Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.O>Cl>[N:27]1([C:24]2[CH:23]=[CH:22][C:21]([O:20][C:17]3[CH:18]=[CH:19][C:14]([O:13][CH2:12][C@H:8]4[CH2:9][CH2:10][CH2:11][N:7]4[CH2:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])=[CH:15][CH:16]=3)=[CH:26][CH:25]=2)[CH:31]=[CH:30][CH:29]=[N:28]1
Reactant: COC(=O)CCCN1CCC[C@@H]1COc1ccc(Oc2ccc(-n3cccn3)cc2)cc1
Agent: Cl
Solvent: O
Product: O=C(O)CCCN1CCC[C@@H]1COc1ccc(Oc2ccc(-n3cccn3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.3 %

Procedure:
To a 20 mL vial which contained a solution of the product from step 1 (40 mg, 0.1 mmol) in HCl (4 N in dioxane 2 mL) was added water (0.3 mL) at 0° C. The mixture was allowed to warm to rt and stir at rt for 24 h. The solvent was removed to yield the crude, which was purified by recrystallization from THF-ether to afford the title product (25 mg, 75%); LCMS; 94%, ESI−, Calcd: 421.5. Found m/z: 420.6 (M-1). 1H NMR (400 MHz, DMSO-d6); δ 1.74-2.09 (m, 5H), 2.16-2.25 (m, 1H), 2.31-2.40 (m, 2H), 3.03 (br, 2H), 3.45-3.80 (m, 3H), 4.16-4.20 (m, 1H), 4.20-4.23 (m, 1H), 6.52 (t, J=2.0 Hz, 1H), 6.87 (s, 1H), 7.04-7.06 (m, 5H), 7.71 (d, J=1.6 Hz, 1H), 7.80 (d, J=9.2 Hz, 2H), 8.42 (d, J=2.4 Hz, 1H):
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.[O:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1>>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([NH:31][CH:28]4[CH2:29][CH2:30][O:25][CH2:26][CH2:27]4)=[O:24])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: NC1CCOCC1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Product: O=C(NC1CCOCC1)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Yield: 90 %

Procedure:
Prepared by the method as described in Example 1 using (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I) and tetrahydro-2H-pyran-4-amine to yield the title compound as a white solid (34 mg, 90% yield). MS (apci) m/z=411.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH:14]([CH3:16])[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4](=[O:17])[CH:3]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:28]#[N:29])=[C:23](B(O)O)[CH:24]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:28]#[N:29])=[C:21]([C:2]2[CH:7]=[CH:6][N:5]([CH:8]([CH:14]([CH3:16])[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4](=[O:17])[CH:3]=2)[CH:20]=1
Reactant: N#Cc1ccc(Cl)cc1B(O)O
Reactant: CCOC(=O)C(C(C)C)n1ccc(Br)cc1=O
Product: CCOC(=O)C(C(C)C)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
240 mg (purity 92%, 0.73 mmol) of ethyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)-3-methylbutanoate (racemate) and 172 mg (0.95 mmol) of 5-chloro-2-cyanophenylboronic acid in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/monodichloromethane adduct were reacted according to General Method 2A. Yield: 117 mg (purity 81%, 36% of theory)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=1.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[CH:11]=1
Reactant: Cc1cc(C)c(-c2cccc(C=O)c2)c(C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C)c(-c2cccc(CO)c2)c(C)c1
Yield: 69.9 %

Procedure:
2′,4′,6′-Trimethylbiphenyl-3-carbaldehyde (2.36 g, 10.5 mmol) was dissolved in ethanol (20 mL), and sodium borohydride (0.40 g, 10.6 mmol) was added to the solution. After stirring under ice-cooling for 3 hrs., aqueous citric acid solution was added to the reaction solution. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5-1:2) to give the title compound (1.66 g, yield 70%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13][CH2:14][NH2:15])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([CH2:13][CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: NCCc1nc(-c2ccc(F)cc2)n[nH]1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCCc1nc(-c2ccc(F)cc2)n[nH]1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 13 %

