Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6]C(=O)CCCCCCCCCCCCC)=[N+:2]=[N-:3].[C:22]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:27][CH:28]=1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Agent: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)NCCN=[N+]=[N-])cc1
Yield: 73 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, 4-tert-butylbenzoyl chloride (0.244 g, 1.23 mmol) was reacted with 2-azidoethanamine (0.106 g, 1.23 mmol) and triethylamine (0.249 g, 2.47 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-4-tert-butylbenzamide (0.221 g, 73%). 1H NMR (300 MHz, CDCl3) δ 7.73 (d, 2H), δ 7.43 (d, 2H), δ 6.95 (t, 1H), δ 3.59 (q, 2H), δ 3.50 (t, 2H), δ 1.31 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.2, 155.4, 131.4, 127.2, 125.8, 51.1, 39.7, 35.2, 31.4 ppm; HRMS (ESI) calcd for C13H18N4O (M+) 246.1480. Found 246.1479.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:35])=[C:6]([N:8]2[CH2:33][CH2:32][C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]([N:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)=[O:24])=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[C:9]2=[O:34])[CH:7]=1.[F:36][C:37]([F:48])([F:47])[C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41](O)=[O:42].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OC(=O)C)C>[CH3:35][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:41](=[O:42])[C:40]2[CH:44]=[CH:45][CH:46]=[C:38]([C:37]([F:36])([F:47])[F:48])[CH:39]=2)=[CH:7][C:6]=1[N:8]1[CH2:33][CH2:32][C:11]2[N:12]=[C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)=[O:24])=[CH:21][CH:22]=3)[N:14]=[CH:15][C:10]=2[C:9]1=[O:34]
Reactant: Cc1ccc(N)cc1N1CCc2nc(Nc3ccc(C(=O)N4CCN(C)CC4)cc3)ncc2C1=O
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N1CCc2nc(Nc3ccc(C(=O)N4CCN(C)CC4)cc3)ncc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
To a solution of 6-(5-Amino-2-methyl-phenyl)-2-[4-(4-methyl-piperazine-1-carbonyl)phenylamino]-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one (70.7 mg, 0.15 mmol), 3-Trifluoromethyl benzoic acid (28.5 mg, 0.15 mmol), and DIPEA (78 μl, 0.45 mmol) in DMF was added HATU (59 mg, 0.15 mmol), and the reaction mixture was stirred for 3 hour at room temperature. The reaction mixture was diluted with ethylacetate and washed with 5% aqueous sodium bisulphate solution, saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography (SiO2, 2-10% methanol in chloroform) to give 69.8 mg (72.3%) of N-(4-Methyl-3-{2-[4-(4-methyl-piperazine-1-carbonyl)phenylamino]-5-oxo-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-phenyl)-3-trifluoromethyl-benzamide [24] as a pale yellow solid.
Reaction SMILES: [S:1]([O:11][CH2:12][C:13]1([CH2:35][O:36][S:37]([C:40]2[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=2)(=[O:39])=[O:38])[CH2:26][C@@H:25]2[C@:16]34[CH2:29][CH2:28][N:27]([CH3:30])[C@@H:24]2[CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:31][CH3:32])=[C:18]([O:33][C@H:15]3[C@@H:14]1[OH:34])[C:17]4=2)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CS(C)=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[S:37]([O:36][CH2:35][C:13]1([CH2:12][O:11][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:2])=[O:3])[CH2:26][C@@H:25]2[C@:16]34[CH2:29][CH2:28][N:27]([CH3:30])[C@@H:24]2[CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:31][CH3:32])=[C:18]([O:33][C@H:15]3[C:14]1=[O:34])[C:17]4=2)([C:40]1[CH:41]=[CH:42][C:43]([CH3:44])=[CH:45][CH:46]=1)(=[O:39])=[O:38]
Reactant: COc1ccc2c3c1O[C@H]1[C@H](O)C(COS(=O)(=O)c4ccc(C)cc4)(COS(=O)(=O)c4ccc(C)cc4)C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Solvent: CS(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c3c1O[C@H]1C(=O)C(COS(=O)(=O)c4ccc(C)cc4)(COS(=O)(=O)c4ccc(C)cc4)C[C@H]4[C@@H](C2)N(C)CC[C@]314
Temperature: 25 °C
Yield: 81.1 %

