Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])[CH2:16][CH2:15][CH:14]([O:17][S:18](=[O:21])(=[O:20])[NH2:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])[CH2:12][CH2:13][CH:14]([O:17][S:18](=[O:20])(=[O:21])[NH:19][C:30](=[O:32])[CH3:31])[CH2:15][CH2:16]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)OC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NS(=O)(=O)OC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Reaction time: 2.5 h

Procedure:
A solution of the product from Example 119 (69 mg, 0.15 mmol) in pyridine (2 mL) was treated with acetic anhydride (2 μL) at room temperature. After stirring for 2.5 hours, ice was added to the mixture until a white precipitate formed. The mixture was extracted with ethyl acetate, washed with water and brine, dried (MgSO4) and evaporated. The product was purified by flash chromatography on silica eluting with 50% ethyl acetate/iso-hexane to obtain the title compound as a white solid (14 mg). MS (ES+) 530 ([MNa]+).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:9](=[O:18])[NH:10][C:11]3[C:16]([N:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)[CH2:33][C:22]=2[CH:21]=1>>[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])[N:2]3[CH2:3][CH2:4][CH:5]([C:8]4[C:9](=[O:18])[NH:10][C:11]5[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=5)[N:17]=4)[CH2:6][CH2:7]3)[CH2:33][C:22]=2[CH:21]=1
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Reactant: O=c1[nH]c2ccccc2nc1C1CCNCC1
Agent: Cl
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(c3nc4ccccc4[nH]c3=O)CC2)C1=O
Yield: 49 %

Procedure:
Title compound was prepared from 3-(piperidin-4-yl)quinoxalin-2(1H)-one hydrochloride in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Material was obtained as white solid in 49% yield. MS m/e (M−H)−=573.2. 1H NMR (500 MHz, DMSO-D6): δ=13.53 (s, 1H), 12.35 (s, 1H), 8.36 (s, 1H), 7.72 (t, J=8.70, 1H), 7.48 (t, J=7.78, 1H), 7.28 (m, 2H), 7.24 (s, 1H), 5.37 (d, J=17.09, 1H), 4.63 (d, J=17.09, 1H), 4.49 (m, 1H), 4.12 (m, 1H), 3.86 (m, 1H), 3.59 (t, J=12.36, 1H), 3.45 (m, 1H), 3.22 (m, 1H), 3.10 (m, 1H), 2.99 (m, 1H), 2.87 (dd, J1=15.56, J2=14.34, 1H), 2.72 (m, 1H), 2.36 (m, 1H), 1.96 (d, J=12.82, 1H), 1.89 (d, J=13.12, 1H), 1.70 (m, 1H), 1.52 (m, 1H), 0.72 (s, 9H).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)(C)C.Cl[C:14]1[N:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1.[I-].C(N(CC)CC)C>COCCOC>[CH3:20][C:17]1[N:16]=[N:15][C:14]([C:5]#[C:6][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: C[Si](C)(C)C#Cc1cccnc1
Agent: [I-]
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: Cc1ccc(C#Cc2cccnc2)nn1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To the solution of 3-[(trimethylsilyl)ethynyl]pyridine (0.175g, 1.0 mmol), 3-chloro-6-methylpyridazine (0.128 g, 1.0 mmol), cupper (I) iodide (0.019 g, 0.1 mmol), triethylamine (0.202 g, 2.1 mmol), in 20 ml Ethylene glycol dimethyl ether was added tetrakis(triphenlyphosphine)palladium (0) (60 mg, 0.052 mmol). The result solution was heated to 80° C. after degasing by argon for 5 minute, and then Tetrabutylammonium fluoride (2.1 ml, 1M/THF) was added dropwise. After stirring at 80° C. for 12 hour, the reaction mixture was quenched with H2O (30 mL), then extracted with EtOAc (3×30 mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude purified by liquid chromatography on silica gel using an ISCO single channel system (Hexane/EtOAc: 9/1 to 1/9) to give 3-methyl-6-(pyridin-3-ylethynyl)pyridazine as brown solid. 1H NMR (CDCl3 300 MHz) δ 8.875-8.87 (m, 1H), 8.65-8.63 (d, 1H), 7.95-7.93 (d, 1H), 7.60-7.58 (dd, 1H), 7.39-7.36 (m, 2H), 2.80 (s, 3H). MS (ESI) 196.10 (M++H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH2:15][CH2:14][C:13](=[O:16])[CH:12]=1>ClCCCl>[Br:1][C:12]1[C:13](=[O:16])[CH2:14][CH2:15][C:11]=1[O:10][CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC1=CC(=O)CC1
Solvent: ClCCCl
Product: COC1=C(Br)C(=O)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
N-Bromosuccinimide (24.92 g, 0.140 mol) is added, portionwise, over 1 hour to a stirred solution of 3-methoxycyclopent-2-enone (14.95 g, 0.133 mol) in 1,2-dichloroethane (300 ml) at 0° C. in an amber flask. The reaction mixture is stirred at 0° C. for a further 90 minutes and then any remaining solid is removed by filtration. The filtrate is evaporated to dryness under reduced pressure, the resultant solid is dissolved in warm toluene (600 ml) and washed quickly with ice-cold water (2×100 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure until approximately 150 ml remains. The residue is cooled with an ice bath and left for 30 minutes. The resultant solid is removed by filtration, washed with hexane (50 ml) and air-dried to give 2-bromo-3-methoxycyclopent-2-enone.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2.[H-].[Na+].[CH3:12][CH:13]1[CH2:18][CH:17]([CH3:19])[CH2:16][N:15]([CH:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21](OCC)=[O:22])[CH2:14]1>C1(C)C=CC=CC=1>[CH3:12][CH:13]1[CH2:18][CH:17]([CH3:19])[CH2:16][N:15]([CH:20]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:21]([O:9][C@@H:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)=[O:22])[CH2:14]1
Reactant: CCOC(=O)C(c1ccccc1)N1CC(C)CC(C)C1
Reactant: O[C@H]1CN2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1CC(C)CN(C(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48 %

