Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]([O:18]C)=[O:17])=[CH:10]2)=[CH:5][CH:4]=1.[OH-].[Li+]>CO.O>[CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]([OH:18])=[O:17])=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(=O)n(-c2ccc(N(C)C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)c1ccc(-n2cc(C(=O)O)ccc2=O)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
After 357 mg (1.31 mmol) of methyl 1-(4-dimethylaminophenyl)-1,6-dihydro-6-oxo-3-pyridinecarboxylate was dissolved in 12 mL of methanol and 4 mL of water, 94 mg (3.93 mmol) of lithium hydroxide was added to the solution. Afterward, the resulting reaction solution was stirred at about 50° C. for about 5 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo, and aqueous HCl was then added to the reaction solution to titrate until a neutral solution was obtained. The resulting solid compound was filtrated and used in Example 113-3 without an additional purification process.
Reaction SMILES: [C:1]([NH:4][C:5]([CH:13]1[CH2:20][C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)(C#N)[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([NH:4][CH:5]([CH:13]1[CH2:20][C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(C#N)(NC(C)=O)C1Cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)NC(C(=O)O)C1Cc2ccccc21

Procedure:
To a mixture of #99 (4.38 mg, <16.1 mmol, 1 eq.) in methanol (30 mL, 0.53 M) was added a 1 N aqueous solution of sodium hydroxide (38 mL, 38 mmol, 2.4 eq.). The reaction mixture was heated at reflux overnight, then concentrated in vacuo, diluted with water (40 mL), and acidified with a 1 N aqueous solution of hydrochloric acid (40 mL). The aqueous layer was extracted with dichloromethane (3×30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting oil was purified by silica gel chromatography (Solvent A: dichloromethane; Solvent B: 20% methanol in dichloromethane containing 0.02% trifluoroacetic acid; Gradient: 0% to 40% B) then by supercritical fluid chromatography (Column: Chiralpak AD-H, 250×21 mm; Eluent: 85:15 carbon dioxide/methanol; Flow Rate: 65 g/min; Detection: 210 nm; Instrument: Berger minigram preparative SFC system.). The second eluting peak was isolated to give #100 (600 mg, 17% over two steps) as a single enantiomer (retention time=3.37 minutes, purity >99%). LC-MS: m/z 220.3 [M+H+], retention time=2.10 minutes; 1H NMR (400 MHz, CD3OD) δ 7.14-7.24 (m, 2H), 7.03-7.09 (m, 2H), 4.59 (d, J=8.6 Hz, 1H), 3.87 (ddd, J=8.5, 5.3, 2.4 Hz, 1H), 3.35 (dd, J=14.5, 5.4 Hz, 1H, assumed; partially obscured by solvent peak), 3.10 (dd, J=14.4, 2.4 Hz, 1H), 2.00 (s, 3H). Optical rotation: [α]D25 +70.9° (c 0.67, methanol)
Reaction SMILES: [N+:1]([O-:15])([O:3][CH2:4][C@H:5]([O:11][N+:12]([O-:14])=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][OH:10])=[O:2].I([O-])(=O)(=O)=[O:17].[Na+].C(#N)C.C(Cl)(Cl)Cl>O.O.[Ru]=O.CO.ClCCl>[N+:12]([O:11][C@@H:5]([CH2:4][O:3][N+:1]([O-:15])=[O:2])[CH2:6][CH2:7][CH2:8][C:9]([OH:17])=[O:10])([O-:14])=[O:13]
Reactant: O=[N+]([O-])OC[C@@H](CCCCO)O[N+](=O)[O-]
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: O=C(O)CCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-]
Reaction time: 16 h

