Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[NH:4][CH2:5][CH:6]([OH:9])[CH2:7][N:8]=1.C[O-].[Na+]>[N+](C1C=CC=CC=1)([O-])=O.CO>[F:11][C:2]([F:1])([F:10])[C:3]1[N:4]=[CH:5][C:6]([OH:9])=[CH:7][N:8]=1
Reactant: OC1CN=C(C(F)(F)F)NC1
Agent: C[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CO
Product: Oc1cnc(C(F)(F)F)nc1
Temperature: 121 °C
Yield: 61.7 %

Procedure:
2-(Trifluoromethyl)-1,4,5,6-tetrahydropyrimidin-5-ol (4.20 g, 25 mmol) was stirred in nitrobenzene at 90° C. Sodium methoxide (5.4 g, 100 mmol) was dissolved in methanol (75 ml) and added portionwise to the reaction mixture, allowing the methanol to distill off before the next addition. The reaction mixture was then warmed to 121° C. for one hour, cooled, shaken with water (150 ml), the organic phase separated off and the aqueous phase washed with ethyl acetate (2×100 ml). The aqueous phase was adjusted to pH 4.0 with 6M aqueous hydrochloric acid, extracted with ethyl acetate (2×100 ml), dried and evaporated to give 2.53 g (61.7%) of an orange coloured product that was used without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](#[N:24])[CH3:23]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:17]([OH:18])[CH2:23][C:22]#[N:24])[CH:19]=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(OCCCCOCc2ccccc2)c1
Reactant: CC#N
Product: N#CCC(O)c1cccc(OCCCCOCc2ccccc2)c1

Procedure:
Addition of acetonitrile to 3-(4-benzyloxybutoxy)benzaldehyde gave 3-[3-(4-benzyloxy-butoxy)-phenyl]-3-hydroxypropionitrile as yellow oil. Yield (6.3 g, 52%): 1H NMR (400 MHz, CDCl3) δ 7.33-7.37 (m, 4H), 7.27-7.32 (m, 2H), 6:93-6.96 (m, 2H), 6.86 (d, J=8.0 Hz, 1H), 5.0 (t, J=6.4 Hz, 2H), 4.52 (s, 2H), 4.01 (t, J=6.2 Hz, 2H), 3.55 (t, J=6.0 Hz, 2H), 2.75 (d, J=6.4 Hz, 2H), 1.87-1.94 (m, 2H), 1.77-1.85 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:19][CH3:20])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:24][CH:25]1[CH2:27][CH2:26]1.C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:19][CH3:20])[C:10]([N:11]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CCc1nn2c(Br)cccc2c1NC(=O)OC(C)(C)C
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1nn2c(Br)cccc2c1N(CC1CC1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl N-(7-bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)carbamate (658 mg) in N,N-dimethylformamide (15 mL) was added sodium hydride (60% in oil; 116 mg) at room temperature under a nitrogen stream, and the reaction mixture was stirred for 30 minutes. (Bromomethyl)cyclopropane (0.286 mL) was added thereto at the same temperature, and the reaction mixture was stirred for 1 hour at 60° C. After completion of the reaction, the reaction mixture was gradually added to ice, ethyl acetate was added and the organic extract was washed with water and brine, after which it was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to afford a crude product of tert-butyl N-(7-bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethylcarbamate.
Reaction SMILES: C([C@H](N[C:24](=[O:43])[C:25]1[CH:30]=[C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C:32]2=[O:36])[CH:28]=[C:27]([N:37]2[CH2:41][CH2:40][CH2:39][C:38]2=[O:42])[CH:26]=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.O=C1CCCN1C1C=C(C=C(N2CCCC2=O)C=1)C(O)=O.[CH:65]12[CH2:71][CH:68]([CH2:69][CH2:70]1)[CH2:67][CH:66]2[NH:72][C:73](=[O:90])[C@H:74]([CH2:87][C:88]#[CH:89])[CH2:75][C@H:76]([OH:86])[C@@H:77]([NH2:85])[CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1>>[CH2:78]([C@H:77]([NH:85][C:24](=[O:43])[C:25]1[CH:30]=[C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C:32]2=[O:36])[CH:28]=[C:27]([N:37]2[CH2:41][CH2:40][CH2:39][C:38]2=[O:42])[CH:26]=1)[C@@H:76]([OH:86])[CH2:75][C@H:74]([C:73](=[O:90])[NH:72][CH:66]1[CH2:67][CH:68]2[CH2:71][CH:65]1[CH2:70][CH2:69]2)[CH2:87][C:88]#[CH:89])[C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Reactant: C#CC[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Agent: O=C(O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1
Product: C#CC[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1)C(=O)NC1CC2CCC1C2

