Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[F:30])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:22]([F:30])[CH:23]=1
Reactant: N#Cc1cc(Br)c2cn[nH]c2c1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1cc(Br)c2cnn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Temperature: 25 °C
Reaction time: 144 h
Yield: 40.7 %

Procedure:
To a solution of 4-bromo-1H-indazole-6-carbonitrile (1.0 g, 4.50 mmol) in dichloromethane (80 mL) was added 4-benzyloxy-3-fluorobenzeneboronic acid (2.2 g, 8.94 mmol), pyridine (0.71 mL, 8.78 mmol), copper acetate (1.2 g, 6.63 mmol) and powdered 4A molecular sieves (2.0 g). The reaction mixture was stirred at room temperature in the presence of air for 6 days. Celite was added to the mixture then the mixture was filtered through a pad of celite and then the filtrate concentrated in vacuo. The product was purified by silica gel chromatography eluting with 5-100% dichloromethane in hexane to yield the title compound (D5) (774 mg).
Reaction SMILES: C([C:4]1[S:8][C:7]2[S:9][C:10]([C:12]([C:14]3[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:11][C:6]=2[CH:5]=1)(O)=O>[Cu]>[S:9]1[C:7]2[S:8][CH:4]=[CH:5][C:6]=2[CH:11]=[C:10]1[C:12]([C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1)=[O:13]
Reactant: O=C(O)Cc1cccc(C(=O)c2cc3cc(C(=O)O)sc3s2)c1
Agent: [Cu]
Product: O=C(O)Cc1cccc(C(=O)c2cc3ccsc3s2)c1
Temperature: 290 °C
Yield: 50.6 %

Procedure:
A homogeneous mixture of 3-(5-carboxythieno[2,3-b]thien-2-yl)carbonyl-phenylacetic acid (24 g), copper powder (4 g) and Fontainebleau sand (100 g) is heated at 290° C. for 1 hour. After cooling, the reaction mixture is washed five times with methylene chloride (total 350 cc). The combined methylene chloride phases are extracted five times with a 10% (w/v) aqueous solution of sodium carbonate (total 400 cc). The combined alkaline liquors are stirred with decolourizing charcoal (1 g), filtered, acidified to pH 1 by addition of a 12N concentrated aqueous solution of hydrogen chloride, and extracted three times with methylene chloride (total 300 cc). The combined methylene chloride solutions are dried over anhydrous sodium sulphate and evaporated. The residue (17.3 g) is dissolved in boiling acetonitrile (50 cc) and the solution is filtered. After cooling for 1 hour at 4° C., the resulting crystals are filtered off, washed three times with iced acetonitrile (total 15 cc) and dried under reduced pressure (20 mm Hg) at a temperature of about 20° C., in the presence of potassium hydroxide pellets used as a dehydrating agent. Crude 3-(thieno[2,3-b]thien-2-yl)carbonyl-phenylacetic acid (10.6 g), melting at 121° C., is thus obtained.
Reaction SMILES: [N:1]1([CH:6]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7](=[O:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH:18]=O.C(=O)([O-])[O-].[K+].[K+].O>CO>[Cl:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:8][C:7](=[O:9])[CH:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:10][CH2:11][CH2:12][CH3:13])[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CCCCC(C(C)=O)n1ccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCCC(C(=O)C=Cc1ccc(Cl)c(Cl)c1)n1ccnc1

Procedure:
2.7 g of 3-(imidazole-1-yl)-2-heptanone and 3.0 g of 3,4-dichlorobenzaldehyde were dissolved in 50 ml of methanol. While stirring this solution under cooling with ice (0°-5° C.), 2.1 g of potassium carbonate was added. Then, the mixture was stirred at the same temperature for 7 hours. The reaction mixture was poured into water and extracted with chloroform. The extraction solution was treated by a usual method, and the obtained oily product was purified by chromatography, whereby 1-(3',4'-dichlorophenyl)-4-(imidazole-1-yl)-1-octene-3-one was obtained as an oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][S:26][C:27]1[S:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[O:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:23][CH2:24][CH2:25][S:26][C:27]3[S:28][C:29]4[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=4[N:31]=3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C(OC2CCNCC2)c2ccccn2)cc1
Reactant: BrCCCSc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Clc1ccc(C(OC2CCN(CCCSc3nc4ccccc4s3)CC2)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 40.6 %

