Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]I.[CH2:3]([N:10]1[CH2:18][C:17]2([C:19]([O:21][CH3:22])=[O:20])[CH:12]([C:13](=NN)[CH2:14][CH2:15][CH:16]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OCC)(=O)C>O1CCCC1>[CH2:3]([N:10]1[CH2:18][C:17]2([C:19]([O:21][CH3:22])=[O:20])[CH:12]([C:13]([I:1])=[CH:14][CH2:15][CH:16]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: II
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=NN)CCC2c1ccccc1OC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2c1ccccc1OC
Yield: 48.5 %

Procedure:
106.1 g (0.418 mol) of iodine in 1.1 dm3 of tetrahydrofuran were added dropwise to a solution of 85 g (0.209 mol) of methyl (3aRS,4SR,7aRS)-2-benzyl-7-hydrazono-4-(2-methoxyphenyl)octahydroisoindole-3a-carboxylate in 2 dm3 of tetrahydrofuran. After addition of 2 dm3 of ethyl acetate, the organic phases were washed with two times 1 dm3 of a saturated aqueous sodium hydrogencarbonate solution, washed with two times 1 dm3 of a saturated aqueous sodium thiosulphate solution, then dried over magnesium sulphate and concentrated under reduced pressure. After purification by chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (95/05 by volume) mixture, 51 g (48%) of methyl (3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-(2-methoxyphenyl)-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate were obtained in the form of a brown oil, the characteristics of which were as follows:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]([C:19]([OH:21])=O)=[CH:13][CH:14]=[CH:15][C:16]=1[O:17][CH3:18])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>C(Cl)Cl>[CH2:26]([N:28]([CH2:29][CH3:30])[C:19]([C:12]1[C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])=[C:16]([O:17][CH3:18])[CH:15]=[CH:14][CH:13]=1)=[O:21])[CH3:27]
Reactant: CCNCC
Reactant: COc1cccc(C(=O)O)c1-c1ccccc1OC(C)C
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cccc(OC)c1-c1ccccc1OC(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 111.3 %

Procedure:
Prepare a stirred solution of 2'-isopropoxy-6-methoxy-biphenyl-2-carboxylic acid (1.432 g, 0.0050 mole) in methylene chloride (50 mL) at -50° C. and under argon. Warm to ambient temperature then add thionyl chloride (0.8415 g, 0.516 mL). Continue stirring for about 45 minutes, observing the color change to light brown. Cool to 0° C. and dropwise add diethylamine (6.00 mL, 4.242 g, 0.058) mole, keeping the temperature of the reaction below 26° C. Continue stirring for about 30 minutes once the addition is complete. Dilute to 150 mL with additional methylene chloride. Wash the methylene chloride layer with water, separate, and extract twice with 100 mL 5% sodium bicarbonate. Separate, wash again with brine , separate and dry over MgSO4. Filter through celite and condense on a rotary evaporator to a light brown, viscous liquid. Elute via chromatography with 30% ethyl acetate/70% hexane to give a clear viscous liquid (1.90 g). Concentrate under high vacuum to give a waxy solid of the title compound. (1.40 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)N)=[CH:4][CH:3]=1.CO[CH:19](OC)[CH2:20][CH2:21][CH2:22][NH:23][CH3:24]>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:8]([CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:19]=[C:20]2[CH2:21][CH2:22][NH:23][CH3:24]
Reactant: NN(CCC1CCCC1)c1ccc(Cl)cc1
Reactant: CNCCCC(OC)OC
Product: CNCCc1cn(CCC2CCCC2)c2ccc(Cl)cc12

Procedure:
The title compound is prepared by General Method 10 using 1-(4-chlorophenyl)-1-(2-cyclopentylethyl)hydrazine (Example 4) and 4,4-dimethoxy-N-methylbutan-1-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1O.[OH-].Cl[C:12]([O:14][CH3:15])=[O:13]>O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: Oc1ccc(F)cc1Cl
Reactant: COC(=O)Cl
Agent: [OH-]
Solvent: O
Product: COC(=O)c1ccc(F)cc1Cl
Yield: 125.6 %

