Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.Br[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:21][C:22]([N:24]3[CH2:25][CH2:26][N:27]([C:30]4[N:31]=[CH:32][CH:33]=[CH:34][N:35]=4)[CH2:28][CH2:29]3)=[O:23])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2n[nH]c(-c3ccc(F)cc3)n2)cc1
Reactant: O=C(CBr)N1CCN(c2ncccn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCN(c2ncccn2)CC1
Yield: 69.1 %

Procedure:
100 mg 3,5-bis-(4-fluoro-phenyl)-1H-(1,2,4)triazole, 111 mg 2-bromo-1-(4-pyrimidin-2-yl-piperazin-1-yl)-ethanon and 237 mg potassiumcarbonat in 5 mL acetone was stirred 24 h at RT. The reaction was filtered and the filtrate was evaporated. The residue was crystallized with acetonitrile to yield 124 mg of the desired compound.
Reaction SMILES: C[C@@H]1CCCN(C(C2C=C(C)C=CC=2C2C=NN(C)C=2)=O)[C@@H]1CNC1C=CC(C(F)(F)F)=CN=1.[NH2:35][CH2:36][C@@H:37]1[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][N:38]1[C:44]([C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=1[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=1)=[O:45].Cl[C:60]1[CH:67]=[CH:66][C:63]([C:64]#[N:65])=[CH:62][N:61]=1>>[CH3:43][C@@H:42]1[CH2:41][CH2:40][CH2:39][N:38]([C:44](=[O:45])[C:46]2[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=2[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=2)[C@@H:37]1[CH2:36][NH:35][C:60]1[CH:67]=[CH:66][C:63]([C:64]#[N:65])=[CH:62][N:61]=1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: N#Cc1ccc(Cl)nc1
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C#N)cn2)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyridin-2-yl)phenyl)methanone and 6-chloronicotinonitrile. ESI-MS (m/z): 426 [M+1]+.
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[S:5][CH:6]=1.BrC1C(C2C=CN=CC=2)=C(C2C=CC(F)=CC=2)NN=1.[CH2:39]1[C@@H:47]2[N:42]([CH2:43][CH2:44][C:45](=O)[CH2:46]2)[CH2:41][CH2:40]1>>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[S:5][CH:6]=[C:2]([C:45]3[CH2:46][C@H:47]4[N:42]([CH2:41][CH2:40][CH2:39]4)[CH2:43][CH:44]=3)[C:3]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:8][CH:9]=1
Reactant: O=C1CCN2CCC[C@H]2C1
Reactant: Fc1ccc(-c2scc(Br)c2-c2ccncc2)cc1
Agent: Fc1ccc(-c2[nH]nc(Br)c2-c2ccncc2)cc1
Product: Fc1ccc(-c2scc(C3=CCN4CCC[C@H]4C3)c2-c2ccncc2)cc1
Yield: 23 %

