Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2](=[C:13]1[C:18](=[O:19])OC(C)(C)OC1=O)[CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:5]=1[F:12].Cl.[F:24][C:25]([F:36])([F:35])[C:26]1[N:30]2[CH2:31][CH2:32][NH:33][CH2:34][C:29]2=[N:28][N:27]=1.C(N(C(C)C)CC)(C)C>C(OC(C)C)(=O)C>[O:19]=[C:18]([N:33]1[CH2:32][CH2:31][N:30]2[C:26]([C:25]([F:36])([F:24])[F:35])=[N:27][N:28]=[C:29]2[CH2:34]1)[CH2:13][C:2](=[O:1])[CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:5]=1[F:12]
Reactant: CC1(C)OC(=O)C(=C(O)Cc2cc(F)c(F)cc2F)C(=O)O1
Reactant: FC(F)(F)c1nnc2n1CCNC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)OC(C)C
Product: O=C(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 85 °C
Reaction time: 4 h
Yield: 93.8 %

Procedure:
A mixture of 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)-ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10 g), 3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine hydrochloride (7.2 g), diisopropyl ethylamine (4.5 g), and isopropyl acetate (100 mL) are heated to about 85° C. and stirred for about 4 hours. The reaction mass is then cooled to about 30° C. and quenched with water (90 mL). The organic layer is separated, washed with 5% sodium chloride solution (3×50 mL) and distilled off completely under vacuum to afford 12 g of the title compound. (Yield: 93.3%; purity by HPLC: 95.7%)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[NH:4].F[P-](F)(F)(F)(F)F.[Cl:15]/[C:16](=[CH:21]\N(C)C)/[CH:17]=[N+](C)C.C(N(CC)CC)C>C(#N)C>[Cl:15][C:16]1[CH:17]=[N:4][C:3]([C:2]([F:7])([F:6])[F:1])=[N:5][CH:21]=1
Reactant: N=C(N)C(F)(F)F
Reactant: CN(C)/C=C(\Cl)C=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ncc(Cl)cn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 38 mmol trifluoroacetamidine in 70 ml acetonitrile was added 37.92 mmol ((Z)-2-Chloro-3-dimethylamino-allylidene)-dimethyl-ammonium hexafluoro phosphate (CAS: 291756-76-8) followed by 45.5 mmol triethylamine. The yellow solution was stirred at room temperature for 5 hours, then poured onto water and extracted 3 times with ether. The combined extracts were dried over sodium sulfate, filtered and distilled at 760 mm Hg to provide the title compound. MS (m/e): 182.2 (M+, 100%)
Reaction SMILES: [OH:1][C:2]([CH3:24])([CH3:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][C:12]2=[O:20])=[CH:7][C:6]=1[O:21][CH3:22].Br[C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([F:38])([F:37])[CH:34]([F:36])[F:35])=[CH:28][CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.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>[OH:1][C:2]([CH3:24])([CH3:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([C:26]3[CH:27]=[CH:28][C:29]([O:32][C:33]([F:37])([F:38])[CH:34]([F:36])[F:35])=[CH:30][CH:31]=3)=[CH:13][C:12]2=[O:20])=[CH:7][C:6]=1[O:21][CH3:22]
Reactant: COc1cc(-n2ccc(B(O)O)cc2=O)ccc1OCC(C)(C)O
Reactant: FC(F)C(F)(F)Oc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-n2ccc(-c3ccc(OC(F)(F)C(F)F)cc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-2-oxo-1,2-dihydropyridin-4-ylboronic acid Part A (20 mg, 0.06 mmol), 1-bromo-4-(1,1,2,2-tetrafluoroethoxy)benzene (24.6 mg, 0.09 mmol), potassium phosphate, tribasic (32 mg, 0.15 mmol), and PalladiumTetrakis (4 mg, 3.00 μmol) in DMF (0.6 mL) was stirred under nitrogen at 80° C. overnight. The mixture was filtered, concentrated, and was purified using HPLC (Phen Luna Axia C18 5μ 10:90:0.1 to 90:10:0.1 MeOH—H2O-TFA). The product was repurified using ISCO flash chromatography (silica gel/hexanes/ethyl acetate/methanol 100:0 to 0:90:10 gradient) to afford the desired product 1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-4-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)pyridin-2(1H)-one B-6 (16.43 mg, 0.032 mmol, 54.0% yield) as a light yellow solid. LC/MS 482 (M+H)+, tR 0.92 min (method 5). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.63-7.67 (2H, m), 7.43 (1H, d, J=7.26 Hz), 7.34 (2H, d, J=8.58 Hz), 6.97-7.03 (2H, m), 6.90-6.96 (1H, m), 6.87 (1H, d, J=1.76 Hz), 6.49 (1H, dd, J=7.26, 1.98 Hz), 5.80-6.11 (1H, m), 3.89 (3H, s), 3.88 (2H, s), 1.37 (6H, s)
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:4]([CH:9]([OH:11])[CH3:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[Br:14]Br>CO>[Br:14][C:7]1[CH:8]=[C:3]([C:2]([F:1])([F:12])[F:13])[C:4]([CH:9]([OH:11])[CH3:10])=[N:5][CH:6]=1
Reactant: CC(O)c1ncccc1C(F)(F)F
Reactant: BrBr
Solvent: CO
Product: CC(O)c1ncc(Br)cc1C(F)(F)F

