F)F)(=O)=O.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][N:27]2[CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37]>>[N+:19]([C:10]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=2[CH:17]=[CH:18][C:9]=1[NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][N:27]2[CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])([O-:21])=[O:20]
Reactant: C[Si](C)(C)CCOCn1ccc2c(N)cccc21
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2c1CCCC2
Product: C[Si](C)(C)CCOCn1ccc2c(Nc3ccc4c(c3[N+](=O)[O-])CCCC4)cccc21

Procedure:
1-Nitro-5,6,7,8-tetrahydronaphthalen-2-yl triflate and 4-amino-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indole were used in a process similar to Example 1(1) to give the titled compound.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:24])([CH3:23])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:7][CH2:6]1.[CH2:25]([N:32]1[CH:37]=[C:36]([CH3:38])[C:35](=[O:39])[NH:34][C:33]1=[O:40])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:32]1[CH:37]=[C:36]([CH3:38])[C:35](=[O:39])[N:34]([CH2:2][C:3]([CH3:24])([CH3:23])[CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:7][CH2:6]2)[C:33]1=[O:40])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(CCl)CN1CCN(c2ccccc2OCC(F)(F)F)CC1
Reactant: Cc1cn(Cc2ccccc2)c(=O)[nH]c1=O
Product: Cc1cn(Cc2ccccc2)c(=O)n(CC(C)(C)CN2CCN(c3ccccc3OCC(F)(F)F)CC2)c1=O

Procedure:
substituting 1-chloro-2,2-dimethyl-3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propane and 1-benzyl-5-methyl-2,4(1H,3H)-pyrimidinedione gave 1-benzyl-3-(3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}-2,2-dimethylpropyl)-5-methyl-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[CH:34][C:35]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[N:36][CH:37]=2)O1>>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:32]5[CH:37]=[N:36][C:35]([N:38]6[CH2:39][CH2:40][O:41][CH2:42][CH2:43]6)=[CH:34][CH:33]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3ccc(N4CCOCC4)nc3)cc1-2
Yield: 58 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine were reacted to give 325 (0.106 g, 58%). 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J=2.1, 1H), 8.49 (d, J=1.8, 1H), 7.93 (s, 1H), 7.76 (dd, J=8.7, 2.4, 1H), 7.42 (dd, J=8.4, 2.2, 1H), 7.14 (d, J=8.3, 1H), 6.73 (d, J=8.8, 1H), 5.88 (dt, J=13.3, 6.6, 1H), 4.45 (t, J=5.0, 2H), 3.95-3.76 (m, 4H), 3.68-3.52 (m, 4H), 3.45 (t, J=5.0, 2H), 1.65 (d, J=6.6, 6H). MS (ESI(+)): m/z 475.2 (M+H)
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH3:16])[CH:4]=1.[C-:17]#[N:18].[Na+].[Cl-].[Na+]>>[C:17]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH3:16])[CH:4]=1)#[N:18]
Reactant: Cc1cc(CCl)ccc1Sc1ccccc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Product: Cc1cc(CC#N)ccc1Sc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 1-chloromethyl-3-methyl-4-phenylthiobenzene obtained above is dissolved in N,N-dimemthylformamide (56 ml), and thereto is added finely divided sodium cyanide (18.16 g), and the mixture is stirred at room temperature overnight. To the reaction mixture are added saturated aqueous sodium chloride solution (300 ml) and ice water (300 ml), and the mixture is extracted with ethyl acetate (300 ml×3). The combined extracts are washed with saturated aqueous sodium chloride solution (200 ml×3), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-cyanomethyl-3-methyl-4phenylthiobenzene (45.95 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:28])[N:8]3[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1C(=O)C2=CC=CC=C2C1=O.O.NN.O>C(O)C>[NH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:8]1[C:9]2[N:5]3[C:4](=[N:3][C:2]([CH3:1])=[C:6]3[C:7]1=[O:28])[CH:12]=[CH:11][CH:10]=2
Reactant: Cc1nc2cccc3n(CCCCN4C(=O)c5ccccc5C4=O)c(=O)c1n23
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1nc2cccc3n(CCCCN)c(=O)c1n23
Yield: 81.1 %

