Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([F:12])[CH:8]=[N:7]2.C([Sn](CCCC)(CCCC)[C:18]([O:20]CC)=[CH2:19])CCC.Cl.CCN(CC)CC>C1(C)C=CC=CC=1.C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)=O>[F:12][C:9]1[CH:8]=[N:7][C:6]2[C:11]([N:10]=1)=[C:2]([C:18](=[O:20])[CH3:19])[CH:3]=[CH:4][CH:5]=2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Fc1cnc2cccc(Br)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1cccc2ncc(F)nc12
Reaction time: 0.08 h
Yield: 10628 %

Procedure:
A solution of 8-bromo-2-fluoroquinoxaline (2.36 g, 10.39 mmol), tributyl(1-ethoxyvinyl)stannane (3.86 ml, 11.43 mmol; Aldrich), and Pd(PPh3)4 (0.360 g, 0.312 mmol) in toluene (74 ml) and THF (29 ml) was heated to reflux for 1.5 h. The reaction mixture was cooled to RT before conc. HCl (1.083 ml, 12.99 mmol) was added to convert the silyl enol ether to the methyl ketone. After stirring for 5 min, Et3N (3.62 ml, 26.0 mmol) was added to quench the HCl. The crude material was concentrated, taken up in DCM, adsorbed onto silica, and purified via automated flash chromatography (silica gel) with 100% hexanes to 60% DCM in hexanes to give 1-(3-fluoroquinoxalin-5-yl)ethanone (210 g, 87% yield) as a pale yellow solid. MS (ESI, pos. ion) m/z: 191.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: ClCCCCOc1ccccn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](NCCCCOc2ccccn2)C1
Temperature: 25 °C
Yield: 22.2 %

Procedure:
3(S)-aminopyrrolidine-1-carboxylic acid tert-butyl ester (0.93 g, 5.0 mmol), 2-(4-chlorobutoxy)pyridine (0.93 g, 5.0 mmol), potassium carbonate (0.83 g, 6.0 mmol) and sodium iodide (0.83 g, 5.5 mmol) were suspended in acetonitrile (20 ml) and heated under reflux for 24 hours. After cooling to room temperature, water (50 ml) was added to the reaction solution and extraction with ethyl acetate (50 ml) was conducted. The organic layer was washed with water twice and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1). The purified product was concentrated under reduced pressure to thereby obtain 372 mg of oily colorless 3(S)-[4-(pyridin-2-yloxy)butylamino]pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH:1]1([N:6]=[C:7]=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:9][C:10]1[C:11](=[O:17])[NH:12][C:13](=[O:16])[NH:14][CH:15]=1>N1C=CC=CC=1>[CH:1]1([NH:6][C:7]([N:14]2[CH:15]=[C:10]([F:9])[C:11](=[O:17])[NH:12][C:13]2=[O:16])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=NC1CCCC1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: c1ccncc1
Product: O=C(NC1CCCC1)n1cc(F)c(=O)[nH]c1=O

Procedure:
Cyclopentylisocyanate, 5.67 g, was allowed to react with 5-fluorouracil, 4.6 g, in 17 g of pyridine at 90° C. for 2 hr, then the pyridine was evaporated and the residue was shaken with 100 ml of dichloromethane and 100 ml of hydrochloric acid water. The lower layer of the mixture was dried and exsiccated. The residue was recrystallized from ethanol and 8.3 g of 1-cyclopentylcarbamoyl-5-fluorouracil (melting point: 137° C.) was obtained (Compound No. 9) was obtained. NMR: 1.00-2.28 (6H b CH) 3.56-4.12 (1H b CH--NHCO) 8.40 (1H d C6 --H) 8.68-9.08 (1H b NHCO) 9.48 (1H b N3 --H).
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([C:14]2[NH:18][N:17]=[C:16]([C:19]([OH:21])=O)[CH:15]=2)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C>S(Cl)(Cl)=O.CN(C=O)C.ClCCl>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:19]([C:16]2[CH:15]=[C:14]([C:11]3[CH:12]=[N:13][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:9][CH:10]=3)[NH:18][N:17]=2)=[O:21])[CH2:25][CH2:24]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cc(-c2cnc(Oc3ccccc3)nc2)[nH]n1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2cc(-c3cnc(Oc4ccccc4)nc3)[nH]n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.1 %