Procedure:
2-Chloro-4-fluorophenol (83.4 g) was added to a solution of sodum hydroxide (27.7 g) in water (450 ml), and methyl chloroformate (69.2 g) was dropwise added thereto at a temperature below 10° C. Precipitated crystals were collected by filtration and washed with water to give methyl (2-chloro-4-fluorophenyl)formate (134.8 g). M.P., 69°-71° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[N:4][C:5]([CH3:9])=[N:6][C:7]=1Cl.[NH2:11][CH2:12][C:13]1[CH:14]=[C:15]([Br:19])[CH:16]=[N:17][CH:18]=1>COCCOC>[Br:1][C:2]1[C:3](=[O:10])[NH:4][C:5]([CH3:9])=[N:6][C:7]=1[NH:11][CH2:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15]([Br:19])[CH:14]=1
Reactant: NCc1cncc(Br)c1
Reactant: Cc1nc(O)c(Br)c(Cl)n1
Solvent: COCCOC
Product: Cc1nc(NCc2cncc(Br)c2)c(Br)c(=O)[nH]1
Temperature: 23 °C

Procedure:
A stirred mixture of 5-bromo-6-chloro-2-methyl-4-pyrimidinol (4.54 g, 20.3 mmol) and 5-aminomethyl-3-bromopyridine (11.4 g, 61.0 mmol) in 1,2-dimethoxyethane (40 mL) was heated at reflux for 18 hours. The mixture was cooled to 23° C. The precipitate which formed was isolated, rinsed with 1,2-dimethoxyethane and water, and then recrystallized from methanol to provide the title compound as a white, analytically pure product (5.16 g, 13.8 mmol, 68% of theory): mp 241-242 C.; Rf 0.62 (20% MeOH in EtOAc); 1H NMR (DMSO-D6, 400 MHz)δ8.56 (d, J=2 Hz, 1H), 8.49 (d, J=2 Hz, 1H), 7.92 (m, 1H), 7.33 (t, J=6 Hz, 1H), 4.55 (d, J=6 Hz, 2H), 2.16 (s, 3H); IR (KBr) 3400 (NH), 2700-3000 (CH), 1640 (C=O) cm-1 ; UV (MeOH)λ278 (ε12,400); mass spectrum m/e 372 (M+, 54%), 374 (M+, 100%), 376 (M+, 52%), 185 (C6H6BrN2, 78%).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[C:7]([C:10]1[N:11]=[C:12]([CH3:16])[O:13][C:14]=1[CH3:15])(=[O:9])[CH3:8]>>[CH3:16][C:12]1[O:13][C:14]([CH3:15])=[C:10]([C:7]([C:2]2[CH:6]=[CH:5][S:4][CH:3]=2)([OH:9])[CH3:8])[N:11]=1
Reactant: Brc1ccsc1
Reactant: CC(=O)c1nc(C)oc1C
Product: Cc1nc(C(C)(O)c2ccsc2)c(C)o1

Procedure:
Starting with 3-bromothiophene and 4-acetyl-2,5-dimethyloxazole and following the general method of Example 4 the title compound was prepared. M.p. 83°-84° C.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([NH2:11])[CH2:3][CH2:2]1.[CH:12](=O)[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15]>C(O)C>[CH:12](=[N:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:1][CH2:2][CH2:3]1)[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15]
Reactant: O=Cc1ccccc1O
Reactant: NC1CCOc2ccccc21
Solvent: CCO
Product: Oc1ccccc1C=NC1CCOc2ccccc21
Reaction time: 8 h

Procedure:
A 90 g (0.60 mole) portion of 4-chromanamine and 450 ml of ethanol were placed in a 2-l, 3-necked flask, equipped with a stirrer and reflux condenser fitted with a drying tube, and treated with 75 g (0.61 mole) of salicylaldehyde. The reaction mixture was refluxed for 8 hrs., stored overnight at room temperature, cooled and filtered. The yellow crystalline solid was washed with 150 ml of ethanol, ether and dried; m.p. 123°-126°. Yield: 126 g (83%).
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:15][C@@H:14]3[CH2:16][C@H:11]2[CH2:12][N:13]3[CH3:17])(=O)=O)=CC=1.[BrH:19]>C(O)(=O)C>[BrH:19].[BrH:19].[CH3:17][N:13]1[CH2:12][C@@H:11]2[CH2:16][C@H:14]1[CH2:15][NH:10]2
Reactant: Cc1ccc(S(=O)(=O)N2C[C@@H]3C[C@H]2CN3C)cc1
Agent: Br
Solvent: CC(=O)O
Product: CN1C[C@@H]2C[C@H]1CN2
Temperature: 25 °C
Yield: 81 %

