Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])([CH3:12])([CH3:11])[CH3:10].CCOCC>C(#N)C>[Br:1][C:17]1[CH:16]=[CH:15][C:14]([OH:19])=[C:13]([C:9]([CH3:12])([CH3:10])[CH3:11])[CH:18]=1
Reactant: CC(C)(C)c1ccccc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)(C)c1cc(Br)ccc1O
Reaction time: 4 h
Yield: 100 %

Procedure:
N-bromosuccinimide (580 g) was gradually added to a solution of 2-(tert-butyl)phenol (489 g) in acetonitrile (4000 ml) while cooling on ice. After stirring for 4 hours at below 20° C., ether (3000 ml) was added and the reaction mixture was washed twice with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to yield a crude product of the title compound (746 g) as a light yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[N:10][NH:11][CH:12]=1.[CH3:13][C:14]1([CH3:29])[CH2:19][CH:18](OS(C)(=O)=O)[CH2:17][CH2:16][CH:15]1[C:25]([O:27][CH3:28])=[O:26]>CN(C=O)C.O>[Br:7][C:8]1[CH:9]=[N:10][N:11]([CH:18]2[CH2:17][CH2:16][CH:15]([C:25]([O:27][CH3:28])=[O:26])[C:14]([CH3:29])([CH3:13])[CH2:19]2)[CH:12]=1
Reactant: COC(=O)C1CCC(OS(C)(=O)=O)CC1(C)C
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1CCC(n2cc(Br)cn2)CC1(C)C
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Cesium carbonate (2.93 g, 9 mmol) and 4-bromopyrazole (482 mg, 3.3 mmol) were added to a solution of methyl 2,2-dimethyl-4-[(methylsulfonyl)oxy]cyclohexanecarboxylate (0.79 g, 3 mmol) in DMF (10 mL). The mixture was stirred at 80° C. for 16 hours. Then the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to give methyl 4-(4-bromo-1H-pyrazol-1-yl)-2,2-dimethylcyclohexanecarboxylate. MS ESI calc'd. for C13H20BrN2O2 [M+H]+ 315 and 317. found 315 and 317. 1H NMR (400 MHz, CDCl3): δ 7.35 (s, 1H), 7.22 (s, 1H), 4.53-4.50 (m, 1H), 3.69 (s, 3H), 2.26-2.18 (m, 1H), 2.06-1.78 (m, 4H), 1.36-1.28 (m, 2H), 1.06 (s, 3H), 0.97 (s, 3H).
Reaction SMILES: [O-][CH2:2][CH3:3].[Na+].[Br:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Br:17])[C:12]=2[OH:16])[C:7]=1[OH:18].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(O)C>[Br:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Br:17])[C:12]=2[O:16][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:7]=1[O:18][CH2:15][CH2:6][CH2:7][CH2:8][CH2:2][CH3:3]
Reactant: CCCCCCBr
Reactant: Oc1c(Br)ccc2c(O)c(Br)ccc12
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCOc1c(Br)ccc2c(OCCCCCC)c(Br)ccc12
Yield: 48 %

Procedure:
Under an inert atmosphere, sodium ethoxide (2.76 g, 40.6 mmol) and 2,6-dibromo-1,5-di hydroxynaphthalene (5 g, 15.7 mmol) were dissolved in ethanol (60 ml). Under reflux, ethanol solution (10 ml) of hexylbromide (6.7 g, 40.6 mmol) was added dropwise in 10 minutes. It was refluxed for 5 hours and then left for cooling. The reaction mixture was added to 1N sodium-hydroxide aqueous solution, and the depositing precipitate was filtrated. The precipitate was washed with methylene chloride, and the washed solution was concentrated under a reduced pressure to obtain a crude product. The desired product was obtained after purifying by silica gel chromatography (toluene:hexane=4:1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][N:37]([C:40](=[O:42])[CH3:41])[CH2:36][CH2:35]2)=[CH:30][CH:29]=1>CC#N.C(O)CCC>[F:9][C:5]1[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]2)=[N:7][C:2]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([N:34]3[CH2:35][CH2:36][N:37]([C:40](=[O:42])[CH3:41])[CH2:38][CH2:39]3)=[CH:32][CH:33]=2)=[N:3][CH:4]=1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: OCC1CCNCC1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CCCCO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(CO)CC4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.5 %

Procedure:
A mixture of 2,4-dichloro-5-fluoropyrimidine (167 mg, 1.00 mmol), 4-piperidinemethanol (115 mg, 1.00 mmol) and DIEA (0.400 mL, 2.30 mmol) in CH3CN (4 mL) was stirred at room temperature for 2 h. It was concentrated in vacuo. The residue was dissolved in nBuOH (6 mL). 3 mL of the nBuOH solution was taken, to which 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (120 mg, 0.55 mmol) was added. The solution was stirred at 116° C. for 20 h. nBuOH was removed in vacuo. The residue was purified by HPLC to give the titled compound (53 mg). MS 429.3 (M+H); UV 207.8, 266.8 nm.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]2[CH:16]=[C:15]([CH:17]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH2:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[NH:14][C:11]2=[N:12][CH:13]=1)(C)(C)C.[Cl:35]CCl>Cl>[ClH:35].[CH:19]1([CH2:18][CH:17]([C:15]2[NH:14][C:11]3=[N:12][CH:13]=[C:8]([NH2:7])[CH:9]=[C:10]3[CH:16]=2)[C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)Nc1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Reactant: ClCCl
Agent: Cl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(N)cnc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of {2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-carbamic acid tert-butyl ester (584 mg, 1.21 mmol) in dichloromethane (20 mL) was bubbled in dry hydrogen chloride gas for 30 min. The resulting mixture was stirred for 3 h at room temperature. The solvent was removed to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-ylamine hydrochloride salt (508 mg, 100%) which was used in the next step without purification: LC/MS m/e calcd for C21H25N3O2S [M+H]+ 384.52, observed 384.2.
Reaction SMILES: N[C:2]1[C:7]([Br:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.N([O-])=O.[Na+].N.[ClH:15]>O>[Br:8][C:7]1[C:2]([Cl:15])=[N:3][CH:4]=[C:5]([CH3:9])[CH:6]=1
Reactant: Cc1cnc(N)c(Br)c1
Reactant: Cl
Agent: N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cnc(Cl)c(Br)c1
Reaction time: 1.5 h

Procedure:
The product from (a) (145 g) was dissolved in concentrated hydrochloric acid (750 ml) and water (450 ml) and the solution cooled to -10° C. Sodium nitrite (54 g) in cold water (450 ml) was added dropwise with stirring over a period of 90 minutes while the mixture was kept at -5° C. The solution was stirred for a further 2 hours, and then basified with concentrated ammonia, keeping the temperature below 20° C. The solid which separated was washed with water, dried, dissolved in ether (1500 ml) and washed with cold sodium hydroxide solution (1M; 1 liter). The ether solution was washed twice with water (1 liter portions), dried, and evaporated to give the required 3-bromo-2-chloro-5-methylpyridine.
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[NH:6][C:7](=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)[NH2:21]>CN(C=O)C.CC(N(C)C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:9]2[C:4]3[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1
Reactant: O=c1ncc2cc(F)ncc2[nH]1
Reactant: Nc1ccc(OCc2cccc(Cl)c2)c(Cl)c1
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Fc1cc2c(Nc3ccc(OCc4cccc(Cl)c4)c(Cl)c3)ncnc2cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A heterogeneous mixture of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one (200) (1.0 g, 6.06 mmol), thionyl chloride (20 mL) and a catalytic amount of DMF (2 drops) was stirred under reflux for 40 min to give a homogeneous mixture. It was evaporated under reduced pressure at 40° C. (bath temperature) to give a light brown solid. To this solid was added a mixture of 3-chloro-4-(3-chlorobenzyloxy)aniline (1.79 g, 6.67 mmol) and dry DMA (10 mL). The residue of 3-chloro-4-(3-chlorobenzyloxy)aniline was washed down with more DMA (2×2 mL). The reaction mixture was stirred at room temperature for 1 h 30 min. It was partitioned in between ethyl acetate (400 mL) and water (400 mL). The ethyl acetate layer was separated and washed further with water (2×200 mL), dried (MgSO4) and evaporated to give a crude product of N-(3-chloro-4-(3-chlorobenzyloxy)phenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine (201). Chromatography on silica gel (dichloromethane/MeOH=25:1) gave pure 201 (2.52 g, 100%) as a yellow/orange solid, mp 196-198° C.; 1H NMR δ [(CD3)2SO] 10.03 (s, 1H), 8.94 (s, 1H), 8.69 (s, 1H), 8.21 (s, 1H), 8.07 (d, J=2.5 Hz, 1H), 7.75 (dd, J=9.0, 2.5 Hz, 1H), 7.57-7.54 (m, 1H), 7.49-7.39 (m, 3H), 7.31 (d, J=9.0 Hz, 1H). Anal. Calcd for C20H13Cl2FN4O: C, 57.85; H, 3.16; N, 13.49. Found C, 57.60; H, 3.45; N, 13.32.