Procedure:
Prepared in an analogous manner to E5 from 3,5-bis-(2-oxopyrrolidin-1-yl)benzoic acid (D8) and (2R,4S,5S)-5-amino-4-hydroxy-6-phenyl-2-prop-2-ynylhexanoic acid bicyclo[2.2.1]hept-2-ylamide (D36).
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[CH3:9][N+:10]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24](=[S:36])[O:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[CH:15]2.C(O)(=O)C>C(Cl)Cl.C(O)(C)C.[Zn]>[CH3:9][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]([C:24](=[S:36])[O:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]1=2
Reactant: C[n+]1c2ccccc2c(C(=S)Oc2cccc3ccccc23)c2ccccc21
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CN1c2ccccc2C(C(=S)Oc2cccc3ccccc23)c2ccccc21
Reaction time: 8 h
Yield: 98.2 %

Procedure:
Naphthyl 10-methylacridinium-9-thiocarboxylate triflate (65.50 g) was suspended in CH2Cl2 (1000 mL) under argon and glacial acetic acid (21.2 ml) and zinc (40.43 g) were added. After stirring overnight, TLC showed the dissappearance of the starting material and the formation of a new product. The reaction mixture was filtered through a bed of silica gel and the CH2Cl2 removed in vacuo. The slightly yellow solid obtained was stirred in isopropanol (500 ml), filtered, washed with 500 ml more isopropanol, and allowed to air dry. The pure product (46.36 g) was thereby obtained. 1H NMR (CDCl3) δ 3.47 (s, 3H) , 5.13 (s, 1H) , 7.00-7.06 (m, 4H) , 7.25-7.49 (m, 7H) , 7.70-7.79 (m, 4H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=N1.[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[N:39]3[N:46]=[C:47]([C:49](O)=[O:50])[CH:48]=[C:38]3[N:37]=2)[CH:32]=[CH:33][C:34]=1[Cl:35].N1C=CC=CC=1CN.C(N(CC)CC)C>O1CCCC1.C(OCC)C>[N:10]1[CH:11]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:12][NH:8][C:49]([C:47]1[CH:48]=[C:38]2[N:37]=[C:36]([C:31]3[CH:32]=[CH:33][C:34]([Cl:35])=[C:29]([Cl:28])[CH:30]=3)[CH:41]=[C:40]([C:42]([F:43])([F:44])[F:45])[N:39]2[N:46]=1)=[O:50]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)c1cc2nc(-c3ccc(Cl)c(Cl)c3)cc(C(F)(F)F)n2n1
Agent: F[P-](F)(F)(F)(F)F
Agent: NCc1ccccn1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccn1)c1cc2nc(-c3ccc(Cl)c(Cl)c3)cc(C(F)(F)F)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
Benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP) (0.141 g, 0.319 mmol) was added to a suspension of 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (0.100 g, 0.265 mmol) and C-Pyridin-2-yl-methylamine (0.033 mL, 0.319 mmol) in tetrahydrofuran (10 mL) containing triethylamine (0.111 mL, 0.795 mmol). The reaction mixture was stirred overnight at room temperature, diluted with ethyl ether (10 mL) and washed with a saturated aqueous solution of sodium bicarbonate (10 mL). The organic layer was collected, concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel to give 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (pyridin-2-ylmethyl)-amide (0.073 g, 59%)
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[CH:13]1([NH2:16])[CH2:15][CH2:14]1>O1CCOCC1.CCOC(C)=O.O.[Cl-].[Na+].O>[CH:13]1([NH:16][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=2[O:11][CH3:12])[CH2:15][CH2:14]1
Reactant: COc1cccc([N+](=O)[O-])c1Br
Reactant: NC1CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc([N+](=O)[O-])c1NC1CC1
Temperature: 25 °C
Reaction time: 66 h

Procedure:
2-bromo-1-methoxy-3-nitrobenzene (10.6 g, 45.7 mmol) and cyclopropylamine (16 mL, 230 mmol) were dissolved in 1,4-dioxane (50 mL). The stirred mixture was heated mixture in sealed flask to 115 C. After 66 h, mixture was cooled to r.t. and was diluted with EtOAc (100 mL), water (100 mL) and brine (50 mL). The phases were separated and extracted with EtOAc (100 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated. The concentrate was purified by silica gel chromatography (0-20% EtOAc in hexanes) to afford N-cyclopropyl-2-methoxy-6-nitroaniline. LCMS-ESI+ (m/z): [M+H]+ calcd for C10H13N2O3: 209.09; found: 209.96.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([CH:19]=[C:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:27]=1.C(N(CC)CC)C>CS(C)=O.O>[F:1][C:2]1[CH:18]=[C:17]([CH:16]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=2)[CH:3]=1)[CH:19]=[C:20]1[CH2:25][CH2:24][N:23]([C:33]([NH:32][C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)=[O:34])[CH2:22][CH2:21]1
Reactant: Fc1cc(C=C2CCNCC2)cc(Oc2ccc(C(F)(F)F)cn2)c1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1cccnc1)N1CCC(=Cc2cc(F)cc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Reaction time: 8 h
Yield: 79.6 %