Procedure:
To a mixture of 0.76 g (2.51 mmol) of 4-[(4-chlorophenyl)-2-pyridylmethoxy]piperidine and 0.73 g (2.53 mmol) of 2-(3-bromopropylthio)benzothiazole, were added 6 ml of acetone and 0.35 g (2.53 mmol) of potassium carbonate, and the mixture was stirred at room temperature for 15 hours. After the reaction, the insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography using chloroform alone first, and then a mixture of chloroform and methanol in the volume ratio 30:1 as the eluent, and the desired fraction was concentrated to give 0.52 g (41%) of 2-[3-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]propylthio]benzothiazole as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:37][C:38]1[N:43]([C:44]2[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=2)[CH2:42][N:41]=[C:40]2[S:51][CH:52]=[CH:53][C:39]=12.CCN(C(C)C)C(C)C.CO.C(NCC)C>CN(C=O)C>[NH2:37][C:38]1[N:43]([C:44]2[CH:45]=[CH:46][C:47]([NH:50][C:10](=[O:12])[CH2:9][C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])=[CH:48][CH:49]=2)[CH2:42][N:41]=[C:40]2[S:51][CH:52]=[CH:53][C:39]=12
Reactant: NC1=c2ccsc2=NCN1c1ccc(N)cc1
Reactant: O=C(O)Cc1cc(F)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCNCC
Solvent: CCN(C(C)C)C(C)C
Product: NC1=c2ccsc2=NCN1c1ccc(NC(=O)Cc2cc(F)ccc2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.25 mmoles of the carboxylic acid of choice (2,5-difluorophenyl-acetic acid; 0.25 mmoles) and 0.25 mmoles of HBTU were dissolved in 1 mL amine-free DMF. To this solution was added dropwise a solution of 4-Amino-3-(4-aminophenyl)thieno[2,3-d]-pyrimidine in 1 mL DMF. The resulting solution was treated with 0.3 mL of Hunig's base. The system was stirred at room temperature overnight and then treated with 0.5 mL of 1:1 MeOH-diethylamine. The system was concentrated to dryness in a Speedvac system, reconstituted in 1 mL DMSO and purified by prep HPLC. MH+=397.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][N:7]([CH2:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5][O:4]1.[Cl:21][C:22]1[CH:23]=[C:24](O)[CH:25]=[CH:26][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:21][C:22]1[CH:27]=[C:26]([CH:25]=[CH:24][CH:23]=1)[O:1][CH2:2][C@@H:3]1[CH2:8][N:7]([CH2:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5][O:4]1
Reactant: O=C(CN1CCO[C@H](CO)C1)N1CCc2ccccc21
Reactant: Oc1cccc(Cl)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(CN1CCO[C@H](COc2cccc(Cl)c2)C1)N1CCc2ccccc21
Yield: 65.9 %

