Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:12]([CH3:24])[C:13](=[O:23])[CH:14]=[C:15]2[C:19](=[O:20])OC(C)(C)[O:16]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C=O.[CH3:27][NH2:28].[CH3:29]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:12]([CH3:24])[C:13]([C:14]2[CH2:27][N:28]([CH3:29])[C:19](=[O:20])[C:15]=2[OH:16])=[O:23])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN
Reactant: CO
Reactant: CN(CCCc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Agent: C=O
Product: CN1CC(C(=O)N(C)CCCc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Yield: 52 %

Procedure:
Reaction of N-[3-(3,4-dichlorophenyl)-propyl]-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methyl-acetamide (0.570 g, 1.53 mmol) with the paraformaldehyde-methylamine adduct in methanol using a procedure similar to the one described in the preparation of compound 44 (method 44B) gave 0.287 g (52% yield) of the title compound as white crystals; mp 138–140° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm); 1.80 (2H, m, CH2), 2.49 (2H, t, J=7.6 Hz, CH2), 2.92 (3H, s, NCH3), 2.95 (3H, s, NCH3), 3.31 (2H, broad t, J=7.3 Hz, NCH2), 3.87 (2H, broad s, NCH2), 6.91 (1H, dd, J=2.0 Hz and J=8.1 Hz, aromatic), 7.16 (1H, d, J=2.0 Hz, aromatic), 7.23 (1H, d, J=8.1 Hz, aromatic), 10.94 (1H, broad s, OH). Anal. Calcd for C6H18Cl2N2O3: C, 53.80; H, 5.08; N, 7.84. Found: C, 53.90; H, 5.17; N, 7.83.
Reaction SMILES: [CH3:1]O.C(Cl)(Cl)Cl.[O:7]=[C:8]1[CH:11]([N:12]2C(=O)C3=CC=CC=C3C2=O)[CH2:10][N:9]1[CH:23]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)[C:24]([O-:26])=[O:25]>C(OCC)(=O)C>[NH2:12][CH:11]1[CH2:10][N:9]([CH:23]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[C:24]([O:26][CH3:1])=[O:25])[C:8]1=[O:7]
Reactant: O=C([O-])C(c1cccs1)N1CC(N2C(=O)c3ccccc3C2=O)C1=O
Reactant: CO
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)C(c1cccs1)N1CC(N)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Dimethqyl-1,3-propanediamine (1.32 g.) was added to a mixture of methanol (30 ml.) and chloroform (18 ml.) containing 2-(2-oxo-3-phthalimido-1-azetidinyl)-2-(2-thienyl)-acetate (2.22 g.), whereafter the mixture was stirred at ambient temperature overnight. After the reaction, the reaction mixture was evaporated to dryness under reduced pressure to give a residue, which was dissolved in ethyl acetate. The solution was extracted with three portions of an aqueous solution consisting of 1N hydrochloric acid (6.4 ml.) and water (10 ml.). The combined aqueous extracts were adjusted to pH 8 with sodium bicarbonate and then saturated with sodium chloride. The solution was extracted with ethyl acetate and the extract was washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. The solution was evaporated to dryness under reduced pressure to give a residue (1.57 g.), which was subjected to column chromatography on silica gel (25 g.). Elution was carried out with chloroform and the fractions containing a desired compound were collected. The solvent was removed by distillation from the solution under reduced pressure to give methyl 2-(3-amino-2-oxo-1-azetidinyl)-2-(2-thienyl)acetate (0.96 g.).
Reaction SMILES: [CH:1]([N:4]([C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[C:5](=[O:28])[CH2:6][N:7]1[C:16](=[O:17])[CH2:15][C:14]2[N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][N:13]=2)[C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]1=2)([CH3:3])[CH3:2].[F:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][CH:42]=[C:41]2[CH:47]=O>>[F:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][CH:42]=[C:41]2[CH:47]=[C:15]1[C:14]2[N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][N:13]=2)[C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=2[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[O:28])[C:16]1=[O:17]
Reactant: COc1ccc(N(C(=O)CN2C(=O)Cc3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Reactant: O=Cc1c[nH]c2ccc(F)cc12
Product: COc1ccc(N(C(=O)CN2C(=O)C(=Cc3c[nH]c4ccc(F)cc34)c3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Yield: 65.4 %

