Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:6][C:5]([C:7]#[N:8])=[CH:4][C:3]1=[O:9].[BH4-].[Na+].C(O)(=O)C>CO>[OH:9][CH:3]1[C:2]([CH3:10])([CH3:1])[CH2:6][C:5]([C:7]#[N:8])=[CH:4]1
Reactant: CC1(C)CC(C#N)=CC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1(C)CC(C#N)=CC1O
Reaction time: 0.33 h

Procedure:
To a stirred solution of 4,4-dimethyl-3-oxocyclopent-1-enecarbonitrile (Step 1, 6 g, 44.4 mmol) in methanol (50 ml) was added sodium borohydride (2.52 g, 66.6 mmol) at 0° C. under nitrogen atmosphere. Reaction mixture was stirred at same temperature for 20 mins. Progress of reaction was monitored by TLC. After completion of reaction, distilled the reaction mixture was concentrated under reduced pressure. To crude reaction mass water (10 ml) was added followed by addition of 1 ml acetic acid. Aqueous reaction mixture was extracted in ethyl acetate (2×25 ml). Combined organic layer was dried on sodium sulphate and concentrated under reduced pressure to get oily compound which was directly used for next reaction without further purification (3.9 g).
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[O:12]1CCBN1.CSC.B>C1COCC1>[CH2:1]1[CH:11]([OH:12])[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1
Reactant: B1CCON1
Reactant: O=C1CCCc2ccccc21
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OC1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Preparation of the Compound of Formula (II) wherein R1 is CH3 ##STR13## Cis, exo-3-amino-2-hydroxybornane (1.0 g, 5.9 mmol), toluene (18 mL), and trimethylboroxine (0.56 mL) were combined at ambient temperature and stirred for 16 hr. Water, toluene and excess boroxine were distilled off until about 8 mL volume remained. The reaction was chased with toluene (3×11 mL), and the remainder of toluene removed under vacuum to afford the oxazaborolidine as a pale yellow oil (1.10 g, 98%). To a solution of α-tetralone (2.92 g, 19.7 mmol), THF (80 mL), and the oxazaborolidine derived from cis, exo-3-amino-2-hydroxybornane (228 mg, 1.2 mmol) under a nitrogen atmosphere was added borane methylsulfide complex (2M in THF, 7.0 mL, 14 mmol) over 75 min. After the addition was complete, the contents stirred for an additional 15 min, cooled to 0° C., and quenched with methanol (27 mL). After stirring the quenched reaction for 18 hrs the solvents were removed under vacuum, the residual oil was dissolved in methylene chloride (50 mL), washed with pH 4 phosphate buffer (50 mL), water (50 mL), treated with magnesium sulfate, and the solvent was removed under vacuum to give the (R) tetralol as a colorless oil 3.16 g (90% ee).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([C:6]1[CH:24]=[CH:23][C:9]2[C:10]3(OCC[O:19]3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH:13]=[CH:14][C:8]=2[CH:7]=1)[CH3:5].S(=O)(=O)(O)O>O>[CH:7]1[C:8]2[CH:14]=[CH:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10](=[O:19])[C:9]=2[CH:23]=[CH:24][C:6]=1[CH:4]([CH3:5])[C:3]([OH:25])=[O:2]
Reactant: COC(=O)C(C)c1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Yield: 70 %

Procedure:
2.0 Gm. of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid methyl ester is stirred in 25 ml. of 1:1 concentrated sulfuric acid:water for 12 hours. The mixture is poured into water and extracted with ethyl acetate and the extract is washed, dried and evaporated to afford a 70% yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid, m.p. (chloroform-hexane) 138°-139° C.; m.p. (acetone-hexane) 113°-115° C. Use of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)acetic acid methyl ester gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetic acid, m.p. (acetone-hexane) 148°-149.5° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:10]([C:13]#[N:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[CH3:28])[NH2:24]>C(O)(C)C>[ClH:2].[C:13]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:15][CH2:16][CH2:17][O:18][CH3:19])[N:6]=[CH:5][CH:4]=[C:3]2[NH:24][C:23]1[CH:25]=[CH:26][C:27]([CH3:28])=[C:21]([OH:20])[CH:22]=1)#[N:14]
Reactant: COCCOc1cc2nccc(Cl)c2cc1C#N
Reactant: Cc1ccc(N)cc1O
Agent: Cl
Solvent: CC(C)O
Product: COCCOc1cc2nccc(Nc3ccc(C)c(O)c3)c2cc1C#N
Yield: 64.8 %

