Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[S:26][N:25]=[C:24]([CH:27]=[CH2:28])[CH:23]=3)[C:19]3[C:29](=[O:39])[N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][C:18]=3[C:17]=2[F:40])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[S:26][N:25]=[C:24]([CH2:27][CH3:28])[CH:23]=3)[C:19]3[C:29](=[O:39])[N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][C:18]=3[C:17]=2[F:40])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C=Cc1cc(-c2nc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)N(C(=O)OC(C)(C)C)C3)sn1
Agent: [Pd]
Solvent: CO
Product: CCc1cc(-c2nc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)N(C(=O)OC(C)(C)C)C3)sn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
To a stirred solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-7-fluoro-3-oxo-4-(3-vinylisothiazol-5-yl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (58 mg, 0.101 mmol) in MeOH (1.0 mL) was added Pd/C (30 mg, 0.282 mmol) under N2 atmosphere. The mixture was stirred at room temperature overnight under H2 atmosphere. The solids were removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (Flash 60 column) eluting with hexane/EtOAc (1:1) to give the title compound as a yellow solid (54.9 mg, 94%). 1H NMR (500 MHz, CDCl3) δ ppm 1.36 (t, J=7.57 Hz, 3H), 1.48 (br s, 9H), 1.61 (s, 9H), 1.71-1.82 (m, 1H), 2.20-2.33 (m, 1H), 2.91 (q, J=7.60 Hz, 2H), 3.64 (t, J=11.72 Hz, 1H), 3.74 (d, J=11.72 Hz, 1H), 3.91-3.99 (m, 1H), 4.01-4.10 (m, 2H), 4.23-4.34 (m, 1H), 4.72 (s, 2H), 5.37 (d, J=6.83 Hz, 1H), 6.47 (br s, 1H), 8.78 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C27H36FN5O6S, 578. found, 578.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>CCOCC>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[OH:20])=[CH:17][CH:16]=1
Reactant: Brc1ccccn1
Reactant: COc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccc(C(O)c2ccccn2)cc1
Reaction time: 0.25 h

Procedure:
To one mole of butyl lithium (15% in hexane) at -40° C under nitrogen is added gradually a solution of 142 g (0.9 mol) of 2-bromopyridine in 340 ml. of ether, maintaining the temperature below -40° C. After stirring for 15 minutes at this temperature, a solution of 122 g (0.9 mol) of 4-methoxybenzaldehyde in 250 ml of ether is added, with the temperature below -15° C. The reaction mixture is stirred for 40 minutes at this temperature, quenched in 1.5 l ice water. The solid is filtered and washed with cold ether to give 4-methoxyphenyl-2-pyridylcarbinol, m.p. 126°-130° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1.C(N(CC)CC)C>C(O)CCC>[S:4]1[CH2:5][CH2:6][N:1]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: C1CSCCN1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: N#Cc1ccc(N2CCSCC2)nc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a round bottom flask was added thiomorpholine 8-1 (3.6 g, 34.8 mmol), 6-chloronicotinonitrile 8-2 (4.0 g, 29 mmol), triethylamine (8 mL, 58 mmol) and butanol (10 mL). The reaction was stirred at 100° C. for 1 hour. After cooling to room temperature, the reaction formed a solid cake. The cake was triturated in 50 mL H2O at 100° C. After cooling, the solid was collected by filtration to give 6-thiomorpholinonicotinonitrile 8-3 as an off-white solid. MS m/z 206.1 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:9]=[C:10]([C:12]3[N:13]=[CH:14][N:15]([CH3:17])[CH:16]=3)[S:11][C:4]=12.[F:18][C:19]1[CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:23][C:24]=1F.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[F:18][C:19]1[CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:23][C:24]=1[N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:9]=[C:10]([C:12]3[N:13]=[CH:14][N:15]([CH3:17])[CH:16]=3)[S:11][C:4]=12
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CNc1ccnc2cc(-c3cn(C)cn3)sc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ccc([N+](=O)[O-])cc1F)c1ccnc2cc(-c3cn(C)cn3)sc12
Temperature: 85 °C
Yield: 18.8 %

