Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[Na+].[Na+].I[CH:31]([F:33])[CH3:32].O>C(#N)C>[F:33][CH2:31][CH2:32][N:21]1[CH2:22][CH2:23][CH:18]([N:15]2[CH2:14][CH2:13][N:12]([C:5]3[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:17][CH2:16]2)[CH2:19][CH2:20]1
Reactant: CC(F)I
Reactant: COc1cc(N2CCN(C3CCNCC3)CC2)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cc(N2CCN(C3CCN(CCF)CC3)CC2)ccc1[N+](=O)[O-]
Yield: 88 %

Procedure:
To 1-[3-(methyloxy)-4-nitrophenyl]-4-(4-piperidinyl)piperazine (Example 89, step D) (0.958 g, 2.99 mmol) and Na2CO3 (0.470 g, 4.43 mmol) in acetonitrile (20 mL) was added iodofluoroethane (0.500 mL, 6.15 mmol) in one portion. The resultant mixture was heated at 70° C. for 48 h. When complete by TLC, the reaction was poured into H2O (150 mL), extracted with DCM and EtOAc, dried (MgSO4) and concentrated. Purification by flash chromatography provided the title compound of step A (0.972 g, 2.63 mmol, 88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32-1.43 (m, 2H), 1.70 (d, J=15.0 Hz, 2H), 1.94 (t, J=12.5 Hz, 2H), 2.12-2.21 (m, 1H), 2.50 (t, J=5.0 Hz, 1H), 2.52-2.58 (m, 5H), 2.88 (d, J=10.4 Hz, 2H), 3.35-3.40 (m, 4H), 3.86 (s, 3H), 4.46 (dt, JHF=47.8 Hz, J=4.9 Hz, 2H), 6.47 (d, J=2.4 Hz, 1H), 6.54 (dd, J=9.3, 2.1 Hz, 1H), 7.83 (d, J=9.3 Hz, 1H).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.Cl[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:3][CH:2]=1
Reactant: Clc1ccccn1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(-c2cccc3c2oc2ccccc23)nc1
Yield: 91.7 %

Procedure:
4-dibenzofuranboronic acid (5.0 g, 23.6 mmol), 2-chloropyridine (2.2 g, 20 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos) (0.36 g, 0.8 mmol), and potassium phosphate (11.4 g, 50 mmol) were mixed in 100 mL of toluene and 10 mL of water. Nitrogen is bubbled directly into the mixture for 30 minutes. Next, Pd2(dba)3 was added (0.18 g, 0.2 mmol) and the mixture was heated to reflux under nitrogen for 8 h. The mixture was cooled and the organic layer was separated. The organic layers are washed with brine, dried over magnesium sulfate, filtered, and evaporated to a residue. The residue was purified by column chromatography eluting with dichloromethane. 4.5 g of desired product was obtained after purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[C:22]([C:24]2[C:25]3[CH:32]=[CH:31][N:30]([Si](C(C)(C)C)(C)C)[C:26]=3[N:27]=[CH:28][CH:29]=2)=[O:23])COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:40]([F:43])([F:42])[F:41].O.CO>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[C:22]([C:24]2[C:25]3[CH:32]=[CH:31][NH:30][C:26]=3[N:27]=[CH:28][CH:29]=2)=[O:23])(=[O:9])=[O:10])=[CH:4][C:3]=1[C:40]([F:43])([F:41])[F:42]
Reactant: COCN(c1cc(Cl)ccc1C(=O)c1ccnc2c1ccn2[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A mixture of 4-chloro-N-[5-chloro-2-(1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-phenyl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (20 mg, 0.029 mmol) in 4N HCl in dioxane (2 mL) and water (0.5 mL) was stirred at 70° C. for overnight. MeOH (0.5 mL) was added and further stirred at the same temperature for 30 min. Then reaction mixture was cooled to room temperature, evaporated to dryness and treated with saturated aqueous NaHCO3 solution till pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was purified by HPLC to afford 4-chloro-N-[5-chloro-2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-phenyl]-3-trifluoromethyl-benzenesulfonamide in 60% yield. ESMS m/z (relative intensity): 514 (M+H)+ (100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:9]=2[N+:18]([O-])=O)[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:18][C:9]1[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11][O:12][C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CCOC(=O)c1noc(-c2cccc(Br)c2)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1noc(-c2cccc(Br)c2)c1N
Yield: 17 %