Procedure:
To a suspension of 5.99 g (16.0 mmol) of 1,2-dihydro-3-methyl-1-[4-(phthalimido)butan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one in 150 ml of ethanol was added 2.40 g (48.0 mmol) of hydrazine monohydrate. The mixture was heated for one hour under reflux. After cooling, and the resulting precipitates were filtered off. The filtrate was concentrated to give the residue, water was water, extracted with chloroform (three times). The extract solution was dried over anhydrous magnesium sulfate. The solvent was distilled off to give 3.17 g of the desired compound (81.1%, pale yellow solid).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[C:9]([CH2:12]O)[CH:10]=2)[C:5]([O:16][CH:17]([CH3:19])[CH3:18])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:39]C(Cl)(Cl)C(Cl)(Cl)Br>ClCCl>[Br:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[C:9]([CH2:12][Br:39])[CH:10]=2)[C:5]([O:16][CH:17]([CH3:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: COc1cc(CO)cc2c(Br)ccc(OC(C)C)c12
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(CBr)cc2c(Br)ccc(OC(C)C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.7 %

Procedure:
To a solution of 4.00 g (12.3 mmol) 1-bromo-7-hydroxymethyl-4-isopropoxy-5-methoxy-naphthalene in 40 mL dry dichloromethane, 3.24 g (12.3 mmol) triphenyl-phosphane and 4.00 g (12.3 mmol) 1,2-dibromotetrachloroethane were added under Ar. After stirring for 30 min at room temperature, the solvent was removed and subsequently the residue was filtered over a short silica gel column (petroleum/ethyl acetate, 4:1) to give 5.00 g (95%) 1-bromo-7-bromomethyl-4-isopropoxy-5-methoxy-naphthalene as a colorless solid (m.p. 126° C.).
Reaction SMILES: C([O-])=O.[C:4]([O:7][CH2:8][C:9]1[CH2:10][S:11][C@@H:12]2[CH:19]([NH:20][C:21](=[O:32])[C:22]([C:26]3[N:27]=[C:28]([NH2:31])[S:29][CH:30]=3)=[N:23][O:24][CH3:25])[C:18](=[O:33])[N:13]2[C:14]=1[C:15]([OH:17])=[O:16])(=[O:6])[CH3:5].C([O-])(=O)C.[Na+:38]>O.C(O)C>[C:4]([O:7][CH2:8][C:9]1[CH2:10][S:11][C@@H:12]2[CH:19]([NH:20][C:21](=[O:32])[C:22]([C:26]3[N:27]=[C:28]([NH2:31])[S:29][CH:30]=3)=[N:23][O:24][CH3:25])[C:18](=[O:33])[N:13]2[C:14]=1[C:15]([O-:17])=[O:16])(=[O:6])[CH3:5].[Na+:38]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Agent: CC(=O)[O-]
Agent: O=C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Yield: 0.95 %

