Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([CH2:8][C:9]1[O:13][C:12]([C:14]([O:16]CC)=O)=[CH:11][CH:10]=1)[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH2:19]([NH2:22])[CH2:20][NH2:21]>>[CH:5]([N:4]([CH2:8][C:9]1[O:13][C:12]([C:14]([NH:21][CH2:20][CH2:19][NH2:22])=[O:16])=[CH:11][CH:10]=1)[CH:1]([CH3:2])[CH3:3])([CH3:6])[CH3:7]
Reactant: NCCN
Reactant: CCOC(=O)c1ccc(CN(C(C)C)C(C)C)o1
Product: CC(C)N(Cc1ccc(C(=O)NCCN)o1)C(C)C

Procedure:
Using Compound f and anhydrous ethylenediamine, the corresponding procedure of Example 1 was followed to give 5-(diisopropylaminomethyl)-N-(2-aminoethyl)-2-furancarboxamide as tan-colored oil. Reduction of this compound in the same manner as Example 1 without prior purification gave 5-(diisopropylaminomethyl)-N-(2-aminoethyl)furfurylamine (Compound g) as light yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][CH:11]3[C:15]([CH3:17])([CH3:16])[CH2:14][N:13]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12]3)=[C:8]([C:22]([NH2:24])=[O:23])[CH:7]=[N:6][N:5]2[CH:25]=1.[CH3:26][N:27]1[C:31]([CH3:32])=[C:30](B(O)O)[CH:29]=[N:28]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:16][C:15]1([CH3:17])[CH2:14][N:13]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12][CH:11]1[NH:10][C:9]1[C:4]2[N:5]([CH:25]=[C:2]([C:30]3[CH:29]=[N:28][N:27]([CH3:26])[C:31]=3[CH3:32])[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:22]([NH2:24])=[O:23]
Reactant: CC1(C)CN(S(C)(=O)=O)CC1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: Cc1c(B(O)O)cnn1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: Cc1c(-c2cc3c(NC4CN(S(C)(=O)=O)CC4(C)C)c(C(N)=O)cnn3c2)cnn1C
Temperature: 90 °C
Reaction time: 0.42 h
Yield: 35.1 %

Procedure:
A solution of (+/−)-6-bromo-4-((4,4-dimethyl-1-(methylsulfonyl)pyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (10 mg, 0.023 mmol) in 1,4-dioxane (0.5 mL), was added (1,5-dimethyl-1H-pyrazol-4-yl)boronic acid (3.25 mg, 0.023 mmol), palladium (II) acetate (0.52 mg, 2.32 μmol), X-Phos (2.22 mg, 4.7 μmol), potassium phosphate (0.04 mL, 0.08 mmol. The reaction vial was purged with nitrogen, sealed and heated at 90° C. overnight. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 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: 25-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (3.6 mg, 35% yield). 1H NMR (500 MHz, METHANOL-d4) δ 8.12 (s, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.63-7.56 (m, 3H), 6.84 (d, J=1.5 Hz, 1H), 4.50 (t, J=5.0 Hz, 1H), 4.32 (br. s., 1H), 3.97 (dd, J=10.9, 5.9 Hz, 1H), 3.83 (s, 3H), 3.44 (dd, J=10.9, 4.5 Hz, 1H), 3.39-3.33 (m, 2H), 2.97-2.80 (m, 3H), 2.43 (s, 3H), 1.27 (d, J=5.4 Hz, 6H). MS (ES+) m/z: 446.2 (M+H); LC retention time: 1.25 min (analytical HPLC Method I).
Reaction SMILES: [C:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[NH:19][C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:21])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[N+:27]([O-])([OH:29])=[O:28]>C(O)(=O)C>[C:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([N+:27]([O-:29])=[O:28])=[CH:11][C:10]=1[NH:19][C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:21])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(=O)Nc1ccc2ccccc2c1NC(=O)C(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)Nc1cc([N+](=O)[O-])c2ccccc2c1NC(=O)C(=O)OCC
Temperature: 25 °C