Procedure:
A mixture of 4-chloro-6-cyano-7-(2-methoxyethoxy)quinoline hydrochloride (220 mg 0.84 mmol), (prepared as described for the starting material in Example 1), and 3-hydroxy-4-methylaniline (123 mg, 1 mmol) in isopropanol (10 ml) was heated at reflux for 1 hour. The mixture was allowed to cool, the solid product was collected by filtration, washed with acetone and dried to give 6-cyano-4-(3-hydroxy-4-methylanilino)-7-(2-methoxyethoxy)quinoline hydrochloride (210 mg, 60%) as an orange solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][C:25]4[S:26][C:27]5[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=5[N:29]=4)=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:35]>C(Cl)Cl.O1CCOCC1>[ClH:35].[ClH:35].[S:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[O:24][C:20]1[CH:19]=[C:18]2[C:23]([C:15]([CH2:14][N:11]3[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]3)=[CH:16][NH:17]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2c[nH]c3cc(Oc4nc5ccccc5s4)ccc23)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1CCN(Cc2c[nH]c3cc(Oc4nc5ccccc5s4)ccc23)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of {1-[6-(benzothiazol-2-yloxy)-1H-indol-3-ylmethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester (500 mg, 1.04 mmol) in DCM (20 mL) was added 4 M HCl in dioxane (20 mL) and the resulting reaction mixture was stirred (rt, 4 h). The reaction mixture was concentrated in vacuo to provide the title compounds as a tan solid (470 mg, 100%). MS (ESI): mass calcd. for C21H22N4OS, 378.5; m/z found, 379.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)(=[O:11])[CH3:10]>CCOC(C)=O>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:19][C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:9](=[O:11])[CH3:10])=[CH:18][CH:17]=2)[N:3]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: Clc1cncc(Cl)n1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(Oc2cncc(Cl)n2)cc1
Yield: 92 %

Procedure:
Using Method DD with 2,6-dichloropyrazine (200 mg, 1.34 mmol) and 4-acetamidophenol (202 mg, 1.49 mmol), and crystallisation in AcOEt, the title compound was obtained (327 mg). Yield: 92%. 1H NMR (250 MHz, DMSO-d6) δ 2.12 (s, 3H, CH3—NH), 7.25 (d, 2H, Harom 3+5, J=8.9 Hz), 7.71 (d, 2H, Harom 2+6, J=8.9 Hz), 8.55 (s, 1H, HPz 5), 8.57 (s, 1H, HPz 3), 10.10 (s, 1H, NH). m/z: 264.0 [(M+H)+, calcd for C12H10ClN3O2 263.0].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:14][C:15]#[CH:16]>CC(C)=O>[CH2:16]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:15]#[CH:14]
Reactant: C#CCBr
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C#CCN1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.8 %

Procedure:
Prepared using methodology as described in US 2005/0026944. To a stirred mixture of piperidine (851 mg, 10.0 mmol), cesium carbonate (3.26 g, 10.0 mmol) and acetone (20 mL) was added 3-bromoprop-1-yne (1.49 g, 10.0 mmol; 80% in toluene) at room temperature. The white suspension was stirred for 18 hours at room temperature. The suspension was filtered, and the filtrate was concentrated. The resulting residue was triturated with diethyl ether (10 mL), filtered, and the filtrate concentrated to obtain the product as an oil (0.70 g, 56%). 1H NMR (400 MHz, CDCl3) δ 3.27 (d, J=2 Hz, 2H), 2.50 (m, 4H), 2.22 (t, J=2 Hz, 1H), 1.62 (m, J=6 Hz, 4H), 1.43 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:27])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:7]2[OH:26].C([O-])([O-])=O.[K+].[K+].Br[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(#N)C>[F:1][C:2]1[C:3]([O:27][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:7]2[OH:26]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(O)c(F)c2C(C)(C)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(OCc3ccccc3)c(F)c2C(C)(C)C1=O
Temperature: 25 °C
Yield: 75.7 %