Procedure:
60 g (225 mmol) of (1S, 4S)-2-(4-Toluenesulfonyl)-5-methyl-2,5-diazabicyclo-[2.2.1]heptane was suspended in 900 ml of 30% hydrogen bromide in acetic acid and the mixture was allowed to stir at room temperature. After 6 hours the acetic acid was removed under aspirator pressure to 1/4 of the original volume and 1800 ml of ethylacetate was then added. A solid precipitated and was filtered under an inert atmosphere. The product was recrystallized by dissolving in a minimum amount of methanol at reflux. Cooling followed by the addition of 400 ml of isopropyl alcohol provided a white solid which was filtered and dried under reduced pressure. The product weighed 48 g which represents an 81% yield. M.P.=258°-259° C. (coloration occurs at 234° C.). [α]D =+13.21° (c=0.946, CH3OH)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:3]=1[CH2:4]O.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:3]=1[CH2:4][Br:13]
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc(F)c(F)cc1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cc(Br)c(CBr)cc1F
Reaction time: 2 h
Yield: 120.7 %

Procedure:
To a solution of 2.4 g (10 mmol) of 2-bromo-4,5-difluorobenzoic acid (prepared according to the procedure of Braish et al., Synthetic Commun., pg 3067–3074, 1992) in 75 mL of tetrahydrofuran was added 2.43 g (15 mmol) of carbonyldiimidazole. The solution was heated under reflux for 3.5 h, cooled to ambient temperature and 0.38 g (10 mmol) of sodium borohydride in 15 mL of water was added. The reaction was stirred for 10 min and partitioned between ethyl acetate and 10% aqueous sodium bicarbonate solution. The organic layer was washed twice with warm water, brine, dried over magnesium sulfate, and concentrated in vacuo. Purification by flash chromatography (silica gel, 4:1 hexane:ethyl acetate) afforded 1.9 g of 2-bromo-4,5-difluorobenzyl alcohol. To a solution of 1.9 g (8.4 mmol) of 2-bromo-4,5-difluorobenzyl alcohol in 30 mL of dichloromethane at 0° C. was added 3.4 g (10 mmol) of carbon tetrabromide and 2.7 g (10 mmol) of triphenylphosphine. The reaction was stirred for 2 h at this temperature, the solvent was removed in vacuo and the residue stirred with 100 mL of diethyl ether. The solution was filtered, concentrated in vacuo, and purified by flash chromatography (silica gel, 20:1 hexane:ethyl acetate) to afford 2.9 g of 2-bromo-4,5-difluorobenzyl bromide contaminated with carbon tetrabromide which was used without further purification. Using the procedures outlined for the preparation of Intermediates 2 and 3, the benzyl bromide derivative was converted to the title compound: LC-MS 394 and 396 (M+1).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=1[C:13](Cl)=[O:14])(=O)C.[CH3:16][O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[F:26]>>[F:11][C:9]1[C:8]([F:12])=[CH:7][C:6]([C:13]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([C:18]([O:17][CH3:16])=[O:27])=[C:20]([F:26])[CH:21]=2)=[O:14])=[C:5]([OH:4])[CH:10]=1
Reactant: CC(=O)Oc1cc(F)c(F)cc1C(=O)Cl
Reactant: COC(=O)c1ccc(N)cc1F
Product: COC(=O)c1ccc(NC(=O)c2cc(F)c(F)cc2O)cc1F
Yield: 67.3 %

