Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[F:23][C:24]1[CH:45]=[CH:44][C:27]([CH2:28][N:29]2[CH2:33][CH2:32][N:31]([C:34]3[S:35][C:36]([C:40](O)=[O:41])=[C:37]([CH3:39])[N:38]=3)[C:30]2=[O:43])=[CH:26][CH:25]=1.[NH2:46][CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:29]2[CH2:33][CH2:32][N:31]([C:34]3[S:35][C:36]([C:40]([NH:46][CH2:47][C:48]4[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=4)=[O:41])=[C:37]([CH3:39])[N:38]=3)[C:30]2=[O:43])=[CH:44][CH:45]=1
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 33 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine in place of benzylamine, the title compound was obtained as a white powder in 33% yield: mp 177-179° C.; 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.50 (d, J=3.9 Hz, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.29-7.21 (m, 3H), 7.04-6.97 (m, 2H), 6.26 (t, J=5.7 Hz, 1H), 4.57 (d, J 5.7 Hz, 2H), 4.42 (s, 2H), 4.04 (t, J=8.1 Hz, 2H), 3.43 (t, J=8.1 Hz, 2H), 2.58 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.1, 162.6, 160.8, 157.3, 155.3, 153.6, 148.5, 136.0, 134.1, 131.3, 129.9, 123.7, 116.9, 115.9, 115.6, 47.2, 42.0, 41.6, 41.3, 17.2; MS (ES+) m/z 475.0 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]([C@@H:11]([NH2:13])[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[C:7]2[N:8]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9]([C@@H:11]([NH:13][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1nc2cccc(F)c2n1-c1ccccc1
Reactant: Clc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccc(F)c2n1-c1ccccc1
Temperature: 100 °C
Reaction time: 48 h
Yield: 19.2 %

Procedure:
A mixture of (S)-1-(7-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 7 (367 mg, 1.44 mmol), 6-chloro-9H-purine (222 mg, 1.44 mmol) and DIPEA (0.74 mL, 4.31 mmol) in n-butanol (3.5 mL) was stirred in a sealed tube for 48 h at 100° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated under reduced pressure. The product thus obtained was further purified by column chromatography (Si—PCC, gradient 0-20% 2M NH3/MeOH in EtOAc) followed by (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) and then sonicated in MeOH. The suspension was then diluted with diethyl ether and the solid collected by filtration affording 124 as a white solid (103 mg, 19%). LCMS: RT 3.40 min [M+H]+ 374.0. 1H NMR (DMSO, 400 MHz): δ 8.17-8.04 (2H, m), 7.98-7.86 (1H, br), 7.75-7.35 (6H, m), 7.19 (1H, td, J=8.09, 4.87 Hz), 7.02 (1H, dd, J=11.60, 8.02 Hz), 5.37 (1H, bs), 1.56 (3H, d, J=6.86 Hz)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH3:16])[C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][N:10]=2)=[C:4]([O:21][CH3:22])[CH:3]=1.[CH3:23][N:24]1[C:28]([Sn](CCCC)(CCCC)CCCC)=[CH:27][N:26]=[CH:25]1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:22][O:21][C:4]1[CH:3]=[C:2]([C:28]2[N:24]([CH3:23])[CH:25]=[N:26][CH:27]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[N:14]=[C:13]([NH:15][CH3:16])[C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][N:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Reactant: CNc1nc(Nc2ccc(Br)cc2OC)ncc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: CNc1nc(Nc2ccc(-c3cncn3C)cc2OC)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 42.3 %

Procedure:
A mixture of N2-(4-bromo-2-methoxyphenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (0.151 g, 0.4 mmol), Pd(dppf)Cl2 (33 mg, 0.04 mmol) and 1-methyl-5-(tributylstannyl)-1H-imidazole (297 mg, 0.8 mmol) in dioxane (5 mL) was degassed under a stream of nitrogen for 10 min. The reaction tube was sealed and heated at 100° C. during 18 hours. The mixture was cooled and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (20 mL) and water (20 mL) and the product extracted into ethyl acetate (2×20 mL). The combined organics were passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification of the residue via preparative HPLC afforded N2-(2-methoxy-4-(1-methyl-1H-imidazol-5-yl)phenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine as a beige solid (64 mg, 42%). LCMS (10 cm_ESCI_Bicarb_MeCN): [MH+]=379 at 3.59 min. 1H NMR (400 MHz, DMSO): δ 8.33 (d, J=8.3, 1H); 8.21 (s, 1H); 8.10 (s, 1H); 7.72 (s, 1H); 7.23 (d, J=5.2, 1H); 7.16-7.07 (m, 3H); 3.95 (s, 3H); 3.74 (s, 3H); 2.96 (d, J=4.3, 3H).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11][CH:12]=[CH2:13])=[C:9]([OH:14])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].I[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:33]=[CH:32][C:23]2[CH2:24][CH2:25][CH:26]([C:28]([O:30][CH3:31])=[O:29])[O:27][C:22]=2[C:21]=1[CH2:34][CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[NH2:6][C:4]([C:3]1[CH:7]=[CH:8][C:9]([O:14][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:33]=[CH:32][C:23]3[CH2:24][CH2:25][CH:26]([C:28]([O:30][CH3:31])=[O:29])[O:27][C:22]=3[C:21]=2[CH2:34][CH2:35][CH3:36])=[C:10]([CH2:11][CH:12]=[CH2:13])[C:2]=1[OH:1])=[O:5]
Reactant: C=CCc1c(O)ccc(C(N)=O)c1O
Reactant: CCCc1c(OCCCI)ccc2c1OC(C(=O)OC)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCc1c(OCCCOc2ccc3c(c2CCC)OC(C(=O)OC)CC3)ccc(C(N)=O)c1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound of Example 20 (550 mg, 2.89 mmol), the compound of Example 23 (1.21 g, 2.89 mmol), and potassium carbonate (800 mg, 5.78 mmol) were added to about 25 to 30 ml of DMF. The reaction mixture as stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate and concentrated under vacuum. The crude material was chromatographed on silica gel with 30% ethyl acetate/hexane as eluant. The fractions containing the product were collected and the solvent was removed under vacuum to give the product as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=[O:15])[CH2:6][CH2:5]2.[C:19]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:19][O:15][C:14]([C:7]1([CH3:17])[CH2:6][CH2:5][C:4]2[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([OH:1])[C:3]=2[CH3:18])[O:8]1)=[O:16]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Solvent: CO
Product: COC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1

Procedure:
A mixture of 6-hydroxy-2,5,7,8-tetramethychroman-2-carboxylic acid (5.0 g), methanol (100 ml) and p-toluenesulfonic acid (5 mg) is heated at reflux for 18 hr. The mixture is allowed to cool to 20°-25° and the solid collected and washed with ether and dried to give methyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylate. Methyl-6-hydroxy-2,5,7,8-tetramethychroman-2-carboxylate in THF (50 ml), is added to a suspension of lithium aluminum hydride (1.58 g) in THF (50 ml) at 0° dropwise over 15-20 min. The mixture is stirred at 0° for 30 min then at 20°-25° for 18 hr. The mixture is cooled to 0° and quenched by dropwise addition of ethyl acetate (10 ml), water (1.6 ml), aqueous sodium hydroxide (15%, 1.6 ml) and then water (4.8 ml). The mixture is stirred at 0° for 30 min then filtered. The solids are washed with THF (25 ml, 2×). The combined washes and filtrate are concentrated at reduced pressure and the residue is dissolved in ethyl acetate (150 ml), washed with water (100 ml), dried over sodium sulfate and the solvent removed at reduced pressure to a solid. A mixture of the solid (3.0 g), pyridine (3 ml) and chloroform (15 ml) is cooled to 0°. To this mixture is added p-toluenesulfonyl chloride (3.6 g ) in several small portions. The mixture is allowed to stand at 15° for 3 days then chloroform (50 ml) is added. The mixture is washed with water (100 ml), aqueous hydrochloric acid (5%, 100 ml), dried