Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]([C:11]1[S:15][C:14]([CH3:16])=[N:13][C:12]=1[CH3:17])([C:6]1[S:7][CH:8]=[CH:9][N:10]=1)[CH3:5])=[N+]=[N-]>C(O)C.[Pd]>[CH3:16][C:14]1[S:15][C:11]([C:4]([NH2:1])([C:6]2[S:7][CH:8]=[CH:9][N:10]=2)[CH3:5])=[C:12]([CH3:17])[N:13]=1
Reactant: Cc1nc(C)c(C(C)(N=[N+]=[N-])c2nccs2)s1
Agent: [Pd]
Solvent: CCO
Product: Cc1nc(C)c(C(C)(N)c2nccs2)s1

Procedure:
The product from Example 19 in ethanol was hydrogenated in the presence of 10% palladium-on-charcoal to give the title compound. 1H Nmr (CDCl3) 2.02, 2.08 and 2.61 (each 3H, s), 2.23 (2H, br s) and 7.28 and 7.73 (each 1H, d, J 3 Hz) ppm.
Reaction SMILES: C1(S)C=CC=CC=1.[Sn](Cl)Cl.C(N(CC)CC)C.[N:18]([C:21]1([CH3:39])[CH2:27][CH2:26][CH2:25][CH2:24][N:23]2[C:28](=[O:38])[CH:29]=[C:30]([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][N:33]=3)[N:31]=[C:22]12)=[N+]=[N-].[OH-].[Na+]>C(#N)C>[NH2:18][C:21]1([CH3:39])[CH2:27][CH2:26][CH2:25][CH2:24][N:23]2[C:28](=[O:38])[CH:29]=[C:30]([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][N:33]=3)[N:31]=[C:22]12
Reactant: CC1(N=[N+]=[N-])CCCCn2c1nc(-c1ccncn1)cc2=O
Agent: Cl[Sn]Cl
Agent: Sc1ccccc1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1(N)CCCCn2c1nc(-c1ccncn1)cc2=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 58 %

Procedure:
A mixture of 23.9 mL (234.1 mmol) of thiophenol, 11.1 g (58.5 mmol) of tin (II) chloride and 24.5 mL (175.6 mmol) triethylamine in acetonitrile (300 mL) was stirred for 5 min at room temperature. 10-Azido-10-methyl-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-a]azepin-4-one residue diluted in 90 mL of acetonitrile was added to this solution and the mixture was stirred for 1 h. A solution of sodium hydroxide (1M) was added and the mixture extracted with dichloromethane. After an acid-basic work-up, the residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol in the proportions 95/5 to afford 6.3 g (58%) of a yellow solid.
Reaction SMILES: C([NH:4][CH:5]([CH2:9][C:10]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[NH2:19])=[O:11])[C:6]([OH:8])=[O:7])(=O)C>CC(O)=O>[NH2:4][C@@H:5]([CH2:9][C:10]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[NH2:19])=[O:11])[C:6]([OH:8])=[O:7]
Reactant: CC(=O)NC(CC(=O)c1cc(Cl)ccc1N)C(=O)O
Solvent: CC(=O)O
Product: Nc1ccc(Cl)cc1C(=O)C[C@H](N)C(=O)O
Yield: 71.4 %

