Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[Li]CCCC.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>C1COCC1>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1
Reactant: Brc1ccsc1
Reactant: BrCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: BrCCCCc1ccsc1
Temperature: -45 °C
Reaction time: 0.17 h
Yield: 50.9 %

Procedure:
3-bromothiophene (9 ml, 96 mmol) was dissolved in 120 ml dry hexanes. The solution was cooled down to −45° C., and 60 ml n-BuLi (60 ml 1.6M, 96 mmol) were added dropwise. The solution was stirred at −45° C. for 10 min, after which 6 ml dry THF were added and the lithium salt precipitated. After stirring at −45° C. for 1 h, the solution was warmed up to −10° C., and an excess of 1,4-dibromobutane (44 ml, 368 mmol) was added. After stirring at room temperature for 2 h, the solution was extracted with ether, washed with water, brine, dried over magnesium sulfate, and the solvent was removed. Excess 1,4-dibromobutane was removed under vacuum. Posterior filtration of the residue through a silica plug (hexanes), and solvent removal afforded the title compound (10.7 g, 51% yield) as a colorless oil. 1H-NMR (ppm, CDCl3): 1.75-1.81 (2H, m), 1.86-1.91 (2H, m), 2.67 (2H, t, J=7.32 Hz), 3.44 (2H, t, J=7.32 Hz), 6.92-6.94 (2H, m), 7.25-7.26 (1H, m); 13C-NMR (ppm, CDCl3): 29.2, 29.5, 32.4, 33.8, 120.4, 125.6, 128.3, 142.3; ESI-MS (m/z) found: 218.9843 [M+H], calculated: 218.9838.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3]1.S(=O)(=O)(O)O.[CH2:15]=[C:16]([CH3:18])[CH3:17].C(=O)([O-])O.[Na+]>ClCCl>[O:1]=[C:2]1[O:6][CH:5]([C:7]([O:9][C:16]([CH3:18])([CH3:17])[CH3:15])=[O:8])[CH2:4][CH2:3]1
Reactant: C=C(C)C
Reactant: O=C1CCC(C(=O)O)O1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCC(=O)O1
Reaction time: 8 h

Procedure:
To a solution of 5.0 g of 5-oxo-2-tetrahydrofurancarboxylic acid in 100 ml of dichloromethane was added 0.3 ml of concentrated sulfuric acid, to which was further added an excess volume (ca. 50 ml) of isobutene. The reaction mixture was left standing overnight at room temperature under tight sealing, which was poured into a cooled saturated aqueous solution of sodium hydrogencarbonate. The dichloromethane layer was separated, washed with water, dried (Na2SO4) and concentrated to give t-butyl 5-oxo-2-tetrahydrofurancarboxylate as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][S:4][C:3]=1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:14].[C:24](OCC)(OCC)(OCC)[CH3:25].C(O)(=O)C.C(OCC)C>CCOC(C)=O>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([N:15]2[C:13](=[O:14])[C:3]3[S:4][CH:5]=[C:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:2]=3[N:1]=[C:24]2[CH3:25])=[CH:21][CH:20]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: COc1ccc(NC(=O)c2scc(-c3ccccc3)c2N)cc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(-n2c(C)nc3c(-c4ccccc4)csc3c2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21 %

Procedure:
3-Amino-N-(4-methoxyphenyl)-4-phenylthiophene-2-carboxamide (57 mg, 0.18 mmol), triethyl orthoacetate (1 ml), and acetic acid (0.1 ml) were placed in a pressure bottle. The mixture was heated with stiffing at 160° C. for 18 hr. After the completion of the reaction was confirmed by TLC, the reaction mixture was cooled to room temperature and solidified with diethyl ether and EtOAc to give 13 mg (0.037 mmol, 21% yield) of the title compound.