Procedure:
Dissolve 1-(3-(trifluoromethyl)pyridin-2-yl)ethanol (8.8 g, 0.046 moles) in anhydrous MeOH (80 mL) and add bromine (2.35 mL) dropwise at room temperature. Reflux the mixture under N2 atmosphere for 3 weeks with the addition of bromine (1.0 mL) on each day. Concentrate the reaction mixture under vacuum, dilute with water (100 mL), neutralize with NaHCO3, extract with EtOAc (3×100 mL) and dry (MgSO4). Filter the dried extract and concentrate under vacuum to afford a yellow oil. Purify the crude product by column chromatography to afford the title compound as a pale yellow oil.
Reaction SMILES: Br.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[C:13]([OH:24])=[CH:14][C:15]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17][C:16]=3[CH:23]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:32][C:33]([F:39])([F:38])[S:34](Cl)(=[O:36])=[O:35]>CC(C)=O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([C:12]2[C:13]([O:24][S:34]([C:33]([F:39])([F:38])[F:32])(=[O:36])=[O:35])=[CH:14][C:15]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17][C:16]=3[CH:23]=2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: CN1CCc2cc(O)c(S(=O)(=O)c3ccc(F)cc3)cc2CC1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN1CCc2cc(OS(=O)(=O)C(F)(F)F)c(S(=O)(=O)c3ccc(F)cc3)cc2CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
To an ice bath cooled solution of D6 (340 mg, 0.82 mmol) in acetone (10 mL) was added triethylamine (0.29 mL, 2.1 mmol) followed by trifluoromethanesulfonyl chloride (0.13 mL, 1.2 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was removed and the residue partitioned between dichloromethane and saturated sodium bicarbonate. The organic layer was removed, dried (MgSO4) and evaporated to yield the title compound D7 as a solid (270 mg). MH+ 468. 1H NMR δ (CDCl3) 2.42 (3H, s), 2.55-2.70 (4H, m), 2.95-3.15 (4H, m), 7.09 (1H, s), 7.15-7.24 (2H, t), 7.93-8.04 (3H, m).
Reaction SMILES: [CH3:1][NH2:2].O=[C:4]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])=[N:7][C:6]2[C:20]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[O:25])=[CH:21][CH:22]=[CH:23][C:5]1=2>CO>[CH3:1][N:2]1[C:4](=[O:9])[C:5]2[C:6](=[C:20]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[O:25])[CH:21]=[CH:22][CH:23]=2)[N:7]=[C:8]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:17])([F:18])[F:19]
Reactant: O=C(Nc1ccccn1)c1cccc2c(=O)oc(-c3ccccc3C(F)(F)F)nc12
Reactant: CN
Solvent: CO
Product: Cn1c(-c2ccccc2C(F)(F)F)nc2c(C(=O)Nc3ccccn3)cccc2c1=O
Temperature: 25 °C
Yield: 22 %

