Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:15][CH2:16][C:17](=[O:39])[C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([C:33](=[O:37])[CH2:34]2)[C@:30]2([CH3:31])[C@H:25]([CH2:26][C@@H:27]([OH:38])[CH2:28][CH2:29]2)[CH2:24][CH2:23]3)[CH2:20][CH2:19]1)(=[O:14])[CH3:13].O>N1C=CC=CC=1>[C:12]([O:15][CH2:16][C:17](=[O:39])[C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([C:33](=[O:37])[CH2:34]2)[C@:30]2([CH3:31])[C@H:25]([CH2:26][C@@H:27]([O:38][S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=4)(=[O:9])=[O:8])[CH2:28][CH2:29]2)[CH2:24][CH2:23]3)[CH2:20][CH2:19]1)(=[O:14])[CH3:13]
Reactant: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
Acetyl chloride (9.71 ml) was added to a stirred solution of (3β,5α)-3-hydroxypregnane-11,20-dione (97.1 g) [prepared as described by Cameron et al., J. Chem. Soc., 1955, 2807] in methanol (2.4 l) and a solution of bromine (18.5 ml) in methanol (1 l) was then added over 30 min at room temperature. The reaction mixture was poured into water (30 l) and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure to give crude (3β,5α)-21-bromo-3-hydroxypregnane-11,20-dione (120 g). δ (CDCl3) 0.61 (s,3H), 1.02 (s,3H), 3.00-3.20 (m,1H), 3.49-3.62 (m,2H) and 3.85 (s,2H). Potassium acetate (240 g), potassium iodide (6 g) and glacial acetic acid (250 ml) were added to a solution of (3β,5α)-21-bromo-3-hydroxypregnane-11,20-dione (120 g) in acetone (4.8 l) and the mixture was heated under reflux for 3 h. The reaction mixture was poured into water (50 l) and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure. The residue was chromatographed over silica gel and the purified product was crystallised from diethyl ether to give (3β,5α)-21-(acetyloxy)-3-hydroxypregnane-11,20-dione (26 g) m.p. 163°-165° C.; [α]D +103.3° (c 0.97). 4-Toluenesulfonyl chloride (52 g) was added to a solution of (3β,5α)-21-(acetyloxy)-3-hydroxypregnane-11,20-dione (26 g) in pyridine (260 ml) and the solution was stirred for 4 h at room temperature. The reaction mixture was poured into water (2.6 l) and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure. Crystallisation of the residue from methanol gave (3β,5α)-21-(acetyloxy)-3-{[(4-methylphenyl)sulfonyl]oxy}pregnane-11,20-dione (35 g). m.p. 155°-156° C.; [α]D +62.4° (c 1.11).
Reaction SMILES: [C:1]1([CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[C:1]1([CH2:17][CH2:18][CH2:19][CH:20]=[O:21])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1
Reactant: OCCCCc1ccc2ccc3cccc4ccc1c2c34
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCCCc1ccc2ccc3cccc4ccc1c2c34
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
10 mL of methylene chloride was added to 1.097 g (4 mmol) of 4-(pyren-1-yl) butyl alcohol and stirred vigorously at room temperature for 10 min hour. The reaction was followed by addition of 1.292 g (1.5 Eq.) of PCC (Pyridinium chlorochromate) in 10 mL methylene chloride and the reaction mixture was stirred for 2 h. The reaction mixture was then diluted with 5 volumes of anhydrous ether (100 mL) and washed with 1:1 brine:water, saturated aq. Na2SO3 solution, and brine, respectively, dried over anhydrous Na2SO4 and concentrated to give the aldehyde. The crude product was purified by silica gel flash chromatography (hexanes: ethyl acetate, 9:1, rf: 0.4) to yield 1.06 g (97%). Most of the crude products were very clean and could be used directly for further applications.
