Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([OH:16])=O)[C:11]=2[CH3:13])[S:6](=[O:18])(=[O:17])[CH2:5][CH2:4]1.S(Cl)(Cl)=O.[CH2:23]([N:25]1[C:29]([OH:30])=[CH:28][CH:27]=[N:26]1)[CH3:24].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>O.O1CCOCC1.C(Cl)(Cl)Cl>[CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:28]3[CH:27]=[N:26][N:25]([CH2:23][CH3:24])[C:29]=3[OH:30])=[O:16])[C:11]=2[CH3:13])[S:6](=[O:18])(=[O:17])[CH2:5][CH2:4]1
Reactant: CCn1nccc1O
Reactant: COC1CCS(=O)(=O)c2ccc(C(=O)O)c(C)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1O

Procedure:
A 100-ml flask was charged with 1.0 g (0.0037 mol) of 4-methoxy-5-methylthiochroman-6-carboxylic acid-1,1-dioxide shown in Table 5, left column, and 5.0 ml of thionyl chloride, and the mixture was allowed to react at 60° C. for 30 minutes. After the reaction was completed, an excess of thionyl chloride was distilled off under reduced pressure. The remaining oil was dissolved in 5,0 ml of chloroform, and was added to a mixture of 0.41 g (0.0037 mol) of 1-ethyl-5-hydroxypyrazole, 0.37 g (0.0037 mol) of triethylamine and 20 ml of chloroform in another 200-ml flask, and the resultant mixture was allowed to react. After the mixture was allowed to react at room temperature for 2 hours, the reaction mixture was washed with 5% hydrochloric acid and dried over anhydrous sodium sulfate, and the chloroform was distilled off under reduced pressure. Added to the remaining oil were 0.77 g (0.0056 mol) of anhydrous potassium carbonate and 1.0 ml of 1,4-dioxane, and the mixture was allowed to react at 130° C. for 2 hours. After allowed to cool, the reaction mixture was dissolved by adding 20 ml of water, and washed with ether. The aqueous layer was separated, and 5% hydrochloric acid was added to adjust the pH to 1. The precipitated oil was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. Then, the ethyl acetate was distilled off under reduced pressure to give 4-methoxy-5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound 34) shown in Table 5, right column.
Reaction SMILES: BrC1C=CC([C@](CC=O)(C(O)CCCCCCCCCC(C)C)C([O-])=O)=CC=1.[OH:29][C@H:30]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:31][C:32]([O:34][CH3:35])=[O:33].O[Li].O.C1CCC(NC2CCCCC2)CC1.BrC[C:68]([C:70]1[CH:75]=[CH:74][C:73]([Br:76])=[CH:72][CH:71]=1)=[O:69]>>[OH:29][C@H:30]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:31][C:32]([O:34][CH2:35][C:68]([C:70]1[CH:75]=[CH:74][C:73]([Br:76])=[CH:72][CH:71]=1)=[O:69])=[O:33]
Reactant: COC(=O)C[C@H](O)CCCCCCCCCCCC(C)C
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CC(C)CCCCCCCCCC(O)[C@](CC=O)(C(=O)[O-])c1ccc(Br)cc1
Agent: [Li]O
Solvent: O
Product: CC(C)CCCCCCCCCCC[C@@H](O)CC(=O)OCC(=O)c1ccc(Br)cc1
Yield: 89.8 %

Procedure:
In a manner similar to the synthesis of 116, compound 115 (960 mg, 3.2 mmol) was hydrolyzed with LiOH.H2O (202 mg, 4.8 mmol), recrystallized by refluxing with DCHA (0.76 mL, 3.84 mmol) and protected by reacting with 2,4′-dibromoacetophenone (979 mg, 3.52 mmol) to afford 118 as an amorphous solid (1.39 g, 90%). Rf=0.35 (DCM); [α]25D=−1.2° (c=1.0, CHCl3); NMR (300 MHz, CDCl3): δ 7.74 (d, 2H, J=8.4 Hz, aromatic), 7.60 (d, 2H, J=8.4 Hz, aromatic), 5.39 (d, 1H, J=16.5 Hz, CH′2a), 5.29 (d, 1H, J=16.5 Hz, CH′2b), 4.08 (m, 1H, H-3), 2.65 (dd, 1H, J2a,2b=15.0 Hz, J2a,3=3.0 Hz, H-2a), 2.54 (dd, 1H, J2a,2b=15.0 Hz, J2b,3=9.0 Hz, H-2b), 1.58-1.46 (m, 3H, H-4, H-15), 1.24-1.13 [m, 20H, H-(5-14)], 0.83 (d, 6H, J15,16=6.6 Hz, H-14). 13C NMR (75 MHz, CDCl3): δ 191.60 (C═O), 171.86 (C═O), 132.49-129.24 (m, aromatic), 68.38 (C-3), 65.74 (C-2′), 41.96 (C-2), 39.00 (C-14), 36.54 (C-4), 22.61 (C-16). HR MS (m/z) calculated for C25H39BrO4 [M+Na]+, 505.1924; found, 505.1160.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:9]\[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.