Procedure:
2-(3-Fluoro-5-(piperidin-4-ylidenemethyl)phenoxy)-5-(trifluoromethyl)pyridine (469 mg, 1.33 mmol) and phenyl pyridin-3-ylcarbamate (273 mg, 1.33 mmol) were dissolved in DMSO (4 mL) and triethylamine (0.53 mL, 3.83 mmol) was added. The reaction was stirred overnight. The reaction mixture was diluted with water and extracted with ethyl acetate three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by silica gel column chromatography (35% acetone in hexane) to give the title compound (500 mg, 80%). 1H NMR (500 MHz, CDCl3): δ 8.51 (s, 1H), 8.45 (s, 1H), 8.27 (d, J=4.5 Hz, 1H), 8.08 (d, J=8 Hz, 1H), 7.95 (d, J=9 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 6.82 (m, 3H), 6.71 (s, 1H), 6.37 (s, 1H), 3.64 (t, J=5.5 Hz, 2H), 3.56 (t, J=5.5 Hz, 2H), 2.63 (m, 2H), 2.49 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 165.15, 163.96, 161.99, 154.67, 153.88, 153.79, 145.40, 143.56, 141.00, 140.15, 140.07, 139.38, 136.97, 136.44, 127.78, 124.64, 123.69, 122.49, 122.23, 121.97, 117.60, 112.87, 112.70, 111.71, 107.56, 107.37, 45.59, 44.54, 35.70, 29.18; m/z (473.4 M+ H+); HPLC: 96.6%.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH:7]=[C:8]([C:14](=O)[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2].[NH:19]1[C:23]([NH2:24])=[N:22][C:21]([NH2:25])=[N:20]1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:24][C:23]1[N:22]=[C:21]2[NH:25][C:14]([CH3:15])=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]([C:6]3[CH:17]=[CH:18][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[N:20]2[N:19]=1
Reactant: Nc1n[nH]c(N)n1
Reactant: CCOC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)Nc2nc(N)nn2C1c1ccc(C#N)cc1
Temperature: 63 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, ethyl 2-(4-cyanobenzylidene)-3-oxobutanoate (12.2 g, 50.1 mmol; preparation see WO 2004/020410-A2, Example 32A) and 1H-1,2,4-triazole-3,5-diamine (6.0 g, 60.5 mmol, 1.2 eq.) were dissolved in DMF (150 ml). Solid sodium bicarbonate (30.7 g, 365.6 mmol, 6 eq.) was added, and the mixture was stirred at 63° C. for 12 h. The mixture was then filtered and the DMF was distilled off from the filtrate under reduced pressure. The residue was suspended in ethanol and stirred, and the product was then filtered off and dried under high vacuum. This gave 12.45 g (76% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:22]([Br:23])=[CH:21][C:20]([Br:24])=[CH:19][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH2:12][C:13]([O:15]CC)=[O:14])=[CH:8][C:7]=1[CH3:18])=[O:5].C(I)CCCCC>>[CH2:12]([C:9]1[N:10]([CH3:11])[C:6]([C:4](=[O:5])[C:3]2[CH:19]=[C:20]([Br:24])[CH:21]=[C:22]([Br:23])[C:2]=2[Br:1])=[C:7]([CH3:18])[CH:8]=1)[CH3:13].[CH2:9]([CH2:12][C:13]([O-:15])=[O:14])[CH2:8][CH2:7][CH2:6][CH2:4][CH3:3]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2cc(Br)cc(Br)c2Br)n1C
Solvent: CCCCCCI
Product: CCCCCCCC(=O)[O-]
Product: CCc1cc(C)c(C(=O)c2cc(Br)cc(Br)c2Br)n1C