Reaction SMILES: [Br-].[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[C:7]1C=CC=CC=1[P+](C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:27]([O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:47]=[CH:46][C:45]([CH:48]=O)=[CH:44][CH:43]=2)=[CH:38][CH:37]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(=O)([O-])O.[Na+].O>C(OCC)C>[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[CH:7]=[CH:48][C:45]1[CH:44]=[CH:43][C:42]([C:39]2[CH:38]=[CH:37][C:36]([O:35][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:41][CH:40]=2)=[N:47][CH:46]=1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1C1OCCO1
Reactant: CCCCCCCCOc1ccc(-c2ccc(C=O)cn2)cc1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(-c2ccc(C=CC3OCCO3)cn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 6.44 g of (1,3-dioxolan-2-yl)-methyl-triphenylphosphonium bromide in 70 ml of diethyl ether is treated with 1.68 g of potassium t-butylate within 5 minutes while gassing with nitrogen. The orange suspension is stirred for 30 minutes, then cooled to 0° C. and treated within 10 minutes with a solution of 3.11 g of 6-[4-(octyloxy)phenyl]-3-pyridinecarboxaldehyde (prepared in accordance with Example 2) in 25 ml of diethyl ether. The reaction mixture is stirred at room temperature for a further 3 hours and then treated with 0.6 g of sodium hydrogen carbonate and with 20 ml of water. The organic phase is washed with water, dried over sodium sulfate and concentrated. The residue is taken up in hexane and 20 ml of 80 percent aqueous methanol. The phases are separated and the hexane phase is washed with 10 ml of 80 percent methanol, dried over sodium sulfate and concentrated. Chromatographic purification of the residue on 50 g of silica gel with hexane/ethyl acetate (vol. 9:1) gives 5-[2-(1,3-dioxolan-2-yl)vinyl]-2-[4-(octyloxy)phenyl]-pyridine.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[NH2:6][C:7]1[N:8]=[C:9]([C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[N:22]([CH2:29][CH2:30][CH3:31])[C:21]3=[O:32])=[O:17])[N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12.CO>N1C=CC=CC=1>[O:28]=[C:23]1[N:22]([CH2:29][CH2:30][CH3:31])[C:21](=[O:32])[C:20]2[C:25](=[CH:26][CH:27]=[C:18]([C:16]([C:9]3[N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]4=[C:7]([NH:6][S:1]([CH3:4])(=[O:3])=[O:2])[N:8]=3)=[O:17])[CH:19]=2)[NH:24]1
Reactant: CS(=O)(=O)Cl
Reactant: CCCn1c(=O)[nH]c2ccc(C(=O)c3nc(N)c4ccccn34)cc2c1=O
Solvent: c1ccncc1
Solvent: CO
Product: CCCn1c(=O)[nH]c2ccc(C(=O)c3nc(NS(C)(=O)=O)c4ccccn34)cc2c1=O
Yield: 32.3 %

Procedure:
0.1 ml (1.2 mmol) of mesyl chloride is added, at 0° C. under an inert atmosphere, to 0.25 g (0.4 mmol) of 6-[(1-aminoimidazo(1,5-a)pyridin-3-yl)carbonyl]-3-propylquinazoline-2,4(1H,3H)-dione in 5 ml of pyridine. After the addition of methanol, the reaction medium is concentrated under reduced pressure. The residue is taken up with dichloromethane. The organic phase is washed with a 1N aqueous solution of hydrochloric acid and then with water, dried over sodium sulphate, filtered, and concentrated under reduced pressure. The residue is recrystallized while hot from methanol, purified on a silica gel frit, elution being carried out with DMF. 0.057 g of an orange solid is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[O:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])=[CH:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([C:24]5[CH:25]=[CH:26][O:22][CH:23]=5)[CH:28]=4)[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: O=C(O)c1cccc(-c2ccoc2)c1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(-c3ccoc3)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Yield: 79.6 %

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (48 mg, 0.17 mmol), 3-fur-3-ylbenzoic acid (32 mg, 0.17 mmol), HATU (65 mg, 0.17 mmol), HOBT (23 mg, 0.17 mmol) and DIPEA (88 μl) were stirred in DMF (1.5 ml) for 18 h at room temperature. The reaction was partitioned between ethyl acetate (100 ml) and hydrochloric acid (0.5M, 20 ml), the organic phase washed with aqueous sodium hydrogen carbonate (saturated) and dried (magnesium sulphate). The solvent was evaporated under vacuum to give N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-3-fur-3-ylbenzamide (61 mg, 79%). NMR; δH [2H6]—DMSO 10.16,(1H, s), 8.35,(1H, t), 8.22,(1H, s), 7-89,(2H, d), 7.79,(2H, t), 7.69-7.65,(2H, m), 7.56,(1H, s), 7.45,(1H, t), 7.35,(2H, d), 7.19,(1H, d), 6.85,(1H, d), 6.49,(1H, m), 3.17,(2H, t), 2.18,(3H, s), 1.04,(1H, m), 0.42,(2H, m), 0.22,(2H, m). LCMS: retention time 3.75 min, MH+451.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9](C(OC)=O)[C:10]([O:12]C)=[O:11])=[C:5]([N+:18]([O-:20])=[O:19])[CH:4]=1.O>CS(C)=O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[C:5]([N+:18]([O-:20])=[O:19])[CH:4]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)Cc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 5 h