Procedure:
(R)-quinuclidin-3-ol (175 mg, 1.38 mmol) and NaH (60% dispersion in mineral oil, 52.3 mg, 1.31 mmol) were suspended in dry toluene (9 ml) under nitrogen atmosphere and stirred at room temperature for 20 minutes. Ethyl 2-(3,5-dimethylpiperidin-1-yl)-2-phenylacetate (200 mg, 0.73 mmol) was added and the resulting mixture was stirred at 100° C. for 24 hours. NaH (60% dispersion in mineral oil, 8.72 mg, 0.36 mmol) was added again and the mixture was refluxed for others 24 hours. The reaction was cooled and partitioned between water and ethyl ether. The organic layer was collected and dried over Na2SO4, filtered and evaporated. The crude compound was purified by flash chromatography (DCM/MeOH=9/1) to obtain (R)-quinuclidin-3-yl 2-(3,5-dimethylpiperidin-1-yl)-2-phenylacetate (125 mg, 48.3% yield) as a colourless oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32]4[S:33][CH:34]=[CH:35][N:36]=4)(=[O:30])=[O:29])=[CH:24][C:23]=3[C:37]#[N:38])=[C:17]([C:39]3[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(C)(C)C.[ClH:46]>ClCCl.O1CCOCC1>[ClH:46].[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32]4[S:33][CH:34]=[CH:35][N:36]=4)(=[O:29])=[O:30])=[CH:24][C:23]=3[C:37]#[N:38])=[C:17]([C:39]3[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Cn1nccc1-c1cc(-c2cccc(CNC(=O)OC(C)(C)C)c2)ccc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1C#N
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1nccc1-c1cc(-c2cccc(CN)c2)ccc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
tert-Butyl-{[4′-{2-cyano-4-[(1,3-thiazol-2-ylamino)sulfonyl]phenoxy}-3′(1-methyl-1H-pyrazol-5-yl)biphenyl-3-yl]methyl}carbamate (Preparation 77, 380 mg, 0.59 mmol) was dissolved in dichloromethane (20 mL), 4M HCl in 1,4-dioxane (4 mL) was added and the reaction was stirred for 18 hours at room temperature. The reaction mixture was concentrated in vacuo, slurried in cold diethyl ether (20 ml) then filtered to afford the title compound (342 mg, 99%) as a yellow solid as the hydrochloride salt.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]3)=[CH:21][CH:20]=1
Reactant: Sc1ccc(Br)cc1
Reactant: O=c1ccc2cc(OCCCCBr)ccc2[nH]1
Product: O=c1ccc2cc(OCCCCSc3ccc(Br)cc3)ccc2[nH]1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p. 198°-199° C.) and 4-bromo-thiophenol.
Reaction SMILES: N1CCNCC1.[CH:7]12[CH2:39][CH:10]([N:11]([CH2:13][CH2:14][N:15]3[C:23]4[C:18](=[CH:19][C:20]([N:24]5[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)=[CH:26][C:25]5=[O:38])=[CH:21][CH:22]=4)[CH:17]=[N:16]3)[CH2:12]1)[CH2:9][O:8]2.[ClH:40]>>[ClH:40].[C@H:7]12[CH2:39][C@H:10]([N:11]([CH2:13][CH2:14][N:15]3[C:23]4[C:18](=[CH:19][C:20]([N:24]5[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=6)=[CH:26][C:25]5=[O:38])=[CH:21][CH:22]=4)[CH:17]=[N:16]3)[CH2:12]1)[CH2:9][O:8]2
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc2c(cnn2CCN2CC3CC2CO3)c1
Agent: C1CNCCN1
Agent: Cl
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc2c(cnn2CCN2C[C@@H]3C[C@H]2CO3)c1
Yield: 18 %

