Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[O:21]([CH2:28][CH2:29][NH2:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)C>[N+:18]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:30][CH2:29][CH2:28][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:10][CH:9]=[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:7]=2)([O-:20])=[O:19]
Reactant: NCCOc1ccccc1
Reactant: O=[N+]([O-])c1cnc2cc(-c3ccccc3)ccc2c1Cl
Solvent: CCOCC
Product: O=[N+]([O-])c1cnc2cc(-c3ccccc3)ccc2c1NCCOc1ccccc1
Yield: 100.3 %

Procedure:
4-Chloro-3-nitro-7-phenylquinoline (6.0 g, 21 mmol) was treated with 2-phenoxyethylamine (3.18 g, 23.2 mmol) according to the method described in Part A of Examples 125-135. The crude solid was triturated with water (100 mL), isolated by filtration, sonicated with diethyl ether, isolated by filtration, and dried for two hours in a vacuum oven at 40° C. to provide 8.12 g of (3-nitro-7-phenylquinolin-4-yl)-(2-phenoxyethyl)amine as a yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=O)[NH:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[CH3:1][C@H:2]1[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([F:17])([F:16])[F:18])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[CH2:5][NH:4][CH2:3]1
Reactant: C[C@@H]1CNC(=O)c2cc3ccc(C(F)(F)F)cc3n21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: C[C@@H]1CNCc2cc3ccc(C(F)(F)F)cc3n21
Reaction time: 2 h
Yield: 100.3 %

Procedure:
(R)-4-Methyl-7-trifluoromethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (2.75 g; 10 mmol) was dissolved in diethylether (200 mL) and lithium aluminium hydride (0.78 g, 21 mmol) was added in portions with cooling. The solution was stirred for 2 h at reflux temperature, cooled and hydrolyzed by sequential addition of water (3.0 mL), sodium hydroxide solution (15%, 6.0 mL) and water (6.0 mL). Diethylether was added (100 mL), the mixture was filtered and the filtrate evaporated. The residue was stirred with hexane (20 mL) and diethylether (1 mL) to give the title compound as white solid (2.55 g, 97%). M.p.: 123–125° C., ISP-MS: m/e=255.1 (M+), αD20=−110.0
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.C1(N)CCCCC1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH:14]([OH:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Cc1ccc(Cl)cc1-c1ccc(C(=O)CCC(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: NC1CCCCC1
Product: Cc1ccc(Cl)cc1-c1ccc(C(O)CCC(=O)O)cc1
Yield: 90 %

Procedure:
Prepared analogous to Example 25 from 4-(5'-chloro-2'-methyl-4-biphenylyl)-4-oxo-butyric acid. Yield: 90% of theory. Melting point of the cyclohexylamine salt: 114°-115° C. (from ethyl acetate).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][N:9]([CH3:31])[CH2:10][CH:11]([OH:30])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[ClH:32]>CC(C)=O.O1CCOCC1>[ClH:32].[C:4]([O:30][CH:11]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:10][N:9]([CH3:8])[CH3:31])(=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7]
Reactant: O=C1CCC(=O)O1
Reactant: CN(C)CC(O)COc1ccccc1CCCCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: CN(C)CC(COc1ccccc1CCCCc1ccccc1)OC(=O)CCC(=O)O
Yield: 93 %

Procedure:
0.57 g of succinic anhydride was added to a solution of 1.79 g of 3-dimethylamino-1-[2-(4-phenylbutyl)phenoxy]-2-propanol [prepared as described in Example 1(b)] in 50 ml of acetone, and the resulting mixture was heated under reflux for 2 hours. At the end of this time, the reaction mixture was cooled, and 1.5 ml of a 4N solution of hydrogen chloride in dioxane were added, and the mixture was allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo, to give 2.20 g (yield 93%) of the title compound as colorless crystals, melting at 123°-125° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[NH4+]=S.C(Cl)Cl.CO>C(O)C>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2]
Reactant: O=C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: Nc1cccc([N+](=O)[O-])c1C(=O)O

