Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].CCN(CC)CC.[C:30](N1C=CN=C1)(N1C=CN=C1)=[O:31].FC(F)(F)C(O)=O.[NH2:49][C@H:50]([CH2:54][CH:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1)[C:51]([OH:53])=[O:52].[N-]1C=CN=C1>CN(C=O)C>[C:19]([O:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][CH2:11][C@H:3]([NH:2][C:30]([NH:49][C@@H:50]([C:51]([OH:53])=[O:52])[CH2:54][CH:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1)=[O:31])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N[C@H](CC1CCCCC1)C(=O)O
Agent: Cl
Agent: c1c[n-]cn1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)N[C@H](CC1CCCCC1)C(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Commercial tert-butyl(S)-2-amino-6-tert-butoxycarbonylaminohexanoate hydrochloride (1.95 g, 5.75 mmol) was mixed in 30 ml of DMF with NEt3 (0.8 ml, 5.754 mmol) and 1,1′-carbonyldiimidazole (0.933 g, 5.754 mmol) and stirred at RT for 30 min. Then (R)-2-amino-3-cyclohexylpropanoic acid trifluoroacetate (1.64 g, 5.754 mmol) and NEt3 (1.6 ml, 11.5 mmol) were added, and the mixture was heated at 80° C. until the imidazolide formed as intermediate was completely converted. The product was purified by flash chromatography on silica gel (CH2Cl2/MeOH gradient). Yield: 2.1 g (73%) of tert-butyl(S)-6-tert-butoxycarbonylamino-2-[3-((R)-1-carboxy-2-cyclohexylethyl)-ureido]-hexanoate.
Reaction SMILES: I[C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].O=[C:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[Si](OCC)(OCC)(OCC)OCC.CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][C:3]2[NH:4][C:12]3[CH:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:15][C:16]=3[C:2]=2[CH:8]=1
Reactant: COc1ccc(N)c(I)c1
Reactant: CCOC(=O)CC1CCCC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCO[Si](OCC)(OCC)OCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OC)cc21
Temperature: 135 °C
Reaction time: 4 h
Yield: 86.6 %

Procedure:
2-Iodo-4-methoxyaniline (2.0 g, 8.03 mmol) and ethyl 2-(2-oxocyclopentyl)acetate (2.05 g, 12.1 mmol) were dissolved in DMF (30 mL) and tetraethyl orthosilicate (2.12 g, 10.4 mmol) and pyridinump-toluenesulfonate (PPTS) (0.081 g, 0.321 mmol) were added. The reaction mixture was heated and stirred at 135° C. for 4 h. After cooling to 120° C., DIEA (3.11 g, 24.09 mmol) and palladium (II) acetate (0.054 g, 0.241 mmol) were added. The reaction mixture was stirred for 3 h and then partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resultant solution was diluted with 50% ethyl acetate in hexanes and filtered through a pad of silica gel. The filtrate was concentrated and purified by silica gel column chromatography to give 1.9 g of ethyl 2-(7-methoxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate containing residual ethyl 2-(2-oxocyclopentyl)acetate. The mixture was dissolved in DCM (80 mL) and cooled to 0° C. Boron tribromide (21.0 mL, 21.0 mmol, 1.0 M in DCM) was added and the reaction was stirred for 1.5 h. Ice water was added and the reaction mixture was allowed to reach room temperature. The aqueous mixture was extracted three times with DCM. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (650 mg). LCMS m/z=260.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (t, J=7.2 Hz, 3H), 2.05-2.14 (m, 1H), 2.50 (dd, J=16.8, 11.2 Hz, 1H), 2.68-2.86 (m, 4H), 3.48-3.58 (m, 1H), 4.16-4.24 (m, 2H), 6.66 (dd, J=8.6, 2.4 Hz, 1H), 6.85 (d, J=2.4 Hz, 1H), 7.15 (d, J=8.7 Hz, 1H), 8.4 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([Cl:16])=[O:13])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CCC(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CCC(=O)Cl)cc1
Temperature: 65 °C