Procedure:
A mixture of (2R)-6-hydroxyhexane-1,2-diyl dinitrate (intermediate 2, 13.5 g, 60.2 mmol) and sodium periodate (38.74 g, 181 mmol) was suspended in water (250 mL)/acetonitrile (250 mL)/chloroform (250 mL). Ruthenium oxide hydrate (0.813 g, 6.11 mmol) was then added, turning the reaction into bright yellow. After 16 hours, the reaction mixture was concentrated in vacuo to remove the organic solvents. It was extracted with dichloromethane (3×200 mL), and the combined organic extracts were washed with brine, dried (magnesium sulfate), filtered, and concentrated in vacuo to afford the crude product. Chromatography over silica eluting with methanol/dichloromethane afforded (5R)-5,6-bis(nitrooxy)hexanoic acid as a yellow liquid. 1H NMR (500 MHz, CDCl3) δ 5.25-5.35 (m, 1H), 4.76 (dd, J=3.1, 12.9 Hz, 1H), 4.49 (dd, J=6.4, 13.0 Hz, 1H), 2.4-2.5 (m, 2H), 1.7-1.9 (m, 4H).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([C:13]1[CH:18]=[N:17][N:16]2[CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28](O)=[O:29])[CH:26]=3)[CH:21]=[C:15]2[C:14]=1[NH:31][C@H:32]1[C@@H:36]([CH3:37])[CH2:35][N:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][N:39]=2)[CH2:33]1)(=[O:12])[NH2:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:71][C:72]1([F:76])[CH2:75][NH:74][CH2:73]1>>[C:44]([C:41]1[CH:42]=[CH:43][C:38]([N:34]2[CH2:35][C@H:36]([CH3:37])[C@H:32]([NH:31][C:14]3[C:15]4[N:16]([CH:19]=[C:20]([C:22]5[CH:23]=[N:24][N:25]([CH2:27][C:28]([N:74]6[CH2:75][C:72]([F:76])([F:71])[CH2:73]6)=[O:29])[CH:26]=5)[CH:21]=4)[N:17]=[CH:18][C:13]=3[C:10]([NH2:11])=[O:12])[CH2:33]2)=[N:39][CH:40]=1)#[N:45]
Reactant: C[C@H]1CN(c2ccc(C#N)cn2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(CC(=O)O)c3)cc12
Reactant: FC1(F)CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2ccc(C#N)cn2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(CC(=O)N4CC(F)(F)C4)c3)cc12
Reaction time: 2.5 h
Yield: 17.8 %

Procedure:
Hunig's base (0.014 mL, 0.079 mmol) was added to a stirred solution of crude 2-(4-(3-carbamoyl-4-(((3S,4S)-1-(5-cyanopyridin-2-yl)-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazin-6-yl)-1H-pyrazol-1-yl)acetic acid (20 mg, from Step 2) and HATU (20.05 mg, 0.053 mmol). After 2.5 h at room temperature, 3,3-difluoroazetidine hydrochloride (6.83 mg, 0.053 mmol) was added. After 40 min at room temperature, the reaction was complete. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-100% B over 15 minutes, then a 7-minute hold at 100% B; Flow: 25 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (4.1 mg). 1H NMR (500 MHz, chloroform-d/methanol-d4) δ ppm 8.31 (br. s., 1H), 8.07 (s, 1H), 7.89 (s, 1H), 7.82 (s, 1H), 7.75 (d, J=1.5 Hz, 1H), 7.63 (dd, J=8.9, 1.5 Hz, 1H), 6.99 (d, J=1.5 Hz, 1H), 6.49 (d, J=8.9 Hz, 1H), 4.99-4.91 (m, 3H), 4.46 (t, J=11.9 Hz, 2H), 4.39 (t, J=11.9 Hz, 2H), 3.94 (br. s., 2H), 3.41 (br. s., 1H), 2.84 (br. s., 1H), 1.29 (d, J=6.9 Hz, 3H); MS (ES+) m/z: 561.1 (M+H); LC retention time: 1.24 min (analytical LCMS Method I).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][O:12][C:13](=[O:18])[C:14](Br)([CH3:16])[CH3:15].O>CC#N>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][C:14]([CH3:16])([CH3:15])[C:13]([O:12][CH3:11])=[O:18])=[CH:3][CH:4]=1
Reactant: Oc1ccc(S)cc1
Reactant: COC(=O)C(C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C(C)(C)Sc1ccc(O)cc1
Reaction time: 48 h
Yield: 84 %