Procedure:
The alkylation procedure of Example 77A is performed upon ethyl 5-(2',3',5'-tribromobenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 91), using an equivalent quantity of n-hexyl iodide instead of methyl iodide used in Example 77A to yield ethyl 5-(2',3',5'-tribromobenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetate.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[CH3:17][C:7]1[C:6]2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=[C:2]([C:26]3[CH:25]=[CH:24][C:23]([O:22][C:21]([F:20])([F:32])[F:33])=[CH:28][CH:27]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]=12
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: Cc1c2n(c3c(-c4ccc(OC(F)(F)F)cc4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, light grey solid (81 mg, 81%), MS (ISP) m/z=400.6 [(M+H)+], mp 218° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 4-trifluoromethoxy-phenylboronic acid (66.9 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][C:2](=[N:20][N+:21]([O-:23])=[O:22])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:10])[NH2:8].[C:24]1([CH2:30][C:31](O)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:1][C:2](=[N:20][N+:21]([O-:23])=[O:22])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:9]([NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)=[O:10])[NH:8][C:31](=[O:32])[CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](N)C(=O)NCc1ccc(O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: NC(=N[N+](=O)[O-])NCCC[C@@H](NC(=O)Cc1ccccc1)C(=O)NCc1ccc(O)cc1
Yield: 61 %

Procedure:
Prepared analogously to Example 5f) from (R)-N5 -[amino (nitroimino) methyl]-N-[(4-hydroxyphenyl) methyl]ornithinamide, phenylacetic acid and TBTU in a yield of 61% of theory. It was further processed without purification.
Reaction SMILES: [NH2:1][C:2](=[N:41][OH:42])[C:3]1[CH:4]=[CH:5][C:6]([CH3:40])=[C:7]([N:9]([CH2:26][C:27]([N:29]([N:31]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32]2)[CH3:30])=[O:28])[CH2:10][C:11]([NH:13][CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH3:18])=[O:12])[CH:8]=1.[F:43][CH:44]([F:48])[C:45](O)=O.CCN=C=NCCCN(C)C>O1CCOCC1.C(OCC)(=O)C.CCCCCC>[F:43][CH:44]([F:48])[C:45]1[O:42][N:41]=[C:2]([C:3]2[CH:4]=[CH:5][C:6]([CH3:40])=[C:7]([N:9]([CH2:26][C:27]([N:29]([N:31]3[CH2:32][C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:39]3)[CH3:30])=[O:28])[CH2:10][C:11]([NH:13][CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:17][CH3:18])=[O:12])[CH:8]=2)[N:1]=1
Reactant: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc(C(N)=NO)ccc1C)C(=O)OC(C)(C)C
Reactant: O=C(O)C(F)F
Agent: CCN=C=NCCCN(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc(-c2noc(C(F)F)n2)ccc1C)C(=O)OC(C)(C)C
Yield: 21.7 %

Procedure:
The compound (406 mg, 0.698 mmol) of step A, difluoroacetic acid (0.12 ml, 1.90 mmol) and WSC (530 mg, 2.76 mmol) were dissolved in 1,4-dioxane (5 ml) and the mixture was heated under reflux for 5 hr. The reaction mixture was diluted with an ethyl acetate-hexane=1:1 mixed solvent, and the organic layer was washed with water, 10% aqueous citric acid solution, diluted aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane→ethyl acetate-methanol) to give the title compound (97 mg, yield 22%) as a pale-yellow amorphous solid
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[O:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+].CC1C=CC(S(O[CH:62]2[CH2:65][CH:64]([C:66]([O:68][CH3:69])=[O:67])[CH2:63]2)(=O)=O)=CC=1>CN(C=O)C>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][NH:19][C:17]([C:15]2[CH:14]=[CH:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH:62]5[CH2:65][CH:64]([C:66]([O:68][CH3:69])=[O:67])[CH2:63]5)=[CH:3][CH:4]=4)[CH:9]=[N:10][C:11]=3[CH:16]=2)=[O:18])[CH:22]=1
Reactant: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1ccc(O)cc1
Reactant: COC(=O)C1CC(OS(=O)(=O)c2ccc(C)cc2)C1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1CC(Oc2ccc(-n3cnc4cc(C(=O)NCc5cccnc5)ccc43)cc2)C1
Temperature: 80 °C