Procedure:
10 g of the formate solvate of the syn isomer of 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylic acid (described in Belgium Pat. No. 850,662) were added at room temperature to a solution of 3.5 g of sodium acetate in 5 ml of water and 300 ml of ethanol and when dissolution was complete, the mixture was filtered. The filtrate was added dropwise over one hour with stirring at room temperature to 160 ml of absolute ethanol and the resulting mixture was stirred at room temperature for 3 hours and at 0° C. for 16 hours. The mixture was vacuum filtered and the crystals were washed with ethanol and dried under reduced pressure to obtain 7.75 g of the crystalline D form of the syn isomer of sodium 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylate containing 0.95% of water.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[Cl:21].[C:22](=[NH:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[Cl:21][C:3]1[CH:4]=[C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)[CH:6]=[CH:7][C:2]=1[N:35]=[C:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Br)c(Cl)c2)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(N=C(c3ccccc3)c3ccccc3)c(Cl)c2)C1
Temperature: 90 °C
Yield: 100.9 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(4-bromo-3-chlorophenyl)morpholine-4-carboxylate (0.50 g) and benzophenone imine (253 mg) in toluene (5 ml) was added sodium tert-butoxide (204 mg). The reaction mixture was purged with argon for 10 min. (R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (82.7 mg) and tris(dibenzylideneacetone)dipalladium(0) (36.5 mg) were added and the reaction mixture was heated at 90° C. overnight. The reaction mixture was poured into EtOAc and extracted sequentially with dilute aq. HCl, water and saturated brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in hexanes) to afford tert-butyl (RS)-2-(3-chloro-4-(diphenylmethyleneamino)phenyl)morpholine-4-carboxylate (639 mg, quant.) as a yellow oil. MS (ISP): 479.1 ([{37Cl}M+H]+), 477.1 ([{35Cl}M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1>>[Cl:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=1)[S:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)(=[O:11])=[O:10]
Reactant: Clc1cccc(CBr)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Product: COc1ccc(CN(Cc2cccc(Cl)c2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-10b) and 1-(bromomethyl)-3-chlorobenzene. MS (M−H, 444.1); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.69 (s, 3H), 4.30 (m, 4H), 6.76-7.24 (m, 8H), 7.99 (m, 2H), 8.13 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14]CC)=O)[NH:3]1.[NH:17]1[CH:21]=[N:20][C:19]([S:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([CH2:32][NH2:33])[CH:29]=[CH:30][CH:31]=2)=[N:18]1.C(N(C(C)C)CC)(C)C>C(O)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:33][CH2:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([O:25][CH2:24][CH2:23][S:22][C:19]3[N:20]=[CH:21][NH:17][N:18]=3)[CH:27]=2)=[O:14])[NH:3]1
Reactant: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Reactant: NCc1cccc(OCCSc2nc[nH]n2)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cccc(OCCSc2nc[nH]n2)c1)c1nc2ccccc2c(=O)[nH]1
Temperature: 90 °C
Reaction time: 15 h
Yield: 8 %

Procedure:
A suspension of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate obtained according to the methods described in Journal of Organic Chemistry (1978), 43(23), 4485-7 and the like (200 mg, 0.917 mmol), 1-(3-{[2-(1H-1,2,4-triazol-3-ylthio)ethyl]oxy}phenyl)methanamine obtained in Reference Example 3 (298 mg, 1.19 mmol) and diisopropylethylamine (237 mg, 1.83 mmol) in ethanol (10 mL) was stirred at 90° C. for 15 hr. The reaction solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate and water. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by preparative HPLC (GILSON 215LIQUD HANDLER, 322PUMP, UV/VIS-156, SHISEIDO CAPCELL PACK C-18 UG120 S-5 (20 mmφ×50 mm), mobile phase: distilled water (containing 0.1% trifluoroacetic acid)/acetonitrile (containing 0.1% trifluoroacetic acid), gradient: distilled water/acetonitrile-90/10→0/100, time: 10 min, flow rate: 25 mL/min, detection wavelength: 220 nm), and the obtained crude crystals were recrystallized from ethanol to give the title compound as a white powder (29.2 mg, 8%).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([Cl:8])=[CH:6][N:5]([CH3:9])[N:4]=1.[CH3:10][C:11]1[N:16]=[C:15]([SH:17])[N:14]=[C:13]([OH:18])[CH:12]=1.C(N(CC)CC)C>C(O)C>[Cl:8][C:7]1[C:3]([CH2:2][S:17][C:15]2[N:14]=[C:13]([OH:18])[CH:12]=[C:11]([CH3:10])[N:16]=2)=[N:4][N:5]([CH3:9])[CH:6]=1
Reactant: Cn1cc(Cl)c(CBr)n1
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2nn(C)cc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of 3-(bromomethyl)-4-chloro-1-methyl-1H-pyrazole (61.7 mmol) in absolute ethanol (250 mL) was added 6-methyl-2-sulfanylpyrimidin-4-ol (5.84 g, 41.1 mmol) and triethylamine (23.0 mL, 165 mmol) at 0° C. The mixture was stirred at room temperature overnight. The white solid was filtered and washed with diethyl ether (300-500 mL). The filtrate was recovered, and the solvent was evaporated. The residue triturated in water, filtered, and washed with water (3×300 mL) and then DCM (50 mL). The solid was died under vacuum overnight. 2-{[(4-chloro-1-methyl-1H-pyrazol-3-yl)methyl)sulfanyl}-6-methylpyrimidin-4-ol was obtained as a white solid (5.48 g, 49% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 2.20 (bs, 3H), 3.78 (s, 3H), 4.35 (s, 2H), 6.05 (bs, 1H), 7.92 (s, 1H); LRMS (ES+) m/z 271 (100%, M+1); 273 (35%, M+3).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36]Br)[CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN1CCCC1=O>[CH2:22]([O:29][C:30]1[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=1)[CH2:36][N:15]1[CH:14]=[CH:13][N:12]=[C:11]1[C@H:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])[CH3:10])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: BrCc1cccc(OCc2ccccc2)c1
Reactant: Cc1cccc([C@H](C)c2ncc[nH]2)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Cc1cccc([C@H](C)c2nccn2Cc2cccc(OCc3ccccc3)c2)c1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of the compound of Example 58 (90 mg, 0.45 mmol) and caesium carbonate (244 mg, 0.75 mmol) in 1-methyl-2-pyrrolidinone (1 ml) was added 1-(benzyloxy)-3-(bromomethyl)benzene (139 mg, 0.50 mmol). The reaction mixture was stirred at room temperature for 48 h and then filtered through a Whatman PTFE filter tube (5 μm).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:13]=[CH:12][C:11]3[CH:10]=[C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:8](=[O:20])[NH:7][C:6]=3[N:5]2[N:21]=1.[Li]C.[C:24](OCC)(=O)C>C1COCC1.O=[Mn]=O>[CH3:1][C:2]1[CH:3]=[C:4]2[N:13]=[C:12]([CH3:24])[C:11]3[C:6](=[N:7][C:8]([OH:20])=[C:9]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:10]=3)[N:5]2[N:21]=1
Reactant: CCOC(C)=O
Reactant: Cc1cc2ncc3cc(-c4ccccc4)c(=O)[nH]c3n2n1
Agent: O=[Mn]=O
Agent: [Li]C
Solvent: C1CCOC1
Product: Cc1cc2nc(C)c3cc(-c4ccccc4)c(O)nc3n2n1
Temperature: -78 °C
Reaction time: 16 h