Procedure:
This material from Example 21B was dissolved in a mixture of EtOH (6 mL) and water (2 mL). Ammonium chloride (160 mg, 3 mmol) and iron powder (1.6 g, 28 mmol) were added at r.t. The reaction mixture was filtered after 1 h. The filtrate was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over MgSO4, concentrated, and purified by flash column chromatography (20% ethyl acetate in hexanes) to provide the titled compound (390 mg, 17% for two steps).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][N:44]([CH3:46])[CH3:45])=[CH:37][CH:36]=2)(O)[CH:16]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:22][CH:21]=2)[CH2:17][CH2:18][OH:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C>C(OC(=O)C)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([C:35]2[CH:36]=[CH:37][C:38]([O:41][CH2:42][CH2:43][N:44]([CH3:46])[CH3:45])=[CH:39][CH:40]=2)=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:22][CH:21]=2)[CH2:17][CH2:18][OH:19])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCOc1ccc(C(O)(c2ccc(OCc3ccccc3)cc2)C(CCO)c2ccc(OCc3ccccc3)cc2)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)Cl
Product: CN(C)CCOc1ccc(C(=C(CCO)c2ccc(OCc3ccccc3)cc2)c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 90 °C

Procedure:
A mixture containing 5.8 g of 1,2-bis(4-benzyloxyphenyl)-1-[4-[2-(N,N-dimethylamino)ethoxy]phenyl]butan-1,4-diol and 20 ml of acetic anhydride is heated at 90° C. for 1 hour. 3.7 g of acetyl chloride is added and the mixture is heated at 80° C. for 0.5 h. The solvent is evaporated. 0.75 g of sodium hydroxide in 200 ml of 80% methanol is added and the mixture is refluxed for 3 hours. The mixture is allowed to cool to room temperature. The crystallized product is collected by filtration. The yield is 4.7 g (83%).
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[CH:6][N:7](C)C)C.[CH3:16][C:17]([CH3:29])([CH3:28])[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26]N)=[N:24][CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:16][C:17]([CH3:29])([CH3:28])[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:4](=[O:15])[C:5]([N:10]3[CH:14]=[CH:13][N:12]=[CH:11]3)=[CH:6][NH:7]2)=[N:24][CH:25]=1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnc1
Reactant: CC(C)(C)COc1ccc(NN)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)COc1ccc(-n2[nH]cc(-n3ccnc3)c2=O)nc1
Temperature: 25 °C

Procedure:
233 mg (1.0 mmol, purity 90%) of the compound from Example 42A are initially introduced into 4 ml ethanol. 260 mg (1.0 mmol, purity 75%) of the compound from Example 12A and 38 mg (0.2 mmol) p-toluenesulfonic acid monohydrate are added and the mixture is stirred under reflux for 16 h. The mixture is then allowed to cool to RT, the solid which has precipitated out is filtered off and washed with a little ethanol and the solid is dried under a high vacuum. A further amount of the target compound is obtained by purifying the mother liquor of the filtration via preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA).
Reaction SMILES: C([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])(=O)C.Cl.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].C(N(CC)CC)C>C1C=CC=CC=1>[OH:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:8]
Reactant: COc1cccc(C(=O)Cl)c1OC(C)=O
Reactant: COC(=O)CCCCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COC(=O)CCCCCNC(=O)c1cccc(OC)c1O
Yield: 54.9 %

