Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][N:6]([CH3:8])[CH2:5][C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:3]1.[H][H]>CO.[Pd]>[OH:1][C@H:2]1[CH2:3][C@@H:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:5][N:6]([CH3:8])[CH2:7]1
Reactant: Cc1ccc(C2=CC(O)CN(C)C2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc([C@@H]2C[C@H](O)CN(C)C2)cc1
Yield: 77.7 %

Procedure:
A solution of 5-hydroxy-1-methyl-3-(4-methylphenyl)-1,2,5,6-tetrahydropyridine (5.1 g, 25 mM) in methanol (200 ml) was hydrogenated in a Parr apparatus at 50 psi (about 3.51×104 kg/sq.m.) and room temperature over 10% palladium-on-charcoal (1 g). After the theoretical uptake of hydrogen had occurred (about 3 hours) the catalyst was removed by filtration and the solvent removed under vacuum. Recrystallisation from cyclohexane gave the title compound (4 g). A portion was converted to the hydrochloride and recrystallized from methanol/ether to give the title compound hydrochloride, m.p. 218°-9°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[CH3:21][N:22]1[CH:26]=[C:25]([CH:27]=O)[CH:24]=[N:23]1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:27]([C:25]3[CH:24]=[N:23][N:22]([CH3:21])[CH:26]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: Cn1cc(C=O)cn1
Product: Cn1cc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Br)cnc3[nH]2)cn1
Yield: 45.5 %

Procedure:
In a similar fashion to Compound LXXVI, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (40.0 mg, 0.118 mmol) and 1-methyl-1H-pyrazole-4-carbaldehyde (14.3 mg, 0.130 mmol) were reacted to produce 23 mg (45%) of the title compound. mp: 255-258° C., 1H NMR (300 MHz, DMSO-d6): 11.99 (s, 1H), 7.99 (d, J=8 Hz, 1H), 7.96 (s, 1H), 7.72 (s, 1H), 7.19 (s, 1H), 6.88 (d, J=8 Hz, 1H), 6.49 (d, J=8 Hz, 1H), 6.35 (m, 2H), 5.30 (t, J=8 Hz, 1H), 4.34 (m, 1H), 3.97 (s, 2H), 3.02 (s, 4H), 2.87 (s, 1H), 2.74 (s, 1H), 2.61 (d, J=8 Hz, 1H), 2.26 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz, 1H). MS: 428, 430 (M+H), HPLC: 1.94 min (G method).
Reaction SMILES: [Br:1]Br.[N:3]1([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1>Br.C(O)(=O)C>[BrH:1].[Br:1][CH2:15][C:14]([C:11]1[CH:10]=[CH:9][C:8]([N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[CH:13][CH:12]=1)=[O:16]
Reactant: BrBr
Reactant: CC(=O)c1ccc(-n2ccnc2)cc1
Agent: Br
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc(-n2ccnc2)cc1
Reaction time: 8 h

Procedure:
Add bromine (5.71 mL, 0.111 mol) to a solution of 4'-(1H-imidazol-1-yl)acetophenone (20.75 g, 0.111 mol) in 30-32% HBr in acetic acid. Stir the mixture overnight and collect the crystals. Wash the crystals with ethanol (3×50 mL) and air dry for 2h at room temperature to afford the title compound.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(O)(=O)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Cc2cccnc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: c1ccc(CC2CCCNC2)cc1
Reaction time: 6 h
Yield: 41.4 %