Procedure:
To a solution consisting of 5-(2-phenoxypyrimidin-5-yl)-1H-pyrazole-3-carboxylic acid (Example 56, 60 mg, 0.21 mmol) in thionyl chloride (10 mL) was added one drop of dry DMF. The solution was heated to reflux for four hours and was subsequently allowed to cool to room temperature. Thionyl chloride was evaporated under reduced pressure and to the residue was added toluene (2×30 mL), which was evaporated and the residue subjected to high vacuum to remove residual thionyl chloride. The residue and 1-methylpiperazine (25 mg, 0.028 mL, 0.25 mmol) were dissolved in dichloromethane (10 mL) followed by the addition of triethylamine (0.14 mL). The solution was stirred at room temperature for 18 hours. The solvent was evaporated and the residue was purified by silica gel flash chromatography using 0-10% methanol in dichloromethane gradient through a 25-g Silicycle® flash silica cartridge to afford the title compound as a white solid (46 mg, 60% yield); Rf 0.30 with 6% methanol in dichloromethane; 1H-NMR (300 MHz; CD3OD) δ 8.96 (s, 2H), 7.43 (m, 2H), 7.25 (m, 1H), 7.19 (d, 2H), 7.02 (s, 1H), 3.74-3.99 (br, 4H), 2.51 (br, 4H), 2.33 (s, 3H); MS (ESI−) m/z 363 (M−1); H-PGDS FPBA IC50: 0.65 μM; H-PGDS inhibitor EIA IC50: 0.42 μM.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][OH:13])=[C:8]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(OCC)(=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][O:13][S:38]([C:35]2[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=2)(=[O:40])=[O:39])=[C:8]([S:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:20][CH:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2CO)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCc2c(SCc3ccc(C(C)(C)C)cc3)cnn(C(C)(C)C)c2=O)cc1
Reaction time: 4 h

Procedure:
To a 15 ml round bottom flask charged with 2-tert-butyl-4-hydroxymethyl-5-(4-tert-butylbenzyl)thio-3(2H)-pyridazinone (1.0 g, 2.77 mmol) is added pyridine. p-Toluenesulfonyl chloride (0.79 g, 4.15 mmol) is then added to it and the mixture stirred for 4 hours. The reaction mixture is diluted with ethyl acetate, washed with 5% copper sulfate solution and then with water and dried. After removing the solvent on the rotary evaporator the crude is purified by flash chromatography using (silica gel; ethyl acetate/hexanes) as the eluting mixture to give the product.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([C:9]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([C:17]([NH2:19])=[O:18])[NH:11][N:10]=1)[CH3:8].Cl[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.O>C(#N)C>[CH2:7]([C:9]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([C:17]([NH2:19])=[O:18])[N:11]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:10]=1)[CH3:8]
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Reactant: ClCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CCc1nn(Cc2ccccn2)c(C(N)=O)c1[N+](=O)[O-]
Temperature: 60 °C
Yield: 30.7 %

Procedure:
Caesium carbonate (1.414 kg, 4.34 mol) was added to a suspension of the title compound of example (4d) (800 g, 4.34 mol) in acetonitrile (51) and the mixture warmed to 60° C. 2-Chloromethylpyridine (664.7 g, 5.23 mol) was added and the reaction heated at 70° C. for 7 hours, then water (9.5 l) added and the reaction mixture cooled to 10° C. Granulation of this mixture gave a precipitate which was filtered and dried to afford 3-ethyl-4-nitro-1-(pyridin-2-yl)methyl-pyrazole-5-carboxamide (367 g). Sodium chloride (1.58 kg) was added to the filtrate and the solution extracted with ethyl acetate (4×1.75 l). The combined organic extracts were distilled to remove approximately 10 l of solvent, toluene (5.6 l) added over 35 minutes to the hot (69-76° C.) solution and the mixture allowed to cool. The resulting suspension was granulated at <10° C. for 30 minutes, filtered, the solid washed with ethyl acetate:toluene (50:50) 600 ml) and dried (60° C.) to afford the title compound (624 g 52%) as a light brown solid. δ (DMSOd6): 1.08 (3H,t), 3.02 (2H,q), 5.53 (2H,s), 7.34 (2H,m), 7.65 (1H,s), 7.82 (1H,m), 7.93 (1H,s), 8.52 (1H,d). LRMS: m/z 276 (M+1)+.
Reaction SMILES: [O:1]([CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24](O)=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](N1C=CN=C1)([N:29]1[CH:33]=[CH:32][N:31]=[CH:30]1)=O.CN(C)CCN>C1COCC1>[CH3:27][N:29]([CH3:30])[CH2:33][CH2:32][NH:31][C:24]([C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([CH2:11][S:10][CH2:9][CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:14]=2)=[CH:23][CH:22]=1)=[O:25]
Reactant: O=C(O)c1ccc(-c2ccc(CSCCOc3ccccc3)cc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)CCN
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)c1ccc(-c2ccc(CSCCOc3ccccc3)cc2)cc1
Yield: 86.2 %