Procedure:
Following the procedure described for Example 1 (A), Step A, N-isopropyl-N-(6-methoxy-pyridin-3-yl)-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-acetamide (Preparation 11) (120 mg, 0.207 mmol) was condensed with 5-fluoro-1H-indole-3-carbaldehyde (48 mg, 0.248 mmol). Purification by medium pressure chromatography eluting with a solvent gradient (1% MeOH in CH2Cl2 to 7% MeOH in CH2Cl2) yielded 85 mg of 2-[4-(5-fluoro-1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide. MS 628.8 (M+1), 626.4 (M−1).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:34]=[CH:33][C:20]2[CH2:21][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][CH2:24][O:25][C:19]=2[CH:18]=1>N1C=CC=CC=1>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH:34]=[CH:33][C:20]2[CH2:21][N:22]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:23][CH2:24][O:25][C:19]=2[CH:18]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(O)ccc2C1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCOc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
Trifluoromethanesulfonic anhydride (0.253 ml, 1.498 mmol) was added to an ice cooled solution of 1,1-dimethylethyl 8-hydroxy-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 30) (0.265 g, 0.999 mmol) in pyridine (4 ml) and stirred for one hour. The reaction mixture was evaporated, dissolved in 40 ml of EtOAc and washed with 20 ml of 2M HCl and 20 ml of saturated sodium bicarbonate then dried (magnesium sulphate) and evaporated to give the title compound (399 mgs) as a yellow gum. MS (ES) C15H18F3NO6S requires 397; found 298 [M+H−100]+.
Reaction SMILES: FC1C=CC=C(F)C=1C=O.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[C@H:19]1[CH2:21][C@H:20]1[NH2:22].[N-:23]=[C:24]=[S:25].N[C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][N:28]=1>>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[C@H:19]1[CH2:21][C@H:20]1[NH:22][C:24]([NH:23][C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][N:28]=1)=[S:25]
Reactant: [N-]=C=S
Reactant: N#Cc1ccc(N)nc1
Reactant: N[C@@H]1C[C@@H]1c1c(F)cccc1F
Agent: O=Cc1c(F)cccc1F
Product: N#Cc1ccc(NC(=S)N[C@@H]2C[C@@H]2c2c(F)cccc2F)nc1

Procedure:
2,6-Difluorobenzaldehyde (Aldrich) was converted to cis-2-(2,6-difluorophenyl)cyclopropylamine according to Example 375 (patent application WO 93/03022) and then converted to an isothiocyanate according to Example 374 (patent application WO 93/03022). This isothiocyanate was reacted with the anion of 2-amino-5-cyanopyridine to give (+,-)-N-(cis-2-(2,6-Difluorophenyl) cyclopropyl)-N'-(5-cyanopyrid-2-yl)-thiourea. 6 mg of this compound was reacted with NBS as described in Example 4 and a final purification on alumina, resulted in 0.7 mg of the title product. Rf:0.30 Silica gel eluent:diethyl ether.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:15]1=[O:26].Cl[C:28]1[N:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][N:29]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:34]([C:31]1[CH:30]=[N:29][C:28]([N:23]2[CH2:22][CH2:21][CH:20]([N:16]3[CH2:17][CH2:18][CH2:19][C@H:14]([NH:13][C:4]4[CH:5]=[CH:6][C:7]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:8][C:3]=4[F:2])[C:15]3=[O:26])[CH2:25][CH2:24]2)=[N:33][CH:32]=1)[CH3:35]
Reactant: CS(=O)(=O)c1ccc(N[C@H]2CCCN(C3CCNCC3)C2=O)c(F)c1
Reactant: CCc1cnc(Cl)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cnc(N2CCC(N3CCC[C@H](Nc4ccc(S(C)(=O)=O)cc4F)C3=O)CC2)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
(S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one hydrochloride (prepared according to the method of Example 45) (0.35 g, 0.862 mmol), 2-chloro-5-ethylpyrimidine (0.123 g, 0.862 mmol) and DIEA (0.334 g, 2.59 mmol) were dissolved in DMF (5 mL) and The reaction was stirred at 100° C. overnight. The reaction was cooled to ambient temperature and concentrated. The residue was purified over silica gel (50-100% EtOAc in hexanes) to afford (S)-1′-(5-ethylpyrimidin-2-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one (0.142 g, 0.299 mmol, 34.6% yield) as a yellow solid. Mass spectrum (apci) m/z=476.2 (M+H).
Reaction SMILES: [C:1]([C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>>[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][CH2:13][C:12]2[CH:15]=[CH:16][C:9]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=2)=[CH:20][CH:19]=1
Reactant: NCc1ccc(Br)cc1
Reactant: CCCCCCC#Cc1ccc(C=O)cc1
Product: CCCCCCC#Cc1ccc(CNCc2ccc(Br)cc2)cc1
Yield: 86 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-oct-1-ynylbenzaldehyde and 4-bromobenzylamine gave the title compound as a colorless oil (86%). 1H NMR (CDCl3, 300 MHz) δ 7.47 (d, J=8.3 Hz, 2H), 7.38 (d, J=8.3 Hz, 2H), 7.30-7.19 (m, 4H), 3.78 (s, 2H), 3.75 (s, 2H), 2.42 (t, J=6.8 Hz, 2H), 1.69-1.55 (m, 2H), 1.54-1.42 (m, 2H), 1.42-1.27 (m, 4H), 0.93 (t, J=6.8 Hz, 3H). M+(LC/MS(ESI)): 384.4 HPLC (Condition A), Rt: 4.18 min (HPLC purity: 97.6%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15].Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C.C(OCC)C>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH3:7])[CH3:23])[CH3:22]
Reactant: COc1ccccc1O
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccccc1OC
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 91.6 %