Procedure:
A solution of 30 wt % methylamine (7 mL) in MeOH and 4-oxo-N-(pyridin-2-yl)-2-(2-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]oxazine-8-carboxamide 25 (90 mg, 0.22 mmol) was heated under gentle reflux for 1 h then cooled to room temperature. The resulting precipitate was collected by filtration, rinsed with H2O, and dried under vacuum to give Compound 212 (20 mg, 22% yield) as a white solid. MS (ESI) calc. for C22H15F3N4O2: 424.11. found: 425 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[CH2:6][S:7][CH2:8][C:9](O)=[O:10].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:12]([C:9](=[O:10])[CH2:8][S:7][CH2:6]2)=[CH:13][CH:14]=1
Reactant: COc1cccc(CSCC(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)CSCC2=O
Reaction time: 0.25 h
Yield: 48.9 %

Procedure:
3-methoxybenzylmercaptoacetic acid from Step 2 (10.82 g) was dissolved in trifluoroacetic acid (50 mL). Trifluoroacetic acid anhydride (25 mL) was added and the reaction stirred under a nitrogen atmosphere for 0.25 hours. At this time, TLC showed no starting material. The solution was carefully poured into 10% Na2CO3 solution (500 mL) which was stirring vigorously. The organics were extracted into ether (500 mL) and washed with brine (300 mL), dried over MgSO4 and concentrated in vacuo. The resulting brown solid was purified by silica gel chromatography eluting with 20% ethyl acetate in hexane to yield 7-methoxyisothiochroman-4-one (4.84 g, 49%): 1H NMR (CDCl3) δ=3.48p (t, 2H, J=0.8 Hz), 3.83p (s, 3H), 3.84p (s, 2H), 6.6p (d, 1H, J=2.4 Hz), 6.83p (dd, 1H, J=2.4, 8.9 Hz), 8.0p (d, 1H, J=8.9 Hz).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([O:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH2:64])[CH:59]=2)=[CH:54][C:53]=1[CH3:65])[CH3:50]>CN(C=O)C>[CH2:49]([O:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH:64][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:59]=2)=[CH:54][C:53]=1[CH3:65])[CH3:50]
Reactant: CCOc1ccc(-c2cccc(N)c2)cc1C
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.5 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.067 mmol) and HATU (0.028 g, 0.072 mmol) in 0.37 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-ethoxy-3′-methyl-biphenyl-3-ylamine (0.015 g, 0.067 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and lyophilized for 48 hours to give 0.011 g of product in 41% yield: LCMS (ESI) m/z 416 (MH+).
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([CH:13]=[CH:14][C:15]([OH:17])=O)=[CH:4]2.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][NH2:32])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].P(C#N)(OCC)(OCC)=O.C(=O)([O-])O.[Na+]>CN(C)C=O.C(N(CC)CC)C>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][NH:32][C:15](=[O:17])[CH:14]=[CH:13][C:5]2[S:6][C:7]3[N:12]4[C:3](=[CH:2][N:1]=[C:11]4[CH:10]=[CH:9][CH:8]=3)[CH:4]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C(O)C=CC1=Cc2cnc3cccc(n23)S1
Agent: CCOP(=O)(C#N)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)C=CC2=Cc3cnc4cccc(n34)S2)CC1
Reaction time: 8 h