Procedure:
This compound was synthesized from 2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)ethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (11 mg, yield 13%). 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.26-8.24 (d, J=7.8 Hz, 1H), 8.07-8.03 (m, 3H), 7.67-7.59 (m, 2H), 7.13-7.09 (t, J=8.7 Hz, 2H), 4.01-3.96 (q, J=5.9 Hz, 2H), 3.24-3.21 (d, J=6.1 Hz, 2H). MS (ESI) m/z: Calculated for C20H14F4N6O2: 446.11. found: 447.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH:17]([CH2:20][C:21]([CH3:26])([N+:23]([O-:25])=[O:24])[CH3:22])[CH:18]=O>C(O)C>[CH3:22][C:21]([N+:23]([O-:25])=[O:24])([CH3:26])[CH2:20][C:17]1[N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:2]2=[N:1][CH:18]=1
Reactant: CC(C)(CC(Br)C=O)[N+](=O)[O-]
Reactant: Nc1ncccc1OCc1ccccc1
Solvent: CCO
Product: CC(C)(Cc1cnc2c(OCc3ccccc3)cccn12)[N+](=O)[O-]
Temperature: 100 °C
Yield: 64.4 %

Procedure:
A mixture of 2-amino-3-benzyloxypyridine (2.7 g, 13.5 mmol) and 2-bromo-4-methyl-4-nitropentanal (3.0 g, 13.5 mmol) in ethanol (20 ml) is heated at 100° C. overnight. The solvent is removed under reduced pressure and the residue is treated with saturated aqueous NaHCO3 solution. The aqueous mixture is extracted two times with ethyl acetate. The combined organic extracts are dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed (silica gel, dichloromethane/ethanol 9:1) to give 2.83 g of 3-(2-methyl-2-nitropropyl)-8-(phenylmethoxy)imidazo[1,2-a]pyridine (64%).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:6]=[CH:5][C:3]=1[NH2:4].[N+:14]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:22]=[C:21]([C:2]2[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:20]=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: CCCCCc1ccc(N)c(Br)c1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: CCCCCc1ccc(N)c(-c2cccc([N+](=O)[O-])c2)c1

Procedure:
2-bromo-4-pentylaniline and 3-nitrobenzene boronic acid can be combined to form 2-(3-nitrophenyl)-4-pentylaniline,
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][CH:27]=[C:4]2[N:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:37]=2)O1.ClCCl.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]1[N:5]2[N:25]=[CH:26][CH:27]=[C:4]2[N:3]=[C:2]([C:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:37]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2ccnn12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a pressure tube was charged 5-chloro-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (Int-9d, 5.36 g, 12.5 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (4.26 g, 13.8 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (510 mg, 0.62 mmol), 2M Na2CO3 (30 ml) and DME (60 ml). The tube was degassed with Ar briefly, capped and heated at 100° C. with stirring overnight. After cooling, the reaction mixture was diluted with EtOAc and water, the organic layer was isolated, washed with brine and dried (MgSO4). After the solvent was removed under reduced pressure, the residue was purified on silica. Elution with EtOAc in hexanes (0-25%) gave tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Int-9e) (5.76 g, 80%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Br:11]Br>C(Cl)(Cl)Cl>[Br:11][C:6]1[C:5]2[S:1][CH:2]=[N:3][C:4]=2[CH:9]=[CH:8][C:7]=1[NH2:10]
Reactant: BrBr
Reactant: Nc1ccc2ncsc2c1
Solvent: ClC(Cl)Cl
Product: Nc1ccc2ncsc2c1Br
Yield: 129.3 %

