Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C@@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)[C:6]([O:8]C)=[O:7])(=O)C.[ClH:22]>>[ClH:22].[NH2:4][C@@H:5]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:15][CH:16]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(OC(F)(F)F)cc1)NC(C)=O
Agent: Cl
Product: N[C@@H](Cc1ccc(OC(F)(F)F)cc1)C(=O)O
Temperature: 100 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
A 6 N hydrochloric acid (330 μL) solution of methyl (2S)-2-(acetylamino)-3-[4-(trifluoromethoxy)phenyl]propanoate (29.9 mg, 0.098 mmol) prepared in Reference Example 3 (3f) was stirred at 100° C. for 4 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The obtained residue was azeotroped with toluene, washed with diethyl ether, and dried under reduced pressure to give 26 mg of the title compound (white powder, yield: 93%).
Reaction SMILES: [CH2:1]([CH:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4].[OH:26]O.[OH-].[Na+]>CO>[CH2:1]([C:5]1([OH:26])[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:7]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1C(=O)N(c2ccccc2)N(c2ccc(OC)cc2)C1=O
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC1(O)C(=O)N(c2ccccc2)N(c2ccc(OC)cc2)C1=O

Procedure:
Prepared from 4-(1-butyl)-1-(4-methoxyphenyl)-2-phenyl-3,5-pyrazolidinedione (1.35 g; 3.8 mmol), 35% H2O2 (4.3 ml; 50 mmol), 2 M NaOH (0.35 ml; 0.7 mmol), and methanol (50 ml) using the procedure of Example 7. Purified by flash chromatography on a 110×65 mm silica gel 60 column eluted with ethyl acetate-heptane (1:1) to give 0.7 g (52%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([Cl:11])=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:43][C:44]1[CH:66]=[CH:65][C:47]2[CH2:48][CH2:49][C:50]3[C:51]([C:62]([NH2:64])=[O:63])=[N:52][N:53]([C:55]4[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=4)[C:54]=3[C:46]=2[CH:45]=1.CC1C(C(O)=O)=CN=C(Cl)C=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([Cl:11])=[CH:9][N:10]=1)[C:5]([NH:43][C:44]1[CH:66]=[CH:65][C:47]2[CH2:48][CH2:49][C:50]3[C:51]([C:62]([NH2:64])=[O:63])=[N:52][N:53]([C:55]4[CH:56]=[CH:57][C:58]([F:61])=[CH:59][CH:60]=4)[C:54]=3[C:46]=2[CH:45]=1)=[O:7]
Reactant: O=C(O)c1cc(Cl)ncc1Cl
Reactant: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(N)cc1-2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1cc(Cl)ncc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(NC(=O)c3cc(Cl)ncc3Cl)cc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
2,5-Dichloroisonicotinic acid (1.65 g, 0.0086 mol), HATU (3.27 g, 0.0086 mol), and Et3N (2.32 mL, 0.0166 mol) were added to a solution of the title compound of Example 244 (1.85 g, 0.00574 mol) in 29 mL of DMF. The reaction mixture was stirred at room temperature for 3 h. The completion of the reaction was confirmed by monitoring the disappearance of the title compound of Example 246 step 2 in LC/MS. The crude reaction mixture was concentrated to about 10 mL of DMF. Upon addition of water to this DMF residue, a white solid was formed. This white solid was triturated in water for 20 min and filtered. The solid was collected, dissolved in THF, and dried with MgSO4. Removal of the solvent afforded a brown solid that was crystallized from CH3CN to give 2.1 g of the title compound as white needles (yield 73%). 1H NMR (300 MHz, d6-DMSO): 2.86–2.91 (m, 4H), 7.18 (d, 1H, J=1.2 Hz), 7.25 (s, 1H), 7.32–7.36 (m, 4H), 7.52–7.56 (m, 3H), 7.75 (s, 1H), 8.57 (s, 1H), 10.49 (s, 1H). M+1=497.
Reaction SMILES: [CH2:1]1[C@H:6]2[CH2:7][NH:8][CH2:9][CH2:10][N:5]2[C:4](=O)[CH2:3][O:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CC(O)C.[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1>[CH2:1]1[C@H:6]2[CH2:7][NH:8][CH2:9][CH2:10][N:5]2[CH2:4][CH2:3][O:2]1
Reactant: O=C1COC[C@H]2CNCCN12
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CC(C)O
Solvent: C1COCCO1
Product: C1CN2CCOC[C@H]2CN1
Yield: 72.1 %