Procedure:
Compound 22s was synthesised by essentially the same procedure as compound 18s (Example 16), using compound 48 (Example 7; 55 mg, 0.2 mmol), 3-chlorophenol (39 mg, 0.3 mmol), triphenylphosphine (78 mg, 0.3 mmol), DEAD (0.05 ml, 0.3 mmol), and THF (1 ml). The crude residue was purified twice by flash column chromatography (silica, DCM/MeOH 1:0 to 8:2) to afford the title compound as a colourless oil (51 mg; 65%). Analyses were performed on the free base, and the free base was converted to the HCl salt for testing.
Reaction SMILES: [CH3:1][C:2]1[CH:15]2[C:6]([CH3:21])([C:7]3[C:8](=[O:20])[CH:9]=[C:10]([CH:17]([CH3:19])[CH3:18])[C:11](=[O:16])[C:12]=3[CH2:13][CH2:14]2)[CH2:5][CH2:4][C:3]=1[C:22]([OH:24])=[O:23].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C1COCC1.O>[OH:20][C:8]1[CH:9]=[C:10]([CH:17]([CH3:19])[CH3:18])[C:11]([OH:16])=[C:12]2[C:7]=1[C:6]1([CH3:21])[CH:15]([CH2:14][CH2:13]2)[C:2]([CH3:1])=[C:3]([C:22]([OH:24])=[O:23])[CH2:4][CH2:5]1
Reactant: CC1=C(C(=O)O)CCC2(C)C3=C(CCC12)C(=O)C(C(C)C)=CC3=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1=C(C(=O)O)CCC2(C)c3c(O)cc(C(C)C)c(O)c3CCC12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
In 10 ml of THF was dissolved 300 mg of 3,4,4a,5,8,9,10,10a-octahydro-1,4a-dimethyl-7-(1-methylethyl)-5,8-dioxo-2-phenanthrenecarboxylic acid obtained by the same extraction procedure as in Example 16, followed by addition of 16 ml of an aqueous solution containing 1.6 g of sodium dithionite, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (eluent=chloroform:methanol=100:1) to provide 290 mg of 3,4,4a,9,10,10a-hexahydro-5,8-dihydroxy-1,4a-dimethyl-7-(1-methylethyl)-2-phenanthrenecarboxylic acid.
Reaction SMILES: N1C=CC=CC1=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C@H:31]4[CH2:35][CH2:34][CH2:33][N:32]4C(OC(C)(C)C)=O)=[CH:25][CH:24]=3)[C:19](=[O:43])[CH:18]=2)=[N:13][CH:14]=1>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C@H:31]4[CH2:35][CH2:34][CH2:33][NH:32]4)=[CH:25][CH:24]=3)[C:19](=[O:43])[CH:18]=2)=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(-n2ccc(OCc3ccc(Cl)cn3)cc2=O)cc1
Agent: O=c1cccc[nH]1
Product: O=c1cc(OCc2ccc(Cl)cn2)ccn1-c1ccc(OC[C@H]2CCCN2)cc1

Procedure:
Example 121 was repeated except that 4-[(5-chloro-2-pyridinyl)methoxy]-1-(4-{[(3R)-1-tert-butoxycarbonyl)-3-pyrrolidinyl]oxy}phenyl)-1H-pyridin-2-one was replaced with 4-[(5-chloro-2-pyridinyl)methoxy]-1-(4-{[(2R)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methyloxy}phenyl)-1H-pyridin-2-one to provide the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].[Cl:9][C:10]1[CH:15]=[C:14](I)[CH:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>C1(C)C=CC=CC=1.[Cu]I>[Cl:9][C:10]1[CH:15]=[C:14]([O:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Clc1cc(I)ccn1
Reactant: OCc1ccccn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Clc1cc(OCc2ccccn2)ccn1
Temperature: 105 °C
Yield: 74.3 %

Procedure:
Pyridin-2-ylmethanol (3.00 g, 27.5 mmol), 2-chloro-4-iodopyridine (6.0 g, 25 mmol), cesium carbonate (10.6 g, 32.5 mmol), CuI (0.95 g, 5.0 mmol) and 1,10-phenanthroline (0.90 g, 5.0 mmol) were stirred in toluene (15 mL) and purged with a nitrogen stream for 10 minutes. The mixture was heated to 105° C. for 16 h, allowed cool and filtered through a silica plug eluting with ethyl acetate. The filtrate was concentrated, and the residue was purified by column chromatography (80 g ISCO column column eluting with ethyl acetate/hexanes; gradient 100% hexanes to 100% ethyl acetate) to provide the title compound (4.1 g, 74%) as a white solid: ESI MS m/z 221 [M+H]+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)[C:11]=2[CH2:12][OH:13])=[O:6])[CH2:3][CH2:2]1.[S:25](Cl)([CH3:28])(=[O:27])=[O:26].C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[CH3:28][S:25]([O:13][CH2:12][C:11]1[N:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)[N:9]=[N:8][C:7]=1[C:5]([NH:4][CH:1]1[CH2:2][CH2:3]1)=[O:6])(=[O:27])=[O:26]
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COS(C)(=O)=O)cc1
Temperature: 0 °C
Yield: 94.7 %

