Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:31]1[CH2:30][CH2:29][CH:28]([NH:27][C:25]([C:21]2[C:17]3=[N:18][CH:19]=[CH:20][C:15]([C:8]4[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)=[C:16]3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:33][CH2:32]1)(=[O:36])[CH3:35]
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCN(C(C)=O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f14) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1)([OH:3])=[O:2].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14]>O1CCCC1.O>[CH2:16]([O:15][C:13]([N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]1[C:1]([OH:3])=[O:2])=[O:14])[CH:17]=[CH2:18]
Reactant: C=CCOC(=O)Cl
Reactant: O=C(O)C1CCCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)N1CCCCC1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-carboxypiperidine (50 g) in tetrahydrofuran (200 ml) and water (200 ml) was adjusted to around pH 9.5 with 20% aqueous sodium hydroxide. To the solution was added dropwise allyl chloroformate (45 ml) at 5° C., while adjusting pH to around 9.5 with 20% aqueous sodium hydroxide. After stirring for 30 minutes at 0° C., the mixture was washed with ethyl acetate. After addition of ethyl acetate (200 ml), the mixture was adjusted to around pH 2.0 with concentrated hydrochloric acid (30 ml) and 1N hydrochloric acid. The mixture was extracted with ethyl acetate (200 ml), washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave an oil of 1-allyloxycarbonyl-2-carboxypiperidine (88.7 g), which was dissolved in methanol (440 ml). To this solution was added dropwise, sulfuric acid (6.9 ml) and the mixture was refluxed for 2 hours. To the mixture was added dropwise triethylamine (29.5 ml) at 20° C. Evaporation of the solvent gave a residue which was taken up into a mixture of ethyl acetate (400 ml) and water (100 ml). The organic layer was separated, washed with water, 1N aqueous hydrochloric acid, brine, 5% aqueous sodium hydrogen carbonate and brine successively, and dried over magnesium sulfate. Evaporation of the solvent gave 1-allyloxycarbonyl-2-methoxycarbonylpiperidine (92.5 g).
Reaction SMILES: [N+]([O:4][C@H:5]([CH2:12][O:13][N+]([O-])=O)[CH2:6][CH2:7][CH2:8][C:9](O)=[O:10])([O-])=O.[N+:17]([O:20][CH:21]([CH2:29][O:30][N+:31]([O-:33])=[O:32])[CH2:22][O:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])([O-:19])=[O:18]>>[N+:17]([O:20][CH:21]([CH2:29][O:30][N+:31]([O-:33])=[O:32])[CH2:22][O:23][CH2:24][CH2:25][C:26]([O:28][C@@H:8]1[CH2:9][O:10][C@@H:6]2[C@H:5]([OH:4])[CH2:12][O:13][C@H:7]12)=[O:27])([O-:19])=[O:18]
Reactant: O=C(O)CCOCC(CO[N+](=O)[O-])O[N+](=O)[O-]
Reactant: O=C(O)CCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-]
Product: O=C(CCOCC(CO[N+](=O)[O-])O[N+](=O)[O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O

Procedure:
The title compound was prepared by following the procedure for the synthesis of EXAMPLE 4, except that in Step F the reagent (S)-5,6-di(nitrooxy)hexanoic acid was replaced by 3-(2,3-bis(nitrooxy)propoxy)propanoic acid obtained as described in Oscar Pamies and Jan-E. Backvall, J. Org. Chem. 2002, 67, 1261-1265) and EXAMPLE 10.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1>CCOC(C)=O>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: COc1cc(OC)cc(B(O)O)c1
Solvent: CCOC(C)=O
Product: COc1cc(OC)cc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)c1

