Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH:21]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:20]3=[O:31])[C:6](=[O:32])[N:5]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:4]=2[N:3]=1.N1CCOCC1>C1COCC1.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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH:21]([CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:20]3=[O:31])[C:6](=[O:32])[N:5]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCCN1CCC(Cc3ccccc3)C1=O)c(=O)n2CCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CCCCCn1c(=O)n(CCCCN2CCC(Cc3ccccc3)C2=O)c(=O)c2[nH]c(Cl)nc21
Reaction time: 4 h

Procedure:
A solution of 8-chloro-1-{4-[2-oxo-3-(phenylmethyl)-1-pyrrolidinyl]butyl}-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.35 g, 0.67 mmol), Pd(PPh3)4 (0.082 g, 0.07 mmol) and morpholine (0.6 ml, 6.7 mmol) in THF (10 ml) was degassed (sequential evacuation followed by addition of nitrogen×3) then stirred for 4 h. The solution was then loaded onto an aminopropyl SPE (5 g) and eluted first with MeOH then 5% AcOH/MeOH to provide the title compound containing a small impurity. Further purification over silica (10 g SPE, gradient elution ether/ethyl acetate 1:0 to 0:1) provided the title compound as a clear oil (0.10 g, 31%).
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[CH3:7][CH:8]([CH3:27])[C:9]([O:11][CH:12]([O:16][C:17](ON1C(=O)CCC1=O)=[O:18])[CH:13]([CH3:15])[CH3:14])=[O:10]>>[CH3:2][N:1]([C:17]([O:16][CH:12]([O:11][C:9](=[O:10])[CH:8]([CH3:27])[CH3:7])[CH:13]([CH3:15])[CH3:14])=[O:18])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CNCC(=O)O
Reactant: CC(C)C(=O)OC(OC(=O)ON1C(=O)CCC1=O)C(C)C
Product: CC(C)C(=O)OC(OC(=O)N(C)CC(=O)O)C(C)C
Yield: 55.8 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, sarcosine (0.108 g, 1.19 mmol) and 1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl 2-methylpropanoate (0.3 g, 0.99 mmol) were reacted to provide 0.152 g (55% yield) of the title compound (37) as a colorless liquid after work-up and mass-guided preparative HPLC purification. 1H NMR (CD3OD, 400 MHz): δ=6.57 (dd, 1H), 4.19 (m, 2H), 3.03 (2s, 3H), 2.6 (m, 1H), 2.01 (br m, 1H), 1.18 (m, 6H), 1.0-0.98 (2m, 6H). MS (ESI) m/z 298.14 (M+Na)+, 274.13 (M−H)−.
Reaction SMILES: [OH-].[K+].[C:3]([NH:6][NH:7][C:8](=[O:10])[CH3:9])(=[O:5])[CH3:4].[CH2:11]([O:14][CH2:15][CH2:16]Cl)[CH2:12]Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.CS(C)=O>[C:3]([N:6]1[N:7]([C:8](=[O:10])[CH3:9])[CH:16]=[CH:15][O:14][CH:11]=[CH:12]1)(=[O:5])[CH3:4]
Reactant: CC(=O)NNC(C)=O
Reactant: ClCCOCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CS(C)=O
Product: CC(=O)n1ccoccn1C(C)=O
Temperature: 70 °C

Procedure:
105.6 g of finely pulverised potassium hydroxide are introduced into a solution of 92.9 g of N,N′-diacetylhydrazine and 1410 g of dimethyl sulfoxide. When the heat of reaction has died away, 229.9 g of 2,2′-dichlorodiethyl ether are added and then 221.1 g of finely ground potassium carbonate are introduced. The reaction mixture is heated to 70° C. and maintained at 70 to 75° C. for 2 hours, then cooled to 20 to 25° C. and filtered, and the filtration residue is washed with dimethyl sulfoxide. Concentration of the combined filtrates by evaporation yields an oil, to which 157 g of isopropanol are added. After cooling to −10° C., filtration is carried out and the crystalline residue is washed with isopropanol. After drying of the residue, 99.4 g (65.1%) of 4,5-diacetyl-[1,4,5]-oxadiazepine are obtained in a purity of 97.6%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[Cl:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][Cl:22]>C(#N)C>[CH2:7]([N:19]([CH2:20][CH2:21][Cl:22])[CH2:18][CH2:17][Cl:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: ClCCN(CCCl)Cc1ccccc1
Temperature: 60 °C
Yield: 65.4 %