Procedure:
Cesium carbonate (53.86 g, 165.3 mmol) was added to a solution of 2-methoxyphenol (10.26 g, 82.6 mmol) in anhydrous DMF (500 mL) at room temperature under an atmosphere of nitrogen. After five minutes, ethyl 2-bromopropionate (10.7 mL, 82.6 mmol, d=1.394) was added rapidly dropwise and the resultant mixture was allowed to stir at 90° C. for 18 h. The reaction mixture was diluted with diethyl ether, then extracted twice with 1N HCl and twice with water. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (25% ether in hexanes) to provide the titled compound (16.97 g, 92%) as a light yellow oil.1H NMR (400 MHz, CDCl3): δ 6.96–6.80 (m, 4H), 4.73 (q, 1H, J=7.04 Hz), 4.23–4.12 (m, 2H), 3.82 (s, 3H), 1.62 (d, 3H, J=6.65 Hz), 1.21(t, 3H, J=7.04 Hz). MS [ES+] m/z exact mass calcd for C12H17O4 225.1127, found 225.1110. Rf=0.19 in 25% ether in hexanes.
Reaction SMILES: C([N:8]1[C:15]2[CH:14]3[CH2:16][CH:13]3[CH2:12][C:11]=2[C:10]([C:17]2[N:18]=[N:19][NH:20][N:21]=2)=[N:9]1)C1C=CC=CC=1.CC([O-])(C)C.[K+]>C1COCC1.CS(C)=O>[N:21]1[NH:20][N:19]=[N:18][C:17]=1[C:10]1[NH:9][N:8]=[C:15]2[C:11]=1[CH2:12][C@H:13]1[CH2:16][C@H:14]12
Reactant: c1ccc(Cn2nc(-c3nn[nH]n3)c3c2C2CC2C3)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: C1c2c(n[nH]c2-c2nn[nH]n2)[C@@H]2C[C@H]12