Procedure:
While 0.708 g (2.898 mM) of 3-(5-thia-1,8b-diazaacenaphthylen-4-yl)acrylic acid, 0.68 g (3.19 mM) of 1-(tert-butoxycarbonyl)piperidin-4-ylmethylamine, and 0.48 ml (3.48 mM) of triethylamine were stirred together in 10 ml of N,N-dimethylformamide, 0.53 ml (3.48 mM) of diethyl cyanophosphate was added dropwise at room temperature and the mixture was stirred at the prevailing temperature overnight. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate to ethyl acetate-methanol=9/1) to provide crude N-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-3-(5-thia-1,8b-diazaacenaphthylen-4-yl)acrylamide.
Reaction SMILES: C[C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].[CH3:12][O-].[Na+]>CO>[CH3:12][CH:4]1[CH2:5][CH2:6][CH:2]([C:8]([O:10][CH3:11])=[O:9])[C:3]1=[O:7]
Reactant: COC(=O)C1(C)CCCC1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCC(C)C1=O
Temperature: 25 °C
Yield: 64 %

Procedure:
Methyl 1-methyl-2-oxocyclopentanecarboxylate (61.0 g, 0.39 mol) was added dropwise to a freshly prepared solution of NaOMe (0.78 mol) in MeOH (1 L) at ambient temperature. The solution was heated under reflux for 3 h and then concentrated. The residue was dissolved in toluene (1 L) and the resulting solution was heated under reflux for 5 h. The mixture was cooled to ambient temperature, washed with saturated aqueous NaHCO3 (500 mL×3) and brine (300 mL×1), dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by distillation to afford methyl 3-methyl-2-oxocyclopentanecarboxylate (39.0 g, 64% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].O.[O:7]=[CH:8][C@@H:9]([C@H:11]([C@@H:13]([C@@H:15]([CH2:17][OH:18])[OH:16])[OH:14])[OH:12])O.N#N>>[CH3:1][O:2][CH2:3][CH2:4][NH:5][CH:17]1[O:18][C@H:9]([CH2:8][OH:7])[C@@H:11]([OH:12])[C@H:13]([OH:14])[C@H:15]1[OH:16]
Reactant: COCCN
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: N#N
Solvent: O
Product: COCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
N-(2-methoxyethyl)-glucosylamine (sugar adduct) is prepared starting with 1728.26 g of 50 wt.% 2-methoxyethylamine in water (11.5 moles, 1.1 mole equivalent of 2-methoxyethylamine) placed under an N2 blanket at 10° C. 2768.57 grams of 50 wt. % glucose in water (10.46 moles, 1 mole equivalent of glucose), which is degassed with N2, is added slowly, with mixing, to the methoxyethylamine solution keeping the temperature below 10° C. The solution is mixed for about 40 minutes after glucose addition is complete. It can be used immediately or stored 0° C.-5° C. for several days.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:19]=[C:18]([CH2:20][CH2:21][C:22]([OH:24])=O)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:37]([NH:39][CH2:40][CH3:41])[CH3:38]>O1CCCC1>[CH2:37]([N:39]([CH2:40][CH3:41])[C:22](=[O:24])[CH2:21][CH2:20][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[N:19]=1)[CH3:38]
Reactant: O=C(O)CCc1nc(-c2ccc([N+](=O)[O-])cc2)nc2ccccc12
Reactant: CCNCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)CCc1nc(-c2ccc([N+](=O)[O-])cc2)nc2ccccc12