Procedure:
To a solution of benzo[d]thiazol-6-amine (100 mg, 0.67 mmol) in 6 ml CHCl3 was added Br2 (42 mg, 0.27 mmol) in CHCl3 (10 ml) dropwise about 15 min. The mixture was concentrated under reduced pressure, and the residue was crystallized from DCM:MeOH (5:1) to give 7-bromobenzo[d]thiazol-6-amine (80 mg, 80%).
Reaction SMILES: [CH3:1][C:2]([OH:8])([CH2:5][CH2:6][CH3:7])[C:3]#[CH:4].Br[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2>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.CN(C=O)C.CCN(CC)CC>[OH:8][C:2]([CH3:1])([CH2:5][CH2:6][CH3:7])[C:3]#[C:4][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(C)(O)CCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC(C)(O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, 3-methyl-1-hexyn-3-ol (98 mg, 0.87 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 1 supra) (127 mg, 0.4 mmol) using (Ph3P)2PdCl2 (46 mg) and Cul (22 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 22 h yielding rac-(Z)-1,3-dihydro-4-(3-hydroxy-3-methyl-1-hexynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 92 mg, 66%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1.[H-].[Na+].[F:10][C:11]([F:25])([F:24])[CH2:12]OS(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C>[F:10][C:11]([F:25])([F:24])[CH2:12][N:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1
Reactant: O=Cc1cn[nH]c1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cnn(CC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Add 1H-pyrazole-4-carbaldehyde (0.400 g, 4.16 mmol) as a solution in DMF (2 mL) dropwise to a suspension of sodium hydride (0.333 g, 8.32 mmol) in DMF (5 mL) at 0° C. Stir for 15 min. at 0° C. Add 2,2,2-trifluoroethyl-p-toluenesulfonate (1.27 g, 5.00 mmol) and DMF (3 mL) to the reaction mixture. Heat to 60° C. for 18 hr. Quench with aqueous saturated sodium bicarbonate solution and add ethyl acetate. Separate organic layer. Extract aqueous layer twice with ethyl acetate, wash combined organics with brine, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 100:0 ethyl acetate:hexanes) to give the title preparation (309 mg, 42%). GC-MS: m/z=178 [M+].
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.[NH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>O1CCOCC1>[CH3:18][O:17][C:7]1[C:5]2[N:6]=[C:2]([NH:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[S:3][C:4]=2[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:8]=1
Reactant: NCc1cccnc1
Reactant: COc1ccc(-c2ccccc2)c2sc(Cl)nc12
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)c2sc(NCc3cccnc3)nc12
Temperature: 100 °C
Reaction time: 18 h
Yield: 30.9 %

Procedure:
To a solution of 2-chloro-4-methoxy-7-phenyl-benzothiazole (150 mg, 0.54 mmol), in dioxane (5 ml) was added 3-(aminomethyl)-pyridine (176 mg, 1.6 mmol) and this mixture was stirred at 100° C. for 18 h. The solvent was then evaporated and the mixture taken up in methanol (8 ml) and ultrasonnicated for 10 min. to precipitate the product, which was washed with methanol (5 ml), and dried under vacuum (0.05 mmHg, 60° C.) to afford the title compound as a white solid (58 mg, 31% yield), MS: m/e=348.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH:26]3[CH2:28][CH2:27]3)[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1.[C:29](Cl)(=[O:31])[CH3:30].O>N1C=CC=CC=1>[C:21]([O:20][C:19](=[O:25])[NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N:11]([C:6]2[N:7]=[CH:8][C:9]3[N:10]=[C:2]([NH:1][C:29](=[O:31])[CH3:30])[S:3][C:4]=3[N:5]=2)[CH:26]2[CH2:28][CH2:27]2)[CH:13]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(N(c2ncc3nc(N)sc3n2)C2CC2)c1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1nc2cnc(N(c3cccc(NC(=O)OC(C)(C)C)c3)C3CC3)nc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl {3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)(cyclopropyl)amino]phenyl}carbamate (1.20 g, 3.01 mmol) in pyridine (20 mL) was added acetyl chloride (859 μL, 12.1 mmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water (60 mL), and the mixture was extracted with ethyl acetate (60 mL, 20 mL). The combined organic layer was washed with saturated brine (10 mL), and filtered through a basic silica gel pad. The filtrate was concentrated under reduced pressure to give tert-butyl(3-{[2-(acetylamino)[1,3]thiazolo[5,4-d]pyrimidin-5-yl](cyclopropyl)amino}phenyl)carbamate as a dark-purple solid. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=1)[CH2:3][OH:4].C(N(CC)CC)C.[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:26]=1[C:27](Cl)=O>O1CCCC1>[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:26]=1[C:27]1[O:4][CH2:3][CH:2]([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:11][CH:12]=2)[N:1]=1
Reactant: CC(C)(C)c1ccc(OCC(N)CO)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(OCC2COC(c3c(F)cccc3F)=N2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.1 %