Procedure:
N-Cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-(hydroxymethyl)-1H-1,2,3-triazole-4-carboxamide (1.12 g, 3.39 mmol) obtained in Example 112 and mesyl chloride (0.293 ml, 3.73 mmol, 1.1 eq.) were dissolved in THF (22 ml), and a solution of triethylamine (0.615 ml, 4.41 mmol, 1.3 eq.) in THF (2 ml) was added dropwise over 10 min with stirring at 0° C. The reaction mixture was stirred at 0° C. for 50 min. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with 10% brine and saturated brine. The aqueous layers were each extracted with ethyl acetate (50 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. Diethyl ether was added and the precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (1.31 g, 3.21 mmol, 94.6%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([B:9]2[O:13][CH2:12][CH2:11]O2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:15]1[CH:20]=[CH:19]C=[CH:17][C:16]=1COCOC>>[B:9]1([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])[C:17]2[CH:16]=[CH:15][CH:20]=[CH:19][C:11]=2[CH2:12][O:13]1
Reactant: COCOCc1ccccc1Br
Reactant: N#Cc1cccc(B2OCCO2)c1
Product: N#Cc1cccc(B2OCc3ccccc32)c1

Procedure:
This was prepared as per the procedure in Example 11, from 2-(3-cyanophenyl)[1,3,2]-dioxaborolane and 1-bromo-2-((methoxymethoxy)methyl)benzene to afford white crystalline product.
Reaction SMILES: [CH3:1][C@@H:2]([C:27]([CH3:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])[C:3]([NH:5][C@@H:6]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:7]([N:9]([CH3:22])[C@@H:10]([CH:19]([CH3:21])[CH3:20])/[CH:11]=[C:12](\[CH3:18])/[C:13]([O:15]CC)=[O:14])=[O:8])=[O:4].O1CCCC1.O.[OH-].[Li+].Cl>CO.O>[CH3:1][C@@H:2]([C:27]([CH3:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])[C:3]([NH:5][C@@H:6]([C:23]([CH3:24])([CH3:25])[CH3:26])[C:7]([N:9]([CH3:22])[C@@H:10]([CH:19]([CH3:20])[CH3:21])/[CH:11]=[C:12](\[CH3:18])/[C:13]([OH:15])=[O:14])=[O:8])=[O:4]
Reactant: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](C)C(C)(C)c1ccccc1)C(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C/C(=C\[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](C)C(C)(C)c1ccccc1)C(C)(C)C)C(=O)O
Temperature: 50 °C
Reaction time: 15 h
Yield: 99.7 %

