Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]([C:12]([F:15])([F:14])[F:13])[CH2:10][C:9](=[O:16])[N:8]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=3[O:26][CH3:27])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.Cl.[N:31]1([CH2:36][CH2:37][N:38]2[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[N:40]=[C:39]2[CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:35][CH2:34][CH2:33][CH2:32]1.CN1CCCC1=O.C(N(C(C)C)CC)(C)C>O>[CH3:27][O:26][C:19]1[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=1[CH2:17][N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([N:50]3[CH2:49][CH2:48][CH:47]([C:39]4[N:38]([CH2:37][CH2:36][N:31]5[CH2:32][CH2:33][CH2:34][CH2:35]5)[CH:42]=[C:41]([C:43]([F:45])([F:46])[F:44])[N:40]=4)[CH2:52][CH2:51]3)[C:3]=2[CH:11]([C:12]([F:13])([F:14])[F:15])[CH2:10][C:9]1=[O:16]
Reactant: FC(F)(F)c1cn(CCN2CCCC2)c(C2CCNCC2)n1
Reactant: COc1ccc(CN2C(=O)CC(C(F)(F)F)c3c(Cl)ncnc32)c(OC)c1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2C(=O)CC(C(F)(F)F)c3c(N4CCC(c5nc(C(F)(F)F)cn5CCN5CCCC5)CC4)ncnc32)c(OC)c1
Temperature: 220 °C

Procedure:
Combine 4-chloro-8-(2,4-dimethoxybenzyl)-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (0.65 g, 1.62 mmol), 4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine trihydrochloride (0.76 g, 1.1 eq), N-methylpyrrolidinone (20 mL) and diisopropylethylamine (1.69 mL, 6.0 eq) in a sealed vessel. Heat at 220° C. for 30 minutes. Dilute the reaction mixture with water and extract with ethyl acetate. Wash the organics with saturated aqueous sodium chloride. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by normal phase chromatography, eluting with a 1-10% methanol/dichloromethane gradient, to give crude 8-(2,4-dimethoxybenzyl)-4-(4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (crude).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]=[C:15]2Cl)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:26][CH2:27][O-:28].[Na+]>C(O)C>[CH2:27]([O:28][C:15]1[N:14]([C:10]2[C:11]([F:13])=[CH:12][C:2]([Cl:1])=[C:3]([CH:9]=2)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]=1)[CH3:26]
Reactant: CC[O-]
Reactant: CCOC(=O)c1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(-n2c(OCC)nc(C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using ethyl 2-chloro-5-[2-chloro-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-4-fluorobenzoate and sodium ethylate in ethanol there is obtained ethyl 5-[2-ethoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-2-chloro-4-fluorobenzoate, m.p. 94°-96° C.;
Reaction SMILES: [OH:1][CH:2]([C:29]([F:32])([F:31])[F:30])[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:14][N:13]=2)=[CH:8][CH:7]=1.[C:33](Cl)(=[O:42])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:33]([O:1][CH:2]([C:29]([F:31])([F:32])[F:30])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:14][N:13]=2)=[CH:10][CH:11]=1)(=[O:42])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(CCCC(O)C(F)(F)F)cc2)nc1
Reactant: CCCCCCCCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCCOc1cnc(-c2ccc(CCCC(OC(=O)CCCCCCCC)C(F)(F)F)cc2)nc1