Procedure:
Following the procedure of Example 27 (step b), but substituting 2-oxa-5-azabicyclo[2.2.1]heptane for piperazine, 1-(1-(2-(2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)-1H-indazol-5-yl)-4-(benzyloxy)pyridin-2(1H)-one was prepared as a yellow powder: 1H NMR (500 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.51 (d, J=8.9 Hz, 1H), 7.44-7.35 (m, 6H), 7.29 (d, J=7.4 Hz, 1H), 6.10-6.05 (m, 2H), 5.06 (s, 2H), 4.48 (t, J=6.9 Hz, 2H), 4.36 (s, 1H), 3.95 (d, J=7.8 Hz, 1H), 3.59 (dd, J=7.6, 1.7 Hz, 1H), 3.40 (s, 1H), 3.15-3.05 (m, 1H), 2.88 (dd, J=9.9, 1.6 Hz, 1H) 2.53 (d, J=9.8 Hz, 1H), 1.80-1.74 (m, 2H), 1.72-1.67 (m, 1H); ESI MS m/z 443 [M+H]+This was converted to the HCl salt to give the title compound (17.4 mg, 18%) as a yellow powder: ESI MS m/z 443 [M+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:5]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])[CH3:8])=[O:6].[N:31]1([S:37](C2C=C(C=C(C(F)(F)F)C=2)C(O)=O)(=[O:39])=[O:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:7]([CH3:8])[C:5](=[O:6])[C:4]2[CH:24]=[C:25]([C:27]([F:28])([F:30])[F:29])[CH:26]=[C:2]([S:37]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)(=[O:39])=[O:38])[CH:3]=2)=[C:16]([O:22][CH3:23])[CH:17]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCOCC2)c1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCOCC2)c1

Procedure:
The title compound was prepared in analogy to example 90, from 4-(4-fluoro-2-methoxyphenyl)-N-methylpyridin-3-amine (example 129, intermediate) and 3-(morpholine-4-sulfonyl)-5-trifluoromethyl-benzoic acid after a reaction time of 64 hours. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (ISCO) system eluting with EtOAc (isocratic). Light yellow solid (34%). MS (ESI): m/z=554.14 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[N:4][CH:3]=1.C(N(CC)CC)C.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1>C(Cl)Cl.Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:18][C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(Cl)c1cncc(Cl)n1
Reactant: Cc1cccc(N)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(NC(=O)c2cncc(Cl)n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
The product from Example 15B (950 mg, 5.37 mmol) was dissolved in CH2Cl2 (20 mL). Triethylamine (1.10 mL, 7.89 mmol) and m-toluidine (0.70 mL, 6.46 mmol) were added, and the reaction stirred at ambient temperature for 2 h. The reaction mixture was diluted with 0.1M HCl (100 mL) and extracted with CH2Cl2 (3×50 mL). The organic extracts were combined, washed with brine (50 mL), dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (2.5% EtOAc in CH2Cl2, Rf=0.39) to afford the title compound as a white solid (1.11 g, 83%). MS (DCI/NH3) m/z 248 (M+H)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[OH:15].C(N(C(C)C)CC)(C)C>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[N:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[OH:15])#[N:5]
Reactant: N#Cc1ccccc1F
Reactant: OC1CCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccccc1N1CCCC1O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 2-fluorobenzonitrile (4.03 g, 33.2 mmol) and pyrolidin-2-ol (2.92 g, 33.5 mmol) was treated with diisopropylethylamine (4.37 g, 33.8 mmol) at room temperature. The mixture was stirred at room temperature (5 d). The resulting mixture was diluted with dichloromethane and sodium carbonate solution and the aqueous layer was extracted with two additional portions of dichloromethane. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed in vacuo. PCTLC (SiO2, 6 mm, 20% EtOAc-80% hexane) afforded the title compound (57).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][C:3]=1[N+:17]([O-])=O>C(O)C.[Pd]>[NH2:17][C:3]1[CH:4]=[C:5]([NH:8][C:9](=[O:16])[CH2:10][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(NC(=O)CN2CCCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(NC(=O)CN2CCCC2)cc1N
Yield: 94.4 %