Procedure:
A solution of 1,2-diethoxalylaminonaphthalene (10.8 g, 0.03 mol) in 150 ml of acetic acid was treated dropwise with nitric acid (1.24 ml, 0.03 mol, d 1.52) and stirred over night at room temperature. Then an additional amount of nitric acid (2.0 ml, d 1.52) was added dropwise and the mixture was stirred for 17 h at room temperature. The mixture was poured into 200 ml of ice/water and the resulting precipitate was isolated by filtration and washed with water, a small amount of cold ethanol and ether affording 3.3 g (27%) of pure product, m.p. 183.0-184.0° C.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Br:6])[CH:8]=1)(=[O:16])[CH3:15]
Reactant: Oc1cccc(Br)c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
Concentrated sulphuric acid (2 ml) was added to a stirred mixture of 3-bromophenol (67 g) and acetic anhydride (20 ml). The mixture was stirred at ambient temperature for 4 hours and evaporated. Ice was added and the mixture was extracted with diethyl ether. The organic phase was dried (MgSO4) and evaporated to give 3-bromophenyl acetate (75.4 g, 90%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:27]1[CH:32]=[CH:31][C:30]([C:33]([C:35]2[N:36]=[CH:37][N:38]3[CH:42]=[C:41]([Sn](CCCC)(CCCC)CCCC)[S:40][C:39]=23)=[O:34])=[CH:29][CH:28]=1>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[C:8]([C:41]3[S:40][C:39]4=[C:35]([C:33]([C:30]5[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=5)=[O:34])[N:36]=[CH:37][N:38]4[CH:42]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3ccncc3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5ccncc5)c4s3)[C@H](C)[C@H]12
Yield: 58.4 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-4-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (1.23 g) was prepared in the same manner as in step a) of Example 1, except that 1.33 g of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 2.00 g of 7-(pyridin-4-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH:18]1([C:21]([CH3:29])([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[NH2:22])[CH2:20][CH2:19]1>>[CH:18]1([C:21]([NH:22][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH3:29])[CH2:20][CH2:19]1
Reactant: Cc1nc(C(C)(N)C2CC2)no1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: Cc1nc(C(C)(NC(=O)c2ccc(C3CC3)c(OCC3CC3)n2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α-cyclopropyl-α,5-dimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1155536-64-3) as starting materials. The product was isolated by chiral chromatography on Lux 5u Amylose-2 using heptane/15% 2-propanol as eluent. The (+)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 383.2090 (M+H)+, αD20 (MeOH)=+49.30
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:34]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH:34]1([NH:39][C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: NC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(NC4CCCC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and cyclopentylamine. ES-MS m/e (%): 454 (M+H+, 100).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:9][C@@H:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.C(OC([N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1)=O)(C)(C)C>>[Cl:20][C:13]1[C:14]([F:19])=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C@H:10]([O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:31]2[CH:32]=[N:28][NH:29][CH:30]=2)[N:3]=1)[CH3:11]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@@H](Oc1nc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Product: C[C@@H](Oc1nc(-c2cn[nH]c2)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared according to procedure 3 using 5-bromo-3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylamine and 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester. 1H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 7.79 (s, 1H), 7.48 (m, 1H), 7.36 (t, 1H), 6.48 (q, 1H), 6.12 (s, 2H), 1.75 (d, 3H); LCMS: 368 [M+1]; c-Met Ki: 0.065 μM.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:13]([Cl:21])=[CH:12][CH:11]=1)=[O:7])(C)(C)C.Cl.[C:23](Cl)(=O)[C:24](C)([CH3:26])[CH3:25]>CCOC(C)=O>[Cl:21][C:13]1[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:15][C:10]([CH2:9][NH:8][C:6](=[O:7])[C:24]([CH3:26])([CH3:25])[CH3:23])=[CH:11][CH:12]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)c1nc(CNC(=O)OC(C)(C)C)ccc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(CNC(=O)C(C)(C)C)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
A solution of ethyl 6-(((tert-butoxycarbonyl)amino)methyl)-3-chloropicolinate (100 mg, 0.318 mmol) in EtOAc saturated with HCl (1 mL) was stirred at rt for 1 h. The reaction mixture was concentrated and the concentrate was dissolved in CH2Cl2 (2 mL). The solution was treated with DIPEA (0.5 mL) followed by pivaloyl chloride (38 mg, 0.318 mmol) at 0° C. The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with EtOAc and was washed with H2O and brine. The organic layer was separated, dried, filtered and concentrated to afford 85 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.26 (br t, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 4.40-4.31 (m, 4H), 1.33-1.10 (m, 12H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[S:25][CH:26]=[C:27]([C:29]#[N:30])[N:28]=1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:37]>C(OCC)(=O)C>[ClH:37].[NH2:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[S:25][CH:26]=[C:27]([C:29]#[N:30])[N:28]=1)=[CH:14][CH:13]=2
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C#N)cs3)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC(C)C)c(=O)c2ccc(-c3nc(C#N)cs3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
Tert-butyl[4-butoxy-6-(4-cyano-1,3-thiazol-2-yl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.20 g, 0.4 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give 2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carbonitrile hydrochloride (0.17 g, 94.4%) as crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[N:17][N:18]([CH:20]4[CH2:26][CH2:25][C:24]5[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=5[N:22]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:21]4=[O:36])[CH:19]=3)=[CH:11][C:10]=2[O:37][CH3:38])[CH:6]=[CH:5][N:4]=1)[CH3:2].[CH:39]([Mg]Br)(C)C.ClC1C=C(C2C=CC(C3N=NN(C4CCC5C=CC=CC=5N(CC(F)(F)F)C4=O)C=3)=CC=2OC)C=CN=1>>[CH:1]([C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[N:17][N:18]([CH:20]4[CH2:26][CH2:25][C:24]5[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=5[N:22]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:21]4=[O:36])[CH:19]=3)=[CH:11][C:10]=2[O:37][CH3:38])[CH:6]=[CH:5][N:4]=1)([CH3:39])[CH3:2]
Reactant: CCc1cc(-c2ccc(-c3cn(C4CCc5ccccc5N(CC(F)(F)F)C4=O)nn3)cc2OC)ccn1
Reactant: CC(C)[Mg]Br
Agent: COc1cc(-c2cn(C3CCc4ccccc4N(CC(F)(F)F)C3=O)nn2)ccc1-c1ccnc(Cl)c1
Product: COc1cc(-c2cn(C3CCc4ccccc4N(CC(F)(F)F)C3=O)nn2)ccc1-c1ccnc(C(C)C)c1