Procedure:
The procedure is as in Example 7, starting with 2-(4-nitrophenyl)-4-quinazolinepropanoic acid (1.35 g), carbonyldiimidazole (0.82 g) and diethylamine (0.9 cc) in anhydrous tetrahydrofuran (20 cc). After chromatography on silica gel with ethyl acetate as eluant, and recrystallization in ethyl acetate, N,N-diethyl-2-(4-nitrophenyl)-4-quinazolinepropanamide (0.35 g), m.p. 168° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CC(N(C)C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:45][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:15])[CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Product: CCOc1nc(C(=O)NCc2ccccc2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a 20 mL scintillation vial, 4-amino-5-cyano-6-ethoxy-pyridine-2-carboxylic acid (19 mg, 0.09 mmol) was dissolved in DMA (0.7 mL). Then TBTU (30 mg, 0.09 mmol) dissolved in DMA (0.7 mL) was added, followed by the addition of benzylamine (11 mg, 0.11 mmol, 1.2 eq.) in DMA (0.6 mL). Then TEA (9.37 mg, 0.09 mmol) dissolved in DMA (0.7 mL) was added. The reaction mixture was shaken at room temperature for 24 hours. The crude mixture was purified using reverse phase HPLC (TFA). 1H NMR (500 MHz, DMSO-D6D2O) δ ppm 1.31 (t, 3H) 4.43-4.54 (m, 4H) 7.06-7.11 (m, 1H) 7.21-7.36 (m, 5H) 9.07-9.14 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=O)[O:17]C3C=CC=CC=3)=[CH:9][CH:8]=2)[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1>>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][NH:15][C:16]([NH:45][S:42]([C:39]3[CH:38]=[CH:37][C:36]([Cl:35])=[CH:41][CH:40]=3)(=[O:43])=[O:44])=[O:17])=[CH:11][CH:12]=2)[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Nc1c(-c2ccccc2)c(C(F)(F)F)nn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Product: Nc1c(-c2ccccc2)c(C(F)(F)F)nn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-{4-[5-amino-4-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}ethylcarbamate (step 4 of Example 80) and 4-chlorobenzenesulfonamide: 1H-NMR (CDCl3) δ 7.85-7.80 (2H, m), 7.51-7.27 (11H, m), 6.08-6.03 (1H, m), 3.99 (2H, br.s), 3.50-3.44 (2H, m), 2.88-2.84 (2H, m).
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5](=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][NH2:14])[CH:8]=1)[CH3:3].[CH:16]1([C:21](=O)[CH2:22][C:23]#[N:24])[CH2:20][CH2:19][CH2:18][CH2:17]1>Cl>[ClH:1].[CH2:2]([O:4][C:5](=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[C:23]([NH2:24])=[CH:22][C:21]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[N:14]2)[CH:8]=1)[CH3:3]
Reactant: CCOC(=O)Cc1cccc(NN)c1
Reactant: N#CCC(=O)C1CCCC1
Agent: Cl
Product: CCOC(=O)Cc1cccc(-n2nc(C3CCCC3)cc2N)c1
Yield: 34 %

Procedure:
To a mixture of (3-aminophenyl)acetic acid ethyl ester (15 g, 84 mmol) in conc. HCl (20 mL) was added sodium nitrite (6 g, 87 mmol) aqueous solution dropwise under ice-salt bath. The resulting mixture was stirred at 0° C. for 30 min and then added a solution of SnCl2.2H2O (38 g, 168 mmol) in conc. HCl dropwise also at such a rate that the reaction mixture never rose above 5° C. After the addition was completed, the mixture was stirred for another 2 h at room temperature. The precipitate was collected by suction and washed with ethyl ether to afford (3-Hydrazinophenyl)acetic acid ethyl ester hydrochloride (17 g, 88%) as a brown solid. MS (ESI) m/z: 195 (M+H+). A solution of (3-hydrazinophenyl)acetic acid ethyl ester hydrochloride (17 g, 74 mmol) and 3-cyclopentyl-3-oxopropionitrile (12.2 g, 88.8 mol) in alcohol (150 mL) containing conc. HCl (10 mL) was heated to reflux overnight. After removed of the solvent, the precipitate was collected by suction and washed with ethyl ether to afford the crude product, which was purified by column chromatography to afford [3-(5-amino-3-cyclopentylpyrazol-1-yl)phenyl]acetic acid ethyl ester hydrochloride (8.8 g, 34% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 7.40-7.66 (m, 4H), 5.68 (s, 1H), 4.05 (q, J=7.2 Hz, 2H), 3.75 (s, 2H), 3.00-3.08 (m, 1H), 1.98-2.00 (m, 2H), 1.58-1.70 (m, 6H), 1.17 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 314 (M+H+).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8]>O>[Cl:4][C:5]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:6]=1[C:7]1[O:8][C:7]([C:6]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:5]=2[Cl:4])=[N:2][N:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: NN
Solvent: O
Product: Clc1ccc(-c2nnc(-c3ccc(Cl)cc3Cl)o2)c(Cl)c1
Temperature: 125 °C
Reaction time: 5 h
Yield: 75.1 %