Procedure:
4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared as described in example 1. 4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (0.8 g, 2.19 mmol, 1 eq.) in THF was treated with 1,1′-carbonyldiimidazole (0.36 g, 2.23 mmol, 1.02 eq.). The resulting acyl imidazole was then treated with N,N-dimethylethylenediamine (0.23 g, 2.63 mmol, 1.2 eq). When complete, the reaction was worked up and the resulting yellow oil purified as described in example 3 to give 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (2-dimethylamino-ethyl)-amide (0.82 g, 86% yield) as a yellow oil.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:13]=NC=[C:16]([C:18](F)(F)[F:19])[CH:17]=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1.N1(CCN2C=C(C3C=CC(F)=[C:50]([O:55][CH3:56])C=3)N=C2C2CCNCC2)CCC1>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:18]([F:19])=[C:50]([O:55][CH3:56])[CH:13]=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCc1c(N)ncnc1N1CCC(c2nc(-c3cncc(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Reactant: COc1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccc1F
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(OC)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine of using 4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-yl)piperidine instead of 3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyridine hydrochloride salt. LC-MS: (M+1=480, obsd.=480).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:44]12[CH2:51][CH2:50][CH:47]([CH2:48][CH2:49]1)[C@@H:46](O)[CH2:45]2>C1COCC1>[N:44]12[CH2:51][CH2:50][CH:47]([CH2:48][CH2:49]1)[C@@H:46]([O:10][C:9](=[O:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)([NH2:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:45]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: Cc1ccc(C(N)(C(=O)O)c2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1ccc(C(N)(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-methyl-phenyl-amino-phenyl-acetic acid (I244) (870 mg, 3.60 mmol) in dry THF (35 mL), are added DCC (891 mg, 4.32 mmol), HOBt (583 mg, 4.32 mmol) and 3(R)-quinuclidinol (915 mg, 7.20 mmol). The resulting mixture is stirred at RT for 48 hours (UPLC-MS monitoring: complete conversion). The solvent is evaporated and the residue is portioned between EtOAc and 1M K2CO3. The organic phase is dried over Na2SO4, filtered and evaporated to dryness. The resulting crude is dissolved in little DCM and filtered to remove the insoluble. The solution is concentrated under vacuum to obtain the title compound as a yellow solid, which is used in the next step without any further purification.
Reaction SMILES: [CH:1]([C:13]1[CH:14]=[N:15][N:16]([CH:18]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:19]([NH:21][C:22]2[C:27]([O:28][CH3:29])=[CH:26][C:25]([O:30][CH3:31])=[CH:24][C:23]=2[O:32][CH3:33])=[O:20])[CH:17]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H][H]>C1COCC1.[Pd]>[CH2:1]([C:13]1[CH:14]=[N:15][N:16]([CH:18]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:19]([NH:21][C:22]2[C:23]([O:32][CH3:33])=[CH:24][C:25]([O:30][CH3:31])=[CH:26][C:27]=2[O:28][CH3:29])=[O:20])[CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCC=Cc1cnn(C(C(=O)Nc2c(OC)cc(OC)cc2OC)c2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1cnn(C(C(=O)Nc2c(OC)cc(OC)cc2OC)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
In addition to the procedures followed in Example 122, (±)-4-(1-dodecenyl)-α-phenyl-N-(2,4,6-trimethoxyphenyl)-1H-pyrazole-1-acetamide (0.46 g, 0.9 mmol) was dissolved in 75 mL THF and 5% Pd/C (0.1 g) was added. Hydrogen gas (50 psi) was added and the reaction mixture was stirred at room temperature for 2 hours. Filtered to remove the catalyst and concentrated the filtrate to give an oil. Triturated with hexanes to give the title compound as a cream-colored solid (0.45 g, 97%); mp 77°-79° C.
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][N:8]3[C:13](=[O:14])[C:12]([OH:15])=[C:11]([C:16]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[O:17])[N:10]=[C:9]3[C:3]([NH:27]C(OCC3C=CC=CC=3)=O)([CH2:4][O:5]2)[CH2:2]1>CO.[Pd]>[CH2:1]1[CH:6]2[CH2:7][N:8]3[C:13](=[O:14])[C:12]([OH:15])=[C:11]([C:16]([NH:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[O:17])[N:10]=[C:9]3[C:3]([NH2:27])([CH2:4][O:5]2)[CH2:2]1
Reactant: O=C(NC12CCC(Cn3c1nc(C(=O)NCc1ccc(F)cc1)c(O)c3=O)OC2)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC12CCC(Cn3c1nc(C(=O)NCc1ccc(F)cc1)c(O)c3=O)OC2
Reaction time: 18 h
Yield: 86.6 %