Procedure:
2.3 g (10 mmol) of 2-acetoxy-3-methoxybenzoyl chloride dissolved in 18 ml of anhydrous benzene were dropwise added to the suspension of 1.80 g (10 mmol) methyl 6-aminohexanoate hydrochloride in 2.2 g (22 mmol) of anhydrous triethylamine and 18 ml of anhydrous benzene under nitrogen at room temperature while stirring. After boiling under reflux for 2 hours while stirring, the reaction mixture was cooled down, the precipitate was filtered by suction and the filtrate was evaporated. 20 ml of water were portionwise added to the residue, the solution was extracted with ethyl acetate, the organic phase was washed with 1 M hydrochloric acid and water, then dried. The solvent was evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column by using a 3:4 mixture of petroleum ether and ethyl acetate to obtain 1.62 g (55%) of the title compound, m.p.: 69°-70° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:9]([CH2:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[CH3:20])(=[O:11])=[O:10])=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1.C(Cl)(Cl)(Cl)[Cl:22].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([S:9]([CH:12]([Cl:22])[C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[CH3:20])(=[O:11])=[O:10])=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1ccc(C)c(CS(=O)(=O)c2c(Cl)ccc[n+]2[O-])c1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C)c(C(Cl)S(=O)(=O)c2c(Cl)ccc[n+]2[O-])c1
Temperature: 15 °C

Procedure:
To a suspension of 2.2 g (0.01 mole) of 3-chloro-2-[[1-(2,5-dimethylphenyl)-methyl]sulfonyl]pyridine-N-oxide in 10 ml of dimethylformamide (DMF) was added 2 g (0.013 mole) of carbon tetrachloride. The mixture was cooled to 15° C. and then treated with 0.5 g (0.013 mole) of NaOFl. The mixture was stirred and allowed to warm to room temperature for two hours. It was then poured into cold water and the solid was filtered off, having a melting point of 125-127° C. Infrared and NMR spectra were consistent with the proposed structure.
Reaction SMILES: C1(OC)C=CC=CC=1.[Cl:9][C:10]1[C:11]([NH:23][C:24]([C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28](CC3C=CC(OC)=CC=3)[N:27]=2)=[O:25])=[CH:12][C:13]([F:22])=[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=1>FC(F)(F)C(O)=O>[Cl:9][C:10]1[C:11]([NH:23][C:24]([C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[NH:28][N:27]=2)=[O:25])=[CH:12][C:13]([F:22])=[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=1
Reactant: CCOC(=O)Cc1cc(Cl)c(NC(=O)c2nn(Cc3ccc(OC)cc3)c3ccccc23)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCOC(=O)Cc1cc(Cl)c(NC(=O)c2n[nH]c3ccccc23)cc1F
Yield: 79.8 %

Procedure:
A mixture of anisole (288 μl, 2.66 mmol), trifluoroacetic acid (10 ml), and ethyl (5-chloro-2-fluoro-4-(1-(4-methoxybenzyl)-3-indazolylcarbonylamino)phenyl)acetate (880 mg, 1.77 mmol) was heated under reflux for 15 hours. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent. Water (50 ml) was added to the residue. The crystals thus precipitated were collected by filtration under reduced pressure and washed with water. The crude crystals thus obtained were recrystallized from chloroform-methanol, whereby ethyl (5-chloro-2-fluoro-4-(3-indazolylcarbonylamino)phenyl)acetate (531 mg, 80%) was obtained as a colorless crystalline powder.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[C:22]([O:26][C:27]([N:29]([CH:36]([CH3:38])[CH3:37])[CH2:30][CH2:31][NH:32][CH:33]1[CH2:35][CH2:34]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(OS(OCCC)(=O)=O)CC>>[C:22]([O:26][C:27]([N:29]([CH:36]([CH3:38])[CH3:37])[CH2:30][CH2:31][N:32]([CH:33]1[CH2:34][CH2:35]1)[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[CH:18][C:8]=3[C:7]=2[CH:6]=1)(=[O:3])=[O:4])=[O:28])([CH3:25])([CH3:24])[CH3:23].[CH2:18]([C:19]([O-:21])=[O:20])[CH2:8][CH3:7]
Reactant: CC(C)N(CCNC1CC1)C(=O)OC(C)(C)C
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Agent: CCCOS(=O)(=O)OCCC
Product: CC(C)N(CCN(C1CC1)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1)C(=O)OC(C)(C)C
Product: CCCC(=O)[O-]

