Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][CH3:25])[CH2:19][CH2:18][CH2:17]4)=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[CH3:2].C1(Cl)C(=O)C(Cl)=C(Cl)C(=[O:29])C=1Cl>C(O)C>[CH2:24]([N:20]1[C:21]2[C:16](=[CH:15][C:14]([C:13]([C:9]3[CH:8]=[C:7]4[C:12](=[CH:11][CH:10]=3)[N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6]4)=[O:29])=[CH:23][CH:22]=2)[CH2:17][CH2:18][CH2:19]1)[CH3:25]
Reactant: CCN1CCCc2cc(Cc3ccc4c(c3)CCCN4CC)ccc21
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CCO
Product: CCN1CCCc2cc(C(=O)c3ccc4c(c3)CCCN4CC)ccc21
Temperature: 25 °C
Yield: 36.4 %

Procedure:
To 400 ml absolute ethanol was added with stirring 16 g (0.0478 mole) bis-(N-ethyl-1,2,3,4-tetrahydro-6-quinolyl)methane, prepared as described in A, and 23.82 g chloranil. The green mixture was heated to reflux for 1 hour, cooled to room temperature over 1 hour and rotary evaporated to dryness. The residue was taken up in methylene chloride and eluted through neutral Woelm Alumina. A red solid remained on the top of the column. The fractions were rotary evaporated to dryness and the oil taken up in ethanol to yield light yellow crystals which were collected by filtration to give 6.06 g, mp 120°-120.5° C. (36.4% yield). An ultraviolet spectrum in ethanol gave a λmax of 382 nm. ε was 40,500.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25](O)=[O:26])[CH:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][NH:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([CH2:25][OH:26])[CH:20]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(NCC2CCN(C(=O)OCc3ccccc3)CC2)ccn1
Agent: B
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(CNc2ccnc(CO)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of 4-[(1-benzyloxycarbonyl-piperidin-4-ylmethyl)-amino]-pyridine-2-carboxylic acid (0.59 gm, 0.0016 mol) in THF (2 mL) under nitrogen was added a solution of 1.0M borane-tetrahydrofuran (6 mL) and the mixture allowed to stir at room temperature for 1 h. The reaction was cooled to 0° C., quenched with 1N HCl (10 mL), concentrated and diluted with 10% aqueous sodium bicarbonate. Extraction with dichloromethane (2×50 mL)and concentration of the organic layer gave 540 mg of crude material. Column chromatography using dichloromethane/methanol/ammonium hydroxide—90/10/2 and crystallization from diethyl ether gave 4-[(2-hydroxymethyl-pyridin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH3:19])[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:25]=[CH:24][N:23]([CH2:26][C:27]([CH3:30])([OH:29])[CH3:28])[N:22]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH3:19])[CH:13]=[N:12]2)[C:8]([NH:20][C:21]2[CH:25]=[CH:24][N:23]([CH2:26][C:27]([OH:29])([CH3:28])[CH3:30])[N:22]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: COc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Product: COc1cnn(C(CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)c(=O)c1
Yield: 29 %