Procedure:
A solution of crude 2 (66.6 g, 99.4 mmole) in CH2Cl2 (250 mL) was added dropwise under argon to a mixture prepared from DMSO (14.2 mL, 200 mmole) in CH2Cl2 (100 mL) and TFAA (21.2 mL, 150 mmole) in CH2Cl2 (70 mL) as reported above for 6. The mixture was stirred in the dry ice acetone bath for 90 min. TEA (40 mL) was added and the mixture then allowed to warm to room temperature. The solution was evaporated, the residue dissolved in CHCl3 and washed 3 times with dilute NH4OH. Evaporation of the dried organic phase gave a foam which crystallized from 95% ethanol to give 53.8 g (81%) of 10 as white crystals, mp 150°-153° C. Recrystallization from 95% ethanol gave analytically pure 10, mp 155°-156° C.; NMR δ 7.2-7.9 (m, 811, tosyl 11's); 7.70 (s, 2H, H1 and H2); 4.47 (s, H5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][N:12]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[CH3:33][C:34](OC(C)=O)=[O:35].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][N:12]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][N:18]([C:34](=[O:35])[CH3:33])[CH2:19][CH2:20]1
Reactant: CC(=O)OC(C)=O
Reactant: Fc1cccc(CN(CCN2CCNCC2)Cc2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N1CCN(CCN(Cc2cccc(F)c2)Cc2nccn2Cc2cc(Cl)cc(Cl)c2)CC1
Yield: 67.5 %

Procedure:
To a solution of [1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylmethyl]-(3-fluoro-benzyl)-(2-piperazin-1-yl-ethyl)-amine (55 mg, 0.12 mmol) in CH2Cl2 at ambient temperature was added dropwise Ac2O (34 μL, 0.36 mmol). The mixture was stirred for 2 h before addition of saturated NaHCO3 (6 mL). The mixture was extracted with CH2Cl2 (2×20 mL) and the combined extracts dried over Na2SO4 then concentrated in vacuo. The residue was purified by semi-preparative HPLC to provide the title compound (42 mg, 66%) as a viscous oil: ESI MS m/z 518 [C26H30Cl2FN5O+H]+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[S:5][CH:6]=1.[Li]CCCC.[F:18][C:19]([F:27])([F:26])[C:20](N(OC)C)=[O:21]>C(OCC)C.C1COCC1>[F:18][C:19]([F:27])([F:26])[C:20]([C:2]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[S:5][CH:6]=1)=[O:21]
Reactant: Brc1csc(N2CCOCC2)n1
Reactant: CON(C)C(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(c1csc(N2CCOCC2)n1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 47 %

Procedure:
To a chilled (−78° C.) solution of 4-(4-bromothiazol-2-yl)morpholine (249 mg, 1.00 mmol) in dry diethyl ether (10 mL) was added n-BuLi (480 μL, 2.5 M in hexanes, 1.20 mmol). After 20 minutes, a solution of 2,2,2-trifluoro-N-methoxy-N-methylacetamide (224 μL, 2 mmol) in THF (10 mL) was added over 10 minutes. After 30 minutes, the mixture was warmed to 0° C. After 30 minutes, the mixture was quenched with 10 mL of water, warmed to room temperature, and extracted with three 10 mL portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was twice purified on SiO2 using ethyl acetate-hexanes (20-100% gradient) to afford 125 mg (47%) of the title compound.
Reaction SMILES: C[O-].[Na+].[CH:4](OCC)=[O:5].[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[CH2:18][C:19]#[N:20].O>C1C=CC=CC=1>[CH:4]([CH:18]([C:11]1[C:12]([CH3:17])=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=1[CH3:9])[C:19]#[N:20])=[O:5]
Reactant: Cc1cc(C)c(CC#N)c(C)c1
Reactant: CCOC=O
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: Cc1cc(C)c(C(C#N)C=O)c(C)c1

