Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH:18][CH:19]2[CH:26]3[CH:22]([CH2:23][N:24](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:25]3)[CH2:21][CH2:20]2)=[O:17])[CH:6]=[C:7]([C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)[CH:8]=1)[CH3:2].O>FC(F)(F)C(O)=O>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH:18][CH:19]2[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[CH2:21][CH2:20]2)=[O:17])[CH:6]=[C:7]([C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)[CH:8]=1)[CH3:2]
Reactant: CCc1cc(NC(=O)NC2CCC3CN(C(c4ccccc4)(c4ccccc4)c4ccccc4)CC32)cc(-c2nnnn2C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCc1cc(NC(=O)NC2CCC3CNCC32)cc(-c2nnnn2C)c1
Reaction time: 2 h
Yield: 90.7 %

Procedure:
N-[3-Ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-[(3aRS,4RS,6aSR)-2-trityloctahydrocyclo-penta[c]pyrrol-4-yl]urea (310 mg, 518 μmol) was dissolved in trifluoroacetic acid (5 mL) to provide a bright yellow solution. This was treated dropwise with water (5 mL) to provide a pale yellow slurry. After 2 hours, the mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate and 1.0 N aqueous hydrochloric acid. The aqueous phase was washed with additional ethyl acetate, and then made strongly basic with 50% aqueous sodium hydroxide. The resulting mixture was extracted three times with ethyl acetate, and these organic phases were combined, dried over sodium sulfate, and concentrated under vacuum to provide a white glass (167 mg, 90%). NMR (300 MHz, CDCl3) δ7.71 (s, 1H), 7.69 (s, 1H), 7.29 (s, 1H), 7.18 (s, 1H), 6.49 (d, J=8 Hz, 1H), 4.27 (m, 1H), 4.20 (s, 3H), 2.97 (m, 2H), 2.8-2.6 (m, 6H), 1.90 (m, 1H), 1.70 (m, 2H), 1.36 (m, 1H), 1.24 (t, J=7 Hz, 3H).
Reaction SMILES: C=C.[C:3]1(C)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[CH2:8]=[CH:3][CH2:4][CH3:5].[CH2:8]=[CH:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Cc1ccccc1
Agent: *CC*
Agent: C=C
Product: C=CCC
Product: C=CCCCC
Temperature: 100 °C

Procedure:
Catalysis was conducted in a 75 ml stainless steel autoclave equipped with an addition funnel, gas inlet valve and a magnetic stirrer bar. The addition funnel was charged with 0.0044 g (0.0108 mmol) of CrCl3(bis-(2-diethylphosphino-ethyl)-amine) dissolved in 20 ml of toluene and to the base of the autoclave was added 5 ml of 1.5M MAO solution in toluene. Over 20 minutes the base of the autoclave was heated to 100° C., after which time the reactor was charged with ethylene to a pressure of 40 bar and the addition funnel was opened such that the Cr complex solution was allowed to mix with the MAO solution. After 30 minutes at a constant ethylene pressure of 40 bar the reaction was stopped by cooling the autoclave to 0° C. and releasing excess ethylene. The gas released was collected and analysed by gas-chromatography (GC). The liquid contained in the autoclave was quenched with ethanol followed by 10% hydrochloric acid, and 1.000 ml of nonane was added as a GC internal standard. The reaction yielded 0.063 g polyethylene, 0.04 g butene, 8.67 g 1-hexene and 0.10 g other hexene isomers.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][OH:11]>C1(C)C=CC=CC=1>[OH:11][CH2:10][CH2:9][CH2:8][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: OCCCBr
Solvent: Cc1ccccc1
Product: OCCCN1CCOCC1
Temperature: 80 °C
Yield: 51 %