Procedure:
A mixture of 1,1-dimethylethyl N-((8-fluoro-4,7-dihydroxy-1,1-dimethyl-2-oxo-naphthalene-3-yl)carbonyl)glycinate (0.29 g, 0.76 mmol, prepared in Example 23A-D) and K2CO3 (0.21 g, 1.5 mmol) in 5 mL ACN stirred at room temperature, was treated with 1-(bromomethyl)benzene (0.26 g, 1.5 mmol), and the resulting mixture was stirred for 12 hours, M+Na=492. The mixture was concentrated in vacuo and purified by column chromatography eluting with 10-30% EtOAc/hexane to give 0.27 g of the title compound as a white solid. MS (m/z)=492 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13](Br)=[C:12]([Cl:17])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([O:28][CH3:29])=[C:23](B(O)O)[CH:24]=1>>[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:21]3[CH:20]=[C:19]([F:18])[CH:24]=[CH:23][C:22]=3[O:28][CH3:29])=[C:12]([Cl:17])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: O=S(=O)(c1ccccc1)c1ccc(Br)c(Cl)c1
Product: COc1ccc(F)cc1-c1ccc(S(=O)(=O)c2ccccc2)cc1Cl

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of step (i) and 5-fluoro-2-methoxybenzene boronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[OH-].[Na+].[CH2:14](Br)[C:15]#[CH:16]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH2:16][C:15]#[CH:14])=[O:6]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: C#CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: C#CCOC(=O)c1ccc(O)c(Cl)c1
Yield: 64.3 %

Procedure:
Using the above procedure, 3-chloro-4-hydroxybenzoic acid (0.0826 mole) and sodium hydroxide (0.0826 mole) were dissolved in 50% isopropyl alcohol (200 ml). Propargyl bromide (0.0826 mole) was added and the solution was heated to reflux for 6 hours. The solution was then cooled and the isopropyl alcohol was removed under vacuum. The residue was taken up in methylene chloride (200 ml), washed with water (200 ml), saturated sodium bicarbonate, saline and dried over magnesium sulfate. Removal of the solvent yielded crude product, which was recrystallized, from CCI4 to give the pure product. (64.3% yield) m.p. 144-145° C.
Reaction SMILES: [I-:1].[C:2]([CH2:5][C:6]1[CH:7]=[C:8]([S+:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]2=3)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])([OH:4])=[O:3].Br[CH:28]1[CH2:32][CH2:31][O:30][C:29]1=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[I-:1].[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]([S+:14]2[C:15]3[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]2=3)=[CH:7][C:6]=1[CH2:5][C:2](=[O:4])[O:3][CH:28]1[CH2:32][CH2:31][O:30][C:29]1=[O:33]
Reactant: O=C1OCCC1Br
Reactant: COc1ccc(-[s+]2c3ccccc3c3ccccc32)cc1CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc(-[s+]2c3ccccc3c3ccccc32)cc1CC(=O)OC1CCOC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5-(3-(carboxymethyl)-4-methoxyphenyl)-dibenzothiophenium iodide (50 g, 105 mmol), 3-bromodihydrofuran-2(3H)-one (17.3 g, 105 mmol), and cesium carbonate (68.3 g, 210 mmol) are dissolved in DMF (400 mL) and stirred at 25° C. for 4 h. The reaction mixture is quenched with water (1 L), extracted with DCM (2×400 mL), the combined organic layers washed with water (4×500 mL), concentrated to a viscous oil and precipitated from MTBE (2 L) to afford the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7]2([CH2:20][O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[C:27]4[C:31]=3[N:30](COCC[Si](C)(C)C)[N:29]=[CH:28]4)[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C(Cl)Cl>>[C:1]1([C:7]2([CH2:20][O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[C:27]4[C:31]=3[NH:30][N:29]=[CH:28]4)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cccc3cnn(COCC[Si](C)(C)C)c23)(c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(C2(COCc3cccc4cn[nH]c34)CCNCC2)cc1