Procedure:
To a solution of (R)-hexahydro-pyrazino[2,1-c][1,4]oxazin-4-one (60 mg, 0.39 mmol) in dioxane (5 mL) was added LiAlH4 (1.5 mL, 1M solution in THF). The resulting mixture was heated at 80° C. for 2.5 h before the addition of iPrOH (0.5 mL) followed by a saturated aqueous solution of Na2SO4 (3 mL). Further Na2SO4 was added and the resulting mixture filtered through celite, washing with EtOAc. The resulting residue was purified by NH2 column to give the title compound as an oil (40 mg, 73%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:25]#[N:26])[C:19]=2[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][C:24]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2c(C#N)cccc21
Product: CC1c2cccc(C#N)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-1,2,3,4-tetrahydro-isoquinoline-5-carbonitrile to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[N:5][N:4]=[C:3]1[SH:10].[OH-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.C(O)C>[NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[N:5][N:4]=[C:3]1[S:10][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1nnc(S)n(N)c1=O
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nnc(SCc2ccccc2)n(N)c1=O
Temperature: 80 °C

Procedure:
0.272 g of 4-amino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-one (which can be prepared by the method of A. Dornow, H. Menzel, P. Marx, Chem. Ber. 97, 2173 (1964)) was suspended in 0.86 ml of a 2N solution of sodium hydroxide in water. A solution of 0.218 g of benzyl chloride in ethanol was subsequently added dropwise, and the mixture was heated at 80° C. for 30 minutes. The resultant precipitate was filtered off with suction, giving 4-amino-3-benzylsulfanyl-6-methyl-4H-1,2,4-triazin-5-one.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:2]#[CH:3].I[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:29][O:28][C:27]1[CH:26]=[CH:25][NH:24][C:23]=1/[CH:22]=[C:14]1\[C:15](=[O:21])[NH:16][C:17]2[C:13]\1=[C:12]([C:3]#[C:2][CH2:1][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:20]=[CH:19][CH:18]=2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#CCOc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCOc3ccccc3)c21

Procedure:
Using Method C above, phenyl propargyl ether (65 mg, 0.49 mmol) (Lancaster) was coupled to (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2) using (Ph3P)2PdCl2 (20 mg) (Aldrich) and CuI (10 mg) (Aldrich) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 18 h, yielding (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-(3-phenoxy-1-propynyl)-2H-indol-2-one. (Yield 92 mg, 62%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].[CH3:14][CH:15]([CH3:19])[CH2:16][CH2:17][NH2:18]>>[CH3:14][CH:15]([CH3:19])[CH2:16][CH2:17][NH:18][C:11]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:10][N:9]=1)=[O:13]
Reactant: CC(C)CCN
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Product: CC(C)CCNC(=O)c1ccc(C(=O)O)cn1
Yield: 58 %

Procedure:
The title compound was synthesized as described for Intermediate example I-94 in 58% yield starting from 5-(methoxycarbonyl)pyridine-2-carboxylic acid and 3-methylbutan-1-amine; MS (APPI/APCI) m/z 237[M+H+].
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][OH:8].[H-].[Na+].Cl[C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][O:8][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1
Reactant: FC(F)(F)c1cncc(Cl)c1
Reactant: CN1CCC[C@@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC[C@@H]1COc1cncc(C(F)(F)F)c1

Procedure:
(R)-1-methyl-2-pyrrolidinemethanol (Aldrich Chemical Co.) was dissolved in 8 mL of DMF and stirred under N2, then 240 mg of NaH (80% dispersion in mineral oil) was added. The reaction mixture was stirred fifteen minutes, and 363 mg of 3-chloro-5-trifluoromethylpyridine (2.0 mmol) was added. The reaction mixture was stirred at 50° C. for 16 hours. The volatiles were removed under vacuum, and the residue was purified by chromatography on silica gel, eluting with 2:1 ethyl acetate:hexane to give 336 mg of the title product. MS (DCI/NH3) m/e: 261 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.50 (d, J=0.6 Hz, 1H), 8.49 (d, J=3.0 Hz, 1H), 7.41 (dd, J=0.6, 3.0 Hz, 1H), 4.12-3.96 (m, 2H), 3.21-3.10 (m, 1H), 2.80-2.65 (m, 1H), 2.51 (s, 3H), 2.44-2.30 (m, 1H), 2.13-1.73 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.Cl.[OH:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:22]([NH:24][NH2:25])=[O:23].C(N(CC)CC)C.S([O-])(O)(=O)=O.[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:25][NH:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:19]([OH:18])[CH:20]=1
Reactant: COc1ccc(C(=O)NN)cc1O
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)NN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1O
Temperature: 25 °C