Procedure:
1.1 g (2.5 mmol) of (-)-2-(4-(4-hydroxy-5,5,5-trifluoro-1-pentyl)phenyl)-5-decyloxypyrimidine was dissolved in 10 ml of pyridine, followed by addition of 0.53 g (3 mmol) of nonanoyl chloride and 2-hour reaction at 20°-30° C. The reaction mixture was diluted with 100 ml of toluene, and the toluene layer was washed with 4N hydrochloric acid, water, a 5% sodium bicarbonate solution and water successively in that order and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using toluene/ethyl acetate as eluent to obtain 1.25 g of (+)-2-(4-(4-nonanoyloxy-5,5,5-trifluoro-1-pentyl) phenyl-5-decyloxypyrimidine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[C:13](=O)[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:2]=1.CCOCC.C([O-])=O.[NH4+].C([BH3-])#[N:27].[Na+]>CO.[Cl-].[Cl-].[Zn+2]>[NH2:27][CH:13]1[CH:12]2[CH2:15][CH2:16][N:9]([CH2:10][CH2:11]2)[CH:8]1[CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1C2CCN(CC2)C1Cc1cccnc1
Reactant: [BH3-]C#N
Agent: O=C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CO
Product: NC1C2CCN(CC2)C1Cc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one (3.00 g, 13.9 mmol) in dry methanol (20 mL), under nitrogen, was added a 1 M solution of ZnCl2 in ether (2.78 mL, 2.78 mmol). After stirring at ambient temperature for 30 min, this mixture was treated with solid ammonium formate (10.4 g, 167 mmol). After stirring another hour at ambient temperature, solid sodium cyanoborohydride (1.75 g, 27.8 mmol) was added in portions. The reaction was then stirred at ambient temperature overnight and terminated by addition of water (˜5 mL). The quenched reaction was partitioned between 5 M NaOH (10 mL) and chloroform (20 mL). The aqueous layer was extracted with chloroform (20 mL), and combined organic layers were dried (Na2SO4), filtered and concentrated. This left 2.97 g of yellow gum. GC/MS analysis indicated that the product was a 90:10 mixture of the cis and trans amines, along with a trace of the corresponding alcohol (98% mass recovery).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[CH3:10][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[CH3:10][O:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1ccc(Cl)c(O)c1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C)ccc1Cl
Reaction time: 8 h
Yield: 55 %

Procedure:
2-Chloro-5-methylphenol (5.0 g, 35.0 mmol) was dissolved in 50% CH2Cl2/methanol (100 mL) and trimethylsilyl diazomethane (2.0 M in hexanes, 25 mL) was added dropwise until a persistent yellow color was observed. The solution was stirred overnight. The solvent was evaporated and the crude product was purified by column chromatography (hexane/EtOAc) to afford the title compound (3.0 g, 55%) as an oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.25 (d, 1H), 6.95 (d, 1H), 6.74 (dt, 1H), 3.81 (s, 3H), 2.28 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[CH3:15][C@@:16]([S:39]([CH3:42])(=[O:41])=[O:40])([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>[Pd+2].O1CCOCC1.O>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([C:27]2[CH:26]=[CH:25][C:24]([CH2:23][CH2:22][C@@:16]([CH3:15])([S:39]([CH3:42])(=[O:41])=[O:40])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:29][CH:28]=2)=[CH:9][CH:10]=1
Reactant: Oc1ccc(I)cc1
Reactant: CCOC(=O)[C@@](C)(CCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)S(C)(=O)=O
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)[C@@](C)(CCc1ccc(-c2ccc(O)cc2)cc1)S(C)(=O)=O
Yield: 54 %

Procedure:
A mixture of palladium (II) EnCat (0.1 equiv), potassium carbonate (3.0 equiv), 4-iodophenol and ethyl(2R)-2-methyl-2-(methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanoate, which may be prepared as in Preparation 8A, was heated to 80° C. in 10:1 1,4-dioxane-water to provide the title compound (54%) after purification by flash chromatography on silica gel. MS (LCMS) m/z 399.5 (M+Na). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (t, J=7.13 Hz, 3H) 1.72 (s, 3H) 2.18-2.28 (m, 1H) 2.47-2.58 (m, 2H) 2.72-2.84 (m, 1H) 3.04 (s, 3H) 4.22-4.31 (m, 2H) 4.91 (s, 1H) 6.85-6.92 (m, 2H) 7.17-7.24 (m, 2H) 7.40-7.51 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14].[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C([O-])([O-])=O.[K+].[K+].O>C1(C)C=CC=CC=1.CCOC(C)=O.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>[CH3:14][O:13][CH2:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH3:24]
Reactant: Cc1ccccc1B(O)O
Reactant: COCc1cc(C(=O)OC)ccc1Br
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: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COCc1cc(C(=O)OC)ccc1-c1ccccc1C
Temperature: 25 °C

