Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:27][CH3:28])=[C:10]([CH2:19][NH:20][C:21](=[O:26])[CH2:22][C:23](O)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:29][C:30]1[CH:31]=[C:32]([CH2:37][NH2:38])[CH:33]=[CH:34][C:35]=1[F:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[Br:29][C:30]1[CH:31]=[C:32]([CH2:37][NH:38][C:23](=[O:24])[CH2:22][C:21]([NH:20][CH2:19][C:10]2[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]3=[N:8][C:9]=2[CH2:27][CH3:28])=[O:26])[CH:33]=[CH:34][C:35]=1[F:36]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)O
Reactant: NCc1ccc(F)c(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(F)c(Br)c1
Yield: 106.3 %

Procedure:
A solution of 3-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3-oxopropanoic acid (0.600 g, 1.541 mmol), 1-(3-bromo-4-fluorophenyl)methanamine (0.432 g, 1.796 mmol), HATU (0.760 g, 1.999 mmol) and triethylamine (0.600 mL, 4.30 mmol) in dichloromethane (35 mL) was stirred overnight at room temperature. The solution was diluted with DCM, washed with saturated NaHCO3, water followed by saturated NaCl, and dried over Na2SO4. The organic layer was evaporated to a pale amber residue. This was purified on 80 g. Combi-Flash column with DCM [0-8% MeOH] to give N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}propanediamide (942.9 mg, 106%, containing 12% impurities). LC-MS m/z 575.3 (M+H)+, 0.84 min (ret time).
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:19][CH3:20])[C:5](=[O:18])[CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([NH:16][CH3:17])[CH2:12][CH2:11]1)[CH3:3].CCN(C(C)C)C(C)C.[F:30][C:31]([F:43])([F:42])[C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:19]([N:4]([CH2:2][CH3:3])[C:5](=[O:18])[CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([N:16]([CH3:17])[S:38]([C:35]2[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:42])[F:43])=[CH:37][CH:36]=2)(=[O:40])=[O:39])[CH2:14][CH2:15]1)[CH3:20]
Reactant: CCN(CC)C(=O)CCCC[C@H]1CC[C@H](NC)CC1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C(=O)CCCC[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.8 g (2.6 mmol) trans-5-(4-Methylamino-cyclohexyl)-pentanoic acid diethylamide. hydrochloride in 20 ml CH2Cl2 was treated with 1.1 ml (6.3 mmol, 2.4 eq) Huenig's base, 706 mg (2.9 mmol, 1.1 eq) 4-(Trifluoromethyl)benzenesulfonyl chloride in 10 ml CH2Cl2 and 32 mg (0.26 mmol, 0.1 eq) DMAP. The solution was stirred at RT over night. Additonal 1.1 ml (6.3 mmol) Huenig's base, 706 mg (2.9 mmol) 4-(Trifluoromethyl)benzenesulfonyl chloride in 10 ml CH2Cl2 and 32 mg (0.26 mmol) DMAP were added and stirring was continued for 3 h. The mixture was partitioned between CH2Cl2 and a saturated aqueous solution of NaHCO3. The organic phase was washed with water, 1M KHSO4 and brine, dried over Na2SO4 and evaporated. Column chromatography with EtOAc/hexane 1:1 gave 1.06 g (84%) trans-5-{4-[Methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyl}-pentanoic acid diethylamide as colorless oil, MS: 477 (MH+).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].Cl.Cl.[CH2:7]([N:9]([CH2:31][CH3:32])[CH2:10][CH:11]([N:13]1[C:26]2[CH:25]=[C:24]([C:27](=[NH:30])OC)[CH:23]=[CH:22][C:21]=2[S:20][C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])[CH3:8].O>CO>[CH2:7]([N:9]([CH2:31][CH3:32])[CH2:10][CH:11]([N:13]1[C:26]2[CH:25]=[C:24]([C:27]([NH:4][CH2:1][CH2:2][CH3:3])=[NH:30])[CH:23]=[CH:22][C:21]=2[S:20][C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])[CH3:8]
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(=N)OC)cc21
Reactant: CCCN
Agent: Cl
Solvent: O
Solvent: CO
Product: CCCNC(=N)c1ccc2c(c1)N(C(C)CN(CC)CC)c1ccccc1S2
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A solution of propylamine (1.95 cc) in methanol (5 cc) is added dropwise in the course of 5 minutes to a solution, cooled to 0°-5° C., of methyl 10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarboximidate dihydrochloride (3.49 g) in methanol (21 cc). The mixture is stirred for 2 hours at 5° C. and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give a residue which is taken up with distilled water (50 cc). The solution is washed with distilled water (50 cc) alkalinized to pH 9 with N sodium hydroxide. The two phases are allowed to settle and the organic phase is separated and washed with half-saturated (sodium chloride) solution (50 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The residue is purified by chromatography on neutral alumina (height: 20 cm; diameter: 2.1 cm), eluting with pure ethyl acetate (375 cc) and finally with mixtures of ethyl acetate and methanol in proportions (by volume) of 99:1 (375 cc), 98:2 (500 cc), 95:5 (500 cc), 90:10 (500 cc) and 80:20 (500 cc) and collecting 25-cc fractions. Fractions 40 to 70 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give 10-[(2RS)-1-diethylamino-2-propyl]-N-propyl-2-phenothiazinecarboxamidine (1.49 g) in the form of a yellow product of meringue-like consistency.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[F:7][C:8]([F:15])([F:14])[C:9]([F:13])=[C:10]([F:12])[F:11].CC(C)C>>[F:11][C:10]([CH:1]1[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)([F:12])[CH:9]([F:13])[C:8]([F:15])([F:14])[F:7]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: C1=CCCCC1
Agent: CC(C)C
Product: FC(C(F)(F)F)C(F)(F)C1C=CCCC1
Yield: 60.5 %