Procedure:
(4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.18 g, 0.64 mmol) and 3-hydroxy-4-methoxy-benzoic acid hydrazide hydrochloride (0.18 g, 0.64 mmol) were coupled in N,N-dimethylformamide (5 mL) with triethylamine (0.30 mL) at 100° C. After cooling to room temperature and addition of 5% aqueous potassium hydrogen sulfate solution, the solid material is collected by Buchner filtration, washed with diethyl ether, water, and methanol, and then dried under house vacuum to give N′-[(Z)-(6-bromo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]-3-hydroxy-4-methoxybenzohydrazide as a tan powder.
Reaction SMILES: [Br:1][CH:2]([C:4]1[N:5]=[C:6]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:7]2[C:8](=[O:10])[CH:9]=1)[CH3:3].[I:16]N1C(=O)CCC1=O>>[Br:1][CH:2]([C:4]1[N:5]=[C:6]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:7]2[C:8](=[O:10])[C:9]=1[I:16])[CH3:3]
Reactant: Cc1cccc2nc(C(C)Br)cc(=O)n12
Reactant: O=C1CCC(=O)N1I
Product: Cc1cccc2nc(C(C)Br)c(I)c(=O)n12
Yield: 98 %

Procedure:
The desired compound was prepared according to the procedure of Example 8, step 3, using 2-(1-bromoethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one and N-iodosuccinimide as the starting materials in 98% yield. LCMS for C11H11BrIN2O (M+H)+: m/z=392.7, 394.7.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:21]([Br:22])[CH2:20][C@@:19]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[C:25](OC(=O)C)(=[O:27])[CH3:26].O>N1C=CC=CC=1>[C:25]([O:1][C@@H:2]1[C@@H:21]([Br:22])[CH2:20][C@@:19]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](Br)C[C@]4(C)[C@H]3CC[C@]12C
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](C(C)=O)CC[C@@H]34)[C@@]2(C)C[C@@H]1Br
Reaction time: 8 h

Procedure:
A solution of 3α-hydroxy-2β-bromo-5α-pregnan-20-one (8.5 g.) in pyridine (25 ml.) was treated with acetic anhydride (12.5 ml.), and the mixture was allowed to stand at room temperature overnight. The reaction mixture was poured into water and the product was extracted with methylene chloride. The extract was washed with water, dried (Na2SO4) and evaporated. A portion (582 mg.) of the residue (8.5 g.) was purified by preparative thin layer chromatography and crystallisation from iso-propyl ether to give the title compound (70 mg.), m.p. 142°-146°, [α]D + 120.9°.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].Cl[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:16][C:15]1[C:10]([N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: Clc1cccnc1Cl
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccn(-c2ncccc2Cl)n1
Temperature: 125 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
10.0 g (88.4 mmol) of 3-nitropyrazole and 14.4 g (97.2 mmol) of 2,3-dichloropyridine were initially charged in 50 ml of dimethylformamide, 23.9 g (173 mmol) of potassium carbonate were added and the reaction mixture was stirred at 125° C. for 18 hours. After cooling, the mixture was poured into water and the precipitated solid was filtered off. Recrystallization from isopropanol/water gave 18.1 g (90% of theory) of 3-chloro-2-(3-nitro-1H-pyrazol-1-yl)pyridine (log P: 1.83; MH+: 225.1; 1H-NMR (400 MHz, CD3CN, δ, ppm): 7.15 (s, 1H), 7.56 (d, 1H), 8.15 (d, 1H), 8.23 (d, 1H), 8.53 (m, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:9][N:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:6]=[CH:7][CH:8]=1)[CH3:2].C(C1C=C(C=CC=1)N)C.C(#N)CC#N.O.[NH2:31][NH2:32]>>[NH2:13][C:12]1[C:11](=[N:10][NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=2)[C:14]([NH2:15])=[N:32][N:31]=1
Reactant: CCc1cccc(NN=C(C#N)C#N)c1
Reactant: NN
Agent: CCc1cccc(N)c1
Solvent: O
Solvent: N#CCC#N
Product: CCc1cccc(NN=C2C(N)=NN=C2N)c1
Yield: 10 %