Procedure:
The title product was prepared according to the procedure described in Method A (step 1) starting from 4-mercaptophenol (0.500 g, 4.0 mmol) in 10 mL of anhydrous CH3CN, to which was added NaH 80% (0.144 g, 4.8 mmol). The mixture was cooled to 0° C. and after 5 minutes methyl-α-bromoisobutyrate (0.724 g, 4.0 mmol) was added. The reaction was left for two days at room temperature under magnetic stirring. After this period, the mixture was poured into H2O and extracted with ethyl acetate; the aqueous phase was then acidified with HCl 1N and extracted again with ethyl acetate. The pooled organic phases were dried on Na2SO4, filtered and evaporated. The residue obtained was purified by silica gel chromatography using CHCl3 as eluent. 0.760 g of product were obtained (yield: 84%); Mp: 110-112° C.; TLC: silica gel, eluent CHCl3, Fr: 0.11; 1H NMR (CDCl3, 300 MHz) δ: 7.30 (d, 2H), 6.73 (d, 2H), 5.57 (brm, 1H), 3.70 (s, 3H), 1.45 (s, 6H); HPLC: Column: Symmetry—C18, (5 μm) 4.6×250 mm, T: 30° C., mobile phase CH3CN/H2O 50/50 (v/v), pH: as is, flow rate: 0.75 mL/min, 205 nm UV detector, retention time 10.14 min; E.A. (elemental analysis) conforming for C11H14O3S.
Reaction SMILES: [ClH:1].[N:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[N:22]=[C:21]([NH2:23])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14]1)=[N+]=[N-].[Sn](Cl)[Cl:25]>CO>[ClH:25].[ClH:1].[NH2:2][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[N:22]=[C:21]([NH2:23])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14]1
Reactant: [N-]=[N+]=NCCc1ccccc1C1N=C(N)c2ccccc2N1
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: CO
Product: NCCc1ccccc1C1N=C(N)c2ccccc2N1
Reaction time: 2 h

Procedure:
To a solution of 2-(2-(2-azidoethyl)phenyl)-1,2-dihydro-4-quinazolinamine hydrochloride (Example 50, 0.38 g, 1.16 mmol) in methanol (10 ml) was added tin dichloride (0.33 g, 1.73 mmol) and the mixture stirred for 2 h (effervescence). Evaporation and purification by RPHPLC eluting with trifluoroacetic acid/water/methanol (1:90:10, increasing the gradient to 1:5:95) gave the product, MS (+FAB) 266 ([M+H]+), 1H NMR (d6 -DMSO) 10.07 (1H, s), 9.29 (1H, s), 8.51 (1H, s), 7.98 (2H, s), 7.91 (1H, s), 7.69 (1H, d), 7.33-7.55 (4H, m), 6.7-7.0 (2H, m), 6.17 (1H, s), 2.9-3.1 (4H, m).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([S:11][CH3:12])[C:8]([S:13][CH3:14])=[CH:7][C:6]=1[S:15]C)(=O)[CH3:2]>P(Cl)(Cl)(Cl)=O>[CH3:2][C:1]1[S:15][C:6]2[CH:7]=[C:8]([S:13][CH3:14])[C:9]([S:11][CH3:12])=[CH:10][C:5]=2[N:4]=1
Reactant: CSc1cc(SC)c(SC)cc1NC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CSc1cc2nc(C)sc2cc1SC
Yield: 91 %

Procedure:
2-Methyl-5,6-dimethylthiobenzothiazole was prepared by combining N-acetyl-2,4,5-trimethylthioaniline (20 g , 0.073 mol) and phosphoryl chloride (40 mL) and heating the mixture on a steam bath for 10 min. During this time the reaction mixture solidified. The solid was collected, washed with ether and dried, affording 27 g of the hydrochloride salt. The free base was prepared by dissolving the salt in a mixture of 300 mL of ether and 300 mL of methanol and adding 35 mL of triethylamine. The solvents were evaporated, the solid was collected, slurried with distilled water, collected, and washed with warm water and dried (16 g, 91% yield), mp 79-81° C.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5]C=CC=1.[H-].[Na+].[S:10]1[CH2:15][CH2:14][CH2:13][S:12][CH:11]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].BrCC1CC1>CN(C=O)C>[CH2:19]([O:18][C:16]([C:11]1([CH2:7][CH:1]2[CH2:6][CH2:5]2)[S:12][CH2:13][CH2:14][CH2:15][S:10]1)=[O:17])[CH3:20]
Reactant: Cc1ccccc1
Reactant: CCOC(=O)C1SCCCS1
Agent: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CC2CC2)SCCCS1
Reaction time: 18 h