Procedure:
Combine 3-benzyl-pyridine (0.524 g, 3.10 mmol) and 10% palladium on carbon (0.165 g) in acetic acid (30 mL) and stir at 60° C. at a H2 pressure of 60 psi. After 6 h, purify the reaction mixture by ion exchange chromatography (SCX resin, methanol→2 M ammonia/methanol) and silica gel chromatography (10:1→13:1 methylene chloride:methanol) to provide 0.225 g (42%) of the title compound as a yellow oil: 1H NMR (DMSO-d6): 7.28 (t, 2H, J=7.3 Hz), 7.22-7.13 (m, 3H), 3.01 (s br, 1H), 2.87-2.76 (m, 2H), 2.50-2.34 (3H), 2.16 (dd, 1H, J=9.3, 11.7 Hz), 1.70-1.49 (m, 3H), 1.29 (tq, 1H, J=3.9, 12.7 Hz), 1.03 (dq, 1H, J=3.9, 12.7 Hz).
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:30]=[C:29]([F:31])[C:28]([N:32]2[C:37](=[O:38])[CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[N:34]([CH3:43])[C:33]2=[O:44])=[CH:27][C:11]=1[O:12][C:13]1[C:14]([O:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:15][CH:16]=[CH:17][CH:18]=1.[ClH:45]>C(#N)C.[Cu]Cl.[Cu](Cl)Cl>[Cl:45][C:10]1[CH:30]=[C:29]([F:31])[C:28]([N:32]2[C:37](=[O:38])[CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[N:34]([CH3:43])[C:33]2=[O:44])=[CH:27][C:11]=1[O:12][C:13]1[C:14]([O:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(C)Oc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Reactant: Cl
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CCOC(=O)C(C)Oc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 3 h

Procedure:
A solution of 10.99 g of isoamyl nitrite in 10 ml of acetonitrile was added to a mixture of 15.46 g of ethyl 2-[3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]propionate, 6.19 g of copper (I) chloride, 12.61 g of copper (II) chloride, and 120 ml of acetonitrile at room temperature, and the mixture was stirred for 3 hours. The reaction mixture was poured into a mixture of ice and hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 13.16 g of ethyl 2-[3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3, 6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]propionate (compound b-10).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[OH:34])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.[Br:44]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([Br:44])[C:25]=1[OH:34])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2O)nc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)cc(Br)c2O)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (1.39 g) is dissolved in chloroform (20 ml) and thereto is added N-bromosuccinimide (475 mg) and the mixture is stirred at room temperature for 2 hours and the reaction solution is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(3-bromo-2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (1.29 g). MS (m/z): 704/706 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Cl)=[CH:25][N:24]=1>>[Cl:22][C:23]1[N:24]=[CH:25][C:26]([CH2:29][O:8][C:6]2[CH:5]=[CH:4][C:3]([C:9]([N:11]3[CH2:15][CH2:14][CH2:13][C@H:12]3[CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:10])=[C:2]([F:1])[CH:7]=2)=[CH:27][CH:28]=1
Reactant: O=C(c1ccc(O)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: ClCc1ccc(Cl)nc1
Product: O=C(c1ccc(OCc2ccc(Cl)nc2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C using (2-Fluoro-4-hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 2-chloro-5-(chloromethyl)pyridine [CAS 70258-18-3]. MS (ES+) 418.3
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[CH3:31])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[CH3:31])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)N(C)CCN(C)C)cc1Br
Product: Cc1ccc(S(=O)(=O)N(C)CCN(C)C)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 3-bromo-N-(2-dimethylamino-ethyl)-4,N-dimethyl-benzenesulfonamide (Intermediate 154), the title compound was obtained as a yellow sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH2:1]1[C@H:6]2[CH2:7][C:8](=[O:10])[CH2:9][C@H:5]2[CH2:4][C:3](=[O:11])[NH:2]1.[CH:12](O)([OH:14])[CH3:13].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]1[C@H:6]2[CH2:7][C:8]3([O:14][CH2:12][CH2:13][O:10]3)[CH2:9][C@H:5]2[CH2:4][C:3](=[O:11])[NH:2]1
Reactant: CC(O)O
Reactant: O=C1C[C@@H]2CNC(=O)C[C@@H]2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1C[C@@H]2CC3(C[C@@H]2CN1)OCCO3
Yield: 71.5 %

