Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=[CH2:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:33][C:34]1[C:42]2[C:41]([CH2:43]O)=[CH:40][S:39][C:38]=2[CH:37]=[CH:36][CH:35]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:43][C:41]2[C:42]3[C:34]([CH3:33])=[CH:35][CH:36]=[CH:37][C:38]=3[S:39][CH:40]=2)[C:5]1=[O:13])([CH3:3])=[CH2:2]
Reactant: Cc1cccc2scc(CO)c12
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(C)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Temperature: 0 °C
Reaction time: 5 h
Yield: 67.3 %

Procedure:
To a solution of 1-isopropenylbenzimidazolone (500 mg, 2.8 mmol) in dry THF (40 mL) are added triphenylphosphine (902 mg, 3.4 mmol) and (4-Methyl-benzo[b]thiophen-3-yl)-methanol (563 mg, 3.2 mmol). Then diisopropyl azodicarboxylate (0.70 mL, 3.4 mmol) is added drop wise into the above solution after it is cooled down to 0° C. The mixture is then stirred at room temperature for 5 hr and then the solvent is removed under vacuum and the residue is purified by flash column chromatography using gradient EtOAc/Hexane from 0% to 20% to give 630 mg (66%) of 1-isopropenyl-3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([C:11]([O:13]C)=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[ClH:15]>>[ClH:15].[NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COC(=O)c1ccc2nc(N)[nH]c2c1
Agent: Cl
Product: Nc1nc2ccc(C(=O)O)cc2[nH]1

Procedure:
320 mg of methyl 2-aminobenzimidazole-5-carboxylate was stirred in 3 M of hydrochloric acid at 65° C. overnight, and the solvent was evaporated to obtain the title compound.
Reaction SMILES: N1C=CC(N)=NC=1N.[Li+].[OH-].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[C:27]([F:28])=[CH:26][N:25]=[C:24]([NH:29][C:30]3[CH:31]=[CH:32][C:33]4[O:37][C:36]([C:38]([O:40]C)=[O:39])=[CH:35][C:34]=4[CH:42]=3)[N:23]=2)=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[C:27]([F:28])=[CH:26][N:25]=[C:24]([NH:29][C:30]3[CH:31]=[CH:32][C:33]4[O:37][C:36]([C:38]([OH:40])=[O:39])=[CH:35][C:34]=4[CH:42]=3)[N:23]=2)=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc(C(C)(C)C)cc4)n3)ccc2o1
Agent: Nc1ccnc(N)n1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)c1ccc(Nc2nc(Nc3ccc4oc(C(=O)O)cc4c3)ncc2F)cc1

Procedure:
In a manner similar to the preparation of N4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine, LiOH treatment with N4-(4-tert-butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine gave N4-(4-tert-butylphenyl)-N2-(2-carboxybenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 9.3 (bd, 2H), 8.25 (s, 1H), 8.10 (s, 1H), 7.65–7.30 (m, 5H), 1.25 (s, 9H); 19F NMR (CD3OD): −21844; LCMS: ret. time: 23.32 min.; purity: 100%; MS (m/e): 421 (MH+).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([F:42])[CH:36]=1)[CH2:18][N:19]([CH:32]([CH3:34])[CH3:33])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH:32]([CH3:33])[CH3:34])=[CH:36][C:37]=1[F:42]
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CC(C)N(C[C@@H](N)c1ccc(Cl)c(F)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CC(C)NC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(Cl)c(F)c1

Procedure:
Compound 54 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(4-chloro-3-fluoro-phenyl)-ethyl]-N-isopropyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [404 (M+H)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]([CH2:17][C@H:18]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]1)[CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.FC(F)(F)C(O)=O.[C:37]([OH:46])(=[O:45])[C@@H:38]([C@H:40]([C:42]([OH:44])=[O:43])[OH:41])[OH:39]>ClCCl.C(O)(C)C>[C:42]([C@@H:40]([C@H:38]([C:37]([OH:46])=[O:45])[OH:39])[OH:41])([OH:44])=[O:43].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]([CH2:17][C@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)[CH:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN(Cc2ccc(Cl)cc2Cl)C2CCOCC2)C1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(C)O
Product: Clc1ccc(CN(C[C@H]2CCNC2)C2CCOCC2)c(Cl)c1