Reaction SMILES: S.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14]2[NH:19][C:18]([CH3:21])([CH3:20])[N:17]=[C:16]([S:22]C)[N:15]=2)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.C(N(CC)CC)C>N1C=CC=CC=1>[ClH:10].[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14]2[NH:19][C:18]([CH3:20])([CH3:21])[N:17]=[C:16]([SH:22])[N:15]=2)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1
Reactant: CSC1=NC(C)(C)NC(NC(=O)c2nc(Cl)c(N)nc2N)=N1
Agent: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC1(C)N=C(S)N=C(NC(=O)c2nc(Cl)c(N)nc2N)N1
Product: Cl

Procedure:
Hydrogen sulfide is slowly bubbled with a solution of 3,5-diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-methylthio-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide (1.0 g., 0.0029 mole) in pyridine (25 ml.) containing triethylamine (1.5 ml.) for a period of five hours. Nitrogen is bubbled into the reaction mixture to remove excess hydrogen sulfide which is then poured into ice water (100 ml.). The collected solid is dissolved in hot water (75 ml.) containing hydrochloric acid (0.5 ml.) then cooled to give 3,5-diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-mercapto-1,3,5-triazin-2-yl)-2-pyrazincarboxamide hydrochloride which melts at 232° C. with decomposition.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:5]2=[N:4][C:3]=1[CH3:15].[F:16][C:17]1[CH:18]=[CH:19][C:20]2=[C:21]([CH:37]=1)[O:22][CH2:23][C:24]1[CH:34]=[C:33]([CH:35]=[O:36])[CH:32]=[CH:31][C:25]=1/[C:26]/2=[C:27](/[CH3:30])\[C:28]#[N:29]>>[F:16][C:17]1[CH:18]=[CH:19][C:20]2=[C:21]([CH:37]=1)[O:22][CH2:23][C:24]1[CH:34]=[C:33]([CH:35]([OH:36])[C:2]3[N:6]4[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:5]4=[N:4][C:3]=3[CH3:15])[CH:32]=[CH:31][C:25]=1/[C:26]/2=[C:27](/[CH3:30])\[C:28]#[N:29]
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Reactant: Cc1nc2cc(C(F)(F)F)ccn2c1I
Product: C/C(C#N)=C1/c2ccc(C(O)c3c(C)nc4cc(C(F)(F)F)ccn34)cc2COc2cc(F)ccc21
Yield: 99.5 %

Procedure:
[step 3] Using 3-iodo-2-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyridine (730 mg, 2.24 mmol) obtained in step 2 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (328 mg, 1.12 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8F, step 4, (E)-2-(3-fluoro-8-{hydroxy[2-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}dibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (550 mg, 99%) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([C:16]#[CH:17])=[CH:10][CH:11]=3)[C:6]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])[C:5]=2[CH:4]=1)#[CH:2].I[C:27]1[S:31][C:30]([CH:32]=[O:33])=[C:29]2[O:34][CH2:35][CH2:36][O:37][C:28]=12>C1(C)C=CC=CC=1.CCN(CC)CC.