[C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)#[CH:36]>O1CCCC1.C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:24][C:14]1[CH:13]=[C:12]([O:11][CH2:10]/[CH:9]=[C:8](\[C:5]2[CH:6]=[CH:7][C:2]([C:36]#[C:35][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)=[CH:3][CH:4]=2)/[C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=2)[CH:23]=[CH:22][C:15]=1[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: C#Cc1ccccn1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#Cc3ccccn3)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate (370 mg, 0.636 mmol; example 4) in a mixture of tetrahydrofuran (5 mL) and triethylamine (5 mL) was degassed and 2-ethynylpyridine (118 mg, 1.144 mmol) was added under argon atmosphere. The solution was cooled; tetrakis(triphenylphosphine)palladium (59.0 mg, 0.051 mmol) and copper(I) iodide (19.3 mg, 0.102 mmol) were added. The reaction mixture was stirred at ambient temperature for 48 h. The mixture was evaporated in vacuo and the residue was dissolved in dichloromethane (60 mL). The solution was washed with water (2×20 mL), dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 7:3) yielding methyl (E)-[2-methyl-4-[3-[4-(pyridin-2-ylethynyl)phenyl]-3-(4-trifluoromethyl phenyl)allyloxy]phenoxy]acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24](O)=[O:25])[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[C:27]([O:31][C:32](=[O:38])[N:33]([CH2:35][CH2:36][NH2:37])[CH3:34])([CH3:30])([CH3:29])[CH3:28].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]([NH:37][CH2:36][CH2:35][N:33]([CH3:34])[C:32](=[O:38])[O:31][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: COc1ccc2c(OCc3nnc4ccc(C(=O)O)cn34)ccnc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(OCc3nnc4ccc(C(=O)NCCN(C)C(=O)OC(C)(C)C)cn34)ccnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (0.072 g, 0.21 mmol) was dissolved in DMF (1.5 mL) then added N-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester (0.054 ml, 0.31 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.12 g, 0.31 mmol) and triethylamine (0.043 ml, 0.31 mmol). The reaction mixture was stirred at room temperature overnight then concentrated under vacuum. The sample was purified by flash chromatography eluting with 6% 7N ammonia in methanol/dichloromethane to afford tert-butyl 2-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)ethyl(methyl)carbamate (0.097 g, 93% yield) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([NH2:19])=[O:18].Br[C:21]1[CH:22]=[C:23]([CH3:33])[C:24]([C:27]2[CH2:28][CH2:29][O:30][CH2:31][CH:32]=2)=[N:25][CH:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)(C)C.C(Cl)(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>[O:30]1[CH2:31][CH:32]=[C:27]([C:24]2[N:25]=[CH:26][C:21]([NH:19][C:17]([C:3]3[CH:4]=[N:5][N:6]([C:7]4[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:9][CH:8]=4)[C:2]=3[CH3:1])=[O:18])=[CH:22][C:23]=2[CH3:33])[CH2:28][CH2:29]1
Reactant: Cc1cc(Br)cnc1C1=CCOCC1
Reactant: Cc1c(C(N)=O)cnn1-c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: Cc1c(C)c(C)c(P(C(C)(C)C)C(C)(C)C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Solvent: ClC(Cl)Cl
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cc3)c2C)cnc1C1=CCOCC1
Temperature: 110 °C
Yield: 58 %

Procedure:
A suspension of 5-methyl-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carboxamide (212 mg), 5-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-3-methylpyridine (200 mg) described in Reference Example 135, 2-(di-tert-butylphosphino)-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl (19 mg), tris(dibenzylideneacetone)dipalladium (0) (7.2 mg) and tripotassium phosphate (200 mg) in tert-butanol (3 ml) was stirred at 110° C. After the reaction, the reaction solution was left stand, diluted with chloroform and filtered through Celite. The organic layer was washed with water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with a silica gel column chromatography (chloroform/methanol), washed with hot ethanol and the resulting solid was filtered and dried at 60° C. in vacuo to give the titled compound (202 mg) as a white solid.