Reaction SMILES: B(C1CCCCC1)C1CCCCC1.[CH3:14][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].[Zn](CC)CC.[CH:25]1([CH:31]=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.CC([O:36]C([C@H](O)[C@@H](O)C(OC(C)C)=O)=O)C>CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:15]([CH:16]1[O:36][CH:17]1[CH:31]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[OH:32])([CH3:19])([CH3:18])[CH3:14]
Reactant: O=CC1CCCCC1
Reactant: CC(C)OC(=O)[C@H](O)[C@@H](O)C(=O)OC(C)C
Reactant: C#CC(C)(C)C
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: B(C1CCCCC1)C1CCCCC1
Agent: CC[Zn]CC
Product: CC(C)(C)C1OC1C(O)C1CCCCC1
Yield: 74 %

Procedure:
The product was prepared by General procedure T using 98 mg (0.55 mmol) Cy2BH, 68 μL (0.55 mmol) 3,3-dimethyl-1-butyne, 0.78 mL (1.55 mmol, 2.0 M in hexanes) Et2Zn, 4.8 mg (0.02 mmol) (−)-MIB, 61 μL (0.50 mmol) cyclohexane carboxaldehyde, 100 μL (0.10 mmol, 1.0 M in hexanes) Ti(OiPr)4, and 21 μL (0.10 mmol) (+)-DIPT. The crude product was purified by column chromatography (5% ethyl acetate in hexanes) to afford the title compound in 74% yield (79 mg, 0.37 mmol). threo-diastereomer: White solid. m.p.: 48-50° C.; [α]D20=+70.7 (c=0.68, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 0.92 (s, 9H), 1.00-1.19 (m, 6H), 1.47 (m, 1H), 1.64-1.87 (m, 5H), 2.79 (d, 1H, J=2.1 Hz), 2.92 (t, 1H, J=2.5 Hz), and 3.57 (t, 1H, J=3.1 Hz) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 25.9, 26.0, 26.2, 26.5, 28.5, 28.8, 30.5, 41.8, 56.5, 6214, and 72.3 ppm; IR (KBr): 3392, 2922, 2853, 1643, 1449, 1391, 1363, 1262, 1245, and 1211 cm−1; HRMS-CI m/z 213.1865 [MH+; calcd for C13H25O2: 213.1855]. erythro-diastereomer: White solid. m.p.: 38-48° C.; [α]D20=−38.9 (c=0.27, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 0.92 (s, 9H), 1.03-1.28 (m, 6H), 1.66 (m, 1H), 1.73 (m, 3H), 1.89 (m, 2H), 2.67 (d, 1H, J=2.0 Hz), 2.87 (dd, 1H, J=5.4, 2.1 Hz), and 3.13 (m, 1H) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 25.8, 26.0, 26.1, 26.4, 28.6, 28.8, 30.7, 42.2, 57.5, 65.0, and 75.9 ppm; IR (KBr): 3503, 2961, 2929, 2852, 1481, 1447, 1391, 1368, 1312, and 1284 cm−1; HRMS-CI m/z 213.1865 [MH+; calcd for C13H25O2: 213.1855].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([Cl:22])=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:23]([O:26][CH2:27][C:28](Cl)=[O:29])(=[O:25])[CH3:24].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[C:23]([O:26][CH2:27][C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:21]([Cl:22])=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1)=[O:29])(=[O:25])[CH3:24]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1ccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCC(=O)Nc1ccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a suspension of 4-amino-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide (2 g; 4.49 mmol; 1 eq) in DCM (100 mL) is added acetoxyacetyl chloride (1.23 mL; 9 mmol; 2 eq) and N-ethyldiisopropylamine (2.3 mL; 13.5 mmol; 3 eq) and the reaction mixture is stirred at room temperature for 30 min. DCM is removed under reduced pressure and the crude residue is dissolved in EtOAc. The organic phase is washed twice with 10% citric acid then brine. The solvent is evaporated and the residue is taken up in iPrOH then refluxed and left at room temperature until precipitation. The precipitate is filtered off then dried under reduced pressure to afford 1.9 g (95%) of the title compound as a yellow powder. 