[Cu]I.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>[CH2:22]([C:6]1([CH2:18][CH2:19][CH2:20][CH3:21])[C:7]2[CH:8]=[C:9]([C:16]#[C:17][C:27]3[S:31][C:30]([CH:32]=[O:33])=[C:29]4[O:34][CH2:35][CH2:36][O:37][C:28]=34)[CH:10]=[CH:11][C:12]=2[C:13]2[C:5]1=[CH:4][C:3]([C:1]#[C:2][C:27]1[S:31][C:30]([CH:32]=[O:33])=[C:29]3[O:34][CH2:35][CH2:36][O:37][C:28]=13)=[CH:15][CH:14]=2)[CH2:23][CH2:24][CH3:25]
Reactant: C#Cc1ccc2c(c1)C(CCCC)(CCCC)c1cc(C#C)ccc1-2
Reactant: O=Cc1sc(I)c2c1OCCO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCC1(CCCC)c2cc(C#Cc3sc(C=O)c4c3OCCO4)ccc2-c2ccc(C#Cc3sc(C=O)c4c3OCCO4)cc21
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
Air was removed from a solution of 2,7-diethynyl-9,9-dibutyl-9H-fluorene and 5-iodo-3,4-ethylenedioxythiophene-2-carboxaldehyde (Jessing, M.; Brandt, M.; Jensen, K. J.; Christensen, J. B.; Boas, U. J. Org. Chem. 2006, 71, 6734) (2.3 equiv) in toluene/Et3N (4/1) by blowing argon for 20 min. Then CuI (2×4 mol %) and Pd(PPh3)2Cl2 (2×4 mol %) were added, and deaeration was continued for 10 min. Thereafter the mixture was stirred at 40° C. for 16 h. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (heptane/CH2Cl2 50:50 then 40:60) to yield 5,5′-(9,9-dibutyl-9H-fluorene-2,7-diyldi-2,1-ethynediyl)bis(3,4-ethylenedioxy-2-thiophenecarboxaldehyde).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([N+:13]([O-])=O)[C:5]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)([O-])=O.Cl>>[NH2:1][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[C:6]([NH2:13])[C:5]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1
Reactant: Cc1ccc(-c2c([N+](=O)[O-])cc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Agent: Cl
Product: Cc1ccc(-c2c(N)cc(N)cc2N)cc1

Procedure:
4-iodotoluene is reacted with picryl chloride in the presence of copper bronze at 215° C. to yield 2′,4′,6′-trinitro-4-methylbiphenyl (1). C 7 ⁢ H 7 ⁢ I + C 6 ⁢ H 2 ⁢ Cl ⁢ N 3 ⁢   ⁢ O 6 ⁢ → Δ Cu ⁢ C 13 ⁢ H 9 ⁢ I 3 ⁢ N 3 ⁢   ⁢ O 6 2′,4′,6′-trinitro-4-methylbiphenyl (1) is reacted with stannous chloride and hydrochloric acid to yield 2′,4′,6′-triamino-4-methylbiphenyl (2). C 13 ⁢ H 9 ⁢ N 3 ⁢   ⁢ O 6 ⁢ → H ⁢   ⁢ Cl Sn ⁢   ⁢ Cl 2 ⁢ C 13 ⁢ H 15 ⁢ N 3 2′,4′,6′-triamino-4-methylbiphenyl (2) is reacted with sodium nitrite and hydrochloric acid to convert the amino groups to diazonium groups. The diazonium groups react with potassium iodide to yield 2′,4′,6′-triiodo-4-methylbiphenyl (3). C 13 ⁢ H 15 ⁢ N 3 ⁢ → H ⁢   ⁢ Cl Na ⁢   ⁢ N ⁢   ⁢ O 2 ⁢ → K ⁢   ⁢ I ⁢   ⁢ C 13 ⁢ H 9 ⁢ I 3 Aromatic nitration of 2′,4′,6′-triiodo-4-methylbiphenyl (3) is performed with nitric acid and