Procedure:
To a suspension of 3-(4-methoxyphenyl)propionic acid (10 g) in 150 ml of toluene are added 8 ml of thionyl chloride and the mixture is heated to 65° C. for 4 hours. The solvent is evaporated off under reduced pressure and the residue is redissolved in toluene and concentrated to dryness. Such a step is repeated twice. 11 g of the product are obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]1[C:16](=[O:17])[N:15]2[CH:10]1[CH2:11][S:12][C:13]([S:31][CH3:32])=[C:14]2[C:18]([O:20]CC1C=CC([N+]([O-])=O)=CC=1)=[O:19])=[O:7])([CH3:4])[CH3:3].O1CCCC1.[H][H].Cl>CO>[CH3:4][C:2]([O:5][C:6]([NH:8][CH:9]1[C:16](=[O:17])[N:15]2[CH:10]1[CH2:11][S:12][C:13]([S:31][CH3:32])=[C:14]2[C:18]([OH:20])=[O:19])=[O:7])([CH3:1])[CH3:3]
Reactant: [H][H]
Reactant: CSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2CS1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CSC1=C(C(=O)O)N2C(=O)C(NC(=O)OC(C)(C)C)C2CS1
Reaction time: 1 h
Yield: 124.6 %

Procedure:
1.45 g of (6RS) (7RS) (4-nitrophenyl)-methyl 7-[(1,1-dimethylethyl)-oxycarbonyl-amino]-3-methylthio-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en 2-carboxylate, 30 ml of tetrahydrofuran, 30 ml of methanol and 1.45 g of 10% palladized carbon were hydrogenated under a pressure of 2 atmospheres of hydrogen, while being vigorously stirred. After one hour, the pressure was taken up to ambient, and under an inert atmosphere, 4 ml of N hydrochloric acid were added. After separation, the solvent was expelled under reduced pressure at 35° C. and the residue was taken up in 100 ml of distilled water. The mixture was extracted with methylene chloride and the organic phase was dried, and evaporated to dryness under reduced pressure to obtain 1.3 g of (6RS) (7RS) 7-[(1,1-dimethylethyl)-oxycarbonyl-amino]-3-methylthio-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid.
Reaction SMILES: FC(F)(F)C1C=C(C=CC=1)C(CCC(O)=O)=O.N1CCC[C@H]1C(O)=O.[F:26][C:27]([F:49])([F:48])[C:28]1[CH:29]=[C:30]([CH:45]=[CH:46][CH:47]=1)[C:31]([CH2:33][CH2:34][C:35]([N:37]1[CH2:44][CH2:43][CH2:42][C@H:38]1[C:39]([OH:41])=[O:40])=[O:36])=[O:32].[Br:50]Br>C(O)(=O)C>[Br:50][CH:33]([C:31](=[O:32])[C:30]1[CH:45]=[CH:46][CH:47]=[C:28]([C:27]([F:26])([F:48])[F:49])[CH:29]=1)[CH2:34][C:35]([N:37]1[CH2:44][CH2:43][CH2:42][C@H:38]1[C:39]([OH:41])=[O:40])=[O:36]
Reactant: BrBr
Reactant: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1cccc(C(F)(F)F)c1
Agent: O=C(O)CCC(=O)c1cccc(C(F)(F)F)c1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CC(=O)O
Product: O=C(c1cccc(C(F)(F)F)c1)C(Br)CC(=O)N1CCC[C@H]1C(=O)O