Procedure:
Analogous to the method described in Ex 1, 2-(chlorocarbonyl)-4,5-difluorophenyl acetate (0.2 g, 0.85 mmol) and methyl-2-fluoro-4-aminobenzoate (0.174 g, 1.1 mmol) were coupled to yield methyl 4-(4,5-difluoro-2-hydroxybenzamido)-2-fluorobenzoate (0.186 g, 64%). RP-HPLC: 2.61 min; ES-MS (M+H)+=326.0. This intermediate was cyclized with formaldehyde, followed by displacement of 7-fluoro with methylamine analogues to method above to give methyl 4-(6-fluoro-7-methylamino-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)benzoate. The methyl ester was hydrolyzed as described in Ex. 55 and then which was coupled with 5-chlorothiophene-2-sulfonamide as described in Ex. 56. The solvent was removed and the product purified on HPLC (C18) to give N-(5-chlorothiophen-2-ylsulfonyl)2-fluoro-4-(6-fluoro-7-(methylamino)-4-oxo-2H-benzo[e] [1,3] oxazin-3(4H)-yl) benzamide (0.005 g, 15%). RP-HPLC: 2.78 min; ES-MS (M+H)+=514; 1H-NMR (MeOH-d4) δ (ppm): 2.8 (s, 3), 5.6 (s, 2), 6.2 (d, 1), 7.1 (d, 1), 7.3 (d, 1), 7.4 (dd, 1), 7.5 (dd, 1), 7.7 (dd, 1), 7.9 (dd, 1).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.[Li].N.[CH2:12](Br)[CH:13]=[CH2:14]>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]([CH2:14][CH:13]=[CH2:12])[CH2:3]1
Reactant: CC1(C)C=CC(=O)CC1
Reactant: C=CCBr
Agent: N
Agent: [Li]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCC1CC(C)(C)CCC1=O
Temperature: -33 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
A solution of 4,4-dimethyl-2-cyclohexen-1-one (500 mg) in dry tetrahydrofuran (2 ml) was added to a well stirred solution of lithium (141 mg) in liquid ammonia (5 ml), The mixture was stirred at -33° C. for 1 hr. And then, to this solution allyl bromide (2.4 g) was added, and stirred for 30 min. The reaction was quenched by addition of methanol, and the ammonia was allowed to evaporate. The residue was diluted with water, and extracted with diethyl ether. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue with silica gel column chromatography (using n-hexane:ethyl acetate=30:1 as an eluent) gave 4,4-dimethyl-2-(2-propenyl)cyclohexanone (345 mg, 52% yield) as a colorless oil.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[CH:34])=[N:31][CH:32]=2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[C:34][C:2]3[CH:3]=[CH:4][C:5]([O:12][CH2:13][CH2:14][N:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)=[C:6]([CH:11]=3)[C:7]([O:9][CH3:10])=[O:8])=[N:31][CH:32]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)c1cc(I)ccc1OCCN1CCCC1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: COC(=O)c1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
Prepared according to general working method I from methyl 5-iodo-2-(2-pyrrolidin-1-yl-ethoxy)-benzoate (3.0 g, 8.0 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (1.76 g, 8.24 mmol).
Reaction SMILES: C[O:2][C:3](=[O:37])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:34]#[N:35])[CH:30]=3)[C:25]2=[O:36])=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[I-].[Li+].N1C=CC=CC=1>O>[C:34]([C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:36])[N:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C@@H:4]([C:3]([OH:37])=[O:2])[NH:5][C:6]([C:8]3([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:7])=[CH:23][CH:22]=1)[C:32]2=[O:33])#[N:35]
Reactant: COCCC1(C(=O)N[C@@H](Cc2ccc(N3C(=O)c4ccc(C#N)cc4C3=O)cc2)C(=O)OC)CCCC1
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: c1ccncc1
Product: COCCC1(C(=O)N[C@@H](Cc2ccc(N3C(=O)c4ccc(C#N)cc4C3=O)cc2)C(=O)O)CCCC1
Temperature: 25 °C
Yield: 34 %

Procedure:
To a mixture of 4-(5-cyano-1,3-dioxo-2H-isoindol-2-yl)-N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (0.3 mmol, 151 mg) and lithium iodide (3.0 mmol, 397 mg) was added pyridine (6 mL) at room temperature. The solution was refluxed for 15 h at which time TLC analysis of the mixture indicated the absence of starting material. Then, it was cooled to room temperature and diluted with water (15 mL) and the bulk of the pyridine was removed by concentration under reduced pressure. The residue was extracted with ether (2×15 mL) to remove any neutral impurities. The aqueous layer was acidified with 1N HCl and the precipitated white solid was collected by filtration and washed with 20 mL of water and 20 mL of hexane. After air-drying, the crude product was purified by reverse phase HPLC to afford 50 mg (34%) of a white solid, mp 143-146° C. HR MS (C27H27N3O6): Obs mass, 490.1990. Calcd mass, 490.1978 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[NH2:7][C:8]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:9]=1[C:10]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:11]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: Nc1cc([N+](=O)[O-])ccc1C(=O)N1CCOCC1
Reaction time: 1 h
Yield: 83 %