Procedure:
Methyl 4-bromo-3-(methoxymethyl)benzoate obtained in step 2 (40 g; 154.38 mmol; 1 eq.), o-tolylboronic acid (23.09 g; 169.82 mmol; 1.10 eq.), K2CO3 (106.68 g; 771.90 mmol; 5 eq.), tetrakis(triphenylphosphine)palladium (0) (1.78 g; 1.54 mmol; 0.01 eq.) were taken up in toluene (200 mL) and water (200 mL) under nitrogen atmosphere. The reaction mixture was purged with vacuum, then degassed with nitrogen and then refluxed for 1 hour. The reaction mixture was cooled to room temperature, filtered over a pad of celite and washed with EtOAc (1000 mL). The filtrate was concentrated to afford a yellow oil which was taken in EtOAc (800 mL). The organic layer was washed with a saturated aqueous solution of NaHCO3 solution (250 mL), water (250 mL) and brine (250 mL), dried over MgSO4 and concentrated affording the title compound as a yellow oil used without further purification (41.9 g, quantitative). HPLC (Method A) Rt 5.34 min (Purity: 89.4%).
Reaction SMILES: [C:1]([O:9][CH:10]([C:16](=[O:19])[CH2:17][CH3:18])[C:11](=[O:15])[CH:12]=[CH:13]O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)CC.C(O)(=O)C(O)=O.Cl.S(=O)(=O)(O)O>C(O)(=O)C.C(O)=O>[C:1]([O:9][C:10]1[C:11](=[O:15])[CH:12]=[CH:13][O:19][C:16]=1[CH2:17][CH3:18])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)C(OC(=O)c1ccccc1)C(=O)C=CO
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCC(=O)O
Solvent: O=CO
Product: CCc1occc(=O)c1OC(=O)c1ccccc1

Procedure:
said 4-benzoyloxy-1-hydroxy-1-heptene-3,5-dione is heated in an acid chosen from the group consisting of formic acid, acetic acid, propionic acid, oxalic acid, dilute hydrochloric acid and dilute sulfuric acid to form 3-benzoyloxy-2-ethyl-4-pyrone, and,
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[NH:20][CH2:19][CH2:18][C@@:15]4([C:16]=2[CH:17]=1)[C@@:10]3([O:22][CH3:23])[CH2:11][CH2:12][C:13](=[O:21])[CH2:14]4.[CH:24]1([CH2:28]Br)[CH2:27][CH2:26][CH2:25]1.C([O-])(O)=O.[Na+]>CN(C)C=O>[CH:24]1([CH2:28][N:20]2[CH2:19][CH2:18][C@@:15]34[C:16]5[CH:17]=[C:4]([O:3][CH3:2])[CH:5]=[CH:6][C:7]=5[CH2:8][C@@H:9]2[C@:10]3([O:22][CH3:23])[CH2:11][CH2:12][C:13](=[O:21])[CH2:14]4)[CH2:27][CH2:26][CH2:25]1
Reactant: BrCC1CCC1
Reactant: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@]1(OC)CCC(=O)C3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)[C@]13CCN(CC4CCC4)[C@H](C2)[C@]1(OC)CCC(=O)C3