Procedure:
1-[2-(3,5-Dimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and (3,5-dimethoxyphenyl)boronic acid following general procedures as described in these Examples. Silica gel chromatography using 10-50% EtOAc in hexanes as eluant provided 90 mg (52%) of a yellow solid. MP 206.9-207.7° C., M+H=340.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:11])[NH:4][CH:5]=[CH:6][C:7]=1[C:8](Cl)=[O:9].[C:12]1([C@@H:18]2[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl>[OH:1][C:2]1[C:3](=[O:11])[NH:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:24][C@H:21]1[CH2:20][CH2:19][C@@H:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:23][CH2:22]1)=[O:9]
Reactant: O=C(Cl)c1cc[nH]c(=O)c1O
Reactant: N[C@H]1CC[C@@H](c2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CC[C@@H](c2ccccc2)CC1)c1cc[nH]c(=O)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-hydroxy-2-oxo-1,2-dihydropyridine-4-carbonyl chloride (Intermediate 17) (38.1 mg, 0.219 mmol) and cis-4-phenylcyclohexanamine (Intermediate 14) (50 mg, 0.29 mmol) in DCM (1 mL) was added Et3N (0.061 mL, 0.44 mmol). The reaction mixture was stirred at rt for 1 h. The reaction mixture was partitioned between H2O and DCM. The DCM layer was dried over Na2SO4 and filtered through a silica gel plug. The solvent was removed under reduced pressure to give Example 36A which was used without further purification.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[NH:4][CH:3]=[CH:2]1.[H-].[Na+].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>CN(C)C=O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:4]1[C:5](=[O:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:1][CH:2]=[CH:3]1
Reactant: O=C1NC=COc2ccccc21
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2OC=CN1CCCCCBr
Reaction time: 0.5 h

Procedure:
250 mg of 4,5-dihydro-1,4-benzoxazepin-5-one was dissolved in 15 ml of dimethylformamide, then 74 mg (1.2 equivalents) of 60% sodium hydride was added under ice cooling. This was agitated for 30 minutes, then 0.51 ml (2.4 equivalents) of 1,5-dibromopentane was added and the resultant mixture was agitated at room temperature for 6 hours.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15]2)[C:10]([CH3:13])(O)[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.[FH:37].[OH-].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15]2)[C:10]([F:37])([CH3:13])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: F
Reactant: CC(C)(O)[C@H](c1cc(F)cc(F)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 42 °C
Reaction time: 15 h

Procedure:
To a solution of 5.5 g (13.5 mmole) of (1S)-1-(3,5-difluorophenyl)-1-[1-(diphenylmethyl) azetidin-3-yl]-2-methylpropan-2-ol in 25 mL of CH2Cl2 was added 15 mL of hydrogen fluoride-pyridine and the two-phase mixture was stirred for 15 h at 42° C. Then the reaction mixture was poured to 100 mL of 5N NaOH, 20 mL of aq NaHCO3, 150 mL of CH2Cl2 and 100 mL ice. The pH was adjusted to 8-9 with 2N NaOH. The water layer was extracted with CH2Cl2 (3×1500 mL). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with 10% methyl tert-butyl ether-hexane to afford the title compound as a white solid; 1H-NMR (CDCl3) δ 1.25 ( t, J=22 Hz, 6H), 2.33 (t, J=6.5 Hz, 1H), 2.83-2.89 (m, 2H), 3.09-3.11 (m, 2H), 3.60 (m, 1H), 4.30 (s, 1H), 6.68-6.71 (m, 3H), 7.21-7.8 (m, 10H); Mass Spectrum: m/e=410 (M+1)
Reaction SMILES: C[C:2]1[CH:10]=[C:9]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[C:22]([NH:34][CH3:35])[N:21]=3)[CH:15]=2)=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O1CCCC1.[OH-].[Na+].[ClH:43]>CO>[ClH:43].[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[C:22]([NH:34][CH3:35])[N:21]=[C:20]2[C:16]1[CH:15]=[C:14]([NH:13][C:11](=[O:12])[C:9]2[CH:10]=[CH:2][C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CNc1nc(-c2cccc(NC(=O)c3ccc(C(=O)O)c(C)c3)c2)c2cc(OC)c(OC)cc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CNc1nc(-c2cccc(NC(=O)c3ccc(C(=O)O)cc3)c2)c2cc(OC)c(OC)cc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.3 %

Procedure:
To a solution of 2.5 g of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid dissolved in a mixed solvent consisting of 50 mL of tetrahydrofuran and 25 mL of methanol was added 11.3 mL of a 5 N sodium hydroxide solution, followed by stirring at room temperature for 12 hours. The reaction mixture was adjusted to be acidic by addition of 5 N hydrochloric acid, and the obtained solid was then filtrated, washed with 10 mL of water and 20 mL of ether, and dried under aeration to yield 2.5 g of a product of interest. Yield: 95.3%.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[O:30]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31]1>>[C:18]([N:13]1[C:12]([C:32]2[CH:33]=[CH:34][O:30][CH:31]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C(C)(C)C)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccoc1
Product: CC(C)(C)n1nc2c(c1-c1ccoc1)CCNCC2
Yield: 50.3 %