over sodium sulfate and the solvent removed at reduced pressure to give a crude tosylate (5.0 g). The crude tosylate is heated at 120° with piperazine (21.5 g) for 5 hr. The mixture was allowed to cool and distributed between dichloromethane (150 ml) and water (100 ml). The phases are separated and the organic phase is washed with water (100 ml), dried over sodium sulfate and the solvent removed at reduced pressure to leave an oil. This material is flash chromatographed on silica gel (200 g) eluting with ammonia, methanol, ethyl acetate (0.5/4.5/95). The appropriate fractions are pooled and concentrated to give a residue. A mixture of the residue (0.3 g), chlorodipyridinylpyrimidine (J.A.C.S., 32, 1591 (1967), 0.27 g), potassium carbonate (0.14 g) and acetonitrile (15 ml) is heated at reflux for 2 days. The solvent is removed at reduced pressure, the residue was distributed between methylene chloride (30 ml) and water (30 ml). The phases are separated and the organic phase is dried over sodium sulfate and the solvent removed at reduced pressure to leave a solid. This material was flash chromatographed on silica gel (30 g) eluting with ammonia, methanol, ethyl acetate (1/9/90) to give a solid which upon crystallization from ethyl acetate give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4].[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4]
Reactant: [H][H]
Reactant: COC(=O)Cc1cc([N+](=O)[O-])ccc1C(=O)OC
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc(N)ccc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
Methyl 2-methoxycarbonylmethyl-4-nitrobenzoate (1.74 g, 6.87 mmol) was dissolved in a mixed solvent of ethyl acetate and methanol under nitrogen atmosphere, and then 10% palladium ddcarbon (30 w/w %) was added thereto. After replacing nitrogen gas with hydrogen gas, the reaction solution was stirred at room temperature overnight. The palladium catalyst was removed by Celite filtration, followed by washing with ethyl acetate. The filtrate and washing solution were combined together, and concentrated under reduced pressure to give the title compound (1.30 g, 84%).
Reaction SMILES: C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[F:13][C:14]1[NH:15][C:16]([NH2:23])=[C:17]2[C:21]([N:22]=1)=[N:20][CH:19]=[N:18]2.C(O[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)(=O)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(#N)C>[F:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)=[C:16]([NH2:23])[N:15]=1
Reactant: Nc1[nH]c(F)nc2ncnc1-2
Reactant: CC(=O)OC1CCCCO1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: Nc1nc(F)nc2c1ncn2C1CCCCO1
Temperature: 0 °C

Procedure:
N,O-bis(trimethylsilyl)acetamide (975 mL, 3.988 mol) was added to a stirred suspension of 2-fluoro-1H-purin-6-amine (200 g, 1.306 mmol) (available from, for example, AlliedSignal, US) in anhydrous acetonitrile (4 L) in a 10 L controlled lab reactor and the resulting mixture heated to reflux and maintained at that temperature for 2 hours. The circulator was then re-programmed and the reaction mixture cooled to 0° C. A solution of tetrahydropyranyl acetate (preparation described in Tetrahedron Letters 2006, 47(27), 4741) (282 g, 1.959 mol) in anhydrous acetonitrile (500 ml) was then added slowly via a dropping funnel followed by trimethylsilyl trifluoromethanesulfonate (283 mL, 1.567 mol) dropwise via a dropping funnel. No significant exotherm was observed. The circulator temperature was re-adjusted to 10° C. and stirring maintained for a further 1 hour. The mixture was then quenched by addition of 1M sodium carbonate (4 L). A solid precipitate was observed and the pH checked to be basic. Additional water was added to the suspension (1 L) and on standing the layers separated with the aqueous layer containing significant solid inorganics. The majority of the aqueous and inorganic solid was separated. The organic layer still contained significant solid and was cooled to 0° C. with stirring to encourage further precipitation. The solid was the collected by filtration and the pad was washed very well with water then dried in vacuo at 40° C. overnight to give the title compound as a cream coloured solid (152.8 g).