Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:11]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1)=[O:12].ClC(Cl)(Cl)[C:28]([N-:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:29].C(=O)([O-])[O-].[K+].[K+].Cl>O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:11]([NH:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:25][C:28]([NH:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:29])(=[O:23])=[O:24])=[CH:20][CH:21]=1)=[O:12]
Reactant: NS(=O)(=O)c1ccc(CCNC(=O)N2Cc3ccccc3C2=O)cc1
Reactant: O=C([N-]C1CCCCC1)C(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(NC1CCCCC1)NS(=O)(=O)c1ccc(CCNC(=O)N2Cc3ccccc3C2=O)cc1
Temperature: 160 °C

Procedure:
3.6 g of 4-[2-(1-oxo-isoindoline-2-carboxamido)-ethyl]-benzenesulfon-amide are carefully mixed with 2.5 g of trichloroacetyl-cyclohexyl amide and 2.8 g of potassium carbonate and the mixture is heated in a bath for 1 hour at 160° C. After cooling, the reaction mixture is treated with water and hydrochloric acid, filtered off with suction and the reaction product is reprecipitated from very dilute ammonia and recrystallized from dilute acetone. The N-(4-[2-(1-oxo-isoindoline-2-carboxamido)-ethyl]-benzenesulfonyl)-N'-cyclohexyl-urea obtained melts at 214°-216° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7]P(=O)(OCC)OCC)[CH:2]=1.C([Li])CCC.[CH:21](=O)[C:22]1[O:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:21][C:22]2[O:26][CH:25]=[CH:24][CH:23]=2)[CH:2]=1
Reactant: O=Cc1ccco1
Reactant: CCOP(=O)(Cc1cccnc1)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C(=Cc1ccco1)c1cccnc1
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
To a stirred -78° C. solution of diethyl 3-pyridylmethylphosphonate (3.0 g, 13 mmol), prepared as in step 3, in THF (50 mL) was added n-butyllithium (25 mL, 55 mmol, 2.5M in hexanes). The cold reaction mixture was stirred 0.5 hours followed by the slow addition of furfuraldehyde (1.24 g, 13 mmol). The reaction was stirred 2 hours at -78° C. and the ice bath removed and allowed to stir at ambient temperature overnight. Saturated NH4Cl was added and the mixture was diluted with ether. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel eluting with 40% ethyl acetate-hexanes to afford 1.1 g of 2-[2-{3-pyridyl}ethenyl]furan.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([C:22]([CH:25]=[CH2:26])=[CH:23][CH:24]=3)[N:11]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1>[Pd].C(O)C>[CH2:25]([C:22]1[N:10]2[N:11]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:9]2=[CH:24][CH:23]=1)[CH3:26]
Reactant: C=Cc1ccc2c(-c3ccc(F)cc3)c(C(=O)OCC)c(C(C)C)nn12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1c(C(C)C)nn2c(CC)ccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 100.5 %

Procedure:
A mixture of ethyl 4-(4-fluorophenyl)-2-isopropyl-7-vinylpyrrolo[1,2-b]pyridazine-3-carboxylate (8.9 g) and 10% palladium on carbon (900 mg) in ethanol (180 mL) was stirred under hydrogen atomosphere (3.5 atm) at ambient temperature. After 10 hours, the mixture was stood overnight. To the mixture was added 10% palladium on carbon (900 mg) and was stirred under hydrogen atomosphere (35 atm) at ambient temperature. After 12 hours, the mixture was stood overnight. To the mixture was added 10% palladium on carbon (900 mg) and was stirred under hydrogen atomosphere (35 atm) at ambient temperature for 8 hours. The mixture was filtered through Celite. The filtrate was concentrated in vacuo to give ethyl 7-ethyl-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate as an yellow oil (9.0 g, 100.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([OH:21])=O)[C:4]=12.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH2:31][CH2:32][NH:33][CH2:34]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([N:33]3[CH2:32][CH2:31][C:30]4[C:35](=[CH:36][CH:37]=[N:38][C:29]=4[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)[CH2:34]3)=[O:21])[C:4]=12
Reactant: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: c1ccc(-c2nccc3c2CCNC3)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)N3CCc4c(ccnc4-c4ccccn4)C3)c12
Temperature: 25 °C
Reaction time: 15.75 h