Procedure:
2,6-Dinitrobenzoic acid (0.5 g, 2.36 mmol) in ethanol (5 mL) was heated to 80° C. Ammonium sulfide (40-48% in water) (0.36 mL, 2.36 mmol) was then added (the yellow solution became a bright orange suspension) the mixture was heated under reflux for 0.5 h. TLC (DCM 80%, MeOH 20%) showed a faint spot below the starting material. Ammonium sulfide (3.6 mL, 20.4 mmol) was added and the mixture became a darker orange. This mixture was then heated under reflux for 1 h after which time TLC indicated that the reaction had gone to completion. The solvents were removed under reduced pressure and then the residue washed with methanol. The methanol solution was decanted off and evaporated to dryness to afford 2-nitro-6-amino benzoic acid as a orange solid. This was then purified using flash chromatography (DCM 90%/MeOH 10%->20% MeOH over 60CV, 12 g column) to afford the desired material (0.2 g, 46%).
Reaction SMILES: [NH:1]1[C:11]2[C:12]3[N:3]([CH2:4][CH2:5][NH:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)[C:2]1=O.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:2]1[N:3]2[CH2:4][CH2:5][NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([C:12]=32)[N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2cccc3c2n1CCN3
Product: Clc1nc2cccc3c2n1CCN3

Procedure:
3 g (0.0155 mol) of 5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-2(1H)-one in 60 ml of phosphoryl chloride are heated at the reflux temperature for 3 hours. The solvent is evaporated to dryness and the residue taken up successively in ice-cold water and in a concentrated aqueous ammonia solution. Extraction is then carried out twice with ether and the organic phases are combined, dried and evaporated to dryness. The residue is purified by chromatography on a column of silica gel, the eluent being ether. There are obtained 1.8 g of product in the oil form which is used as is in the following stage.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([F:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:42])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[O:32][N:31]=[C:30]([CH2:33][O:34]C3CCCCO3)[CH:29]=2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([F:17])=[CH:10][C:9]2[NH:18][C:19](=[O:42])[CH2:20][C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[O:32][N:31]=[C:30]([CH2:33][OH:34])[CH:29]=4)[CH:23]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(COC4CCCCO4)no3)c2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1F)NC(=O)CC(c1cccc(-c3cc(CO)no3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-dimethylamino-4-fluoro-2-(3-oxo-3-{3-[3-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-5-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert.-butyl ester (Example M40) (314 mg, 0.53 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (95 mg).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1.B(Br)(Br)Br>C(Cl)Cl.CO>[OH:2][C:3]1[CH:8]=[C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1
Reactant: COc1cc(C(=O)c2ccccc2)ccc1-c1cccc(C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Cc1cccc(-c2ccc(C(=O)c3ccccc3)cc2O)c1
Temperature: -78 °C
Reaction time: 12 h
Yield: 46.5 %

Procedure:
Ketone 17 was dissolved in dry DCM and the resulting solution was cooled to −78° C. BBr3 (1.5 eq, 0.49 mM) was then added drop wise and the reaction mixture was allowed to warm to room temperature and was stirred for an additional 12 hours. After the completion of the reaction as determined by TLC, the reaction mixture was diluted with methanol, and then washed with bicrab, water brine. The product was then subjected to column chromatography using 20% EtOAc/hexanes as the solvent system. Yield=46.5% (Rf=0.3 1; 20% EtOAc/Hexanes) 1H NMR, 300 MHz Varian, CDCl3 δ 7.88 (d, J=8.4 Hz, 2H), 7.59 (t, J=7.2 Hz, 1H), 7.54 (d, J=7.5 Hz, 1H), 7.47 (m, 2H), 7.43 (d, J=6.3 Hz, 2H), 7.38 (s, 1H), 7.34 (s, 2H), 7.27 (m, 1H), 2.46 (s, 3H), MS: m/z (ESI, pos.)=325.5 ([M+23]). HPLC retention time: 11.246 min. and 10.804 min; purity 97.92%.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:29][N:28]=[N:27][N:26]=3)=[CH:15][CH:14]=2)[C:8]([C:30]#[N:31])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C(O)(=[O:34])C>[OH-].[K+]>[CH2:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:29][N:28]=[N:27][N:26]=3)=[CH:17][CH:18]=2)[C:8]([C:30]([NH2:31])=[O:34])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C#N)c(NCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)n1
Reactant: CC(=O)O
Agent: [K+]
Agent: [OH-]
Product: CCCCc1ncc(C(N)=O)c(NCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)n1

Procedure:
2-Butyl-4-{N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}pyrimidine-5-carbonitrile, the product of Example 14, is heated in dilute aqueous potassium hydroxide. Neutralization with acetic acid affords the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[N:19](COCC[Si](C)(C)C)[N:20]=[C:21]([NH:22][CH:23]3[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]3)[C:11]=2[N:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[NH:19][N:20]=[C:21]([NH:22][CH:23]3[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:27][CH2:28]3)[C:11]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1nc(NC2CCN(S(C)(=O)=O)CC2)c2nc(-c3c(F)cccc3F)c3ccccc3c21
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2ccccc23)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 16.3 %