Procedure:
A mixture was prepared by slowly adding 10 grams (g) of hydrazine hydrate to 400 g of vigorously stirring polyphosphoric acid at ~50° C. To this mixture was added 76 g (0.4 mole) of 2,4-dichlorobenzoic acid. A slurry developed and it was stirred at 125° C (+5°) for 5 hours. The reaction products were cooled slightly and poured into ~1.5 liter (1) of cold water. The solid which precipitated was recovered by filtration, washed with water, dried and recrystallized from chlorobenzene to give 54 g (75% of theoretical) of the desired 2,5-bis(2,4-dichlorophenyl)-1,3,4-oxadiazole.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]2=[O:21])=[CH:7][CH:6]=1.[Cl:24][C:25]1[C:30]([S:31](Cl)(=[O:33])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=1>>[Cl:24][C:25]1[C:30]([S:31]([N:18]2[CH2:17][CH2:16][C:13]3([C:12](=[O:21])[N:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:22])[F:23])=[CH:6][CH:7]=4)[CH2:15][CH2:14]3)[CH2:20][CH2:19]2)(=[O:33])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: O=C1N(c2ccc(OCC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Product: O=C1N(c2ccc(OCC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1Cl)CC2

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one (prepared in analogy to example 180 step B-D using 1-benzyl-4-(2-methoxyethyl)-piperidine-4-carboxylic acid ethyl ester and 4-(2,2,2-trifluoro-ethoxy)aniline) and 2-chloro-pyridine-3-sulfonyl chloride. White solid. MS (ESI): 504.1 (MH+).
Reaction SMILES: C(OC(N1CC2C([CH2:11][N:12]([CH2:16][C:17]3[S:25][C:24]4[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[N:22][C:21]([Cl:32])=[N:20][C:19]=4[CH:18]=3)[CH2:13]2)C1)=O)(C)(C)C.C1NC[CH2:36][N:35]2[CH2:39][CH2:40][CH2:41][C@H:34]12>>[Cl:32][C:21]1[N:22]=[C:23]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:24]2[S:25][C:17]([CH2:16][N:12]3[CH2:11][CH2:36][N:35]4[CH2:39][CH2:40][CH2:41][C@@H:34]4[CH2:13]3)=[CH:18][C:19]=2[N:20]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Reactant: C1C[C@@H]2CNCCN2C1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCN4CCC[C@@H]4C3)cc2n1

Procedure:
Prepared according to the method used in the preparation of 5-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using (R)-octahydro-pyrrolo[1,2-a]pyrazine in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as white solid (90 mg, 61%).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[F:19][C:20]([F:24])([F:23])[CH2:21][NH2:22].C(N(CC)CC)C>>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:22][CH2:21][C:20]([F:24])([F:23])[F:19])[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reactant: NCC(F)(F)F
Solvent: CCN(CC)CC
Product: C=CCNc1nc(NCC(F)(F)F)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.6 %

Procedure:
A mixture of 150 mg (0.57 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline, 772 mg (5.70 mmol) of 2,2,2-trifluoroethylamine and 1.15 g (11.4 mmol) of triethylamine was stirred in a sealed tube at room temperature for 16 hours. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with chloroform (10 ml×3). After the organic layer was washed with brine and then dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by a silica gel chromatography to give 57 mg (yield: 30.8%) of the title compound.