Procedure:
To a suspension of 2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (0.062 g, 0.205 mmol), 5-(pyridin-2-yl)-1,2,3,4-tetrahydro-2,6-naphthyridine (0.062 g, 0.205 mmol), and TBTU (0.086 g, 0.267 mmol) in DMF (3 mL) was added Hunig's Base (0.2 mL, 1.145 mmol). The mixture was stirred at rt for 15.75 h and quenched with 5 mL of water and concentrated under reduced pressure. The residue was dissolved in DMF, filtered through a plug of glass wool, and was purified by prep HPLC. The fractions containing the expected product were combined and concentrated. The residue was dissolved in dichloromethane and washed with sat. aq. NaHCO3. The organic layer was dried with MgSO4, was filtered, and was concentrated under reduced pressure to give the expected product as a light pink solid. The compound was further purified using BIOTAGE® flash chromatography with a 0-6% MeOH in dichloromethane gradient. The expected product, 1-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydro-2,6-naphthyridin-2(1H)-yl)ethane-1,2-dione, 1.4 H2O (0.041 g, 0.077 mmol, 37.7% yield), was isolated as an off-white solid. LC/MS: m/z 495.19 (M+H)+, 0.922 min (method 4). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.04 (br. s., 1H) 9.07-9.12 (m, 1H) 8.48-8.71 (m, 2H) 8.20-8.26 (m, 1H) 7.79-7.90 (m, 2H) 7.71-7.74 (m, 1H) 7.27-7.37 (m, 1H) 7.00-7.23 (m, 1H) 4.80-5.00 (m, 2H) 3.75-3.96 (m, 5H) 3.22-3.36 (m, 2H) 2.50-2.61 (m, 3H) 1.57 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9]([OH:10])=[C:8]([C:11]3[NH:16][C:15]4[CH:17]=[CH:18][C:19](I)=[CH:20][C:14]=4[S:13](=[O:23])(=[O:22])[N:12]=3)[C:7](=[O:24])[N:6]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[N:5]2[CH:30]=1.[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+].N(CC(O)=O)C.[CH3:55][S:56]([NH2:59])(=[O:58])=[O:57]>[Cu]I.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9]([OH:10])=[C:8]([C:11]3[NH:16][C:15]4[CH:17]=[CH:18][C:19]([NH:59][S:56]([CH3:55])(=[O:58])=[O:57])=[CH:20][C:14]=4[S:13](=[O:23])(=[O:22])[N:12]=3)[C:7](=[O:24])[N:6]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[N:5]2[CH:30]=1
Reactant: CS(N)(=O)=O
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(I)ccc3N2)c(O)c2cc(F)cn21
Agent: [Cu]I
Agent: CNCC(=O)O
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)c(O)c2cc(F)cn21
Temperature: 100 °C
Reaction time: 16 h
Yield: 15.5 %

Procedure:
6-Fluoro-4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1-(3-methyl-butyl)-pyrrolo[1,2-b]pyridazin-2-one (Example 14j, 0.047 g, 0.086 mmol), potassium triphosphate (0.055 g, 0.258 mmol), sarcosine (0.0046 g, 0.0516 mmol), and copper (I) iodide (0.0066 g, 0.0344 mmol) were combined. Anhydrous N,N-dimethylformamide (3 mL) was added followed by methanesulfonamide (0.0245 g, 0.258 mmol). The flask was purged with nitrogen and the mixture was stirred at 100° C. for 16 h. Upon cooling, the mixture was filtered over Celite, washed with ethyl acetate and the solvent was removed in vacuo. Purification by preparative HPLC (Column Luna 5μ C18 (2) 100 Å size 150×21.2 mm, 5 micron, 40%-95% in 11 min 25 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water) afforded the desired product, N-{3-[6-fluoro-4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.0068 g, 0.0133 mmol, 15.4% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.96 (3H, s), 0.97 (3H, s), 1.53-1.59 (2H, m), 1.66-1.76 (1H, m), 3.07 (3H, s), 4.32 (2H, t, J=7.5 Hz), 6.83 (1H, bs), 7.51-7.63 (3H, m), 8.06 (1H, bs), 10.17 (1H, bs). LC-MS (ESI) calcd for C20H22FN5O6S2 511.10. found 512.3 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>CN(C=O)C.O>[NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[CH:3]=1
Reactant: N#Cc1cc([N+](=O)[O-])c(N)cc1F
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])c(N)cc1-n1ccnc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
In 5 ml of DMF were dissolved 1 g of 4-amino-2-fluoro-5-nitrobenzonitrile and 1.1 g of imidazole, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was then diluted with water and the resulting crystals were recovered by filtration to provide 1.2 g of 4-amino-2-(1-imidazolyl)-5-nitrobenzonitrile. Physicochemical properties:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[C:16](I)[C:15]([O:19][CH3:20])=[CH:14][C:13]=1[F:21].[F:22][C:23]([F:62])([F:61])[C:24]1[CH:25]=[C:26]([C@H:34]2[O:38][C:37](=[O:39])[N:36]([CH2:40][C:41]3[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[CH:43][C:42]=3B3OC(C)(C)C(C)(C)O3)[C@H:35]2[CH3:60])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1.C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[F:62][C:23]([F:22])([F:61])[C:24]1[CH:25]=[C:26]([C@H:34]2[O:38][C:37](=[O:39])[N:36]([CH2:40][C:41]3[CH:46]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:44]=[CH:43][C:42]=3[C:16]3[CH:17]=[C:12]([C:3]4[CH:4]=[CH:5][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7][C:2]=4[F:1])[C:13]([F:21])=[CH:14][C:15]=3[O:19][CH3:20])[C@H:35]2[CH3:60])[CH:27]=[C:28]([C:30]([F:31])([F:33])[F:32])[CH:29]=1
Reactant: COC(=O)c1ccc(-c2cc(I)c(OC)cc2F)c(F)c1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cc(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c(OC)cc2F)c(F)c1