Procedure:
3,5-Diamino-4-[(3-ethylphenyl)hydrazono]pyrazole was prepared using 99 mg (0.5 mmol) of 2-[(3-ethylphenyl)hydrazono]malononitrile, which was derived from 3-ethylaniline (124 μL, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Precipitate formed in the reaction tube approximately 10 min after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, precipitated from an ethyl acetate solution by the addition of hexanes, and dried to yield 12 mg (10%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:13]=[CH:12][N:11]=1.Cl.Cl.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][C:33]=2[C:41]([F:44])([F:43])[F:42])[CH2:27][CH2:26]1>>[CH3:24][N:25]1[CH2:26][CH2:27][N:28]([CH2:31][C:32]2[CH:40]=[CH:39][C:35]([C:36]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([NH:9][C:10]4[CH:15]=[C:14]([C:16]5[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=5)[N:13]=[CH:12][N:11]=4)[CH:4]=3)=[O:37])=[CH:34][C:33]=2[C:41]([F:44])([F:42])[F:43])[CH2:29][CH2:30]1
Reactant: Cc1ccc(N)cc1Nc1cc(-c2cccnc2)ncn1
Reactant: CN1CCN(Cc2ccc(C(=O)Cl)cc2C(F)(F)F)CC1
Agent: Cl
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1Nc1cc(-c2cccnc2)ncn1
Reaction time: 92 h

Procedure:
This compound was prepared in the same manner as in Example 1, except that 4-methyl-3-[6-(3-pyridyl)pyrimidin-4-ylamino]aniline (Reference Example 20) and 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylbenzoyl chloride dihydrochloride (Reference Example 2) were used, and that the reaction was conducted at room temperature for 92 hours and the resulting crude crystals were washed with ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.CN(C)CCN(C)C.C([Li])CCC.CCCCCC.[Br:42][CH2:43][CH2:44][CH2:45][CH2:46]Br>C1COCC1>[Br:42][CH2:43][CH2:44][CH2:45][CH2:46][C:7]1[N:8]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[C:9]2[C:5]([N:6]=1)=[C:4]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:3]=[C:2]([Cl:1])[N:10]=2
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Reactant: BrCCCCBr
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Clc1nc(N2CCOCC2)c2nc(CCCCBr)n(C3CCCCO3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
A solution of 4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (Example 118) (5.0 g, 15 mmol) and N,N,N′,N′-tetramethylethylenediamine (3.5 mL, 23 mmol) in THF (110 mL) was cooled to −42° C. and treated with a solution of 2.5M n-Butyllithium in hexane (22 mL, 54 mmol) drop-wise over 5 minutes. After 30 minutes at −42° C., 1,4-dibromo-butane (8.9 mL, 75 mmol) was added and the reaction mixture was slowly warmed to 0° C. over 1 hr and then warmed to ambient temperature for 90 minutes. The mixture was quenched with a saturated solution of NH4Cl, and diluted with ethyl acetate. The aqueous layer was extracted into ethyl acetate (3×), and the combined organics were dried over sodium sulfate, filtered, and absorbed onto celite for purification by flash chromatography to afford 4-(8-(4-bromobutyl)-2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine as a white solid (1.1 g, 15%). LC/MS (ESI+): m/z 459 (M+H)
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]([OH:13])=[O:12])[NH:3]1.S(=O)(=O)(O)O>C(O)C>[O:1]=[C:2]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH:4]([C:11]([OH:13])=[O:12])[NH:3]1
Reactant: O=C1NC(C(=O)O)c2ccccc21
Agent: O=S(=O)(O)O
Solvent: CCO
Product: O=C1NC(C(=O)O)C2CCCCC12