Procedure:
As described in Example 15, 3-(3-trifluoromethylbenzoyl)propionic acid, hydroxysuccinimide ester is prepared and coupled to L-proline as in Example 16. The 1-[3-(3-trifluoromethylbenzoyl)propionyl]-L-proline in acetic acid is reacted with bromine as in Example 20 to give 1-[3-bromo-3-(3-trifluoromethylbenzoyl)propionyl]-L-proline. The preceding compound is reacted with potassium thioacetate in ethanol-water (1:1) as in Example 21 to give the product of the Example as a glass.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([NH:20][C:21]#[N:22])=[N:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[N:15]3)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.N1C=CC=CC=1>C(OCC)(=O)C>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:9][C:10]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:11]=3[CH:12]=[CH:13][CH:14]=[N:15]4)=[N:20][C:21]#[N:22])=[CH:23][CH:24]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: N#CNC(=Nc1cccc2ncccc12)NCc1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: N#CN=C(NCc1ccc(NS(=O)(=O)c2ccc(Cl)cc2)cc1)Nc1cccc2ncccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
N-(4-Amino-benzyl)-N′-cyano-N″-quinolin-5-yl-guanidine (50 mg, 0.16 mmol) and 4-chloro-benzenesulfonyl chloride (41 mg, 0.19 mmol) were added to pyridine (1 mL). An exothermic reaction occurred and the suspension became homogeneous. This solution was shaken at room temperature for 12 hours. The reaction mixture was then diluted with ethyl acetate (8 mL) and washed with water (5 mL×3). The organic phase was dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was triturated with diethyl ether to give a solid product in 76% yield. 1H NMR (DMSO-d6, ppm): 10.37 (s, 1H), 9.39 (s, 1H), 8.96 (m, 1H), 8.12 (m, 1H), 8.02 (d, 1H), 7.69 (m, 3H), 7.63 (d, 2H), 7.49 (m, 2H), 7.39 (m, 1H), 7.08 (m, 4H), 4.21 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18]([OH:20])=O)[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH2:22]([NH2:26])[CH:23]([CH3:25])[CH3:24].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C([O-])(O)=O.[Na+]>CCOC(C)=O.C1COCC1>[CH2:22]([NH:26][C:18]([CH:16]1[CH2:17][C:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:2]([F:1])[CH:3]=2)([OH:21])[CH2:15]1)=[O:20])[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)CN
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CNC(=O)C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.7 %

Procedure:
A THF solution of crude ˜0.12M intermediate 15, 3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (160 mL, 19.3 mmol) was combined with isobutylamine (3.8 mL, 38.2 mmol) and T3P (50% wt in EtOAc, 13.8 mL, 23.2 mmol) and stirred at room temperature for 20 h. The mixture was made basic with saturated aqueous NaHCO3 and EtOAc (50 mL) was added. The phases were separated and the aqueous phase was extracted again with EtOAc. The combined organics were washed with brine, dried over MgSO4 and concentrated to yield an orange oil. Flash chromatography on a 2″×4″ silica gel column flushing first with EtOAc (1 L) and 10% MeOH/EtOAc (500 mL) to remove higher Rf impurities followed by elution with an additional 500 mL of 10% MeOH/EtOAc and 500 mL 20% MeOH/EtOAc afforded 4.22 g (63%) of the title compound as an waxy, orange solid: Rf=0.3 (30% MeOH/EtOAc); 1H NMR (CDCl3) δ 7.34 (t, J=7.9 Hz, 1H), 7.20-7.13 (m, 2H), 5.84 (br s, 1H), 3.66 (d, JH-F=1.3 Hz, 2H), 3.11 (t, J=6.4 Hz, 2H), 2.84-2.76 (m, 3H), 2.55-2.45 (m, 6H), 1.81-1.72 (m, 4H), 0.91-0.87 (d @ 0.90 (J=6.6 Hz, 6H) overlapping m (1H)); LRMS m/z Calcd for C20H29FN2O2, 348.5, found, 349.4 (M+H) APCI.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@H:33]([CH3:36])[CH2:34][OH:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:35][CH2:34][C@H:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:19]=1)=[O:22])[CH3:36]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: C[C@@H](N)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.15 g, 0.33 mmol), (R)-2-aminopropan-1-ol (49 mg, 0.66 mmol), HBTU (155 mg, 0.41 mmol), and HOBT (58 mg, 0.49 mmol). Then added DMF (1.1 mL) followed by N,N-diisopropylethylamine (0.17 mL, 0.97 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (30 mL). The organic layer was washed once with saturated NaHCO3 and water. The combined aqueous layers were back extracted with EtOAc (25 mL). The combined organic layers was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/hexanes (gradient: 0-60% EtOAc) to afford 110 mg (65%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-hydroxy-1-methyl-ethyl)-amide as an off-white solid. MS: [M+H]+=515.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:8][CH:7]=1.[OH-].[K+].O.Cl>C(O)C>[CH2:13]([O:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([OH:29])=[O:2])=[CH:11][CH:10]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)O)cc1
Reaction time: 18 h
Yield: 57.9 %

