Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>CCO>[N:1]1([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: COc1ccc2ncnc(Cl)c2c1
Solvent: CCO
Product: COc1ccc2ncnc(N3CCCc4ccccc43)c2c1
Yield: 59 %

Procedure:
Utilizing a procedure analogous to that described in Example 2, this product was prepared in 59% yield from 1,2,3,4-tetrahydroquinoline (2 eq.) and 4-chloro-6-methoxy-quinazoline (1.0 eq) in EtOH. (M.P. 98° C.; LC-MS: 292 (MH+).
Reaction SMILES: B.O1CCCC1.[C:7]([O:11][C:12]([N:14]1[CH2:22][CH2:21][CH:17]([C:18](O)=[O:19])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].O.C([O-])([O-])=O.[K+].[K+]>O1CCCC1>[C:7]([O:11][C:12]([N:14]1[CH2:22][CH2:21][CH:17]([CH2:18][OH:19])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
Borane-tetrahydrofuran (1 M, 25 mL, 25 mmol) was added slowly to N-tert-butoxycarbonylisonipecotic acid (5.73 g, 25 mmol), as prepared in the preceding step, in tetrahydrofuran (50 mL) at 0° C. (ice-bath) over 30 min. The mixture was stirred at 0° C. overnight and then warmed up to room temperature for 6 h. Water (10 mL) was added slowly and then K2CO3 (5 g in 50 mL water) was added. The mixture was extracted with ethyl acetate (3×50 mL). The organic phase was washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), and dried over Na2SO4. The solvent was removed in vacuo, and the residue was purified by flash column chromatography (1:1 hexane/ethyl acetate) to give the title compound as white crystals (4.55 g, 84%). 1H-NMR (300 MHz, CDCl3) δ 1.13 (m, 2 H), 1.42 (s, 9 H), 1.67 (m, 4 H), 2.67 (t, 2 H, J=12.5 Hz), 3.46 (d, 2 H, J=3.0 Hz), and 4.09 (d, 2 H, J=3.6 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].O>C1COCC1>[CH3:20][S:21]([O:12][CH:10]1[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reaction time: 1.5 h

Procedure:
Tert-Butyl-3-hydroxyazetidine-1-carboxylate (0.20 g, 1.2 mmol, Aldrich) in THF (10 mL) at 0° C. was treated with triethylamine (0.32 mL, 2.3 mmol) and methanesulfonyl chloride (0.11 mL, 1.4 mmol, Aldrich). After 1.5 hours, water was added, and the aqueous mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford crude tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate, which was used in further step without purification.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[OH-].[Na+].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH3:53][O:54][C:55](=[O:59])[CH2:56][CH2:57][NH2:58].CCN(C(C)C)C(C)C>CCOC(C)=O.O.C(Cl)Cl.C1COCC1.CO>[CH3:53][O:54][C:55](=[O:59])[CH2:56][CH2:57][NH:58][C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)CCN
Reactant: COC(=O)c1nc(-c2ccccn2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)CCNC(=O)c1nc(-c2ccccn2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.2 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-2-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (80 mg, 0.17 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. for 16 h. The mixture was concentrated to approximately one-third of its original volume, and then acidified to pH about 3-4. The resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. To the residue were then added HOBt (37 mg, 0.28 mmol), CH2Cl2 (3 mL), and EDC (60 mg, 0.31 mmol), and the resulting mixture was stirred for 10 min. β-Alanine methyl ester HCl salt (39 mg, 0.28 mmol) and Hunig's base (0.11 mL, 0.62 mmol) were added, and the mixture was stirred for 48 h. The mixture was diluted with EtOAc and water, and acidified to pH about 3-4. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-70% EtOAc/hexanes+1% AcOH) to give 62 mg of the title compound. MS: (+) m/z 535.58 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:6]=[CH:5]2.C(N(CC)CC)C.[C:27](Cl)(Cl)=[S:28]>CN(C)C(=O)C.C(#N)C>[N:1]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[CH:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:6]=[CH:5]2)=[C:27]=[S:28]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc2nc(C=Cc3ccccc3)ccc2c1
Solvent: CC#N
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: S=C=Nc1ccc2nc(C=Cc3ccccc3)ccc2c1
Reaction time: 5 h