Procedure:
21 g (152 mmol) of potassium carbonate and then 8 ml (67 mmol) of benzyl bromide are added to a solution of 10 g (56 mmol) of bis(2-chloroethyl)amine hydrochloride in 130 ml of acetonitrile, and then the reaction medium is heated at 60° C. for 24 h. After filtration, the filtrate is concentrated under vacuum. The crude residue is purified by chromatography on silica gel, elution being carried out with a 90/10 heptane/ethyl acetate mixture, to give 8.5 g (65%) of benzylbis(2-chloroethyl)amine.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:23][NH:24][CH2:25][CH2:26][OH:27]>>[Br:1][C:2]1[C:3]([N:24]([CH2:25][CH2:26][OH:27])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: CNCCO
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(Br)c1
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1Br

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage 169.2) and 2-methylamino-ethanol to afford as a white crystalline solid. HPLC (Condition 4) tR=5.72 min, UPLC-MS (Condition 3) tR=1.14 min, m/z=452.2 [M+H]+.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10](=[O:22])[C:11]([C:19](=[O:21])[CH3:20])=[CH:12][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:7])[CH3:4]>Br>[Br:1][CH2:20][C:19]([C:11]1[C:10](=[O:22])[NH:9][C:8]([C:6]([O:5][CH2:3][CH3:4])=[O:7])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=1)=[O:21]
Reactant: BrBr
Reactant: CCOC(=O)c1cc(C(C)=O)c(=O)[nH]c1C(=O)OCC
Agent: Br
Product: CCOC(=O)c1cc(C(=O)CBr)c(=O)[nH]c1C(=O)OCC
Temperature: 0 °C

Procedure:
Bromine (8.0 g, 0.050 mol) in 48% HBr is added dropwise to a stirred solution of diethyl-5-acetyl-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate (14.05 g, 0.05 mol) in 48% HBr (200 mL). Upon completion of this bromine addition the reaction mixture is poured onto ice (200 g) and the mixture is stirred until the ice has melted. The crude product is collected by filtration and crystallized twice from an ethyl acetate-hexane mixture (1/2) affording diethyl 5-(bromoacetyl)-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate with mp 141°-142° C.
Reaction SMILES: Cl.[C:2]1([C@@H:14]2[CH2:19][CH2:18][C@H:17]([NH2:20])[CH2:16][CH2:15]2)[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[N:9]=[CH:10][C:5]2=[N:4][N:3]=1.[C:21]([CH2:23][C:24](OC1C(F)=C(F)C(F)=C(F)C=1F)=[O:25])#[N:22]>C(Cl)Cl>[C:2]1([C@@H:14]2[CH2:15][CH2:16][C@H:17]([NH:20][C:24](=[O:25])[CH2:23][C:21]#[N:22])[CH2:18][CH2:19]2)[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[N:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: N[C@H]1CC[C@@H](c2nnc3cnc4[nH]ccc4n32)CC1
Reactant: N#CCC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Solvent: ClCCl
Product: N#CCC(=O)N[C@H]1CC[C@@H](c2nnc3cnc4[nH]ccc4n32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of cis-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexanamine hydrochloride (0.106 g, 0.206 mmol, Example #D.1.1) in DCM (4 mL) was added TEA (0.086 mL, 0.62 mmol). The reaction mixture was sonicated until the reaction was homogeneous. To the reaction solution was added perfluorophenyl 2-cyanoacetate (0.078 g, 0.31 mmol, Preparation #6). The resulting solution was stirred at ambient temperature for about 16 h. The crude reaction mixture was purified by silica gel chromatography (40 g) eluting with a gradient of 0-20% EtOAc in DCM and then further purified by RP-HPLC (Table 2, Method e) to give N-(cis-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexyl)-2-cyanoacetamide with 3 equiv NH4OAc as an excipient (0.025 g, 22%). LC/MS (Table 2, Method a) Rt=1.33 min; MS m/z: 324 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][NH:25][CH2:26]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][N:25]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:26]2
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: Brc1cccc2c1CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC1COc2c(N3Cc4cccc(Br)c4C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 44.4 %