Procedure:
methyl 2,2′-difluoro-5′-iodo-4′-methoxybiphenyl-4-carboxylate (100 mg, 0.247 mmol), (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (INTERMEDIATE 9, 179.2 mg, 0.30 mmol), sodium carbonate (247 μL, aq., 2M, 0.494 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (40 mg, 0.049 mmol) and 1,4-dioxane (2.1 ml) were heated in a 80° C. oil bath for 8 hours. Aliquot indicated formation of the desired product. Crude mixture was concentrated under reduced pressure. The pot residue was worked up w/H2O/EtOAc/Na2SO4/filtration followed by concentration to afford a dark oil. This oil was purified by a by reverse-phase prep-HPLC (Waters SunFire PrepC18 OBD 5μ, 30×100 mm) eluting w/a MeCN (0.05% TFA, v/v)/H2O (0.05% TFA, v/v) gradient mixture (10 to 100% in 12 min, hold 100% for 3 min) Related fractions were pooled & evaporated in vacuo to afford a dark oil. The oil was further purified by SiO2 (Prep-TLC 30% EtOAc/hex) to afford the title compound. LCMS (ESI) calc.=747.15; found=748.20 (M+1)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C:5]([CH2:7][CH:8](C=C)[CH3:9])=[O:6])[CH3:3].[C:12](=[O:15])(O)[O-:13].[Na+].I([O-])(=O)(=O)=O.[Na+].[Mn]([O-])(=O)(=O)=O.[K+].S(=O)(O)[O-].[Na+]>O>[CH3:9][CH:8]([CH2:7][C:5](=[O:6])[CH2:4][CH:2]([CH3:3])[CH3:1])[C:12]([OH:13])=[O:15]
Reactant: C=CC(C)CC(=O)CC(C)C
Reactant: O=C([O-])O
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: O
Product: CC(C)CC(=O)CC(C)C(=O)O

Procedure:
The method of claim 1, wherein the 2,6-dimethyl-4-oxo-heptanoic acid is obtained by (i) mixing the purified dihydrotagetone with sodium bicarbonate, sodium metaperiodate, potassium permanganate, alumina, and water to produce a mixture; (ii) irradiating the mixture for about 2 to 20 minutes in a microwave oven; (iii) adding the irradiated mixture to a saturated solution of sodium bisulphite; (iv) passing the resultant mixture through a Celite bed and washing with acetone; (v) concentrating the filtrate and washes under reduced pressure; and (vi) cooling and acidifying the reaction mixture, from which 2,6-dimethyl-4-oxo-heptanoic acid is isolated.
Reaction SMILES: C([Li])(CC)C.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH2:19][CH3:20])=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH2:21]([N:28]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@@H:29]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:30]=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)C>[C:6]([O:10][C:11]([N:13]1[CH:14]([CH2:19][CH3:20])[CH2:15][CH2:16][CH2:17][CH:18]1[CH:30]([OH:31])[C@@H:29]([N:28]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CCC1CCCCN1C(=O)OC(C)(C)C
Reactant: O=C[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CCC1CCCC(C(O)[C@H](Cc2ccccc2)N(Cc2ccccc2)Cc2ccccc2)N1C(=O)OC(C)(C)C
Temperature: -35 °C
Reaction time: 1 h