Procedure:
Using the method described in Example 80, Step 3,3-cyclopentyl-2-(4-methoxy-6-oxo-6H-pyridazin-1-yl)-propionic acid (as prepared in Example 80, Step 2) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methoxy-6-oxo-6H-pyridazin-1-yl)-propionamide as an off-white solid (45.1 mg, 29%); ES+-HRMS m/e calcd for C20H29N5O4 [M+H+] 404.2293 found 404.2292. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.04 (m, 1H), 1.05 (s, 3H), 1.06 (s, 3H), 1.18-1.77 (m, 8H), 1.91 (m, 1H), 2.26 (m, 1H), 3.81 (s, 3H), 3.89 (s, 2H), 4.67 (s, 1H), 5.46 (dd, J=4.1, J=11.3 Hz, 1H), 6.29 (d, J=2.7 Hz, 1H), 6.39 (s, 1H), 7.52 (s, 1H), 7.84 (d, J=2.7 Hz, 1H), 10.73 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Br[C:29]1[CH:34]=[C:33]([CH3:35])[N:32]=[C:31]([CH3:36])[CH:30]=1>>[CH3:36][C:31]1[CH:30]=[C:29]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:12][C:11]3=[O:27])[CH3:9])=[CH:4][CH:3]=2)[CH:34]=[C:33]([CH3:35])[N:32]=1
Reactant: Cc1cc(Br)cc(C)n1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc(C)n1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-bromo-2,6-dimethylpyridine in Step 4. LC-MS Method 2 tR=1.049, m/z=459.1; 1H NMR (CD3OD) 0.94 (s, 3H), 1.24 (s, 3H), 1.55 (d, 3H), 2.15 (s, 2H), 2.23 (m, 1H), 2.45 (m, 1H), 2.51 (s, 6H), 3.05 (m, 1H), 5.57 (m, 1H), 7.04 (d, 2H), 7.24 (s, 2H), 7.26-7.38 (m, 5H), 7.45 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:9])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[CH2:11][CH2:12][N:13]([CH2:21][CH2:22]Cl)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17]>C(N(C(C)C)CC)(C)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1([N:9]2[CH2:22][CH2:21][N:13]([C:14]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:20])[CH2:12][CH2:11]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(N)CC1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)C1(N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-aminocyclopropane-1-carboxylic acid ethyl ester (440 mg, 2.6 mmol) was suspended in diisopropylethylamine (2 ml). Tert-Butyl bis(2-chloroethyl)carbamate (610 mg, 2.5 mmol, prepared according to Evans et al. J. Med. Chem. 1992, 35, 3919) was added at room temperature. The suspension was stirred at room temperature for 10 minutes before being heated to 100° C. for 18 h. The resulting biphasic mixture was cooled to room temperature. Brine was added and the mixture was extracted three times with EtOAc. Combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 20% EtOAc/hexanes) to give tert-butyl 4-(1-(ethoxycarbonyl)cyclopropyl)piperazine-1-carboxylate as a colorless oil (60 mg, 8% 2 steps). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm: 0.91 (m, 2 H), 1.22 (t, J=7.2 Hz, 3 H), 1.25 (m, 2H), 1.43 (s, 9 H), 2.87 (bs, 4 H), 3.27 (bs, 4 H), 4.09 (q, J=7.2 Hz, 2 H); 13C NMR (100 MHz, CHLOROFORM-D) δ ppm 14.3, 19.0, 28.4, 45.7, 49.0, 60.2, 79.4, 154.8, 174.0; ESI-MS: m/z 299.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]([CH:20]2[CH2:22][CH2:21]2)[CH2:18][CH3:19])[C:11]=1[N+:23]([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]([CH:20]2[CH2:21][CH2:22]2)[CH2:18][CH3:19])[C:11]=1[NH2:23]
Reactant: CCC(Nc1nccc(-c2ccc(OC)cc2Cl)c1[N+](=O)[O-])C1CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CCC(Nc1nccc(-c2ccc(OC)cc2Cl)c1N)C1CC1
Yield: 89.8 %

Procedure:
[4-(2-Chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine (0.17 g, 0.47 mmol) and Na2S2O4 (0.66 g, 3.79 mmol) were treated substantially as described in Part E of Example 9 to give 0.14 g (88%) crude 4-(2-chloro-4-methoxy-phenyl)-N2-(1-cyclopropyl-propyl)-pyridine-2,3-diamine: MS (AP) m/z 331.8 [(M+H)+, 100].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:15]([CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:2][CH2:3][CH2:4][C:5]#[N:6])=[CH:9][CH:10]=1)#[N:16]
Reactant: N#CCc1ccc(O)cc1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCCCOc1ccc(CC#N)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 26.6 %