Procedure:
To a stirred mixture of sodium methoxide (2.78 g, 51 mmol) and ethyl formate (4.0 g, 54 mmol) in 100 mL of benzene was added 2,4,6 trimethylphenylacetonitrile (8.0 g, 50 mmol) over 5 min. After stirring for an additional hour it was treated with water (100 mL) and the layers were separated. The aqueous layer was separated and acidified with 10% HCl and extracted with ethyl acetate. After drying the solvent was removed in vacuo to afford a-formyl-2,4,6-trimethylphenylacetonitrile as colorless crystals melting at 120°-122° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[NH:6][C:5]2=[O:15].N[CH2:17][C@@H:18]([OH:21])[CH2:19][OH:20].N1C=CN=C1>C(O)CCCC>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[N:6]([CH2:17][C@@H:18]([OH:21])[CH2:19][OH:20])[C:5]2=[O:15]
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)NC2=O
Reactant: NC[C@@H](O)CO
Agent: c1c[nH]cn1
Solvent: CCCCCO
Product: Nc1cc2c(cc1[N+](=O)[O-])C(=O)N(C[C@@H](O)CO)C2=O
Temperature: 25 °C
Yield: 83.2 %

Procedure:
A mixture of 5-amino-6-nitroisoindoline-1,3-dione (2.27 g, 10.98 mmol), (R)-3-aminopropane-1,2-diol (1.0 g, 10.98 mmol), and imidazole (0.75 g, 10.98 mmol) in 100 mL of pentanol was heated to reflux and maintained for 8 h and allowed to cool down to rt. The precipitate was filtered and washed with heptanes and dried to give a yellow crystalline solid (2.57 g, 9.14 mmol, 83%). 1H NMR (500 MHz, DMSO-d6) δ58.38 (s, 2H), 8.31 (s, 1H), 7.45 (1, 1H), 4.90 (d, J=5.0 Hz, 1H), 4.66 (t, J=5.5 Hz, 1H), 3.82-3.74 (m, 1H), 3.55 (d, J=6.5 Hz, 2H), 3.42-3.18 (m, 2H). ESI MS: m/z 279.8 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[N:8][NH:7][C:6]1=[S:13].[OH-].[Na+].[CH3:21]I>C(O)C.O>[Br:1][C:2]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[N:8][N:7]=[C:6]1[S:13][CH3:21]
Reactant: Cc1n[nH]c(=S)n(Cc2cc(F)ccc2Br)c1=O
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1nnc(C)c(=O)n1Cc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 4-(2-bromo-5-fluorobenzyl)-6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one (16, 914 mg, 2.77 mmol) in ethanol (15 mL) was added NaOH (111 mg, 2.77 mmol) followed by MeI (787 mg, 5.54 mmol). The mixture was stirred at RT for 10 min to produce a clear yellow solution. The reaction was diluted with water (100 mL), and extracted with EtOAc (30 mL×2). The extracts were washed with brine, dried over MgSO4 and concentrated to give the crude product. This was purified by silica gel column, and eluted with 20-25% ethyl acetate in petroleum ether to give 4-(2-bromo-5-fluorobenzyl)-6-methyl-3-(methylthio)-1,2,4-triazin-5(4H)-one (17). 1H NMR (400 MHz, DMSO, ppm): δ 7.73 (m, 1H), 7.16 (br, 1H), 7.05 (d, 1H), 5.09 (s, 2H), 2.56 (s, 3H), 2.32 (s, 3H). MS: m/z, 344 (100%, M+1), 346 (100%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]3[O:11][CH2:12][C:13](=[O:17])[NH:14][C:15]=3[N:16]=2)[CH2:5][C@H:4]([CH2:18][N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[O:3]1.Cl[C:26]1[N:35]=[C:34]2[C:29]([C:30](=[O:43])[C:31]3[C:41](=[O:42])[NH:40][S:39][C:32]=3[N:33]2[CH:36]2[CH2:38][CH2:37]2)=[CH:28][C:27]=1[F:44]>>[CH:36]1([N:33]2[C:34]3[C:29](=[CH:28][C:27]([F:44])=[C:26]([N:22]4[CH2:23][CH2:24][N:19]([CH2:18][C@@H:4]5[O:3][C:2](=[O:1])[N:6]([C:7]6[CH:8]=[CH:9][C:10]7[O:11][CH2:12][C:13](=[O:17])[NH:14][C:15]=7[N:16]=6)[CH2:5]5)[CH2:20][CH2:21]4)[N:35]=3)[C:30](=[O:43])[C:31]3[C:41]([OH:42])=[N:40][S:39][C:32]2=3)[CH2:38][CH2:37]1
Reactant: O=C1COc2ccc(N3C[C@H](CN4CCNCC4)OC3=O)nc2N1
Reactant: O=c1[nH]sc2c1c(=O)c1cc(F)c(Cl)nc1n2C1CC1
Product: O=C1COc2ccc(N3C[C@H](CN4CCN(c5nc6c(cc5F)c(=O)c5c(O)nsc5n6C5CC5)CC4)OC3=O)nc2N1
Yield: 49 %

