Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[N:11][C:10]=2[C:18]([NH:20][O:21][CH2:22][CH2:23][O:24]C=C)=[O:19])=[C:4]([F:27])[CH:3]=1.Cl.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>CO.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[N:11][C:10]=2[C:18]([NH:20][O:21][CH2:22][CH2:23][OH:24])=[O:19])=[C:4]([F:27])[CH:3]=1
Reactant: C=COCCONC(=O)c1ncc2cncn2c1Nc1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(NOCCO)c1ncc2cncn2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 5-(4-bromo-2-fluorophenylamino)-N-(2-(vinyloxy)ethoxy)-imidazo[1,5-a]pyrazine-6-carboxamide (150 mg, 0.34 mmol) in methanol (4.5 mL) and dichloromethane (8.9 mL) was added 4M HCl in 1,4-dioxane (0.13 mL, 0.5 mmol, 1.5 eq.), and the reaction mixture was stirred at ambient temperature under N2 for 1 h. Solid sodium carbonate (50 mg) was added to the reaction mixture. The reaction mixture was absorbed onto silica and then subjected to flash chromatography (Si-PPC, gradient 0% to 15%, methanol in dichloromethane) to afford the title compound as a white solid. (112.1 mg, 79.5%). 1H NMR (DMSO-d6, 400 MHz) δ ppm 11.85 (broad s, 1H), 10.32 (broad s, 1H), 8.83 (s, 1H), 7.97 (s, 1H), 7.92 (s, 1H), 7.64 (dd, J=10.4 Hz, 2.6 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 6.77 (t, J=8.8 Hz, 1H), 4.68 (t, J=5.6 Hz, 1H), 3.89 (t, 4.8 Hz, 2H), 3.59 (q, J=5.4 Hz, 2H); LCMS (method D1): RT=0.786 min, [M+H]+=410/412.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[N+:16]([C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([NH2:27])=[N:24][C:23]=2[CH:28]=1)([O-:18])=[O:17]>>[OH:14][CH:3]1[CH:4]([NH:27][C:25]2[S:26][C:22]3[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:28][C:23]=3[N:24]=2)[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=2)[O:11][C:2]1([CH3:15])[CH3:1]
Reactant: Nc1nc2cc([N+](=O)[O-])ccc2s1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Product: CC1(C)Oc2ccc(C#N)cc2C(Nc2nc3cc([N+](=O)[O-])ccc3s2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 5-nitro-benzothiazol-2-ylamine as starting material, the title compound was prepared as white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.Cl.[C@H:13]12[CH2:19][C@H:16]([NH:17][CH2:18]1)[CH2:15][N:14]2[C:20]([C@@:22]1([CH2:36][CH:37]([F:39])[F:38])[CH2:26][CH2:25][C@@H:24]([NH:27][C@@H:28]2[C@H:33]([O:34][CH3:35])[CH2:32][O:31][CH2:30][CH2:29]2)[CH2:23]1)=[O:21].C(N(CC)CC)C>CS(C)=O>[F:39][CH:37]([F:38])[CH2:36][C@:22]1([C:20]([N:14]2[CH2:15][C@@H:16]3[CH2:19][C@H:13]2[CH2:18][N:17]3[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=2)=[O:21])[CH2:26][CH2:25][C@@H:24]([NH:27][C@@H:28]2[C@H:33]([O:34][CH3:35])[CH2:32][O:31][CH2:30][CH2:29]2)[CH2:23]1
Reactant: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@](CC(F)F)(C(=O)N2C[C@@H]3C[C@H]2CN3)C1
Reactant: FC(F)(F)c1cccc(Cl)n1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@](CC(F)F)(C(=O)N2C[C@@H]3C[C@H]2CN3c2cccc(C(F)(F)F)n2)C1
Temperature: 120 °C

Procedure:
Prepared as described in example 24 using 2-chloro-6-(trifluoromethyl)pyridine in place of 4-chloro-6-(trifluoromethyl)pyrimidine and modifying step 9 as follows. To a solution of HCl salt of 1,5-anhydro-2,3-dideoxy-3-{[(1R,3S)-3-{[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-(2,2-difluoroethyl)cyclopentyl]amino}-4-O-methyl-D-erythro-pentitol (183 mg, 0.43 mmol) in DMSO (2 ml) was added triethylamine (0.2 ml, 1.43 mmol) and 2-chloro-6-(trifluoromethyl)pyridine (179 mg, 1.05 mmol). The reaction was heated to 120° C. for 14.5 hours. The reaction was cooled to room temperature, and