sulfuric acid to yield a mixture of 2′,4′,6′-triiodo-2-nitro-4-methylbiphenyl (4) and 2′,4′,6′-triiodo-3-nitro-4-methylbiphenyl (5). The products are separated using column chromatography. C 13 ⁢ H 9 ⁢ I 3 ⁢ → H 2 ⁢   ⁢ S ⁢   ⁢ O 4 H ⁢   ⁢ N ⁢   ⁢ O 3 ⁢ C 13 ⁢ H 8 ⁢ I 3 ⁢ N ⁢   ⁢ O 2 The methyl group of 2′,4′,6′-triiodo-3-nitro-4-methylbiphenyl (5) is oxidized by potassium permanganate to yield 2′,4′,6′-triiodo-3-nitrobiphenyl-4-carboxylic acid (6). C 13 ⁢ H 8 ⁢ I 3 ⁢ N ⁢   ⁢ O 2 ⁢ → K ⁢   ⁢ Mn ⁢   ⁢ O 4 ⁢ C 13 ⁢ H 6 ⁢ I 3 ⁢ N ⁢   ⁢ O 4 2′,4′,6′-triiodo-3-nitrobiphenyl-4-carboxylic acid (6) is reacted with thionyl chloride to yield 2′,4′,6′-triiodo-3-nitrobiphenyl-4-carbonyl chloride (7). C 13 ⁢ H 6 ⁢ I 3 ⁢ N ⁢   ⁢ O 4 ⁢ → S ⁢   ⁢ O ⁢   ⁢ Cl 2 ⁢ C 13 ⁢ H 5 ⁢ Cl ⁢ I 3 ⁢ N ⁢   ⁢ O 3 The hydroxyl groups of D-Glucosamine (8) are protected by reaction with acetic anhydride in the presence of pyridine to yield 1,3,4,6-tetra-O-acetyl-D-glucosamine (9). C 6 ⁢ H 13 ⁢ N ⁢   ⁢ O 5 ⁢ → C 5 ⁢   ⁢ H 5 ⁢ N C 4 ⁢   ⁢ H 6 ⁢   ⁢ O 3 ⁢ C 14 ⁢ H 21 ⁢ N ⁢   ⁢ O 9 1,3,4,6-tetra-O-acetyl-D-glucosamine (9) is reacted with 2′,4′,6′-triiodo-3-nitrobiphenyl-4-carbonyl chloride (7) to yield 2-nitro-4-(2′,4′,6′-triiodophenyl)-benzoyl-1,3,4,6-tetra-O-acetyl-D-glucosamine (10). C14H21NO9+C13H5ClI3NO3→C27H25I3N2O12 2-nitro-4-(2′,4′,6′-triiodophenyl)-benzoyl-1,3,4,6-tetra-O-acetyl-D-glucosamine (10) is treated with stannous chloride in the presence of hydrochloric acid to yield 2-amino-4-(2′,4′,6′-triiodophenyl)-benzoyl-D-glucosamine (11). C 27 ⁢ H 25 ⁢ I 3 ⁢ N 2 ⁢   ⁢ O 12 ⁢ → Sn ⁢   ⁢ Cl 2 ,   ⁢ H ⁢   ⁢ Cl ⁢ C 19 ⁢ H 19 ⁢ I 3 ⁢ N 2 ⁢   ⁢ O 6
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)[CH3:2].[CH2:11]1[CH2:16]CC[CH2:13][CH2:12]1.C(OOC(C)(C)C)(C)(C)C>>[C:1]1([O:4][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:13]=[CH:12][CH:11]=[CH:16][CH:2]=1
Reactant: CC(=O)Oc1ccccc1
Reactant: C1CCCCC1
Agent: CC(C)(C)OOC(C)(C)C
Product: c1ccc(OC2CCCCC2)cc1
Temperature: 90 °C

Procedure:
Into a pressure vessel phenyl acetate (126 μL, 1 mmol, 1 eq) was added and diluted with cyclohexane (1.080 mL, 10 mmol, 10 eq). To this stirring solution was added 1 mol % of a stock solution of {[Cl2NN]Cu}2(benzene) from the catalyst stock solution described in Example 4 (200 μL=0.01 mmol). After adding of tert-butyl peroxide (220 μL, 1.2 mmol), the pressure vessel was sealed and heated to 90° C. for 24 hr. The catalyst was separated by exposing the mixture to air and filtering through Celite®. After removing cyclohexane under vacuum, the residue was analyzed by 1H NMR and GC/MS to determine the yield and consumption of starting materials.