Procedure:
Add N,N,N′,N′-tetrametlhylethylenediamine (1.4 mL, 9.11 mmol), then sec-butyllithium (1.4 M in cyclohexane, 7.2 mL, 10.1 mmol) to 2-ethylpiperidine-1-carboxylic acid tert-butyl ester in diethyl ether (18 mL) at −78° C. under a nitrogen atmosphere. Warm to −35° C. and stir for 1 h. Cool to −78° C. and add (2S)-2-(dibenzylamino)-3-phenylpropanal (3.0 g, 9.11 mmol) in diethyl ether (4 mL) and stir for 30 min. Quench at −78° C. with water, warm to room temperature and extract with diethyl ether. Combine the organic layers, dry (magnesium sulfate) and concentrate. Separate the two major diastereomers of 2-((2S)-2-dibenzylaniino-1-hydroxy-3-phenylpropyl)-6-ethylpiperidine-1-carboxylic acid tert-butyl ester using normal-phase preparative HPLC (Kromasil Si 60, 10 μm, 80×180 mm; 98:2 Hexane:Acetone; 130 mL/min).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]1([O:15][CH2:14][CH2:13][O:12]1)[CH2:10][Cl:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:16][O:1][N:2]=[C:3]([C:9]1([O:12][CH2:13][CH2:14][O:15]1)[CH2:10][Cl:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(=NO)C1(CCl)OCCO1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CCOC(=O)C(=NOC)C1(CCl)OCCO1
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-hydroxyimino-3,3-ethylenedioxy-4-chlorobutyrate (syn isomer, 0.5 g) in dried acetone (5 ml) was added potassium carbonate (0.29 g), and then dimethyl sulfate (0.265 g) was added dropwise thereto at ambient temperature with stirring. The mixture was stirred for 7 hours at ambient temperature and then filtered. The filtrate was evaporated to give ethyl 2-methoxyimino-3,3-ethylenedioxy-4-chlorobutyrate (syn isomer).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:15]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]2)CS(C)(=O)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:26]1([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27]1>C(Cl)Cl>[CH:26]1([O:31][CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:15]2[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:18]2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: OC1CCCC1
Reactant: CC(C)(C)OC(=O)N1CC(C(CS(C)(=O)=O)c2ccc(Cl)c(Cl)c2)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(C(OC2CCCC2)c2ccc(Cl)c(Cl)c2)C1

Procedure:
Tertiary butyl 3-(1-(3,4-dichlorophenyl)-2-(methylsulfonyl)ethyl)azetidine-1-carboxylate (0.2 g, 0.49 mmol) and cyclopentanol (3.0 mL, 2.4 mmol) were stirred at 80° C. for one day. The reaction mixture was dissolved in methylene chloride (70 mL), and the organic layer was washed with saturated sodium carbonate (Na2CO3) and distilled water once, respectively, and dried over anhydrous magnesium sulfate to remove the solvent. Finally, a colorless liquid was obtained, and purified by flash chromatography (n-hexane:ethyl acetate (2:1, v/v)). The product was identified as a single compound by TLC (n-hexane:ethyl acetate (2:1, v/v)).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)[CH3:25]
Reactant: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)O)cn1
Reactant: CCN
Product: CCNC(=O)c1ccc(OCc2c(-c3ccncn3)noc2C)nc1
Yield: 78 %

Procedure:
As described for example 313b, 6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (53 mg, 0.17 mmol) was converted, using ethylamine (2 M solution in THF) instead of isopropylamine, to the title compound (45 mg, 78%) which was obtained as a white solid. MS: m/e=340.0 [M+H]|.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([NH:20][C:21]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:22]([O:24]CC)=[O:23])=[O:19])=[N:8][C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([NH:20][C:21]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:22]([OH:24])=[O:23])=[O:19])=[N:8][C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1)C(=O)O

Procedure:
In analogy to the procedure described in Example 252 b), ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethylbutanoate was treated with sodium hydroxide to give the title compound as white solid. MS: 383.3 [M−H]−.
Reaction SMILES: [CH2:1](N1C=C2C(C=C(Br)C=C2)=N1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[N:24][NH:25]2)=[CH:21][C:20]=1[F:28]>>[CH2:1]([N:24]1[CH:23]=[C:22]2[C:26]([CH:27]=[C:19]([Cl:18])[C:20]([F:28])=[CH:21]2)=[N:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2cn(Cc3ccccc3)nc2c1
Reactant: Fc1cc2cn[nH]c2cc1Cl
Product: Fc1cc2cn(Cc3ccccc3)nc2cc1Cl

