Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]1=[N:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1N1CCOCC1
Reactant: CC1CCN(Cc2ccccc2)C1=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC1CCN(Cc2ccccc2)C1=Nc1ccccc1N1CCOCC1

Procedure:
In a similar manner to that described in Example 1, 1-benzyl-3-methyl-2-pyrrolidone (14.1 g) in benzene (80 ml) was reacted with 4-(2-aminophenyl)morpholine (8.9 g) in benzene (30 ml) in the presence of phosphorus oxychloride (6.86 ml) for 24 hours at 70° C. to give 4-[2-(1-benzyl-3-methyl-2-pyrrolidinylideneamino)phenyl]morpholine (m.p. 96°-97° C.) which was recrystallised from hexane.
Reaction SMILES: F[C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>>[O:30]([C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(C#Cc2ccccc2)cc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(c1ccc(C#Cc2ccccc2)cc1)c1ccc(Oc2ccccc2)cc1

Procedure:
The phenylethynyl group has several unexpected advantages over the ethynyl based analog. See the Hergenrother and Delfort references supra. When 4-fluoro-4'-phenylethynyibenzophenone was treated with phenol in the presence of an alkali metal base such as potassium carbonate in a polar aprotic solvent at 160° C., the expected 4-phenoxy-4'-phenylethynylbenzophenone was afforded in nearly quantitative yield. However, when 4-ethynyl-4'-fluorobenzophenone was used in the same procedure, the result was a mixture of products with a total yield of 60%. Several variations in the procedure were tried, but the resulting product was not exclusively the expected ethynyl arylene-ether. This indicates that when the phenylethynyl endcapping compound is used to terminate nucleophilic reagents, the reaction proceeds qualitatively to afford the phenylethynyl terminated reactive oligomers exclusively. If the ethynyl adduct is used, a variety of products results.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[S:87]1[CH2:92][CH2:91][N:90]([CH2:93][C:94](O)=[O:95])[CH2:89][CH2:88]1>>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][C:94](=[O:95])[CH2:93][N:90]1[CH2:91][CH2:92][S:87][CH2:88][CH2:89]1)[CH2:19][CH2:18]2
Reactant: O=C(O)CN1CCSCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3CCSCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 44 %

Procedure:
The title compound was prepared in 44% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-thiomorpholinoacetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 671.8 (M−H)−, 2.37 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=8.2 Hz, 2H), 7.47 (s, 1H), 7.20 (d, J=8.2 Hz, 2H), 5.29 (d, J=4.3 Hz, 1H), 4.75 (s, 1H), 3.79-3.63 (m, 2H), 3.58 (td, J=6.5, 12.9 Hz, 1H), 3.47-3.35 (m, 3H), 2.95 (br. s., 4H), 2.68-2.57 (m, 2H), 2.37 (dd, J=8.4, 12.4 Hz, 1H), 2.13 (dd, J=6.4, 17.1 Hz, 1H), 1.92-1.82 (m, 2H), 1.81-1.76 (m, 1H), 1.73 (br. s., 1H), 1.71 (s, 3H), 1.69-1.64 (m, 1H), 1.60-1.31 (m, 12H), 1.30-1.22 (m, 1H), 1.19-1.11 (m, 2H), 1.09 (s, 3H), 1.03 (s, 3H), 1.01 (s, 3H), 0.94 (br. s., 3H), 0.93 (br. s., 3H).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=C.N1C(C)=CC=CC=1C.C(Cl)Cl.[O:21]1CCOCC1>O.[Os](=O)(=O)(=O)=O>[O:21]=[CH:5][CH2:4][CH2:3][CH2:2][C:1]([O:8][CH3:9])=[O:7]
Reactant: C1COCCO1
Reactant: C=CCCCC(=O)OC
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)CCCC=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A colorless solution of commercially available methyl hex-5-enoate (5.000 g; 39.01 mmol) in dioxane (290 ml) and water (95 ml) was treated successively with 2,6-lutidine (8.360 g; 78.02 mmol), a solution of osmium tetroxide (2.5 wt. % in 2-methylpropan-2-ol; 0.50 ml), and NaIO4 (33.375 g; 156.04 mmol). The resulting beige heterogeneous reaction mixture was further stirred at rt, under nitrogen, for 16 h. The resulting milky heterogeneous mixture was treated with water (100 ml) and DCM (500 ml). The layers were separated, and the aq. layer was further extracted with DCM (200 ml/150 ml). The mixed slightly yellow organic layers were then washed with brine (200 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure to give crude methyl 5-oxopentanoate as a green oil which was directly used for the next step without additional purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:14])[CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])=[CH:2]1>CO.O.C1COCC1.[OH-].[Na+]>[O:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:14])[CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:2]1
Reactant: CCOC(=O)CCC(=O)c1ccoc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCC(=O)c1ccoc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The keto ester from Step 1 (38.9 g, 0.193 mmoL) was dissolved in a mixture of MeOH:H2O:THF (3:1:2) (150 mL) and NaOH 1N (213 mL, 0.213 mmoL) was added. The reaction was stirred at r.t. overnight. The mixture was concentrated, acidified with HCl 1N extracted (2×) with EtOAc, washed with brine, dried over MgSO4, filtered and evaporated to afford the title product as a beige solid.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[N:10]=[C:11]([N:14]3[CH2:17][CH:16]([OH:18])[CH2:15]3)[S:12][CH:13]=2)=[O:8])[CH2:3][CH2:2]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[S:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[N:10]=[C:11]([N:14]3[CH2:17][CH:16]([O:18][S:20]([CH3:19])(=[O:22])=[O:21])[CH2:15]3)[S:12][CH:13]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1csc(N2CC(O)C2)n1)N1CCSCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CCSCC3)cs2)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78 %