Procedure:
Morpholine (94 g, 1.08 mol) was added dropwise to a solution of 3-bromo-1-propanol (75 g, 0.54 mol) in toluene (750 ml) and the reaction then heated at 80° C. for 4 hours. The mixture was allowed to cool to ambient temperature and the precipitated solid was removed by filtration. The volatiles were removed from the filtrate and the resulting yellow oil was purified by distillation at 0.4-0.7 mmHg to give 4-(3-hydroxypropyl)morpholine (40 g, 50%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:6]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])=[C:7]([F:9])[CH:8]=1)[NH2:5].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33](Cl)=[O:34].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([N:10]2[C:11](=[O:20])[C:12]3=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]3[C:14]2=[O:15])=[C:4]([NH:5][C:33]([C:24]2[CH:25]=[CH:26][C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:23]=2)=[O:34])[C:3]=1[O:21][CH3:22]
Reactant: COc1c(Cl)cc(F)c(N2C(=O)c3ccccc3C2=O)c1N
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1c(Cl)cc(F)c(N2C(=O)c3ccccc3C2=O)c1NC(=O)c1ccc2ccccc2c1

Procedure:
3-Chloro-5-fluoro-2-methoxy-6-(phthalimido)aniline (0.32 g, 1 mmol), 2-naphthoyl chloride (0.23 g, 1.2 mmol), and triethyl amine (0.12 g, 1.2 mmol) were dissolved in tetrahydrofuran (20 ml) and solution refluxed for 3 hr. Solvent was then removed under reduced pressure and the residue subjected to column chromatography on silica gel. Title compound was eluted with hexane-ethyl acetate (7:3; 0.12 g).
Reaction SMILES: CO[C:3]([C:5]1[C:10]2[N:11]=[CH:12][N:13]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)[C:9]=2[CH:8]=[CH:7][N:6]=1)=[O:4].[CH3:23][NH2:24].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36]>>[CH3:23][NH:24][C:3]([C:5]1[C:10]2[N:11]=[CH:12][N:13]([C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:33]([NH:32][C:29]4[CH:30]=[CH:31][C:26]([Cl:25])=[C:27]([C:35]([F:36])([F:37])[F:38])[CH:28]=4)=[O:34])=[CH:18][CH:19]=3)[C:9]=2[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CN
Reactant: COC(=O)c1nccc2c1ncn2-c1ccc([N+](=O)[O-])cc1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: CNC(=O)c1nccc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-(4-nitrophenyl)-1H-imidazo[4,5-c]pyridine-4-carboxylic acid methyl ester, methylamine and 4-chloro-3-(trifluoromethyl)phenyl isocyanate in the same manner as in Steps C and D of Example 92.
Reaction SMILES: Cl.[N:2]1[C:3]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:21])[C:18]([OH:20])=O)=[CH:13][CH:12]=2)=[CH:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.S(Cl)(Cl)=O.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH2:30]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH:30][C:18](=[O:20])[CH:17]([C:14]1[CH:13]=[CH:12][C:11]([C:3]2[N:2]=[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][N:5]3[CH:4]=2)=[CH:16][CH:15]=1)[CH3:21]
Reactant: CN(C)CCN
Reactant: CC(C(=O)O)c1ccc(-c2cn3ccccc3n2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC(C(=O)NCCN(C)C)c1ccc(-c2cn3ccccc3n2)cc1
Reaction time: 3 h