Procedure:
This compound was prepared in a manner similar to the procedure described for the preparation of 2-benzyl-6-bromo-2H-indazole, using 6-chloro-5-fluoro-1H-indazole in place of 6-bromoindazole. 1H-NMR (300 MHz, DMSO-d6) 8.54 (s, 1H), 7.90 (d, 1H), 7.71 (d, 1H), 7.36 to 7.29 (m, 5H), 5.64 (s, 2H); ES-MS m/z 261.0 [M+H]+, RT (min) 3.56.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[CH2:18][N:19](C(C)C)[CH:20](C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CNC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([N:19]([CH3:20])[CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 11.2 g of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid in 50 ml of DCM is cooled to 0° C., 8.45 ml of DIPEA and then 21.2 g of BOP are added and the resulting mixture is stirred for 10 minutes. Dimethylamine gas is then added by sparging and the mixture is stirred for 3 hours at RT. The reaction mixture is partially concentrated under vacuum to a volume of 20 ml and an insoluble material is filtered off. The filtrate is chromatographed on silica gel, eluting with a DCM/MeOH mixture (94/6; v/v) and the product obtained is re-chromatographed on alumina, eluting with a DCM/MeOH mixture (96/4; v/v). 11.1 g of the expected product are obtained.
Reaction SMILES: CS(O)(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C@H:14]1[CH2:20][N:19]2[C:21]([C:24]([O:27][CH3:28])([CH3:26])[CH3:25])=[CH:22][N:23]=[C:18]2[C@H:17]([NH:29]C(=O)OC(C)(C)C)[CH2:16][CH2:15]1.[C:37](=[O:40])(O)[O-].[Na+]>C(O)CO>[NH2:29][C@@H:17]1[CH2:16][CH2:15][C@@H:14]([C:8]2[C:7]([F:6])=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])[CH2:20][N:19]2[C:21]([C:24]([CH3:26])([O:27][CH2:28][CH2:37][OH:40])[CH3:25])=[CH:22][N:23]=[C:18]12
Reactant: O=C([O-])O
Reactant: COC(C)(C)c1cnc2n1C[C@H](c1c(F)cccc1F)CC[C@H]2NC(=O)OC(C)(C)C
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: OCCO
Product: CC(C)(OCCO)c1cnc2n1C[C@H](c1c(F)cccc1F)CC[C@H]2N
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Methanesulfonic acid (78 μL, 1.19 mmol) was added to a solution of tert-butyl [(6S,9R)-6-(2,6-difluorophenyl)-3-(1-methoxy-1-methylethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]carbamate (104 mg, 0.24 mmol) in ethylene glycol (4 mL). The reaction mixture was heated to 60° C. After 18 h, the mixture was allowed to cool to ambient temperature and saturated aqueous sodium bicarbonate was added. The mixture was extracted with dichloromethane (3×). The organic extracts were washed with saturated aqueous sodium bicarbonate, saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. MS 366.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](B(O)O)[CH:7]=1.Br[C:14]1[CH:19]=[CH:18][C:17](/[C:20](/[CH3:27])=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:14]2[CH:19]=[CH:18][C:17](/[C:20](/[CH3:27])=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=2)[CH:7]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(Br)cc1
Reactant: COc1ccc(Cl)cc1B(O)O
Product: CCOC(=O)/C=C(\C)c1ccc(-c2cc(Cl)ccc2OC)cc1
Yield: 90.6 %

Procedure:
(E)-Ethyl 3-(5′-chloro-2′-methoxy-biphenyl-4-yl)-but-2-enoate (1.07 g, 91% yield) was prepared from 5-chloro-2-methoxyphenylboronic acid (1.0 g, 5.36 mmol) and (E)-ethyl 3-(4-bromophenyl)-but-2-enoate (0.96 g, 3.57 mmol) by a procedure analogous to that described in example 52 a.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][C@H:42]2[O:44][CH2:43]2)=[CH:36][C:35]=1[S:45]([CH3:48])(=[O:47])=[O:46])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>C(O)C>[CH2:1]([N:8]([CH2:43][C@H:42]([OH:44])[CH2:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:35]([S:45]([CH3:48])(=[O:47])=[O:46])[CH:36]=1)[C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=2)[CH2:13][CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(C2CCC(NCc3ccccc3)CC2)cc1
Reactant: CS(=O)(=O)c1cc(OC[C@@H]2CO2)ccc1OCc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc([C@H]2CC[C@H](N(Cc3ccccc3)C[C@H](O)COc3ccc(OCc4ccccc4)c(S(C)(=O)=O)c3)CC2)cc1

Procedure:
This product is obtained by carrying out the procedure as described in Preparation 1.2 above, using ethyl 4-[4-(benzylamino)cyclohexyl]benzoate and 4-benzyloxy-3-methylsulfonyl-1-((2S)-2,3-epoxypropoxy)benzene, described in patent application WO 99/65895, and without adding thereto the hydrochloric acid solution in ethanol. [M+H+]=672.