Procedure:
A stirred suspension of 421 (500 mg, 2 mmol), 3,4-difluoronitrobenzene (795 mg, 5 mmol) and cesium carbonate (1.63 g, 5 mmol) in anhydrous DMF (50 ml) was heated at 85° C. under nitrogen for 7 hrs. It was then cooled down to room temperature poured in water, and extracted with dichloromethane. The combined organic extracts was concentrated and purified twice by flash column chromatography (eluents 2% of NH4OH in methanol/CH2Cl2: 5/95 to 10/90) to afford title compound 422 (144 mg, 19% yield) as a sticky yellow solid. LCMS: 384.0 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:13]2[O:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]=[C:8]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.I(O)(=O)(=O)=[O:29]>C(#N)C.[Fe](Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[C:13]2[O:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]=[C:8]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[O:29]
Reactant: COC(=O)c1ccc(C2=Nc3ccccc3Oc3c(SC)cccc32)cc1
Reactant: [O-][I+3]([O-])([O-])O
Agent: Cl[Fe](Cl)Cl
Solvent: CC#N
Product: COC(=O)c1ccc(C2=Nc3ccccc3Oc3c2cccc3S(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a stirring suspension of compound 98 (100 mg, 0.266 mmol) and iron (III) chloride (1.296 mg, 7.99 μmol) in acetonitrile (2 mL) after 5 minutes was added periodic acid (66.8 mg, 0.293 mmol) in one portion. The reaction mixture was left to stir at room temperature overnight then quenched with saturated sodium thiosulfate solution and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over MgSO4, filtered and solvent evaporated. Purification via ISCO (0-40% EtOAc/Hexanes; 40 g silica gel column) afforded title compound 99 (60 mg, 57%) as a yellow solid. LRMS (ESI): (calc) 391.09. (found) 392.4 (MH)+.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].I[CH2:7][C:8]1([N:32]=[C:33]=[S:34])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[C:21]#[N:22])[CH:16]=2)[O:11][CH:10]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:9]1>C(Cl)(Cl)Cl>[C:1]([NH:5][C:33]1[S:34][CH2:7][C:8]2([C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=4)[C:21]#[N:22])[CH:16]=3)[O:11][CH:10]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:9]2)[N:32]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1cccc(-c2ccc3c(c2)C(CI)(N=C=S)CC(c2ccccc2)O3)c1
Reactant: CC(C)(C)N
Solvent: ClC(Cl)Cl
Product: CC(C)(C)NC1=NC2(CS1)CC(c1ccccc1)Oc1ccc(-c3cccc(C#N)c3)cc12
Reaction time: 0.33 h
Yield: 20.6 %

Procedure:
t-BuNH2 (55 mg, 0.75 mmol) was added to 3-(4-iodomethyl-4-isothiocyanato-2-phenyl-chroman-6-yl)-benzonitrile (190.5 mg, 0.375 mmol) in CHCl3 above and the mixture was stirred for 20 minutes. The solvent was removed in vacuo to give the residue, which was purified by preparative TLC to give 3-(2′-(tert-butylamino)-2-phenyl-5′H-spiro[chroman-4,4′-thiazole]-6-yl)benzonitrile (35 mg, 21%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[S:5]([C:8]1[CH:9]=[C:10]([C:18]([OH:20])=[O:19])[C:11]2[O:16][CH2:15][CH2:14][O:13][C:12]=2[CH:17]=1)(=[O:7])=[O:6]>CC(C)=O>[CH3:1][N:2]([CH3:3])[S:5]([C:8]1[CH:9]=[C:10]([C:18]([OH:20])=[O:19])[C:11]2[O:16][CH2:15][CH2:14][O:13][C:12]=2[CH:17]=1)(=[O:7])=[O:6]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cc2c1OCCO2
Reactant: CNC
Solvent: CC(C)=O
Product: CN(C)S(=O)(=O)c1cc2c(c(C(=O)O)c1)OCCO2
Temperature: 0 °C
Yield: 89.3 %