Procedure:
A solution of 24.6 g of 6-amino-2-styrylquinoline and 22.3 g of triethylamine in 100 ml of N,N-dimethylacetamide was added dropwise to 12.5 g of thiophosgene in 25 ml of acetonitrile with the temperature kept at or below -10° C. using a dry ice bath. After reacting for 5 hours at room temperature, the solid was filtered off and 500 ml of chloroform were added to the filtrate. The deposited solid was filtered off and the filtrate was separated and purified by silica gel column chromatography (the developing solution: chloroform). The obtained solid was recrystallized by using ethyl acetate to yield 19.3 g (67% of the theoretical yield) of 6-isothiocyanato-2-styrylquinoline.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][O:7][CH:6]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][N+:14]([O-])=[C:13]([CH3:18])[C:12]=3[CH3:19])[O:5][CH2:4]2)[CH2:2]1.C(OC(=O)C)(=[O:22])C.[OH-].[Na+]>>[CH2:1]1[C:3]2([CH2:8][O:7][CH:6]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([CH2:18][OH:22])[C:12]=3[CH3:19])[O:5][CH2:4]2)[CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(OCC2OCC3(CC3)CO2)cc[n+]([O-])c1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(OCC2OCC3(CC3)CO2)ccnc1CO
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 28.9 %

Procedure:
The 4-(5,7-dioxaspiro[2.5]oct-6-ylmethoxy)-2,3-dimethylpyridine 1-oxide (1.8 g, 6.78 mmol) obtained by the step (2c) was mixed with acetic anhydride (5.77 ml, 61 mmol). The mixture was stirred at 85° C. for 45 minutes and then acetic anhydride was distilled off. The residue was cooled on ice and dissolved in methanol. To this, a 5N aqueous sodium hydroxide solution (2.98 ml, 14.9 mmol) was added under ice-cool and the mixture was stirred at room temperature for 2 hours. Methanol was distilled off and water was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate, and thereafter the solvent was distilled off. Purification was performed by silica gel column chromatography (silica gel: 100 g, elution solvent: ethyl acetate/heptane=1/4 to 4/1). To the purified product, heptane (15 ml) was added and the mixture was refluxed. After the solution was confirmed to reach a homogeneous state, it was gradually cooled. The precipitated product was obtained by filtration. In this manner, the title compound (520 mg, yield: 28.9%) was obtained as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][C:6]=2[Cl:12].C([Li])CCC.[O:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>C1COCC1>[Cl:12][C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[C:5]=1[N:4]=[CH:3][C:2]([C:19]1([OH:18])[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:23][CH2:24]1)=[CH:11]2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Clc1ccnc2cc(Br)cnc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cnc3c(Cl)ccnc3c2)CC1
Temperature: -78 °C
Yield: 38 %

Procedure:
Dissolved 3-bromo-8-chloro-1,5-naphthyridine (210 mg, 862 μmol) in 8 mL of THF and cooled to −78° C. Then added butyllithium (517 μl, 1294 μmol) and stirred for 15 min. Added tert-butyl 4-oxopiperidine-1-carboxylate (258 mg, 1294 μmol) and let warm to room temperature over 1 h. The reaction was quenched with saturated NH4Cl and extracted with dichloromethane (3×20 mL), dried over NaSO4 and concentrated. Intermediate was purified via MPLC (DCM/MeOH/NHOH) to yield tert-butyl 4-(8-chloro-1,5-naphthyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (120 mg, 38% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C1C(=O)N([Br:18])C(=O)C1.O>C(Cl)Cl>[Br:18][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: Clc1ncnc2[nH]cc(Br)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5.91 g, 38 mmol) in DCM (250 mL) was added NBS (7.93 g, 44 mmol). The suspension was stirred at room temperature for 3 hours. Water (200 mL) was added to the reaction mixture. The mixture was sonicated for 5 min. The solid was collected by filtration and washed with water, then taken into 100 mL of MeOH. The suspension was sonicated for 3 min. The solid was collected by filtration as the desired product (6.47 g, 72%). LCMS[M+1]: 232.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[C:18]([NH2:21])(=[O:20])[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[N+:15]([C:12]1[N:11]=[CH:10][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:21][C:18](=[O:20])[CH3:19])[CH:7]=2)=[CH:14][CH:13]=1)([O-:17])=[O:16]
Reactant: CC(N)=O
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])nc2)ccn1
Temperature: 80 °C
Yield: 67.9 %