Procedure:
In a 20 mL scintillation vial, Compound [IV] (0.15 g, 0.543 mmol, 1.0 eq.) was dissolved in THF (10 mL). The solution was cooled to −78° C. and MeLi (15 mL of 1.6 M THF solution, 24 mmol, 44.19 eq.) was added dropwise and the reaction mixture was stirred for 16 hours at 0-20° C. The reaction mixture was carefully and slowly poured into ethyl acetate 20 (mL) and stirred for 10 minutes. The quenched reaction mixture was concentrated. The residue was treated with 100 mL of THF and the THF solution was separated from the solid by filtration. The organic solution was stirred with MnO2 (0.47 g, 5.4 mmol, 10 eq.) for 4 hours at room temperature. The reaction was filtered and the solids washed with CHCl3/MeOH (10%) (50 mL). The combined organic solution was concentrated and the crude was purified by silica gel chromatography using CHCl3/MeOH (10%) as the eluant to give Compound [CIX]: LCMS m/e 291 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.51 (s, 3H) 2.77 (s, 3H) 6.40 (s, 1H) 7.36-7.51 (m, 3H) 7.71 (d, J=7.22 Hz, 2H) 7.97 (s, 1H).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1.[CH3:12][NH2:13]>O>[CH:9]([C:6]1[S:7][CH:8]=[C:4]([CH2:3][NH:13][CH3:12])[N:5]=1)([CH3:11])[CH3:10]
Reactant: CN
Reactant: CC(C)c1nc(CCl)cs1
Agent: Cl
Solvent: O
Product: CNCc1csc(C(C)C)n1
Reaction time: 1 h
Yield: 55 %