Procedure:
A solution of N-(4-methyl-3-nitrophenyl)-2-(1-pyrrolidinyl)acetamide (0.86 g, 3.27 mmol) in absolute ethanol (50 mL) was hydrogenated with 10% Pd/C (˜0.200 g, Lancaster) at 50 psi overnight. The catalyst was removed by vacuum filtration through a celite pad, rinsed with methanol, and the filtrate was concentrated under reduced pressure to give N-(3-amino-4-methylphenyl)-2-(1-pyrrolidinyl)acetamide (0.72 g, 95%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.70 (dt, J=6.55, 3.23 Hz, 4 H) 1.95 (s, 3 H) 2.53 (t, J=5.86 Hz, 4 H) 3.13 (s, 2 H) 4,78 (s, 2 H) 6.62 (dd, J=7.87, 2.01 Hz, 1 H) 6.76 (d, J=8.06 Hz, 1 H) 6.93 (d, J=2.01 Hz, 1 H) 9.23 (s, 1 H). ESIMS (M+H)+=234.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][N+:4]([CH2:7][C:8]([NH:10][NH2:11])=[O:9])=[CH:3][CH:2]=1.[Cl-:12].[C:13]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)(=O)[CH3:14]>CO>[Cl-:12].[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:13](=[N:11][NH:10][C:8]([CH2:7][N+:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[O:9])[CH3:14])[CH:17]=1
Reactant: NNC(=O)C[n+]1ccccc1
Reactant: CC(=O)c1cccnc1
Agent: [Cl-]
Solvent: CO
Product: CC(=NNC(=O)C[n+]1ccccc1)c1cccnc1
Yield: 70.9 %

Procedure:
To 5.63 gm (0.03 mole) of Girard's Reagent P in 50 ml of anhydrous methanol is added 3.63 gm (0.03 mole) of 3-acetylpyridine. The solution is refluxed 3 hr and cooled. The solvent is evaporated The residue is slurried in 100 ml of anhydrous ether and filtered. The crude product is recrystallized from absolute ethanol to afford 6.18 gm (71%) of the title compound; mp 237.2° (decomp).
Reaction SMILES: FC1C=CC(C(F)(F)F)=CC=1[N+]([O-])=O.COC1C=C(OC)C=CC=1CN.[CH2:27]([O:29][P:30]([CH2:35][C:36]1[N:40]2[C:41]3[C:46]([N:47](CC4C=CC(OC)=CC=4OC)[C:48](=[O:49])[C:39]2=[N:38][N:37]=1)=[CH:45][CH:44]=[C:43]([C:61]([F:64])([F:63])[F:62])[CH:42]=3)([O:32][CH2:33][CH3:34])=[O:31])[CH3:28].FC(F)(F)C(O)=O>>[CH2:33]([O:32][P:30]([CH2:35][C:36]1[N:40]2[C:41]3[C:46]([NH:47][C:48](=[O:49])[C:39]2=[N:38][N:37]=1)=[CH:45][CH:44]=[C:43]([C:61]([F:62])([F:64])[F:63])[CH:42]=3)([O:29][CH2:27][CH3:28])=[O:31])[CH3:34]
Reactant: CCOP(=O)(Cc1nnc2c(=O)n(Cc3ccc(OC)cc3OC)c3ccc(C(F)(F)F)cc3n12)OCC
Agent: COc1ccc(CN)c(OC)c1
Agent: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(Cc1nnc2c(=O)[nH]c3ccc(C(F)(F)F)cc3n12)OCC