Procedure:
8-{[2-(tert-Butoxycarbonyl-isopropyl-amino)-ethyl]-cyclopropyl-sulfamoyl}-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-propyl carboxylate is prepared according to synthesis 111, from 326 mg (1 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid and 288 mg (1.2 mmol) of N-tert-butoxycarbonyl-N′-cyclopropyl-N-isopropyl-ethane-1,2-diamine to give, after esterification according to general method C (using di-n-propylsulfate as the dialkylsulfate) and purification by chromatography on silica (eluent cyclohexane/ethyl acetate 1/1 then 1/3), 201 mg (35% in two stages) of 8-{[2-(tert-butoxycarbonyl-isopropyl-amino)-ethyl]-cyclopropyl-sulfamoyl}-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-propyl carboxylate in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
Methyl 4-methylbenzoate 3 (2.9 g, 19.3 mmol) was dissolved in tetrachloromethane (CCl4, 20 mL) at room temperature. N-bromosuccinimide (NBS, 3.5 g, 19.0 mmol) and benzoyl peroxide (BPO, 0.26 g, 1.9 mmol) was added. The resulting mixture was stirred at reflux for 5 hr, then cooled to room temperature, washed with saturated sodium bicarbonate solution and brine, dried with anhydrous sodium sulfate and condensed under vacuum. The residue was purified by silica gel chromatography (petrol ether:ethyl acetate=50:1 to 10:1) to get a white solid of methyl 4-(bromomethyl)benzoate (4.3 g, 97%), LC-MS (ESI) m/z 230 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH2:13][C:5]=3[C:4]=2[CH:3]=1.Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN1CCCC1=O>[ClH:1].[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]3[CH2:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH2:13][C:5]=3[C:4]=2[CH:3]=1
Reactant: Brc1ccccc1
Reactant: CC(C)N1Cc2[nH]c3ccc(Cl)cc3c2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)N1Cc2c(n(-c3ccccc3)c3ccc(Cl)cc23)C1
Product: Cl

Procedure:
A mixture of 7.8 g. (33.2 m moles) of 7-chloro-2-i-propyl-1,2,3,4-tetrahydropyrrolo[3,4-b]indole, 18.23 g. (0.116 mole) of bromobenzene, 10.4 g. (0.0364 mole) of cuprous bromide and 4.51 g. (0.0364 mole) of sodium carbonate in 125 ml. of N-methyl-2-pyrrolidinone is heated under a nitrogen atmosphere at an internal temperature of 184° C. for 9 hrs. The mixture is cooled, decanted into 300 ml. of water containing 30 ml. of ethylene diamine and sodium chloride and extracted with benzene. The combined extracts are back-washed with a saturated brine solution, dried over magnesium sulfate and concentrated in vacuo.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:38])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[C:28]([O:30]CC1C=CC=CC=1)=[O:29])=[O:22])=[O:10])C1C=CC=CC=1>CO.[Pd]>[C:28]([C@H:24]1[CH2:25][CH2:26][CH2:27][N:23]1[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:38])([OH:30])=[O:29]
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)CCCCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@H]1CCCN1C(=O)CCCCC(=O)N1CCC[C@@H]1C(=O)O
Yield: 59.5 %