Reaction SMILES: [F:1][C:2]([F:19])([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1)[CH:3]([F:9])[O:4][C:5]([F:8])([F:7])[F:6].[C:20]([N:24]1[C:29](=[O:30])[C:28]([Cl:31])=[C:27]([SH:32])[CH:26]=[N:25]1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCOCC>[C:20]([N:24]1[C:29](=[O:30])[C:28]([Cl:31])=[C:27]([S:32][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][C:2]([F:19])([F:1])[CH:3]([F:9])[O:4][C:5]([F:8])([F:7])[F:6])=[CH:12][CH:13]=2)[CH:26]=[N:25]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Reactant: FC(OC(F)(F)F)C(F)(F)Oc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)n1ncc(SCc2ccc(OC(F)(F)C(F)OC(F)(F)F)cc2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
1.4 g of 4-(1,1,2-trifluoro-2-trifluoromethoxy-ethoxy)-benzyl bromide (Example 4) and 1 g of 2-tert.-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone are added to a suspension of 0.8 g of potassium carbonate in 10 cc of dimethylformamide. The resulting reaction mixture is stirred for 1 hour at room temperature, is diluted with ether, is washed with diluted HCl and brine; the washed solution is thoroughly dehydrated, the solvent is evaporated off and the so obtained raw reaction product is chromatographed on silica gel with 9/1 hexane/ethyl acetate. 1.4 g of pure product is obtained.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([N:15]1[CH2:34][CH2:33][C:18]2[N:19]=[C:20]([NH:23][C:24](=[O:32])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[N:21]=[CH:22][C:17]=2[CH2:16]1)=[O:14])(C)(C)C.CCN(C(C)C)C(C)C.[CH3:44][C:45]1[CH:53]=[CH:52][CH:51]=[CH:50][C:46]=1C(O)=O.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[C:24]([NH:23][C:20]1[N:21]=[CH:22][C:17]2[CH2:16][N:15]([C:13](=[O:14])[C:46]3[CH:50]=[CH:51][CH:52]=[CH:53][C:45]=3[CH3:44])[CH2:34][CH2:33][C:18]=2[N:19]=1)=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(NC(=O)c3cccc(Cl)c3)ncc2C1
Reactant: Cc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1C(=O)N1CCc2nc(NC(=O)c3cccc(Cl)c3)ncc2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
Trifluoroacetic acid 4.0 ml (54 mmol) was added to a solution of 2-(3-chloro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 307 mg (0.789 mmol) in CH2Cl2 (8 ml) under nitrogen as inert gas and stirring was performed for 2 h at RT. After removal of the solvent, the intermediate (3-chloro-N-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-benzamide trifluoroacetate) was dissolved in CH2Cl2 (10 ml) and DIPEA 380 μl and 2-methylbenzoic acid 118 mg (0.868 mmol) were added. After cooling the reaction mixture to 0° C., EDCI 166 mg (0.868 mmol) and HOAt 16 mg (0.12 mmol) were added. The reaction mixture was stirred for 1 h at 0° C. and then overnight at RT. After removal of the solvent, purification was performed by means of column chromatography and the product 3-chloro-N-[6-(2-methyl-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-benzamide 260 mg (0.64 mmol, 81% of theoretical) was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C:16]1([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[C:35](=[O:36])[C:34]4[C:29](=[C:30]([C:37]([OH:39])=[O:38])[CH:31]=[CH:32][CH:33]=4)[O:28][C:27]=3[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:22][CH:21]=2)[CH2:19][CH2:18][CH2:17]1)=O)(C)(C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[NH2:15][C:16]1([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[C:35](=[O:36])[C:34]4[C:29](=[C:30]([C:37]([OH:39])=[O:38])[CH:31]=[CH:32][CH:33]=4)[O:28][C:27]=3[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:24][CH:25]=2)[CH2:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(C(=O)O)cccc4c3=O)cc2)CCC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(C(=O)O)cccc4c3=O)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
trifluoro-acetic acid: 3-[4-(1-tert-Butoxycarbonylamino-cyclobutyl)-phenyl]-4-oxo-2-phenyl-4H-chromene-8-carboxylic acid (18 mg, 0.035 mmol) was treated with a solution of 25% TFA in DCM (4 mL) and stirred at RT for 1 h. The reaction mixture was diluted with toluene and concentrated in vacuo. The resultant residue was triturated with diethyl ether and DCM, and concentrated in vacuo to give the title compound as a light tan solid (10 mg, 54%). 1H NMR (400 MHz, DMSO-d6): δ 13.44 (bs, 1H), 8.44 (s, 3H), 8.28-8.23 (m, 2H), 7.57 (t, J=7.7 Hz, 1H), 7.48-7.36 (m, 5H), 7.33-7.27 (m, 4H), 2.64-2.53 (m, 2H), 2.51-2.42 (m, 2H), 2.18-2.05 (m, 1H), 1.85-1.73 (m, 1H). LCMS (Method E): RT=2.89 min, [M+H]+=412.