Procedure:
Ethyl (E,4S)-4-[((2S)-2-{[(2S)-2,3-dimethyl-3-phenylbutanoyl]amino}-3,3-dimethylbutanoyl)(methyl)amino]-2,5-dimethyl-2-hexenoate (0.17 g, 0.35 mmol, from Example 91) is dissolved in methanol (1.2 mL) and tetrahydrofuran (1.2 mL) and cooled to 0° C. (ice water bath). To this solution is added water (0.6 mL) and aqueous lithium hydroxide monohydrate (30 mg, 0.70 mmol). The cooling bath is removed, and the resulting mixture is stirred at 50° C. for 15 hours. Solvents are removed in vacuo to provide a beige foam, which is then dissolved in water. The solution is acidfied to pH 1 with 10% aqueous hydrochloric acid solution and then extracted thrice with ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, decanted, and concentrated under reduced pressure to afford a white solid (0.16 g, 100%). MS (ES+): (M+H)=459.0
Reaction SMILES: [C:1]([C:3]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:4]=1[NH:18][C:19](=O)[CH3:20])#[N:2].P(=O)(O)(O)[OH:23]>>[CH3:20][C:19]1[NH:2][C:1](=[O:23])[C:3]2[CH:7]=[C:6]([CH3:8])[N:5]([C:9]3[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[CH3:17])[C:4]=2[N:18]=1
Reactant: O=P(O)(O)O
Reactant: CC(=O)Nc1c(C#N)cc(C)n1-c1c(C)cc(C)cc1C
Product: Cc1cc(C)c(-n2c(C)cc3c(=O)[nH]c(C)nc32)c(C)c1
Temperature: 130 °C
Yield: 67 %

Procedure:
A mixture of compound (4) (32.1 g, 0.144 mol) and 85% phosphoric acid (30 mL) was heated at 130° C. for 30 minutes. The resulting mixture was cooled to room temperature, poured into ice water with vigorous stirring, and the resulting precipitate was filtered and dried under vacuum to afford 21.6 g (67%) of compound (5) as a pink solid.
Reaction SMILES: [C:1]([OH:16])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH3:17][C:18]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:19]=1[OH:20].B(F)(F)F.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:17][C:18]1[CH:24]=[C:23]([C:22]([C:1](=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:21][C:19]=1[OH:20])[OH:25]
Reactant: Cc1cc(O)ccc1O
Reactant: CCCCCCCCCCCCCC(=O)O
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCCC(=O)c1cc(O)c(C)cc1O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
228 g (1 mole) of myristic acid and 136 g (1.1 mole) of monomethylhydroquinone were melted together whilst stirring a 100° C. and saturated with boron trifluoride for 4 h. After being stirred for 2 h at 100° C. the mixture was poured into 3 l of water. The product formed was pulverized under water and neutralized with a solution of 110 g of sodium carbonate in 400 ml of water, suction-filtered, washed with water, dried, and recrystallized from benzine. Yield: 305 g of compound Y1a. Melting point: 83° C.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[CH:15][CH:16]=2)[C:11]([CH:26]([O:28][CH2:29]/[CH:30]=[CH:31]/[CH3:32])[CH3:27])=[CH:10][C:9]1([CH3:34])[CH3:33])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:29]([O:28][CH:26]([C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[CH:13]=2)[NH:8][C:9]([CH3:34])([CH3:33])[CH:10]=1)[CH3:27])/[CH:30]=[CH:31]/[CH3:32]
Reactant: C/C=C/COC(C)C1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(-c3ccccc3OC)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C/C=C/COC(C)C1=CC(C)(C)Nc2ccc(-c3ccccc3OC)cc21
Reaction time: 1 h