Procedure:
Air was bubbled through a stirring solution of 2-benzyl-4-(2H-tetrazol-5-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene (10.4 g, 37.4 mmol) and KOt-Bu (374 mL of a 1M solution in THF, 374 mmol) in DMSO (300 mL) for 20 h at rt. The remaining THF was removed in vacuo and the reaction was acidified to pH=2 by the addition of HCl (3M aq). The mixture was concentrated in vacuo to near dryness. The residue was dissolved in HCl (1N aq., 250 mL) and extracted with EtOAc (5×250 mL). The organics were dried over MgSO4, filtered, and concentrated. The product was purified and converted to the ammonium salt by loading material (as a solution in MeOH) on to a column containing Bondesil SCX SPE resin (˜250 g). The column was flushed with MeOH (200 mL) to remove unbound impurities. The product was eluted using 2N NH3/MeOH (approx. 200 mL). Concentration of the basic eluant yielded the ammonium salt of Compound 4 as a white solid. 1H NMR (400 MHz, MeOD): δ 3.02 (1H, dd, J=16.4, 6.0 Hz), 2.90 (1H, d, J=16.0 Hz), 2.19 (2H, m), 1.17 (1H, m), 0.33 (1H, m). HPLC/MS: Discovery® C18 column (5 μ, 50×2.1 mm), 5% v/v CH3CN (containing 1% v/v TFA) in H2O (containing 1% v/v TFA) gradient to 99% v/v CH3CN in H2O, 0.75 mL/min, tr=1.21 min, ESI+=189.0 (M+H). [α]25D+35.7 (c 0.39, MeOH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([O:20][CH3:21])[CH:14]=3)=[CH:11][CH:12]=2)=[CH:4][C:3]=1[O:22][CH3:23].[C:24]1([NH2:35])[C:29](F)=[C:28](F)[C:27](F)=[C:26]([NH2:33])C=1F.Cl.Cl>CN(C=O)C.O>[CH3:23][O:22][C:3]1[CH:4]=[C:5]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]=[N:33][C:26]4[CH:27]=[CH:28][CH:29]=[CH:24][N:35]=4)=[C:15]([O:20][CH3:21])[CH:14]=3)=[CH:11][CH:12]=2)[CH:6]=[CH:7][C:2]=1[N:1]=[N:33][C:26]1[CH:27]=[CH:28][CH:29]=[CH:24][N:35]=1
Reactant: COc1cc(-c2ccc(-c3ccc(N)c(OC)c3)o2)ccc1N
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2ccc(-c3ccc(N=Nc4ccccn4)c(OC)c3)o2)ccc1N=Nc1ccccn1
Yield: 70 %

Procedure:
2,5-Bis[3-methoxy-4-(2-pyridylimino)aminophenyl]furan (4o, DB746) was prepared according to the procedure for 4f using diamine 3i and S-(2-naphthylmethyl)-2-pyridylthioimidate hydrobromide as starting materials. Free base: yellow crystalline solid, mp 212-213° C. (DMF/H2O). Yield: 70%. 1H NMR (DMSO-d6): 3.82 (s, 6H), 6.89 (d, 2H), 6.98 (s, 2H), 7.38 (m, 4H), 7.54 (dd, 2H), 7.95 (dd, 2H), 8.32 (d, 2H), 8.62 (d, 2H). Dihydrochloride: yellow solid. 1H NMR (DMSO-d6): 3.97 (s, 6H), 7.36 (s, 2H), 7.47 (d, 2H), 7.62 (d, 4H), 7.85 (dd, 2H), 8.20 (d, 2H), 8.45 (d, 2H), 8.89 (d, 2H), 9.37 (br s, 2H), 10.10 (br s, 2H), 11.86 (br s, 2H). Anal. Calcd. for C30H26N6O.2.0HCl.1.0H2O (609.5): C, H, N, Cl.
Reaction SMILES: O[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[O:12])[CH2:3]1)[CH2:9]2.[IH:13]>>[I:13][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[O:12])[CH2:3]1)[CH2:9]2
Reactant: I
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Product: O=C1C2CC3CC1CC(I)(C3)C2