Procedure:
(cis)-2,4,4a,5,7,7a-hexahydro-1H-cyclopenta[c]pyridine-3,6-dione 14d (1.20 g, 7.80 mmol), ethanediol (1.34 g, 21.50 mmol) and p-toluenesulfonic acid (24 mg, 0.13 mmol) were dissolved in 60 mL of toluene, heated to reflux for 8 hours with stirring, then added dropwise with saturated sodium bicarbonate solution to adjust pH to 7 around and extracted with dichloromethane (50 mL). The aqueous phase was extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (cis)-spiro[1,3-dioxolane-2,6′-2,4,4a,5,7,7a-hexahydro-1H-cyclopenta[c]pyridine]-3′-one 14e (1.10 g, yield: 70.0%) as a white solid.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:38](O)(=[O:44])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:38](=[O:44])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCCCCC(=O)O
Product: CCCCCC(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 31.2 %

Procedure:
A procedure similar to that described in Example 3, above, was followed, but using 1.0 g (1.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] and 423 mg (3.6 mmol) of hexanoic acid, to provide 364 mg of the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:17])=[CH:9][C:10]=1[CH2:11][C:12]([O:14]CC)=[O:13])=[O:5])C.[Li+].[OH-].Cl>CO.O>[C:12]([CH2:11][C:10]1[CH:9]=[C:8]([CH3:17])[NH:7][C:6]=1[C:4]([OH:5])=[O:3])([OH:14])=[O:13]
Reactant: CCOC(=O)Cc1cc(C)[nH]c1C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(CC(=O)O)c(C(=O)O)[nH]1
Yield: 87.1 %

Procedure:
A solution of 3-ethoxycarbonylmethyl-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (7 g, 29.26 mmol), LiOH (7 g, 10 eq.) in methanol (90 mL) and water (30 mL) was heated in a 70° C. oil bath for 3 hours. The cooled reaction was adjusted to pH 3 with 3N HCl, the resulted precipitate was collected by filtration, washed with water and dried to give 4.67 g (87%) of 3-carboxymethyl-5-methyl-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[C:16]1([C:3]2[C:2]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:31])=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: Cc1ccccc1B(O)O
Product: Cc1ccccc1-c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Yield: 86.1 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and o-tolylboronic acid (78.9 mg, 0.58 mmol, 2.00 equiv) as reactants. Purification via silica gel column (dichloromethane/methanol (10:1)) afforded 85 mg (84%) of 2-phenyl-3-o-tolylquinoxaline-6-carboxylic acid as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:26][CH:27]([CH3:33])[CH2:28][CH2:29][C:30](O)=[O:31].CN(C)CCCN=C=NCC.O>O1CCCC1>[F:23][C:22]([F:25])([F:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]([N:11]1[CH2:10][CH2:9][N:8]([C:5]2[N:6]=[N:7][C:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][CH:27]([CH3:33])[CH3:26])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1)=[O:15]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: CC(C)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.1 %

Procedure:
To a stirred solution of [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethyl-phenyl)methanone (0.226 g, 0.645 mmol) in tetrahydrofuran (10.0 mL) was added 4-methylpentanoic acid (0.500 g, 4.30 mmol) followed by (3-dimethylaminopropyl)-ethyl carbodiimide (1.0 mL). The mixture was stirred at ambient temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The combined organic layer was dried with Na2SO4, concentrated, and the residue was dissolved again in a small amount of ethyl acetate. The solid, which precipitated by dropwise addition of hexane was filtered off and dried in vacuum to give the title product (0.070 g) as a white solid in 24% yield. 1H NMR (300 MHz, CDCl3) δ 9.15, 8.36, 7.74, 7.63, 7.56, 7.36, 7.05, 4.03-3.98, 3.93-3.89, 3.69-3.62, 3.55-3.53, 3.33-3.31, 2.51, 1.63-1.61, 0.91.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[N:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.Cl.[F:24][C:25]([F:34])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[F:34][C:25]([F:24])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH:32][C:20]([C:10]2[N:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=2)=[O:21])[O:28][N:27]=1
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Agent: Cl
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1