Procedure:
A 10 ml round-bottomed flask is charged with 71 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline in 3 ml of DCM. After cooling to 0° C. using an ice bath, 0.3 ml of TFA is added and the reaction mixture is stirred at RT for 16 h. It is concentrated under RP and the solid obtained is taken up in 20 ml of water and extracted with three times 20 ml of AcOEt. The organic phase is dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with DCM and with a mixture of DCM and methanol (95/5 by vol.), to give 9 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline (beige solid). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.67 (m, 2 H) 2.11 (m, 2 H) 2.88 (s, 3 H) 2.90 (m, 2 H) 3.56 (m, 2 H) 3.79 (broad s, 1 H) 6.04 (broad m, 1 H) 7.32 (m, 2 H) 7.52-7.74 (m, 3 H) 7.92 (m, 1 H) 8.40 (d, 1 H) 12.76 (broad s, 1 H); LC-MS-DAD-ELSD: 458 (+)=(M+H)(+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([NH2:7])[CH2:5][CH3:6].[C:8](#N)[CH3:9]>>[CH3:8][CH:9]1[NH:7][CH:4]([CH2:5][CH3:6])[CH2:3][CH2:2][NH:1]1
Reactant: CCC(N)CCN
Reactant: CC#N
Product: CCC1CCNC(C)N1
Reaction time: 21 h
Yield: 98 %

Procedure:
Sixty grams of 1,3-diaminopentane (96.7% purity, 0.569 mole), 60 g acetonitrile (1.46 moles) and 1 g of wet Raney® nickel (Raney 2800) catalyst were charged to a 300 ml stainless steel autoclave reactor. The mixture was stirred and heated at 90° C. and 500 psig hydrogen pressure for 6 hours. Capillary GC analysis of the cooled product indicated a 36% conversion of 1,3-diaminopentane and 97.4% yield of 2-methyl-4-ethylhexahydropyrimidine. The reactor was recharged with 25 ml (19.5 g) additional acetonitrile and run at 90° C. and 500 psig for 21 hours. Capillary GC analysis of the mixture indicated a 92.1% conversion of 1,3-diaminopentane and 98% yield of 2-methyl-4-ethylhexahydropyrimidine, b.p. 71° C./20 mm Hg. The structure was confirmed by comparison with a mass spectrum of the hexahydropyrimidine obtained by the condensation of 1,3-diaminopentane and acetaldehyde at 50° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([CH:21]=[C:22]1[S:26][C:25](=[S:27])[NH:24][C:23]1=[O:28])=[CH:10][CH:9]=2)(=[O:4])=[O:3].IC.[CH:31](N(C(C)C)CC)(C)C>C(#N)C>[CH3:1][S:2]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([CH:21]=[C:22]1[S:26][C:25]([S:27][CH3:31])=[N:24][C:23]1=[O:28])=[CH:10][CH:9]=2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cnc2ccc(C=C3SC(=S)NC3=O)cc2c1-c1ccccc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: CC#N
Product: CSC1=NC(=O)C(=Cc2ccc3ncc(S(C)(=O)=O)c(-c4ccccc4)c3c2)S1