Procedure:
Starting from 1.03 g. of (+)-2-acetamido-4-(2-amino-5-chlorophenyl)-4-oxo-butyric acid as described above for the preparation of (R)-enantiomer, 0.65 g (71.4%) of (S)-(-)-2-amino-4-(2-amino-5-chlorophenyl)-4-oxo-butyric acid were obtained (m.p. 208°-209° C. (dec.); [α]20D =-12.6° (1%, CH3COOH); ee=96%).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10](I)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[Cu][C:18]#[N:19].O>N1C=CC=CC=1>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:18]#[N:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(I)ccc2[nH]1
Reactant: N#C[Cu]
Solvent: c1ccncc1
Solvent: O
Product: CCCCc1nc(=O)c2cc(C#N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
A mixture of 6.4 g of 2-butyl-6-iodo-4(1H)-quinazolinone in 25 ml of pyridine is added 3.6 g of copper(I) cyanide followed by heating at reflux for 16 hours. The reaction mixture is poured into water and stirred at room temperature for 8 hours. The suspension is filtered and the cake washed well with water and air dried. The solid is dissolved in 3:1 chloroform-methanol and dried with MgSO4. The volatiles are evaporated in vacuo to give 3.2 g of the desired product as a solid. m.p. 243°-45° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=O)=[CH:5][CH:4]=1.O=S(Cl)Cl.[CH3:18][O:19][C:20](=[O:30])[C:21]1[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][C:22]=1[NH2:29].CCCCCC>CCOC(C)=O>[CH3:18][O:19][C:20](=[O:30])[C:21]1[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][C:22]=1[NH:29][C:10](=[O:12])[CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH3:13]
Reactant: COC(=O)c1c(N)cc(Cl)cc1Cl
Reactant: COc1ccc(C(C)C(=O)O)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1c(Cl)cc(Cl)cc1NC(=O)C(C)c1ccc(OC)cc1
Yield: 84.8 %

Procedure:
The objective compound was prepared by the same procedure for the intermediate 1, using a 2-(4-methoxy-phenyl)-propionic acid (1.45 g, 8.0 mmol), SOCl2 (2.09 mL, 24.0 mmol), and 2-amino-4,6-dichloro-benzoic acid methyl ester (1.54 g, 7.0 mmol). After normal workup, the pure objective compound (2.27 g, 85%) was obtained as pale yellow syrup by a flash column chromatography (n-hexane:EtOAc=10:1): 1H NMR (200 MHz, CDCl3) δ 1.56 (d, J=7.0 Hz, 3H, CH3), 3.77 (s, 3H, CO2CH3), 3.81 (s, 3H, OCH3), 3.84-3.95 (m, 1H, CH), 6.83-6.97 (m, 2H, ArH), 7.12 (d, J=2.0 Hz, 1H, ArH), 7.21-7.27 (m, 2H, ArH), 8.41 (d, J=2.0 Hz, 1H, ArH), 8.98 (s, 1H, NH); HRMS(EI) calcd. for C18H17O4NCl2 m/e 381.0536 [M+], found 381.0539.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:8][NH:7][C@H:6]([C:9]([OH:11])=O)[C@@H:5]([C:12]([O:14][CH3:15])=[O:13])[CH2:4]1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[CH3:1][O:2][C@@H:3]1[CH2:8][NH:7][C@H:6]([C:9]([N:25]2[CH2:26][CH2:27][N:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24]2)=[O:11])[C@@H:5]([C:12]([O:14][CH3:15])=[O:13])[CH2:4]1
Reactant: COC(=O)[C@H]1C[C@H](OC)CN[C@@H]1C(=O)O
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)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: COC(=O)[C@H]1C[C@H](OC)CN[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (2S,3S,5S)-5-methoxy-3-(methoxycarbonyl)piperidine-2-carboxylic acid (14.0 mg, 0.0000644 mol), 1-phenyl-piperazine (0.01231 mL, 8.056E-5 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (35.63 mg, 8.056E-5 mol) in N,N-dimethylformamide (0.20 mL, 0.0026 mol) was added N,N-diisopropylethylamine (0.01403 mL, 8.056E-5 mol). The mixture was stirred at rt for 2 h. After quenched with water, the mixture was extracted with ethyl acetate. The combine organic lyers were washed with brine, dried and concentrated to dry. The residue was used directly in next step without further purification. MS (ESI): (M+H)+=362.1.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:35])([CH3:34])[CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([O:17]C(=O)C1C=CC=CC=1)[C:11]([N:26]1[CH2:30][C:29](=[O:31])[NH:28][S:27]1(=[O:33])=[O:32])=[CH:10]2.[OH-].[Na+].[OH-].[K+]>>[OH:17][C:12]1[C:11]([N:26]2[S:27](=[O:33])(=[O:32])[NH:28][C:29](=[O:31])[CH2:30]2)=[CH:10][C:9]2[C:14]([CH:13]=1)=[CH:15][CH:16]=[C:7]([CH2:6][CH2:5][CH2:4][C:3]([CH3:34])([CH3:35])[CH2:2][OH:1])[CH:8]=2
Reactant: CC(C)(CO)CCCc1ccc2cc(OC(=O)c3ccccc3)c(N3CC(=O)NS3(=O)=O)cc2c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(CO)CCCc1ccc2cc(O)c(N3CC(=O)NS3(=O)=O)cc2c1