Procedure:
A solution of (3R)-N-{[2,4-dichlorophenyl]methyl}-N-(tetrahydro-2H-pyran-4-yl)-1-tert-butyloxycarbonylpyrrolidine-3-yl-methylamine (0.36 g, 0.81 mmol) in dichloromethane (10 ml) is stirred at room temperature with trifluoroacetic acid (0.93 g, 8.10 mmol) overnight. The reaction mixture is concentrated in vacuo and the oil is dissolved in methanol, purified using a SCX-2 column (10 g), then washed with methanol. The basic product elutes with methanolic ammonia (2M). Evaporation to an oil and further purification by preparative LC-MS gives a colourless oil. Dissolve the oil in isopropyl alcohol and add L-tartaric acid (1 eq) then heat to give a clear solution. Crystallise by cooling to give the title compound as a colourless solid. 1H NMR (300 MHz, DMSO) δH: 7.57-7.56 (2H, m), 7.44-7.40 (1H, m), 3.88-3.85 (4H, m), 3.70 (2H, s), 3.24-3.03 (5H, m), 2.77-2.70 (1H, m), 2.59-2.51 (2H, m), 2.44-2.31 (1H, m), 1.94-1.88 (1H, m), 1.66-1.48 (6H, m), LCMS: Rt=4.22 (12 min method) [M+H]=343/5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH2:21][NH:22][C@H:23]([C:35]2[NH:36][CH:37]=[C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:39]=2)[CH2:24][C:25](OCC2C=CC=CC=2)=[O:26])=[CH:13]1>C1COCC1>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH2:21][N:22]2[C@H:23]([C:35]3[NH:36][CH:37]=[C:38]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[N:39]=3)[CH2:24][C:25](=[O:26])[N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:10]2=[O:11])=[CH:13]1
Reactant: COc1ccc(N=C=O)cc1
Reactant: O=C(C[C@H](NCc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1)OCc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(N2C(=O)C[C@@H](c3nc(-c4ccccc4)c[nH]3)N(Cc3c[nH]c4ccccc34)C2=O)cc1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
4-methoxyphenylisocyanate (40 μl, 1.2 eq.) is added to a solution of benzyl (3S)-3-[(1H-indol-3-ylmethyl)amino]-3-(4-phenyl-1H-imidazol-2-yl)propanoate (100 mg, 1 eq.) in THF (2 ml). The mixture is stirred for 5 hours at a temperature of approximately 20° C. then diluted with 2 ml of THF. An aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 138 mg, 2 eq.) is added. The mixture is stirred for 3 hours at a temperature of approximately 20° C. then filtered on frit. The filtrate is concentrated under reduced pressure at 40° C. 2 ml of THF and 2 ml of triethylamine are added to the residue. The mixture is taken to reflux for 24 hours then concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: ethyl acetate/heptane 8:2) yields the expected compound (80 mg, yield 74
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[CH2:11])[CH2:9][OH:10])[CH:5]=[N:6][CH:7]=1.[OH-:12].[Na+].OO>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:11][OH:12])[CH2:9][OH:10])[CH:5]=[N:6][CH:7]=1
Reactant: C=C(CO)c1cncc(Br)c1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCC(CO)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.7 %