Procedure:
To a solution of 1-(4-thiomorpholinocarbonyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (599 g, 2.50 mmol) (obtained as described in Reference Example 25(2)) in methylene chloride (30 ml) were added methanesulfonyl chloride (0.49 ml, 6.30 mmol) and triethylamine (0.88 ml, 6.30 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 40 minutes. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using 5% methanol in ethyl acetate as the eluant to afford 1-(4-thiomorpholinocarbonyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (709 mg, yield 93%) as a pale yellow solid.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[C:12]2[CH:11]=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:15][C:14]3=[O:27])[CH:9]=[CH:8][C:7]=2[C:6]2[CH2:28][NH:29][CH2:30][CH2:31][C:5]1=2.[C:32](Cl)(=[O:34])[CH3:33].C(N(CC)CC)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:32]([N:29]1[CH2:30][CH2:31][C:5]2[N:4]([CH3:3])[C:12]3[CH:11]=[C:10]([N:13]4[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:15][C:14]4=[O:27])[CH:9]=[CH:8][C:7]=3[C:6]=2[CH2:28]1)(=[O:34])[CH3:33]
Reactant: Cn1c2c(c3ccc(N4CCN(CCc5ccccc5)CC4=O)cc31)CNCC2
Reactant: CC(=O)Cl
Agent: CCN(CC)C(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CC(=O)N1CCc2c(c3ccc(N4CCN(CCc5ccccc5)CC4=O)cc3n2C)C1
Reaction time: 16 h

Procedure:
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-phenethylpiperazin-2-one dihydrochloride (170 mg, 0.368 mmol), acetyl chloride (˜120 μL, 1.5 mmol) and i-PrNEt2 (400 μL, 2.23 mmol) were combined in methylene chloride (20 mL) and stirred for 16 h. Sodium bicarbonate solution (4 mL) was added and the organics removed and concentrated. The residue was purified by flash chromatography (12 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 85% methylene chloride over 30 min) to provide the title compound as a white solid; 1H NMR (500 MHz, DMSO-d6) δ 11.86 (m, 1H), 7.50-7.48 (dd, J=8.3, 5.0 Hz, 1H), 7.40-7.31 (m, 5H), 7.31-7.26 (m, 1H), 6.98-6.95 (overlapping ddd, J=4.0, 1.5 Hz, 1H), 4.65 (d, J=11.2 Hz, 2H), 4.23-3.97 (m, 3H), 3.97-3.75 (m, 3H), 3.64-3.61 (m, 3H), 3.57-3.42 (m, 4H), 3.19-3.08 (m, 2H), 2.93-2.87 (m, 1H), 2.82-2.77 (m, 1H), 2.13-2.11 (2×s, 3H); ESI MS m/z 431 [M+H]+; HPLC (Method B)>99% (AUC), tR=13.8 min.
Reaction SMILES: [CH2:1]([C@H:8]1[C:12](=[O:13])[NH:11][CH:10]([CH2:14][CH2:15][C:16]([O:18]CC(C)C)=O)[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH2:1]([C@@H:8]1[N:9]2[C:16](=[O:18])[CH2:15][CH2:14][CH:10]2[NH:11][C:12]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)COC(=O)CCC1NC(=O)[C@H](Cc2ccccc2)N1
Solvent: Cc1ccccc1
Product: O=C1NC2CCC(=O)N2[C@H]1Cc1ccccc1
Yield: 50.4 %