Procedure:
The title compound is prepared analogously to Example 11 from benzoic acid 6-(5-hydroxy-4,4-dimethylpentyl)-3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-naphthalen-2-yl ester and 1 N NaOH solution to replace KOH: Retention time=1.05 min (Method A); (M−H)−=391.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[C:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[CH:3][CH:2]=1.C(Cl)(Cl)Cl.[OH:23]O.Cl>O.C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[O:23][C:8]32[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]3=[O:18])=[CH:3][CH:2]=1
Reactant: O=C1C(=Cc2ccncc2)CCc2ccccc21
Reactant: OO
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2CCC12OC2c1ccncc1

Procedure:
To a mixture of 10 g. of 2-(4-pyridylmethylene)-3,4-dihydro-1(2H)-naphthalenone in 100 ml of water and 200 ml of ethanol is added sufficient chloroform to dissolve the reactants. The pH is adjusted to between 7 and 9 and a 3 molar excess of 30% hydrogen peroxide in water is added dropwise at room temperature. The reactants are stirred for 5 hours after which sufficient ferrous sulfate is added to neutralize the excess peroxide. The mixture is then acidified with hydrochloric acid and the organic solvent evaporated off. The water solution remaining is made basic and extracted with chloroform. The chloroform is evaporated off yielding 3'-(4-pyridyl)-spiro[1,2,3,4-tetrahydronaphthalene-2,2'-oxirane]-1-one.
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[C:8]([OH:23])[C:9]([CH:13]([CH:15]2[CH2:20][CH2:19][CH2:18][O:17][C:16]2([CH3:22])[CH3:21])[CH3:14])=[C:10]([OH:12])[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[OH:12][C:10]1[C:9]2[CH:13]([CH3:14])[CH:15]([CH2:20][CH2:19][CH2:18][OH:17])[C:16]([CH3:21])([CH3:22])[O:23][C:8]=2[CH:7]=[C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:11]=1
Reactant: CCCCCc1cc(O)c(C(C)C2CCCOC2(C)C)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCc1cc(O)c2c(c1)OC(C)(C)C(CCCO)C2C
Temperature: 25 °C
Yield: 36.2 %