Procedure:
Similar procedure as described in example 41b was used, starting from 5-(3-methanesulfonyl-4-phenyl-quinolin-6-ylmethylene)-2-thioxo-thiazolidin-4-one (example 61j), iodomethane, and DIEA (diisopropylethylamine) in acetonitrile to give 5-(3-methanesulfonyl-4-phenyl-quinolin-6-ylmethylene)-2-methylsulfanyl-thiazol-4-one. LC-MS m/e 441 (MH+).
Reaction SMILES: [SH:1][C:2]([CH3:14])([CH3:13])[CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][C:9]([CH3:12])([SH:11])[CH3:10].N.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CO>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][S:1][C:2]([CH3:14])([CH3:13])[CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][C:9]([CH3:12])([S:11][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH3:10])=[CH:20][CH:19]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(S)CNCCNCC(C)(C)S
Agent: N
Solvent: CO
Product: COc1ccc(CSC(C)(C)CNCCNCC(C)(C)SCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A solution of N,N′-bis(2-mercapto-2-methylpropyl)ethylenediamine (11.23 g, 47.5 mmol; see, DiZio et al., 1991, Bioconjugate Chem 2: 353 and Corbin et al., 1976, J. Org. Chem. 41: 489) in methanol (500 mL) was cooled in ice/water bath and then saturated with gaseous ammonia over 45 min. To this was added 4-methoxybenzyl chloride (17.0 mL, 125 mmol, 264 mol %). The reaction was allowed to warm to room temperature overnight with stirring under argon. The solution was concentrated to a paste and then partitioned between diethyl ether (150 mL) and 0.5 M KOH (200 mL). The aqueous layer was further extracted with diethyl ether (2×50 mL). The combined organic layers were washed with NaCl solution and concentrated to a clear colorless oil. The oil dissolved in diethyl ether (200 mL) and then acidified with 4.0 M HCl in dioxane until no further precipitation was seen. The white precipitate was collected by filtration and washed with diethyl ether. The white solid was recrystallized from hot water at a pH of ˜2. The product was collected by filtration to afford 29.94 g as a mix of mono- and di-HCl salts. The HCI salts were partitioned between 1 M KOH (100 mL) and ethyl acetate (100 nmL). The aqueous was extracted with ethyl acetate (2×30 mL) and the combined organic layers were washed with NaCl solution, dried with Na2SO4 and concentrated to give pure product as the free base as a light yellow oil (18.53 g, 82% yield). Nuclear magnetic resonance characterization experiments yielded the following molecular signature:
Reaction SMILES: C([S-])#N.[K+:4].[CH2:5]([O:12][CH:13]1[CH2:16][CH:15]([S:17]([O:20]CCCC)(=[O:19])=[O:18])[CH2:14]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(OCC)(=O)C>COCCOC.O.CCCCCC>[CH2:5]([O:12][CH:13]1[CH2:14][CH:15]([S:17]([O-:20])(=[O:19])=[O:18])[CH2:16]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[K+:4]
Reactant: CCCCOS(=O)(=O)C1CC(OCc2ccccc2)C1
Agent: N#C[S-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: O=S(=O)([O-])C1CC(OCc2ccccc2)C1
Yield: 65 %

Procedure:
KSCN (68 mg, 0.66 mmol) and butyl 3-(benzyloxy)cyclobutane-1-sulfonate (0.18 g, 0.604 mmol) in DME-water mixture (1:1 ratio, 4 mL) were heated at 85° C. overnight. The reaction was monitored by TLC (50% ethyl acetate in hexane). The reaction mass was concentrated under reduced pressure and the crude residue obtained was washed with ether to afford 0.11 g of the product (70% yield).
Reaction SMILES: [I:1][C@H:2]1[C@H:8]2[CH2:9][C@H:5]([C:6](=[O:10])[O:7]2)[CH2:4][CH2:3]1.[O:11]1CCCC1>O.Cl>[OH:7][C@H:8]1[C@H:2]([I:1])[CH2:3][CH2:4][C@@H:5]([C:6]([OH:10])=[O:11])[CH2:9]1
Reactant: O=C1O[C@@H]2C[C@H]1CC[C@H]2I
Reactant: C1CCOC1
Agent: Cl
Solvent: O
Product: O=C(O)[C@@H]1CC[C@@H](I)[C@H](O)C1

Procedure:
(1R*,4R*,5R*)-4-Iodo-6-oxabicyclo[3.2.1]octan-7-one (2.8 g) was dissolved in a mixed solvent of tetrahydrofuran (27 ml) and water (3 ml), concentrated hydrochloric acid (0.1 ml) was added, and the mixture was heated under reflux for 1 hour. The solvent was distilled off under reduced pressure to obtain (1R*,3R*,4R*)-3-hydroxy-4-iodocyclohexanecarboxylic acid (3.23 g) as a colorless solid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=1[O:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[F:28][C:13]([F:12])([F:27])[C:14]1[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=1[O:16][CH:17]1[CH2:22][CH2:21][N:20]([C:2]2[N:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=2)[CH2:19][CH2:18]1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Reactant: COC(=O)c1ccc(Cl)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1