added to stirring ice water. The mixture was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over MgSO4 concentrated under reduced pressure and purified with the Biotage (0-100% methanol/ethyl acetate, 15 column volumes) to give 1,5-anhydro-2,3-dideoxy-3-{[(1R,3S)-3-(2,2-difluoroethyl)-3-({(1S,4S)-5-[6-(trifluoromethyl)pyridin-2-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}carbonyl)cyclopentyl]amino}-4-O-methyl-D-erythro-pentitol as a brown foam (58 mg 28%). LC/MS (M+H)=533.2551 exp, 533.2546 obs; 1H NMR (400 MHz, CDCl3) δ ppm 7.54-7.51 (1H), 6.91-6.89 (1H), 6.51-6.38 (1H), 5.94-5.54 (1H), 5.11-4.70 (2H), 4.06-4.01 (1H), 3.93-3.87 (1H), 3.70-3.53 (2H), 3.51-3.31 (6H), 3.27-3.20 (3H), 2.78-2.61 (1H), 2.53-2.36 (1H), 2.20-1.80 (7H), 1.68-1.38 (5H)
Reaction SMILES: O=[CH:2][CH2:3][C@H:4]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[NH2:20][C:21]1([C:26]([O:28][CH3:29])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.O>[C:14]([O:13][C:12]([NH:11][C@H:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:2][NH:20][C:21]1([C:26]([O:28][CH3:29])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)C1(N)CCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(NCC[C@H](NC(=O)OC(C)(C)C)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of tert-butyl [(1S)-3-oxo-1-phenylpropyl]carbamate from Step B (0.820 g, 3.29 mmol) and methyl 1-aminocyclopentanecarboxylate hydrochloride (0.591 g, 3.29 mmol) in chloroform (33 mL) was added Hunig's base (0.574 mL, 3.29 mmol). After stirring at ambient temperature for 20 min, NaHB(OAc)3 (1.74 g, 8.22 mmol) was added as a solid. Upon completion of the reaction, saturated aqueous NaHCO3 (3 mL) was added and the mixture was allowed to stir for at least 2 h. Water (5 mL) and additional saturated NaHCO3 (3 mL) was then added to form two layers. The aqueous layer was extracted once with chloroform (50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by silica gel chromatography, eluting with a gradient of MeOH:DCM 1:99 to 6:94, to give the title compound. MS: m/z=377 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][CH2:11][C:12]2([CH2:17][CH2:18][CH3:19])[O:16][CH2:15][CH2:14][O:13]2)[CH:5]=[CH:4][N+:3]=1[O-]>C(OC(=O)C)(=O)C>[C:12]([O:16][CH2:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][CH2:11][C:12]2([CH2:17][CH2:18][CH3:19])[O:16][CH2:15][CH2:14][O:13]2)[CH:5]=[CH:4][N:3]=1)(=[O:13])[CH3:11]
Reactant: CCCC1(CCOc2cc[n+]([O-])c(C)c2C)OCCO1
Solvent: CC(=O)OC(C)=O
Product: CCCC1(CCOc2ccnc(COC(C)=O)c2C)OCCO1
Temperature: 80 °C
Reaction time: 8 h
Yield: 135.3 %

Procedure:
The 2,3-dimethyl-4-(2-(2-propyl-1,3-dioxolan-2-yl)ethoxy)pyridine1-oxide (1.53 g, 5.44 mmol) obtained in the step (3c) was mixed with acetic anhydride (30 ml) and the mixture was stirred at 80° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate and then subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=1/1) to obtain the title compound (1.19 g, 67.6%) as a light yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]([CH:14]3[CH2:16][CH2:15]3)=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22](B(O)O)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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>[CH:14]1([C:11]2[O:10][C:9]([C:4]3[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:22]4[CH:21]=[C:20]5[C:25](=[CH:24][CH:23]=4)[NH:17][CH:18]=[CH:19]5)[CH:3]=3)=[N:13][N:12]=2)[CH2:16][CH2:15]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Nc1ncc(Br)cc1-c1nnc(C2CC2)o1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncc(-c2ccc3[nH]ccc3c2)cc1-c1nnc(C2CC2)o1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