Procedure:
A solution of 9.4 g of 5-Pentyl-2-[1-(tetrahydro-2,2-dimethyl-2H-pyran-3-yl)ethyl]-1,3-benzenediol in 400 mL of toluene containing a catalytic amount of pyridinium para-toluenesulfonic acid (Aldrich) was heated to 60° C. under argon for 2 hr. The reaction was cooled to RT, diluted with EtOAc, washed with 0.1N aq. HCl (×2), water (×2), sat. aq. NaHCO3, dried and evaporated under reduced pressure. The material obtained was purified by extensive chromatography to give 3.4 g (35%) of rac-3,4-Dihydro-5-hydroxy-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-propanol as a pale yellow amorphous solid. HR EI MS: Calc M+, 320.2351; Observed, 320.2377. Ratio of 3:1 diastereoisomers as shown by 1 H-NMR.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[NH:11][C:12]([CH2:17][OH:18])=[C:13](CO)[N:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:9][C:10]1[NH:11][C:12]([CH2:17][OH:18])=[C:13]([Cl:1])[N:14]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1nc(CO)c(CO)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1nc(Cl)c(CO)[nH]1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
3.86 Grams (28.9 mmol) of the N-chlorosuccinimide was added little by little to a solution consisting of 3.87 g (27.2 mmol) of a 2-methyl-4,5-bis(hydroxymethyl) imidazole and 50 ml of water maintained at room temperature with stirring over a period of about 40 minutes. The mixture was then stirred at the same temperature for 20 hours followed by the addition of sodium carbonate thereto to make the mixture alkaline. Water was then distilled off under reduced pressure. The resulting reaction mixture was extracted with ethanol, and the extract was evaporated dryness under reduced pressure. The resulting solid product was then extracted with acetone and the extract was evaporated under reduced pressure to obtain a yellowish oily product. The oily product was then subjected to the column chromatography (silica gel-acetone) to obtain a yellowish brown crystalline 2-methyl-4-chloro-5-(hydroxymethyl) imidazole in an amount of 2.4 g (yield, 60.2%). By using acetonitrile, the recrystallization was repeated two times to obtain a colorless powdery product in pure form. The TLC and spectra of this compound were the same as the properties exhibited by the above-mentioned 2-methyl-4-chloro-5-(hydroxymethyl) imidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][CH:9]([C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[O:14])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CC(=O)c1ccc(Cl)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COC(=O)C(Br)C(=O)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a chloroform (20 mL) solution of methyl 3-(4-chlorophenyl)-3-oxopropanoate (1.0 g), bromine (0.12 mL) was added, and the resultant was stirred at 70° C. for 1 hour under sealed conditions. Then, bromine (0.12 mL) was further added thereto, and the resultant was further stirred at 70° C. for 1 hour under sealed conditions. The reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=100/0→75/25) to obtain the title compound (0.44 g) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]=2[CH:21]=1.[I-].CC(=[NH2+])C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][N:13]=[N:14][C:10]3=[CH:9][N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]=2[CH:21]=1
Reactant: Fc1ccc2c(c1)C(c1ccccn1)=NCc1nncn1-2
Agent: CC(C)=[NH2+]
Agent: [I-]
Product: Fc1ccc2c(c1)C(c1ccccn1)=NC=C1N=NCN12

Procedure:
In manner given in Example 5, 8-fluoro-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is treated with dimethylmethylene ammonium iodide to give 8-fluoro-6-(2-pyridyl)-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[C:11]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH:10]=[N:9]1)C1C=CC=CC=1.[Al+3].[Cl-].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:11]2[CH:10]=[N:9][NH:8][C:13](=[O:14])[C:12]=2[C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)=[CH:26][CH:25]=1
Reactant: O=c1c(-c2ccncc2)c(-c2ccc(Cl)cc2)cnn1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=c1[nH]ncc(-c2ccc(Cl)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 2-benzyl-5-(4-chlorophenyl)-4-(pyridin-4-yl)pyridazin-3(2H)-one (7.0 g, 18.73 mmol) in toluene (50 mL) in a round bottomed flask was added AlCl3 (7.5 g, 56.25 mmol) under a stream of argon. The flask was placed in an oil bath preheated at 80° C. After 2 hours, the reaction mixture was cooled to RT and then poured into crushed ice (200 g). The precipitate formed was collected by filtration, washed with water (2×50 mL) followed by ether (50 mL) and dried in a vacuum oven at 40° C. to give the title compound, 5-(4-chlorophenyl)-4-(pyridin-4-yl)pyridazin-3(2H)-one (5.1 g, 96%) as a white solid. HPLC: 1.37 min; MS, M+H=284.
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=O)C1C=CC=CC=1.O.[H][H]>C(O)C.[C].[Pd]>[CH3:20][N:19]([CH3:21])[C:17]([C@@H:12]1[CH2:13][C@@H:14]([OH:16])[CH2:15][NH:11]1)=[O:18]
Reactant: [H][H]
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-dimethylaminocarbonyl-4-hydroxypyrrolidine (5.97 g) in ethanol (60 ml), 10% palladium-carbon (containing water 50 (1.20 g) was added, and the mixture was hydrogenated at room temperature for 3 hours under an atmospheric pressure of hydrogen. After removal of the catalyst by filtration, the filtrate was evaporated to remove the solvent to give (2S,4R)-2-dimethylaminocarbonyl-4-hydroxypyrrolidine.
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C@H:29]([OH:51])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:34]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH:33]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([N:8]([CH2:28][C@H:29]([OH:51])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:34]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH:33]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:26][CH:27]=2)[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)COc1ccc([C@H]2CC[C@H](N(Cc3ccccc3)C[C@H](O)COc3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(OCC(=O)O)cc3)CC2)ccc1OCc1ccccc1