Procedure:
To a flamed dried flask is added dry toluene (80 mL) and sodium hydride (60%, 33.5 mmol, 1.34 g). The reaction is cooled in a ice bath and a solution of ethyl 1,3 dithiane carboxylate (52 mmol, 10 g) and bromomethyl cyclopropane (62.4 mmol, 8.42 g) in DMF (24 mL) are added dropwise over 10 minutes. The ice bath is removed and the reaction is stirred for 18 h. Water is added (50 mL) and the organic layer is separated. The organic layer is washed with brine, dried (Na2SO4), and concentrated to a yellow oil (12 g, 92%). LC-ES/MS: 247.0 (M+1).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9](=O)[CH:10]([CH3:12])[CH3:11]>>[CH:9](=[N:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)C=O
Reactant: NCc1ccccc1
Product: CC(C)C=NCc1ccccc1

Procedure:
the procedure described in Example 1A was repeated using benzylamine (32 parts) in place of benzhydrylamine and isobutyraldehyde (22 parts) to give isobutylidenebenzylamine (49 parts).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH2:15][CH2:16][CH2:17][N:18]1[C:30]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[C:22]([NH2:31])[C:21]=2[N:20]=[C:19]1[CH2:32][O:33][N:34]=[C:35]([CH3:37])[CH3:36])(C)(C)C>ClCCl>[NH2:31][C:22]1[C:21]2[N:20]=[C:19]([CH2:32][O:33][N:34]=[C:35]([CH3:37])[CH3:36])[N:18]([CH2:17][CH2:16][CH2:15][NH2:14])[C:30]=2[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:23]=1
Reactant: CC(C)=NOCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)=NOCc1nc2c(N)nc3ccccc3c2n1CCCN
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 243.6 %