Procedure:
A solution of isobutyl (4S)-4-benzyl-5-oxo-2-imidazolidinepropanoate (2.3 g, 7.33 mmol) in toluene (100 ml) was refluxed for 8 days. After evaporation of the solvent, the residue was chromatographed over silica gel (dichlorometane-methanol 9:1). The appropriate fractions were collected and evaporated; the residue was triturated with diethyl ether to afford 850 mg (50%) of the title compound, m.p. 141°-145° C. NMR (CDCl3): deltaH =7.25 (s, 5H, PhH); 7.02 (b.s., 1H, NH); 4.52 (t, J=4.5 Hz, 1H, PhCH2CH); 4.37 (t, J=5 Hz, 1H, NCHNH); 3.13 (d, J=4.5 Hz, 2H, PhCH2); 2.80-1.6 (c.a., 4H, CH2CH2). MS (E.I., 70 eV, 1.5 mA) m/z=230 (M+), 139 (M--C7H7)+, 91 (C7H7)+, 84 (C4H6NO)+.
Reaction SMILES: [CH2:1]1[CH2:11]CN2C(=NCCC2)C[CH2:2]1.[OH:12][CH:13]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)/[CH:14]=[CH:15]/[C@H:16]1[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[N:17]1[CH2:23][C:24]#[C:25][CH2:26][O:27][CH2:28][C:29]([OH:31])=[O:30].IC(C)C>CC(C)=O.CCOC(C)=O>[CH:1]([O:30][C:29](=[O:31])[CH2:28][O:27][CH2:26][C:25]#[C:24][CH2:23][N:17]1[C:18](=[O:22])[CH2:19][CH2:20][CH2:21][C@@H:16]1/[CH:15]=[CH:14]/[CH:13]([OH:12])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)([CH3:11])[CH3:2]
Reactant: O=C(O)COCC#CCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC(C)I
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)OC(=O)COCC#CCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Reaction time: 0.08 h
Yield: 57 %

Procedure:
DBU (10 μL, 0.067 mmol) was added to a solution of {4-[(R)-2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-but-2-ynyloxy}-acetic acid (16.6 mg, 0.045 mmol) in acetone (0.5 mL). After 5 min, 2-iodopropane (22.5 μL, 0.225 mmol) was added. After 18 h, the reaction mixture was diluted with EtOAc (25 mL) and washed sequentially with aqueous HCl (0.1 M, 10 mL), saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to afford 10.6 mg (57%) of the title compound.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.CN1CCN(C2C=CC(C(O)=O)=CC=2)CC1.CCN(C(C)C)C(C)C.[C:43]([O:47][C:48]([N:50]1[C:58]2[C:53](=[CH:54][CH:55]=[C:56]([O:59][CH2:60][CH2:61][O:62][CH2:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH:57]=2)[C:52]([NH2:70])=[N:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]>C1COCC1>[C:43]([O:47][C:48]([N:50]1[C:58]2[C:53](=[CH:54][CH:55]=[C:56]([O:59][CH2:60][CH2:61][O:62][CH2:63][C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[CH:57]=2)[C:52]([NH:70][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:9]([N:6]3[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]3)=[CH:10][CH:11]=2)=[N:51]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)n1nc(N)c2ccc(OCCOCc3ccccc3)cc21
Reactant: CN1CCN(c2ccc(C(=O)Cl)cc2)CC1
Agent: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(C(=O)Nc3nn(C(=O)OC(C)(C)C)c4cc(OCCOCc5ccccc5)ccc34)cc2)CC1
Temperature: 50 °C
Reaction time: 12 h
Yield: 57 %