Yield: 92.7 %

Procedure:
6M Aqueous hydrochloric acid (200 mL) was added to a stirred solution of dimethyl 2-(4-bromo-2-nitrophenyl)malonate (preparation 1a, 55.45 g, 170 mmol) in dimethylsulphoxide (250 mL) at room temperature and then mixture was warmed to 130° C. with stirring. After 5 hours, the mixture was cooled and water (400 mL) was added with stirring and the mixture was left to cool overnight. The precipitate was filtered, washed with water and dried in vacuo to give the title compound (41.0 g, 94%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1>CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(Cl)Cl>[O:1]=[CH:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]([S:11]([NH:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1
Reactant: O=S(=O)(Nc1ccccc1)c1cccc(C#CCO)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CC#Cc1cccc(S(=O)(=O)Nc2ccccc2)c1
Yield: 86.7 %

Procedure:
3-(3-Hydroxyprop-1-ynyl)-N-phenylbenzenesulfonamide (53a) (0.55 g, 1.9 mmol) was dissolved in a solution of Dess-Martin reagent in methylene chloride (0.157 g/ml) (8.2 ml) and the resultant mixture was stirred at ambient temperature for 30 min. The mixture was partitioned between water (50 ml) and ether (50 ml), and ether solution was washed successively with 5% Na2CO3, water, and dried (Na2SO4). The solvents were removed under reduced pressure to give the title compound (0.47 g, 72%) as an oil. The crude product 54a was used in the further step without an additional purification. 1H NMR (DMSO-d6, HMDSO) δ: 6.96-7.41 (5H, m, C6H5); 7.54-8.07 (4H, m, C6H4); 9.45 (1H, s, CH); 10.41 (1H, s, NH).
Reaction SMILES: Br[C:2]1[C:3]2[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:16][C:4]=2[N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:6]=1.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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]>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[C:2]1[C:3]2[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:16][C:4]=2[N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:6]=1
Reactant: CCOC(=O)c1cc2c(Br)nn(Cc3ccc(OC)cc3)c2s1
Reactant: OB(O)c1ccc(F)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc2c(-c3ccc(F)cc3F)nn(Cc3ccc(OC)cc3)c2s1
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
Ethyl 3-bromo-1-(4-methoxybenzyl)-1H-thieno[2,3-c]pyrazole-5-carboxylate (1.1422 g, 2.89 mmol), 2,4-difluorophenylboronic acid (1.867 g, 11.82 mmol), sodium carbonate (1.614 g, 15.23 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.426 g, 0.582 mmol) were dissolved in dioxane (14.45 ml) at 25° C. under Ar in a sealed heavy-walled reaction vessel. The reaction mixture was heated to 80° C. and allowed to stir for 2 h. Cesium carbonate (1.52 g, 4.67 mmol) was added. The reaction was allowed to stir for 2 h. The reaction was stopped, cooled to room temperature, quenched by addition of saturated aqueous ammonium chloride (20 mL), and the mixture extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated aqueous sodium chloride (1×15 mL), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography (RediSep SiO2, 120 g column) on a CombiFlash purification system eluting with ethyl acetate-hexanes (0-15%). The title compound (1.0147 g, 2.368 mmol, 82% yield) was recovered as a white solid. LC-MS [M+1]=429.3
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6]Br.[CH2:9]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH2:10][CH2:11][CH3:12].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6][N:16]1[CH2:17][CH2:18][CH:13]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:14][CH2:15]1
Reactant: CCCCC1CCNCC1
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCC1CCN(CCCC(=O)OC)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-bromo-butyric acid methyl ester (1.35 g, 7.5 mmol) in dry acetonitrile (10 ml) was added 4-butylpiperidine (1.00 g, 7.1 mmol) and K2CO3 (1.10 g, 7.8 mmol). After stirring at rt for 12 h, the reaction mixture was evaporated to dryness followed by addition of water (15 ml). The aqueous phase was extracted with ethyl acetate (3×20 ml) and the combined organic phases were dried (Na2SO4) and concentrated in vacuo to produce 1.71 g of the crude title compound 76. The crude product was purified by flash chromatography (MeOH:ethyl acetate; 2:8) to give the pure title compound. Yield 1.27 g (74%). 1H NMR (CD3OD): δ 3.65 (s, 3H), 2.93 (d, 2H), 2.33 (q, 4H), 1.98 (t, 2H), 1.81 (qv, 2H), 1.69 (d, 2H), 1.35–1.18 (m, 9H), 0.90 (t, 3H).