1H NMR (DMSO-d6) δ 10.70 (s, 1H), 8.25 (m, 2H), 8.09 (m, 4H), 7.88 (m, 2H), 4.71 (s, 2H), 2.13 (s, 3H). HPLC (max plot) 98%; Rt 4.03 min. UPLC/MS (ES+) 435.2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C[Si]([C:27]#[N:28])(C)C.[OH-].[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([F:15])=[CH:17][CH:18]=2)([C:27]#[N:28])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Nc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: N#CC1(Nc2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 120 g (634 mmol) 1-benzyl-4-piperidone, 77.5 g (697 mmol) 4-fluoroaniline and 62.9 g (634 mmol) trimethylsilyl cyanide in 400 ml acetic acid was stirred at ambient temperature for 18 h. The reaction mixture was poured onto 500 g ice, pH is adjusted to 9 by addition of 5N NaOH and the aqueous mixture extracted with dichloromethane. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated. The crystalline residue was re-crystallised from Et2O: 152 g 1-benzyl-4-(4-fluoro-phenylamino)-piperidine-4-carbonitrile as colorless crystals: MS (ISP): 310.1 MH+.
Reaction SMILES: Cl.[CH3:2][S:3]([NH:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[CH2:11][C:12]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)(=[O:5])=[O:4].Cl.C(C1C=CC(CN2C(CCl)=CN=C2)=CC=1)#N.Cl.[C:44]([C:46]1[CH:60]=[CH:59][C:49]([CH2:50][N:51]2[C:55]([CH2:56]Cl)=[CH:54][N:53]=[C:52]2[CH3:58])=[CH:48][CH:47]=1)#[N:45]>>[C:44]([C:46]1[CH:47]=[CH:48][C:49]([CH2:50][N:51]2[C:55]([CH2:56][N:15]3[CH2:16][CH2:17][C:12]([CH2:11][C:10]4[CH:23]=[CH:24][CH:25]=[C:8]([CH2:7][NH:6][S:3]([CH3:2])(=[O:4])=[O:5])[CH:9]=4)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13][CH2:14]3)=[CH:54][N:53]=[C:52]2[CH3:58])=[CH:59][CH:60]=1)#[N:45]
Reactant: Cc1ncc(CCl)n1Cc1ccc(C#N)cc1
Reactant: CCOC(=O)C1(Cc2cccc(CNS(C)(=O)=O)c2)CCNCC1
Agent: Cl
Agent: N#Cc1ccc(Cn2cncc2CCl)cc1
Product: CCOC(=O)C1(Cc2cccc(CNS(C)(=O)=O)c2)CCN(Cc2cnc(C)n2Cc2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using the protocol described in Example 61, Step C substituting methyl 4-(3-methylbenzyl)piperidine-4-carboxylate hydrochloride salt with ethyl 4-[3-(methanesulfonylamino-methyl)benzyl]piperidine-4-carboxylate hydrochloride salt, and 1-(4-cyanobenzyl)-5-chloromethylimidazole hydrochloride salt with 1-(4-cyanobenzyl)-5-chloromethyl-2-methylimidazole hydrochloride salt (Example 53, Step B). After column chromatography on silica gel, the free base obtained was triturated with anhydrous diethyl ether. The white solid precipitated was filtered, and residual solvent was removed under vacuum overnight to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]1[O:20][C:19]([NH:21][CH2:22][C:23](O)=[O:24])=[N:18][N:17]=1.[CH3:26][N:27](C=O)[CH3:28].C1N=CN(C(N2C=NC=C2)=O)C=1.CNC>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]1[O:20][C:19]([NH:21][CH2:22][C:23]([N:27]([CH3:28])[CH3:26])=[O:24])=[N:18][N:17]=1
Reactant: O=C(O)CNc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Reactant: CN(C)C=O
Agent: CNC
Agent: O=C(n1ccnc1)n1ccnc1
Product: CN(C)C(=O)CNc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