Procedure:
A solution of 24.5 g of product from Example 85, 10.14 g of potassium hydroxide, 10 ml of water and 250 ml of ethyl alcohol is heated at reflux for 3 hours; followed by standing at 50° C. for 18 hours. The reaction is poured into dilute hydrochloric acid, extracted with chloroform, dried and concentrated. The residue is recrystallized from hexane/carbon tetrachloride to give 13.7 g of the desired product as a white solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=O)=[CH:9][CH:8]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[NH2:30][C:31]1[C:39]([NH2:40])=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([NH2:35])=[O:34]>N1C=CC=CC=1.CN(C)C=O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]2[NH:40][C:39]3[CH:38]=[CH:37][CH:36]=[C:32]([C:33]([NH2:35])=[O:34])[C:31]=3[N:30]=2)=[CH:9][CH:8]=1
Reactant: NC(=O)c1cccc(N)c1N
Reactant: O=C(O)c1ccc(CC2OCCO2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: NC(=O)c1cccc2[nH]c(-c3ccc(CC4OCCO4)cc3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(1,3-dioxolan-2-ylmethyl)benzoic acid (1.0 g, 4.80 mmol) in pyridine (5 mL) and N,N-dimethylformamide (5 mL) was treated with 1,1′-carbonyldiimidazole (0.856 g, 5.28 mmol) at 45° C. for 2 hours. 2,3-Diaminobenzamide dihydrochloride (synthesized as described in U.S. Pat. No. 6,737,421, column 11, EXAMPLE 2, step (e), 1.08 g, 4.80 mmol) was added and the mixture stirred at ambient temperature overnight. The mixture was concentrated and the residue heated in acetic acid (30 mL) at 80° C. for 3 hours. After cooling, the mixture was concentrated and the residue partitioned between ethyl acetate and sodium bicarbonate solution. After filtering, the filtrate was concentrated and the residue purified by flash chromatography on silica gel (0-15% methanol in 2:1 ethyl acetate/hexane) to give 1.14 g of the title compound. MS (DCI) m/z 324 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[CH2:4][C:5]1[C:6]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:7]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)[C:8]2[C:15](=[O:16])[N:14]3[C@@H:10]([CH2:11][CH2:12][CH2:13]3)[C:9]=2[N:17]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[N:58]1([NH2:67])[C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH2:60][CH2:59]1>ClCCl>[F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[CH2:4][C:5]1[C:6]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:7]([C:18]2[CH:19]=[CH:20][C:21]([C:22]([NH:67][N:58]3[C:66]4[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=4)[CH2:60][CH2:59]3)=[O:23])=[CH:25][CH:26]=2)[C:8]2[C:15](=[O:16])[N:14]3[C@@H:10]([CH2:11][CH2:12][CH2:13]3)[C:9]=2[N:17]=1
Reactant: CCOC(=O)c1c(Cc2ccc(F)cc2F)nc2c(c1-c1ccc(C(=O)O)cc1)C(=O)N1CCC[C@@H]21
Reactant: NN1CCc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)c1c(Cc2ccc(F)cc2F)nc2c(c1-c1ccc(C(=O)NN3CCc4ccccc43)cc1)C(=O)N1CCC[C@@H]21
Reaction time: 3 h
Yield: 38.2 %