Procedure:
The title compound was synthesized in analogy to Example 41, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid (example M) and C-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylamine hydrochloride (CAS registry No. 944905-93-5; example AK) as starting materials; LC-MS (UV peak area/ESI) 100.0%, 482.0 (M+H)+.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[C:18]([NH:24][C:25]2[S:26][CH:27]=[C:28]([CH2:30][CH3:31])[N:29]=2)=[N:19][CH:20]=[C:21]([Br:23])[CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)(=O)C>C(#N)C>[CH2:9]([O:16][C:17]1[C:18]([NH:24][C:25]2[S:26][C:27]([Cl:1])=[C:28]([CH2:30][CH3:31])[N:29]=2)=[N:19][CH:20]=[C:21]([Br:23])[CH:22]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCc1nc(Nc2ncc(Br)cc2OCc2ccccc2)sc1Cl
Reaction time: 1 h
Yield: 56.6 %

Procedure:
1-Chloropyrrolidine-2,5-dione (0.103 g, 0.769 mmol) was added to a solution of 3-(benzyloxy)-5-bromo-N-(4-ethylthiazol-2-yl)pyridin-2-amine (0.25 g, 0.641 mmol) in acetonitrile (6 mL). The reaction mixture was stirred for 1 hour and then partitioned between ether and water. The organic layer was washed with brine, dried, and concentrated. The residue was purified by MPLC (Biotage) eluting with 6:1 hexane:ethyl acetate to afford 3-(benzyloxy)-5-bromo-N-(5-chloro-4-ethylthiazol-2-yl)pyridin-2-amine (0.154 g, 56.6% yield) as a light yellow powder. 1H NMR (DMSO-d6) δ 1.17 (t, 3H), 2.58 (q, 2H), 5.28 (s, 2H), 7.30-7.43 (m, 3H), 7.59 (d, 2H), 7.66 (s, 1H), 7.98 (s, 1H), 10.79 (bs, 1H).
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([N+:22]([O-:24])=[O:23])[CH:3]=1.[CH3:25][N:26](C)C=O>[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.O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:8]2[C:7]3=[C:2]([C:25]#[N:26])[CH:3]=[C:4]([N+:22]([O-:24])=[O:23])[CH:5]=[C:6]3[O:11][C:10]([CH3:13])([CH3:12])[C:9]2=[O:14])=[CH:16][CH:17]=1
Reactant: CC1(C)Oc2cc([N+](=O)[O-])cc(Br)c2N(c2ccc(F)cc2)C1=O
Reactant: CN(C)C=O
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
Product: CC1(C)Oc2cc([N+](=O)[O-])cc(C#N)c2N(c2ccc(F)cc2)C1=O
Temperature: 175 °C

Procedure:
A mixture of 5-bromo-4-(4-fluorophenyl)-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (compound obtained in Reference Example 53(6), 2.00 g), zinc cyanide (0.60 g), tetrakis(triphenylphosphine)palladium(0) (0.60 g) and N,N-dimethyl-formamide (30 mL) was heated at 175° C. under microwave irradiation for 5 minutes under argon atmosphere. After cooling, to the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent; n-hexane/ethyl acetate=95/5→65/35) to give 4-(4-fluorophenyl)-2,2-dimethyl-7-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-5-carbonitrile (1.42 g) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29]O)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.S(Cl)([Cl:33])=O>C(Cl)Cl.C1COCC1>[Cl:33][CH2:29][CH2:28][O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)=[C:2]([Cl:1])[CH:3]=1)=[N:18][CH:19]=[N:20]2
Reactant: O=S(Cl)Cl
Reactant: OCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Solvent: ClCCl
Solvent: C1CCOC1
Product: ClCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12