Procedure:
To a stirred solution of 2-(5-bromopyridin-3-yl)prop-2-en-1-ol (0.600 g, 2.79 mmol) in tetrahydrofuran (5 mL) at 0° C. under nitrogen was added borane-methyl sulfide complex (0.85 g, 11 mmol). The reaction mixture was heated to 25° C. and stirred for 5 h. The reaction mixture was cooled to 0° C. and 1.0 N sodium hydroxide (0.8 mL) was added drop wise followed by the addition of hydrogen peroxide (1.0 mL, 35 wt % solution in water). The reaction mixture was stirred at 0° C. for 2 h then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The organic portions were combined, washed with water, aqueous sodium sulfite and brine, dried with Na2SO4, filtered, and concentrated under reduced pressure. 2-(5-Bromopyridin-3-yl)propane-1,3-diol (0.29 g, 44.7%) was isolated by silica gel column chromatography using 50% EtOAc in hexanes as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.53 (d, 1H, J=2 Hz), 8.43 (d, 1H, J=4.8 Hz), 4.92 (s, 1H), 4.69 (t, 1H, J=4.4 Hz), 3.71-3.64 (m, 2H), 3.62-3.58 (m, 2H), 2.87 (t, J=6.4 Hz). LCMS Method W: retention time 0.80 min; [M+1]=232.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:32])=[N:5]1)([CH3:3])[CH3:2].Br[C:34]1[N:35]=[CH:36][N:37]([CH2:39][C:40]([CH3:43])([OH:42])[CH3:41])[CH:38]=1>>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([C:34]5[N:35]=[CH:36][N:37]([CH2:39][C:40]([CH3:43])([OH:42])[CH3:41])[CH:38]=5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:32])=[N:5]1)([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(B4OC(C)(C)C(C)(C)O4)cc2OCC3)n(C(C)C)n1
Reactant: CC(C)(O)Cn1cnc(Br)c1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cn(CC(C)(C)O)cn4)cc2OCC3)n(C(C)C)n1

Procedure:
2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene was reacted with 1-(4-Bromo-imidazol-1-yl)-2-methyl-propan-2-ol to give 252. MS(ESI+) 448.3
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[C:11]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)(=O)[CH3:12].CC([O-])(C)C.[K+]>C1COCC1>[Cl:10][C:6]1[CH:7]=[CH:8][N:9]=[C:2]2[C:3]=1[CH:4]=[CH:12][C:11]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)=[N:1]2
Reactant: Nc1nccc(Cl)c1C=O
Reactant: CC(=O)c1ncccc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cccnc1-c1ccc2c(Cl)ccnc2n1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
Dissolve 2-amino-4-chloronicotinaldehyde (156 mg, 1.0 mmol) and 2-acetyl-3-methylpyridine (136 mg, 1.0 mmol) in anhydrous THF (5.0 mL) and cool it to −20° C. under N2 atmosphere. Add in portion t-BuOK (224 mg, 2.0 mmol) to the reaction mixture and stir the mixture at 110° C. for 2 hours. Concentrate the reaction mixture under vacuum, dilute the residue with water (10 mL), filter the solid, wash the solid with water and dry under high vacuum to afford the title product as a yellow colored solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([NH:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:15])=[CH:13][C:8]=2[N:7]=[C:6]1[C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1.[H][H]>CO.Cl.[Pd]>[NH2:30][CH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:6]2[N:5]([CH2:4][CH2:3][CH2:2][NH2:1])[C:9]3[CH:10]=[CH:11][C:12]([C:14]([NH:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:15])=[CH:13][C:8]=3[N:7]=2)=[CH:28][CH:27]=1
Reactant: [H][H]
Reactant: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C#N)cc1)n2CCCN
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(CN)cc1)n2CCCN