Procedure:
The intermediate octahydro-3-oxo-1H-isoindole-1-carboxylic acid is prepared as follows. 2,3-Dihydro-3-oxo-1H-isoindole-1-carboxylic acid (J. Prakt. Chem., 146, 307(1936)), 20 g is heated at reflux for 2 hours with 250 ml of absolute ethanol and 5.6 g of concentrated sulfuric acid. On cooling, the solution deposits crystalline ethyl 2,3-dihydro-3-oxo-1H-isoindole-3-carboxylate. Recrystallization of this from ethanol gives pure material, mp 178°-183° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)[C:5]([Cl:24])=[CH:4][N:3]=1.Cl.[CH:26]1([C:29]2[NH:33][N:32]=[C:31]([NH2:34])[CH:30]=2)[CH2:28][CH2:27]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:24][C:5]1[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)=[N:7][C:2]([NH:34][C:31]2[CH:30]=[C:29]([CH:26]3[CH2:28][CH2:27]3)[NH:33][N:32]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Cl)ncc3Cl)CC2C1
Reactant: Nc1cc(C2CC2)[nH]n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Nc4cc(C5CC5)[nH]n4)ncc3Cl)CC2C1
Temperature: 150 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a suspension of tert-butyl 5-[(2,5-dichloropyrimidin-4-yl)amino]-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (373.3 mg, 1.00 mmol) and 5-cyclopropyl-1H-pyrazol-3-amine hydrochloride (376.4 mg, 2.36 mmol) in dioxane (10 mL) were added Pd(OAc)2 (75.9 mg, 0.34 mmol), BINAP (164.0 mg, 0.25 mmol) and Cs2CO3 (1.08 g, 3.31 mmol). The reaction mixture was stirred at 150° C. under microwave radiation for 2 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=2/1) to give the title compound as a pale yellow solid (0.29 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]([O:26]C)=O)=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[NH2:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]([NH:30][CH2:31][C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)=[O:26])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: NCc1cccnc1
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Product: CN(C(=O)c1cc2c(s1)-c1ccc(C(=O)NCc3cccnc3)cc1OCC2)c1ccccc1Cl

Procedure:
Following Example 47 and General Procedure C, methyl 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate 138 and 3-aminomethylpyridine gave 173. MS: (ESI+) 504.0
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][NH:16][CH:15]([N:19]4[CH2:23][CH2:22][CH2:21][CH:20]4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[OH:30])[C:14]3=[O:31])[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][CH2:41][CH2:42][Cl:43]>C(#N)C.O>[Cl:43][CH2:42][CH2:41][CH2:40][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH:20]1[CH2:21][CH2:22][CH2:23][N:19]1[C:15]1[C:14](=[O:31])[N:13]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=2[CH3:12])[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:32])[CH:18]=[CH:17][N:16]=1
Reactant: ClCCCBr
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N1C=CNC(N2CCCC2c2ccccc2O)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(N2CCCC2c2ccccc2OCCCCl)c1=O
Temperature: 83 °C
Reaction time: 10 h

Procedure:
A solution of N-cyclopropyl-3-{3-[2-(2-hydroxyphenyl)pyrrolidin-1-yl]-2-oxo-3,4-dihydropyrazin-1(2H)-yl}-4-methylbenzamide (Example 324a, 0.2 g) in acetonitrile (5 mL) was treated with potassium carbonate (0.642 g) and 1-bromo-3-chloropropane (0.459 mL) under nitrogen. The resulting suspension was stirred at 83° C. for 10 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and evaporated to give the subtitle compound (0.23 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25]([NH:27][CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[C:24]([N+:33]([O-])=O)=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[NH2:33][C:24]1[C:25]([NH:27][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)=[N:26][C:21]([NH:20][C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH2:12][CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10]3)=[CH:19][CH:18]=2)=[N:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3ncc([N+](=O)[O-])c(NC4CCCC4)n3)cc2)C1
Agent: [Pd]
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3ncc(N)c(NC4CCCC4)n3)cc2)C1

Procedure:
Hydrogenation of 2-[[4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]phenyl]amino]-4-(cyclopentylamino)-5-nitropyrimidine (from Example 2(10) above) over Pd/C gave the title compound as a solid.
Reaction SMILES: [C:1]([N:8]([CH3:12])[CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.Cl[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=1[O-].C([O-])(O)=O.[Na+]>C(O)(CC)(C)C.CCO>[C:1]([N:8]([CH3:12])[CH2:9][CH2:10][NH:11][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: [O-][n+]1ccccc1Cl
Reactant: CN(CCN)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCC(C)(C)O
Product: CN(CCNc1ccccn1)C(=O)OC(C)(C)C
Reaction time: 41.5 h

Procedure:
A mixture of N-Boc-N-(methyl)ethylenediamine (Synth. Commun. 1993, 23, 2443-2449)(849.2 mg, 4.87 mmol), 2-chloropyridine N-oxide hydrochloride (970 mg, 5.84 mmol), and NaHCO3 (2.05 g, 24.4 mmol) in tert-amyl alcohol (12 mL) was heated at reflux under argon. After 41.5 h, the reaction was cooled, diluted with EtOH, filtered, and concentrated. The residue was reconcentrated from toluene and chromatographed (silica gel, 5% CH3OH/CHCl3) to give the title compound as a viscous, yellow oil which was used without further purification (863.1 mg, 66%), MS (ES) m/e 268 [M+H]+.