Procedure:
A mixture of methyl 6-chloropyridazine-3-carboxylate (500 mg, 0.2.9 mmol), 4-[2-(trifluoromethyl)phenoxy]piperidine (851 mg, 0.3.5 mmol), potassium carbonate (802 mg, 5.8 mmol) and tetrabutylammonium iodide (20 mg, 0.06 mmol) in dioxane (30 mL) was refluxed for 24 h. After cooling, the mixture was filtered through celite, washed with EtOAc and concentrated. CombiFlash chromatography (40 g, 60-90% EtOAc in hexanes in 20 min, 35 mL/min, 18 mL/fraction) gave the title compound as a white solid. 1H NMR (400 MHz, acetone-d6): δ 1.93-1.99 (m, 2H), 2.14-2.20 (m, 2H), 3.93 (s, 3H), 3.97-4.09 (m, 4H), 5.03-5.07 (m, 1H), 7.13 (t, 1H), 7.31 (d, 1H), 7.40 (d, 1H), 7.65 (dd, 2H), 7.89 (d, 1H).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([CH2:16][S:17][C:18]2[N:19]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:20]([C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([O:33][CH3:34])[CH:27]=3)([CH3:25])[CH3:24])=[CH:21][N:22]=2)=[C:11]([F:42])[CH:10]=1)(=O)=O.[N-:43]=[N+:44]=[N-:45].[Na+]>CN(C=O)C>[N:43]([CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([F:42])[C:12]([CH2:16][S:17][C:18]2[N:19]([C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[C:20]([C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([O:33][CH3:34])[CH:27]=3)([CH3:24])[CH3:25])=[CH:21][N:22]=2)=[C:13]([F:15])[CH:14]=1)=[N+:44]=[N-:45]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCOS(C)(=O)=O)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCN=[N+]=[N-])cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a solution of 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)ethyl methanesulfonate (400 mg, 0.624 mmol) in DMF (6 mL) at 0° C. was added NaN3 (60 mg, 0.922 mmol). After stirring 1 h, the residue was partitioned in EtOAc (20 mL) and water (20 mL). The organic layer was washed with 1M HCl (10 mL) and water (10 mL) successively, dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography (CH2Cl2/MeOH=20:1) to give 2-(4-(2-azidoethoxy)-2,6-difluorobenzylthio)-5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (320 mg, 87% yield) as a white foam. 1H NMR (400 MHz, CDCl3) δ 7.22 (s, 1H), 7.16 (d, J=8.24 Hz, 1H), 6.77 (t, 2H), 6.55 (d, J=2.09 Hz, 1H), 6.51 (dd, J=8.25 Hz, 1H), 6.39-6.32 (m, 4H), 4.05 (m, 4H), 3.78 (s, 3H), 3.60 (t, 2H), 1.49 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[OH:11][C:12]1C=NC=CC=1OC.NO>>[CH3:1][C:2]1[C:6]2[N:7]=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]=2[O:4][N:3]=1
Reactant: Cc1noc2cccnc12
Reactant: COc1ccncc1O
Agent: NO
Product: COc1ccnc2c(C)noc12

Procedure:
Scheme I-16-2 depicts the preparation of a 3-methyl-4-azabenzisoxazole ti derivative which may be used as starting material for Scheme I-16. Steps a, b, AP and c of equation 1 may be carried out as previously described for Scheme I-14-2. The acetyl derivative may then be treated with hydroxylamine to provide the oxime as depicted in step d and then cyclized as depicted in step e (as described for steps f and g of Scheme I-14, respectively) to provide the 3-methyl-4-azabenzisoxazole shown. In equation 2 of Scheme I-16-2 the 3-hydroxy-4-methoxypyridine is first acetylated (step a) then is treated with hydroxylamine and cyclized as previously described to provide 3-methyl-7-methoxy-4-azabenzisoxazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].C(Cl)(=O)C(Cl)=O.Cl.[NH:22]1[CH2:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[N:22]1([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:8]=2)=[O:13])[CH2:25][CH2:24][CH2:23]1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: C1CNC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Li+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc2nccc(Cl)c2s1)N1CCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
A 50 mL round bottom flask was charged with lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (0.500 g, 2.28 mmol), methylene chloride (15 ml), and 12 drops of DMF. Oxalyl chloride (0.298 ml, 3.42 mmol) was added dropwise, and the mixture was stirred at room temperature for 3 hours and concentrated to yield a tan solid. This was redissolved in methylene chloride (15 ml). Azetidine hydrochloride (0.426 g, 4.55 mmol) was added in one portion and Hunig's Base (1.59 ml, 9.11 mmol) was added dropwise. This mixture was stirred at room temperature overnight, then diluted with methylene chloride (15 mL) and washed with water (25 mL), sat. NaHCO3 (25 mL), and brine (25 mL). The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield azetidin-1-yl(7-chlorothieno[3,2-b]pyridin-2-yl)methanone (0.58 g, 100% yield) as a tan solid.