Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:24]1[CH:25]=[C:26]([CH:30]([NH:32][C:33](=[O:36])[CH2:34][CH3:35])[CH3:31])[CH:27]=[N:28][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[C:24]1[CH:25]=[C:26]([CH:30]([NH:32][C:33](=[O:36])[CH2:34][CH3:35])[CH3:31])[CH:27]=[N:28][CH:29]=1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc21
Reactant: CCC(=O)NC(C)c1cncc(Br)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(=O)NC(C)c1cncc(-c2cc3c(cc2F)N(C)C(=O)CC3)c1
Temperature: 100 °C
Yield: 19.7 %

Procedure:
To a mixture of 7-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-22, 168 g, 0.55 mmol) and (rac)-N-[1-(5-bromo-pyridin-3-yl)-ethyl]-propionamide (125 mg, 0.5 mmol) in DMF (3 mL), purged with argon for 1 min, was added bis(triphenylphosphine)palladium(II)chloride (38 mg, 0.054 mmol) and 1 N aq. Na2CO3 (2.5 mL). Then, the resulting reaction mixture was heated in a microwave at 100° C. for 45 min. After cooling to room temperature, it was diluted with EtOAc (5 mL), and poured into satd. aq. solution of NaHCO3 (10 mL). The aqueous layer was extracted with EtOAc (3×5 mL) and combined organics were washed with water and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was the purified by prep-HPLC to give the title compound (35 mg, 20%) as a white solid. MS: 356.3 (M+H+)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:30]=[C:18]3[N:19]=[C:20]([CH3:29])[C:21]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:22](O)[N:17]3[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:33]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:30]=[C:18]3[N:19]=[C:20]([CH3:29])[C:21]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:22]([Cl:33])[N:17]3[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)Cc1c(C)nc2cc(-c3cccc(OCc4ccccc4)c3)nn2c1O
Product: COC(=O)Cc1c(C)nc2cc(-c3cccc(OCc4ccccc4)c3)nn2c1Cl
Temperature: 0 °C
Yield: 84 %

Procedure:
To methyl 2-(2-(3-(benzyloxy)phenyl)-7-hydroxy-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.3 g, 0.75 mmol) was added POCl3 (3 mL). The reaction mixture was heated at reflux for 2 h. After cooling, the reaction mixture was added drop-wise to ice-water. A brown solid precipitated. The solid was filtered and washed with water, then dissolved in ethyl acetate. The organic solution was washed with saturated NaHCO3 and dried over sodium sulfate. The solvent was evaporated to give the title compound (2.77 g, 84%). 1H-NMR (400 MHz, DMSO-d6) δ 2.56 (s, 3H), 3.69 (s, 3H), 4.01 (s, 2H), 5.20 (s, 2H), 7.10 (dd, 1H), 7.29 (s, 1H), 7.32-7.37 (m, 1H), 7.39-7.45 (m, 3H), 7.51 (d, 2H), 7.63-7.69 (m, 2H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].C(O)(=O)[C@H]([C@@H](C(O)=O)O)O.[OH-].[Na+].Cl.[Na+].[Cl-]>[Fe].O>[C:1]([OH:10])(=[O:9])[C@@H:2]([C@@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: [Fe]
Agent: Cl
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: O
Product: O=C(O)[C@@H](O)[C@@H](O)C(=O)O
Temperature: 25 °C

Procedure:
A mesotartaric acid containing treatment solution was prepared by heating a solution of 95 g L(+)-tartaric acid, also known as d-tartaric acid, in 1 kg of aqueous 30% w/w NaOH at 118° C. for two hours. After cooling to room temperature, HCl-solution was added to adjust the pH to 6. Depending on the amount and the type of HCl solution used, NaCl or water was added in order to obtain a solution containing 20% w/w of NaCl. Hereafter FeCl2 was added in such an amount that the solution contained 4.8 g Fe″ per 25.5 g of (meso)tartaric acid. In the resulting treatment solution 29.8% w/w of the original L(+)-tartaric acid was transformed into the meso form.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:5]=1[O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)([O-])=O>[Pd].CCOC(C)=O>[NH2:1][C:4]1[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:5]=1[O:6][CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CCOc2ccc(C(F)(F)F)cc2N)CC1
Reaction time: 8 h
Yield: 72.2 %