Procedure:
500 cm3 of acetone and a solution of 99 g of dimethylamine in 250 cm3 of acetone were introduced into a balloon flask provided with an agitator and a thermometer. The mixture was cooled to 0° C. and then 139 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were introduced. The mixture was agitated at ambient temperature, the acetone distilled off and the residue dissolved in 1 liter of water. The solution was rendered alkaline, filtered and treated with 70 cm3 of hydrochloric acid. The precipitate was dried off, washed and dried. 128 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 220°-221° C.; yield: 89%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[N:22]1[CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:6]
Reactant: Cc1ncc(C(CN)N2CCCOCC2)cn1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: Cc1ncc(C(CNC(=O)c2cccc(F)c2Cl)N2CCCOCC2)cn1

Procedure:
From 2-chloro-3-fluorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(1,4-oxazepan-4-yl)ethanamine.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=1)=[CH:6][NH:7]2.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)=[CH:6][NH:7]2
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)c[nH]c12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(O)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.4 %

Procedure:
A dichloromethane solution (5 ml) of 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (249 mg, 0.76 mmol) was cooled to −10° C. in a methanol-ice bath. A 1N boron tribromide (4.08 ml) was added thereto, and the mixture was stirred at room temperature for 6 hours. Ice water and dichloromethane were added to the reaction mixture, and the resultant insoluble matter was collected by filtration. The filtrate was separated and the organic layer was concentrated under reduced pressure. The residue and the substance remaining on the filter were mixed, and the mixture was purified by silica gel column chromatography (dichloromethane:methanol=60:1→25:1). The purified product was concentrated under reduced pressure. Ethyl acetate was added to crystallize the residue. The crystals were collected by filtration, washed with ethyl acetate, and then dried to thereby obtain 220 mg of powdery pale yellow 5-fluoro-3-(4-hydroxyphenyl)-8-propoxy-1H-quinolin-4-one (yield: 92%). Melting point 271-272° C.
Reaction SMILES: [OH:1][C:2]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)[CH:11]=[CH:12][CH:13]=1)([CH2:4][CH2:5][CH2:6][CH3:7])[CH3:3].N.CO>C(OCC)(=O)C>[NH2:17][CH2:16][CH2:15][CH2:14][C:10]1[CH:9]=[C:8]([C:2]([OH:1])([CH2:4][CH2:5][CH2:6][CH3:7])[CH3:3])[CH:13]=[CH:12][CH:11]=1
Reactant: CCCCC(C)(O)c1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: N
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCC(C)(O)c1cccc(CCCN)c1

Procedure:
Deprotection of 2-(3-(3-(2-hydroxyhexan-2-yl)phenyl)propyl)isoindoline-1,3-dione followed by flash chromatography (0-10% (7N NH3/MeOH)/ethyl acetate gradient), gave Example 120 a colorless oil. Yield (0.157 g, 90%): 1H NMR (400 MHz, CDCl3) δ 7.20-7.27 (m, 3H), 7.03-7.07 (m, 1H), 2.73 (t, J=7.2 Hz, 2H), 2.66 (t, J=8.0 Hz, 2H), 1.70-1.84 (m, 4H), 1.53 (s, 3H), 1.42 (brs, 3H), 1.18-1.30 (m, 3H), 1.06-1.16 (m, 1H), 0.84 (t, J=7.2 Hz, 3H). ESI MS m/z 236.2 [m+H]+, 218.2 [m+H—H2O].
Reaction SMILES: [Mg].[OH:2][C:3]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:5]([O:7][CH3:8])=[O:6].C1COCC1.[C:19](Cl)(=[O:23])[CH:20]([CH3:22])[CH3:21].Cl>C1(C)C=CC=CC=1>[C:19]([CH:9]([C:3](=[O:2])[CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:10]([O:12][CH3:13])=[O:11])(=[O:23])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)C=C(O)CC(=O)OC
Agent: Cl
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CC(=O)C(C(=O)OC)C(=O)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 167.9 %