Procedure:
To a mixture of 1.46 g (6.54 mmol.) of 2-amino-3-[4-(1,1-dimethylethyl)phenoxy]propanol, 0.86 g (8.50 mmol.) of triethylamine and 20 ml of anhydrous tetrahydrofuran, there was added dropwise a solution of 1.15 g (6.54 mmol.) of 2,6-difluorobenzoylchloride in 10 ml of anhydrous tetrahydrofuran with stirring at a temperature of from 5° C. to 10° C. for 5 minutes. After addition, the reaction mixture was stirred at room temperature for one hour. After the reaction was completed, the resultant mixture was concentrated under reduced pressure. To the residue, there was added 20 ml of benzene and 10 ml of thionyl chloride and the reaction mixture was refluxed by heating with stirring for 3 hours. Then the reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the residue, there was added 20 ml of ethanol and further added dropwise 1.4 ml of a 5N aqueous solution of sodium hydroxide with stirring at a temperature of 60° C. for 5 minutes. The reaction mixture was then stirred at the same temperature for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the residue, there was added 100 ml of ethyl acetate. The mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 1.72 g of 2-(2,6-diflurophenyl)-4-{[4 -(1,1-dimethylethyl)phenoxy]methyl}-2-oxazoline as a colorless oily substance (nD19.1 1.5391).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].C(Cl)(=O)C([Cl:15])=O>CN(C)C=O.ClCCl>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:15])=[O:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(CBr)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(CBr)c1
Reaction time: 48 h

Procedure:
a solution of 12 g of m-bromomethylbenzoic acid 10.62 g of oxalyl chloride, 100 ml of dichloromethane and 5 drops of dimethylformamide was allowed to stand 48 hours and then evaporated. Hexane and ether were added, the mixture evaporated and the residue distilled on a Kugelroher, giving 12.5 g of m-bromomethylbenzoyl chloride as a yellow liquid.
Reaction SMILES: C1(C)C=CC=CC=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]#[N:18])=[CH:11][CH:10]=1.[C:19](OCC)(=[O:22])[CH2:20][CH3:21]>C1COCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([C:19](=[O:22])[CH2:20][CH3:21])[C:17]#[N:18])=[CH:13][CH:14]=1
Reactant: N#CCCc1ccc(Br)cc1
Reactant: CCOC(=O)CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCC(=O)C(C#N)Cc1ccc(Br)cc1
Reaction time: 0.33 h

Procedure:
A 1.7 M solution of potassium tert. pentylate in toluene (81 ml, 139 mmol) was added dropwise to a solution of 3-(4-bromo-phenyl)-propionitrile (9.70 g, 46.2 mmol) in 200 ml of THF at rt, followed by addition of ethyl propionate (18.9 ml, 185 mmol). Stirring was continued for 20 min. The reaction mixture was quenched by careful addition of 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2 SO4 and evaporated. The residue was purified by column chromatography (silica gel, EtOAc/n-hexane 3:7) to yield 1 as a yellow oil.
Reaction SMILES: NCCCCCC([C:9]1[C:18](N)=[CH:17][CH:16]=[C:11]([C:12]([NH:14][OH:15])=[O:13])[C:10]=1[O:20]C)=O>C([O-])(O)=O.[Na+]>[C:12]([NH:14][OH:15])(=[O:13])[C:11]1[C:10](=[CH:9][CH:18]=[CH:17][CH:16]=1)[OH:20]
Reactant: COc1c(C(=O)NO)ccc(N)c1C(=O)CCCCCN
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(NO)c1ccccc1O