Procedure:
Cyclohexene (2.8 g., 34.2 mmole) and hexafluoropropene (1.71 g., 11.4 mmole), heated at 320° for 4 days in a Pyrex ampoule gave: (i) hexafluoropropene (0.06 g., 0.40 mmole; 4% recovery), (ii) cyclohexene (1.9 g., 23.2 mmole; 67% recovery), b.p. 83°, (iii) a liquid mixture (2.5 g.), b.r. 50°-110°/13 mm. Hg., from which was isolated (preparative g. l. c.) 3-(1,1,2,3,3,3-hexafluoropropyl)-cyclohexene (1.6 g., 6.9 mmole; 63% based on C3F6 consumed). Found: C, 47.0; H, 4.3; F, 48.5%; M (mass spectrometry), 232. C9H10F6 requires C, 46.6; H, 4.3; F, 49.1%; M, 232, b.p. 160°-161° C.
Reaction SMILES: [C:1]1([N:7]=[C:8]2[NH:12][CH2:11][CH2:10][NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C1COCC1.CCCCCC>[S:24]([N:12]1[CH2:11][CH2:10][NH:9][C:8]1=[N:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25]
Reactant: c1ccc(N=C2NCCN2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)N2CCNC2=Nc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
2-(Phenylimino)imidazolidine (0.773 g, 4.8 mmoles) is dissolved in dry THF (15 ml), cooled to -78° C. under nitrogen protected from moisture and 2.4 N butyllithium in hexane (2.0 ml) is added. Then p-toluenesulfonyl chloride (0.953 g, 5 mmoles) in THF (3 ml) at -78° C. is added. The mixture is stirred for 90 minutes and allowed to warm to ambient temperature. The volatiles are evaporated in vacuo and water and ether are added. Crystals separate in the ether layer which are filtered and recrystallized from isopropanol to remove some bistosyl derivative. The major product, confirmed by n.m.r is N'-Tosyl-2-(phenylimino)imidazolidine, (610 mg, 40%), m.p. 174°-177° C.
Reaction SMILES: CC([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH2:7][C@H:8]([C:10]1[N:11]([CH3:29])[C:12](=[O:28])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[OH:9])(C)C.[CH3:42][C:43](=[CH2:45])[CH3:44].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O1CCCC1>ClCCl>[C:43]([O:9][C@@H:8]([C:10]1[N:11]([CH3:29])[C:12](=[O:28])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][OH:6])([CH3:45])([CH3:44])[CH3:42]
Reactant: Cc1ccc(-c2c([C@H](O)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)n(C)c(=O)c3ccccc23)cc1C
Reactant: C=C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(-c2c([C@@H](CO)OC(C)(C)C)n(C)c(=O)c3ccccc23)cc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.6 %