Procedure:
A mixture of 4-(4-methyl-piperazin-1-yl)-benzoyl chloride hydrochloride, prepared from 248 mg (1.13 mmol) of 4-(4-methyl-piperazin-1-yl)-benzoic acid as described above in preparation 3, and DIPEA (0.386 ml, 2.25 mmol) in dry THF (10 ml) was treated dropwise at r.t., under argon atmosphere, with a solution of 3-amino-6-(2-benzyloxy-ethoxy)-indazole-1-carboxylic acid tert-butyl ester (143 mg, 0.374 mmol) in 10 ml of dry THF. The reaction mixture was heated up to 50° C. and stirred for 12 h. The volatiles were removed under reduced pressure, the residue taken up in DCM (100 ml) and washed with a saturated solution of NaHCO3 (75 ml). The organic layer was separated, dried over sodium sulfate and evaporated to dryness and the crude residue purified by flash chromatography over silica gel eluting with DCM/MeOH 98:2 then 90:10 affording 124 mg (yield: 57%) of the title compound as a white solid.
Reaction SMILES: [OH:1][CH:2]([CH2:44][OH:45])[CH2:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[C:14]1[C:23]2[C:18](=[CH:19][C:20]([S:24]([N:27](CC3C=CC(OC)=CC=3OC)[C:28]3[S:29][CH:30]=[CH:31][N:32]=3)(=[O:26])=[O:25])=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>C(Cl)Cl>[F:49][C:48]([F:51])([F:50])[C:46]([OH:52])=[O:47].[OH:1][CH:2]([CH2:44][OH:45])[CH2:3][C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[C:14]1[C:23]2[C:18](=[CH:19][C:20]([S:24]([NH:27][C:28]3[S:29][CH:30]=[CH:31][N:32]=3)(=[O:25])=[O:26])=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4CC(O)CO)nccc3c2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1nccs1)c1ccc2c(-c3ccc(C(F)(F)F)cc3CC(O)CO)nccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(2-(2,3-dihydroxypropyl)-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.120 g, 0.182 mmol) was dissolved in DCM and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature. The reaction was concentrated and the material was triturated in diethyl ether. The solids were filtered and washed with diethyl ether, then vacuum dried overnight to afford 1-(2-(2,3-dihydroxypropyl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide 2,2,2-trifluoroacetate as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.89 (br. s., 1H), 8.71 (dd, J=2.0, 5.7 Hz, 1H), 8.59 (d, J=4.1 Hz, 1H), 8.25-8.12 (m, 1H), 7.94-7.83 (m, 2H), 7.76-7.64 (m, 2H), 7.51 (t, J=7.8 Hz, 1H), 7.28 (d, J=4.4 Hz, 1H), 6.88 (d, J=4.6 Hz, 1H), 4.04 (d, J=4.9 Hz, 1H), 3.53-3.44 (m, 1H), 3.29 (d, J=3.8 Hz, 1H), 3.10-3.02 (m, 1H), 3.02-2.94 (m, 1H), 2.87 (dd, J=4.0, 14.3 Hz, 1H), 2.37-2.29 (m, 1H). m/z (ESI) 510.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[N:19]=2)[C:3]1=[O:25].Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([N:33]2[CH2:44][CH2:43][N:42]3[C:35](=[CH:36][C:37]4[CH2:38][C:39]([CH3:46])([CH3:45])[CH2:40][C:41]=43)[C:34]2=[O:47])[C:28]=1[CH:48]=[O:49].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[CH3:1][N:2]1[C:3](=[O:25])[C:4]([NH:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[N:19]=2)=[CH:5][C:6]([C:27]2[C:28]([CH:48]=[O:49])=[C:29]([N:33]3[CH2:44][CH2:43][N:42]4[C:35](=[CH:36][C:37]5[CH2:38][C:39]([CH3:45])([CH3:46])[CH2:40][C:41]=54)[C:34]3=[O:47])[N:30]=[CH:31][CH:32]=2)=[CH:7]1
Reactant: Cc1nccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)n1
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: Cc1nccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3C=O)cn(C)c2=O)n1
Temperature: 100 °C
Yield: 57.3 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 1-methyl-3-(2-methylpyrimidin-4-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 213b (510 mg, 1.5 mmol), 4-chloro-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridine-3-carbaldehyde 108a (343 mg, 1.0 mmol), K3PO4 (424 mg, 2.0 mmol), sodium acetate (272 mg, 2.0 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (40 mg, 0.044 mmol), acetonitrile (20 mL), and water (0.5 mL). After bubbling nitrogen through the mixture for 30 minutes, it was was heated at 100° C. under N2 protection for 2 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with dichloromethane (30 mL) and water (30 mL). The aqueous layer was separated and extracted with dichloromethane (3×20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80/1 to 30/1) to afford 179a (300 mg, 57%) as a yellow solid. MS-ESI: [M+H]+ 524
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7](C=O)=[CH:6][C:3]=1[C:4]#[N:5].C(O)C.[CH:15]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])OCC>[Cl-].[NH4+]>[CH2:23]([O:22][CH:15]([O:19][CH2:20][CH3:21])[C:7]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[C:4]#[N:5])[CH3:24]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: CCOC(OCC)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(OCC)c1ccc(F)c(C#N)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a stirred solution of 2-fluoro-5-formylbenzonitrile (5.96 g, 40 mmol) in ethanol (5.6 g, 120 mmol) was added ammonium chloride (85.6 mg, 1.6 mmol). After the addition, the mixture was cooled to 0° C. and triethyl orthoformate (6.52 g, 44 mmol) was added dropwise. After the addition, the mixture was stirred at room temperature overnight. The mixture was concentrated, then filtered and the cake washed with ethyl acetate (20 mL×2). The filtrate was concentrate to give the title compound (8.8 g, yield 98%) as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.22-1.29 (m, 6H), 3.50-3.70 (m, 4H), 5.50 (s, 1H), 7.19-7.24 (t, J=8.8 Hz, 1H), 7.70-7.74 (m, 1H), 7.76-7.78 (dd, J1=6.4 Hz, J2=2.4 Hz, 1H). LC-MS (ESI) m/z: 224 (M+1)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]([C:24](O)=[O:25])[CH:15]=[N:16][C:17]=1[O:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:58][C@@H:59]1[CH2:64][CH2:63][CH2:62][CH2:61][C@H:60]1[OH:65]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:9])[F:11])=[CH:4][C:3]=1[C:12]1[C:17]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[N:16][CH:15]=[C:14]([CH:13]=1)[C:24]([NH:58][C@@H:59]1[CH2:64][CH2:63][CH2:62][CH2:61][C@H:60]1[OH:65])=[O:25]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cnc(OC2CCCC2)c(-c2cc(C(F)(F)F)ccc2Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OC2CCCC2)c(-c2cc(C(F)(F)F)ccc2Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.9 %