Procedure:
A mixture of 3,14-dimethoxymorphinan-6-one hydrochloride (6b) (1.0 g, 2.96 mmol), cyclobutylmethyl bromide (0.662 g, 4.44 mmol) and NaHCO3 (1.492 g, 17.76 mmol) in 25 ml of dimethylformamide (DMF) was refluxed at an oil bath temperature of 110° under nitrogen for 16 hours. The mixture was filtered and the residue washed with DMF whereupon the filtrate was distilled under reduced pressure (oil bath temperature 30°-40° C.) and the residual material was taken up in methylene chloride (50 ml) and water (50 ml). The two layers were separated and the aqueous layer re-extracted with methylene chloride (2×50 ml). The organic layers were combined, washed with water (20 ml), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting solid was chromatographed on Florisil, and eluted with graded methanol/chloroform mixtures to give 17-cyclobutylmethyl-3,14-dimethoxymorphinan-6-one as a yellow oil. This material was converted to its HCl salt (7) by treatment with ethereal hydrogen chloride to give 0.507 g of a light-colored solid (42% theory), m.p. 230° C. (decomposed).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[C:22]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=[C:19]([CH:29]([NH2:31])[CH3:30])[CH:18]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:31]([CH:29]([C:19]3[CH:18]=[C:17]([CH3:16])[C:22]([O:23][CH2:24][C:25]([F:28])([F:26])[F:27])=[CH:21][N:20]=3)[CH3:30])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)ncc1OCC(F)(F)F
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ncc1OCC(F)(F)F
Yield: 78 %

Procedure:
The title compound is prepared in 78% yield (320 mg, pale brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (300 mg, 1.1 mmol, Step-1 of Intermediate-1) and 1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine hydrochloride (330 mg, 1.1 mmol, Amine-49, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: OCCSc1cccc2nccn12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCSc1cccc2nccn12
Yield: 99.9 %

Procedure:
To a solution of 5-[2-(hydroxy)ethylthio]imidazo[1,2-a]pyridine (9.71 g, 50 mmoles) and triethylamine (10.5 ml, 75.3 mmoles) in methylene chloride (300 ml) was added methanesulfonyl chloride (4.26 ml, 55 mmoles) with stirring under ice-cooling and the mixture was stirred under ice-cooling for 2 hours. The reaction solution was washed in turn with an aqueous saturated sodium bicarbonate solution and saturated saline and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off to obtain 13.6 g of the desired product (quantitative, brown oily product).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:23][O:24][C:25](=[O:39])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[CH:37]=[CH:36][C:35]([NH2:38])=[N:34]2)=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:23][O:24][C:25](=[O:39])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[CH:37]=[CH:36][C:35]([NH:38][C:13](=[O:15])/[C:12](/[C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=3)=[N:16]/[O:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:34]2)=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccc(Cn2ccc(N)n2)cc1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(Cn2ccc(NC(=O)/C(=N/OC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)cc1
Reaction time: 2 h
Yield: 74.7 %

Procedure:
(E)-(3-chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 157 mg, 0.45 mmol), 4-(3-amino-pyrazol-1-ylmethyl)-benzoic acid methyl ester (117 mg, 0.50 mmol) and N,N-diisopropylethylamine (237 μL, 1.36 mmol) were combined in methylene chloride (20 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (173 mg, 0.45 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) to afford (E)-4-{3-[2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-acetylamino]-pyrazol-1-ylmethyl}-benzoic acid methyl ester (188 mg, 74%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C26H27ClN4O6S [M+] 558.13, found 559 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.63 (m, 4 H, 2×CH2), 1.85 (m, 4 H, 2×CH2), 3.29 (s, 3 H, SO2CH3), 3.92 (s, 3 H, CO2CH3), 4.86 (m, 1 H, OCH), 5.29 (s, 2H, NCH2), 6.79 (d, J=2.3 Hz, 1 H, Ar), 7.23 (d, J=8.3 Hz, 2 H, Ar), 7.40 (d, J=2.3 Hz, 1 H, Ar), 7.55 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.65 (d, Jm=1.5 Hz, 1 H, Ar), 8.02 (d, J=8.3 Hz, 2 H, Ar), 8.18 (d, Jo=8.2 Hz, 1 H, Ar), 9.20 (s, 1 H, NH).
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])[C:6]([C:20]([O:22]CC)=[O:21])=[CH:5]1)[CH:2]=[CH2:3].[OH-].[Na+]>CCO>[CH2:1]([N:4]1[C:9](=[O:10])[CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cc(C(=O)OCC)c(Nc2ccc(I)cc2F)cc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CCn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Yield: 99 %