Procedure:
410 mg (0.79 mmol) (R)-1-[6-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid benzyl ester in 100 ml methanol were hydrogenated in theosence of 50 mg 5% Pd on carbonotration and evaporation of the solvent yielded 160 mg (59%) (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]2[S:10][C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=3)=[CH:12][N:13]=2)[CH2:7][CH2:6][O:5][CH:4]1[CH3:8].Cl.[NH2:25][OH:26]>>[CH3:1][O:2][C:3]1([C:9]2[S:10][C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18](/[C:21](=[N:25]/[OH:26])/[CH3:22])=[CH:17][CH:16]=3)=[CH:12][N:13]=2)[CH2:7][CH2:6][O:5][CH:4]1[CH3:8]
Reactant: COC1(c2ncc(Sc3ccc(C(C)=O)cc3)s2)CCOC1C
Reactant: NO
Agent: Cl
Product: COC1(c2ncc(Sc3ccc(/C(C)=N/O)cc3)s2)CCOC1C
Yield: 98 %

Procedure:
Using an analogous procedure to that described in Example 66, 4'-{2-[(2RS,3RS)-3-methoxy-2-methyltetrahydrofuran-3-yl]thiazol-5-ylthio}acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-{2-[(2RS,3RS)-3-methoxy-2-methyltetrahydrofuran-3-yl]thiazol-5-ylthio}acetophenone oxime in 98% yield as a gum.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@H:10]([C:11](=[O:19])[N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[O:9][C:8]([C:20]([O:22]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:21])=[CH:7][C@@H:6]1[NH:36][CH2:37]C(=O)C(F)(F)F)(=[O:3])[CH3:2].[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>ClCCl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[C:1]([NH:4][C@H:5]1[C@H:10]([C:11](=[O:19])[N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[O:9][C:8]([C:20]([OH:22])=[O:21])=[CH:7][C@@H:6]1[NH:36][CH3:37])(=[O:3])[CH3:2]
Reactant: CCCN(CCC)C(=O)[C@@H]1OC(C(=O)OC(c2ccccc2)c2ccccc2)=C[C@H](NCC(=O)C(F)(F)F)[C@H]1NC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(CCC)C(=O)[C@@H]1OC(C(=O)O)=C[C@H](NC)[C@H]1NC(C)=O
Temperature: 23 °C
Reaction time: 18 h

Procedure:
A solution of (4S,5R,6R)-5-acetylamino-6-(dipropylcarbamoyl)-4-(2,2,2-trifluoroacetylmethylamino)-5,6-dihydro-4H-pyran-2-carboxylic acid, benzhydryl ester (0.430 g) in dichloromethane (2.5 ml) and trifluoroacetic acid (2.5 ml) was stirred at 23° C. for 2 hours. The solvent was removed in vacuo and the residue was azeotroped with toluene (2×25 ml). The residue was taken up in a water/methanol mixture (20 ml, 1:1 v/v) and stirred at 23° C. with potassium carbonate (1.0 g) for 18 hours. The solvent was removed in vacuo and the residue was purified using HPLC on a reverse phase column eluted in a gradient procedure with water and acetonitrile containing trifluoroacetic acid. The required fractions were combined and solvent was removed in vacuo to give the title compound as a white solid (0.182 g). 1H NMR (250 MHz, D6 -DMSO,) 9.00 (2H, broad s), 8.35 (1H, d, J=8 Hz), 5.92 (1H, d, J=3 Hz), 5.05 (1H, d, J=8 Hz), 4.34 (1H, m), 3.46-3.30 (2H, m), 3.25-3.10 (1H, m), 3.08-2.90 (1H, m), 2.6 (3H, s), 1.75 (3H, s), 1.60-1.48 (2H, m), 1.48-1.30 (2H, m), 0.80 (3H, t, J=8 Hz), 0.75 (3H, t, J=8 Hz). Mass spec (Low Resolution): MH+ =342. Mass spec (High Resolution): MH+ =342.202998, fits for molecular formula C16H28N3O5, error=0.3 ppm.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]P(=O)(OC)OC.[CH2:17]([O:19][C:20](=[O:35])[CH2:21][O:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][N:27]1[C:31](=[O:32])[CH2:30][CH2:29][C@@H:28]1[CH:33]=O)[CH3:18]>COCCOC>[CH2:17]([O:19][C:20](=[O:35])[CH2:21][O:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][N:27]1[C@@H:28](/[CH:33]=[CH:5]/[C:4](=[O:3])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:29][CH2:30][C:31]1=[O:32])[CH3:18]
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Reactant: CCOC(=O)COC/C=C\CN1C(=O)CC[C@@H]1C=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCC(=O)/C=C/[C@H]1CCC(=O)N1C/C=C\COCC(=O)OCC
Reaction time: 1 h