Procedure:
6.2 g of 2-[4-(imidazo[1,2-a]pyridin-2-yl)phenyl]propionyl chloride, which is produced by treating 2-[4-(imidazo[1,2-a]pyridin-2-yl)phenyl]-propionic acid hydrochloride with thionyl chloride in chloroform, is added to a solution of 2.6 g of N,N-dimethylethylenediamine in 50 ml of pyridine. The mixture is allowed to stand at room temperature for 3 hours, and concentrated under reduced pressure. The residue is neutralized with aqueous sodium bicarbonate solution. The crystalline precipitate is washed with water and recrystallized from toluene to give 2.3 g of N-(2-dimethylamino-ethyl)-2-[4-(imidazo[1,2-a]pyridin-2-yl)phenyl]propionamide melting at 149°-150°C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH3:19])[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:20])[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:27](Br)[C:28]#[CH:29].O>CN(C=O)C>[CH3:19][C@@H:15]1[N:14]2[C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([O:20][CH2:29][C:28]#[CH:27])[CH:8]=4)[N:3]=[C:2]([NH2:1])[C:11]=3[N:12]=[C:13]2[CH2:18][O:17][CH2:16]1
Reactant: C[C@H]1COCc2nc3c(N)nc4ccc(O)cc4c3n21
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1ccc2nc(N)c3nc4n(c3c2c1)[C@@H](C)COC4
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
A solution of (11S)-6-amino-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-2-ol (100 mg, 0.370 mmol) dissolved in 15 mL of DMF was treated with cesium carbonate (241 mg, 0.740 mmol) and propargyl bromide (49 mg, 0.410 mmol) and stirred overnight at ambient temperature. The dark brown mixture was then poured into 150 mL of H2O and stirred for 30 minutes. The mixture was filtered to give a dark brown solid. Chromatography (SiO2, 0-30% CMA/CHCl3) followed by crystallization from ethyl acetate gave 51 mg of the title compound as an off-white solid, mp 184-186° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]#[C:10][C:11]#[N:12].[CH2:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)[CH2:14][CH3:15].N1C=CC=CC=1.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:20]([C:19]2[CH:23]=[CH:24][C:16]([CH2:13][CH2:14][CH3:15])=[CH:17][CH:18]=2)=[O:21])[CH:5]=[CH:4][C:3]=1[C:9]#[C:10][C:11]#[N:12]
Reactant: N#CC#Cc1ccc(O)cc1F
Reactant: CCCc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCc1ccc(C(=O)Oc2ccc(C#CC#N)c(F)c2)cc1
Yield: 40 %

Procedure:
To a solution of 20 mmol of 2-fluoro-4-hydroxyphenylpropiolonitrile and 21 mmol of 4-propylbenzoyl chloride in 50 ml of methylene chloride were added dropwise 25 mmol of pyridine, while stirring under ice-cooling and the solution was stirred for a further 3 hours. Water was added to the reaction solution which was extracted with toluene. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a brown oily product. Purification of the product by a silica gel column chromatography and recrystallization from ethanol gave 8 mmol of the title compound.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].S(=O)(=O)(O)O.C(O[C:20](=[O:22])[CH3:21])(=O)C.[C:23]([OH:26])(=O)[CH3:24]>CO.N1C=CC=CC=1>[C:2]([O:1][C@@H:2]1[O:8][C@H:7]([CH2:9][O:10][C:20](=[O:22])[CH3:21])[C@@H:5]([O:6][C:23](=[O:26])[CH3:24])[C@H:3]1[O:4][C:5](=[O:6])[CH3:7])(=[O:1])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 55 %

Procedure:
In Non-Patent Document 5, D-ribose is used as a starting material, the alkylation of the hydroxyl group at 1-position is carried out in methanol in the presence of sulfuric acid, the acetylation is carried out with acetic anhydride in pyridine, and the acetolysis is carried out in acetic acid and acetic anhydride in the presence of concentrated sulfuric acid. By recrystallizing from ethanol, 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose is obtained at a total yield of 55%. Moreover, the hydroxyl group at 1-position is methylated, and thereafter, acetylation and the subsequent acetolysis are carried out in acetic acid and acetic anhydride in the presence of concentrated sulfuric acid. Thereafter, by recrystallizing from ethanol, 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose is obtained at a total yield of 53%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[CH:13]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19])=O.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH2:49]=[C:50]([CH3:52])[CH3:51]>C(#N)C>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:13]([C:15]1[CH:22]=[CH:21][CH:20]=[C:17]([C:18]#[N:19])[CH:16]=1)[CH2:49][C:50]2([CH3:52])[CH3:51])=[O:12])[CH3:2]
Reactant: N#Cc1cccc(C=O)c1
Reactant: C=C(C)C
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C#N)c1)N2
Temperature: 0 °C
Reaction time: 12 h
Yield: 44.9 %