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N+:47]([C:50]1[CH:55]=[CH:54][C:53]([NH:56][CH:57]2[CH2:62][CH2:61][CH:60]([O:63][CH2:64][C:65](O)=[O:66])[CH2:59][CH2:58]2)=[CH:52][C:51]=1[C:68]([F:71])([F:70])[F:69])([O-:49])=[O:48]>ClCCl>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([C:65](=[O:66])[CH2:64][O:63][CH:60]3[CH2:61][CH2:62][CH:57]([NH:56][C:53]4[CH:54]=[CH:55][C:50]([N+:47]([O-:49])=[O:48])=[C:51]([C:68]([F:70])([F:69])[F:71])[CH:52]=4)[CH2:58][CH2:59]3)[CH2:14][CH2:13]2)[CH:3]=1
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: Cc1cc(N2CCNCC2)nc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCN(C(=O)COC3CCC(Nc4ccc([N+](=O)[O-])c(C(F)(F)F)c4)CC3)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
To a solution of 4-methyl-2-(piperazin-1-yl)quinoline (100 mg, 0.44 mmol) in dichloromethane (20 ml) was added EDAC.HCl (126 mg, 0.66 mmol, 1.5 eq), HOBt (88.8 mg, 0.66 mmol, 1.5 eq), triethylamine (133 mg, 1.31 mmol, 3 eq) and 2-[(4-[4-nitro-3-(trifluoromethyl)phenyl]aminocyclohexyl)oxy]acetic acid (190 mg, 0.52 mmol, 1.2 eq). The resulting solution was stirred overnight at room temperature and then quenched by the addition of water (50 ml) and extracted with dichloromethane (3×30 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and then concentrated under vacuum to give a residue. The crude material was purified by Pre-TLC with 50% ethyl acetate in dichloromethane to afford 1-[4-(4-methylquinolin-2-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoro-methyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one as a yellow solid (117 mg, 47%); (ES, m/z) [M+H]+ 572.20; 1H NMR (300 MHz, CDCl3): δ 8.02 (d, J=9.0 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.74 (s, 1H), 7.54-7.62 (m, 1H), 7.32-7.38 (m, 1H), 6.87 (s, 2H), 6.63-6.67 (m, 1H), 4.48 (d, J=7.5 Hz, 1H), 4.28 (s, 2H), 3.75-3.85 (m, 7H), 3.39-3.52 (m, 2H), 2.65 (s, 3H), 2.16 (d, J=9.9 Hz, 1H), 1.46-1.53 (m, 2H), 1.25-1.36 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]([N:15]2[CH2:20][CH2:19][CH2:18][C@@H:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16]2)=O)[C@H:10]([NH2:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.C(O)(=O)C>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13][N:15]2[CH2:20][CH2:19][CH2:18][C@@H:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16]2)[C@H:10]([NH2:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)C1
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](CN2CCC[C@@H](Cc3ccc(F)cc3)C2)[C@H](N)C1
Reaction time: 20 h
Yield: 41.4 %

Procedure:
(3S,4R)-3-Amino-4-[(S)-3-(4-fluorobenzyl)-piperidine-1-carbonyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (75 mg, 185 μmol) was treated with borane-tetrahydrofuran complex in tetrahydrofuran (1.0 M; 7.4 mL, 7.4 mmol) and stirred for 20 h . The mixture was treated slowly with 20% acetic acid in methanol (10 mL), and the resulting mixture was stirred at room temperature for 1 h . The solvents were removed, and the residue was dissolved in water, made basic (pH 11) with 50% sodium hydroxide, and extracted with methylene chloride. The combined organic phases were dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (5% methanol/dichloromethane) to provide the product (30 mg, 40%). 1H NMR (300 mHz, CD3OD) δ7.20 (m, 2H), 6.98 (m, 2H), 3.18-2.42 (15H), 1.80-1.50 (4H), 1.41 (s, 9H); mass spec. (ES+) m/z 392.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8](CC=C)[C:7]=2[N:16]=1.C[N+]1([O-])CC[O:21]CC1.O1CCCC1.O.[CH3:31][C:32]([CH3:34])=[O:33]>C(Cl)(Cl)Cl.[Os](=O)(=O)(=O)=O>[OH:33][CH:32]([CH2:34][OH:21])[CH2:31][N:8]1[C:9](=[O:12])[CH:10]=[N:11][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:16][C:7]1=2