5-Bromo-3-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-pyridin-2-ylamine (200 mg, 0.71 mmol), 5-indolyl boronic acid (112 mg, 0.78 mmol), K2CO3 (290 mg, 2.13 mmol), 1,4-dioxane (10.0 mL) and water (4.0 mL) were taken in a sealed tube and degassed with nitrogen for 15 min. Then Pd(PPh3)4 (41 mg, 0.03 mmol) was added and stirred for 18 h at 100° C. The reaction mixture was diluted with ice-cold water and extracted with EtOAc. The combined extracts were dried over Na2SO4 and evaporated under reduced pressure to get crude 3-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-5-(1H-indol-5-yl)-pyridin-2-ylamine. Crude compound was purified by column chromatography using silica gel (100-200 mesh). The column was eluted with 30% EtOAc in petroleum ether to afford the title compound as a pale yellow solid.
Reaction SMILES: IC1C=CC(C2NC([C@@H](N3C(=O)[C@@H](CCC(O)=O)NC3=O)C(C)C)=NC=2)=CC=1.C(OC(=O)N[C@H](C1NC(C2C=CC=CC=2F)=CN=1)[C@H](C1C=CC=CC=1)C)(C)(C)C.ClN1C(=O)CCC1=O.C(OC(N[C@H](C1C=CC(OCC(=O)N(C)C)=CC=1)C(O)=O)=O)(C)(C)C.[C:91]([O:95][C:96]([NH:98][C@H:99]([C:103]1[CH:108]=[CH:107][C:106]([O:109][CH2:110][CH2:111][O:112][C:113](C)(C)C)=[CH:105][CH:104]=1)[C:100]([OH:102])=[O:101])=[O:97])([CH3:94])([CH3:93])[CH3:92].BrCCOC>>[C:91]([O:95][C:96]([NH:98][C@H:99]([C:103]1[CH:104]=[CH:105][C:106]([O:109][CH2:110][CH2:111][O:112][CH3:113])=[CH:107][CH:108]=1)[C:100]([OH:102])=[O:101])=[O:97])([CH3:94])([CH3:93])[CH3:92]
Reactant: CC(C)(C)OCCOc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CC(C)[C@@H](c1ncc(-c2ccc(I)cc2)[nH]1)N1C(=O)N[C@H](CCC(=O)O)C1=O
Agent: CN(C)C(=O)COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: COCCBr
Product: COCCOc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
Prepared by the same method as described in example 1 except that (i) (2S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid was used in place of (2S,3S)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid in step 53-E; (ii) chlorination of the 5-position of the imidazole ring with N-chlorosuccinimide in step 53-F was omitted and (iii) (R)-tert-butoxycarbonylamino-[4-(2-methoxy-ethoxy)-phenyl]-acetic acid was in place of (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid in step 53-G. (R)-tert-Butoxycarbonylamino-[4-(2-methoxy-ethoxy)-phenyl]-acetic acid was prepared as described in example 1 for the preparation of (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid except that 1-bromo-2-methoxy-ethane was used in place of 2-(2-iodo-ethoxy)-2-methyl-propane. HR-MS: calcd for C29H26FlN4O4 [M+H+] 641.1056. Found 641.1053.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1.O>C([O-])(O)=O.[Na+].C(OCC)C>[OH:5][C:4]1[CH:3]=[C:2]([O:10][S:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[CH:13]=2)(=[O:20])=[O:19])[CH:9]=[C:7]([CH3:8])[CH:6]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.6 %

Procedure:
Orcinol monohydrate (1.42 g, 10 mmol) and 3-chlorobenzenesulfonyl chloride (2.43 g, 11 mmol) were mixed in saturated NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at room temperature for 2 days. After adding water (50 mL) to the mixture, the mixture was extracted with ethyl acetate (3×50 mL). The organic phase was then washed with brine (2×50 mL) and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (2% ethyl acetate in methylene chloride) to give the title compound as a pale-yellow liquid (2.08 g, 69%). 1H-NMR (300 MHz, CDCl3) δ 2.24 (s, 3 H), 5.32 (s, 1 H), 6.33 (t, 1 H, J=2.2 Hz), 6.40 (s, 1 H), 6.57 (s, 1 H), 7.48 (t, 1 H, J=8.0 Hz), 7.65 (m, 1 H), 7.73 (m, 1 H), and 7.86 (t, 1 H, J=1.8 Hz).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:7][OH:8])([CH2:5][OH:6])[CH3:4].[CH3:9][C:10]([CH3:12])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(=O)C.[Na+]>O>[OH:1][CH2:2][C:3]1([CH3:4])[CH2:7][O:8][C:10]([CH3:12])([CH3:9])[O:6][CH2:5]1