Procedure:
Following a procedure similar to that described in Example 2-2), but using 4-bromo-2-(4-fluorophenyl)-3-(pyridin-4-yl)thiophene prepared as described in 5) instead of 3-bromo-5-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole, and using (S)-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one instead of (±)-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one, the resulting product was subjected to a dehydration reaction as described in Example 3 and then treated by column chromatography through silica gel (eluent, ethyl acetate:methanol:isopropylamine=10:10:1), to give the title compound (Rf=0.50, 263 mg) as a brown amorphous solid (yield 23%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12]Br.COCC1C=C(C(O)=O)C=CC=1C1C=CC=CC=1C.C1COCC1.[CH3:38][S-:39].[Na+]>CC#N>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][S:39][CH3:38]
Reactant: COC(=O)c1ccc(Br)c(CBr)c1
Reactant: C[S-]
Agent: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Br)c(CSC)c1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of methyl 4-bromo-3-(bromomethyl)benzoate, which preparation is described above, under Intermediate 28, Step 1, (2 g; 6.49 mmol; 1 eq.) in CH3CN (10 mL) and THF (10 mL) was added sodium thiomethoxide (0.50 g; 7.14 mmol; 1.10 eq.) and the mixture was stirred at reflux for 1 hour and at RT overnight. After concentration under vacuum, the mixture was partitioned between EtOAc and water. The organic layer was washed with NaCl sat. solution, dried over magnesium sulfate, filtered off and dried under vacuum to give the title compound as a yellow oil (1.7 g, 94%). 1H NMR (CDCl3) δ 7.99 (d, J=2.3 Hz, 1H), 7.77 (dd, J=8.3, 2.1 Hz, 1H), 7.65 (d, J=8.3 Hz, 1H), 3.92 (s, 3H), 3.83 (s, 2H), 2.06 (s, 3H). HPLC (Method A) Rt 4.31 min (Purity: 87.4%).
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])=[CH:4][CH:3]=1.[Cl:15]C1C=CC=CC=1CBr.COP(OC)OC>>[Cl:15][C:13]1[CH:14]=[CH:2][CH:3]=[CH:4][C:5]=1[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COP(=O)(Cc1ccc(F)cc1)OC
Reactant: Clc1ccccc1CBr
Agent: COP(OC)OC
Product: COP(=O)(Cc1ccccc1Cl)OC

Procedure:
Following the procedure of Compound 11, 2-chlorobenzyl bromide is reacted with trimethylphosphite.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[C:34]([CH3:36])[N:35]=[C:9]23)[CH2:4][CH2:3]1.[N+](=[CH:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N-]>C([O-])(=O)C.[Rh+].C1(C)C=CC=CC=1>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([CH:5]3[CH2:6][CH2:7][CH:2]([O:1][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:3][CH2:4]3)[C:9]3[N:10]([N:33]=[C:34]([CH3:36])[N:35]=3)[C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:17][CH:18]=1)#[N:29]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(O)CC2)c2nc(C)nn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OCC(=O)OCC)CC2)c2nc(C)nn12
Reaction time: 1 h
Yield: 76 %

Procedure:
To a mixture of 4′-{[4-(4-hydroxycyclohexyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.2 g), rhodium(I) acetate (0.055 g) and toluene (40 mL) was added dropwise ethyl diazoacetate (1.2 mL) at 80° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography to give the title compound as a colorless solid (1.1 g, 76%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].[N:25]1[CH:30]=[CH:29][CH:28]=[N:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>O1CCCC1.O>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[N:25]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH2:32][CH2:33]2)=[O:12])[CH2:8]1
Reactant: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(N1CCN(c2ncccn2)CC1)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A stirred mixture of 2.8 g (0.01 mole) of 3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 1.4 g (0.01 mole) of potassium carbonate in 25 ml of tetrahydrofuran was treated with 1.6 g (0.01 mole) of 1-(2-pyrimidyl)piperazine added dropwise. After stirring for 30 min, a few pieces of ice were added and stirring continued for 16 hr. The reaction mixture was diluted with 200 ml of water and the oil which separated slowly crystallized. Recrystallization from isopropyl ether yielded 2.7 g (66.3%) of fine white crystals, m.p. 127°-128° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:8][C:7]2[S:9][CH:10]=[CH:11][C:6]=2[C:5]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[I-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:3][C:4]1[N:8]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[C:7]2[S:9][CH:10]=[CH:11][C:6]=2[C:5]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)Cc1c(C)[nH]c2sccc12
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2)c2sccc12
Temperature: 25 °C
Yield: 59.6 %

Procedure:
Sodium hydride (0.014 g, 0.583 mmol) was added to a solution of methyl 2-(5-methyl-6H-thieno[2,3-b]pyrrol-4-yl)acetate (0.109 g, 0.52 mmol) in DMF (5 mL) at 0° C. The mixture was stirred 1 h at 0° C. before sequential addition of the 1-(chloromethyl)-4-(methylsulfonyl)benzene (0.156 g, 0.762 mmol) and sodium iodide (0.0935 g, 0.624 mmol). The reaction mixture was allowed to warm up to ambient temperature over 4 h. EtOAc was added and the resulting solution washed with water. The layers were separated and the organic solution was dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel (heptane/EtOAc: 80/20 to 50/50) to give the title compound (0.117 g, 59.6%): LC/MS (Table 1, Method b) Rt=2.45 min; MS m/z 395 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[OH:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH2:20][CH2:19][OH:18])[CH:23]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=Cc1cccc(OCCO)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1cccc(OCCO)c1

