Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[CH2:11]([Li])CCC.[CH2:16]([C:20]1[C:24]([CH:25]=[O:26])=[C:23]([CH3:27])[O:22][N:21]=1)[CH2:17][CH2:18][CH3:19]>C1COCC1.CCCCCC>[CH3:11][O:9][C:8]([C:4]1[S:3][C:2]([CH2:1][CH:25]([C:24]2[C:20]([CH2:16][CH2:17][CH2:18][CH3:19])=[N:21][O:22][C:23]=2[CH3:27])[OH:26])=[N:6][C:5]=1[CH3:7])=[O:10]
Reactant: CCCCc1noc(C)c1C=O
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCc1noc(C)c1C(O)Cc1nc(C)c(C(=O)OC)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79 %

Procedure:
To a stirred solution of 2,4-dimethyl-thiazole-5-carboxylic acid (7.52 g, 47.8 mmol) in THF (400 mL) at −78° C. and under argon was added n-butyllithium (59.8 mL of a 1.60M solution in hexane, 95.7 mmol) dropwise. After 1.5 h, a solution of 3-butyl-5-methyl-isoxazole-4-carbaldehyde (8.0 g, 47.8 mmol) in THF (200 mL) was added dropwise over 30 min. After 3 h the reaction mixture was quenched with HCl (1 N, 80 mL) and water (100 mL), warmed to room temperature, then the reaction mixture was adjusted to pH 6 with 10% aqueous citric acid. The reaction mixture was concentrated to remove most of the THF then was extracted with ethyl acetate. The combined extracts were dried, filtered and concentrated. The resultant oil was redissolved in methanol (400 mL) and ether (200 mL) then (trimethylsilyl)diazomethane (71.8 ml, of a 2M solution in ether, 144 mmol) was added dropwise. After 30 min, further (trimethylsilyl)diazomethane (71.8 mL of a 2M solution in ether, 144 mmol) was added. After 30 min, the reaction mixture was quenched with acetic acid then saturated aqueous sodium bicarbonate (200 mL) added. The mixture was filtered and the filtrates concentrated to ˜200 mL then extracted with in ethyl acetate. The combined organic extracts were dried, filtered and concentrated then purified by chromatography (silica, 10 to 40% ethyl acetate in heptane) to give the title compound (12.8 g, 79%) as a yellow solid. MS: m/e=321.2 [M+H—H2O]+.
Reaction SMILES: S([O-])(O[O-])(=O)=[O:2].[K+].[K+].[F:9][C:10]1[CH:11]=[C:12]([C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])[CH:13]=[C:14]([F:19])[C:15]=1[S:16]([CH3:18])=[O:17].O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O.[Mg+2]>O.CO.ClCCl>[F:19][C:14]1[CH:13]=[C:12]([C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])[CH:11]=[C:10]([F:9])[C:15]=1[S:16]([CH3:18])(=[O:2])=[O:17]
Reactant: O=S(=O)([O-])O[O-]
Reactant: Cc1onc(-c2ccccc2)c1-c1cc(F)c(S(C)=O)c(F)c1
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Cc1onc(-c2ccccc2)c1-c1cc(F)c(S(C)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 93.5 %

Procedure:
Potassium peroxymonosulfate (0.25 g, 0.40 mmol) and water (7 mL) were added to a mixture of 4-[3,5-difluoro-4-(methyl-sulfinyl)phenyl]-5-methyl-3-phenylisoxazole (0.10 g, 0.30 mmol), dichloromethane (4 mL), and methanol (4 mL). The mixture was stirred for four days at room temperature. To the mixture was added magnesium monoperoxyphathalate hexahydrate (0.50 g, 0.80 mmol), dichloromethane (20 mL), methanol (10 mL). The mixture was stirred vigorously for 18 hours. To the mixture was added potassium peroxymonosulfate (0.35 g, 0.57 mmol), and the reaction continued for 18 hours. The mixture was poured into water and extracted with dichloromethane (4×75 mL). The combined extracts were dried with magnesium sulfate, concentrated, and the residue purified by silica gel chromatography using 30% ethyl acetate in hexanes. A white solid (98 mg, 93%) was obtained. MP 140.4-143.4° C. 1H NMR (CDCl3/400 MHz) 7.35-7.45 (m, 5H), 6.84 (d, 2H, J=9.4), 3.32 (s, 3H) 2.52 (s, 3H). ESHRMS m/z 350.0642 (M+H+, Calcd 350.0662).
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:4]=2[O:3]1.[N+:14]([CH3:17])([O-:16])=[O:15].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[CH:17][N+:14]([O-:16])=[O:15])=[CH:10][C:4]=2[O:3]1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1ccc2c(c1)OC(F)(F)O2
Yield: 56.8 %