Procedure:
A mixture of 12.15 g (0.03 mol) of product of Step A in 50 ml of toluene was refluxed using a Dean-Stark trap for 1 hour. The resulting clear solution was cooled to room temperature and 50 ml of anhydrous THF were added. To this solution 6.4 g (6.3 ml, 0.06 mol) of isobutyryl chloride was added and stirred for 18 hours. Crude was poured into 3.7% HCl, extracted with EtOAc, the EtOAc layer was washed again with 3.7% HCl and saturated NaCl. Organic layer was dried (MgSO4) and removed in vacuo affording 12.3 g of crude dimethyl 2-(isobutyryl)-3-oxo-1,5-pentanedioate. The crude was purified by HPLC using 10% EtOAc/cyclohexane as eluting solvent affording 8.87 g (61%) of this intermediate as a light yellow oil; nD25 1.4783.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@H:22]([NH:24]C(OC(C)(C)C)=O)[CH2:21][C@H:20]([C:32]([OH:34])=[O:33])[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[ClH:35].CCCCCC>O1CCOCC1>[ClH:35].[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@H:22]([NH2:24])[CH2:21][C@H:20]([C:32]([OH:34])=[O:33])[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Agent: Cl
Solvent: CCCCCC
Solvent: C1COCCO1
Product: N[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of (3S*,5R*)-5-tert-butoxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester (4.7 g, 10.1 mmol) (see Starting Material 1 above) in dioxane (25 mL), HCl (4M in dioxane, 25 mL, 100 mmol) is added and the reaction mixture is stirred for 16 h at RT. Hexane (50 mL) is added and the crystals are filtered off, washed with hexane and dried in vacuo to afford the title compound as a white solid. MS: 367.4 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 4.48 min.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]=[C:11]([C:18](=O)[CH3:19])[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[CH:8][CH:7]=[CH:6][C:5]=12.C(=O)(O)[O-].[Na+].S(O)(O)(=O)=O.[CH3:31][O:32][C:33](=[NH:35])[NH2:34]>CN(C)C=O.C(OCC)(=O)C>[N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:11]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[C:18]([CH3:19])[NH:35][C:33]([O:32][CH3:31])=[N:34]3)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(=O)C(=Cc1cccc2nonc12)C(=O)OC(C)C
Reactant: COC(=N)N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC1=NC(c2cccc3nonc23)C(C(=O)OC(C)C)=C(C)N1
Temperature: 65 °C
Yield: 24.4 %

Procedure:
A mixture of 2-[(2,1,3-benzoxadiazol-4-yl)methylene]-3-oxobutanoic acid, 1-methylethyl ester (2.04 g, 7.43 mmol), sodium bicarbonate (1.87 g, 22.3 mmol) and O-methylisourea hydrogen sulfate (1.66 g, 9.66 mmol) in dimethylformamide (7.5 ml) was heated at 65° C. (oil bath) overnight under argon. The reaction was then diluted with ethyl acetate, washed several times with water, washed with saturated sodium chloride, dried (potassium carbonate), and evaporated. The residue was flash chromatographed over Merck silica gel (400 ml) eluting with 10% ethyl acetate/dichloromethane to give 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2-methoxy-6-methyl-5-pyrimidinecarboxylic acid, 1-methylethyl ester as a dark solid (0.60 g, 25%). TLC (10% ethyl acetate/dichloromethane) single spot, Rf =0.17.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27](Cl)=[N:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CC(C)([O-])C.[K+].C(O)(C)(C)C.[Cl:42][C:43]1[CH:48]=[C:47]([CH2:49][OH:50])[CH:46]=[CH:45][N:44]=1>CO>[F:29][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([O:50][CH2:49][C:47]4[CH:46]=[CH:45][N:44]=[C:43]([Cl:42])[CH:48]=4)=[N:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: OCc1ccnc(Cl)c1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nccnc2Cl)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CO
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nccnc2OCc2ccnc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 21 %