Procedure:
Ethyl 1-allyl-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate was dissolved in EtOH and treated with 1 M NaOH, as for example 1, step C, to hydrolyse the ester to give 1-allyl-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid as a white solid (99%), used directly in the next step. 1H NMR [(CD3)2SO, 400 MHz] δ 13.25 (v br s, 1H), 9.73 (br s, 1H), 8.41 (s, 1H), 7.75 (dd, J=10.1, 1.9 Hz, 1H), 7.60 (ddd, J=8.4, 2.0, 0.8 Hz, 1H), 7.32 (t, J=8.5 Hz, 1H), 5.98-5.86 (m, 1H), 5.49 (d, J=1.1 Hz, 1H), 5.19 (dd, J=10.3, 1.4 Hz, 1H), 5.14 (ddd, J=17.1, 3.0, 1.5 Hz, 1H), 4.52 (d, J=5.6 Hz, 2H). HRMS (EI+) calcd C15H12FIN2O3 (M+) 413.9877, found 413.9874.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:14][CH3:15])[C:6]2[O:10][C:9]([CH2:11][OH:12])=[CH:8][C:7]=2[CH:13]=1.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:18]>C1COCC1>[C:17](=[O:18])([O:19][C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1)[O:12][CH2:11][C:9]1[O:10][C:6]2[C:5]([O:14][CH3:15])=[CH:4][C:3]([O:2][CH3:1])=[CH:13][C:7]=2[CH:8]=1
Reactant: COc1cc(OC)c2oc(CO)cc2c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: COc1cc(OC)c2oc(COC(=O)Oc3ccc([N+](=O)[O-])cc3)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
A solution of (5,7-dimethoxybenzofuran-2-yl)methanol 6 (100 mg, 0.48 mmol) in THF (3 mL) was cooled to 0° C. TEA (69 uL, 0.48 mmol) was added dropwise followed by the portionwise addition of p-nitrophenyl chloroformate (100 mg, 0.72 mmol). The resulting solution was stirred at room temperature for 2 h. Solvent was evaporated off in vacuo and the crude residue was purified by flash chromatography, eluting with hexane:EtOAc (3:1), to give 61 (120 mg, 67%) as a white solid. H1 NMR (500 MHz, CDCl3): δ=8.29 (2H, d, J=9.0 Hz, ArH), 7.40 (2H, d, J=9.0 Hz, ArH), 6.82 (1H, s, ArH), 6.63 (1H, s, ArH), 6.52 (1H, s, ArH), 5.39 (2H, s, CH2), 4.00 (3H, s, OCH3), 3.85 (3H, s, OCH3).
Reaction SMILES: CN[C:3](=[O:30])[CH2:4][N:5]1[C@H:14]2[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@H:13]2[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:25]([F:28])([F:27])[F:26])[C:7]=2[C:6]1=[O:29].Cl.[O:32]1CCOCC1>>[C:21]([O:20][C:18]([N:16]1[CH2:17][C@H:13]2[C@@H:14]([N:5]([CH2:4][C:3]([OH:30])=[O:32])[C:6](=[O:29])[C:7]3[C:8]([C:25]([F:28])([F:26])[F:27])=[CH:9][CH:10]=[CH:11][C:12]=32)[CH2:15]1)=[O:19])([CH3:22])([CH3:24])[CH3:23]
Reactant: CNC(=O)CN1C(=O)c2c(cccc2C(F)(F)F)[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]21
Reactant: C1COCCO1
Agent: Cl
Product: CC(C)(C)OC(=O)N1C[C@@H]2c3cccc(C(F)(F)F)c3C(=O)N(CC(=O)O)[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of (3aR,9bS)-tert-butyl 4-(2-(methylamino)-2-oxoethyl)-5-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate (30 mg, 0.07 mmol) in 4 mL of 1,4-dioxane was added 1 mL of 12N HCl. The resulting solution was stirred at ambient temperature for 1 h and then was concentrated. The residue was azeotroped with toluene and dried in vacuo to afford a foam. This foam was triturated 3× with ether and dried in vacuo to afford 20 mg (80%) of the title compound of Example 19 as a pale yellow powder. 1H NMR (DMSO-D6): δ 9.73 and 9.61 (broad singlets, 2H), 8.08 (m, 1H), 7.86 (d, 1H, J=8.3 Hz), 7.76 (t, 1H, J=7.7 Hz), 7.58 (d, 1H, J=7.2 Hz), 4.12 (s, 2H), 4.02-3.95 (m, 2H), 3.70-3.60 (m, 2H), 3.35-3.25 (m, 2H), 2.60 (d, 3H, J=5.0 Hz). LRMS (ESI): 328.17 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[CH:8]=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:10]([CH3:17])=[N:11]2.C(O)C.[OH-].[Li+]>O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:26])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:17])[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)=[CH:8]2
Reactant: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(Cl)cc3)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc2c(Cl)ccc(OCC(=O)O)c2cc1Cc1ccc(Cl)cc1