Procedure:
3 g of 1-(3-amino-propyl)-2-(4-cyano-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl]-benzimidazole are treated in a mixture of 50 ml of methanol and 10 ml of methanolic hydrochloric acid with 5 bars of hydrogen in the presence of 1 g of 10% palladium/charcoal for 20 hours at ambient temperature. After the catalyst has been filtered off the mixture is evaporated to dryness in vacuo and the residue is purified by chromatography on silica gel (eluant:methanol/2N ammonia=5:1.5 to 5:2). Yield: 1.5 g (55% of theory), Rf value: 0.24 (silica gel; methanol/2N ammonia=5:1.5 after developing twice)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[F:33][C:34]1[CH:35]=[N:36][C:37]([C:40]2([NH2:43])[CH2:42][CH2:41]2)=[N:38][CH:39]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:43][C:40]5([C:37]6[N:38]=[CH:39][C:34]([F:33])=[CH:35][N:36]=6)[CH2:42][CH2:41]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: NC1(c2ncc(F)cn2)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(F)cn5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.04 g, 0.092 mmol, 1 eq), 1-(5-fluoropyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.062 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.028 g, 0.3 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.03 g (57%). 1H NMR (400 MHz, CD3OD): δ 8.59 (s, 2H), 8.04-7.93 (m, 2H), 7.90 (s, 1H), 7.65 (s, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.34 (dd, J=1.8, 8.5 Hz, 1H), 7.31-7.25 (m, 2H), 7.15 (s, 1H), 4.07 (s, 3H), 3.00-2.92 (m, 3H), 2.37 (s, 3H), 1.80-1.72 (m, 2H), 1.54-1.43 (m, 2H). 19F NMR (376.47 MHz, CD3OD): δ −113.44, 146.33 LCMS: (ES+) m/z=569.2 (M+H)+
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[N+:6]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1O)=[N:16][CH:15]=[CH:14][CH:13]=2)([O-:8])=[O:7].CC(C)=O.[CH2:24]([NH2:28])[CH:25]([CH3:27])[CH3:26]>CN(C)C=O>[CH3:26][CH:25]([CH3:27])[CH2:24][NH:28][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[N:11]=[CH:10][C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1O
Reactant: CC(C)CN
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CNc1c([N+](=O)[O-])cnc2cccnc12
Temperature: 25 °C

Procedure:
Phosphorous oxychloride (0.6 mL, 6.44 mmol) was reacted with N,N-dimethylformamide then added to a solution of 3-nitro[1,5]naphthyridin-4-ol (1.0 g, 5.23 mmol) in N,N-dimethylformamide (20 mL). The reaction mixture was warmed using a jacketed flask with refluxing acetone as a heat source. After 3 hours the reaction mixture was poured into ice water, isobutylamine (2.0 mL, 20.1 mmol) was added and the mixture was heated on a steam bath. After several hours the reaction mixture was cooled to ambient temperature, filtered and washed with water. The aqueous layer was extracted with dichloromethane. The dichloromethane extract was washed with aqueous sodium bicarbonate, washed with water, dried over magnesium filtrate then loaded onto a layer of silica gel. The silica gel was eluted initially with dichloromethane to remove an impurity then with 5% methanol in dichloromethane to recover the product. The eluant was concentrated to dryness to provide N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine as a solid, m.p. 97-99° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:8][C:9]([C:13]#[N:14])=[N:10]2)=[CH:5][CH:4]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[OH-:28].[Na+].O>C(#N)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:7]2[C:6]3[C:11](=[CH:12][C:3]([CH2:2][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:4][CH:5]=3)[N:10]=[C:9]([C:13]([NH2:14])=[O:28])[CH:8]=2)=[CH:16][CH:17]=1
Reactant: N#Cc1cc(-c2ccc(F)cc2)c2ccc(CBr)cc2n1
Reactant: C1COCCN1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(CN3CCOCC3)cc2n1
Temperature: 50 °C
Reaction time: 96 h
Yield: 89 %