Procedure:
Trifluoroacetic acid (7 mL) was added to a suspension of tert-butyl[3-(4-amino-2-isopropylideneaminoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]carbamate (4.12 g) in dichloromethane (70 mL). The reaction became homogeneous and was stirred at ambient temperature for 2.5 hours. More trifluoroacetic acid (10 mL) was added and the reaction was stirred for another hour. The reaction mixture was concentrated under reduced pressure and placed under high vacuum overnight to provide 7.68 g of propan-2-one O-{[4-amino-1-(3-aminopropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl}oxime a white solid. Based on the weight this material was assumed to contain 5 equivalents of trifluoroacetic acid.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:10]([OH:18])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[C:27]([C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=1)[C:28]([O:30][CH3:31])=[O:29])=[N-]>C1C=CC=CC=1.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:10]([O:18][C@@H:27]([C:28]([O:30][CH3:31])=[O:29])[C:32]1[CH:33]=[C:34]([C:42]([F:43])([F:44])[F:45])[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1)[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=[N+]=[N-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](O)CC[C@@H]1N2Cc1ccccc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: COC(=O)[C@H](O[C@@H]1CC[C@H]2[C@H](C#N)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-8-benzyl-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 31; 7.186 g, 22.6 mmol) and rhodium(II) acetate dimer (0.216 g, 0.452 mmol) in benzene (30 ml) was heated to reflux, and treated slowly with a solution of methyl 2diazo-2-(3,5-bis(trifluoromethyl)phenyl)-acetate [prepared by the method of R. T. Lewis et al. J. Org. Chem., 2000, 65, 2615] (7.7563 g, 24.86 mmol) in benzene (30 ml). After the addition was complete the mixture was concentrated in vacuo and the residue purified by flash column chromatography, eluting with 10-20% ethyl acetate/hexane to give a mixture of diastereomers (6.0 g, 2.6:1 ratio). The major diastereomer was separated by crystallisation with ethyl acetate/hexane to afford the title compound in two crops (3.81 g).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH:12][C:13](=[O:18])[CH2:14][C:15]([OH:17])=O)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Cl:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1>CN(C=O)C.O>[Cl:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][CH:60]1[CH2:65][CH2:64][N:63]([C:15](=[O:17])[CH2:14][C:13]([NH:12][C:10]2[S:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][N:9]=2)=[O:18])[CH2:62][CH2:61]1
Reactant: O=C(O)CC(=O)Nc1ncc(-c2ccccc2)s1
Reactant: Clc1ccccc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(CC(=O)N1CCC(Nc2ccccc2Cl)CC1)Nc1ncc(-c2ccccc2)s1
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To a stirred solution of N-(5-phenyl-thiazol-2-yl)-malonamic acid (0.075 g, 0.00028 mole) in DMF (2 mL) was added DIPEA (0.11 g, 0.00085 mole), HOBt (0.038 g, 0.00028 mole) and EDCI.HCl (0.065 g, 0.00034 mol). After 2 minutes (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride (0.077 g, 0.00031 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate and hexane to afford 0.035 g (28%) of 3-[4-(2-chloro-phenylamino)-piperidin-1-yl]-3-oxo-N-(5-phenyl-thiazol-2-yl)-propionamide. LC-MS purity: 455.11 (M+1)+, 98.03%, 1H NMR (CDCl3): δ 11.6 (s, 1H), 7.9 (d, 2H), 7.4 (t, 3H), 7.3 (t, 2H), 7.2 (m, 2H), 7.1, 6.70 (m, 2H), 4.5 (d, 1H), 4.2 (d, 1H), 3.9 (d, 1H), 3.6 (s, 3H), 3.3 (t, 1H), 3.1 (t, 1H), 2.2 (s, 2H), 1.5 (m, 2H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:35][O:36][C:37](=[O:39])[CH3:38])(=[O:3])[CH3:2].[Cr]([O-])([O-])(=O)=[O:41].[K+].[K+]>C(O)(=O)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([C:33](=[O:41])[CH3:34])=[CH:31][CH:32]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:35][O:36][C:37](=[O:39])[CH3:38])(=[O:3])[CH3:2]
Reactant: O=[Cr](=O)([O-])[O-]
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(C(C)=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 37 %

Procedure:
To a stirred solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethylbenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (10 g, 10.8 mmol) in acetic acid (130 mL) at 120° C. was added potassium chromate (6.3 g, 21.4 mmol) in one portion. The mixture was stirred for 22 hours at this temperature, and the reaction was cooled to RT. The volatiles were removed under reduced pressure, ethyl acetate was added, and the solids were filtered off. The organic layer was washed with a saturated solution of sodium bicarbonate and then with brine, and dried over sodium sulfate. Concentration of the organic solution and purification of the resulting residue by silica gel column (3:1 petroleum ether:ethyl acetate) gave 2.3 g of title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.90 (d, J=8.0 Hz, 2H), 7.39 (d, J=8.4 Hz, 1H), 7.26 (d, J=8.4 Hz, 2H), 7.22 (dd, J=8.4, 2.2 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 5.31 (t, J=9.4 Hz, 1H), 5.22 (t, J=9.8 Hz, 1H), 5.09 (t, J=9.4 Hz, 1H), 4.35 (d, J=10.0 Hz, 1H), 4.29 (dd, J=12.4, 4.8 Hz, 1H), 4.18-4.13 (m, 3H), 3.85-3.81 (m, 1H), 2.60 (s, 3H), 2.09 (s, 3H), 2.07 (s, 3H), 2.01 (s, 3H), 1.75 (s, 3H); MS ESI (m/z): 575 [M+H]+, 619 [M+HCO2]−.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[Br:10]Br.N1C=CC=NC=1>C(Cl)(Cl)Cl>[Br:10][C:7]1[CH:8]=[C:2]([F:1])[C:3]([NH2:4])=[C:5]([F:9])[CH:6]=1
Reactant: BrBr
Reactant: Nc1c(F)cccc1F
Solvent: c1cncnc1
Solvent: ClC(Cl)Cl
Product: Nc1c(F)cc(Br)cc1F