Procedure:
Into a 1-neck round-bottom flask was added tert-butyl 4-{2-[2-nitro-4-(trifluoromethyl)phenoxy]ethyl}piperazine-1-carboxylate (2.44 g, 0.0058 mol), 5% palladium/carbon (0.20 g), and EtOAc (74 mL). The mixture was allowed to stir under an atmosphere of hydrogen overnight and then filtered through Celite. The filtrate was concentrated to give tert-butyl 4-{2-[2-amino-4-(trifluoromethyl)phenoxy]ethyl}piperazine-1-carboxylate (1.63 g, 68%) as a white solid. LCMS: (FA) ES+390.1.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[S:16](Cl)(=[O:18])=[O:17]>C(O)C>[C:1]([NH:5][S:16]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:7]=1[Cl:6])[C:11]([OH:13])=[O:12])(=[O:17])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)N
Solvent: CCO
Product: CC(C)(C)NS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Temperature: 30 °C

Procedure:
To a mixture of 36.5 g (0.5 mol) of tert.-butylamine and 250 ml of ethanol were added 25.5 g (0.1 mol) of 4-chloro-3-chlorosulfonylbenzoic acid in small portions while stirring and cooling, the reaction temperature being maintained at about 30° C. After a dwelling time over night at room temperature, the solvent was distilled off, the residue was dissolved in about 200 ml of water, the pH was adjusted to 1 with concentrated HCl and the crystals were filtered off. Melting point: 250° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:39])[CH2:35][CH:36]([CH3:38])[CH3:37])=[CH:30][N:29]=1)(C(C)(C)C)(C)C>C1COCC1>[OH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:39])[CH2:35][CH:36]([CH3:37])[CH3:38])=[CH:30][N:29]=1
Reactant: CC(C)CC(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)CC(=O)c1ccc(CO)nc1
Reaction time: 1 h
Yield: 158.7 %

Procedure:
Add tetrabutylammonium fluoride (2.13 mL, 2.13 mmol, 1M solution in THF) to a solution of 2-(tert-butyldimethylsilyloxymethyl)-5-(3-methyl-butyryl)-pyridine (330 mg, 1.066 mmol) in anhydrous THF (20 mL) at 0° C. and stir at this temperature for 1 h. Concentrate the solvent in vacuo and purify the crude mixture by chromatography on silica gel eluting with EtOAc to provide the desired intermediate (327 mg, 100%).
Reaction SMILES: [CH:1]([C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([NH:13][C:14](=[O:23])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:10]2)=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([NH:13][C:14](=[O:23])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Nc2ccc3ccc(C=O)nc3n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(=O)Nc2ccc3ccc(CO)nc3n2)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a solution of N-(7-formyl-1,8-naphthyridin-2-yl)-4-methoxybenzamide (6.65 g) in methanol (150 cc), sodium borohydride (0.41 g) is added during 15 minutes at 20° C., and the mixture is left stirred for 1 hour at 20° C. until the evolution of gas has ceased. The suspension produced is poured into distilled water (800 cc) which is acidified to pH 4 with acetic acid. The solid obtained by filtration and drying (6.15 g; m.p. 212° C.) is dissolved in boiling dioxane (180 cc). After the mixture has been cooled for 3 hours at a temperature in the region of 20° C., the crystallised solid is separated by filtration, washed with dioxane (2×15 cc) and dried at 50° C. under reduced pressure (0.067 kPa). N-(7-Hydroxymethyl-1,8-naphthyridin-2-yl)-4-methoxybenzamide (4.4 g) is produced, m.p. 218° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=O.C(=O)([O-])O.[Na+].O>C(O)CC>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:1]=[C:2]3[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]3[CH:10]=2)=[CH:14][CH:15]=1
Reactant: Nc1ccc(I)cn1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCO
Solvent: O
Product: Clc1ccc(-c2cn3cc(I)ccc3n2)cc1
Temperature: 80 °C
Yield: 68.5 %