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCn1c(=O)cnc2ccc(OC)nc21
Agent: O=[Os](=O)(=O)=O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2ncc(=O)n(CC(O)CO)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
In a mixed solvent (25 ml) of tetrahydrofuran/water/acetone (2:1:2) was dissolved 6-methoxy-4-(2-propen-1-yl)pyrido[2,3-b]pyrazin-3(4H)-one (1.20 g, 5.54 mmol), to the solution N-methylmorpholineoxide (1.50 g, 11.08 mmol) was added under cooling on ice and subsequently a 4% aqueous solution of osmium tetroxide (0.70 ml, 0.11 mmol) was added thereto. The reaction solution was stirred for 24 hours while the temperature was raised to room temperature. The reaction solution was diluted with chloroform and washed with saturated sodium bicarbonate water and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to yield 1.34 g (96%) of the title compound in the form of a grayish brown solid.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([OH:5])=O.[CH3:14][O:15][C:16]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[C:17]=1[NH2:18].[Cl-].[NH4+]>S(Cl)(Cl)=O.N1C=CC=CC=1>[Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([NH:18][C:17]1[C:19]([O:25][CH3:26])=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=1[O:15][CH3:14])=[O:5]
Reactant: CCCCCCCCC(Br)C(=O)O
Reactant: COc1cc(OC)c(N)c(OC)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCC(Br)C(=O)Nc1c(OC)cc(OC)cc1OC
Reaction time: 1.5 h
Yield: 69.5 %

Procedure:
2-Bromodecanoic acid (1 g, 3.8 mmol) was heated under reflux in thionyl chloride (10 ml) for 1 hour. The thionyl chloride was evaporated and the residue was dissolved in dry ether (10 ml) and added dropwise to a solution of 2,4,6-trimethoxyaniline (0.7 g, 3.8 mmol) in pyridine (20 ml) at 0° C. and the mixture was stirred for 1.5 hours. The reaction mixture was poured into saturated aqueous ammonium chloride and extracted three times with ethyl acetate (60 ml). The combined organics were extracted with water and brine and dried and concentrated. Recrystallization from isopropyl ether afforded 1.1 g (65%) of the title compound, m.p. 109°-110° C. This material was used directly in the next step.
Reaction SMILES: CC(C)=O.[Cl:5][C:6]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1.C(N(CC)CC)C.Br[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:25](=[O:26])[O:24]1>O>[Cl:5][C:6]1[C:11]([C:12]([O:14][CH:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:25](=[O:26])[O:24]2)=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: O=C1OC(Br)c2ccccc21
Reactant: O=C(O)c1cccnc1Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1OC(OC(=O)c2cccnc2Cl)c2ccccc21
Yield: 66.8 %

Procedure:
To 600 ml of acetone, 31.5 g of 2-chloro-3-pyridinecarboxylic acid is added and suspended by stirring. Triethylamine (40 ml) is added and after 30 minutes 42.6 g of 3-bromophthalide is poured with stirring into the resulting reaction mixture. The mixture is refluxed for 4 hours and then poured into 2000 ml of water at 50° C. To obtain a precipitated compound, the reaction mixture is cooled with continuous stirring. The solid precipitate is collected by filtration, washed with cooled water and then dried under vacuum at a temperature of 40° C. A yield of 38.7 g (67% of theory) of phthalidyl 2-chloro-3-pyridinecarboxylate is obtained (m.p. 137°-8° C.).