Procedure:
To a room temperature solution of 7-(bromomethyl)-4-(4-fluorophenyl)quinoline-2-carbonitrile (2-1, 311.0 mg, 0.895 mmol, 1.0 equiv.) in acetonitrile (10.0 mL) was added morphline (85.77 mg, 0.985 mmol, 1.1 equiv.) and 5.0 M aqueous NaOH (2.69 mL, 13.43 mmol, 15 equiv.), and the resulting mixture was stirred at 50° C. for 4 days. After cooling to room temperature, water (100.0 mL) was added and the mixture was stirred for 30 minutes. A yellow solid was collected via suction filtration, washed with water, dried in vacuo. The solid was purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA modifier) to afford 4-(4-fluorophenyl)-7-(morpholin-4-ylmethyl)quinoline-2-carboxamide (4-1, 291.0 mg, 80.0%) as a colorless solid. 1H NMR (500 MHz, CDCl3): δ 8.216 (s, 1H); 8.098 (br s, 2H); 7.911 (d, J=8.54 Hz, 1H); 7.642 (d, J=8.55 Hz, 1H); 7.503-7.529 (m, 2H); 7.219-7.263 (m, 2H); 5.798 (br s, 1H); 3.734 (br s, 6H); 2.528 (br s, 2H). LRMS m/z (M+H)+ 366.2 found, 366.2 required.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.[CH3:25][O:26][CH2:27][CH2:28][NH2:29]>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([NH:29][CH2:28][CH2:27][O:26][CH3:25])=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: COCCN
Product: COCCNc1ccc2c(C(=O)NCC3CCC(F)(F)CC3)c(Cl)ccc2n1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, and 2-Methoxy-ethylamine. 1H NMR (400 MHz, DMSO-d6): δ 8.70 (t, J=5.81 Hz, 1H), 7.59 (d, J=9.21 Hz, 1H), 7.45-7.50 (m, 2H), 7.32 (t, J=5.32 Hz, 1H), 6.88 (d, J=9.21 Hz, 1H), 3.55-3.54 (m, 2H), 3.51-3.52 (m, 2H), 3.28 (s, 3H), 3.22 (t, J=6.31 Hz, 2H), 2.01-2.03 (m, 2H), 1.73-1.85 (m, 5H), 1.22-1.31 (m, 2H). m/z: 412.0 [M+H]+
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][N:17](CC4C=CC=CC=4)[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>C(O)=O.CO.C(Cl)Cl.CN(C1C=CN=CC=1)C.[Pd]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][N:17]([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Agent: [Pd]
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: O=CO
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Temperature: 25 °C
Yield: 39.4 %

Procedure:
trans-3-(3-Cyclopentoxy-4-methoxyphenyl)-4-methoxycarbonyl-1-(phenylmethyl)pyrrolidine (3.1 g, 7.5 mmol) was dissolved in 50 mL of 4% HCO2H:methanol. While stirring at room temperature, 10% Pd/C (400 mg) was added in small portions. After 16 hrs the reaction was diluted with methanol. Filtration through Celite followed by concentration under reduced pressure yielded a yellow oil residue. This residue was dissolved in CH2Cl2 and DMAP (1.19 g, 9.75 mmol) and benzyl chloroformate (1.5 g, 8.2 mmol) were added. The resulting solution was stirred at room temperature. When reaction was judged complete by TLC analysis the mixture was partitioned between CH2Cl2 and 1M H3PO4. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×). The organic layers were combined, dried (MgSO4), filtered, and concentrated under reduced pressure to afford a pale oil. Chromatography on silica gel (3:2, hexanes:ethyl acetate) provided trans-3-(3-cyclopentoxy-4-methoxyphenyl)-4-methoxycarbonyl-1-(phenylmethoxycarbonyl)pyrrolidine as a white solid (1.34 g, 40%). m.p. 85° C. Anal. Calcd for C26H31NO6 : C, 68.86; H, 6.89; N, 3.09. Found: C, 68.81; H, 6.94; N, 2.99.
Reaction SMILES: N1CCCCC1.FC(F)OC1C=C(C=CC=1OC(F)F)C=O.C(CC(N[C:30]1[CH:38]=[CH:37][C:36]([Br:39])=[CH:35][C:31]=1[C:32]([OH:34])=[O:33])=O)(O)=O>C1(C)C=CC=CC=1>[Br:39][C:36]1[CH:37]=[CH:38][CH:30]=[C:31]([CH:35]=1)[C:32]([OH:34])=[O:33]
Reactant: O=C(O)CC(=O)Nc1ccc(Br)cc1C(=O)O
Agent: O=Cc1ccc(OC(F)F)c(OC(F)F)c1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C(O)c1cccc(Br)c1
Temperature: 25 °C
Yield: 107.1 %