Procedure:
12.2 g (82.6 mmol) of 4-bromobutyronitrile, 10 g (95.1 mmol) of (4-hydroxyphenyl)acetonitrile and 31.1 g (225 mmol) of potassium carbonate are dissolved in 100 mL of DMF. The mixture is heated to 80° C. overnight. After 20 hours, the reaction mixture is partitioned between EtOAc and water. The organic phase is washed repeatedly with brine, dried over sodium sulphate, filtered and concentrated by rotary evaporation. Purification by column chromatography on silica gel using ethylacetate:hexane 1:1 as eluent yields to 4.4 g of 4-[4-(cyanomethyl)phenoxy]butanenitrile as a thick yellow oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:13][C@H:10]1[CH2:11][CH2:12][C@@H:7]([CH3:6])[CH2:8][CH2:9]1)(=[O:4])=[O:3]
Reactant: C[C@H]1CC[C@@H](O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CC[C@@H](C)CC1
Temperature: 0 °C

Procedure:
Methanesulfonyl chloride (19.3 mL) was slowly added dropwise to a solution of cis-4-methylcyclohexanol (14.2 g) and triethylamine (34.5 mL) in methylene chloride (250 mL) with stirring at 0° C. The mixture was heated to room temperature, stirred for 3 hours, and then separated into aqueous and organic layers by the addition of water, followed by extraction with methylene chloride. The organic layer was washed with saturated sodium bicarbonate and saturated sodium chloride solution and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product of cis-4-methylcyclohexyl methanesulfonate (approximately 24 g) was used without further purification in the next reaction. Cesium carbonate (60.1 g) and cis-4-methylcyclohexyl methanesulfonate (approximately 24 g) were added to a solution of ethyl 1H-imidazol-4-ylacetate (9.48 g) in N,N-dimethylformamide (120 mL). The mixture was stirred at 110° C. for 9 hours and then separated into aqueous and organic layers by the addition of water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain the title compound (1.77 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[N:5]=[C:4]([NH2:17])[N:3]=1.Cl.[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>C(O)C.O1CCOCC1>[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=3[O:15][CH3:16])[N:5]=[C:4]([NH2:17])[N:3]=2)=[CH:22][CH:21]=1
Reactant: Nc1ccc(Br)cc1
Reactant: COc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccc(Cl)cc1-c1cc(Nc2ccc(Br)cc2)nc(N)n1
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a stirred suspension of 4-chloro-6-(5-chloro-2-methoxy-phenyl)-pyrimidin-2-yl-amine (0.054 g, 0.20 mmol) in ethanol (7.5 ml) was added a solution of hydrogen chloride in dioxane (4.0 M, 0.025 ml) followed by 4-bromoaniline (0.069 g, 0.40 mmol). After heating under reflux for 45 minutes, volatiles were removed under reduced pressure. The residue was treated with 1.0 M hydrochloric acid (10 ml) and stirred for 30 minutes. Filtration provided the hydrochloride salt of the title compound (0.08 g, 90% yield). 1H NMR (DMSO-d6) δ 3.90 (s, 3H, CH3), 6.71 (s, 1H, Ar), 7.30 (d, 1H, J=9.0 Hz, Ar), 7.57-7.59 (m, 2H, Ar), 7.65 (dd, 1H, J=9.0 Hz, J=2.4 Hz, Ar), 7.70 (d, 1H, J=2.4 Hz, Ar), 7.80-7.86 (m, 2H, Ar), 11.08 (s, 1H, NH).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9](=O)[N:8]([CH3:21])[C:6]=2[N:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>N1C=CC=CC=1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9](=[S:31])[N:8]([CH3:21])[C:6]=2[N:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(N)nc21
Solvent: c1ccncc1
Product: Cn1c(=S)c(-c2c(Cl)cccc2Cl)cc2cnc(N)nc21
Reaction time: 24 h