To a solution of {5-[3-(2-Fluoro-4-iodo-phenylamino)-pyridin-4-yl]-[1,3,4]oxadiazol-2-ylamino}-acetic acid (75 mg, 0.16 mmol, 1 eq) in DMF CDI (35 mg, 0.21 mmol, 1.3 eq) was added. The reaction mixture was stirred at RT under argon for 3 hrs. Then diisopropanlethylamine (352 mg, 0.41 mmol, 2.5 eq), and dimethylamine hydrichloride (40 mg, 0.41 mmol, 2.5 eq) was added and the mixture was stirred for another 2 hrs. It was then directly purified by reverse phase preparative HPLC to give the desired product (35 mg). LC/MS (Method A) [4.87 min; 483 (M+1)]
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:14]=[C:13]([C:15](=[O:27])[C:16]2[CH:21]=[CH:20][C:19]([S:22](=[O:26])(=[O:25])[NH:23][CH3:24])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:28])[CH:11]=2)[CH:6]=1.[H][H].COC(=O)CC1C=C(CC2C=CC(S(=O)(=O)NC)=CC=2)C2C(=CC=C(F)C=2)C=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]([OH:27])[C:16]2[CH:17]=[CH:18][C:19]([S:22](=[O:26])(=[O:25])[NH:23][CH3:24])=[CH:20][CH:21]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:28])[CH:11]=2)[CH:6]=1
Reactant: CNS(=O)(=O)c1ccc(C(=O)c2cc(CC(=O)OC)cc3ccc(F)cc23)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: CNS(=O)(=O)c1ccc(Cc2cc(CC(=O)OC)cc3ccc(F)cc23)cc1
Solvent: CO
Product: CNS(=O)(=O)c1ccc(C(O)c2cc(CC(=O)OC)cc3ccc(F)cc23)cc1

Procedure:
A solution of [6-fluoro-4-(4-methylsulfamoyl-benzoyl)-naphthalen-2-yl]-acetic acid methyl ester (prepared in an analogous manner to example 2-1) in methanol (20 mL) was hydrogenated using a H-cube hydrogenation reactor with a flow rate of 1 mL/min and a 10% palladium on carbon catalyst cartridge at 30° C. under 10 bar hydrogen pressure. The reaction gave a mixture of alcohol {6-fluoro-4-[hydroxy-(4-methylsulfamoyl-phenyl)-methyl]-naphthalen-2-yl}-acetic acid methyl ester and the corresponding fully hydrogenated product [6-fluoro-4-(4-methylsulfamoyl-benzyl)-naphthalen-2-yl]acetic acid methyl ester. Reverse-phase preparative HPLC (using a Waters® Delta-Prep™ 3000 with a Varian Pursuit® C-18 column [10 μm, 20×150 mm]) was used to separate these products, giving {6-fluoro-4-[hydroxy-(4-methylsulfamoyl-phenyl)-methyl]-naphthalen-2-yl}-acetic acid methyl ester (4.0 mg) as 3.0 mg of a white solid. MS cald. for C21H20FNO5S [(M−H)−] 417, obsd. 416.
Reaction SMILES: O[N:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1.[OH-:26].[K+]>C(O)(=O)C>[CH2:5]([O:4][C:3]([NH:2][C:13]1[CH:18]=[CH:17][C:16]([C:23]2[N:24]=[CH:25][C:20](=[O:26])[NH:21][CH:22]=2)=[CH:15][CH:14]=1)=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [OH-]
Reactant: Clc1cnccn1
Reactant: O=C(OCc1ccccc1)N(O)c1ccccc1
Agent: [K+]
Solvent: CC(=O)O
Product: O=C(Nc1ccc(-c2c[nH]c(=O)cn2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of benzyl N-hydroxy-N-phenylcarbamate (8.0 g) in ethanolic potassium hydroxide (0.27N; 120 ml) was treated with chloropyrazine (4.18 g) and molecular sieve (0.5 g). The mixture was stirred for 2 hours at room temperature and then allowed to stand for 4 days. Evaporation of the reaction mixture under reduced pressure gave an orange residue which was suspended in dilute acetic acid, filtered off, and heated in hot 1-propanol (about 200 ml). On cooling, the resulting solution gave a golden precipitate of 5-(4-benzyloxycarbonylaminophenyl)-2(1H)-pyrazinone m.p. 240°-4° C.