Procedure:
To a solution of 2,2-difluoro-benzo[1,3]dioxole-5-carbaldehyde [5.48 g, 29.44 mmol, Intermediate (60)] and nitromethane (4.78 mL, 88.32 mmol) in acetic acid (90 mL) is added ammonium acetate (5.67 g, 73.6 mmol). The reaction mixture is heated to reflux for 5.5 hours. Acetic acid is removed in vacuo and the residue is added water (20 mL) and extracted with DCM (3×50 mL), organic layers are combined and washed with 2 N sodium hydroxide, water and brine, dried over sodium sulfate and concentrated. The solid obtained is crystallized in methanol/DCM (1:1) to yield intermediate 2,2-difluoro-5-(2-nitro-vinyl)-benzo[1,3]dioxole [3.83 g, Intermediate (61)] as a solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C(OC(=O)[NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)=[CH:30][C:29]=1[NH2:39])(C)(C)C.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>CN(C=O)C>[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)=[CH:30][C:29]=1[NH:39][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:12]([C:6]2([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reactant: O=C(O)c1ccc(C2(c3nccs3)CCOCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(C2(c3nccs3)CCOCC2)cc1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A solution of 4-(4-thiazol-2-yl-tetrahydro-pyran-4-yl)-benzoic acid (0.9 g, 3.11 mmol), 2-Amino-4-thiophen-2-yl-phenyl-carbamic acid tert-butyl ester (1.08 g, 1.1 eq), HATU (1.42 g, 1.2 eq), and DIPEA (1.04 mL, 2.0 eq) were dissolved in DMF and stirred at 45° C. overnight. After the reaction was complete, it was cooled down and precipitated with water and a saturated solution of NaHCO3. The solid formed was collected and used for next step without further purification. Solid {2-[4-(4-thiazol-2-yl-tetrahydro-pyran-4-yl)-benzoylamino]-4-thiophen-2-yl-phenyl}-carbamic acid tert-butyl ester was re-dissolved in DCM/TFA (1:1) and stirred for 1 hour. After the reaction was complete, the reaction mixture was evaporated and purified by reverse phase chromatography to afford title compound, Example 64. MS found for C28H26N7FOS as (M+H)+ 461.12. 1H NMR (400 MHz, dmso-d6): 1H-NMR (DMSO) δ: 9.74 (s, 1H), 8.04 (d, J=8.0 Hz, 2H), 7.67 (d, J=8.8 Hz, 2H), 7.44 (s, 1H), 7.32 (d, J=5.2 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.21 (d, J=3.6 Hz, 1H), 7.01 (q, J=3.6, 4.8 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 5.14 (s, 1H), 4.02-4.00 (m, 2H), 3.69-3.65 (m, 2H), 2.11-2.08 (m, 4H).
Reaction SMILES: [C:1]([NH:22][CH2:23][CH2:24][O:25][P:26](=[O:28])=[O:27])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:29](O)(=O)[CH2:30]C/C=C\CC=CCC=CCC=CCC=CCC=CCC>>[C:1]([NH:22][CH2:23][CH2:24][O:25][P:26](=[O:28])=[O:27])(=[O:21])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:29][CH3:30]
Reactant: CCC=CCC=CCC=CCC=CCC=CC/C=C\CCC(=O)O
Reactant: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)NCCOP(=O)=O
Product: CCC=CCC=CCC=CCC=CCC=CC/C=C\CCC(=O)NCCOP(=O)=O

Procedure:
This compound was prepared as described above for (5), using 0.5 mmol (164 mg) of cis-4,7,10,13,16,19-docosahexaenoic acid; yield 99 mg (44%); Rf 0.10-0.15 (system B); 1H NMR (CD3SOCD3, 200 MHz) δ0.9-1.0 (t, 3H, ω-CH3); 2.0-2.1 (t, 2H, CH2CO); 2.2-2.4 (m, 4H, 2CH2CH═CH); 2.7-2.9 (br s, 10H, 5HC═CHCH2CH═CH); 3.4-3.5 (br s, 2H, CH2NH); 3.9-4.0 (br s, 2H, CH2OP); 5.2-5.4 (br s, 12H, 6HC═CH); 8.2-8.4 (m, 3H, NH and 2POH).
Reaction SMILES: CC1[O:7]C([O:8][CH:9]2[C:15]3[C:16]([OH:33])=C4C(=O)C5C(=CC(OC)=CC=5O)C(=O)C4=CC=3[C:12](=[O:13])[C:11]([OH:35])(C)[CH:10]2[O:36]C)C(OC)C(O)C1OC.CN(C)C=[O:46]>C(Cl)(Cl)Cl.CO>[OH2:7].[O:13]=[CH:12][C@@H:11]([C@H:10]([C@@H:9]([C@@H:15]([CH2:16][OH:33])[OH:46])[OH:8])[OH:36])[OH:35]
Reactant: CN(C)C=O
Reactant: COc1cc(O)c2c(c1)C(=O)c1cc3c(c(O)c1C2=O)C(OC1OC(C)C(OC)C(O)C1OC)C(OC)C(C)(O)C3=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 12 h