Procedure:
A mixture of 0.321 g (1.0 mmol) of 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-(8H)-one from Example 12 and 0.404 g (1.0 mmol) of Lawesson's Reagent in 10 mL of pyridine was heated at reflux with stirring for 24 hours. The solvent was evaporated under reduced pressure, and the residue was triturated with 20 mL of water, filtered, and the cake washed well with water. Purification was by silica gel chromatography to afford the desired compound identified as 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]-pyrimidin-7(8H)-thione.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:11]C(C)([O-])C.[K+].CI>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:11])[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: Ic1n[nH]c2ccccc12
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc(I)c2ccccc21
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 85.7 %

Procedure:
In a 50 ml round-bottomed flask, 3-iodo-1H-indazole (1.0 g, 3.9 mmol) was dissolved in THF (12 ml) and the solution was cooled to 0° C. Potassium tert-butoxide (612 mg, 5.45 mmol) was added and the reaction mixture was stirred at 0° C. for 1.25 h. Methyl iodide (0.29 ml, 4.64 mmol) was added dropwise then the ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over silica gel with EtOAc/Hexanes (gradient 0-10% EtOAc) to afford 863 mg (86%) of 3-iodo-1-methyl-1H-indazole as a yellow oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.42-7.53 (m, 2H), 7.33-7.40 (m, 1H), 7.22 (ddd, J=8.0, 6.9, 0.9 Hz, 1H), 4.11 (s, 3H).
Reaction SMILES: C[N:2]([CH3:12])[CH:3]=[C:4]([N+:10]#[C-:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:13]1(N)[CH2:16]C[CH2:14]1>>[CH2:8]([O:7][C:5]([C:4]1[N:10]=[CH:11][N:2]([CH:12]2[CH2:16][CH2:13][CH2:14]2)[CH:3]=1)=[O:6])[CH3:9]
Reactant: NC1CCC1
Reactant: [C-]#[N+]C(=CN(C)C)C(=O)OCC
Product: CCOC(=O)c1cn(C2CCC2)cn1

Procedure:
Ethyl 3-(dimethylamino)-2-isocyanoacrylate (WO 2007042545) (45 g, 0.27 mol) was added to cyclobutylamine (50 g, 0.70 mol) and heated to reflux for 2 hours. The solution was then cooled and concentrated. The residue was purified by column chromatography over silica gel (3:1 EtOAc:Heptane). The oily residue was triturated with TBME:heptane (1:1) and the resulting solid was collected and dried, giving 1-cyclobutyl-1H-imidazole-4-carboxylic acid ethyl ester (35 g, 67%, second crop not harvested). 1-Cyclobutyl-1H-imidazole-4-carboxylic acid ethyl ester (35 g, 0.21 mol) was dissolved in 6 N HCl (300 mL) and refluxed for 1 day. The solution was concentrated to dryness in vacuo. The solid was azeotroped with toluene, triturated with toluene and then dried under vacuum, giving the title compound 88% yield, 37.2 g, m/z 167 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([N:8]2[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]2)[O:6][CH:7]=1)#[N:2].[C:17]([O-:20])(=[S:19])[CH3:18].[K+]>CN(C)C=O>[C:17]([S:19][CH:10]1[CH2:9][N:8]([C:5]2[O:6][CH:7]=[C:3]([C:1]#[N:2])[N:4]=2)[CH2:11]1)(=[O:20])[CH3:18]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC1CN(c2nc(C#N)co2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C#N)co2)C1
Temperature: 80 °C
Reaction time: 5 h
Yield: 55.4 %