Procedure:
In analogy to Example 2, starting from 6-((S)-2-oxo-5-piperazin-1-ylmethyl-oxazolidin-3-yl)-4H-pyrido[3,2-b][1,4]oxazin-3-one (intermediate 19.1; 133 mg) and 7-chloro-9-cyclopropyl-6-fluoro-isothiazolo[5,4-b][1,8]naphthyridine-3,4(2H,9H)-dione (93 mg; prepared according to Chu et al., J. Heterocycl. Chem. (1990), 27(5), 1191-1195), the title compound was obtained as a beige solid (90 mg; 49% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][C:12]1[C:24]([CH3:25])=[C:23]([CH3:26])[C:15]2[O:16][C:17]([CH2:21][OH:22])([CH3:20])[CH2:18][CH2:19][C:14]=2[C:13]=1[CH3:27].C(N(CC)CC)C>C(Cl)Cl>[OH:11][C:12]1[C:24]([CH3:25])=[C:23]([CH3:26])[C:15]2[O:16][C:17]([CH:21]=[O:22])([CH3:20])[CH2:18][CH2:19][C:14]=2[C:13]=1[CH3:27]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CO)O2
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C=O)O2
Temperature: -78 °C
Reaction time: 0.2 h
Yield: 71.1 %

Procedure:
A solution prepared by the sequential addition of oxalyl chloride (2.9 g, 23 mmol) and dimethyl sulfoxide (3.7 g, 47 mmol) to methylene chloride which had been cooled to -78° C. was allowed to stir for 12 minutes. A solution of 6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[1,2-b]pyran-2-yl methanol (4.0 g, 18 mmol) in 50 mL methylene chloride was then added dropwise to the reaction mixture. After stirring for 40 min., triethylamine (7.3 g, 72.6 mmol) was added dropwise over 5 min. The reaction mixture was stirred at -78° C. for 15 min and then at ambient temperature for 30 min. The reaction mixture was diluted with methylene chloride (100 mL). The resulting solution was washed (water 100 mL, brine 100 mL, water 100 mL), dried (magnesium sulfate), and concentrated under reduced pressure to give a yellow oil. The oil was chromatographed (SiO2, 200 g, ethyl acetate-hexane, 1:9) to give 6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[1,2-b]pyran-2-yl methanal as a white solid (3.0 g, 70% yield).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:11]#[N:12].[OH-:19].[Na+]>S(=O)(=O)(O)O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:13]1[N:14]=[CH:15][CH:16]=[CH:17][N:18]=1)[C:11]([NH2:12])=[O:19]
Reactant: N#CC(=C1Nc2ccccc2S1)c1ncccn1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)C(=C1Nc2ccccc2S1)c1ncccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
2-[Benzothiazol-2(3H)-ylidene]-2-(pyrimidin-2-yl)acetonitrile (0.1 g, 0.39 mmol) was dissolved in concentrated sulfuric acid (2 mL) and stirred at room temperature for 5 hr. The mixture was cooled to 0° C., poured over ice, and neutralized with 50% aqueous sodium hydroxide. The precipitate that formed was collected by filtration and purified by reverse phase preparative HPLC to give 2-[benzothiazol-2(3H)-ylidene]-2-(pyrimidin-2-yl)acetamide (42 mg, 40% yield) as a yellow solid.
Reaction SMILES: NC1C(C(N)=[O:9])=C(N2CCC(C3N(C)C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=CN=1.[NH2:34][C:35]1[C:40]([C:41]#[N:42])=[C:39]([N:43]2[CH2:48][CH2:47][CH:46]([C:49]3[N:50]([CH2:64][CH2:65][N:66]4[CH2:69][CH2:68][CH2:67]4)[CH:51]=[C:52]([C:54]4[CH:59]=[CH:58][C:57]([O:60][CH:61]([F:63])[F:62])=[CH:56][CH:55]=4)[N:53]=3)[CH2:45][CH2:44]2)[N:38]=[CH:37][N:36]=1>>[NH2:34][C:35]1[C:40]([C:41]([NH2:42])=[O:9])=[C:39]([N:43]2[CH2:48][CH2:47][CH:46]([C:49]3[N:50]([CH2:64][CH2:65][N:66]4[CH2:67][CH2:68][CH2:69]4)[CH:51]=[C:52]([C:54]4[CH:55]=[CH:56][C:57]([O:60][CH:61]([F:63])[F:62])=[CH:58][CH:59]=4)[N:53]=3)[CH2:45][CH2:44]2)[N:38]=[CH:37][N:36]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(OC(F)F)cc3)cn2CCN2CCC2)CC1
Product: NC(=O)c1c(N)ncnc1N1CCC(c2nc(-c3ccc(OC(F)F)cc3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(4-difluoromethoxy-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=513, obsd.=513).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:24]3[CH:29]=[CH:28][N+:27]([O-])=[CH:26][CH:25]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.O.[PH2]([O-])=O.[Na+]>[Pd].C(O)(=O)C>[O:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[N:9]=2)=[CH:16][CH:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2-c1cc[n+]([O-])cc1
Agent: [Pd]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2-c1ccncc1
Reaction time: 2 h
Yield: 20 %