Procedure:
The title compound (60 mg) was prepared according to Example 215 using 203 mg of 2-(tert-butyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 215, Step A) and 154 mg of 3-furanboronic acid. MS (ESI): exact mass calculated for C15H21N3O, 259.17. found, m/z 260.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.69-7.68 (m, 1H), 7.61 (br s, 1H), 6.50-6.49 (m, 1H), 3.38-3.36 (m, 2H), 3.27-3.25 (m, 2H), 3.13-3.11 (m, 2H), 2.63-2.61 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]([F:32])=[C:6]([CH:28]=[CH:29][C:30]=1[F:31])[O:7][CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20]C(=O)OC(C)(C)C)=[CH:16][CH:15]=2)[N:10]=1)=[O:3].O1CCOCC1.[ClH:39]>>[ClH:39].[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[N:10]=[C:9]([CH2:8][O:7][C:6]3[C:5]([F:32])=[C:4]([C:2]([NH2:1])=[O:3])[C:30]([F:31])=[CH:29][CH:28]=3)[O:13][N:12]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2noc(COc3ccc(F)c(C(N)=O)c3F)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1c(F)ccc(OCc2nc(-c3ccc(N)cc3)no2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
tert-Butyl N-[4-(5-[3-(aminocarbonyl)-2,4-difluorophenoxy]methyl-1,2,4-oxadiazol-3-yl)phenyl]carbamate (300 mg, 0.67 mmol, 1 equiv.) was dissolved in 4N HCl in dioxane (7 ml, 28 mmol, 42 equiv.) and the reaction mixture was stirred at r.t. overnight. Volatiles were removed under reduced pressure, the residue was triturated with dry Et2O and the solid formed was filtered and rinsed with dry Et2O. The crude product (200 mg) was taken-up in EtOH (2 ml) and was triturated with 2N HCl in Et2O solution (0.3 ml) and dry Et2O. The white solid was filtered and washed with dry Et2O, to give 110 mg of the desired product (43% yield). HPLC-MS (method 1): m/z 347 [M+H−HCl]+, Rt=2.98 min.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]([O:13][CH3:14])[C:6]=1[Cl:15].[BH4-].[Li+]>C1COCC1.CCOCC>[Cl:15][C:6]1[C:7]([O:13][CH3:14])=[C:8]([C:11]#[N:12])[CH:9]=[CH:10][C:5]=1[CH2:4][CH2:3][OH:2]
Reactant: COC(=O)Cc1ccc(C#N)c(OC)c1Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1c(C#N)ccc(CCO)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl(2-chloro-4-cyano-3-methoxyphenyl)acetate (700 mg, 2.92 mmol) in THF (30 mL) was added 2M lithium borohydride (1.46 mL, 2.92 mmol) and the reaction was stirred at RT for 16 hours. The reaction was diluted with ether and quenched into water containing 2N HCl. The mixture was extracted twice with ethyl acetate and the organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The product mixture was separated by flash chromatography (10-40% ethyl acetate/hexanes) to afford the title product. 1H-NMR (400 MHz, CDCl3) δ ppm 3.10 (t, J=6.4 Hz, 2H), 3.94 (t, J=6.4 Hz, 2H), 4.08 (s, 3H), 7.175 (d, J=7.8 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([OH:16])=[C:7]([NH:9][C:10](=O)[C:11](F)(F)F)[CH:8]=1.BrCC=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[O:16][CH2:11][CH:10]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH:9][C:7]=2[CH:8]=1
Reactant: CCOC(=O)C=CCBr
Reactant: O=C(Nc1cc(Cl)ccc1O)C(F)(F)F
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC1COc2ccc(Cl)cc2N1
Temperature: 0 °C
Yield: 72.1 %