Procedure:
To a stirred solution of 4-[(9aS)-2-(2,4-difluorobenzyl)-3-(ethoxycarbonyl)-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-α]pyrrolizin-4-yl]benzoic acid (0.150 g, 0.305 mmol) in 2 mL of dichloromethane, EDCI (0.070 g, 0.365 mmol), HOBT (0.049 g, 0.365 mmol) and 1-indolinamine (ref. Wijngaarden, I. et. al., J Med Chem, 1993, 36, 3693–99) (0.082 g, 0.609 mmol) were added. The reaction mixture was allowed to stir for ˜3 h. The reaction mixture was concentrated and redissolved in 1 mL of ethyl acetate. The organics were then washed with saturated aqueous NaHCO3 and brine. Filtration and concentration provided a brown oil which was purified by radial chromatography (dichloromethane/methanol (10:1)) to yield 0.071 g (38%) of the desired product as a tan solid: 1H NMR (CDCl3, 400 MHz) δ 7.90–7.85 (d, 2H, J=8.27), 7.53–7.45 (m, 2H), 7.23–7.11 (m, 3H), 6.83–6.73 (m, 2H), 4.74–4.67 (dd, 1H, J=10.5, J=6.38), 4.42–4.23 (q, 2H, J=15.34), 3.99–3.90 (m, 2H), 3.74–3.65 (m, 3H), 3.40–3.32 (m, 1H), 3.14–3.06 (m, 2H), 2.50–2.42 (m, 1H ), 2.37–2.26 (m, 2H), 1.70–1.50 (m, 3H), 1.46–1.31 (m, 1H), 0.95–0.84 (t, 3H, J=7.24); low resolution MS (ES+) m/e 609 (MH+); RP-HPLC (BDS Hypersil C-18 25 cm×4.6 mm; 10–100% CH3CN in H2O with 0.1% TFA buffer; 30 minutes; 1 mL/min) tr=8.12 min, 93.3% purity.
Reaction SMILES: [Cl:1][CH:2]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:24][CH2:25][NH2:26]>C(Cl)Cl>[ClH:1].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:24][CH2:25][NH:26][CH:2]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(c1ccccc1)C(Cl)OCc1ccccc1
Reactant: COc1ccc(CCN)cc1OC
Solvent: ClCCl
Product: COc1ccc(CCNC(OCc2ccccc2)C(=O)c2ccccc2)cc1OC
Product: Cl
Yield: 47.2 %

Procedure:
A solution of 5 g of α-chloro-2-benzyloxyacetophenone in 15 ml of methylene chloride is added dropwise to 10.5 g of 3,4-dimethoxyphenethylamine. The mixture is refluxed for 1 hour. Then, the mixture is treated in the same manner as described in Example 1-(a). 4 g of α-(3,4-dimethoxyphenethylamino)-2-benzyloxyacetophenone hydrochloride are obtained. M.p. 177° - 180° C (recrystallized from ethanol).
Reaction SMILES: [CH2:1]([C:3]1[C:11](C(O)=O)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].S(=O)(=O)(O)O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O>[CH2:1]([C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nn2ccccc2c1C(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1cc2ccccn2n1
Temperature: 70 °C
Yield: 80.8 %

Procedure:
2-Ethylpyrazolo[1,5-a]pyridine-3-carboxylic acid (4.1 g, 22 mmol) was stirred in water (100 mL) and sulfuric acid (2.5 mL) was added. The mixture was heated at 70° C. for 2 h and cooled to 20° C. The mixture was poured into ethyl acetate and neutralized with saturated sodium bicarbonate. The extracts were separated and the aqueous layer was extracted with ethyl acetate. The combined extracts were dried (sodium sulfate) and evaporated to give the desired compound (2.6 g, 82%). LCMS for C9H11N2 (M+H)+: m/z=147.1. 1H NMR (300 MHz, DMSO-d6): δ 8.52 (m, 1H), 7.57 (m, 1H), 7.11 (m, 1H), 6.75 (m, 1H), 6.38 (s, 1H), 2.73 (m, 2H), 1.22 (m, 3H).
Reaction SMILES: [CH2:1]([S:23][CH2:24][CH2:25][C:26]([O:28]CC)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O.[NH2:32][NH2:33]>C(O)CC>[CH2:1]([S:23][CH2:24][CH2:25][C:26]([NH:32][NH2:33])=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCCSCCC(=O)OCC
Reactant: NN
Solvent: CCCO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCCSCCC(=O)NN
Temperature: 25 °C