Procedure:
Morpholine (2.152 mL, 24.71 mmol) was added to a stirred suspension of 2-amino-4-nitrobenzoic acid (1.5 g, 8.24 mmol) and HATU (3.44 g, 9.05 mmol) in acetonitrile (15 mL) at room temperature. After 1 h at room temperature, the mixture was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (100 mL). The EtOAc layer was washed with saturated NH4Cl (10 mL) and brine (10 mL), dried (MgSO4), and concentrated. The resulting syrup was triturated with hot CH2Cl2 and a yellow solid precipitated out. The solid was washed with CH2Cl2 and collected by filtration (1.7195 g, 83% yield). LCMS: (M+H)+=252.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.54 (1H, d, J=2.26 Hz), 7.35 (1H, dd, J=8.28, 2.26 Hz), 7.24 (1 H, d, J=8.53 Hz), 5.86 (2H, s), 3.60 (8H, br. s.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6](Cl)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:3]=1.[NH3:24]>O1CCOCC1>[NH2:24][C:6]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:2]([Cl:1])[N:3]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:5]=1
Reactant: N
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1Cl
Solvent: C1COCCO1
Product: COc1ccccc1Oc1c(N)nc(-c2ccncc2)nc1Cl
Reaction time: 18 h

Procedure:
4,6-Dichloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (2.9 g, Referential Example 1d)) was suspended in dioxane (30 ml) and ammonia (gaseous) was introduced until the solution was saturated. Stirring was continued for 7 days while the saturation of the reaction mixture with ammonia (gaseous) was repeated every 16 to 20 h. The solvent was evaporated, water was added to the residue and the precipitate was filtered off. After drying at HV/50° C. 4-amino-6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (2.7 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[OH-].[Na+].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>O.C(O)C>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N:5][N:6]=1
Reactant: Nc1nnc(S)s1
Reactant: CCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCSc1nnc(N)s1
Reaction time: 3 h
Yield: 78.7 %

Procedure:
In 24 ml of water and 24 ml of ethanol, 11.6 g of 2-amino-5-mercapto-1,3,4-thiadiazole and 3.8 g of sodium hydroxide were dissolved, 14.0 g of 1-bromohexane was added to this solution, and the mixture was heated to 70°-80° C. and stirred for 3 hours. After cooling, water was added and the mixture was filtered. The residue was washed with water, dried under reduced pressure, and recrystallized from an ethanol/n-hexane (1:1) mixture. Thus 14.5 g of 2-amino-5-hexylthio-1,3,4-thiadiazole was obtained. m.p. 113°-115° C. Yield 77%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:37]=[CH:36][C:21]([O:22][CH2:23][CH:24]3[CH2:28][CH2:27][CH2:26][N:25]3C(OC(C)(C)C)=O)=[CH:20][CH:19]=2)=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH3:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:12]1([C:9]([CH2:10][CH3:11])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[C:18]2[CH:37]=[CH:36][C:21]([O:22][CH2:23][C@@H:24]3[CH2:28][CH2:27][CH2:26][NH:25]3)=[CH:20][CH:19]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCC2CCCN2C(=O)OC(C)(C)C)cc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OC[C@@H]2CCCN2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.7 %