Reaction SMILES: C1(C2C=CC=CC=2)C=CC=CC=1C(P(C)C)P(C)C.CC(C)([O-])C.[Na+].N#N.F[C:29]1[CH:30]=[C:31](CNC(=O)C)[C:32]([NH:45][C@H:46]([C:48]2[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=2)C)=[N:33][C:34]=1[NH:35]C1C=C(OC(C)C)NN=1.[CH:60]1([C:63]2[NH:67][N:66]=[C:65](N)[CH:64]=2)[CH2:62][CH2:61]1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:60]1([C:63]2[NH:67][N:66]=[C:65]([N:45]([CH2:46][C:48]3[CH:49]=[CH:50][C:51]([F:54])=[CH:52][CH:53]=3)[C:32]3[CH:31]=[CH:30][CH:29]=[C:34]([NH2:35])[N:33]=3)[CH:64]=2)[CH2:62][CH2:61]1
Reactant: CC(=O)NCc1cc(F)c(Nc2cc(OC(C)C)[nH]n2)nc1N[C@@H](C)c1ccc(F)cc1
Reactant: Nc1cc(C2CC2)[nH]n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Nc1cccc(N(Cc2ccc(F)cc2)c2cc(C3CC3)[nH]n2)n1
Temperature: 110 °C
Yield: 2 %

Procedure:
To a flask was added Pd(OAc)2 (22.4 mg, 0.1 mmol), (biphenyl-2-ylmethylene)bis(dimethylphosphine) (60 mg, 0.2 mmol) and sodium tert-butoxide (240 mg, 2.5 mmol). The flask was sealed and refilled with N2. To the mixture was added a solution of 6-bromo-N-(4-fluorobenzyl)pyridin-2-amine (Method 19; 281 mg, 1.0 mmol) and 5-cyclopropyl-1H-pyrazol-3-amine (123 mg, 1.0 mmol) in toluene (5 ml). The reaction mixture was heated at 110° C. overnight. The solvent was removed and EtOAc was added and the mixture was washed with brine and was concentrated. Semi-prep HPLC (Gilson) purification gave the title compound (6.4 mg, 2%). 1H NMR (CDCl3) δ 0.65 (m, 2H), 0.95 (m, 2H), 1.80 (m, 1H), 4.43 (m, 2H), 4.91 (br s, 1H), 5.60 (br s, 1H), 5.80 (m, 1H), 6.18 (m, 1H), 6.73 (m, 1H), 7.00 (m, 2H), 7.25 (m, 3H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1.[C:20](O)(=[O:42])[CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34]/[CH:35]=[CH:36]\[CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH3:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[C:20]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1)(=[O:42])[CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34]/[CH:35]=[CH:36]\[CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH3:41]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)O
Reactant: NCCNC(=O)c1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The TFA salt of N-(2-aminoethyl)nicotinamide (5.0 mmol) was taken up in CH3CN (20 mL) along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (5.0 mmol), HATU (5.5 mmol) and DIEA (15 mmol). The resulting reaction mixture was stirred at room temperature for 2 h and diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (5% MeOH—CH2Cl2) afforded N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)nicotinamide. MS calculated for C30H41N3O2: 475.32. Found: [M+H]+ 476.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.Cl[C:13]1[N:18]=[C:17]([CH3:19])[N:16]=[C:15]([N:20]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:14]=1.C([O-])(=O)C.[K+]>O1CCOCC1.O.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:1][C:2]1[C:7]([C:13]2[N:18]=[C:17]([CH3:19])[N:16]=[C:15]([N:20]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[N:14]=2)=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1ccc(B(O)O)c(F)n1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccc(C)nc3F)n2)cc1
Temperature: 110 °C
Yield: 81.1 %

Procedure:
A mixture of 2-fluoro-6-picoline-3-boronic acid (Asynchem Laboratories, Inc.) (430 mg, 2.77 mmol), 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (970 mg, 2.52), potassium acetate (742 mg, 7.56 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Aldrich) (89 mg, 0.126 mmol) in 8 mL of dioxane and 2 mL of water was heated in a microwave at 110° C. for 30 min. It was diluted with EtOAc and washed with 1 N NaOH. The organic layer was dried and concentrated. The residue was purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 25-50% EtOAc in hexanes to give 4-(2-fluoro-6-methylpyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (939 mg, 2.043 mmol, 81% yield) as a yellow amorphous solid. 1H NMR (400 MHz, d6-DMSO) δ 8.53 (1H, m); 7.37 (1H, d, J=6.5 Hz); 7.24 (4H, dd, J=8.6, 1.2 Hz); 6.89 (4H, t, J=Hz); 4.75 (4H, d, J=6.5 Hz); 3.74 (3H, s); 3.72 (s, 3H); 2.51 (3H, s); 2.45 (3H, s). m/z (ESI, +ve ion) 460 (M+H)+.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[S:34])[NH:18][C:19](=[O:33])[N:20]([CH2:22][C:23]4[N:28]=[C:27]([C:29]([O:31]C)=[O:30])[CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>CO.O>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([C:16]3[C:17](=[S:34])[NH:18][C:19](=[O:33])[N:20]([CH2:22][C:23]4[N:28]=[C:27]([C:29]([OH:31])=[O:30])[CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=S)[nH]c2=O)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=S)[nH]c2=O)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of the product from step (vi) (1.37 g) and lithium hydroxide monohydrate (0.588 g) in methanol (20 ml) and water (15 ml) was stirred at room temperature for 3 hours. A precipitate formed which was filtered off and partitioned between ethyl acetate and 1N HCl. The organic phase was dried (MgSO4) and concentrated under reduced pressure to 10 ml. The product was precipitated by the addition of diethyl ether. Yield 0.56 g.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]3[C:14]([CH3:18])=[C:15]([CH3:17])[S:16][C:10]=3[N:9]([CH2:19][C:20]([O:22]CC)=[O:21])[C:8]2=[O:25])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[C:20]([CH2:19][N:9]1[C:10]2[S:16][C:15]([CH3:17])=[C:14]([CH3:18])[C:11]=2[C:12](=[O:13])[N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:27][CH:26]=2)[C:8]1=[O:25])([OH:22])=[O:21]
Reactant: CCOC(=O)Cn1c(=O)n(Cc2ccc(Cl)cc2)c(=O)c2c(C)c(C)sc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1sc2c(c1C)c(=O)n(Cc1ccc(Cl)cc1)c(=O)n2CC(=O)O
Yield: 61 %

Procedure:
A 0.7 g quantity of 3-(4-chlorobenzyl)-1-ethoxycarbonylmethyl-5,6-dimethylthieno[2,3-d]pyrimidin-2,4(1H, 3H)-dione (Compound IV-1) prepared in Reference Example 5 was dissolved in 30 ml of methanol. To the solution was added 0.3 g of sodium hydroxide dissolved in 2 ml of water. The mixture was allowed to react at 60° C. for 30 minutes, and then the reaction mixture was concentrated. Diluted hydrochloric acid was added thereto with ice-cooling to acidify the resulting solution. The solution was filtrated and the separated crystals were recrystallized from methanol, giving 0.4 g of 1-carboxymethyl-3-(4-chlorobenzyl)-5,6-dimethylthieno[2,3-d]pyrimidin-2,4(1H, 3H)-dione having m.p. of 173° to 176° C. in a yield of 61%.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[OH:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1>CN(C=O)C>[OH:24][CH:25]1[CH2:26][CH2:27][N:28]([CH2:31][C:32]2[CH:38]=[CH:37][C:35]([NH:36]/[C:4](=[C:11]3\[C:12](=[O:23])[NH:13][C:14]4[C:19]\3=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)/[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:34][CH:33]=2)[CH2:29][CH2:30]1
Reactant: Nc1ccc(CN2CCC(O)CC2)cc1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(CN2CCC(O)CC2)cc1)c1ccccc1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(4-hydroxypiperidinomethyl)-aniline in DMF.