Procedure:
A mixture of 4-aminobenzoic acid ethyl ester (3.3 g, 20 mmol), 3-formyl-benzonitrile (2.62 g, 20 mmol) and ytterbium(III) triflate hydrate (1.86 g, 3 mmol) in acetonitrile (150 mL) was cooled to 0° C. in a sealed reaction bottle. Then a cooled solution of isobutene (5.6 g, 100 mmol) was added into. The reaction mixture was heated to 90° C. and stirred for 12 h. The solvent was removed in vacuo and the residue was purified on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(10% ethyl acetate/hexanes) to afford 2-(3-cyano-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.0 g, 45%) as a white solid: MS (ESI) M+1=335.3.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[O:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[C:19](=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>C(Cl)Cl>[CH2:23]([O:22][C:20](=[O:21])[C:19]([C:9]1[CH:10]=[CH:11][C:6]([O:5][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][CH:8]=1)=[O:25])[CH3:24]
Reactant: CCOC(=O)C(=O)Cl
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
To 301 g (2.26 mol) of AlCl3 in CH2Cl2 (750 ml) a mixture of 383 g (2.25 mol) of 4-phenoxybenzene and 205 g (1.50 mol) of ethyl chloroglyoxylate in CH2Cl2 (750 ml) is added dropwise at ice-bath temperature during one hour. Thereafter, the mixture is gradually warmed up to room temperature and stirred overnight. Then, the reaction mixture is poured onto ice. The aq. solution is acidified to pH 3 with aqueous HCl solution, followed by an extraction with CH2Cl2. The extract is dried over anhydrous MgSO4. The desired product is purified by silica gel column chromatography using CH2Cl2-hexane mixture as eluent. 338 g of colorless oily 4-phenoxyphenyl glyoxylic acid ethyl ester is obtained (83%).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)[CH2:7][C@@H:6]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O.[OH-].[Li+]>C1COCC1>[CH2:25]([C@H:6]1[CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)[CH2:9][CH2:10][N:5]1[CH2:4][C:3]([OH:32])=[O:2])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)CN1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(CC(=O)O)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of [(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid methyl ester (342 mg, 0.78 mmol) in THF (5 mL) at room temperature was treated with an aqueous solution (1 mL) containing lithium hydroxide monohydrate (36 mg, 0.86 mmol). The reaction mixture was allowed to stir for 2 h and then evaporated to a small volume. The reaction mixture was then dissolved in water (5 mL) and the pH adjusted to ˜7 with 1 N HCl to precipitate a solid. The precipitate was then triturated with water (2×5 mL) and dried under a stream of nitrogen to afford the title compound as a colorless solid (318 mg, 96%). 1H NMR (CDCl3) 7.27-7.18 (m, 5H), 6.67 (d, J=8.6, 1H), 6.55 (br s, OH), 6.31-6.24 (m, 2H), 4.59-4.57 (m, 1H), 3.89-3.77 (m, 2H), 3.74 (s, 3H), 3.51 (br s, 2H), 3.27 (br s, 3H), 3.15-3.02 (m, 3H), 1.79-1.77 (m, 6H), 1.57-1.43 (m, 2H). LC/MS (Method A) 5.34 min, [M+1]+ 425.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]2[N:14]=[C:15]([OH:17])[CH:16]=[C:12]2[C:11]([CH3:18])=[N:10][N:9]=1.[Br:19]Br>C(O)(=O)C.O>[Br:19][C:16]1[C:15]([OH:17])=[N:14][N:13]2[C:12]=1[C:11]([CH3:18])=[N:10][N:9]=[C:8]2[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: BrBr
Reactant: Cc1nnc(-c2ccccc2F)n2nc(O)cc12
Solvent: O
Solvent: CC(=O)O
Product: Cc1nnc(-c2ccccc2F)n2nc(O)c(Br)c12
Yield: 94.5 %