Procedure:
To a solution of sodium hydride (95%, 0.02 g, 0.78 mmol) in 10 mL of anhydrous 1,2-dimethoxyethane at 0° C. under a nitrogen atmosphere was added dimethyl 2-oxoheptylphosphonate (0.17 mL, 0.78 mmol), and the reaction was stirred for 1 hour. A solution of [(Z)-4-((R)-2-formyl-5-oxo-pyrrolidin-1-yl)-but-2-enyloxy]-acetic acid ethyl ester (0.21 g, 0.78 mmol) in 2 mL anhydrous 1,2-dimethoxyethane was added. The reaction was allowed to come to room temperature, stirred for 3 hours and then quenched with an aqueous solution of saturated ammonium chloride. After extraction with ethyl acetate, the organic solution was dried (brine, Na2SO4), evaporated and purified by chromatography to yield {(Z)-4-[(R)-2-oxo-5-((E)-3-oxo-oct-1-enyl)-pyrrolidin-1-yl]-but-2-enyloxy}-acetic acid ethyl ester as an oil. This material was taken directly on to the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH:9]=O)([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]([F:26])([F:25])[C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][N:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:13][CH:12]([CH3:14])[CH2:11][CH:8]([NH:7][C:6](=[O:15])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9][NH:24][C:21]1[CH:20]=[N:19][C:18]([C:17]([F:26])([F:16])[F:25])=[CH:23][CH:22]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: CC(C)CC(C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)CC(CNc1ccc(C(F)(F)F)nc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude product of tert-butyl(4-methyl-1-oxopentan-2-yl)carbamate was dissolved in chloroform, 2-trifluoromethyl-5-aminopyridine (1.35 g) and sodium triacetoxyborohydride (3.52 g) were added thereto, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the mixture, followed by extraction with chloroform and drying over anhydrous magnesium sulfate. The dissicant was filtered off, and then the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate) to afford tert-butyl (4-methyl-1-{[6-(trifluoromethyl)pyridin-3-yl]amino}pentan-2-yl)carbamate (2.58 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]2[N:22]([CH2:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=3[N:19]=2)=[C:6]([CH2:8][CH2:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#N)=[CH:12][CH:11]=2)[CH:7]=1.[OH-:34].[K+].C[OH:37]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]2[N:22]([CH2:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=3[N:19]=2)=[C:6]([CH2:8][CH2:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]([OH:37])=[O:34])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: CO
Reactant: [OH-]
Reactant: N#Cc1ccc(CCc2cc(Cl)ccc2-c2nc3ccccc3n2CC2CCCCC2)cc1
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(CCc2cc(Cl)ccc2-c2nc3ccccc3n2CC2CCCCC2)cc1
Yield: 31 %

Procedure:
To a solution of 4-[2-[5-chloro-2-(1-cyclohexylmethyl-1H-benzoimidazol-2-yl)-phenyl]-ethyl]-benzonitrile (64 mg, 0.14 mmol; Example 74, intermediate a) in methanol (10 ml) was added a solution of potassium hydroxide (78 mg, 1.39 mmol) in water (5 ml) and the mixture was heated to reflux for 12 h. Solvents were removed under reduced pressure and the residue was diluted with water (10 ml) and acidified to pH 4 with 2M aqueous hydrochloric acid solution. It was then extracted three times with ethyl acetate (20 ml each), the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography over silica gel (65% ethyl acetate/n-hexane) to give the desired final product as a colorless powder (31%). MS (Turbo Spray): m/z=473.3 (M+H).