Procedure:
A solution of [8-chloro-3-(4-chlorobenzyl)-2-methylquinolin-5-yloxy]acetic acid methyl ester (0.10 g), ethanol (6.0 mL), water (2.0 mL) and saturated aqueous lithium hydroxide solution (2.0 mL) was stirred at room temperature for 5 hours. The ethanol was removed under reduced pressure and the pH of the residue adjusted to 4 by the addition of glacial acetic acid. The resulting precipitate was collected by filtration, washed with water and purification by preparative reverse-phase HPLC using a gradient over 37 minutes of acetonitrile in water (20% to 95% of organic modifier) gave title compound as an off-white solid, 0.039 mg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:8](Cl)=[O:9])=[O:4].CC(C)=O.[NH2:21][CH2:22][C:23]([OH:25])=[O:24].C(=O)(O)[O-].[Na+]>O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:8]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:9])=[O:4]
Reactant: NCC(=O)O
Reactant: COC(=O)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cc(C(=O)NCC(=O)O)cc([N+](=O)[O-])c1

Procedure:
Under agitation and during the course of 21/2 hours, 183.0 g. (0.75 mole) of 3-methoxycarbonyl-5-nitrobenzoyl chloride in 750 ml. of acetone is added dropwise to a solution of 62.0 g. (0.825 mole) of glycine and 189.0 G. of sodium bicarbonate in 3 l. of water. The first-obtained precipitate is gradually dissolved again after an additional three hours of agitation. Thereafter, the reaction mixture is extracted twice with ether, the aqueous phase is acidified with concentrated hydrochloric acid, the thus-precipitated oil is extracted repeatedly with ethyl acetate, and the combined ethyl acetate extracts, after washing with water and drying with sodium sulfate, are mixed with a stoichiometric amount of dicyclohexylamine. After allowing the reaction mixture to stand for some time, it is filtered off from the precipitated dicyclohexylammonium salt (m.p. 204°-205° C. form chloroform/ether), washed several times with ether, and the acid is liberated again by distributing the reaction mixture between ethyl acetate and 2 N sulfuric acid. After washing the ethyl phases with water, drying with sodium sulfate, and concentrating under vacuum, 181.0 g. of the above-identified compound is obtained. M.P. 142°-143° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([S:19]([CH3:22])(=O)=O)[N:3]=1.[CH2:23](S)C.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([S:19][CH2:22][CH3:23])[N:3]=1
Reactant: CCS
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CCSc1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N

Procedure:
From 2-amino-4-benzo[1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, ethyl mercaptan and DBU in DME. EI-MS m/e (%): 300 (M+, 74), 299 ([M—H]+, I100).