Procedure:
Between about 36 and 48 hours of fermentation time, steffimycin B is added to the fermentation as a dimethylformamide solution (25 mg/ml) to a final medium concentration of 25 mg/l. The fermentation is monitored using tlc on silica gel plates with CHCl3 :CH3OH (925:75) as the developing solvent system. The tlc procedure is conducted at half day intervals between the first half day and five days.
Reaction SMILES: [CH2:1]([C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]1=[O:10])[CH3:2].[CH:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19].N1C=CC=C[CH:30]=1>C(Cl)Cl>[CH2:1]([C:3]1([C:11]2[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=2)[O:17][C:24]2[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=2)[CH:18]=[O:19])[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:30])[C:4]1=[O:10])[CH3:2]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CCC1(c2cccc(O)c2)CCCCNC1=O
Reactant: c1ccncc1
Solvent: ClCCl
Product: CCC1(c2cccc(Oc3cccc(C=O)c3)c2)CCCCN(C)C1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-Ethyl-3-(3-hydroxy-phenyl)-1-methyl-azepan-2-one (as described in Example 8, Step B) (0.10 g, 0.4 mmol), 3-formylphenyl-boronic acid (0.12 g, 0.8 mmol), cupric acetate (0.073 g, 0.4 mmol) and powdered 4A molecular sieves (0.12 g) were combined under Ar, diluted with anhydrous CH2Cl2 (2 mL) and pyridine (0.162 mL, 2.0 mmol) and stirred at ambient temperature for 48 hrs. The reaction mixture was filtered, and the filtrated concentrated to dryness and partitioned between EtOAc and H2O. The aqueous layer was washed with EtOAc, the organics combined, washed with H2O, 10% aqueous NaOH solution, H2O, brine, and dried (Na2SO4). Filtration and concentration to dryness gave the title compound as a white solid after trituration with diethyl ether/hexane.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:10][C:9](=[O:22])[N:8]([CH2:23][C@@H:24]3[CH2:26][O:25]3)[C:7]=2[N:27]=1>CN(C=O)C>[OH:25][CH2:26][C@H:24]1[N:27]2[C:7]3[N:8]([C:9](=[O:22])[CH2:10][N:11]([C:12]([O:14][CH2:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[O:13])[C:6]=3[CH:5]=[CH:4][C:3]2=[O:2])[CH2:23]1
Reactant: COc1ccc2c(n1)N(C[C@@H]1CO1)C(=O)CN2C(=O)OCc1ccccc1
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CC(=O)N2C[C@@H](CO)n3c2c1ccc3=O
Temperature: 120 °C
Yield: 30.9 %