Procedure:
22.1 Grams of ethyl 3-(docosylthio)propionate, 150 ml of n-propanol and 12.5 g of hydrazine monohydrate were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and refluxed with heating for 20 hours. The reaction mixture was cooled to room temperature and the precipitated crystal was filtered off under reduced pressure and washed with distilled water. The crystal was recrystallized from 2-propanol to obtain 17.2 g of the desired product. m.p. 106° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:20][CH:21]([CH:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:24]1)[CH3:22]>CN(C=O)C.C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:32]([O:31][C:29]([N:25]1[CH2:26][CH2:27][CH2:28][CH:23]([CH:21]([NH:20][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH3:22])[CH2:24]1)=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: CC(N)C1CCCN(C(=O)OCc2ccccc2)C1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCN(C(=O)OCc2ccccc2)C1
Yield: 54.8 %

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 1) (1.1 g, 4.0 mmol) was dissolved in DMF (10 mL), and to this was added 3-(1-aminoethyl)-1-(Benzyloxycarbonyl)piperidine (950 mg, 3.6 mmol) in toluene (10 mL). The mixture was placed in an oil bath at 100° C. and heated for 5 h. After cooling, the reaction mixture was diluted with EtOAc (80 mL) and was washed with H2O (4×40 mL) followed by brine. The organic extract was dried over Na2SO4 and purified by flash chromatography using 3:7 acetone:hexane as an eluent to obtain the title compound (900 mg). Partial 1H NMR (500 MHz, CDCl3): δ 8.6 (s, 1H); 8.36 (br s, 1H); 8.15 (d, J=8 Hz, 1H); 7.85 (d, J=8.5 Hz, 1H); 7.36 (m, 7H); 6.76 (d, J=5.4 Hz, 1H); 5.12 (s, 2H); 4.17 (m, 1H); 1.29 (br d, J=5 Hz, 3H). Mass spectrum 457.6 (ESI, M+1). The enantiomers of the title compound were separated on HPLC (Chiralcel OJ column; 85:15 hexane:EtOH system).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[NH:7]1[C:11]([C:12]2[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=2)[NH2:15])=[N:10][N:9]=[N:8]1.C(COC)[O:20]C>>[NH:10]1[C:11]([C:12]2[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=2)[NH:15][C:1](=[O:5])[C:2]([OH:20])=[O:3])=[N:7][N:8]=[N:9]1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: COCCOC
Reactant: O=C(Cl)C(=O)Cl
Product: O=C(O)C(=O)Nc1cccc(-c2nnn[nH]2)c1
Reaction time: 1 h
Yield: 74.8 %

Procedure:
Oxalyl chloride (12 g) was dissolved in 50 ml of anhydrous dimethoxyethane and a solution of 3-(1H-tetrazol-5-yl)aniline (5 g) in 250 ml of anhydrous dimethoxyethane was dropwise added to the solution obtained above over 3 hours at room temperature while stirring. Insolubles were removed by filtering the solution, then 50 ml of water was gradually added to the reaction mixture under ice cooling and stirring was continued for one hour at room temperature. Then, 500 ml of ethyl acetate was added thereto to carry out extraction, the extract was washed with water, dried over anhydrous sodium sulfate and then the solvent was distilled off to obtain 5.4 g of the objective product, 3-(1H-tetrazol-5-yl)oxanilic acid (yield 74.8%). The physical properties and spectral data of this product were consistent with those described in EXAMPLE 1.