Procedure:
Piperidine (100 μL, 1.01 mmol) was added to a suspension of 3,4-bis(difluoromethoxy)benzaldehyde (240 mg, 1.01 mmol) and 2-[(carboxyacetyl)amino]-5-bromobenzoic acid (277 mg, 0.92 mmol) in toluene (5.0 mL). The reaction flask was fitted with a Dean-Stark apparatus and heated to reflux for 30 min. The reaction was then cooled to rt and the resulting suspension was filtered and washed with toluene. The piperidinium salt was dissolved in MeOH (5 mL) and water (2 mL) and the solution was acidified with 50% aqueous AcOH. The crude product was collected by filtration and recrystallised from EtOH/water and filtered to afford (E)-2-[[3,4-bis(difluoromethoxy)phenyl)-1-oxo-2-propenyl]amino]-5-bromobenzoic acid (198 mg, 45%) as a colourless crystalline solid; mp 223-226° C.; δH (400 MHz, DMSO-d6) 6.96 (d, J=15.6 Hz, 1H, CH═CHCO), 7.26 (t, J=73 Hz, 1H, OCHF2), 7.27 (t, J=73 Hz, 1H, OCHF2), 7.38 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.61 (d, J=15.6 Hz, 1H, CH═CHCO), 7.68 (dd, J5′,6′=8.0, J2′,6′=1.6 Hz, 1H, H6′), 7.78 (d, J2′,6′=1.6 Hz, 1H, H2′), 7.80 (dd, J3,4=9.2, J4,6=2.8 Hz, 1H, H4), 8.08 (d, J4,6=2.8 Hz, 1H, H6), 8.55 (d, J3,4=9.2 Hz, 1H, H3), 11.28 (s, 1H, NH); δC (100 MHz, DMSO-d6) 116.3 (t, J=259 Hz), 116.5 (t, J=259 Hz), 116.5, 119.3, 120.1, 120.8, 122.6, 123.5, 126.7, 132.7, 133.2, 136.4, 139.7, 139.8, 141.9, 142.8, 163.6, 168.0; HRMS (ESL) calculated for C18H12BrF4NO5 [M-H ]− 475.9751, found 475.9752; νmax 1102, 1152, 1509, 1595, 1673, 1694, 3128 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[NH:10]2)=[CH:5][CH:4]=1.[F:16][C:17]([F:25])([F:24])[C:18](=[O:23])[C:19]([O:21][CH3:22])=[O:20]>C(Cl)(Cl)Cl>[CH3:22][O:21][C:19](=[O:20])[C:18]([OH:23])([C:17]([F:25])([F:24])[F:16])[C:12]1[C:13](=[O:14])[N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:10][C:11]=1[CH3:15]
Reactant: COc1ccc(-n2[nH]c(C)cc2=O)cc1
Reactant: COC(=O)C(=O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)C(O)(c1c(C)[nH]n(-c2ccc(OC)cc2)c1=O)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a chloroform solution (5 ml) of 1-(4-methoxyphenyl)-3-methyl-5-pyrazolone (102 mg, 0.5 mmol), methyl trifluoropyruvate (78 mg, 0.5 mmol) was added at room temperature and the mixture was stirred at 80° C. for 2 hours. After removing the solvent under reduced pressure, the title compound was obtained as a pale yellow solid (180 mg).