Reaction SMILES: [CH:1]12[O:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:8]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23].O>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:21]([O:13][C:8]1([CH:2]2[CH2:3][CH:4]3[O:7][CH:1]2[CH2:6][CH2:5]3)[CH2:9][CH2:10][CH2:11][CH2:12]1)(=[O:24])[CH:22]=[CH2:23]
Reactant: OC1(C2CC3CCC2O3)CCCC1
Reactant: C=CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)OC1(C2CC3CCC2O3)CCCC1
Reaction time: 1 h
Yield: 83.5 %

Procedure:
In 80 ml of toluene were dissolved 18.2 g of 1-(7-oxanorbornan-2-yl)cyclopentanol, 15.2 g of triethylamine, and 0.5 g of 4-(N,N-dimethylamino)pyridine. Then 12.5 g of acrylic chloride was added to the solution at 50° C., which was stirred at the temperature for one hour. Water, 50 ml, was added to the solution below 30° C., followed by ordinary post-treatment. Vacuum distillation yielded 19.7 g of 1-(7-oxanorbornan-2-yl)cyclopentyl acrylate. The two-step yield was 84%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][O:12][C:11]2=[O:16])=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]3[C:14](=[O:15])[CH2:13][O:12][C:11]3=[O:16])=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C1COC(=O)N1CCc1ccc(Br)cc1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: O=C1COC(=O)N1CCc1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 8 h

Procedure:
A 250 ml three-necked round-bottomed flask placed under an inert atmosphere is charged with 2 g (7.04 mmol) of 3-[2-(4-bromophenyl)ethyl]-1,3-oxazolidine-2,4-dione, obtained in step 3.1., 2.2 g (14.08 mmol) of 4-chlorophenylboronic acid and 6.5 g (28.16 mmol) of potassium phosphate hydrate in suspension in 100 ml of 1,2-dimethoxyethane. Subsequently 0.80 g (0.70 mmol) of palladium tetrakis(triphenylphosphine) is added. The reaction mixture is subsequently refluxed overnight. The salts are separated by filtration over Celite and then the filtrate is concentrated under reduced pressure. The residue is taken up in ethyl acetate and water. The organic phase is separated and is washed with saturated aqueous sodium chloride solution. The filtrate is concentrated under reduced pressure and the residue is purified by chromatography on silica gel, eluting with dichloromethane.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].[CH3:12][Si:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][O:16][CH2:17]Cl>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH2:17][O:16][CH2:15][CH2:14][Si:13]([CH3:20])([CH3:19])[CH3:12])[N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=c1[nH]nc(Cl)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(Cl)cc(Br)c1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
A 500-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with anhydrous DMF (150 mL) and 4-bromo-6-chloro-pyridazin-3(2H)-one (10.0 g, 47.8 mmol). The reaction mixture was cooled to 0° C. and sodium hydride was added. The reaction was stirred at 0° C. for 20 min. After this time, 2-(trimethylsilyl)ethoxymethyl chloride (11.9 g, 71.6 mmol) was added and the cooling bath was removed, and the reaction was stirred at room temperature for 3 h. The reaction was then quenched with saturated aqueous sodium bicarbonate (30 mL). The mixture was extracted with ethyl acetate (2×300 mL). The extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 253a in a 56% yield (9.00 g) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 8.02 (s, 1H), 5.42 (s, 2H), 3.79 (t, 2H, J=5.4 Hz), 0.96 (t, 2H, J=5.4 Hz), 0.01 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:26])([CH3:25])[CH2:9][CH:10](I)[Sn:11]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:26])([CH3:25])[CH:9]=[CH:10][Sn:11]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:20][CH2:21][CH2:22][CH3:23])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C(I)CC(C)(C)c1ccc(F)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](C=CC(C)(C)c1ccc(F)cc1)(CCCC)CCCC