Procedure:
5.0 g of 2-amino-5-iodopyridine, 5.3 g of 2-bromo-1-(4-chlorophenyl)ethanone and 2.67 g of sodium hydrogen carbonate in 150 ml of n-propanol are placed in a round-bottomed flask. The mixture is heated at 80° C. for 40 h and left to cool, and 700 ml of water are added. The precipitate is recovered by filtration, washed with water and dried under reduced pressure. 5.51 g of compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:74]([NH2:78])([CH3:77])([CH3:76])[CH3:75]>CN(C=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:36][CH2:37][CH:38]([CH3:41])[CH2:39][CH2:40]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:78][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:24])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42]
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC(C)(C)C)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and t-butylamine (8.71 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (17.6 mg, 51%). LC-MS m/z 629 (M+H)+.
Reaction SMILES: Cl.Cl.[CH2:3]([O:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[N:17]1[CH2:21][CH2:20][C@@H:19]([NH2:22])[CH2:18]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[C:28]([NH:30][CH2:31][C:32](O)=[O:33])=[O:29].CCN(CC)CC.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CCOC(C)=O>[CH2:3]([O:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[N:17]1[CH2:21][CH2:20][C@@H:19]([NH:22][C:32](=[O:33])[CH2:31][NH:30][C:28](=[O:29])[C:27]2[CH:35]=[CH:36][CH:37]=[C:25]([C:24]([F:23])([F:39])[F:38])[CH:26]=2)[CH2:18]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N[C@@H]1CCN([C@@H]2CCCC[C@H]2OCc2ccccc2)C1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN([C@@H]2CCCC[C@H]2OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a stirred solution of (3R)-1-[trans-2-(benzyloxy)cyclohexyl]pyrrolidin-3-amine 2 HCl salt (0.14 g, 0.45 mmol) and (3-trifluoromethyl-benzoylamino)-acetic acid (0.111 g, 0.45 mmol) in CH2Cl2 (5 mL) was added Et3N (0.188 mL, 1.35 mmol) followed by EDC (0.0863 g, 0.45 mmol) and HOBt (0.069 g, 0.45 mmol). The mixture was stirred at room temperature overnight. Then the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3 and brine. The organic layers was dried (MgSO4), concentrated and flash chromatographed (EtOAc to 10% MeOH/EtOAc) to give 0.186 g of the title compound. MS (EI) calcd: M+1=504.2. Found: 504.4.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][N:15]=[CH:16]OCC)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>CO>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([NH:33][CH:16]=[N:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:9]=2)(=[O:31])=[O:32])=[CH:28][CH:29]=1
Reactant: CCOC=NCCCOc1cccc(CN2CCCCC2)c1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Solvent: CO
Product: O=S(=O)(NC=NCCCOc1cccc(CN2CCCCC2)c1)c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To the crude product composed by ethyl N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]formimidate, 7.7 g of p-bromobenzenesulfonamide in 50 ml of methanol are dropwise added under stirring and at room temperature. The mixture is kept under stirring for 1 hour at room temperature, the solvent is removed by distillation under reduced pressure, and the obtained residue is purified by 60-silica gel column chromatography. 14.0 g of N-p-bromobenzene-sulphonyl-N'-[3-[3-(1-pipidinylmethyl)phenoxy]propyl]formamidine.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.COC(O)C>C(Cl)Cl.CCCCCC>[CH:7]1[C:6]2[C:5](=[O:17])[C:4]3[C:13](=[CH:14][CH:15]=[CH:2][CH:3]=3)[C:12](=[O:16])[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C1c2ccccc2C(=O)c2cc(Cl)ccc21
Agent: COC(C)O
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
Using the procedure outlined in Examples 1A, 2-chloroanthraquinone (Aldrich) and methoxyethanol (Aldrich) gave a 44.3% yield of 2-[2-(methoxy)ethoxy)]anthraquinone, mp 126°, (C,H), (CH2Cl2 /hexane).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:26][CH3:27])[CH:4]([N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:16]=2)=[N:7]1)[CH3:5].Br[C:29]1[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[CH:31][C:30]=1[CH3:38].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:27][O:26][CH:3]([O:2][CH3:1])[CH:4]([N:6]1[C:10]([NH:11][C:29]2[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[CH:31][C:30]=2[CH3:38])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[CH:16]=2)=[N:7]1)[CH3:5]
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Reactant: COc1ccc(Cn2cc(-c3cc(N)n(C(C)C(OC)OC)n3)cn2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccc(Cn2cc(-c3cc(Nc4cc([N+](=O)[O-])ccc4C)n(C(C)C(OC)OC)n3)cn2)cc1
Temperature: 150 °C