Procedure:
420 ml of ethanol are introduced into a 3 litre reactor, with magnetic stirring, cooled to 0° C., and 3.8 g (0.166 mol) of sodium are added slowly, in small portions, followed by successive and dropwise addition of 40 g (0.166 mol) of N-(5-chloro-2-hydroxyphenyl)trifluoroacetamide and 40 g (0.155 mol) of 75% pure ethyl 4-bromo-2-butenoate, and the mixture is heated at 85° C. for 2 hours. The solvent is evaporated off and the residue is taken up in 100 ml of water and 40 ml of 1N sodium hydroxide and extracted with diethyl ether. The organic phase is separated out, washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated. 28.58 g of product are obtained, which product is purified by chromatography on a column of silica gel, eluting with a cyclohexane/isopropyl ether (1/1 ratio) mixture.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]2[C:11]3[C:12](O)=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:9]=2[C:8]([O:19][CH3:20])=[CH:7][CH:6]=1)=[O:4].P(Cl)(Cl)([Cl:23])=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][O:2][C:3]([C:5]1[C:10]2[C:11]3[C:12]([Cl:23])=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:9]=2[C:8]([O:19][CH3:20])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(OC)c2oc3ccnc(O)c3c12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(OC)c2oc3ccnc(Cl)c3c12

Procedure:
A solution of Methyl-1-hydroxy-6-Methoxybenzo[4,5]furo[3,2-c]pyridine-9-carboxylate (from step 10) (1.1 g) and phosphorous oxychloride (25 mL) was refluxed for 15-16 hours. Excess of phosphorous oxychloride was removed under vacuo. The residue obtained was diluted with water (10.0 mL) and made alkaline with solid sodium carbonate. The solid separated was filtered, washed with water and dried to get crude intermediate-12 (1.0 g) as brown solid. Purification by silica gel column using chloroform: ethyl acetate (9:1) as an eluent gave pure intermediate-12 (350 mg) as light yellow solid
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][C:13]([OH:15])=[O:14])[C:6]([CH3:16])=[C:5]2[C:17](=[O:28])[C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][C:13]([OH:15])=[O:14])[C:6]([CH3:16])=[C:5]2[CH:17]([OH:28])[C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=1
Reactant: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C(O)c1ccc(S(C)(=O)=O)cc1
Yield: 18.2 %

Procedure:
A solution of [6-fluoro-4-(4-methanesulfonyl-benzoyl)-3-methyl-naphthalen-2-yl]-acetic acid (60 mg, 0.15 mmol) (example 6-1) in methanol (12 mL) was hydrogenated using a H-cube hydrogenation reactor with a flow rate of 1.7 mL/min and a 10% palladium on carbon catalyst cartridge at 20° C. under 10 bar hydrogen pressure. The reaction mixture was concentrated in vacuo. The crude product was purified using flash chromatography (RediSep® Flash column, 230-400 mesh, 2%-5% methanol in dichloromethane) to give 11 mg (18%) of {6-fluoro-4-[hydroxy-(4-methanesulfonyl-phenyl)-methyl]-3-methyl-naphthalen-2-yl}-acetic acid as an oil. 1H NMR (300 MHz, CDCl3) δ ppm: 7.82 (d, J=8.2 Hz, 2 H), 7.74 (dd, J=9.1, 6.0 Hz, 1 H), 7.61-7.70 (m, 2 H), 7.49 (d, J=8.2 Hz, 2 H), 7.15 (td, J=8.3, 2.1 Hz, 1 H), 6.73 (s, 1 H), 3.86 (br. s, 1 H), 3.48 (s, 2 H), 3.01 (s, 3 H), 2.41 (br. s, 3 H); HRMS (ESI+) cald. for C21H19FO5S [(M+Na)] 425.0829, obsd. 425.0827.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7](=[O:19])(=[O:18])[C:6]=2[CH:5]=1)([OH:3])=[O:2].[C:20](Cl)(Cl)(Cl)Cl>S(Cl)(Cl)=O>[CH3:20][O:2][C:1]([C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7](=[O:19])(=[O:18])[C:6]=2[CH:5]=1)=[O:3]
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1O2
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2c(c1)S(=O)(=O)c1ccccc1O2