Yield: 88.2 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 17.2 grams (0.030 mole ) of 3-(4-fluorophenyl)-3-methyl-1-iodo-1-tributylstannylbutane and 13.7 grams (0.090 mole) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in 100 mL of tetrahydrofuran is heated at reflux for about 18 hours. The reaction mixture is cooled and poured into about 500 mL of water. The mixture is then made acidic with aqueous 2N hydrochloric acid and extracted with three 200 mL portions of diethyl ether. The combined extracts are dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel, using 5% methylene chloride in petroleum ether as the eluant. The product-containing fractions are combined and concentrated under reduced pressure, yielding 12.0 grams of 3-(4-fluorophenyl)-3-methyl-1-tributylstannyl-1-butene. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[OH-].[Na+].O.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](=[O:13])[CH:12]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(C=CC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C=CC(=O)C=Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.9 %

Procedure:
1-(4-Methoxyphenyl)-1-buten-3-one (35e, 0.29 g, 1.6 mmol) was dissolved in methanol (5 ml) and stirred for 5 min at room temperature. A solution of sodium hydroxide (0.14 g, 3.5 mmol) and water (5 ml) was added and the mixture stirred for 30 min at room temperature. Benzaldehyde (1b, 0.17 ml, 1.7 mmol) was added dropwise and the mixture stirred for 18 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethanol to give 0.41 g (94%) of a yellow solid: mp 85-89° C. [expected mp 118-119° C.]; 1H NMR: δ 3.82 (s, 3H), 6.91 (d, 2H, J=8.5 Hz), 6.94 (d, 1H, J=15.9 Hz), 7.06 (d, 1H, J=16.1 Hz), 7.38 (m, 4H), 7.57 (m, 3H), 7.71 (dd, 2H, J=15.9, 2.0 Hz); 13C NMR: δ 55.4, 114.4, 123.3, 125.5, 127.4, 128.2, 128.8, 130.0, 130.2, 134.8, 142.6, 143.0, 161.5, 188.6.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:14]([O:16]C)=[O:15].[OH-].[Li+].O.C1COCC1>CO>[NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[S:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: COC(=O)c1sc(-c2ccc(F)cc2)cc1N
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(-c2ccc(F)cc2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The mixture consisting of 500 mg of methyl 3-amino-5-(4-fluorophenyl)thiophene-2-carboxylate, 160 mg of lithium hydroxide, 2 ml of water, 2 ml of THF and 2 ml of methanol is stirred at RT for 3 days. After dilution with 15 ml of water, unhydrolyzed ester is removed by extraction with ethyl acetate. The aqueous phase is adjusted to pH 5 using hydrochloric acid and stirred, and the precipitated solid is filtered off with suction and dried.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](Cl)=[CH:10][CH:9]=2)=[CH:4][CH2:3]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[Na+].[C:49](=[N:62][NH2:63])([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CCO.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][CH:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:55]3[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=3[C:49](=[N:62][NH2:63])[C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[CH:10][CH:9]=2)=[CH:4][CH2:3]1
Reactant: NC1CC=C(c2ccc(Cl)cc2)CC1
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCO
Product: NN=C(c1ccccc1)c1ccccc1-c1ccc(C2=CCC(N)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