Reaction SMILES: [OH:1][C:2]1([C:15]#[C:16][C:17]2[C:18]([F:34])=[CH:19][C:20]3[O:29][CH2:28][CH2:27][N:26]4[C:22](=[N:23][C:24]([C:30]([NH2:32])=[O:31])=[CH:25]4)[C:21]=3[CH:33]=2)[CH2:5][CH:4]([O:6]C(=O)C2C=CC=CC=2)[CH2:3]1>CO.ClCCl.O>[OH:1][C:2]1([C:15]#[C:16][C:17]2[C:18]([F:34])=[CH:19][C:20]3[O:29][CH2:28][CH2:27][N:26]4[C:22](=[N:23][C:24]([C:30]([NH2:32])=[O:31])=[CH:25]4)[C:21]=3[CH:33]=2)[CH2:3][CH:4]([OH:6])[CH2:5]1
Reactant: NC(=O)c1cn2c(n1)-c1cc(C#CC3(O)CC(OC(=O)c4ccccc4)C3)c(F)cc1OCC2
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1cn2c(n1)-c1cc(C#CC3(O)CC(O)C3)c(F)cc1OCC2

Procedure:
In a 25-mL round-bottom flask, a suspension of 9-(1-hydroxy-3-benzoyloxy-cyclobutylethynyl)-8-fluoro-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide (190 mg, ˜0.4 mmol), lithiumol (96 mg, 4.01 mmol) in methanol (0.5 mL) and water (1 mL) was stirred at room temperature overnight. The resulting solution was diluted with 20 mL of dichloromethane and 10 mL water. The organic layer was washed with 10 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (1:10). This resulted in 7 mg of 9-(1,3-Dihydroxy-cyclobutylethynyl)-8-fluoro-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as a light yellow solid (single undetermined diasteromer). LC-MS (ES, m/z):358[M+H]+; 1H-NMR (400 MHz, DMSO-d6, ppm) δ: 8.570 (d, 1H), 7.783 (s, 1H), 7.591 (br s, 1H), 7.139 (br s, 1H), 7.015 (d, 1H), 5.982 (s, 1H), 5.200 (d, 1H), 4.520-4.496 (m, 4H), 4.000-3.949 (m, 1H), 2.760-2.716 (m, 2H), 2.164-2.115 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH3:13].C([Li])CCC.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25].O>O1CCCC1>[CH3:13][O:12][C:3]1[C:4]([O:10][CH3:11])=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[C:24](=[O:25])[C:23]1[CH:22]=[C:21]([O:20][CH3:19])[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=1
Reactant: COc1ccc(Br)c(OC)c1OC
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)c2ccc(OC)c(OC)c2OC)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 19.5 %

Procedure:
To a solution of bromobenzene 9 (0.21 g) in dry tetrahydrofuran (5 mL) cooled to −78° C. was added n-butyl lithium (0.38 mL, 2.5 M, 1.1 eq.). The solution was stirred for 30 min. and 3,4,5-trimethoxybenzoyl chloride (0.2 g) in anhydrous tetrahydrofuran was added. The resulting solution was then stirred for an additional 28 hours. The reaction was stopped with water, extracted with ethyl acetate and the solvent removed (in vacuo) to give a yellow oil. Separation by flash column chromatography (hexane-ethyl acetate, 3:1) afforded a colorless solid (0.06 g, 20.5%). The solid was recrystallized twice from ethyl acetate-hexane: m.p. 124.6-125.9° C., lit22 m.p. 121° C.; EIMS m/z 362 (M+), 345, 317, 181, 169, 151; 1H NMR δ 7.11 (1H, d, J=9.0 Hz, H6), 7.08 (2H, s, H2,6), 6.72 (1H, d, J=9.0 Hz, H5′), 3.94 (3H, s, OCH3), 3.93 (3H, s, OCH3), 3.90 (3H, s, OCH3), 3.85 (6H, s, OCH3,3,5), 3.80 (3H, s, OCH3).