Reactant: CC(C)=O
Reactant: CC(CO)(CO)CO
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Product: CC1(CO)COC(C)(C)OC1
Yield: 90 %

Procedure:
A mixture of 30 g of 1,1,1-tris(hydroxymethyl)ethane (Aldrich Chemical Co., Milwaukee, WI), 85 ml of acetone and 80 ml of petroleum ether (b.p. 30°-75° C.) was acidified with 1.0 g of p-toluenesulfonic acid monohydrate and this mixture was refluxed for 24 hours with removal of water by azeotropic distillation. This was followed by neutralization with 1 g of sodium acetate and complete drying with anhydrous sodium sulfate. The liquid was filtered and the solvents removed under reduced pressure. The residue was distilled under vacuum to give 5-hydroxymethyl-2,2,5-trimethyl-1,3-dioxane in 90% yield.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.OO>CO>[CH:8]1[CH:7]=[C:5]2[N:6]=[C:2]([S:1][S:1][C:2]3[S:3][C:4]4[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:6]=3)[S:3][C:4]2=[CH:10][CH:9]=1
Reactant: Sc1nc2ccccc2s1
Agent: OO
Solvent: CO
Product: c1ccc2sc(SSc3nc4ccccc4s3)nc2c1
Temperature: 20 °C

Procedure:
To a reactor fitted with a stirrer, condenser and addition funnel was charged 20 parts of mercaptobenzothiazole (MBT) and 160 parts of methanol. The mixture was heated and refluxed at atmospheric pressure until the MBT dissolved. To the solution was then mixed, by adding dropwise, 46.8 parts of a methanol solution of 30 weight percent hydrogen peroxide which had been prepared by dissolving 6.8 parts of 30 weight percent hydrogen peroxide in 40 parts methanol while stirring the mixture at reflux. After the addition, the resultant mixture was stirred for an additional 20 minutes. The mixture was then allowed to cool to about 20° C. and was filtered. The dibenzothiazolyl disulfide produced was dried under vacuum at 40° C. and its melting point determined to be 180° C. The melting point was determined with a capillary tube with a heating rate of 1° C. per minute. In the conduct of the reaction, only water was formed as a byproduct instead of the typical organic impurity precipitates mixed with the disulfide which typically occur during the oxidation of the sodium salt of the mercaptobenzothiazole in an aqueous solution.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[N:9]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:12]2[CH2:13][CH2:14][CH2:15][N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11]2)[CH:7]=1
Reactant: Cc1ccnc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccnc(N2CCCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 140 °C

Procedure:
2-Bromo-4-methylpyridine (400 mg, 2.326 mmol), tert-butyl 1,4-diazepane-1-carboxylate (2.1 g, 10.5 mmol) and potassium carbonate (2.8 g, 20 mmol) were combined in anhydrous DMF (20 ml) and heated under microwave heating at 140° C. for 5 hours. The mixture was poured into water and extracted with ethyl acetate (4×). The combined organic layers were washed with brine (2×) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified two times by column chromatography (silica, gradient from 0 to 50% ethyl acetate in heptane) to yield 97 mg (0.33 mmol, 14%). MS (ESI) m/z=292.2 [M+1]+.