Procedure:
To a stirred solution of tert-butyl 2-((4-(1-(4-hydroxyphenyl)-2-phenylbut-1-enyl)phenoxy)methyl)pyrrolidine-1-carboxylate (400 mg, 1.0 eq) in 20 mL CH2Cl2 was added 1 mL TFA dropwise at 0° C. The reaction was stirred at rt for 3 h, then quenched with sat. NaHCO3, and extracted with CH2Cl2. The extract was dried, concentrated and purified by column chromatography to give the desired product (210 mg, 68% yield, Z/E=1/1). 1H NMR (400 MHz, CDCl3) δ 7.07-7.17 (m, 6H), 7.05 (d, J=8.4 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 6.74 (d, J=8.8 Hz, 1H), 6.68 (d, J=8.4 Hz, 1H), 6.49 (d, J=8.8 Hz, 1H), 6.44 (d, J=8.4 Hz, 1H), 3.96-4.00 (m, 0.5H), 3.89-3.93 (m, 0.5H), 3.82-3.85 (m, 0.5H), 3.73-3.77 (m, 0.5H), 3.53-3.59 (m, 0.5H), 3.43-3.49 (m, 0.5H), 2.90-3.11 (m, 2H), 2.44-2.51 (m, 2H), 1.77-1.99 (m, 3H), 1.52-1.66 (m, 1H), 0.92 (t, J=7.2 Hz, 3H); m/z=400[M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=3)[C:3]=12.N1C=CN=C1.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C=O)C.O>[Si:27]([O:17][C:13]1[CH:12]=[C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[NH:8][N:9]=2)[CH:16]=[CH:15][CH:14]=1)([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28]
Reactant: Nc1ncnc2[nH]nc(-c3cccc(O)c3)c12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(-c2n[nH]c3ncnc(N)c23)c1
Reaction time: 16 h
Yield: 85.8 %

Procedure:
To a stirred solution of compound (2) (4.69 g, 20.66 mmol) and imidazole (2.10 g, 30.99 mmol) in dry DMF (100 mL) was added TBDMSCl (4.70 g, 30.99 mmol). After 16 hr, further aliquots of imidazole (2.10 g, 30.99 mmol) and TBDMSCl (4.70 g, 30.99 mmol) were added and the mixture was stirred for 48 hr. The reaction mixture was diluted with water (120 mL) and extracted with DCM (2×200 mL). The combined organic extracts were washed with water (2×200 mL), dried, filtered and the volume reduced to approximately 100 mL by evaporation in vacuo. The resulting slurry was filtered and the solid washed with heptane (50 mL) to afford the title compound (3) (6.05 g, 85%) as an off-white solid: m/z 343 (M+H)+ (ES+).
Reaction SMILES: [NH:1]([C:73]([O:75][CH2:76][C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)=[O:74])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:22][C@H:23]([C:28]([NH:30][C@H:31]([C:35]([NH:37][C@H:38]([C:43]([NH:45][C@H:46]([C:53]([NH:55][C@H:56]([C:69]([O:71][CH3:72])=[O:70])[CH2:57][CH2:58][CH2:59][CH2:60][NH:61]C(OC(C)(C)C)=O)=[O:54])[CH2:47][C:48]1[N:52]=[CH:51][NH:50][CH:49]=1)=[O:44])[C@H:39]([CH2:41][CH3:42])[CH3:40])=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>FC(F)(F)C(O)=O>[NH:1]([C:73]([O:75][CH2:76][C:77]1[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=1)=[O:74])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:22][C@H:23]([C:28]([NH:30][C@H:31]([C:35]([NH:37][C@H:38]([C:43]([NH:45][C@H:46]([C:53]([NH:55][C@H:56]([C:69]([O:71][CH3:72])=[O:70])[CH2:57][CH2:58][CH2:59][CH2:60][NH2:61])=[O:54])[CH2:47][C:48]1[N:52]=[CH:51][NH:50][CH:49]=1)=[O:44])[C@H:39]([CH2:41][CH3:42])[CH3:40])=[O:36])[CH:32]([CH3:33])[CH3:34])=[O:29])[CH2:24][CH:25]([CH3:26])[CH3:27])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCN)C(=O)OC
Reaction time: 0.03 h

Procedure:
80 mg of Z-Phe-His-Leu-Val-Ile-His-Lys(BOC)-OMe (Example 55) are dissolved in 800 μl of 95% trifluoroacetic acid (duration approximately 1 minute) and left to stand for 2 minutes. The product is then precipitated by the addition of 8 ml of diisopropyl ether, left to stand for 15 minutes at 0°, filtered off, and the precipitate is washed with diisopropyl ether and dried over KOH in a high vacuum. The powder is then dissolved in 1 ml of 90trifluoroethanol, precipitated by the addition of 10 ml of 3% MaHCO3 solution, filtered off, washed with H2O and dried over potassium hydroxide and phosphorus pentoxide in a high vacuum. To convert the resulting acid-free title compound into the acetate, the product is dissolved in 2 ml of 90% acetic acid and lyophilised. The title compound is a chromatographically homogeneous amorphous powder; Rf (B17)=0.08, Rf (B21)=0.65.