Procedure:
In chloroform, commercially available compound [U], 2,6-difluoroaniline, is brominated with bromine in the presence of pyrimidine to yield compound [V], 4-bromo-2,6-difluoroaniline. In NMP, compound [V] is cyanated with copper (I) cyanide to form a copper complex. The copper complex is decomposed with EDA, to yield compound [W], 4-amino-3,5-difluorobenzonitrile. Compound [W] is converted into its corresponding diazonium salt with concentrated sulfuric acid in glacial acetic acid. In hydrobromic acid, the diazonium salt is brominated with copper (I) bromide to yield compound [X], 4-bromo-3,5-difluorobenzonitrile. Compound [X] is reacted with gaseous hydrogen chloride in anhydrous ethanol to yield compound [Y], 4-bromo-3,5-difluorobenzimidate hydrogen chloride. In ethanol, compound [Y] is reacted with gaseous ammonia to yield compound [Z], 4-bromo-3,5-difluorobenzamidine hydrogen chloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:20][N:8]2[C:9](=[O:19])[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=[C:7]2[N:6]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:22]=2)[CH2:5]1.[CH3:36][C:37]([CH3:39])=O.ClCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH:37]([NH:1][CH2:2][CH2:3][CH:4]1[CH2:20][N:8]2[C:9](=[O:19])[CH:10]=[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:12]=[C:7]2[N:6]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:22]=2)[CH2:5]1)([CH3:39])[CH3:36]
Reactant: CC(C)=O
Reactant: NCCC1CN(c2ccnc(NCCc3ccccc3)n2)c2nc(-c3ccccc3)cc(=O)n2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)NCCC1CN(c2ccnc(NCCc3ccccc3)n2)c2nc(-c3ccccc3)cc(=O)n2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7-(2-Amino-ethyl)-9-(2-phenethylamino-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (70 mg, 0.15 mmol), acetone (0.02 mL), dichloromethane (0.5 mL) and methanol (0.5 mL) was added sodium triacetoxyborohydride (38 mg, 0.18 mmol) Reaction stirred for 2 h at room temperature. Solvents removed under vacuum. Residue partitioned between dichloromethane and 5% sodium bicarbonate. Organics purified on silica to afford a white solid. M+1=510. 1NMR (CDCl3) d (6H, 1.17 ppm), m (2H, 1.68 ppm), m (1H, 2.32 ppm), m (3H, 2.78 ppm), t (2H, 2.94 ppm), m (1H, 3.55 ppm), dd (2H, 3.70 ppm), d (1H, 4.40 ppm), dd (1H, 4.53 ppm), m (1H, 5.10 ppm), s (1H, 6.60 ppm), m (3H, 7.24 ppm), m (2H, 7.32 ppm), m (3H, 7.44 ppm), m (2H, 7.90 ppm) d (1H, 8.18 ppm).
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][CH:10]([N:13]([CH:27]3[CH2:29][CH2:28]3)[C:14](=[O:26])[C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][CH:24]=[N:23][CH:22]=4)=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)[S:4][N:3]=1.[CH:30]([NH2:33])([CH3:32])[CH3:31]>CN1CCCC1=O>[CH:27]1([N:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:5]3[S:4][N:3]=[C:2]([NH:33][CH:30]([CH3:32])[CH3:31])[N:6]=3)[CH2:8][CH2:9]2)[C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:25][CH:24]=[N:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:29][CH2:28]1
Reactant: CC(C)N
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(Cl)ns2)CC1
Solvent: CN1CCCC1=O
Product: CC(C)Nc1nsc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)n1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A mixture of N-[1-(3-chloro-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-N-cyclopropyl-4-oxazol-5-yl-benzamide (43 mg) and isopropylamine (0.50 mL) in N-methyl-2-pyrrolidinon (1.50 mL) is stirred at 120° C. for two days. The mixture is concentrated in vacuo and the residue is purified by HPLC on reversed phase (MeOH/H2O/NH4OH). LC (method 5): tR=1.95 min; Mass spectrum (ESI+): m/z=453 [M+H]+.