Procedure:
A mixture of 0.36 g of ethyl trans-(4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}phenoxy)acetate (0.49 mmol) and of 6 ml of a molar aqueous sodium hydroxide solution in ethanol (10 ml) is heated at 45° C. for 22 h. The solvents are subsequently evaporated under reduced pressure and water is added. A molar aqueous hydrochloric acid solution is subsequently added to pH=1. The title product is obtained in the form of a white solid (0.3 g, 89%) after filtration and drying under vacuum. {M+H+]=689.7
Reaction SMILES: CS(O[CH2:6][C@H:7]1[O:12][CH2:11][C@@H:10]([CH3:13])[N:9]([C:14]2[CH:19]=[C:18]([Cl:20])[N:17]=[C:16]([NH:21][CH3:22])[N:15]=2)[CH2:8]1)(=O)=O.[CH3:23][NH:24][CH3:25].C([O-])(O)=O.[Na+]>O>[Cl:20][C:18]1[CH:19]=[C:14]([N:9]2[C@H:10]([CH3:13])[CH2:11][O:12][C@H:7]([CH2:6][N:24]([CH3:25])[CH3:23])[CH2:8]2)[N:15]=[C:16]([NH:21][CH3:22])[N:17]=1
Reactant: CNc1nc(Cl)cc(N2C[C@@H](COS(C)(=O)=O)OC[C@H]2C)n1
Reactant: CNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CNc1nc(Cl)cc(N2C[C@@H](CN(C)C)OC[C@H]2C)n1
Temperature: 120 °C
Reaction time: 32 h
Yield: 45 %

Procedure:
A mixture of {(2S,5R)-4-[6-chloro-2-(methylamino)-4-pyrimidinyl]-5-methyl-2-morpholinyl}methyl methanesulfonate (161 mg, 0.46 mmol) and dimethylamine (2.0 M in THF, 5.0 mL, 10.0 mmol) was stirred at 120° C. in a sealed tube for 32 hours. The mixture was cooled, poured into saturated aqueous NaHCO3 (15 mL), diluted with water (5 mL), and extracted with EtOAc (3×15 mL). The extracts were washed with brine (15 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (24 g SiO2, CH2Cl2 to 95/5/0.5 CH2Cl2/CH3OH/NH4OH gradient) to give the title compound (62 mg, about 85% purity) as an off-white foam. LC-MS (ES) m/z=300, 302 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:35])([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:9](=[CH2:18])[CH2:10][CH:11]([CH3:17])[C:12](OCC)=[O:13].CC[O:38]CC>>[F:35][C:8]([F:7])([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:9](=[CH2:18])[CH2:10][CH:11]([CH2:12][OH:13])[CH2:17][OH:38]
Reactant: C=C(CC(C)C(=O)OCC)C(F)(F)CCCCCCCCCCCCCCCC
Reactant: CCOCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C=C(CC(CO)CO)C(F)(F)CCCCCCCCCCCCCCCC
Temperature: 25 °C