Procedure:
A −78° C. suspension of 3-((1S)-2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-1-hydroxyethyl)-4-(3,4-dimethylphenyl)-2-methyl-1(2H)-isoquinolinone (12 mg, 0.021 mmol) and amberlyst 15 resin (6 mg, 0.036 mmol) in Dichloromethane (DCM) (290 μl) was treated with isobutylene until the volume approximately doubled. The reaction mixture was sealed and allowed to warm to ambient temperature. After 48 h, the reaction mixture was cooled to −78° C. and then opened to the atmosphere. The reaction mixture was filtered through a short pad of silica and rinsed with EtOAc. The filtrate was concentrated in vacuo. The residue was dissolved in Tetrahydrofuran (THF) (290 μl) and treated with 1.0 M TBAF in THF (145 μl, 0.145 mmol). After 2 h, the reaction mixture was filtered through a short pad of silica gel and washed with EtOAc. The filtrate was concentrated in vacuo and purified by reverse phase hplc to afford the title compound (6 mg, 0.016 mmol, 43.6% yield) as a white solid: Rt=1.02, ES+ MS: 380 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+]([O-])=O)=[C:8]([S:10]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[CH3:23][S-:24].[Na+].C(O)(=O)C>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:24][CH3:23])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: C[S-]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cncc(Br)c2)c([N+](=O)[O-])s1
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cc(S(=O)(=O)c2cncc(Br)c2)c(SC)s1

Procedure:
The procedure described in Example 27: step a was followed using 4-(5-Bromo-pyridine-3-sulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (151 mg, 0.37 mmol, Example 127: step c) and sodium thiomethoxide (1.0 M in EtOH, 26.3 mg, 0.37 mmol). The reaction was quenched with acetic acid (21 uL, 0.37 mol) and the solvents were removed in vacuo. The residue was then dissolved into EtOAc and washed with saturated NaHCO3 and brine solutions. The organic layer was dried (Na2SO4) and removal of the solvents in vacuo was followed by purification by flash column chromatography SiO2 (30% EtOAc in hexanes) to yield the title compound. ESI-MS (m/z): Calcd. for C12H10BrNO4S3: 407.9 (M+1) found: 408.1.
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=2[NH:7][CH:6]=1)C.[N+:16]([CH:19]([CH3:21])[CH3:20])([O-:18])=[O:17]>>[CH3:15][O:14][C:11]1[CH:10]=[C:9]2[C:8](=[CH:13][CH:12]=1)[NH:7][CH:6]=[C:5]2[CH2:4][C:19]([CH3:21])([N+:16]([O-:18])=[O:17])[CH3:20]
Reactant: CC(C)[N+](=O)[O-]
Reactant: COc1ccc2[nH]cc(CN(C)C)c2c1
Product: COc1ccc2[nH]cc(CC(C)(C)[N+](=O)[O-])c2c1

Procedure:
This material was prepared by the reaction of 5-methoxygramine (Procedure 69B) and 2-nitropropane substantially as described in Procedure 67C. The product was initially recovered as a dark oil which crystallized from i-Pr2O solution after treatment thereof with activated carbon, yield 31.3 g. (from 33 g. of 5-methoxygramine), m.p. 83°-85°. The identity of the product was confirmed by inspection of its NMR spectrum.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH:16]2[CH2:18][CH2:17]2)C(=O)OC(C)(C)C)[N:5]2[N:19]=[CH:20][C:21](/[CH:22]=[C:23]3\[NH:24][C:25](=[O:29])[NH:26][C:27]\3=[O:28])=[C:4]2[N:3]=1.[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[OH:39])[C:34]#[N:35].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[O:39][C:2]1[CH:7]=[C:6]([NH:8][CH:16]2[CH2:18][CH2:17]2)[N:5]2[N:19]=[CH:20][C:21](/[CH:22]=[C:23]3\[NH:24][C:25](=[O:29])[NH:26][C:27]\3=[O:28])=[C:4]2[N:3]=1)[C:34]#[N:35]
Reactant: N#Cc1ccc(O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N(c1cc(Cl)nc2c(/C=C3\NC(=O)NC3=O)cnn12)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2cc(NC3CC3)n3ncc(/C=C4\NC(=O)NC4=O)c3n2)c(Cl)c1
Reaction time: 24 h
Yield: 57.4 %