Procedure:
To a solution of 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide (115 mg, 0.254 mmol) and 1M solution of potassium tert-butoxide in tert-butanol (0.80 mL, 0.80 mmol) was added 2-Chloro-4-pyridinemethanol (81.8 mg, 0.568 mmol). The resulting suspension was stirred at room temperature for 15 h. The crude reaction mixture was diluted with methanol and purified by preparative HPLC (50 mM NH4OAc(aq), Acetonitrile system). The product was isolated by lyophilization of pure fractions yielding N-[3,5-bis(trifluoromethyl)phenyl]-4-(3-{[(2-chloropyridin-4-yl)methyl]oxy}pyrazin-2-yl)piperazine-1-carboxamide (29.9 mg, 21% yield). 1H NMR (CDCl3) 8.41 (d, 1H), 7.91 (s, 2H), 7.82 (d, 1H), 7.61 (d, 1H), 7.54 (s, 1H), 7.39 (s, 1H), 6.70 (s, 1H), 5.47 (s, 2H), 3.70-3.65 (m, 8H) ppm.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:4][CH2:3]1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CC(C)=O.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[C:18]([F:21])([F:19])[F:20])[CH2:4][CH2:3]1
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Yield: 64.9 %

Procedure:
A suspension of 1-methyl-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine (1.23 g, 4 mmol) and sodium hydrosulfite (7.0 g, 85% pure from Aldrich, 40 mmol) in acetone and water (1:1, 20 mL) was refluxed for 3 h. Upon cooling, the volatile components (mainly acetone) were removed on rotavap, and the resulting mixture was subjected to filtration. The solid was thoroughly washed with EtOAc. The combined filtrate was extracted with n-BuOH (4×), and the combined organic layer was washed with saturated aq. NaHCO3, dried (Na2SO4), filtered, concentrated, and the resulting residue was purified by silica gel chromatography (eluted with 5% MeOH/DCM, MeOH was pre-saturated with ammonia gas) to provide 0.71 g of product as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl:28][C:29]1[C:30]([F:40])=[CH:31][C:32]([F:39])=[C:33]([S:35](Cl)(=[O:37])=[O:36])[CH:34]=1>O1CCCC1>[Cl:28][C:29]1[C:30]([F:40])=[CH:31][C:32]([F:39])=[C:33]([S:35]([N:6]([CH2:5][C:4]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=2[O:2][CH3:1])[C:7]2[S:11][N:10]=[CH:9][N:8]=2)(=[O:37])=[O:36])[CH:34]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (Preparation 14, 40.6 g, 0.1619 mol) in anhydrous tetrahydrofuran (600 mL), cooled to −70° C., under nitrogen was added lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (1 M in tetrahydrofuran, 161.9 mL, 0.161.9 mol) drop wise. The reaction mixture was warmed to room temperature and stirred for 1 hour before cooling to −70° C. A solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride (40 g, 0.1619 mol) in tetrahydrofuran (200.0 mL) was added dropwise. After complete addition, the reaction mixture was gradually warmed to room temperature and stirred for 1 hour. Reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. Organic layer was washed with water and saturated aqueous sodium chloride solution. Crude residue was purified by column chromatography eluting with ethyl acetate:hexane (gradient 1:19 to 3:17, by volume) to afford the title compound as a white solid, 46 g.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[C:26]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:19]1([CH2:18][CH2:17][CH2:16][CH:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:35]3[CH2:36][CH2:37][CH:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:33][CH2:34]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[C:13]([OH:15])=[O:14])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)C(CCCc1ccccc1)NS(=O)(=O)c1ccc(F)cc1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Product: O=C(O)C(CCCc1ccccc1)NS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1

Procedure:
In a manner similar to Example 3(b), (±)-2-(4-fluoro-benzenesulfonylamino)-5-phenyl-pentanoic acid was condensed with 4-phenyl-piperidine hydrochloride to give the title compound, mp=59-62° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH2:23])[CH2:22][CH2:21]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1.[CH3:31][C:32]1[O:36][C:35]([C:37](O)=[O:38])=[N:34][N:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH:23][C:37]([C:35]4[O:36][C:32]([CH3:31])=[N:33][N:34]=4)=[O:38])[CH2:21][CH2:22]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(N)CC2)no1
Reactant: Cc1nnc(C(=O)O)o1
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(NC(=O)c3nnc(C)o3)CC2)no1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-yl}-amide (example 24) was coupled with 5-methyl-[1,3,4]oxadiazole-2-carboxylic acid to yield the title compound as light yellow solid. MS: 534.2 (MH+, 1Cl).