Procedure:
Phenylmethyl 6-(methyloxy)-4-[(2R)-2-oxiranylmethyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine-1(2H)-carboxylate (crude, 15.93 g, estimated 32.8 mmol) was dissolved in DMF (250 ml) at room temperature and heated at 130° C. for 2 nights and at 120° C. for one night. The reaction was complete so DMF was evaporated and the residue treated with water/brine (350/50 ml) and DCM (500 ml). The layers were separated and the aqueous layer was extracted once more with DCM (500 ml). The combined organic extracts were dried over MgSO4, filtered and evaporated to afford a brown oil which was dried under high vacuum over the weekend. The crude product was purified by silica chromatography using a 0-10% MeOH/DCM gradient to afford the desired product as a golden foam (3.6 g, 30.9%).
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].[CH:12]1[C:24]2[CH:23]([C:25](O)=[O:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:12]1[C:24]2[CH:23]([C:25]([CH:8]3[C:9](=[O:10])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:11])[C:6]3=[O:7])=[O:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Reactant: O=C(O)C1c2ccccc2-c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN1C(=O)C(C(=O)C2c3ccccc3-c3ccccc32)C(=O)N(C)C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
A mixture of 1,3-dimethylbarbituric acid (2.5 g, 16.01 mmol), 9-fluorenylcarboxylic acid (5.05 g, 24.01 mmol), 4-dimethylaminopyridine (0.98 g, 8.00 mmol) in dry CH2Cl2 (15 ml) was cooled to 0° C. and 1,3-dicyclohexylcarbodiimide (3.30 g, 16.01 mmol) added. The reaction mixture was stirred at room temperature overnight and filtered. The solid was washed with CH2Cl2 (50 ml) and the combined solution was washed with 2 N HCl solution (5 ml). The organic phase was dried over MgSO4 and evaporated. The residue was crystallised from recrystallised from MeOH giving 5-(9-fluorenyl-carbonyl)-1,3-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione 5 (2.85 g, 69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[Te:10][C:9]([CH3:11])=[N:8][C:7]=2[CH:12]=1.[F:13][C:14]([F:23])([F:22])[S:15]([O:18][CH2:19][CH:20]=[CH2:21])(=[O:17])=[O:16]>ClCCl>[F:13][C:14]([F:23])([F:22])[S:15]([O-:18])(=[O:17])=[O:16].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[Te:10][C:9]([CH3:11])=[N+:8]([CH2:21][CH:20]=[CH2:19])[C:7]=2[CH:12]=1
Reactant: C=CCOS(=O)(=O)C(F)(F)F
Reactant: COc1ccc2[te]c(C)nc2c1
Solvent: ClCCl
Product: C=CC[n+]1c(C)[te]c2ccc(OC)cc21
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 21 h

Procedure:
5-Methoxy-2-methylbenzotellurazole (Example 20) (0.91 g, 0.033 mole), dissolved in dichloromethane (25 ml), was added at room temperature under a nitrogen atmosphere to the solution of 2-propen-1-yl trifluoromethanesulfonate (0.004 mole) from a dropping funnel. The mixture was stirred at room temperature for another 21 hours after the addition was complete, maintaining the nitrogen atmosphere. The solid was isolated by filtration, washed with diethyl ether, and dried at room temperature under vacuum. Yield 0.90 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]4[CH:21]=[CH:20][CH:19]=[CH:18][C:14]4=[CH:15][CH:16]=3)[NH:11][C:10](=[O:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[O:22]=[C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:31])=[O:30])[CH:7]=[CH:6][CH:5]=2)[C:17]2[C:12](=[C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]3=[CH:15][CH:16]=2)[NH:11]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cccc(-c2nc(=O)[nH]c3c2ccc2ccccc23)c1
Solvent: c1ccncc1
Product: O=c1nc(-c2cccc(NS(=O)(=O)c3ccccc3)c2)c2ccc3ccccc3c2[nH]1
Temperature: 80 °C
Reaction time: 5 h
Yield: 15 %

Procedure:
To a solution of 4-(3-aminophenyl)-1H-benzo[h]quinazolin-2-one (20 mg, 0.07 mmol) in pyridine (3 mL) was added benzenesulfonyl chloride (127 μL, 0.99 mmol), and stirred at 80° C. for 5 hours. After the solution was cooled to room temperature, the solvent was removed under reduced pressure. The residue was diluted with chloroform, washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1), to give the titled compound as a yellow amorphous form (5 mg, yield 15%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].Cl[CH2:45][CH:46]=[C:47]([CH3:49])[CH3:48]>>[CH3:43][O:42][C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[N:29]([CH2:45][CH:46]=[C:47]([CH3:49])[CH3:48])[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[N:32]=3)[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: CC(C)=CCCl
Reactant: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Product: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5n4CC=C(C)C)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 35.1 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine and 1-chloro-3-methylbut-2-ene to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1O)[CH:5]=[O:6].[C:11](=[O:14])([O-])[O-].[Cs+].[Cs+].S(O[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=O)(=O)C>COCCOCCOC>[CH2:22]([O:1][C:2]1[C:3]([O:14][CH2:11][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCC/C=C\CCCCCCCCOS(C)(=O)=O
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOCCOC
Product: CCCCCCCC/C=C\CCCCCCCCOc1cccc(C=O)c1OCCCCCCCC/C=C\CCCCCCCC
Temperature: 100 °C
Yield: 89.2 %