Procedure:
142 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7--oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 149 mg of 4-bromoisoindoline, 114 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 103 mg of the target compound.
Reaction SMILES: [CH2:1]([S:4][C:5]1[S:9][C:8]([SH:10])=[N:7][N:6]=1)[CH:2]=[CH2:3].[H-].[Na+].Cl[C:14]1[C:15]([C:20]#[N:21])=[N:16][CH:17]=[CH:18][N:19]=1>CN(C=O)C.C1C=CC=CC=1>[CH2:1]([S:4][C:5]1[S:9][C:8]([S:10][C:14]2[C:15]([C:20]#[N:21])=[N:16][CH:17]=[CH:18][N:19]=2)=[N:7][N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCSc1nnc(S)s1
Reactant: N#Cc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: C=CCSc1nnc(Sc2nccnc2C#N)s1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
The title compound was prepared according to the procedure described in Example 1 by using 5-(allylthio)-1,3,4-thiadiazole-2-thiol (460 mg, 2.42 mmol), NaH (60% dispersion in mineral oil, 107 mg, 2.66 mmol), and 3-chloropyrazine-2-carbonitrile (338 mg, 2.42 mmol) in DMF and benzene (8 ml, 1/1) by stirring at 85° C. under nitrogen atmosphere overnight.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].C(N(CC)CC)C.[N+:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1F)([O-:27])=[O:26]>>[CH3:17][N:13]1[CH2:14][CH2:15][CH2:16][CH:12]1[CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[N+:25]([O-:27])=[O:26])[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCN(CC)CC
Product: CN1CCCC1Cc1c[nH]c2ccc(Nc3ccccc3[N+](=O)[O-])cc12
Yield: 48 %

Procedure:
(R)-5-Amino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and o-nitrofluorobenzene were used. Triethylamine was used as base, o-nitrofluorobenzene was used as solvent, and the reaction was heated at reflux for 24 hours. Column chromatography afforded the title compound (48%) as a red amorphous solid: 1H NMR (CDCl3) δ 9.62 (br s, NH), 8.77 (br s, NH), 8.19 (dd, J=8.7 and 1.5 Hz,1H), 7.47 (d, J=1.6 Hz, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.29-7.23 (m, 1H), 7.09-7.00 (m, 3H), 6.69-6.64 (m, 1H), 3.20-3.12 (m, 2H), 2.63 (dd, J=14.0 and 9.5 Hz, 1H), 2.54-2.45 (m, 1H), 2.45 (s, 3H), 2.25 (dd, J=17.1 and 9.2 Hz, 1H), 1.91-1.54 (m, 4H); 13C NMR (CDCl3) δ 145.4, 135.7, 134.8, 132.1, 130.1, 128.6, 126.5, 123.6, 120.7, 116.4, 116.4, 116.1, 114.1, 112.2, 66.7, 57.5, 40.8, 31.5, 29.8, 21.9; FAB HRMS calculated for [C20H22N4O2.H] 351.1823, found 351.1797.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:16]([O-])=O)[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].Cl.[H][H]>C(O)C.CO.[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH2:16])[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: COc1c(OC(C)=O)cc(C(=O)O)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: COc1c(N)cc(C(=O)O)cc1OC(C)=O
Yield: 103.4 %

Procedure:
3-Acetoxy-4-methoxy-5-nitro-benzoic acid (4.50 g, 17.6 mmol) (R. T. Borchardt et al., J. Med. Chem. 25 (1982), 312-323; F. Tiemann et al., Ber. dt. Chem. Ges. 9 (1876), 937) was dissolved in ethanol (180 ml) and 0.5 M hydrogen chloride in methanol (4 ml) and hydrogenated in an H-Cube™ hydrogenation reactor with 100 bar hydrogen at 40° C. over a 10% palladium on charcoal cartridge. The mixture was evaporated to dryness to give 4.1 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]([CH3:16])=C)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[O:20]CC1>O.CCOC(C)=O.O=[Os](=O)(=O)=O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14](=[O:20])[CH3:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: C=C(C)CC1CCN(Cc2ccccc2)C1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)CC1CCN(Cc2ccccc2)C1
Reaction time: 16 h