Procedure:
To a slurry of 250 mg of lithium aluminum hydride in 10 ml of ether, cooled to 0° C. is added dropwise a solution of 1.48 g of ethyl (3,3-difluoro-2-methylene-nonadecyl)propanoate in 10 ml of ether followed by warming to ambient temperature, heating at reflux for 3 hours, then allowing to cool to ambient temperature. The reaction mixture is washed with dilute hydrochloric acid, water and dilute sodium bicarbonate, dried and evaporated to a gum which is purified on silica gel using 40-60% ethyl acetate:hexanes. The fractions containing product are collected, evaporated and the residue crystallized from hexane giving 1.04 g of the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[NH:16]1[CH2:19][CH2:18][CH2:17]1>CS(C)=O>[N:16]1([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: Brc1cccc(Br)n1
Reactant: C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Brc1cccc(N2CCC2)n1
Temperature: 80 °C
Yield: 33.2 %

Procedure:
To a solution of 2,6-dibromopyridine (100 mg, 0.424 mmol) in dimethylsulfoxide (5 mL) was added potassium carbonate (175.4 mg, 1.27 mmol) and azetidine hydrogen chloride (24.2 mg, 0.424 mmol) at room temperature. The reaction mixture was heated to 80° C. for 16 h, then was poured into ice cold water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, and concentrated under reduced pressure to afford 2-(azetidin-1-yl)-6-bromopyridine (30 mg)
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[CH:25]=[N:26][CH:27]=[N:28][CH:29]=1>>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([N:19]4[CH:23]=[CH:22][N:21]=[C:20]4[C:24]4[CH:29]=[N:28][CH:27]=[N:26][CH:25]=4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:18][CH2:17]1
Reactant: c1ncc(-c2ncc[nH]2)cn1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CC1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3-c3cncnc3)nc2N1C1CC1

Procedure:
The title compound was prepared similarly to the methods described in Example 77, with Intermediate O instead of Intermediate C and with 5-(1H-imidazol-2-yl)pyrimidine instead of 2-phenyl-1H-imidazole. LCMS: 377.1 m/z (M+H)+; ret. Time: 4.44 min (Analytical Method C).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:34]=[CH:33][C:16]([CH2:17][O:18]/[N:19]=[C:20](/[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)\[CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)(O)[O-].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.CCCCCC.CO.O>[C:35]1([C:2]2[N:7]3[CH:8]=[C:9]([CH2:11][O:12][C:13]4[CH:34]=[CH:33][C:16]([CH2:17][O:18]/[N:19]=[C:20](/[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)\[CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2cn3c(Cl)cccc3n2)cc1)c1ccccc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CC/C(=N\OCc1ccc(OCc2cn3c(-c4ccccc4)cccc3n2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
A mixture of methyl E-4-[4-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyrate (550 mg), phenylboronic acid (168 mg), sodium bicarbonate (348 mg), toluene (20 ml), water (2 ml) and methanol (2 ml) was stirred at room temperature for 30 minutes under argon atmosphere. To this was added tetrakis(triphenylphosphine)palladium (0) (80 mg) and heated to reflux for 36 hours. The reaction mixture was cooled to room temperature, the organic layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain methyl E-4-[4-(5-phenylimidazo[1,2-a]pyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyrate (490 mg, yield 82%) as a colorless oil from an ethyl acetate-hexane (3:2, v/v)-eluted fraction.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[H-].[Na+].[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:13]Cl>CN(C=O)C>[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:13][N:4]1[CH:5]=[N:6][C:2]([NH2:1])=[N:3]1
Reactant: Nc1nc[nH]n1
Reactant: ClCc1cc(Cl)cc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncn(Cc2cc(Cl)cc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Amino-1,2,4-triazole (420 mg, 5.0 mmol) was dissolved in DMF (3 mL) under argon atmosphere, sodium hydride (55%, 218 mg, 5.0 mmol) was added at room temperature in small portions and stirred at room temperature for 1 hour. The reaction mixture was cooled to 0° C., 3,5-dichlorobenzyl chloride (977 mg, 5.0 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured onto water and the aqueous phase extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, filtered, the solvents were evaporated and the residue purified by silica gel chromatography using dichloromethane/methanol as eluent. The title compound was obtained as a white solid (357 mg, 29%).