An oven-dried, 1-L, 3necked flask was equipped with Teflon-coated magnetic stirring bar, reflux condenser, and argon inlet. The apparatus was flushed with Ar for 30 minutes. The flask was charged with 3 (10.0 g, 27.2 mmol), Pd(OAc)2 (143 mg, 0.64 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (490 mg, 1.23 mmol), sodium tert-butoxide (9.4 g, 98 mmol), and benzophenone hydrazone (9.6 g, 49.0 mmol). The apparatus was purged for 5 more minutes with Ar and then placed under a static Ar atmosphere (balloon). Toluene (120 mL) was added via cannula and stirring initiated. The resulting mixture was placed in an 80° C. oil bath (external temperature) for 20 h. The reaction mixture was allowed to cool to ambient temperature, and the toluene was removed in vacuo. The crude product was dissolved in 200 mL acetonitrile and filtered through a pad of silica gel (150 g in a 350 mL fritted funnel). The plug was washed with 6×100 mL acetonitrile then 10×100 mL MeOH. The product containing fractions were combined and concentrated to produce a red solid, which was dissolved in hot EtOH (30 mL) and treated with hexanes (20 mL) to induce crystallization. The flask was cooled to ambient temperature and then placed in an ice bath for 1 h. The resultant solid (4) was collected by filtration and washed with cold hexanes (2×30 mL) to provide 13.75 g (76% yield).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH3:6][C:7]1([CH3:27])[C:15]2[C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[CH:12]=[CH:11][C:10]=2[N+:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:8]1[CH3:26].C(OCC)C.[OH-].[K+]>C1C=CC=CC=1.O>[CH3:6][C:7]1([CH3:27])[C:15]2[C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[CH:12]=[CH:11][C:10]=2[N:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]1=[CH2:26]
Reactant: CC1=[N+](c2ccccc2)c2ccc3ccccc3c2C1(C)C
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Solvent: CCOCC
Product: C=C1N(c2ccccc2)c2ccc3ccccc3c2C1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,1,2-Trimethyl-3-phenyl-1H-benzo[e]indolium perchlorate (11) (0.386 g) was suspended in 50 ml of benzene or diethyl ether and a solution 0.1 g potassium hydroxide in 2 ml water was added. The mixture was stirred at room temperature under nitrogen for one hour. The organic solvent layer was separated and washed with water and filtered through silica gel and then dried and evaporated. The resultant oily product (0.2 g) was sufficiently pure for the next synthetic step. 1H NMR (400 MHz, DMSO) δ 8.05 (d, 1H, J=8.5), 7.81 (d, 1H, J=8.1), 7.67 (d, 1H, J=8.8), 7.59 (t, 2H, J=7.8), 7.43 (dt, 4H, J=6.9, 20.3), 7.22 (t, 1H, J=7.3), 6.75 (d, 1H, J=8.7), 4.05 (d, 1H, J=1.7), 3.88 (d, 1H, J=1.7), 1.71 (s, 6H).
Reaction SMILES: CC(C)([O-])C.[Na+].[F:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1.[O:15]=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:21]2[C:16](=[O:15])[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20]2)=[CH:10][CH:9]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(=O)C(c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12.4 %

Procedure:
(±)-BINAP (0.90 g), sodium tert-butoxide (5.02 g), tris(dibenzylideneacetone)dipalladium(0) (0.55 g) and toluene (200 ml) were mixed under nitrogen atmosphere, and 4-fluorobromobenzene (10.54 g), and then tert-butyl 4-oxo-1-piperidmecarboxylate (8.0 g) were added thereto. The mixture was stirred at room temperature for 5 minutes, and then at 60° C. for 7 hours (under nitrogen atmosphere). After cooling to room temperature, the reaction solution was washed with water and saturated brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was isolated and purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain tert-butyl 3-(4-fluorophenyl)-4-oxo-1-piperidinecarboxylate (1.46 g) as colorless crystals.