Reaction SMILES: [C:1]([CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][CH:5]=[CH2:6])#N.S(=O)(=O)(O)[OH:14].[CH2:18]([OH:20])[CH3:19]>O>[C:7]1([CH:3]([CH2:4][CH:5]=[CH2:6])[C:1]([O:20][CH2:18][CH3:19])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: CCO
Reactant: C=CCC(C#N)c1ccccc1
Solvent: O
Product: C=CCC(C(=O)OCC)c1ccccc1
Temperature: 0 °C

Procedure:
4-Cyano-4-phenyl-1-butene (15 g) is dissolved in 50 ml of ethanol and 3 drops of water whereupon 20 ml of sulfuric acid is added dropwise. The resulting mixture is warmed slowly and then heated under reflux for 6 hours. The reaction mixture is then poured into 100 ml of ice-cold water and extracted with 100 ml of benzene. The extract is dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is distilled to give 7.0 g of ethyl 2-phenyl-4-pentenoate, boiling at 133°-137° C. (20 mmHg).
Reaction SMILES: [NH3:1].[N+:2]([C:5]1[C:14]2[O:13][C:12]([C:15](OCC)=[O:16])=[CH:11][C:10](=[O:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([O-:4])=[O:3]>C(O)C.O1CCCC1>[N+:2]([C:5]1[C:14]2[O:13][C:12]([C:15]([NH2:1])=[O:16])=[CH:11][C:10](=[O:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: N
Reactant: CCOC(=O)c1cc(=O)c2cccc([N+](=O)[O-])c2o1
Solvent: CCO
Solvent: C1CCOC1
Product: NC(=O)c1cc(=O)c2cccc([N+](=O)[O-])c2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
Gas ammonia was bubbled for 30 minutes in a solution of ethyl 8-nitro-4-oxo-4H-benzopyran-2-carboxylate (2.109 g, 8.02 mmol) in anhydrous ethanol (50 ml) and anhydrous tetrahydrofuran (50 ml). After that the mixture was evaporated to dryness and the resulting solid residue was suspended in concentrated hydrochloric acid (20 ml) stirring at room temperature for 4 h. Then the mixture was diluted with water, the solid was recovered by filtration, washed repeatedly with water and dried under vacuum on phosphorous pentoxyde, to obtain 1.515 g of the title product (81% yield).
Reaction SMILES: [C:1]([NH:4][CH2:5][C@H:6]1[C@H:10]([C:11]([O:13][CH3:14])=[O:12])[CH2:9][C@H:8]([C:15]([OH:17])=[O:16])[C@H:7]1[CH2:18][NH:19]C(OC(C)(C)C)=O)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[Cl:34]CCl>>[ClH:34].[NH2:19][CH2:18][C@H:7]1[C@@H:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C@H:10]([C:11]([O:13][CH3:14])=[O:12])[CH2:9][C@@H:8]1[C:15]([OH:17])=[O:16]
Reactant: ClCCl
Reactant: COC(=O)[C@@H]1C[C@H](C(=O)O)[C@@H](CNC(=O)OC(C)(C)C)[C@H]1CNC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@H](C(=O)O)[C@@H](CN)[C@H]1CNC(C)=O
Product: Cl
Yield: 75 %

Procedure:
A solution of (±)-(1S,2S,3R,4R)-3-Acetamidomethyl-2-(N-t-butoxycarbonylamino)methyl-4-methoxycarbonylcyclopentane-1-carboxylic acid (62 mg, 0.16 mmol) in of dichloromethane (4 mL) was reacted with trifluoroacetic acid (1.0 mL) for 1 hour, at room temperature. The solution was concentrated in vacuo, at 25° C. The residue was treated with 1 N HCl and concentrated in vacuo to provide the title compound as a white solid (yield: 39 mg, 75%).
Reaction SMILES: [C:1]1(=[O:21])[N:5]([CH2:6][CH2:7][CH2:8][S:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12.[BH4-].[Na+]>C(O)C>[OH:21][CH:1]1[C:2]2[C:3](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:4](=[O:16])[N:5]1[CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCSc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1c2ccccc2C(O)N1CCCSc1ccncc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.4 %

Procedure:
To a solution of 5.97 g (20.0 mmol) of 4-(3-phthalimidopropylthio)pyridine in 300 ml of ethanol, 1.51 g (40 mmol) of sodium borohydride was added, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off and saturated saline was added to the residue. The mixture was extracted with chloroform and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent:ethanol/ethyl acetate=1:10) to give 3.27 g of the desired compound (54.4% yield, colorless crystals), mp. 132°-134° C.