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in EtOH and 3-(2-hydroxyethoxy)-benzaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [H-].[Na+].[Br-].[CH2:4]([O:6][C:7]([CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:8])[CH3:5].[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O.[CH3:38]N(C=O)C>C(OCC)(=O)C>[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1/[CH:32]=[CH:9]/[C:7]([O:6][CH:4]([CH3:5])[CH3:38])=[O:8]
Reactant: CCOC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1F
Reactant: CN(C)C=O
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)/C=C/c1ccccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
400 mg of sodium hydride (60% in oil, 10 mmol) were added to a stirred solution of 4.4 g of ethoxycarbonylmethyltriphenylphosphonium bromide (10 mmol) in 20 ml of DMF and the mixture was stirred further at RT for 10 min. 1.24 g of 2-fluoro-benzaldehyde (10 mmol) were added and the mixture was stirred for 5 h at RT. The reaction mixture was taken up in 100 ml of ethyl acetate and washed with a common salt solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification took place using a silica gel chromatography (ethyl acetate/heptane 1:1). 1.25 g of the title compound were obtained. Yield: 60%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][CH2:21][O:20][CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:33])[NH:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][CH2:21][O:20][CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C2(CC(C3CCCOC3)Oc3ccc(Br)cc32)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: O=C1NC(=S)NC12CC(C1CCCOC1)Oc1ccc(Br)cc12
Temperature: 120 °C
Yield: 38.2 %

Procedure:
A suspension of 6-bromo-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (300 mg, 0.79 mmol) and Lawesson's Reagent (319 mg, 0.79 mmol) in dry 1,4-dioxane (4 mL) was heated at 120° C. for 30 minutes in microwave. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(tetrahydro-2H-pyran-3-yl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (120 mg, 40%).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:31]=[C:30]([NH:32][C:33]([NH:35][C:36](=[O:44])[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[S:34])[CH:29]=[CH:28][C:5]=1[O:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:26][CH3:27])=[C:14]([C:17]([NH:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[O:18])[CH:15]=2)[N:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH2:52]([N:54]=[C:55]=[O:56])[CH3:53]>O1CCCC1>[CH2:52]([NH:54][C:55]([N:23]1[CH2:22][CH2:21][CH:20]([NH:19][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][C:13]=2[O:26][CH3:27])[N:10]=[CH:9][CH:8]=[C:7]3[O:6][C:5]2[CH:28]=[CH:29][C:30]([NH:32][C:33]([NH:35][C:36](=[O:44])[CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[S:34])=[CH:31][C:4]=2[F:3])=[O:18])[CH2:25][CH2:24]1)=[O:56])[CH3:53]
Reactant: CCN=C=O
Reactant: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2cc1C(=O)NC1CCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)N1CCC(NC(=O)c2cc3c(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)ccnc3cc2OC)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 81 %