Procedure:
To a stirred solution of 7-(2-fluorophenyl)-2-hydroxy-4-methylpyrazolo[1,5-d][1,2,4]triazine (1.48 g, 6.06 mmol) in glacial acetic acid (20 ml) was added, dropwise, bromine (0.343 ml, 6.66 mmol) and the mixture was stirred at room temperature for 20 min. The mixture was then diluted with water (80 ml) and the resulting solid was collected by filtration, washed with water and dried at 60° C. under vacuum to afford 1.85 g (94%) of the title compound as a cream solid: 1NMR (360 MHz, DMSO-d6) δ 2.88 (3H, s), 7.42-7.47 (2H, m), 7.67-7.76 (2H, m); MS (ES+) m/e 323/325 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]=[C:6]([C:8]1[O:12][C:11]2[C:13]([C:17]3[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]=3[O:31][CH2:32][CH3:33])=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)[CH3:7])C.C1COCC1.[Li+].[OH-]>CO>[CH2:32]([O:31][C:18]1[C:19]([C:27]([CH3:30])([CH3:28])[CH3:29])=[CH:20][C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:22][C:17]=1[C:13]1[C:11]2[O:12][C:8]([C:6]([CH3:7])=[CH:5][C:4]([OH:34])=[O:3])=[CH:9][C:10]=2[CH:16]=[CH:15][CH:14]=1)[CH3:33]
Reactant: CCOC(=O)C=C(C)c1cc2cccc(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3OCC)c2o1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1c(-c2cccc3cc(C(C)=CC(=O)O)oc23)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 25 °C

Procedure:
A mixture of 210 mg (0.450 mmol) of 3-[7-(2-ethoxy-3,5-di-tert-butylphenyl)-benzo[b]furan-2-yl]-but-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room temperature, the mixture was acidified to pH=2 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and after evaporation of the solvents, the crude acid was recrystallized from acetonitrile. 3-[7-(2-Ethoxy-3,5-di-tert-butylphenyl)-benzo[b]furan-2-yl]-but-2-enoic acid was isolated as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([O:23][CH3:24])=[C:15]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:14]=2)=[CH:7][CH:6]=1.[OH-].[Na+].C(O)C.O>C(#N)C>[C:25]([C:15]1[CH:14]=[C:13]([C:12]#[C:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:29])=[O:2])=[CH:6][CH:7]=2)[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]=1[O:23][CH3:24])([CH3:26])([CH3:27])[CH3:28]
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC#N
Solvent: O
Product: COc1c(C(C)(C)C)cc(C#Cc2ccc(CC(=O)O)cc2)cc1C(C)(C)C

Procedure:
Following General Procedure I and using [4-(3,5-di-tert-butyl-4-methoxy-phenylethynyl)-phenyl]-acetic acid methyl ester (Compound 142, 0.114 g, 0.29 mmol), 5M aqueous sodium hydroxide solution (2 mL) and ethanol (4 mL), followed by preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase, the title compound was obtained as a white solid (0.097 g, 88%).
Reaction SMILES: S1C=CC=C1S([NH:9]C1C=CC=CC=1N)(=O)=O.[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26]>>[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25](=[O:26])[NH2:9]
Reactant: O=C=Nc1ccccc1Br
Reactant: Nc1ccccc1NS(=O)(=O)c1cccs1
Product: NC(=O)Nc1ccccc1Br
Yield: 134.9 %