Procedure:
980 mg (2.64 mmol) of the compound of Example 3A and 627 mg (2.90 mmol) of 2-bromo-4-nitrotoluene were dissolved in 13 ml of dioxane, the mixture was degassed with argon and 59 mg (0.26 mmol) of palladium(II) acetate, 229 mg (0.40 mmol) of xantphos [4,5-bis(diphenylphosphino)-9,9-dimethylxanthene] and 2.57 g (7.91 mmol) of caesium carbonate were added. The mixture was heated in a microwave oven (Biotage Initiator, with Dynamic Field Tuning) at 150° C. for 30 min. The reaction was then filtered through kieselguhr, the filtrate was concentrated under reduced pressure and the residue was subjected to flash chromatography on silica gel (mobile phase dichloromethane/ethyl acetate 2:1). This gave 980 mg (73% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:20]2[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]2)[CH:8]=[C:9]([N:12]([CH3:19])[CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:10]=1[CH3:11])=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:22]1[CH2:21][CH:20]([C:7]2[CH:8]=[C:9]([N:12]([CH3:19])[CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:10]([CH3:11])=[C:5]([CH:6]=2)[C:3]([O:2][CH3:1])=[O:4])[CH2:23]1
Reactant: COC(=O)c1cc(C2CN(C(=O)OC(C)(C)C)C2)cc(N(C)C2CCOCC2)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(C2CNC2)cc(N(C)C2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 121 %

Procedure:
To a stirred solution of tert-butyl 3-[3-(methoxycarbonyl)-4-methyl-5-[methyl(oxan-4-yl)amino]phenyl]azetidine-1-carboxylate (400 mg, 0.96 mmol) in DCM (4 ml) was added TFA (1 ml) and the solution was stirred at room temperature for 45 min after which the solvent was evaporated to dryness and saturated aqueous NaHCO3 was added until pH7-8. The aqueous phase was extracted with DCM (3×30 ml), washed with brine (30 ml), dried with MgSO4, filtered and evaporated to afford the title compound as an orange oil (370 mg, 95%). LC-MS 96%, m/z=319.1, 1H NMR (500 MHz, Chloroform-d) δ 7.49 (d, J=1.4 Hz, 1H), 7.20 (d, J=1.3 Hz, 1H), 4.32-4.10 (m, 5H), 3.98 (d, J=11.0 Hz, 2H), 3.90 (d, J=8.4 Hz, 3H), 3.34 (t, J=10.8 Hz, 2H), 2.99 (ddd, J=14.7, 10.9, 3.8 Hz, 1H), 2.65 (d, J=8.3 Hz, 3H), 2.51-2.41 (m, 3H), 1.73 (ddd, J=15.7, 12.1, 4.3 Hz, 2H), 1.64 (d, J=11.2 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][OH:19])[CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([O:19][CH2:18][CH2:17][C:13]2[CH:12]=[C:11]([CH2:10][CH:4]([O:3][CH2:1][CH3:2])[C:5]([OH:7])=[O:6])[CH:16]=[CH:15][CH:14]=2)=[O:29])=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(Cc1cccc(CCO)c1)OCC
Reactant: O=C=Nc1ccc(Cl)cc1
Product: CCOC(Cc1cccc(CCOC(=O)Nc2ccc(Cl)cc2)c1)C(=O)O

Procedure:
Using ethyl 2-ethoxy-3-[3-(2-hydroxyethyl)phenyl]propanoate and 4-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 160b).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:22])[C:7]1[CH:12]=[C:11]([O:13][CH:14]([F:16])[F:15])[N:10]=[C:9]([NH:17][C@H:18]([CH2:20][CH3:21])[CH3:19])[CH:8]=1)C.Cl>C(O)C>[C@@H:18]([NH:17][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([O:13][CH:14]([F:16])[F:15])[N:10]=1)[C:6]([OH:22])=[O:5])([CH2:20][CH3:21])[CH3:19]
Reactant: CCOC(=O)c1cc(N[C@@H](C)CC)nc(OC(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC[C@H](C)Nc1cc(C(=O)O)cc(OC(F)F)n1
Reaction time: 3 h
Yield: 85 %