Procedure:
5-(2-Chloro-5-trifluoromethyl-phenyl)-6-cyclopentyloxy-3-pyridinecarboxylic acid (0.14 g, 0.3 mmol) was dissolved in DMF (5 mL). To the solution was added TBTU (0.12 g, 0.4 mmol), N,N-diisopropylethyl amine (0.3 mL, 1.7 mmol) and (1R,2R)-2-amino-cyclohexanol (58 mg, 0.4 mmol). The reaction mixture was stirred for 18 h at room temperature. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica (n-heptane/ethyl acetate gradient) to yield 0.11 g of the title compound as a colorless solid oil, MS (ISP) 483.4 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7](OCC)(=[O:29])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(OCC)(=O)C.[Cl-].[Na+]>C(OCC)C>[CH:7]([OH:29])=[CH:8][CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)OCC
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCCCCCCCC=CC=CC=CC=CC=CC=CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
1.28 g (33.7 mmol) of lithium aluminum hydride (LiAlH4) and 100 ml of anhydrous dietylether were placed into an eggplant-shape flask of which air had been replaced by argon gas, and kept at 0° C. To the mixture was added dropwise over about 30 minutes the solution of 10 g (28.1 mmol) of ethyl docosahexaenate in diethylether (20 ml of anhydrous diethylether), and then stirred at 0° C. for 30 minutes. After stirring, ethyl acetate and the saturated solution of sodium chloride were added to the reaction mixture, followed by removal of the precipitate by filtration. The filtrate was concentrated under reduced pressure, and purified by silica gel open column chromatography (hexane:ethyl acetate=5:1), to give 5.67 g of docosahexaenol (abbreviated as DHA-OH somewhere hereinafter).