Procedure:
To a rapidly stirred solution of 1-4 (7.0 g, 33 mmol) in THF (200 mL) and H2O (150 mL) was added NaIO4 (21 g, 100 mmol) followed by addition of OsO4 (10 mL; 2.5% solution). After 16 hrs, an additional amount of OsO4 (10 mL) was added, and the reaction was stirred for 6 hrs. The reaction was diluted with EtOAc, washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated to give 1-5 as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]([CH3:38])([C:22]2[N:26]([CH3:27])[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])=[N:24][N:23]=2)[CH3:21])=[C:6]([CH:18]=1)[C:7]([NH:9][CH2:10][CH:11]1[CH2:15][O:14]C(C)(C)[O:12]1)=[O:8].Cl.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]([CH3:38])([C:22]2[N:26]([CH3:27])[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:36])([F:37])[F:35])=[N:24][N:23]=2)[CH3:21])=[C:6]([CH:18]=1)[C:7]([NH:9][CH2:10][CH:11]([OH:12])[CH2:15][OH:14])=[O:8]
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1C(=O)NCC1COC(C)(C)O1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1C(=O)NCC(O)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
5-chloro-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzamide (362 mg) was suspended in THF (10 ml), 1M hydrochloric acid (10 ml) was added thereto, followed by stirring at room temperature for 2 hours, warming to 50° C. and stirring for 30 minutes. The reaction solution was cooled to room temperature, and water and 1M hydrochloric acid were added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and concentrated under reduced pressure. The resulting solid was washed with diisopropylether to obtain, as a white solid, 5-chloro-N-(2,3-dihydroxypropyl)-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-yl}ethoxy)benzamide (293 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:21]=[CH:20][C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.C([Li])CCC.[CH2:41]([C@H:48]1[CH2:52][O:51][C:50](=[O:53])[NH:49]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.O1CCNC1=O>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]([N:49]3[C@@H:48]([CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH2:52][O:51][C:50]3=[O:53])=[O:19])=[CH:20][CH:21]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: N#Cc1ccc(-c2ccc(OCCCC(=O)O)cc2)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C1NCCO1
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2ccc(OCCCC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 82 %

Procedure:
To a -70° C. solution in THF (100 mL) of 4-[4-(4-cyanophenyl)phenoxy]butanoic acid (1.00 g, 3.66 mmol), prepared as in Example 3, was added triethylamine (0.64 mL, 4.62 mmol) and pivaloyl chloride (0.49 mL, 3.91 mmol). The reaction mixture was stirred for 15 minutes at -70° C., 45 minutes at 0° C., and then was cooled back to -70° C. In a separate flask, n-butyllithium (2.5M in hexanes, 2.56 mL, 6.40 mmol) was added via syringe to a -78° C. a solution in THF (50 mL) of (S)-(-)-4-benzyl-2-oxazolidinone. The oxazolidinone anion solution was then added to the mixed anhydride solution via cannula. The reaction mixture was then warmed slowly to ambient temperature and stirred overnight. The reaction mixture was quenched with aqueous 1M HCl and extracted with ethyl ether. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The resulting white solid was azeotroped with ethyl ether and purified by chromatography on silica gel (2% methanol-dichloromethane) to give N-[4-(4-(4-cyanophenyl)phenoxy)butanoyl]-(S)-(-)-4-benzyl-2-oxazolidinone (1.30 g, 82%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[O:34][CH:33]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.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>[O:34]1[C:33]2=[CH:32][CH:36]=[CH:37][C:38]2=[CH:39][C:40]([C:14]2[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([N:16]3[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]3)[CH:11]=[CH:12][CH:13]=2)=[CH:35]1
Reactant: CC1(C)OB(c2coc3ccccc23)OC1(C)C
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
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: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CN(c2cccc(-c3coc4cccc-4c3)c2OCc2ccccc2)S(=O)(=O)N1
Temperature: 80 °C
Reaction time: 7 h

Procedure:
A mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (80 mg, 0.18 mmol), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzofuran (44 mg, 0.18 mmol), Cs2CO3 (235 mg, 0.72 mmol) and Pd(PPh3)4 (8 mg) in DMF (5 mL) is stirred at 80° C. for 7 h. The mixture is cooled to RT and is diluted with EtOAc, washed with water and bride and dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5]([CH:11]=[N:12][OH:13])=[CH:4][CH:3]=1.[Cl:14]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:1][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5]([C:11]([Cl:14])=[N:12][OH:13])=[CH:4][CH:3]=1
Reactant: ON=Cc1ccc(Br)c2nsnc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: ON=C(Cl)c1ccc(Br)c2nsnc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.6 %

Procedure:
To a solution of 7-bromo-benzo[1,2,5]thiadiazole-4-carbaldehyde oxime (16.65 g) (Example I4) in N,N-dimethylformamide (150 ml) was added N-chlorosuccinimide (“NCS”) (10.34 g). The reaction mixture stirred at ambient temperature for 16 hours. Water (750 ml) was added to the reaction mixture and the resulting solid was isolated by filtration to obtain 7-bromo-N-hydroxybenzo[1,2,5]thiadiazole-4-carbimidoyl chloride (15.77 g) as a yellow solid which was used without further purification.
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][C:10]([CH3:14])([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:34])[C:32]#[CH:33])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1>ClCCl.CO>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:34])[C:32]#[C:33][C:2]3[CH:16]=[CH:15][C:5]([CH2:6][N:7]4[CH2:12][CH2:11][C:10]([OH:13])([CH3:14])[CH2:9][CH2:8]4)=[CH:4][CH:3]=3)=[CH:26][CH:25]=2)=[CH:22][CH:23]=1
Reactant: CC1(O)CCN(Cc2ccc(I)cc2)CC1
Reactant: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1
Solvent: CO
Solvent: ClCCl
Product: CC1(O)CCN(Cc2ccc(C#CC(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1