Procedure:
To a mixture of benzyl (2-((4-fluorobenzyl)carbamoyl)-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-7,10-(epoxymethano)pyrimido[1,2-a]azepin-10(4H)-yl)carbamate (110 mg, 0.216 mmol) in methanol (3 mL) was added 10% Pd/C (115 mg, 0.108 mmol) and the mixture stirred under 1 atm H2 for 18 h. The mixture was then filtered through a pad of CELITE® and the pad washed with ethyl acetate. The filtrate was concentrated to afford the title compound (70 mg, 86% yield) as a light yellow solid. 1H NMR (500 MHz, CDCl3) δ: 7.84 (brs, 1H), 7.29 (dd, 2H, J=8.09 & 5.34 Hz), 7.02 (t, 2H, J=8.55 Hz), 4.56 (d, 2H, J=6.1 Hz), 4.43-4.50 (m, 2H), 4.04-4.11 (m, 2H), 3.87 (d, 1H, J=10.99 Hz), 2.28-2.32 (m, 2H), 1.98-2.09 (m, 3H), 1.55-1.61 (m, 1H). LCMS (M+H)=375.2.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl.[O:8]=[S:9]1(=[O:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1F>CS(C)=O.O>[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1[N:12]1[CH2:13][CH2:14][S:9](=[O:15])(=[O:8])[CH2:10][CH2:11]1
Reactant: O=S1(=O)CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCS(=O)(=O)CC2)c(F)c1
Temperature: 100 °C
Yield: 110.1 %

Procedure:
To a suspension of K2CO3 (5.53 g, 40 mmol) and 1,1-dioxo-thio-morpholinehydrochloride (3.60 g, 21 mmol) in DMSO (50 mL) was added 3,4-difluoronitrobenzene (3.18 g, 20 mmol). The reaction was heated at 100° C. for 12 h. The mixture was diluted with water (150 mL) and extracted with CH2Cl2 (100 mL×2). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a yellow solid (6.04 g, 70%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][C:15]=2[F:23])=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([O:7]C)=[O:6]>CCO>[F:1][C:2]1[C:3]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][C:15]=2[F:23])=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(F)c(F)c1Nc1ccc(CCO)cc1F
Solvent: CCO
Product: O=C(O)c1ccc(F)c(F)c1Nc1ccc(CCO)cc1F
Yield: 93 %

Procedure:
Methyl 3,4-difluoro-2-[2-fluoro-4-(2-hydroxyethyl)anilino]benzoate was deprotected using EtOH/1 M NaOH as above to afford 3,4-difluoro-2-[2-fluoro-4-(2-hydroxyethyl)anilino]benzoic acid as a crystalline cream solid (93%); m.p. (EtOAc/hexane) 196-200° C. 1H NMR [400 MHz, (CD3)2SO] δ 13.67 (v br s, 1 H), 9.28 (br s, 1 H), 7.80 (ddd, J=8.4, 6.1, 1.8 Hz, 1 H), 7.13-6.93 (m, 4 H), 4.65 (br s, 1 H), 3.63-3.55 (br m, 2 H), 2.69 (t, J=6.8 Hz, 2 H). Anal. calcd. for C15H12F3NO3: C, 57.9; H, 3.9; N, 4.5. Found C, 58.3; H, 4.1; N, 4.7.
Reaction SMILES: O[N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O.C(=O)(O)[O-].[Na+]>[NH2:2][CH:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C#N)=NO
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(N)C#N
Temperature: 35 °C
Yield: 17.7 %