Procedure:
tert-Butyl 4-phenyl-4-(((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methoxy)methyl)piperidine-1-carboxylate (34 mg, 0.06 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 4 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvent was evaporated and the compound purified by reverse phase HPLC to afford 11 mg (56%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 8.91 (s, 1H), 8.24 (m, 1H), 7.76 (d, J=8.2 Hz, 1H), 7.40-7.43 (m, 2H), 7.28-7.35 (m, 4H), 7.22-7.25 (m, 1H), 4.81 (s, 2H), 3.48 (s, 2H), 3.38-3.41 (m, 2H), 2.96-2.97 (m, 2H), 2.39-2.41 (m, 4H). Mass spec.: 322.08 (MNa)+. Accurate mass spec.: m/z 322.1909 [MH]+, Δ=3.2 ppm.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH:5](Br)[CH:6](Br)[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[C:9](=[O:12])[C:10]=2[CH:11]=1.C1CCN2C(=NCCC2)CC1.[CH3:30][OH:31]>>[Br:1][C:2]1[S:3][C:4]2[C:5]([O:31][CH3:30])=[CH:6][C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[C:9](=[O:12])[C:10]=2[CH:11]=1
Reactant: CO
Reactant: O=C1c2ccccc2C(Br)C(Br)c2sc(Br)cc21
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc2ccccc2c(=O)c2cc(Br)sc12

Procedure:
A methanol (1100 mL) solution of the compound obtained in Example 13 (90.2 g, 200 mmol) was refluxed while heating overnight. After allowing the mixture to cool in the air, DBU (63.4 g, 417 mmol) was further added thereto, and the mixture was refluxed while heating for another overnight. The reaction mixture was allowed to cool in the air, and the precipitated crystals were separated by filtration and dried, to give the captioned compound in an amount of 55.7 g, 173 mmol (2 steps, 87%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:12]=2[O:11][N:10]=1)=[O:2].C(N1C=CN=C1)([N:23]1C=CN=C1)=O.N>CN1CCCC1=O>[CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([NH2:23])=[O:20])=[CH:17][C:12]=2[O:11][N:10]=1)=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=Cc1ccccc1-c1noc2cc(C(=O)O)ccc12
Agent: N
Solvent: CN1CCCC1=O
Product: NC(=O)c1ccc2c(-c3ccccc3C=O)noc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a solution of 3-(2-formylphenyl)benzo[d]isoxazole-6-carboxylic acid (Compound 6) (60.2 g) in N-methyl-2-pyrrolidinone (600 mL) at room temperature was added in one portion 1,1′-carbonyldiimidazole (40.2 g) and the solution stirred at room temperature under nitrogen for 2 h then poured into specific gravity 0.880 aqueous ammonia solution. The suspension was stirred mechanically at room temperature for 2 h then filtered. The still moist collected solid was triturated in methanol (200 mL) at room temperature then filtered, this material was triturated again with methanol (100 mL) then filtered and dried in vacuo to give the title product (54.92 g).
Reaction SMILES: [Mg].BrCC.[CH2:5]([OH:9])[CH2:6][C:7]#[CH:8].Br[CH2:11][C:12]#[C:13][CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O1CCCC1>[CH2:5]([OH:9])[CH2:6][C:7]#[C:8][CH2:11][C:12]#[C:13][CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C#CCCO
Reactant: CCCCCC#CCC#CCBr
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Product: CCCCCC#CCC#CCC#CCCO
Reaction time: 1 h
Yield: 72.3 %