Procedure:
Add 2 N NaOH (0.67 mL) to (S)-2-sec-butylamino-6-difluoromethoxy-isonicotinic acid ethyl ester in ethanol (5 mL). Stir 3 h and acidify to about pH=4 with 1 N HCl and extract with ethyl acetate. Wash organic layer with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound (0.1 g, 85%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH:17]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C:16](=[O:32])[NH:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[C:16](=[O:32])[NH:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N2NC(=O)C(c3ccc(Cl)cc3)C2c2ccncc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(n2[nH]c(=O)c(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Temperature: 50 °C

Procedure:
To a solution of 4-[4-(4-Chloro-phenyl)-3-oxo-5-pyridin-4-yl-pyrazolidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester 0.42 gin ethanol 25 mL was added palladium on carbon 0.02 g. the reaction was heated to 50° C. for 48 hours. The reaction was cooled to room temperature, filtered and concentrated. Purification by flash chromatography gave the title compound as colorless oil. MS (ES+): 455 (M+H)+; (ES−): 453 (M−H).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6]C)=[O:5].CO[CH:14](OC)[N:15](C)C.O.Cl.NO>CO>[CH2:8]([C:2]1[O:1][N:15]=[CH:14][C:3]=1[C:4]([OH:6])=[O:5])[CH2:9][CH2:10][CH3:11]
Reactant: COC(OC)N(C)C
Reactant: CCCCC(=O)CC(=O)OC
Agent: Cl
Agent: NO
Solvent: O
Solvent: CO
Product: CCCCc1oncc1C(=O)O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Methyl 3-oxoheptanoate (0.16 g, 1 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (0.12 g, 1 mmol) was mixed and heated for 1 h at 60° C. The bright yellow oil was dissolved in methanol (2 mL) and water (1 mL) whereby and hydroxylamine hydrochloride (0.07 g, 1 mmol) was added, resulting in a pH of ca 5. The reaction was heated at 60° C. for 3 days. The solvents were evaporated and the residue refluxed in acetic acid: conc. HCL (1+1 mL) for 4 h. The solvents were evaporated to dryness and the residue dissolved in water at ca pH 10, filtered and acidified with HCl and extracted to DCM, dried (Na2SO4) and evaporated to yield the title compound as a light brown solid. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.93 (t, J=7.32 Hz, 3 H) 1.33-1.45 (m, 2 H) 1.69-1.78 (m, 2 H) 3.12 (t, J=7.57 Hz, 2 H) 8.50 (s, 1H)
Reaction SMILES: [CH:1]1([C:10]([O:12]C)=O)[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O-:9])=[O:8])[CH2:2]1.Cl.[NH3:15]>>[C:10]([CH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=[O:8])[CH2:2]1)(=[O:12])[NH2:15]
Reactant: COC(=O)C1CCCC(C(=O)[O-])C1
Reactant: N
Agent: Cl
Product: NC(=O)C1CCCC(C(=O)O)C1
Reaction time: 408 h

Procedure:
In 70 ml of aqueous conc. ammonia were dissolved 6.7 g of monomethyl 1,3-cyclohexanedicarboxylate, and the resulting mixture was allowed to stand at room temperature for 17 days. The pH of the mixture was adjusted to 1 with conc. hydrochloric acid under ice-cooling and the mixture was extracted with ethyl acetate. The extracts were washed with an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2.64 g of the desired compound as a colorless crystalline solid. m.p.: 102°-128° C.; NMR spectrum (d6 -DMSO) δ ppm: 1.00-2.70(10H,m), 6.69(1H,s), 7.20(1H,s)
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][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:7]=[C:6]([N+:29]([O-:31])=[O:30])[CH:5]=1.[OH-].[Na+]>CO.O1CCOCC1>[N+:29]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH2:11][CH2:12][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:7]=1)[C:3]([OH:32])=[O:2])([O-:31])=[O:30]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)OC)cc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1
Yield: 61.9 %

Procedure:
A solution of 4.5 g of 3-nitro-5-(octadecyloxy)benzoic acid methyl ester and 4 ml of 6N NaOH in 200 ml of methanol and 50 ml of dioxane was stirredat reflux for 2.5 hours. The solvents were removed at reduced pressure and the residue was acidified with 1N HCl. The solid was filtered and recrystallized from methanol-water to give 2.7 g (62% yield, mp 101°-103°) of 3-nitro-5-(octadecyloxy)benzoic acid.