Procedure:
This compound was prepared by the procedure described in example 18 starting from 4-fluoro-3-nitrobenzotrifluoride and 2,4-dimethoxybenzylamine, except that the intermediate 1-[(diethoxyphosphoryl)methyl]-5-(2,4-dimethoxybenzyl)-8-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one was deprotected by treatment with trifluoroacetic acid at room temperature overnight. The mixture was evaporated to dryness and the residue was recrystallized from ethanol to give the pure title compound, m.p. 204°-208° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.Cl.[C:15]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].CCN(C(C)C)C(C)C.O>CC#N.CCOC(C)=O>[C:18]([O:17][C:15]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][C:6]2[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(Cl)nc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
The mixture of ethyl 2,4-dichloropyrimidine-5-carboxylate (442 mg, 2.00 mmol), 1-Boc-4-aminomethylpiperidine hydrochloride (502 mg, 2.00 mmol) and DIEA (1.00 mL, 5.75 mmol) in CH3CN (12 mL) was stirred at room temperature for 3 h. Water and EtOAc were added. The organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give ethyl 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methylamino)-2-chloropyrimidine-5-carboxylate (797 mg).
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:9][CH2:8][CH2:7][N:6]1[CH2:10][CH:11]1[CH2:15][CH2:14][O:13][CH2:12]1)([O-:3])=[O:2].[CH:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH:20]=O.Cl>C(#N)C>[N+:1]([C:4]1[CH:16]2[O:22][CH:20]([CH2:19][CH2:18][CH2:17]2)[N:9]2[CH2:8][CH2:7][N:6]([CH2:10][CH:11]3[CH2:15][CH2:14][O:13][CH2:12]3)[C:5]=12)([O-:3])=[O:2]
Reactant: O=CCCCC=O
Reactant: O=[N+]([O-])C=C1NCCN1CC1CCOC1
Agent: Cl
Solvent: CC#N
Product: O=[N+]([O-])C1=C2N(CC3CCOC3)CCN2C2CCCC1O2
Temperature: 25 °C
Yield: 36 %

Procedure:
To a 50 ml round bottom flask was added 1.065 g (0.005 mol) 2-(nitromethylene)-1-((tetrahydrofuran-3-yl)methyl)imidazolidine, 30 ml acetonitrile, 3 ml 25% glutaraldehyde aqueous solution and catalytic concentrated HCl. The reaction was stirred at r.t. and monitored by TLC. After completion, the mixture was evaporated to remove solvent and purified by column chromatography to afford final product as yellow powder with 36% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:37][C:38]1[CH:43]=[CH:42][N:41]=[C:40](B(O)O)[CH:39]=1>O1CCOCC1.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>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:40]4[CH:39]=[C:38]([F:37])[CH:43]=[CH:42][N:41]=4)=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCCC2NS(=O)(=O)c1ccc(Br)cc1
Reactant: OB(O)c1cc(F)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)COc1cccc2c1CCCC2NS(=O)(=O)c1ccc(-c2cc(F)ccn2)cc1
Temperature: 25 °C

Procedure:
To a degassed, stirred mixture of [5-(4-bromo-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester (150 mg, 0.30 mmol) in 1,4-dioxane (10 mL) and a 1 M aqueous solution of potassium carbonate (0.89 mL, 0.89 mmol) was added 4-fluoro-pyridine-2-boronic acid (51 mg, 0.36 mmol) and tetrakis(triphenylphosphine)palladium(0) (16 mg, 0.014 mmol) under argon at room temperature. The mixture was heated at reflux for 4 hours. After being cooled to room temperature, the solvents were removed under reduced pressure. The crude residue was diluted with ethyl acetate (50 mL), washed with water (10 mL×2), dried over anhydrous sodium sulfate, and concentrated in vacuo to give crude {5-[4-(4-fluoro-pyridin-2-yl)-benzenesulfonylamino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid tert-butyl ester, which was used without further purification. MS cald. for C27H29FN2O5S 512, obsd. 513 [(M+H)+].
Reaction SMILES: [CH:1]1([C:4]([N:6](C)C)=[CH2:5])[CH2:3][CH2:2]1.[F:9][C:10]([F:23])([F:22])[C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([N:15]=[C:16]=[O:17])=O.C([O-])(=O)C.[NH4+].C(O)(=O)C>O1CCCC1.O>[CH:1]1([C:4]2[N:6]=[C:13]([C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[C:10]([F:23])([F:22])[F:9])[NH:15][C:16](=[O:17])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C=C(C1CC1)N(C)C
Reactant: O=C=NC(=O)c1ccccc1C(F)(F)F
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc(C2CC2)nc(-c2ccccc2C(F)(F)F)[nH]1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of (1-cyclopropyl-vinyl)-dimethylamine in tetrahydrofuran (400 mL) at 0° C. under nitrogen was added a solution of 2-trifluoromethylbenzoyl isocyanate in tetrahydrofuran (50 mL), in a dropwise fashion. The reaction was stirred for 0.5 hour, then ammonium acetate (78 g, 1000 mmol) and acetic acid (400 mL) was added. The reaction mixture was heated at reflux for 3 hours with continuous removal of tetrahydrofuran, then cooled and poured into water (1.2 L). The resulting precipitate was collected by filtration, washing with water and ether to provide 6-cyclopropyl-2-(2-trifluoromethyl-phenyl)-3H-pyrimidin-4-one (28.79 g, 56% yield) as a white solid which is a mixture of the title compound and (2-trifluoromethyl-benzoyl)-urea (91:9 by HPLC).