Reaction SMILES: [CH2:1]([C:8]1[N:12]([CH:13]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:14]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[C:11]2[CH:29]=[C:30]([Cl:34])[C:31]([F:33])=[CH:32][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([CH:41]=[O:42])CCCCC1.[CH3:43][O:44]C1C=CC(C=O)=CC=1.ClC1C=C(CC(O)=O)C=CC=1.C1(C(OC)C(O)=O)CCCCC1>>[Cl:34][C:30]1[C:31]([F:33])=[CH:32][C:10]2[N:9]=[C:8]([CH:1]([CH:2]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)[O:44][CH3:43])[N:12]([CH:13]([C:23]3[CH:28]=[CH:27][C:26]([O:42][CH3:41])=[CH:25][CH:24]=3)[C:14]([NH:16][CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)=[O:15])[C:11]=2[CH:29]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=CC1CCCCC1
Reactant: O=C(NC1CCCCC1)C(C1CCCCC1)n1c(Cc2ccccc2)nc2cc(F)c(Cl)cc21
Agent: COC(C(=O)O)C1CCCCC1
Agent: O=C(O)Cc1cccc(Cl)c1
Product: COc1ccc(C(C(=O)NC2CCCCC2)n2c(C(OC)C3CCCCC3)nc3cc(F)c(Cl)cc32)cc1

Procedure:
The title compound was prepared in analogy to Example 1, replacing (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester with (2-amino-4-chloro-5-fluoro-phenyl)-carbamic acid tert-butyl ester (([CAS RN 579474-50-3]), Example 47), cyclohexanecarbaldehyde with anisaldehyde ([CAS RN 123-11-5]) and (3-chloro-phenyl)-acetic acid with DL-cyclohexyl-methoxy-acetic acid ([CAS RN 15540-18-8]). MS (ISP): 542.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:21])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=3F)=[CH:9][CH:10]=2)[NH:5][C:4](=[O:22])[CH2:3]1.Cl.Cl.[NH:26]1[C:30]2=[N:31][CH:32]=[CH:33][C:34]([CH2:35][NH2:36])=[C:29]2[CH2:28][CH2:27]1>>[NH:26]1[C:30]2=[N:31][CH:32]=[CH:33][C:34]([CH2:35][NH:36][C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13]([NH:12][C:8]3[CH:7]=[C:6]4[C:11]([C:2]([CH3:23])([CH3:1])[CH2:3][C:4](=[O:22])[NH:5]4)=[CH:10][CH:9]=3)=[O:21])=[C:29]2[CH2:28][CH2:27]1
Reactant: CC1(C)CC(=O)Nc2cc(NC(=O)c3cccnc3F)ccc21
Reactant: NCc1ccnc2c1CCN2
Agent: Cl
Product: CC1(C)CC(=O)Nc2cc(NC(=O)c3cccnc3NCc3ccnc4c3CCN4)ccc21

Procedure:
The titled compound was prepared from N-(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-2-fluoro-nicotinamide and C-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine dihydrochloride by the method described in Step A of Example 1. MS (ES+): 437 (M+H). Calc'd. for C25H26N6O2—442.52.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[CH2:14]([N:16]([CH2:25][CH3:26])[C:17](=[O:24])[CH:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)[CH3:15]>N1C=CC=CC=1>[CH2:25]([N:16]([CH2:14][CH3:15])[C:17]([CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:19]1)=[O:24])[CH3:26]
Reactant: CCN(CC)C(=O)C1CCCNC1
Reactant: N#Cc1ccc(F)c2ccccc12
Solvent: c1ccncc1
Product: CCN(CC)C(=O)C1CCCN(c2ccc(C#N)c3ccccc23)C1

Procedure:
A solution of 1-cyano-4-fluoronaphthalene in pyridine (0.6 M, 1 mL) was transferred to a Pyrex tube and N,N-diethylnipecotamide (447 mg, 2.4 mmol) was added. The tube was capped and the reaction tube was exposed to microwave irradiation (220° C., 10 min). The reaction mixture was concentrated and purified according to Purification Method A.