Procedure:
To a solution of 1-(4-cyano-1,3-oxazol-2-yl)-3-methanesulfonyloxyazetidine (309 mg, 1.27 mmol) (obtained as described in Reference Example 23(3)) in dimethylformamide (15 ml) was added potassium thioacetate (0.87 g, 7.62 mmol) at room temperature. The reaction mixture was stirred in an oil bath (80° C.) for 5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (2:1) as the eluant to afford 3-acetylthio-1-(4-cyano-1,3-oxazol-2-yl)azetidine (157 mg, yield 55%) as a colorless oil.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]([C:24]1[CH:25]=[C:26]([C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=1)[CH2:5][C:6]1[CH:23]=[CH:22][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[O:11])=[CH:8][CH:7]=1.Cl.[C:42]1([NH:48]N)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>[Cl-].[Cl-].[Zn+2].C(O)(=O)C>[NH:48]1[C:42]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:3]([CH:4]([C:24]2[CH:25]=[C:26]([C:30]3[CH:31]=[CH:32][C:33]([O:36][C:37]([F:38])([F:39])[F:40])=[CH:34][CH:35]=3)[CH:27]=[CH:28][CH:29]=2)[CH2:5][C:6]2[CH:7]=[CH:8][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:11])=[CH:22][CH:23]=2)=[CH:2]1
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(CC(CC=O)c2cccc(-c3ccc(OC(F)(F)F)cc3)c2)cc1
Reactant: NNc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: O=C(O)CCNC(=O)c1ccc(CC(c2cccc(-c3ccc(OC(F)(F)F)cc3)c2)c2c[nH]c3ccccc23)cc1
Temperature: 80 °C

Procedure:
A glacial acetic acid solution (4 mL) containing the intermediate from Step C (150 mg, 0.27 mmol), phenyl hydrazine hydrochloride (51 mg, 0.35 mmol) and ZnCl2 (110 mg, 0.81 mmol) was heated at 80° C. for 1 hour. The solution was concentrated and partitioned between aqueous 1N HCl and ethyl acetate. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by RP-HPLC and the isolated material was resolved using chiral OJ SFC-HPLC to give the title compounds. Isomer A: Chiral LC1 4.85 min, LCMS1 3.80 min. (M+H)=572. Isomer B: Chiral LC1 12.09 min, LCMS1 3.80 min. (M+H)=572. Representative 1H NMR (400 MHz, CD3OD): δ 7.58 (d, J=8.2 Hz, 2H); 7.47 (d, J=8.6 Hz, 2H); 7.37-7.14 (m, 11H); 7.01 (t, J=7.5 Hz, 1H); 6.85 (t, J=7.5 Hz, 1H); 4.57 (t, J=7.9 Hz, 1H); 3.63 (dd, J=6.7, 13.4 Hz, 1H); 3.56 (t, J=6.9 Hz, 2H); 3.36 (dd, J=9.1, 13.3 Hz, 1H); 2.57 (t, J=7.0 Hz, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:12](=S)[NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][NH2:17]>CC(O)C.C1COCC1>[CH2:1]([N:8]1[CH2:14][CH2:13]/[C:12](=[N:16]/[NH2:17])/[NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: S=C1CCN(Cc2ccccc2)CCN1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: N/N=C1/CCN(Cc2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound from Step A (1.00 g, 4.54 mmol) in 2-propanol (8.0 mL) and THF (20 mL), hydrazine (0.68 g, 21.7 mmol) was added. The mixture was stirred at room temperature overnight. The crude product was concentrated, and the residue purified by preparative TLC (silcia gel, 1:9 10% ammonium hydroxide in methanol:dichloromethane) to yield the desired compound.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[S:6]1([C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=[O:11])[NH:9]1)(=[O:8])=[O:7].[Na]>>[CH2:2]([N:9]1[C:10](=[O:11])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:8])=[O:7])[C:3]([CH3:4])=[O:5]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: CC(=O)CCl
Agent: [Na]
Product: CC(=O)CN1C(=O)c2ccccc2S1(=O)=O
Temperature: 110 °C
Yield: 73.6 %

Procedure:
26 ml (324 millimoles) of chloroacetone were slowly added dropwise to 40.0 g (200 millimoles) of sodium saccharin, while stirring (exothermic reaction). The temperature was gradually increased to 110° C., and the reaction mixture was stirred at this temperature for 5 hours, after which it was cooled. An excess of ice-water was added, and stirring was continued for a further hour. The precipitated solid was filtered off under suction, recrystallized from ethanol and dried in a drying oven under reduced pressure at 50° C. to give 35.2 g (74%) of N-acetonylsaccharin of melting point 142°-143° C.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:28][C:29](O)=[O:30])[CH:25]=[CH:26][CH:27]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: COc1cccc(CC(=O)O)c1
Product: COc1cccc(CC(=O)Nn2nc(-c3ccc(Cl)cc3)c3ccccc3c2=O)c1