Reaction SMILES: [OH:1]CC1NC(=O)CC1.[CH:9]1([C@H:15]2[CH2:19][NH:18][C@H:17]([CH2:20][OH:21])[CH2:16]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C1([C@@H]2N3C(=O)CCC3CO2)C=CC=CC=1>>[CH:9]1([C@H:15]2[CH2:19][NH:18][C@H:17]([C:20]([OH:1])=[O:21])[CH2:16]2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=C1CCC(CO)N1
Reactant: OC[C@@H]1C[C@@H](C2CCCCC2)CN1
Agent: O=C1CCC2CO[C@H](c3ccccc3)N12
Product: O=C(O)[C@@H]1C[C@@H](C2CCCCC2)CN1

Procedure:
(trans)-4-Cyclohexyl-L-proline was prepared from 5-hydroxymethyl-2-pyrrolidone using the procedure described in Example 1, but substituting the following methodology for preparing (2-S-trans)-4-cyclohexyl-2-pyrrolidinemethanol from (R)-tetrahydro-3-phenyl-3H,5H-pyrrolo[1,2-c]oxazol-5-one:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]([OH:19])=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[NH2:20][C@@H:21]([CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)=[O:23]>>[CH2:41]([O:40][CH2:39][C@H:21]([NH:20][C:17](=[O:19])[CH2:16][N:13]1[CH2:12][CH2:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=2)[CH2:15][CH2:14]1)[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)=[O:23])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: COc1ccc(N2CCN(CC(=O)O)CC2)cc1
Agent: Cl
Product: COc1ccc(N2CCN(CC(=O)N[C@@H](COCc3ccccc3)C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)CC2)cc1
Yield: 35.1 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(4-methoxyphenyl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 224, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(4-methoxyphenyl)piperazin-1-yl)acetamido)propanamide (17.2 g, 35.1%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 8.00 (d, 1H), 7.60 (d, 2H), 7.30-7.65 (m, 5H), 7.19-7.25 (m, 2H), 6.98-7.04 (m, 4H), 6.87-6.90 (d, 2H), 6.81-6.84 (d, 2H), 4.71 (m, 1H), 4.52 (s, 2H), 3.70-3.80 (m, 2H), 3.69 (s, 3H), 3.06 (s, 2H), 3.02 (m, 4H), 2.59-2.67 (m, 4H). MS (EI) for C35H37FN4O5. found 613.6 (MH+).