Procedure:
3-{4-[4-(2-Isopropylpyridin-4-yl)-3-methoxyphenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one was prepared by using the same procedure described for 3-{4-[4-(2-ethylpyridin-4-yl)-3-methoxyphenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one with isopropyl magnesium bromide (1M in THF, 189 μl, 0.189 mmol), and 3-{4-[4-(2-chloropyridin-4-yl)-3-methoxyphenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (50 mg, 0.095 mmol).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][CH2:10][N:11]2[C:19]([O:20][CH3:21])=[N:18][C:17]3[C:12]2=[N:13][C:14]([O:23][C@@H:24]([CH3:28])[CH2:25][CH2:26][CH3:27])=[N:15][C:16]=3[NH2:22])[CH2:4]1)[CH3:2].[CH3:29][C@H](OC1N=C2C(N=C(OC)N2CCCC2CCNCC2)=C(N)N=1)CCC.ICC>>[CH2:4]([N:3]1[CH2:1][CH2:2][CH:6]([CH2:5][CH2:9][CH2:10][N:11]2[C:19]([O:20][CH3:21])=[N:18][C:17]3[C:12]2=[N:13][C:14]([O:23][C@@H:24]([CH3:28])[CH2:25][CH2:26][CH3:27])=[N:15][C:16]=3[NH2:22])[CH2:7][CH2:8]1)[CH3:29]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCNCC3)c2n1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1
Solvent: CCI
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCN(CC)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 46 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-[3-(4-piperidinyl)propyl]-9H-purin-6-amine and 2-iodoethane.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:9][C:10]1[N:15]=[C:14]([CH2:16]Cl)[CH:13]=[CH:12][CH:11]=1.[O-]CC.[Na+]>>[CH3:16][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:9][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:15]=1
Reactant: Cc1cccc(CCl)n1
Reactant: Sc1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1cccc(CSc2ccccc2)n1