Procedure:
Compound 14 (335 mg) was suspended in tetrahydrofuran (5 mL), and triethylamine (212 μL) and ethyl isocyanate (71.2 μL) were added to the suspension, followed by stirring at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the formed solid was filtrated, to thereby yield titled compound 15 (271 mg, yield: 81%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[O:17][N:16]=[C:15]([CH2:18][CH3:19])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9]C.B(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CO.C(Cl)(Cl)Cl>[CH2:18]([C:15]1[N:14]=[C:13]([CH:12]=[CH:11][C:5]2[CH:4]=[C:3]([OH:2])[C:8]([OH:9])=[CH:7][CH:6]=2)[O:17][N:16]=1)[CH3:19]
Reactant: CCc1noc(C=Cc2ccc(OC)c(OC)c2)n1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCc1noc(C=Cc2ccc(O)c(O)c2)n1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-ethyl-[1,2,4]oxadiazole (compound of Example 2, Method A, Step 2; 0.3 g, 1.15 mmol) was dissolved in dichloromethane (6 mL) and cooled to −78° C. A solution of boron tribromide (0.41 mL, 4.40 mmol) in dichloromethane (4 mL), which was cooled to −50° C., was added slowly over a period of 30 min. After 3 h, the reaction mixture was allowed to warm to room temperature and stirred for 12 h. After the completion of the reaction, the mixture was quenched by dropwise addition of methanol (5 mL) at 0° C. and stirred for 30 min at room temperature. The solvent was evaporated and the residue obtained was redissolved in 10% methanol in chloroform at 0° C., and stirred with solid sodium carbonate to obtain pH ˜9. The solvent was evaporated and the crude product obtained was purified by column chromatography (silica gel, 0.5% methanol in chloroform) to afford the title compound.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:1]2[C:5]3[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=3[N:3]=[CH:2]2)=[CH:14][CH:13]=1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(Cn2cnc3cc(N)ccc32)cc1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), 4-methylbenzylbromide (407 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.109 g (32.0%); MS m/z: 342.1 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 2.23 (s, 6H); 4.57 (s, 4H); 6.66 (br s, 1H); 6.71 (dd, 1H, 4J=2.1 Hz, 3J=8.9 Hz); 7.09 (d, 4H, 3J=7.9 Hz); 7.14 (d, 4H, 3J=7.9 Hz); 7.30 (d, 1H, 3J=8.5 Hz); 7.88 (s, 1H); 11.88 (br s, 1H); HPLC (METHOD [A]): rt 17.36 min (98.1%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]([CH3:18])[C:7](=[O:17])[CH:8]=[C:9]1[C:13](=[O:14])OC(C)(C)[O:10]1.[CH2:23]=O.[NH2:25][CH:26]([CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)[CH2:27][OH:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]([CH3:18])[C:7]([C:8]1[CH2:23][N:25]([CH:26]([CH2:27][OH:28])[CH2:29][C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)[C:13](=[O:14])[C:9]=1[OH:10])=[O:17]
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: C=O
Reactant: NC(CO)Cc1c[nH]c2ccccc12
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(C(CO)Cc2c[nH]c3ccccc23)C1