Procedure:
A degassed solution of Example A1 (2.0 g, 7.95 mmol) in dioxane (30 mL) added treated with acetamide (1.878 g, 31.8 mmol), Cs2CO3 (2.59 g, 7.95 mmol), X-Phos (0.189 g, 0.397 mmol), and Pd2(dba)3 (0.364 g, 0.397 mmol) and heated at 80° C. for 16 h. The mixture was cooled to RT, treated with EtOAc, the solids removed via filtration through diatomaceous earth and rinsed well with EtOAc. The filtrate was washed with water, then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)acetamide (1.48 g, 68%). MS (ESI) m/z: 275.1 (M+H+).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20]([CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].[CH3:29][C:30](=[CH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:31]=O.[BH4-].[Na+]>C(OCC)(=O)C.O.ClCCl>[CH2:12]([O:19][C:20]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:29][C:30]([CH3:31])=[CH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCCCC(=O)OCc1ccccc1
Reactant: CC(C=O)=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=Cc1ccccc1)CNCCCCC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 15 %

Procedure:
13.7 g (36 mM) of 4-(benzyloxycarbonyl)butylamine para toluene sulphonate salt was stirred vigorously in ethyl acetate-water whilst being treated with aqueous sodium hydroxide to pH 9.5. The organic phase was washed with saturated brine, dried (anhydrous magnesium sulphate), benzyl alcohol (100 cm3) added, and the ethyl acetate evaporated. The solution was treated with one equivalent of α-methylcinnamaldehyde and stirred for 1/2 hour. Dichloromethane (50 cm3) was added and the reaction mixture treated with excess sodium borohydride. The mixture was filtered and the filtrate diluted with dichloromethane (100 cm3), washed with saturated brine (4×150 cm3) and dried (anhydrous magnesium sulphate). The dichloromethane was removed by evaporation under reduced pressure and the residue diluted with diethyl ether (300 cm3). This solution was treated with excess para toluene sulphonic acid in ether. The resultant crystals were filtered off, washed with ether and dried to yield 2.7 g (15%) of the title compound as a para-toluene sulphonate salt. This salt was extracted into ethyl acetate with aqueous sodium hydroxide (pH 9-10). The organic phase was washed with saturated brine, dried (anhydrous magnesium sulphate) and evaporated to an oil, yield=1.85 g (15%), (film) 3330, 1735, 1450, 1155, 750, 700 cm-1 ; (CDCl3) 1.35-2.00 (5H, m), 1.85 (3H, d, J 1 Hz), 2.37 and 2.62 (4H, 2 x t, J 6.5 Hz), 3.27 (2H, s), 5.10 (2H, s), 6.42 (1H, broad s), 7.26 and 7.34 (10H, 2×s).
Reaction SMILES: [F:1][C:2]1[C:3]2[O:14][CH2:13][O:12][C:9]([C:10]=1[F:11])=[CH:8][C:4]=2[C:5](O)=[O:6].C(Cl)(=O)C([Cl:18])=O>C(OCC)C.CN(C)C=O>[F:1][C:2]1[C:3]2[O:14][CH2:13][O:12][C:9]([C:10]=1[F:11])=[CH:8][C:4]=2[C:5]([Cl:18])=[O:6]
Reactant: O=C(O)c1cc2c(F)c(F)c1OCO2
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2c(F)c(F)c1OCO2
Temperature: 0 °C
Reaction time: 60 h
Yield: 101.4 %

Procedure:
A solution of 15.0 grams (0.0742 mole) of 3,4-difluoromethylenedioxybenzoic acid in 200 mL of diethyl ether was stirred and cooled to 0° C. To this was added one drop of dimethylformamide followed by the dropwise addition of 11.3 grams (0.0890 mole) of oxalyl chloride. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it stirred for 60 hours. After this time the reaction mixture was concentrated under reduced pressure to yield 16.6 grams of 3,4-difluoromethylenedioxybenzoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](C2C=CC=CC=2)(C2C=CC=CC=2)[O:16][SiH2]C(C)(C)C)[CH:10]=1.C(O)(=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O.CCOCC>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][OH:16])[CH:10]=1
Reactant: COC(=O)CCCCCc1cccc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)CCCCCc1cccc(CO)c1
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a solution of 6-[3-(tert-butyl-diphenyl-silanyloxymethyl)-phenyl]-hexanoic acid methyl ester (2.37 g, 5 mmol) in THF (10 mL) is added acetic acid (283 μL, 5 mmol) and 1M TBAF (5 mL). The solution is stirred for 2 hrs then diluted with EtOAc/ether (1:1). The organic layer is washed with water, brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 35% ethyl acetate/hexanes) to give 1.12 g of title compound. MS (EI) 236 (M+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][N:8]=[C:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][C:16]=3[F:25])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.CS(C)=O.F[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1>CO>[N:1]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH2:6][CH2:5][CH:4]([O:7][N:8]=[C:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:17][C:16]=3[F:25])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(N2CCC(=NOC3CCNCC3)CC2)c(F)c1
Reactant: Fc1ccccn1
Solvent: CS(C)=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(N2CCC(=NOC3CCN(c4ccccn4)CC3)CC2)c(F)c1
Temperature: 120 °C