Procedure:
To a stirred solution of the ethyl (hydroxyimino)cyanoacetate (10 g, 70.4 mmol) in water and sodium bicarbonate saturated solution (80 mL) was added sodium dithionite (34.3 g, 197 mmol). The reaction was heated up to 35° C. for 3 h. The solution was then saturated with sodium chloride and extracted with ethyl acetate (3×200 mL). The combined organic phases were dried over sodium sulfate and concentrated, giving an oil of ethyl 2-amino-2-cyanoacetate (1.6 g). 1H NMR (400 MHz, CDCl3) δ 4.42 (s, 1H), 4.32 (q, 2H), 1.33 (t, 3H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:28][CH2:29][CH2:30][OH:31]>>[OH:31][CH2:30][CH2:29][CH2:28][N:22]1[CH2:21][CH2:20][N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Reactant: OCCCBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(CCCO)C2=O)CC1
Yield: 66 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 3-bromo-1-propanol, to give the desired product as a white solid (66%).
Reaction SMILES: N1CCCCC1.[I-].[K+].Cl[CH2:10][CH:11]1[S:19][C:18]2[N:13]([C:14](=[O:24])[N:15]([CH2:21][CH2:22][CH3:23])[C:16](=[O:20])[CH:17]=2)[CH2:12]1>C(O)C>[CH2:10]=[C:11]1[S:19][C:18]2[N:13]([C:14](=[O:24])[N:15]([CH2:21][CH2:22][CH3:23])[C:16](=[O:20])[CH:17]=2)[CH2:12]1
Reactant: CCCn1c(=O)cc2n(c1=O)CC(CCl)S2
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCNCC1
Product: C=C1Cn2c(cc(=O)n(CCC)c2=O)S1
Temperature: 60 °C
Reaction time: 42 h
Yield: 64 %

Procedure:
Piperidine (0.66 g) and potassium iodide (0.1 g) were added to a solution of 2-chloromethyl-6-propyl-2,3-dihydro-5H-thiazolo[3,2-c]pyrimidine-5,7(6H)-dione (1g) in ethanol (20 ml). The reaction mixture was stirred at 60° C. for 42 hours. The reaction solution was concentrated to dryness, and the residue was dissolved in chloroform. After washing with water and drying, the organic layer was concentrated to dryness. The resulting residue was purified by column chromatography on silica gel. The resulting crystals were recrystallized from methylene chloride-isopropyl ether-hexane to give colorless crystals (0.55 g, 64%).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:15](=[O:29])[N:16]([CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=3)[N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[CH:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)CCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[CH:6]=[CH:5][N:4]3[C:15](=[O:29])[N:16]([CH2:18][C:19]4[CH:20]=[N:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=4)[N:17]=[C:3]3[C:2]=2[C:35]2[CH:36]=[CH:37][C:32]([CH:30]=[O:31])=[CH:33][CH:34]=2)=[CH:13][CH:12]=1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(Br)c(-c3ccc(Cl)cc3)ccn12
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCO
Product: O=Cc1ccc(-c2c(-c3ccc(Cl)cc3)ccn3c(=O)n(Cc4ccc(C(F)(F)F)nc4)nc23)cc1
Temperature: 110 °C

Procedure:
To a stirring solution of 8-bromo-7-(4-chlorophenyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (100 mg, 0.21 mmol) in n-butanol (1.6 mL) at room temperature under argon was added 4-formylphenylboronic acid (40.4 mg, 0.27 mmol), Pd2(dba)3 (7.6 mg, 0.008 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (13.6 mg, 0.03 mmol) and K3PO4 (88.1 mg, 0.41 mmol). The resulting suspension was purged of oxygen by bubbling with argon for 15 min, sealed in a vial under argon, heated at 110° C. for 5 h, and then cooled to room temperature. The reaction mixture was diluted with EtOAc and washed once with water. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by automated silica gel chromatography (eluted with EtOAc/hexanes). Pooling of the desired fractions provided the title compound as a yellow solid, 38.8 mg, 36%. HPLC/MS: retention time=2.73 min, [M+H]+=509.