Procedure:
Methyl 3-hydroxycyclobutanecarboxylate (671 mg, 5.16 mmol) was dissolved in CH2Cl2 (20 mL). Pyridine (0.63 mL, 7.73 mmol) was then added followed by p-toluenesulfonic anhydride (1.85 g, 5.67 mmol) and the reaction was stirred at rt for 14 h. The reaction was concentrated in vacuo, dissolved in ether, and washed with H2O, 2M HCl, 2M NaHCO3, brine, and dried over MgSO4. The solution was then filtered, and concentrated in vacuo to give methyl 3-{[(4-methylphenyl)sulfonyl]oxy}cyclobutanecarboxylate as a colorless oil, which was taken on crude. 1-(4-Hydroxyphenyl)-N-(pyridin-3-ylmethyl)-1H-benzimidazole-5-carboxamide (0.88 g, 2.56 mmol), 18-crown-6 (1.36 g, 5.13 mmol), and K2CO3 (0.71 g, 5.13 mmol) were dissolved in DMF (26 mL) in a 50 mL round bottom flask. The reaction was heated to 80° C. under N2 atmosphere upon which methyl 3-{[(4-methylphenyl)sulfonyl]oxy}cyclobutanecarboxylate was added drop-wise. After heating at 80° C. for 48 h, the reaction was cooled to rt, concentrated in vacuo, and purified using silica gel chromatography (5% methanol:CH2Cl2). To remove residual p-toluenesulfonic acid and 18-crown-6, the foamy white solid was washed with ethyl acetate. The combined organic washes were then washed with water and dried over MgSO4, filtered, and concentrated in vacuo to provide methyl 3-(4-{5-[(pyridin-3-ylmethylamino)carbonyl]-1H-benzimidazol-1-yl}phenoxy)cyclobutanecarboxylate as an off-white foamy solid (3:1 trans:cis isomers). MS (ES+): m/z 457 (100) [MH+].
Reaction SMILES: [BH4-].[Li+].CO[C:5](=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:14][C:13]2[CH:15]=[C:16]([CH:19]([OH:27])[CH2:20][CH2:21][C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[CH:17]=[CH:18][C:12]=2[O:11]1.CC[O:31]CC>>[OH:27][CH:19]([C:16]1[CH:17]=[CH:18][C:12]2[O:11][CH:10]([CH:9]([OH:31])[CH2:8][CH2:7][CH2:6][CH3:5])[O:14][C:13]=2[CH:15]=1)[CH2:20][CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOCC
Reactant: COC(=O)CCCCC1Oc2ccc(C(O)CCc3cccs3)cc2O1
Agent: [BH4-]
Agent: [Li+]
Product: CCCCC(O)C1Oc2ccc(C(O)CCc3cccs3)cc2O1
Reaction time: 1 h
Yield: 98 %

Procedure:
Lithium borohydride (2.1 mg, 0.096 mmol) was added to a solution of (±)-methyl-5-[[6-(1-hydroxy-3-(2-thienyl)propyl]-1,3-benzodioxolyl]pentanoate (Compound 73, 36.0 mg, 0.096 mmol) in Et2O (2.0 mL) at 23° C. After 12 hours the reaction was quenched with 1N NaOH, stirred 1 hour, and extracted with EtOAc. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 2:1 hex/EtOAc) provided 32.6 mg (98%) of the title compound. 1H NMR (300 MHz, CDCl3) δ 7.14 (d, J=5.5 Hz, 1H), 7.01 (s, 1H), 6.93 (dd, J=3.3, 5.5 Hz, 1H), 6.84 (d, J=3.3 Hz, 1H), 6.61 (s, 1H), 5.92 (s, 2H), 4.88-4.92 (m, 1H), 3.63 (t, J=5.7 Hz, 2H), 2.97-3.03 (m, 2H), 2.43-2.49 (m, 2H), 1.84-2.20 (m, 3H), 1.26-1.59 (m, 7H).
Reaction SMILES: [F:1][CH:2]([F:16])[CH:3]([OH:15])[CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[O:8][N:7]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C.C1COCC1>O>[F:16][CH:2]([F:1])[CH:3]([O:15][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[O:8][N:7]=1
Reactant: COC(=O)c1cc(OCC(O)C(F)F)no1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1cc(OCC(OS(C)(=O)=O)C(F)F)no1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 3-(3,3-difluoro-2-hydroxypropoxy)isoxazole-5-carboxylate (370 mg), methanesulfonyl chloride (0.362 mL), triethylamine (0.652 mL) and THF (10 mL) was stirred at 0° C. for 1 hr, and then at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a colorless oil (432 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][CH:24]([C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1)[CH3:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20]([NH:32][CH2:31][C:29]3[O:28][N:27]=[C:26]([CH:24]([CH3:25])[CH3:23])[N:30]=3)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1noc(CN)n1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Product: CC(C)c1noc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(OCC(F)(F)F)cn2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example D) and 3-(1-methylethyl)-1,2,4-oxadiazole-5-methanamine (CAN 936940-67-9) as starting materials, LC-MS (UV peak area/ESI) 97.2%, 455.1099 (M+H)+.