Procedure:
Simple unit processes allow the conversion of several of the abovementionedX or X1 substituents, or others known in the art, to 5-X- or 5-X1-adamantane-2-ones where X or X1 may be trialkylsilyloxy, iodo or cyano groups. These moities are stable under the mild conditions used in step 4 of the foregoing reaction sequence. For example, when 5-hydroxyadamantan-2-one is refluxed for 7 hours with 57% hydriodic acid, 5-iodoadamantan-2-one (m.p. 73°-76° C.) is obtained. 5-Carboxyadamantan-2-one, prepared as described in Lantvoev, J.Obshch.Khim., 12, 2361 (1976) or Le Noble, et al., J.Org. Chem., 48, 1101 (1983), after saponification of the methyl ester, can be converted to5-cyanoadamantan-2-one by the three step procedure of Tabushi, et al., J.Org.Chem., 38, 3447 (1973), used for access to the isomeric 1-cyanoadamantan-2-one through the intermediacy of a keto amide. 5-Trimethylsilyloxyadamantan-2-one (m.p. 34°-38° C.), usefulas a protected version of 5-hydroxyadamantan-2-one, allows the use of only one equivalent of base in step 4 of the foregoing reaction sequence to prepare the corresponding enol ether, which can then be desilylated using standard techniques.
Reaction SMILES: [C:1](OC(OC(OC(C)(C)C)=O)=O)(OC(C)(C)C)=[O:2].[NH2:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1.C(F)(F)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)N(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F.[C:79]1([N:85]2[CH2:90][CH2:89][NH:88][CH2:87][CH2:86]2)[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1>C(Cl)Cl>[C:79]1([N:85]2[CH2:90][CH2:89][N:88]([C:1]([NH:19][C:20]3[CH:29]=[C:28]4[C:23]([CH:24]=[CH:25][CH:26]=[N:27]4)=[CH:22][CH:21]=3)=[O:2])[CH2:87][CH2:86]2)[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Nc1ccc2cccnc2c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(=O)OC(C)(C)C
Agent: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)N(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc2cccnc2c1)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of di-tert-butyl tricarbonate (60 mg, 0.23 mmol) in DCM (1 ml) was added in one portion, a solution of 7-aminoquinoline (D55) (30 mg, 0.21 mmol) in DCM (1 ml). After 5 mins, when gas evolution was complete, tris -amine resin (12 mg 0.04 mmol) was added, then after 1 h a solution of 4-phenylpiperazine (32 ul, 0.21 mmol) was added and the reaction stirred at room temperature overnight. The reaction mixture was then purified directly by SPE column chromatography, eluting with an EtOAc/60-80° C.-petroleum ether gradient, followed by treatment with excess methyl isocyanate resin to remove unreacted 7-aminoquinoline starting material from the product. On completion the resin was removed by filtration and filtrate concentrated in vacuo to give the title compound as an orange gum. 1H NMR (250 MHz, CDCl3) δ (ppm): 8.85 (dd, 1H), 8.09 (dd, 1H), 7.93 (dd, 1H), 7.82 (s, 1H), 7.76 (d, 1H), 7.30 (m, 3H), 6.94 (m, 3H), 6.83 (br, 1H), 3.72 (m, 4H), 3.28 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([CH3:10])[N:3]=1.[OH-].[K+].[Cl:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18](Cl)[C:17]([N+:24]([O-:26])=[O:25])=[CH:16][C:15]=1[C:27]([F:30])([F:29])[F:28].Cl>O.CN(C)C=O>[Cl:8][C:7]1[C:2]([NH:1][C:18]2[C:17]([N+:24]([O-:26])=[O:25])=[CH:16][C:15]([C:27]([F:28])([F:29])[F:30])=[C:14]([Cl:13])[C:19]=2[N+:20]([O-:22])=[O:21])=[N:3][C:4]([CH3:10])=[C:5]([Cl:9])[CH:6]=1
Reactant: Cc1nc(N)c(Cl)cc1Cl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(Nc2c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c2[N+](=O)[O-])c(Cl)cc1Cl
Reaction time: 3 h