Reaction SMILES: [C:1]1(/[CH:11]=[C:12]2/[CH:13]([OH:22])[C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21]/2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:23]([O:30][CH2:31][C:32](Cl)=[O:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C1C=CN=CC=1)C>[CH2:23]([O:30][CH2:31][C:32]([O:22][CH:13]1[C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21]/[C:12]/1=[CH:11]\[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: OC1C#CCCCCC#C/C1=C\c1cccc2ccccc12
Agent: CN(C)c1ccncc1
Product: O=C(COCc1ccccc1)OC1C#CCCCCC#C/C1=C\c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.1 %

Procedure:
To a solution of Compound 20b (12.1 mg, 4.37×10−2 mmol) and DMAP (57.5 mg, 0.44 mmol) in dry Ch2Cl2 (5 mL) cooled in an ice-water bath was added benzyloxyacetyl chloride (16.1 mg, 8.74×10−2 mmol) followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 20 percent EtOAc in hexane) to give 13.5 mg (73 percent) of Compound 38: pale yellow oil; Rf=0.52 (20 percent EtOAc in hexane); IR (neat) 2956, 2212, 1755, 1188, 1069 cm−1; 1H NMR (300 MHz, CDCl3) δ8.32 (d, J=7.44 Hz, 1H), 8.09-8.00 (m, 1H), 7.92-7.79 (m, 2H), 7.58-7.46 (m, 3H), 7.44-7.28 (m, 6H), 6.33 (t, J=1.35 Hz, 1H), 4.68 (s, 2H), 4.24 and 4.18 (AB q, J=16.59 Hz, 2H), 2.52-2.22 (m, 4H), 1.98-1.66 (m, 4H); 13C NMR (75 MHz, CDCl3) δ170.5, 134.2, 133.4, 132.6, 131.9, 129.8, 129.3, 129.2, 128.9, 128.7, 127.1, 127.0, 126.5, 125.9, 124.1, 123.4, 121.3, 103.4, 94.5, 80.8, 79.0, 74.1, 70.2, 68.0, 28.2, 28.1, 22.5, 21.4; MS (+CI) m/z (relative intensity) 435 (M+, 1), 271 (100).
Reaction SMILES: C(=O)([O-])O[CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[C:4]([CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=1[Br:14])#[CH:3]
Reactant: O=C([O-])OCC=Cc1ccccc1
Reactant: Nc1ccccc1Br
Product: C#CC(Nc1ccccc1Br)c1ccccc1
Reaction time: 16 h
Yield: 66 %

Procedure:
The general procedure was followed with cinnamyl carbonate (0.188 g, 0.979 mmol) and o-bromoaniline (0.215 g, 1.25 mmol). The reaction was conducted at room temperature for 16 h. 1H NMR analysis of the crude reaction mixture indicated the ratio of regioisomers to be 93/7. The mixture was purified by flash column chromatography on silica gel (1.5% ethyl acetate in hexanes) to give the title compound (0.185 g, 66%). HPLC analysis indicated the enantiomeric excess of the product was 94% [Diacel CHIRALCEL OD-H (0.46 cm×25 cm); hexane/2-propanol=99.75/0.25; flow rate=0.6 mL/1 min; detection wavelength=254 nm; TR=14.8 (minor), 23.9 (major) min]: [α]DRT=(c, CHCl3). 1H NMR (400.13 MHz, CDCl3) δ 7.46-7.25 (m, 6H), 7.07 (td, J=7.6, 0.8 Hz, 1H), 6.55 (t, J=7.6 Hz, 2 H), 6.07 (ddd, J=16.8, 10.4, 6.0 Hz, 1H), 5.27 (d, J=10.0 Hz, 1H), 5.24 (t, J=1.2 Hz, 1H), 4.98 (t, J=5.6 Hz, 1H), 4.75 (d, J=5.2 Hz, 1H). 13C NMR (100.59 MHz, CDCl3) δ 143.82, 141.13, 138.58, 132.26, 128.79, 128.26, 127.54, 126.94, 118.05, 116.25, 112.71, 109.91, 60.53. Anal. Calcd for C15H14NBr: C, 62.52; H, 4.90; N, 4.86; Br, 27.73. Found: C, 62.77; H, 4.92; N, 4.87; Br, 27.46.