Procedure:
In a 1 L three-necked, flame-dried round bottom flask fitted with a reflux condenser and a rubber septum was placed 3.86 g (159 mmol) of magnesium in 250 mL of anhydrous tetrahydrofuran. Bromoethane (17.3 g; 1586 mmol) in 250 mL anhydrous tetrahydrofuran was added dropwise, under argon, and the reflux rate was controlled with the aid of an ice-water bath. The mixture was heated to reflux and stirred for 1 hour. 3-Butyn-1-ol (5.56 g, 79.3 mmol), dissolved in 150 mL of anhydrous tetrahydrofuran, was slowly added dropwise with stirring (2 hours). Following addition, the reaction was heated to reflux. After stirring for 90 minutes, 0.5 g (2.63 mmol) of cuprous (I) iodide was added. After 75 minutes 9.0 g (39.65 mmol) of 1-bromo-2,5-undecadiyne dissolved in 150 mL of anhydrous tetrahydrofuran was added. The mixture was heated at reflux for 12 h and an additional 0.25 g (1.32 mmol) of cuprous (I) iodide was added. The mixture was heated at reflux for 7 hours, cooled and quenched by addition of 400 mL of ice-water saturated with ammonium chloride. After filtration (Celite), the filtrate was extracted with 3×400 mL of ether. The ether layers were washed with 2×300 mL of saturated ammonium chloride solution, 3×200 mL of water, 250 mL of brine, dried (Na2SO4), and concentrated in vacuo to yield 6.2 g of yellow-brown oil. The residue was partially purified by crystallization (petroleum ether) at -20° C. to produce 5.75 g (75%) of an unstable yellow oil (room temperature) which was utilized immediately in the next reaction. IR (neat,cm-1) 3365, 2956, 2933, 2225; 1H NMR (CDCl3) δ 3.70 (t, J=6.2 Hz, 2H), 3.17-3.13 (m, 4H), 2.45 (dt, J=1.5, 5.9, 12.0 Hz, 2H), 2.15 (dt, J=2.1, 6.9, 13.9 Hz, 2H), 1.68 (br, 1H), 1.55-1.43 (m, 2H), 1.43-1.26 (m, 4H), 0.89 (t, J=6.9 Hz, 3H); HRMS calculated for C15H20O (M+) 216.1514, found 216.1519.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[Cl:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:3]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)c1ccc(-c2cccc(Cl)c2)cc1Nc1ccc(F)cc1
Temperature: 110 °C
Reaction time: 19 h

Procedure:
To N,N-dimethylacetamide 2.5 mL solution of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 80 mg were added 3-chlorophenylboronic acid 51 mg, sodium carbonate 58 mg and polymer-carried di(acetato)dicyclohexylphenylphosphine palladium(II) 7 mg, and it was stirred at 110° C. for 19 hours. After the reaction mixture was cooled to room temperature, polymer-carried di(acetato)dicyclohexylphenylphosphine palladium(II) 7 mg was added to it, and it was stirred at 110° C. for 30 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution and saturated sodium chloride aqueous solution, the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=4:1] to give tert-butyl 4-(3-chlorophenyl)-2-(4-fluoroanilino)benzoate.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Cl)=[CH:29][CH:28]=1.O>CN(C=O)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:3]2[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]3/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/3)[CH2:5][CH2:4]2)=[CH:29][CH:28]=1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Reactant: ClCc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) were added potassium carbonate (345 mg) and 1-chloro-4-(chloromethyl)benzene (103 mg). The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (110 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CN(C=O)C.O>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2cc(O)ccc21
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2cc(OCCN3CCOCC3)ccc21
Temperature: 80 °C
Yield: 68.1 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-5-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one (60 mg, 0.18 mmol) obtained in Step 5 in DMF (2 mL) was added K2CO3(75 mg, 0.54 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (50 mg, 0.27 mmol). The mixture was heated to 80° C. for 3 h and cooled to room temperature. The resulting solution was diluted with H2O and extracted with EtOAc (5 mL×3). The extracts were washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (2% MeOH/CH2Cl2) to afford the title compound (55 mg, 68%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:16]1[CH2:22][S:19](=[O:21])(=[O:20])[O:18][CH2:17]1>CC(C)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:17][CH2:16][CH2:22][S:19]([OH:21])(=[O:20])=[O:18])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: O=S1(=O)CCCO1
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCN(CCCS(=O)(=O)O)CC2)cc1
Temperature: 25 °C

Procedure:
To a solution of 1-(4-nitrophenyl)piperazine (2.58 g, 12.1 mmol) in acetone (25 mL) was added 1,3-propane sultone (1.06 g, 8.6 mmol). The mixture was stirred at reflux for 2 h. The reaction was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. This allowed the isolation of compound N, 2.85 g (71%).