Procedure:
The product of Example 86A and 2-(3-methoxyphenyl)acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.41-8.43 (m, 1H), 7.96-8.01 (m, 2H), 7.72-7.74 (m, 1H), 7.60-7.67 (m, 4H), 7.27 (t, J=7.9 Hz, 1H), 6.98 (d, J=2.4 Hz, 1H), 6.96 (d, J=7.6 Hz, 1H), 6.85 (dd, J=8.2, 2.6 Hz, 1H), 3.76 (s, 3H), 3.67-3.67 (bs, 2H; MS (ESI−) M/Z 418 (M−H)−.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH2:9][C@@H:4]([CH2:5][CH2:6][C@H:7]2[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:11])[N:3]1[O:19][S:20]([O-:23])(=[O:22])=[O:21].C([N+](CCCC)(CCCC)CCCC)CCC.FC(F)(F)C(O)=O>ClCCl>[O:1]=[C:2]1[N:8]2[CH2:9][C@@H:4]([CH2:5][CH2:6][C@H:7]2[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:11])[N:3]1[O:19][S:20]([OH:23])(=[O:22])=[O:21]
Reactant: O=C(NC1CCNCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CCNCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a solution of N,N,N-tributylbutan-1-aminium [({(2S,5R)-7-oxo-2-[(piperidin-4-ylamino)carbonyl]-1,6-diazabicyclo[3.2.1]oct-6-yl}oxy)sulfonyl]oxidanide (22.4 mg, 0.050 mmol) in anhydrous dichloromethane (2 mL) at 0° C. under nitrogen was added trifluoroacetic acid (0.1 mL, 1.298 mmol) dropwise. The reaction mixture was stirred for 1 hour then concentrated under vacuum. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was washed with ether (2× to afford the title compound contaminated with tetrabutylammonium hydrogen sulfate and pyridine. The solid was triturated with acetonitrile (2×) and the white solid was collected by centrifugation to afford the title compound as a white solid. LC-MS (negative ionization) m/e 347 (M−H); LC-MS (positive ionization) m/e 349 (M+H), 381 (M+Na); 1H NMR (600 MHz, D2O; unreferenced) (δ, ppm) 4.19 (1H, br d, J=2.5 Hz), 3.98-4.06 (2H, m), 3.47 (2H, br d, J=13 Hz), 3.31 (1H, br d, J=12 Hz), 3.12 (2H, br dd, J=13, 3 Hz), 3.06 (1H, d, J==12 Hz), 2.04-2.21 (m, 4H), 1.87-1.95 (1H, m), 1.72-1.83 (m, 3H).
Reaction SMILES: Cl(O)(=O)(=O)=O.C(O)C.[CH:9]1([C:12]2(N3CCCC3)[O:16][N:15]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:13]2)[CH2:11][CH2:10]1>O>[CH:9]1([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:13]=2)[CH2:11][CH2:10]1
Reactant: c1cncc(C2=NOC(C3CC3)(N3CCCC3)C2)c1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCO
Solvent: O
Product: c1cncc(-c2cc(C3CC3)on2)c1

Procedure:
A solution containing 1.43 g. of perchloric acid (70%) in 5 ml. of absolute ethanol is added dropwise with stirring to a solution of 2.57 g. of 3-[5-cyclopropyl-5-(1-pyrrolidinyl)-2-isoxazolin-3-yl]-pyridine in 25 ml. of absolute ethanol. The resulting solution is diluted with 25 ml. of water and then heated vigorously on a steam bath for 0.5 hours. The hot solution is poured directly onto 200 g. of ice. The precipitate is collected by filtration, washed well with water and air dried. This gives a white solid, melting point 72°-75°C. and the nmr spectrum δ6.82 (DMSO-d6, s, 4-isoxazolyl H).