Procedure:
A mixture of 58 mg of [4-{1-[((E)-but-2-enyl)oxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester in 2 mL of methylene chloride was treated with 0.05 mL of 99% trifluoroacetic acid (TFA) at room temperature. The reaction mixture was allowed to stir at the same temperature for 1 hour. TLC showed starting material was still remaining so another 0.05 mL of TFA was added. Ten minutes later, the reaction was quenched with water and extracted with EtOAc three times. The organic layers were combined, washed sequentially with water, saturated aqueous sodium bicarbonate, water, brine, dried with magnesium sulfate, and the solvent evaporated in vacuo. The residue was purified by flash chromatography to yield 28 mg of the title compound as an oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C@@H:14]1[C@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:17][C:16](=[O:25])[N:15]1[C:26](=[O:35])[CH2:27][CH2:28][C@H:29]([CH3:34])[CH2:30][CH2:31][CH2:32][CH3:33].Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>C1COCC1>[C:41]([O:40][C:38](=[O:39])[CH2:37][C@@H:27]([C:26]([N:15]1[C@H:14]([CH3:13])[C@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:17][C:16]1=[O:25])=[O:35])[CH2:28][C@H:29]([CH3:34])[CH2:30][CH2:31][CH2:32][CH3:33])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCC[C@@H](C)CCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[C@@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
To a solution of diisopropylamine (1.8 mL, 12.6 mmol) in 30 mL THF at −78° C. was added n-butyl lithium (1.6 M solution in hexanes, 7.6 mL, 12.1 mmol), and the mixture stirred 10 minutes at which time oxazolidinone 137 (3.2 g, 10.1 mmol) in 10 mL THF was added dropwise. The solution was stirred for 30 minutes, t-butyl bromoacetate (1.8 mL, 12.1 mmol) was added quickly dropwise at −50° C., and the mixture was allowed to warm slowly to 10° C. over 3 hours. The mixture was partitioned between Et2O and sat. NH4Cl (aq), the phases were separated, and the organic phase dried (MgSO4), and concentrated. The residue was purified by flash chromatography (16:1 to 8:1 hexanes:EtOAc) to provide 2.65 g (61%) of ester 138 as a colorless crystalline solid, mp=84-86° C. [α]D23+17.1 (c=1.00, CHCl3); 1H NMR (CDCl3): δ 7.34 (m, 5H), 5.62 (d, J=7.3 Hz, 1H), 4.73 (quint, J=6.8 Hz, 1H), 4.29 (m, 1H), 2.67 (dd, J=9.8, 16.4 Hz, 1H), 2.40 (dd, J=5.1, 16.4 Hz, 1H), 1.69 (m, 1H), 1.38 (s, 9H), 1.28 (m, 7H), 1.08 (m, 1H), 0.88 (m, 9H); 13C NMR (CDCl3) δ 176.45, 171.22, 152.71, 133.64, 128.86, 125.86, 80.83, 78.87, 55.33, 40.02, 38.21, 37.59, 36.31, 30.86, 29.29, 28.22, 23.14, 20.41, 14.36, 14.26. Anal. Calcd for C25H37NO5: C, 69.58; H, 8.64; N, 3.25. Found: C, 69.37; H, 8.68; N, 3.05.
Reaction SMILES: [C:1]1([CH2:7][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]#[CH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[CH:31]=[N:30][CH:29]=[CH:28]3)[CH:21]=1>CCN(CC)CC.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.[Cu]I>[CH:31]1[C:32]2[C:27](=[CH:26][C:25]([C:22]3[CH:21]=[C:20]([C:10]#[C:9][C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[O:24][N:23]=3)=[CH:34][CH:33]=2)[CH:28]=[CH:29][N:30]=1
Reactant: C#C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: Ic1cc(-c2ccc3cnccc3c2)no1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](C#Cc1cc(-c2ccc3cnccc3c2)no1)Cc1ccccc1
Temperature: 65 °C
Yield: 50.6 %

Procedure:
To a solution of (S)-tert-butyl 1-phenylbut-3-yn-2-ylcarbamate (0.16 g, 0.65 mmol) in 6 mL of Et3N in a sealable tube were added 6-(5-iodoisoxazol-3-yl)isoquinoline (0.18 g, 0.54 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.019 g, 0.027 mmol), and copper(I) iodide (0.016 g, 0.082 mmol). The tube was sealed and heated to 65° C. for 12 hours. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel, affording tert-butyl(S)-4-(3-(isoquinolin-6-yl)isoxazol-5-yl)-1-phenylbut-3-yn-2-ylcarbamate (0.12 g, 50% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.30 (s, 1H), 8.63-8.57 (m, 1H), 8.20-8.17 (m, 1H), 8.09-8.03 (m, 2H), 7.73-7.69 (m, 1H), 7.39-7.27 (m, 5H), 6.81 (s, 1H), 5.05-4.94 (m, 1H), 4.86-4.74 (m, 1H), 3.17-3.03 (m, 2H), 1.46 (s, 9H).