Procedure:
To a stirred solution of the 2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethanol (20 g) in DCM (200 ml) and THF (200 ml) was added thionyl chloride (20 ml) at ambient temperature. The solution was then heated under reflux for 2 hours. The solution was cooled and product filtered off to give 5-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine as its hydrochloride salt (25 g, 98%); NMR spectrum (DMSO-d6) 4.20-4.40 (t, 2H), 4.60-4.80 (t, 2H), 5.40 (s, 2H), 7.20-7.60 (m, 3H), 7.60-7.80 (m, 3H), 7.90-8.10 (m, 3H), 8.60-8.70 (d, 1H), 8.9 (s, 1H), 10.65-10.83 (bs, 1H); Mass spectrum MH+ 441.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH3:18])[N:5]=[C:4]([C:19]2[CH:28]=[CH:27][C:26]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[N:20]=2)[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].CO>[CH3:18][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[C:6]1[CH:7]=[CH:2][N:3]=[C:4]([C:19]2[CH:28]=[CH:27][C:26]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[N:20]=2)[N:5]=1
Reactant: Cc1c(-c2cc(Cl)nc(-c3ccc4c(n3)CCCC4)n2)ccc2ccccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(-c2ccnc(-c3ccc4c(n3)CCCC4)n2)ccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
50 mg of palladium on charcoal (5%) were added to a suspension of 2.0 g (0.0052 mol) of 4-chloro-6-(methylnapth-2-yl)-2-(5,6,7,8-tetrahydroquinolin-2-yl)-pyrimidine and 0.64 g (0.006 mol) of sodium carbonate in 150 ml of absolute methanol, under argon. The mixture was stirred vigorously for 16 hours at 25° C. under a hydrogen atmosphere. The solid was filtered off, the filtrate was concentrated, and the residue was subjected to flash chromatography (silica gel/ethyl acetate). 1.3 g (71%) of a white solid of melting point 156° C. to 158° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4]C=[C:6]2[C:11](=O)[NH:10]C(=O)[C:7]=12.CS(O)(=O)=O.[C:18](O)([C:20](F)(F)F)=[O:19]>[Pd]>[NH2:1][C:2]1[CH:7]=[C:6]2[C:20](=[CH:4][CH:3]=1)[C:18](=[O:19])[NH:10][CH2:11]2
Reactant: Nc1cccc2c1C(=O)NC2=O
Reactant: O=C(O)C(F)(F)F
Agent: [Pd]
Agent: CS(=O)(=O)O
Product: Nc1ccc2c(c1)CNC2=O

Procedure:
A solution of 16.2 g (100 mmol) of 6-aminophthalimide, 9.6 g (100 mmol) of methanesulfonic acid, and 4.0 g of 10% Pd/C in 140 mL of TFA was hydrogenated overnight at 50 psi. The catalyst was filtered off and and the filtrate concentrated on a rotary evaporator. The residue was diluted with 70 mL of ice water, adjusted to pH 8 with K2CO3, and chilled in an ice bath. The resulting solid was filtered to give 6.7 g of a 5:4 ratio of 5-amino:6-amino lactam isomers. Recrystallization from hot ethanol/water afforded 1.45 g of undesired isomer. The filtrate was preabsorbed onto silica gel and chromatographed with TEA:MeOH:methylene chloride (1:2:47). The resulting solid was slurried in methylene chloride/MeOH and filtered to afford a low yield of 5-amino-2,3-dihydro-isoindol-1-one: 1H NMR (DMSO-d6): δ 4.13 (s, 2H), 5.67 (s, 2H), 6.55 (dd, J=8.7, 1.9 Hz, 1H), 6.55 (d, J=1.9 Hz, 1H), 7.25 (d, J=8.7 Hz, 1H), 7.83 (s, 1H); APCI-MS m/z 149 (M+H)+.