Reaction SMILES: [F:1]/[C:2](=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)/[CH:3]=O.Cl[C:25](Cl)([F:30])[C:26]([O:28][CH3:29])=[O:27]>>[F:30]/[C:25](=[CH:3]\[C:2](\[F:1])=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)/[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)C(F)(Cl)Cl
Reactant: O=C/C(F)=C/CCCCCCCOc1ccc2ccccc2n1
Product: COC(=O)/C(F)=C/C(F)=C/CCCCCCCOc1ccc2ccccc2n1

Procedure:
(Z)-2-Fluoro-10-(2-quinolinyloxy)dec-2-ene-1-al, prepared as in compound 45 was reacted with methyl dichlorofluoroacetate as in compound 40 to give (2Z,4Z) methyl 2,4-difluoro-12-(2-quinolinyloxy)dodeca-2,4-dienoate. The latter was converted to the title compound an analogy with compound 33.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:23][C:24]1[C:28]([C:29]([OH:31])=O)=[C:27]([CH2:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:26][N:25]=1.C(N(C(C)C)C(C)C)C.[CH2:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:53][CH2:52][NH:51]1>CN(C=O)C.C(Cl)(Cl)Cl>[CH2:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:53][CH2:52][N:51]1[C:29]([C:28]1[C:24]([CH3:23])=[N:25][O:26][C:27]=1[CH2:32][C:33]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:40])=[O:31]
Reactant: Cc1noc(CC(=O)c2ccccc2)c1C(=O)O
Reactant: c1ccc2c(c1)CCNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1noc(CC(=O)c2ccccc2)c1C(=O)N1CCc2ccccc2C1
Temperature: 25 °C

Procedure:
A solution of TBTU (0.48 g, 1.5 mmol, 1.5 eq.) in DMF (2 mL) was added to a mixture of 3-methyl-5-(2-oxo-2-phenylethyl)isoxazole-4-carboxylic acid (0.24 g, 1 mmol, 1 eq), N-ethyl-N-isopropylpropan-2-amine (0.18 mL, 1 eq) and 1,2,3,4-tetrahydroisoquinoline (0.12 mL, 1 eq) in DMF (1 mL). The resulting solution was stirred at room temperature. Chloroform (25 mL) was added and the solution was washed with water and 1 M HCl, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (SiO2 1:2 heptane/EtOAc) to afford the title compound. MS (ESI, POS. ION) M/Z Calcd for C22H20N2O3: 360.1474, found 360.1472.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[OH-].[Na+].[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1>CO>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][O:9][C:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:21])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)O1
Reactant: Cc1ncc([N+](=O)[O-])n1CCO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ncc([N+](=O)[O-])n1CCOC(=O)CCC(=O)O
Temperature: 8 °C
Reaction time: 12 h
Yield: 94 %

Procedure:
In a 100 mL reactor with 10 mL of methanol at a temperature about 60° C., add 0.315 g of metronidazole, 2.0 mL of NaOH 1N, 0.2 g of succinic anhydride and keep the reaction medium under stirring and heating for about 2 hours. Cool the reaction medium to a temperature around 8° C. and allow it to stand for 12 hours. The reaction medium is filtered and the solvent is evaporated to dryness yielding 0.47 g of metronidazole monosuccinate. (Yield=94%)
Reaction SMILES: [Al].[Cl:2][C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[I:12]N1C(=O)CCC1=O>CN(C=O)C>[Cl:2][C:3]1[N:8]=[CH:7][NH:6][C:5]2=[N:9][CH:10]=[C:11]([I:12])[C:4]=12
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1ncnc2[nH]ccc12
Agent: [Al]
Solvent: CN(C)C=O
Product: Clc1nc[nH]c2ncc(I)c1-2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 250 ml round-bottomed flask, protected from light with aluminum foil, are added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine 1 (2.15 g, 14.0 mmol) and N-iodosuccinimide (3.37 g, 14.98 mmol) dissolved in anhydrous DMF. The reaction mixture is stirred at room temperature under nitrogen for 16 hrs. The solvent is removed in vacuo, and the residue is dissolved in methylene chloride (250 ml). The reaction mixture is washed with brine (50 ml), and the organic layer is separated, dried over Na2SO4, and concentrated in vacuo. The crude residue is purified by flash-chromatography on silica gel and eluted with 60% EtOAc in cyclohexane. Fractions containing the desired product (TLC) are pooled and evaporated to afford 4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidine as a pale-yellow solid.