Procedure:
2-carboxyphenoxathiin-10,10-dioxide (0.50g.) in carbon tetrachloride (25ml.) and thionyl chloride (2.0 ml.) was boiled under reflux for 2 hr. The solvent was evaporated and methanol (20. ml.) added. The mixture was boiled under reflux for 20 min., and cooled, whereupon 2-methoxycarbonylphenoxathiin-10,10-dioxide crystallised out and was filtered off and dried, m.pt. 160° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.[C:23](O)(=[O:25])[CH3:24]>C(O)C.[Pd]>[C:23]([O:14][C:11]1([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)(=[O:25])[CH3:24]
Reactant: OC1(Cc2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Reactant: CC(=O)O
Agent: [Pd]
Solvent: CCO
Product: CC(=O)OC1(Cc2ccc(F)cc2)CCNCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1-benzyl-4-(4-fluoro-benzyl)-piperidin-4-ol (5.87 g, 19.6 mmol) in ethanol (80 ml) is treated with acetic acid (1 ml) and with 10% Pd on carbon (1 g). The mixture is stirred at RT under an atmosphere of hydrogen for 20 hours. The mixtre is filtered and the filtrate evaporated. The crude product is treated with dichloromethane. The resultant suspension is filtered and the white solid obtained is washed with cold dichloromethane to afford 4-(4-fluoro-benzyl)-piperidin-4-ol acetate [MH]+ 210.1
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([NH:29]C(=O)OC(C)(C)C)([CH2:25][CH2:26][O:27][CH3:28])[CH2:6][NH:7][C:8](=[O:24])[O:9][CH2:10][CH:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:29][C:5]([CH2:4][CH2:3][O:2][CH3:1])([CH2:25][CH2:26][O:27][CH3:28])[CH2:6][NH:7][C:8](=[O:24])[O:9][CH2:10][CH:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2
Reactant: COCCC(CCOC)(CNC(=O)OCC1c2ccccc2-c2ccccc21)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCC(N)(CCOC)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 5 h

Procedure:
To a solution of (9H-fluoren-9-yl)methyl tert-butyl (4-methoxy-2-(2-methoxyethyl)butane-1,2-diyl)dicarbamate (G22, 269 mg) in methylene chloride (2 mL), trifluoroacetic acid (2 mL) was added at room temperature, and the mixture was stirred at the same temperature for 5 hours. The solvent was evaporated under reduced pressure, and then ethyl acetate and saturated aqueous sodium hydrogencarbonate were added to the residue. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain (9H-fluoren-9-yl)methyl (2-amino-4-methoxy-2-(2-methoxyethyl)butyl)carbamate (G23, 186 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:5]=[C:4]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[N:3]=1.[NH2:26][CH2:27][CH:28]([OH:31])[CH2:29][OH:30]>O1CCOCC1.CN1CCCC1=O>[Cl:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([Cl:15])[C:9]=1[CH2:8][C:6]1[N:7]=[C:2]([NH:26][CH2:27][CH:28]([OH:31])[CH2:29][OH:30])[N:3]=[C:4]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[N:5]=1
Reactant: NCC(O)CO
Reactant: N#Cc1ccc(Nc2nc(Cl)nc(Cc3c(Cl)cccc3Cl)n2)cc1
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: N#Cc1ccc(Nc2nc(Cc3c(Cl)cccc3Cl)nc(NCC(O)CO)n2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.2 %

Procedure:
A mixture of intermediate (27) (0.00256 mol) and 3-amino-1,2-propanediol (0.00563 mol) in 1,4-dioxane (10 ml) and 1-methyl-pyrrolidinone (2 ml) was stirred at RT for 48 hours under argon. The reaction mixture was concentrated, quenched with DCM/H2O and stirred. The precipitate was filtered off, yielding 1.12 g (86.9%) of (±)-4-[[4-[(2,6-dichlorophenyl)methyl]-6-[(2,3-dihydroxypropyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile (compound 26).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][N:27]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([S:36](Cl)(=[O:38])=[O:37])[C:30]=2[CH:29]=[CH:28]1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:36]([C:31]4[CH:32]=[CH:33][CH:34]=[C:35]5[C:30]=4[CH:29]=[CH:28][N:27]5[CH3:26])(=[O:37])=[O:38])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: Cn1ccc2c(S(=O)(=O)Cl)cccc21
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc5c4ccn5C)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 1-methyl-1H-indole-4-sulfonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.