Procedure:
3,4-Dihydroxybenzaldehyde (2.76 g, 20.0 mmol) was weighed into a 200 mL round bottomed flask with a stir bar. The flask was charged with diglyme (100 mL), septum sealed and flushed with argon. Cesium carbonate (19.5 g, 60.0 mmol) was added to the solution slowly in portions. Oleyl mesylate (15.2 g, 44.0 mmol) was added via syringe. The reaction mixture was heated to 100° C. under slight positive pressure of argon. The reaction mixture was cooled to room temperature and filtered. The solids were washed with 1,2-dichloroethane. The combined filtrate and washes were concentrated and then dried under high vacuum at 65° C. to remove residual diglyme. The resultant yellow oil was purified via flash chromatography (5% ethyl acetate in hexanes) to afford 11.4 g (89%) of a yellow oil that turned to yellow wax upon standing at room temperature.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2C(OCC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:17].[Na+].Cl.[CH2:20]([OH:22])C>>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:20]([OH:22])=[O:17])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cnoc1-c1ccccc1
Reactant: [OH-]
Reactant: CCO
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1cc(-c2ccccc2)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.4 g of ethyl 5-phenyl-4-isoxazole carboxylate was dissolved in 10 ml ethanol, and 2 ml of 5N sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with 2 N hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated, to give 0.25 g of 5-phenyl-3-isoxazolecarboxylic acid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:11][CH:12]([CH3:16])[C:13](O)=[O:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:13](=[O:14])[CH:12]([SH:11])[CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(S)C(=O)O
Reactant: OCCCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(S)C(=O)OCCCc1ccccc1

Procedure:
Into a 100 ml reaction flask equipped with reflux condenser, hot plate (with stirring apparatus contained within) and spin bar are placed 13.6 grams phenylpropyl alcohol; 4.0 grams of 2-mercaptopropionic acid; and 0.1 grams of para-toluene sulphonic acid. The reaction mass is maintained at reflux for a period of 9 hours with stirring. At the end of the 9 hour period, the reaction mass is cooled and fractionally distilled on a micro distillation apparatus yielding the compound having the structure: ##STR64## (as confirmed by GLC, mass spectral, NMR and IR analyses).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:30]=[CH:29][C:14]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:13][CH:12]=1>C(O)(=O)C>[NH2:8][C:6]1[C:5]([CH3:9])=[CH:4][N:3]=[C:2]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:18][CH2:17]3)=[CH:29][CH:30]=2)[N:7]=1
Reactant: Cc1cnc(Cl)nc1N
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Solvent: CC(=O)O
Product: Cc1cnc(Nc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1N
Temperature: 70 °C
Yield: 94.7 %

Procedure:
A mixture of 2-chloro-5-methylpyrimidin-4-amine (540 mg, 3.7 mmol), tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate (1.1 g, 3.7 mmol) was suspended in acetic acid (20 mL) and heated at 70° C. for 1 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH˜7. The resulting solution was extracted with EtOAc (30 mL) and the organic layer separated. The organic layer washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to afford the title compound (1.4 g, 95%) as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([CH2:11][CH2:12][NH2:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16](OC)=O.C(N)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.ClCCl>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][CH2:12][NH:13][CH3:16])=[CH:14][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC=O
Reactant: NCCc1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: NC=O
Solvent: ClCCl
Product: CNCCc1ccc(-c2ccccc2)cc1
Reaction time: 20 h
Yield: 18 %

Procedure:
4-Phenylphenethyl amine, 0.48 g (2.4 mmol), was added to an excess of methyl formate (5 mL) and dichloromethane (5 mL) was added to improve solubility. The heterogeneous reaction mixture was refluxed to give a solution within 20 hours. NMR analysis of a sample showed almost complete conversion to N-formyl amine. The reaction mixture was evaporated to give 0.47 g (87%). The formyl compound, 0.47 g (2.09 mmol), was dissolved in THF and 2.1 mL of 1.0 M lithium aluminium hydride (2.1 mmol) in THF was added. TLC analysis after 20 hours showed only starting material and 2 mL (2 mmol) of lithium aluminium hydride solution was added. Analysis after 1 hour showed starting material and the mixture was heated to reflux. After 1.5 hours a precipitate was formed, the starting material consumed and tetrahydrofuran (15 ml) was added. The mixture was quenched by successive addition of water (0.15 g), 15% aqueous sodium hydroxide (0.15 g) and water (0.45 g). The mixture was filtered and evaporated to give 0.33 g crude product. The crude product was purified by silica gel chromatography (100 mL) using dichloromethane/methanol/concentrated ammonia (90+10+1) as eluant. Evaporation of pure fractions gave 78 mg (18%) of the sub-titled compound.