Procedure:
SHA-Sepharose 4B was prepared by mixing 130 mg of (6-aminohexanoyl)-4-amino-methylsalicylhydroxamic acid (SHA-Z-NH2), dissolved in 30 mL 0.2 M NaHCO3, with. 6.5 g HCl washed CNBr activated Sepharose 4B (Phannacia) overnight at room temperature. After the coupling reaction, 2 mL 0.5 M Tris, pH 8.5 were added and the gel slurry mixed at room temperature for 1 hour, and washed with water, 0.5 M NaCl, and water again. The resulting SHA-Sepharose 4B was suspended in 30 mL of 20% ethanol, and stored at 4° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([O:7][C:8]2[CH:9]=[C:10]([CH3:25])[C:11]3[CH:15]([CH:16]([CH3:22])[C:17]([O:19]CC)=[O:18])[O:14][B:13]([OH:23])[C:12]=3[CH:24]=2)=[N:4][N:3]=1.O.[OH-].[Li+]>O.C1COCC1>[NH2:1][C:2]1[S:6][C:5]([O:7][C:8]2[CH:9]=[C:10]([CH3:25])[C:11]3[CH:15]([CH:16]([CH3:22])[C:17]([OH:19])=[O:18])[O:14][B:13]([OH:23])[C:12]=3[CH:24]=2)=[N:4][N:3]=1
Reactant: CCOC(=O)C(C)C1OB(O)c2cc(Oc3nnc(N)s3)cc(C)c21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2nnc(N)s2)cc2c1C(C(C)C(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask was placed a solution of ethyl 2-(6-(5-amino-1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)propanoate (500 mg, 1.32 mmol, 1.00 equiv, 96%) in H2O/THF (10/10 mL), then added lithium hydroxide hydrate (230 mg, 5.48 mmol, 4.00 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residual solution was adjusted to pH 3 with HCl (1 mol/L) and stirred for 30 min at room temperature. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions: Column, Xbridge Prep Phenyl, 5 μm, 19×150 mm; Mobile phase, water (with 0.05% TFA) and CH3CN; Gradient, 17% CH3CN up to 30% in 8 min, up to 100% in 1.5 min; Detector, UV 220 & 254 nm. This resulted in 30.2 mg (6%) of 2-(6-(5-amino-1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)propanoic acid as a white solid. H-NMR (300 MHz, DMSO-d6, ppm): δ1.284 (3H, d, J=7.2 Hz), 2.332 (3H, s), 3.120 (2H, m), 5.301 (1H, d, J=2.7 Hz), 7.082-7.141 (3H, m), 7.295 (1H, d, J=2.1 Hz), 9.180 (1H, s). MS (ESI) m/z: 336 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH2:13][CH:12]3[CH2:16][CH2:17][S:18][C:19]4[S:23][CH:22]=[CH:21][C:20]=4[C:11]3=[N:10]2)=[CH:5][CH:4]=1.CS(C)=O>Br.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]3[CH2:16][CH2:17][S:18][C:19]4[S:23][CH:22]=[CH:21][C:20]=4[C:11]3=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2N=C3c4ccsc4SCCC3CC2=O)cc1
Agent: Br
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: COc1ccc(-n2nc3c(cc2=O)CCSc2sccc2-3)cc1
Temperature: 25 °C
Yield: 68 %

Procedure:
To a solution of 14.8 g of 2-(4-methoxyphenyl)-4,4a,5,6-tetrahydrothieno[2',3':2,3]thiepino[4,5-c]-pyridazin-3(2H)-one in 100 ml of 30% hydrogen bromide-acetic acid is added 6.1 ml of dimethylsulfoxide with stirring at room temperature. The mixture is stirred for 4 hours at room temperature, poured into ice-cold water and extracted with chloroform. The extract is washed with water, dried and concentrated under reduced pressure. The resulting crystals are recrystallized from a mixed solvent of toluene and isopropyl ether to give 10 g of 2-(4-methoxyphenyl)-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as white crystals, melting at 126°-128° C.
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21]Cl)=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>CO>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: C1CCNC1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2oc(Cl)cc2c1
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCN2CCCC2)cc1)c1ccc2oc(Cl)cc2c1
Yield: 68 %

Procedure:
According to the same procedure as example 1, step E described, 4-(2-(2-chlorobenzofuran-5-yl)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol (70 mg, 1.0 eq, made by example 11, step D) was reacted with pyrrolidine (1 mL) in MeOH (3 mL) under reflux to give the desired product (51 mg, 68%, Z/E=1/2.6) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 7.20 (d, J=9.2 Hz, 1H), 7.09 & 7.06 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.8 Hz, 1H), 6.78 & 6.72 (d, J=8.2 Hz, 2H), 6.68 (d, J=8.6 Hz, 2H), 6.46 & 6.45 (s, 1H), 6.41 & 6.27 (d, J=8.4 Hz, 2H), 4.10 & 3.89 (t, J=5.8 Hz, 2H), 2.94 & 2.83 (t, J=6.2 Hz, 2H), 2.68 & 2.61 (m, 4H), 2.49 (q, J=7.4 Hz, 2H), 1.84 & 1.81 (m, 4H), 0.91 (t, J=7.4 Hz, 3H); m/z=488[M+1]+.