Procedure:
In 30 ml. of dimethylformamide, 1.8 g. of 2-amino-3,5-dichloro-6-methylpyridine was dissolved in 0.67 g. of powdery potassium hydroxide was gradually added with stirring. After the addition, a solution of 3.07 g. of 2,4-dichloro-3,5-dinitrobenzotrifluoride in 10 ml. of dimethylformamide was added dropwise at room temperature and the reaction was continued for about 3 hours. The reaction mixture was acidified with conc. HCl and was poured into water. The precipitate was filtered and recrystallized from methanol to obtain 2.96 g. of the object compound having a melting point of 128° to 130° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].Cl.[F:28][CH2:29][CH2:30][CH2:31][NH2:32].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:12]([NH:32][CH2:31][CH2:30][CH2:29][F:28])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: NCCCF
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](NC(=S)NCCCF)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanatotetrahydro-2H-pyran-2,4,5-triyl triacetate (0.850 g, 2.19 mmol) and 3-fluoropropylamine hydrochloride (0.251 g, 2.21 mmol) in DCM (10 mL), was added DIPEA (0.415 g, 4.00 mmol). The reaction mixture was stirred at room temperature for 30 min, and then concentrated under reduced pressure. The residue was purified on silica gel by flash column chromatography (EtOAc/hexanes, 2:1 in), affording (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-(3-fluoropropyl)thioureido)tetrahydro-2H-pyran-2,4,5-triyl triacetate as a white solid (0.91 g, 88%).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][NH:9][C:10]([C:11]3C=C(C=CC=3)C#N)=[C:6]2[C:5](=[O:19])[N:4]([CH3:20])[C:3]1=[O:21].IC1[S:24][CH:25]=[C:26]([CH3:28])[N:27]=1>>[CH3:1][N:2]1[C:7]2=[CH:8][NH:9][C:10]([C:11]3[S:24][CH:25]=[C:26]([CH3:28])[N:27]=3)=[C:6]2[C:5](=[O:19])[N:4]([CH3:20])[C:3]1=[O:21]
Reactant: Cc1csc(I)n1
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)[nH]cc2n(C)c1=O
Product: Cc1csc(-c2[nH]cc3c2c(=O)n(C)c(=O)n3C)n1

Procedure:
The title compound was prepared by an analogous method to 3-(1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Intermediate Ga) by replacing 3-bromobenzonitrile (step 3) with 2-iodo-4-methylthiazole (Intermediate F).
Reaction SMILES: [NH:1]1[C:5]2[S:6][C:7]([C:9]#[N:10])=[CH:8][C:4]=2[CH:3]=[N:2]1.[Br:11]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Br:11][C:3]1[C:4]2[CH:8]=[C:7]([C:9]#[N:10])[S:6][C:5]=2[NH:1][N:2]=1
Reactant: N#Cc1cc2cn[nH]c2s1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc2c(Br)n[nH]c2s1
Reaction time: 2 h
Yield: 85.8 %

Procedure:
To a solution of 168 mg of 1H-thieno[2,3-c]pyrazole 5-carbonitrile in 5 mL of dimethylformamide was added 200 mg of N-bromosuccinimide at room temperature and stirred at this temperature for 2 hours. After adding 1 mL of 10% sodium thiosulfate aqueous solution, the solution was diluted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. This afforded 3.7 g of the title compound as a colorless oil. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:10), to afford 220 mg of the title compound as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:39](OC)=[O:40])=[N:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:16]=2)=[N:6][C:7]=1[NH:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[NH2:43]C1C(C(OC)=O)=NC(Cl)=NC=1NC1CCOCC1.C([Si](C(C)C)(C(C)C)[O:66][C:67]1C=CC=C([Sn](C)(C)C)C=1)(C)C>CN(C)C=O>[OH:21][C:17]1[CH:16]=[C:15]([C:5]2[N:6]=[C:7]3[C:2]([NH:1][C:67](=[O:66])[N:8]3[CH:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[C:3]([C:39]([NH2:43])=[O:40])[N:4]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1nc(Cl)nc(NC2CCOCC2)c1N
Reactant: COC(=O)c1nc(-c2cccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)nc(NC2CCOCC2)c1N
Reactant: CC(C)[Si](Oc1cccc([Sn](C)(C)C)c1)(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2C1CCOCC1
Temperature: 100 °C
Yield: 51 %

Procedure:
Methyl 5-amino-2-(3-(tert-butyldiphenylsilyloxy)phenyl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidine-4-carboxylate. Methyl 5-amino-2-chloro-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidine-4-carboxylate. (0.400 g, 1.39 mmol) triisopropyl(3-(trimethylstannyl)phenoxy)silane (0.810 g, 1.95 mmol) and bisdichloro(triphenylphosphine)palladium (0) (0.292 g, 0.410 mmol) were combined in dimethyl formamide (6 mL) and heated to 100° C. The reaction was monitored via thin layer chromatography. Once starting materials were consumed, the solution was condensed under reduced pressure and purified via Biotage chromatography (0 to 50% EtOAc in hexanes) to afford the title compound (0.361 g, 51%). MS (ESI) m/z 501.5 [M+1]+.