Procedure:
A solution of 40 g of 4-(chloromethyl)-2-isopropylthiazole hydrochloride in 100 ml of water was added dropwise with stirring to 400 ml of 40% aqueous methylamine. The resulting solution was stirred for 1 h, then concentrated in vacuo. The residue was taken up in chloroform, dried over Na2SO4, and concentrated in vacuo. Purification of the residue by silica gel chromatography using 10% methanol in chloroform provided 21.35 g (55%) of the desired compound. 1H NMR (DMSO-d6) δ 1.34 (d, J=7 Hz, 6 H), 2.56 (s, 3 H), 3.30 (heptet, J=7 Hz, 1 H), 4.16 (s, 2 H), 7.63 (s, 1 H). Mass spectrum: (M+H)+ =171.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[CH2:7]([O:14][N:15]1[C:21](=[O:22])[N:20]2[CH2:23][C@H:16]1[CH2:17][CH2:18][C@H:19]2[C:24]1[O:25][C:26]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:27][N:28]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.COS(OC)(=O)=O>CC(C)=O>[CH2:7]([O:14][N:15]1[C:21](=[O:22])[N:20]2[CH2:23][C@H:16]1[CH2:17][CH2:18][C@H:19]2[C:24]1[O:25][C:26]([CH:29]2[CH2:34][CH2:33][N:32]([CH3:1])[CH2:31][CH2:30]2)=[N:27][N:28]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1N2C[C@@H](CC[C@H]2c2nnc(C3CCNCC3)o2)N1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CN1CCC(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 19.3 %

Procedure:
K2CO3 (621 mg, 4.5 mmol) was added to a solution of crude (2S,5R)-6-(benzyloxy)-2-(5-(piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (988 mg) in acetone (30 mL). Me2SO4 (105 μl, 1.6 mmol) was slowly added at 0° C. The mixture was stirred at rt for 6 h, then concentrated and purified by reverse phase column chromatography (gradient elution 0-80% of acetonitrile in water) to give (2S,5R)-6-(benzyloxy)-2-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (198 mg, 33% for two steps) as a yellow solid. ESI-MS (EI+, m/z): 398.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:11]([O-])([OH:13])=[O:12]>OS(O)(=O)=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1
Reactant: Nc1ncccc1[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Nc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a stirred solution of 2-amino-3-nitropyridine in conc. H2SO4 (50 mL) at 0° C. was added HNO3 (3.10 mL, d=1.49) dropwise over 10 min. The mixture was warmed to r.t. for 20 min then heated to 50° C. for 90 min. The reaction mixture was cooled and poured into 400 g of ice. The resulting precipitate was filtered and air dried to give 10.3 g of 2-amino-3,5-dinitropyridine as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:19][C:20]1[CH:21]=[C:22]([CH:33]=[CH:34][C:35]=1[Cl:36])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)=[O:24].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1[O:32][C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:23](=[O:24])[C:22]2[CH:33]=[CH:34][C:35]([Cl:36])=[C:20]([Cl:19])[CH:21]=2)=[CH:27][CH:28]=1)#[N:2]
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(F)c(C#N)c1
Reactant: O=C(Nc1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C(=O)OC(C)(C)C)c1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(C#N)c1
Temperature: 125 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
To a stirred solution of tert-butyl 2-(3-cyano-4-fluorophenyl)propanoate (360 mg, 1.44 mmol) from Step A and 3,4-dichloro-N-(4-hydroxyphenyl)benzamide (488 mg, 1.73 mmol) from Step B in DMSO (4 ml) was added K2CO3 (240 mg, 1.73 mmol). The reaction was stirred at 125° C. overnight, then cooled to ambient temperature and diluted with EtOAc and 10% aqueous sodium carbonate. The aqueous phase was extracted with EtOAc and the combined organics washed with 10% aqueous sodium carbonate and brine, dried over MgSO4, concentrated and purified on a Biotage Horizon (40+M 5% to 50% B:EtOAc, 21 ml-1008 ml). The appropriate fractions were then combined and concentrated to give tert-butyl 2-(3-cyano-4-(4-(3,4-dichlorobenzamido)phenoxy)phenyl)propanoate (0.476 g, 0.797 mmol, 55%). 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.84 (bs, N—H), 7.72 (d, J=9.3 Hz, 1H), 7.67 (d, J=8.7 Hz, 2H), 7.60 (m, 2H), 7.42 (d, J=8.6 Hz, 1H), 7.11 (d, J=7.7, 2H), 6.83 (d, J=8.7 Hz, 1H), 3.61 (q, J=7.1 Hz, 1H), 1.45 (d, J=7.5 Hz, 3H), 1.42 (s, 9H).