Procedure:
Prepared analogously to Example 1.1.d. from 1-(4-iodobenzyl)-4-methylpiperidin-4-ol and propynoic acid-(4′-chlorobiphenyl-4-yl)amide. Yield: 25 mg (13% of theory); melting point: 192° C.-193° C.; C28H27ClN2O2 (M=458.99); calc.: molecular ion peak (M+H)+: 459/461; found: molecular ion peak (M+H)+: 459/461; Rf value: 0.2 (silica gel, dichloromethane/methanol (10:1)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].CCOC(C)=O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:9]([S:11]([CH3:10])(=[O:13])=[O:12])[S:11]([CH3:10])(=[O:13])=[O:12])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ncc(Br)cc1N
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ncc(Br)cc1N(S(C)(=O)=O)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
To a solution of 5-bromo-2-methylpyridin-3-amine (PharmaBlock) (2.000 g, 10.69 mmol) in pyridine (15.0 mL) was added 4-dimethylaminopyridine (Aldrich) (0.131 g, 1.069 mmol) and methanesulfonyl chloride (2.5 mL, 32.1 mmol). The resulting mixture was heated to 100° C. under N2 for 2 h. Reaction was cooled to rt. The reaction mixture was poured into the beaker which filled with EtOAc (50 ml) and hand stirred for 10 minutes. The organic layer was decanted into a round-bottom flask. The original mixture (black paste) was dissolved into DCM (3 ml) followed by adding EtOAc (20 ml) and hand stirred for 10 min and decanted to the same round-bottom flask that was mentioned earlier. The combined organic layers were concentrated in-vacuo. The crude product was purified by column chromatography (120 g, 10% to 20% acetone in hexanes) to afford the desired product as light brown solid (1.1 g). MS (ESI pos. ion) m/z: 342.8. 1H NMR (300 MHz, CDCl3) δ ppm 2.64 (s, 3H) 3.47 (s, 6H) 7.73 (d, J=2.05 Hz, 1H) 8.67 (d, J=2.05 Hz, 1H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:13][CH3:14])=[N:9][NH:10]2)=[CH:6][CH:5]=1.[CH:15]1(Br)[CH2:19][CH2:18][CH2:17][CH2:16]1.O>CN(C=O)C>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:13][CH3:14])=[N:9][N:10]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:6][CH:5]=1
Reactant: CCc1n[nH]c2cc(Br)ccc12
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nn(C2CCCC2)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.8 %

Procedure:
2.46 g (61.4 mmol, 1.05 equiv) sodium hydride, 60% oil dispersion, was added in 0.5 g portions to a 10° C. solution of 13.17 g (58.5 mmol, 1.0 equiv) 6-bromo-3-ethyl-1H-indazole in 500 mL anhydrous DMF. The mixture was stirred at room temperature for 20 minutes, then a solution of 8.8 mL (81.9 mmol, 1.4 equiv)cyclopentyl bromide in 10 mL anhydrous DMF was added dropwise. After 18 hours, the reaction mixture was poured into 2 L H2O and extracted 2×1L ethyl acetate. The organic extracts were combined, washed 2×750 mL H2O, 1×500 mL brine, and dried over Na2SO4. Filtration, concentration of filtrate and drying gave 20.7 g of crude product, which was purified on a silica gel column (1.1 kg silica gel, 3% ethyl acetate/hexanes) to give 10.6 g (62%) of an amber liquid: IR (CHCl3)2972, 2875, 1606, 1501, 1048 cm−1; 1H NMR (300 MHz, CDCl3) d 7.56 (d, 1H, J=1.3 Hz), 7.52 (d, 1H, J=8.7 Hz), 7.17 (dd, 1H, J=1.5, 8.5 Hz), 4.83 (quintet, 1H, J=7.6 Hz), 2.96 (q, 2H, J=7.6 Hz), 2.15 (m, 4H), 2.0 (m, 2H), 1.65 (m, 2H), 1.36 (t, 3H, J =7.7 Hz); MS (thermospray, NH4OAc) m/z 295/293 (M+H+, base); Anal. calcd for C14H17N2Br: C, 57:35; H, 5.84; N, 9.55. Found: C, 57.48; H, 5.83; N, 9.90.