Procedure:
Following the method of Example 1 thiophenol is reacted with 6-methyl-2-picolyl chloride hydrochloride in the presence of sodium ethoxide to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22](I)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].N1CCCC1=O.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+]>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].O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[C:28]([C:36]([F:37])([F:38])[F:39])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(I)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2nccc(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 100 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-iodopyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (350 mg) is dissolved in 1,4-dioxane (1 ml), then thereto are added pyrrolidin-2-one (100 mg), tris(dibenzylideneacetone)-dipalladium (23 mg), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (21 mg) and cesium carbonate (241 mg) and the mixture is stirred at 100° C. under nitrogen flow overnight. After allowing to cool to room temperature, water is added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, then thereto is added a small amount of NH-silica gel, the mixture is filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=4:1) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(pyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (105 mg). MS (m/z): 584 [M+H]+
Reaction SMILES: [C:1]([NH:9][NH2:10])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[OH-].[Na+].S(O)(O)(=O)=O.CS[C:20](=[NH:22])[NH2:21]>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]2[N:21]=[C:20]([NH2:22])[NH:10][N:9]=2)[CH:3]=1
Reactant: CSC(=N)N
Reactant: NNC(=O)c1cccnc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(-c2cccnc2)n[nH]1
Temperature: 230 °C
Yield: 78.3 %

Procedure:
Nicotinic acid hydrazide (10.0 g, 72.92 mmol) was dissolved in aq. NaOH (4.38 g, 109.38 mmol), and 2-methyl-2-thiopseudourea sulfate (12.16 g, 87.50 mmol) was slowly added thereto. The resultant mixture was stirred at room temperature. The reaction mixture was filtered, washed with water and Et2O, and dried. The solid obtained was heated to 230° C. to obtain the desired compound, 5-(pyridin-3-yl)-2H-[1,2,4]triazol-3-amine (9.2 g, 78%).
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=O)[C:4]=1[CH3:12])=[O:2].[NH2:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[N:16]1([CH2:15][CH2:14][NH:13][C:9]([C:5]2[C:4]([CH3:12])=[C:3]([CH:1]=[O:2])[NH:7][C:6]=2[CH3:8])=[O:11])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NCCN1CCCC1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Product: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Yield: 73 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (0.5 g, 2.99 mmol) was reacted with 1-(2-aminoethyl)pyrrolidine (0.42 mL) to give 0.57 g (73% yield) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide using General Amidation Procedure 1. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 11.79 (br s, 1H, NH), 9.53 (s, 1H, CHO), 7.41 (m, 1H, NH), 3.28–3.34 (m, 2H, CH2), 2.53–2.60 (m, 6H, CH2 and 2×CH2), 2.35 (s, 3H, CH3), 2.3 (s, 3H, CH3), 1.68 (m, 4H, 2×CH2). MS m/z 264 [M+1].
Reaction SMILES: Cl[CH:2]([C:8]([CH3:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:11]([NH2:15])(=[S:14])[CH2:12][CH3:13].O>C(O)C>[CH2:12]([C:11]1[S:14][C:8]([CH3:10])=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:15]=1)[CH3:13]
Reactant: CCC(N)=S
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1nc(CC)sc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.33 ml ethyl 2-chloroacetoacetate and 1.5 g thiopropionamide were dissolved in 30 ml ethanol, followed by stirring at room temperature for 16 hours. The reaction solution was ice-cooled and water was added thereto, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=14:1), to give 0.8 g of ethyl 2-ethyl-5-methyl-1,3-thiazole-4-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](OS(C(F)(F)F)(=O)=O)=[C:8]([O:20][CH3:21])[CH:7]=1)[CH3:2].[CH3:23][N:24](C)C=O>O.C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:23]#[N:24])=[C:8]([O:20][CH3:21])[CH:7]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(C#N)c(OC)c1
Temperature: 80 °C