Procedure:
(Z)-tert-butyl 5-chloro-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (75 mg, 0.18 mmol) was dissolved in anhydrous DMF (0.6 mL). 3-chloro-4-hydroxybenzonitrile (41 mg, 0.27 mmol) and K2CO3 (75 mg, 0.54 mmol) were added. After 24 h, H2O (3.5 mL) was added to the reaction and the bright yellow precipitate was filtered and dried. The crude solid was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL). After 1 h, the reaction was concentrated to dryness and the residue was triturated with Et2O (3 mL) and filtered to provide (Z)-3-chloro-4-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yloxy)benzonitrile (45 mg, 57% over two steps) as a bright yellow solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([CH2:21]O)[CH:18]=[CH:17][N:16]=1.S(Cl)([Cl:25])=O>>[Cl:25][CH2:21][C:19]1[CH:18]=[CH:17][N:16]=[C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])[CH:20]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(CO)ccn1
Product: Cc1oc(-c2ccccc2)nc1COc1cc(CCl)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A mixture of 2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-4-pyridylmethanol (1.19 g) and thionyl chloride (4 ml) was stirred at room temperature for 1 hour. After the reaction mixture was concentrated, saturated aqueous sodium bicarbonate solution was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 4-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (680 mg, yield 54%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 104–105° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)N.N(OCCC(C)C)=O.[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCCCCCC>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccccc1
Reactant: Cc1c(N)cccc1Cl
Agent: CC(C)CCON=O
Solvent: CCCCCCC
Product: Cc1c(Cl)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.6 %

Procedure:
During a 45 minute period 3-chloro-2-methylaniline (141.6 g, 1.0 mole) was added to a stirred solution of isoamyl nitrite (175.6 g, 1.5 moles) in benzene (842 g, 10.0 moles). The reaction mixture was stirred at room temperature for two hours, heated at reflux for one hour, then cooled to room temperature. Approximately 2 l of n-heptane was added to the reaction mixture. Most of the solvents were distilled from the mixture under reduced pressure, followed by distillation at atmospheric pressure (until a head temperature of 95° was reached). The pot residue was dissolved in 2 l of n-heptane and the solution filtered through 250 g of silica gel. The filtrate was subjected to column chromatography on 250 g of silica gel, elution with n-heptane, to give an oil. The oil was rechromatographed on 250 g of silica gel, elution with n-heptane, to give an oil. The oil was distilled in a Kugelrohr distillation apparatus (90°/0.05 mm) to give 3-chloro-2-methyl-[ 1,1'-biphenyl] (23.5 g) as an oil.
Reaction SMILES: C(C1N=C(N2CC[C@H](O)C2)C2C(=NN(CC3C(C)=NON=3)N=2)N=1)(C)(C)C.[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([O:45]C(=O)C(F)(F)F)[CH2:41]2)[C:34]2[N:39]=[N:38][NH:37][C:35]=2[N:36]=1)([CH3:30])([CH3:29])[CH3:28].[Cl:52][C:53]1[C:54]([CH2:60]Cl)=[N:55][C:56]([Cl:59])=[CH:57][CH:58]=1>>[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41]2)[C:34]2[C:35](=[N:37][N:38]([CH2:60][C:54]3[C:53]([Cl:52])=[CH:58][CH:57]=[C:56]([Cl:59])[N:55]=3)[N:39]=2)[N:36]=1)([CH3:29])([CH3:30])[CH3:28]
Reactant: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Reactant: ClCc1nc(Cl)ccc1Cl
Agent: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Product: CC(C)(C)c1nc(N2CC[C@H](O)C2)c2nn(Cc3nc(Cl)ccc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 3,6-dichloro-2-(chloromethyl)pyridine and isolated as light yellow gum. MS (m/e): 422.3 (MH+).
Reaction SMILES: [Mg].[CH3:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1.BrCCBr.[Br-].[CH2:22](Br)[CH:23]=[CH2:24]>O1CCCC1.C(OCC)C.C1C=CC=CC=1>[CH3:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:24][CH:23]=[CH2:22])=[CH:12][CH:11]=1
Reactant: C=CCBr
Reactant: COCCOCCOc1ccc(Br)cc1
Agent: [Br-]
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCc1ccc(OCCOCCOC)cc1
Temperature: -78 °C
Yield: 47.1 %