Procedure:
30 mg of 63a (0.08 mmol), diisopropylethylamine (75 μL, 0.43 mmol), DMSO (0.3 mL) and 2-fluoropyridine (11.7 mg, 0.12 mmol) were combined and heated to 120° C. overnight. The mixture was diluted with methanol and purified on preparative HPLC to give 63-1: LC-MS 447.4 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N-:13][CH3:14])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.O.NN>C(O)C.[Ni]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH3:14])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: C[N-]S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CNS(=O)(=O)c1ccc(N)cc1
Reaction time: 1 h

Procedure:
To a solution of the crude 4-nitrobenzenesulfonyl methylamide prepared above in 45 mL of ethanol, was added a 1 mL slurry of Raney Nickel. Hydrazine monohydrate (18 mmol) was added slowly in several portions. A change in the solution colour from yellow to colourless indicated the reaction was complete. The mixture was stirred for an additional 1 hr. The solids were removed by filtration and the solvent was evaporated. The resulting crude material was purified by flash column chromatography eluting with CH2Cl2:MeOH=10:1 to yield 2.09 g (90% for two steps) of the title compound as a pale orange powder.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:5]([NH2:6])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.C(N(CC)CC)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1.CCCCC>[Cl:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:10])[CH3:11])[C:5]([N:6]=[C:23]=[O:25])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1
Reactant: CC(C)c1cc(Cl)cc(C(C)C)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCCCC
Product: CC(C)c1cc(Cl)cc(C(C)C)c1N=C=O
Yield: 279 %

Procedure:
To a stirred solution of 4-chloro-2,6-diisopropylaniline (32 grams) and triethylamine-(7.8 mL) in tetrahydrofuran (505 mL) was added triphosgene (14.9 grams). The mixture was refluxed for two hours with stirring. The tetrahydrofuran was then revolved in vacuo and the resulting oil was taken up in pentane and filtered through silica gel to afford 33.3 grams of the product. 1H NMR δ 7.18 (s, 2), 3.22 (qq, 2, J=7.1Hz), 1.25 (d, 6, J=7.1Hz), 1.25 (d, 6, J=7.1 Hz).
Reaction SMILES: Cl.[NH2:2][C:3]1([CH3:13])[C:8](=[O:9])[N:7]([CH3:10])[C:6](=[O:11])[NH:5][C:4]1=[O:12].[F:14][C:15]1[C:16]([F:28])=[C:17]([F:27])[C:18]([F:26])=[C:19]2[C:24](=O)[O:23][C:21](=[O:22])[C:20]=12.CCN(CC)CC>CC(O)=O>[CH3:10][N:7]1[C:8](=[O:9])[C:3]([CH3:13])([N:2]2[C:21](=[O:22])[C:20]3[C:19](=[C:18]([F:26])[C:17]([F:27])=[C:16]([F:28])[C:15]=3[F:14])[C:24]2=[O:23])[C:4](=[O:12])[NH:5][C:6]1=[O:11]
Reactant: CN1C(=O)NC(=O)C(C)(N)C1=O
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CN1C(=O)NC(=O)C(C)(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C1=O
Temperature: 25 °C