Procedure:
The crude ethyl(3-methoxy-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)acetate (16.61 g) was subsequently dissolved in anhydrous dimethylformamide (100 mL). Zinc cyanide (3.42 g, 29.1 mmol) was added, and the solution was purged thoroughly with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (5.61 g, 4.85 mmol) was then added and the reaction mixture was heated to 80° C. for 4 h. After allowing the reaction mixture to cool to ambient temperature and diluting with water (200 mL), ethyl acetate (400 mL) was added. The combined layers were filtered to remove any solids, the filtrate transferred to a separatory funnel, and the layers separated. The aqueous layer was re-extracted with ethyl acetate (2×100 mL), the organic portions were combined and dried over magnesium sulfate. The dry organics were then filtered and evaporated to dryness under reduced pressure and excess dimethylformamide was removed by evaporation in vacuo at 65° C. for 1.5 h to yield the crude title compound (20 g). The crude product was purified through silica gel chromatography (ethyl acetate/hexanes, 2:3) to yield ethyl(4-cyano-3-methoxyphenyl)acetate. NMR (500 MHz, DMSO-d6), δ 7.67 (d, J=8.0 Hz, 1H), 7.18 (s, 1H), 7.0 (d, J=8.0 Hz, 1H), 4.10 (q, J=7.1 Hz, 2H), 3.89 (s, 3H), 3.78 (s, 2H), 1.19 (t, J=7.1 Hz, 3H); LC/MS (M+1)+=220.17; tR=1.36 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:25]2[CH:29]([CH3:30])[C:28](=[O:31])[NH:27][C:26]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=2)[CH2:12][CH2:11]1)=[O:9].[CH3:33]I>>[F:1][C:2]1[CH:3]=[C:4]([N:25]2[CH:29]([CH3:30])[C:28](=[O:31])[N:27]([CH3:33])[C:26]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: CI
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4C)cc3F)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4C)cc3F)CC2)nc1C

Procedure:
Using 1-{3-fluoro-4-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-5-methylimidazolidine-2,4-dione (50 mg) described in Example 552 and methyl iodide (7.8 μL) and by the reaction and treatment in the same manner as in Example 551, the title compound (27 mg) was obtained.
Reaction SMILES: C1(COC(=O)[NH:10][CH2:11][C@@H:12]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[N:27]=4)[N:22]=[CH:21][C:20]=3[Cl:31])[CH2:13]2)C=CC=CC=1.[OH-].[K+].O>CO>[Cl:31][C:20]1[CH:21]=[N:22][C:23]2[C:28]([C:19]=1[CH2:18][CH2:17][N:14]1[CH2:15][CH2:16][C@@H:12]([CH2:11][NH2:10])[CH2:13]1)=[N:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2
Reactant: COc1ccc2ncc(Cl)c(CCN3CC[C@@H](CNC(=O)OCc4ccccc4)C3)c2n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2ncc(Cl)c(CCN3CC[C@@H](CN)C3)c2n1
Temperature: 100 °C
Yield: 51 %

Procedure:
A solution of phenylmethyl[((3S)-1-{2-[3-chloro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]carbamate (1.0 g, 2.2 mmol) in MeOH (30 mL) was treated with 40% KOH (15 mL, 107 mmol) and heated at 100° C. for 3 h. The MeOH was stripped off at reduced pressure and the residue was treated with water. The product was extracted into CHCl3 and the combined organic phases were dried (K2CO3) and filtered. Purification of silica gel provided the product as a light brown oil (0.36 g, 51%): LC/MS (ES) m/e 321 (M+H)+.