Procedure:
The urea was synthesized from 2-(2-thiophenesulfonylamino) aniline(1 mmol) and 2-bromophenylisocyanate(1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.29 g, 64%). EI-MS m/z 450(M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](Cl)[S:8][C:4]=2[CH:3]=1.[CH3:12][Mg]Br.Cl.C(OCC)(=O)C>C1COCC1.CN1C(=O)CCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:12])[S:8][C:4]=2[CH:3]=1
Reactant: C[Mg]Br
Reactant: Clc1nc2ccc(Br)cc2s1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(Br)cc2s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
In a mixed solvent of THF (200 mL) and NMP (20 mL) were dissolved 6-bromo-2-chlorobenzothiazole 1 (15 g, 60.4 mmol) and Fe(acac)3 (1.07 g, 3.02 mmol). To the obtained mixture was added at 0° C. 3M methyl magnesium bromide ethereal solution (24.14 ml, 72.4 mmol). It was stirred at room temperature for 1.5 hours. To the reaction mixture was added at 0° C. 3M methyl magnesium bromide ethereal solution (10.1 ml, 30.2 mmol). It was stirred at room temperatures for 1 hour. To the reaction mixture 1N aqueous hydrochloric acid and ethyl acetate. After extraction, the organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with column chromatography to give Compound 53 (10.6 g, 46.5 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH2:38][CH3:39])=[C:9](\[C:25]2[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:27][CH:26]=2)/[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:14]=[CH:13]3)=[CH:4][CH:3]=1.[O:40]1[CH2:44][CH2:43]OC1=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[OH:40][CH2:44][CH2:43][O:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[CH2:38][CH3:39])=[C:9](\[C:25]2[CH:26]=[CH:27][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][CH:30]=2)/[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:14]=[CH:13]3)=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(O)cc2)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(OCCO)cc2)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Temperature: 90 °C
Yield: 47.9 %

Procedure:
A mixture of (E)-ethyl 3-(4-((E)-2-(4-hydroxyphenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate (352 mg, 0.67 mmol; Compound 339, Step 1), 1,3-dioxolan-2-one (296 mg, 3.37 mmol), and potassium carbonate (185 mg, 1.34 mmol) in DMF (7 mL) was heated to 90° C. overnight. The mixture was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with brine (3×), dried over sodium sulfate, and purified by flash chromatography on silica gel eluting with 0 to 100% ethyl acetate/hexanes to afford 182 mg of the title compound as a yellow foam. NMR (400 MHz, DMSO-d6): δ 8.11 (s, 1H), 7.72 (d, 1H), 7.62 (s, 1H), 7.47 (d, 1H), 7.40 (d, 2H), 7.21 (dd, 1H), 7.08 (d, 2H), 6.88 (d, 2H), 6.78 (d, 2H), 6.48 (d, 1H), 5.85 (dd, 1H), 4.83 (t, 1H), 4.14 (qt, 2H), 4.17-3.88 (m, 3H), 3.76 (m, 1H), 3.69 (m, 2H), 2.44-2.37 (m, 3H), 2.00 (m, 2H), 1.75 (m, 1H), 1.60 (m, 2H), 1.21 (t, 3H), 0.89 (t, 3H). LCMS: 483 [(M-THP+H)+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[O:23])[CH2:18][CH2:17]2)[C:5]2[C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][S:8][C:6]=2[N:7]=1.[OH-].[Na+]>C(O)C.C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:23])[NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[CH2:20][CH2:21]2)[C:5]2[C:10]([C:11]([OH:13])=[O:12])=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)c1csc2nc(N)nc(N3CCN(C(=O)Nc4ccc(OC)cc4)CC3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(NC(=O)N2CCN(c3nc(N)nc4scc(C(=O)O)c34)CC2)cc1
Temperature: 50 °C
Yield: 54.5 %

Procedure:
To a solution of Example 21 (900 mg, 1.97 mmol) in ethanol/THF (1:1, 10 mL) was added aqueous NaOH solution (2M, 10 mL). The reaction mixture was heated to 50° C. for 12 hours. On completion, the reaction mixture was concentrated in vacuo and then re-dissolved in warm water. The pH was adjusted to pH 5-6 with 2M HCl, and the precipitate was filtered and dried on a sinter to give the title compound (460 mg) as a white solid. δH (DMSO-d6, 300 MHz) 8.43 (1H, s), 7.68 (1H, s), 7.35 (2H, d, J 8.8 Hz), 6.82 (2H, d, J 8.8 Hz), 6.44 (2H, br s), 3.70 (3H, s), 3.49-3.34 (8H, br m+H2O). LCMS (pH 10) MH+ 429, RT 0.79 minutes. LCMS (pH 3) MH+ 429, RT 1.15 minutes.