Procedure:
Magnesium turnings (0.83g, 0.032 mol) and 10 mL of anhydrous tetrahydrofuran (THF) were placed in a dry 3-necked round bottom flask. The mixture was stirred under reflux in an argon atmosphere for about 20 minutes. The previously prepared 4-[2-(2-methoxyethoxy)ethoxy]bromobenzene (7-Og, 0.025 mol) in 30 mL of anhydrous THF was slowly dripped into the stirring magnesium mixture. A small amount (about 0.1 mL) of 1,2-dibromoethane was initially added to start the Grignard reaction. After the bromide was added, the mixture was refluxed overnight under an argon atmosphere. The mixture was then cooled to -78° C. and 15 mL (0.17 mol) of allyl bromide in 30 mL of spectral grade benzene was added. The resulting mixture was stirred and allowed to slowly warm to room temperature and then refluxed overnight. The mixture was cooled and exacted with ethyl ether. The ethyl ether layer was washed with aqueous 3N hydrochloric acid, aqueous saturated brine and then with water until the organic layer was neutral. The ethyl ether solution was dried over anhydrous magnesium sulfate and the solvent was removed. The product was distilled to give 2.78 g (47%) of the desired 3-(4-[2-(2-methoxyethoxy) ethoxy]phenyl]-1-propene, bp 105°-113° C./0.2mm; NMR(δ): 3.30(2H,d), 3.36(3H,s), 3.46-3.92(6H,m), 4.12(2H,m), 5.00(2H,m), 5.95(1H,m), 6.80(2H,d), 7.04(2H,d).
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[C:6]([N:11]2[C:15]([C:16]([NH:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[C:27](=O)[C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[O:17])=[CH:14][C:13]([C:36]([F:39])([F:38])[F:37])=[N:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1.C([O-])(=O)C.[Na+]>O.C(O)C>[Cl:4][C:5]1[C:6]([N:11]2[C:15]([C:16]([NH:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3/[C:27](=[N:2]/[OH:3])/[C:28]([N:30]([CH2:31][CH3:32])[CH2:33][CH3:34])=[O:29])=[O:17])=[CH:14][C:13]([C:36]([F:38])([F:37])[F:39])=[N:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCN(CC)C(=O)C(=O)c1cc(C)cc(C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCN(CC)C(=O)/C(=N\O)c1cc(C)cc(C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C

Procedure:
A solution of hydroxylamine hydrochloride (50 mg, 0.71 mmol) in water (0.5 mL) was added to a solution of 1-(3-chloro-2-pyridinyl)-N-[2-[(diethylamino)oxoacetyl]-4,6-dimethylphenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (i.e. the title product of Example 2, 124 mg, 0.24 mmol) in ethanol (5 mL) at 25° C. The resulting mixture was treated with a solution of sodium acetate (200 mg) in water (2 mL). The resulting mixture was heated at reflux for 3 days and then cooled to 25° C., diluted with ethanol (30 mL) and concentrated onto silica gel (0.5 g). The residue was purified by flash chromatography on silica gel eluted with 35% ethyl acetate in hexanes to give 50 mg of the title product, a compound of the present invention, as a yellow glassy solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH:11]([C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:19])[OH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CS(C)=O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9][CH2:10][C:11]([C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25]([NH:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])=[O:19])=[O:12])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCC(O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)OCCC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 37.2 %

Procedure:
A sulfur trioxide-pyridine complex (985 mg) was added to a solution of (S)-2-[[(S)-2-[3-(tert-butyldimethylsilyloxy)-1-hydroxypropyl]-1-pyrrolidinyl]carbonyl]-N-(phenylmethyl)-1-pyrrolidinecarboxamide (1.01 g) in a mixture of toluene (2 ml), DMSO (3 ml) and triethyl amine (0.94 ml), under ice-cooling, and the mixture was stirred for 3 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with 10% citric acid, water, saturated sodium hydrogencarbonate, 1% hypochlorous acid, and water in order, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent: chloroform-methanol) to give (S)-2[[(S)-2-[3-(tert-butyldimethylsilyloxy)-1-oxopropyl]-1-pyrrolidinyl]carbonyl]-N-(phenylmethyl)-1-pyrrolidinecarboxamide (374 mg) and the title compound (280 mg) (see Table 5).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C:13](=O)[CH2:14]2)[N:11]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:9])#[N:2].Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>C(O)C.O>[C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12](/[C:13](=[N:26]/[OH:27])/[CH2:14]2)[N:11]1[C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])=[O:9])#[N:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](CC2=O)[C@H]1C(=O)N1CCC[C@H]1C#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C/C2=N\O)[C@H]1C(=O)N1CCC[C@H]1C#N
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
To a solution of tert-butyl (1R,3S,4S)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-6-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 22-1 (296 mg) in ethanol (5 mL) and water (1 mL),were added hydroxylamine hydrochloride (123 mg) and sodium acetate (153 mg). The mixture was stirred at 80° C. for 20 minutes.