Procedure:
Compound 768 was prepared from N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide, paraformaldehyde and 2-amino-3-(1H-indol-3-yl)-propan-1-ol according to the procedures described for compound 86-A and compound 767. The title compound was isolated as a yellow solid (0.0038 g, 8% yield). 1HNMR (300 MHz, CDCl3) δ: 7.52 (1H, d, J=8.05 Hz), 7.36–7.29 (3H, m), 7.14–6.98 (4H, m), 4.46 (2H, s), 4.40–4.36 (1H, m), 3.99 (2H, s), 3.81–3.78 (2H, m), 3.11–3.08 (3H, m), 2.85 (3H, s).
Reaction SMILES: C1COCC1.C([O:13][C@H:14]1[C@H:19]([O:20]CC2C=CC=CC=2)[C@@H:18]([O:28]CC2C=CC=CC=2)[C@H:17]([O:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=2[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([CH2:51][CH3:52])=[CH:47][CH:46]=2)[C@@H:16]([OH:53])[C@@H:15]1[CH2:54][O:55]CC1C=CC=CC=1)C1C=CC=CC=1>[Pd].CO>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([O:36][C@@H:17]2[C@@H:16]([OH:53])[C@H:15]([CH2:54][OH:55])[C@@H:14]([OH:13])[C@H:19]([OH:20])[C@H:18]2[OH:28])=[C:38]([CH2:44][C:45]2[CH:46]=[CH:47][C:48]([CH2:51][CH3:52])=[CH:49][CH:50]=2)[CH:39]=1
Reactant: CCc1ccc(Cc2cc(Cl)ccc2O[C@@H]2[C@@H](O)[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc(Cl)ccc2O[C@H]2[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
14 mL of THF and methanol (1:1) was added to the flask containing the (1S,2S,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-2-(4-ethylbenzyl)phenoxy)cyclohexanol (28, 55 mg, 0.070 mmol). 55 mg of Pd/C (10%) was added in one portion to the reaction mixture. The mixture was degassed five times with H2 and the resulting suspension was stirred under an atmosphere of H2 for 3 h at ambient temperature. The reaction mixture was filtered and concentrated, and the residue was purified by preparative LC-MS to obtain 25 mg of (1R,2S,3R,4R,5S,6R)-4-(4-chloro-2-(4-ethylbenzyl)phenoxy)-6-(hydroxymethyl)cyclohexane-1,2,3,5-tetraol (29). 1H-NMR (D2O): δ 7.22˜7.2 (1H, d, J=9.2 Hz), 7.17˜7.11 (4H, q), 7.08˜7.06 (1H, dd), 6.92˜6.91 (1H, d, J=3.2 Hz), 4.11˜4.08 (1H, t J=9.2 Hz), 4.01 (2H, s), 3.92˜3.91 (2H, m), 3.69˜3.665 (1H, dd, J=10.8, 8.8 Hz), 3.46˜3.39 (2H, m), 3.35˜3.30 (1H, m), 2.66˜2.58 (2H, q), 1.52˜1.46 (1H, tt), 1.24˜1.19 (3H, t).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH2:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:19]([C:28]([F:31])([F:30])[F:29])=[N:20][N:21]([CH2:24][C:25](O)=[O:26])[C:22]=1[CH3:23].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:17][C:18]1[C:19]([C:28]([F:30])([F:29])[F:31])=[N:20][N:21]([CH2:24][C:25]([NH:16][C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH:13]([CH3:14])[CH3:15])=[O:26])[C:22]=1[CH3:23]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: CC(C)c1c(N)cnn1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)Nc1cnn(-c2ccc(F)cc2)c1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.1 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-isopropylpyrazol-4-amine (0.035 g, 0.16 mmol) in DMF (1.0 mL) was added 2-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]acetic acid (0.039 g, 0.16 mmol), followed by diisopropylethylamine (0.042 g, 0.32 mmol) and HATU (0.073 g, 0.19 mmol). After stirring at room temperature for 1 h, the reaction was diluted with water, and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.020 g, 0.045 mmol, 28%). 1H NMR (400 MHz, CDCl3) δ 7.99 (t, J=0.5 Hz, 1H), 7.74 (s, 1H), 7.35-7.24 (m, 2H), 7.20-7.11 (m, 2H), 4.92 (s, 2H), 3.02-2.90 (m, 1H), 2.39 (s, 3H), δ 1.13 (d, J=7.2 Hz, 6H); MS: (ES) m/z calculated for C19H18ClF4N5O [M+H]+ 444.1, found 443.9.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)(=O)[CH3:12]>>[CH3:12][C:11]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=1
Reactant: CC(=O)Nc1ccccn1
Reactant: O=[N+]([O-])c1ccccc1I
Product: Cc1nc2ccccc2n1-c1ccccn1
Yield: 38.2 %

Procedure:
Method A applied to 1-iodo-2-nitrobenzene (125 mg, 0.5 mmol) and 2-acetamido-pyridine (82 mg, 0.6 mmol) yielded the title compound as yellowy oil (40 mg, 38%). 1H NMR (DMSO) δ 2.74 (s, 3H), 7.42-7.49 (m, 2H), 7.56 (d, 1H), 7.70 (dd, 1H), 7.78-7.88 (m, 2H), 8.22 (dd, 1H), 8.77 (dd, 1H); 13C NMR δ 13.6, 112.0, 116.1, 121.0, 124.7, 124.9, 133.0, 135.2, 140.1, 147.2, 150.0, 151.7.