Procedure:
A mixture of 5-amino-1,5-dimethylbarbituric acid hydrochloride (0.31 g, 1.50 mmol), tetrafluorophthalic anhydride (0.40 g, 1.80 mmol) and Et3N (0.21 mL, 0.15 g, 1.50 mmol) in glacial AcOH (11 mL) was stirred under reflux for 3 hours. The yellow solution was then allowed to cool down to room temperature and evaporated to dryness under reduced pressure. The oily residue was recrystallized from 70% EtOH to give 1,5-dimethyl-5-(tetrafluorophthalimido)-barbituric acid (19a) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([NH:21][C:22](OCC3C=CC=CC=3)=O)=[CH:16][C:15]=2[F:32])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)=O.CC(C)=O.[Li]CCCC.[CH2:45]([O:49][C:50](=[O:54])CCC)[C@@H:46]1[O:48]C1>C1COCC1.C(Cl)Cl.CO.C(Cl)(Cl)Cl>[F:20][C:19]1[CH:18]=[C:17]([N:21]2[CH2:22][CH:45]([CH2:46][OH:48])[O:49][C:50]2=[O:54])[CH:16]=[C:15]([F:32])[C:14]=1[N:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(F)cc(NC(=O)OCc3ccccc3)cc2F)CC1
Reactant: CCCC(=O)OC[C@H]1CO1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2c(F)cc(N3CC(CO)OC3=O)cc2F)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
The 1-(tert-butoxycarbonyl)-4-[2,6-difluoro-4-(benzyloxycarbonyl)aminophenyl]piperazine (14.05 g, 31 mmol) was dissolved in dry THF (150 mL) and then cooled to -78° C. (dry ice/acetone). The reaction was next treated with n-BuLi (21.6 mL, 35 mmol) dropwise over a 25 minute period. The reaction was allowed to stir at -78° C. for 30 minutes and then (R)-(-)-glycidylbutyrate (4.89 mL, 35 mmol) was dropwise over 7 minutes. The reaction was maintained at -78° C. for an additional 15 minutes and then the bath was removed, allowing the reaction to slowly warm up to room temperature overnight. The reaction was determined to be complete by TLC (5% MeOH/CHCl3, UV short wave). The reaction mixture was diluted with 500 mL CH2Cl2 and then washed with both H2O (3×300 mL) and brine (300 mL). The aqueous portions were back-extracted with more CH2Cl2 (3×400 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give a creamy yellow solid. The crude solid was purified by recrystallization from hot EtOAc/hexane to give 11.063 g (85%) of the title compound as a white solid with mp 164°-166° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][C:3]=1[C:9]#[N:10].[CH3:11][N:12]1[CH:16]=[C:15]([NH:17]C(=O)C)[C:14]([CH3:21])=[N:13]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O.[OH-].[Li+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:17][C:15]2[C:14]([CH3:21])=[N:13][N:12]([CH3:11])[CH:16]=2)[N:5]=[CH:4][C:3]=1[C:9]#[N:10]
Reactant: CC(=O)Nc1cn(C)nc1C
Reactant: N#Cc1cnc(Cl)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: C1COCCO1
Product: Cc1nn(C)cc1Nc1cc(Cl)c(C#N)cn1
Temperature: 90 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
4,6-Dichloropyridine-3-carbonitrile (9.60 g, 55.49 mmol), N-(1,3-dimethylpyrazol-4-yl)acetamide (8.5 g, 55.49 mmol, see Example 2.02), palladium(II) acetate (0.374 g, 1.66 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (1.926 g, 3.33 mmol) and cesium carbonate (27.1 g, 83.23 mmol) were weighed out in a flask. Dioxane (110 mL) was added and argon was bubbled through the reaction mixture for 5 minutes at room temperature. The resulting suspension was stirred at 90° C. for 2 hours. The reaction mixture was allowed to cool to room temperature with stirring, water (275 mL) was added followed by the portionwise addition of lithium hydroxide hydrate (6.99 g, 166.47 mmol). The solution was left to stir at room temperature for 30 minutes. The resulting precipitate was collected by filtration, washed with water and dried. The crude product was purified by flash chromatography on silica gel eluting with 0 to 5% MeOH in EtOAc/DCM (1:1). The solvent was evaporated to dryness. The residue was triturated in Et2O, and the resulting precipitate was collected by filtration, washed with Et2O and dried to a constant weight to afford 4-chloro-6-(1,3-dimethylpyrazol-4-ylamino)pyridine-3-carbonitrile (6 g, 43.7%) as a pale yellow solid. 1H NMR spectrum (500 MHz, CDCl3): δ 2.15 (s, 3H), 2.88 (s, 3H), 6.43 (s, 1H), 6.45 (s, 1H), 7.44 (s, 1H), 8.36 (s, 1H); Mass spectrum: m/z (ESI+) (M+H)+=248.