Procedure:
A suspension of 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyridiniumolate (0.100 g, 0.00025 mol) and 10% palladium on carbon (0.016 g, 0.00002 mol) in acetic acid (3 mL) was reacted with sodium hypophosphite monohydrate (0.033 g, 0.00038 mol) at 60° C. After 2 hours, an additional 10% palladium on carbon (0.016 g, 0.00002 mol) was added. The mixture was stirred 18 hours after which time additional 10% palladium on carbon (0.016 g, 0.00002 mol) and sodium hypophosphite monohydrate (0.033 g, 0.00038 mol) was added. The mixture was stirred for an additional 24 hours. The mixture was filtered through Celite® 521, washing with acetic acid. The solvent was removed in vacuo, and the residue was purified by preparative RP-HPLC (Rainin C18, 8 mm, 300 A, 25 cm; 40% isocratic for five minutes, then 40%-100% acetonitrile—0.1M ammonium acetate over 30 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give 3-(4-phenoxyphenyl)-1-(4-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.020 g, 0.00005 mol) as a white solid:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[C:31]([F:37])[CH:30]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15][N:11]2[C:12](=[O:14])[N:13]=1)#[N:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[NH:17][CH2:16][CH2:15][N:11]3[C:12](=[O:14])[N:13]=2)[CH:25]=[CH:26][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[C:31]([F:37])[CH:30]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(C#N)c(F)c3)c(C#N)c1)nc2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(Oc2ccc(COc3cc4n(c(=O)n3)CCN4)cc2C#N)cc1F

Procedure:
Prepared in a manner similar to that described for E60 using tert-butyl 7-((3-cyano-4-(4-cyano-3-fluorophenoxy)benzyl)oxy)-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate (70 mg, 0.139 mmol) in DCM (4 mL) and TFA (0.5 mL).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][CH:21]([OH:29])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[OH:29][CH:21]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:20][CH2:19][CH:14]1[CH2:15][CH2:16][C:17](=[O:18])[N:13]1[CH2:12][CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:30])=[O:2])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(CCCN2C(=O)CCC2CCC(O)Cc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CCCN2C(=O)CCC2CCC(O)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.2 %

Procedure:
To a solution of 4-{3-[2-(3-hydroxy-4-phenyl-butyl)-5-oxo-pyrrolidin-1-yl]-propyl}-benzoic acid methyl ester (2.28 g, 5.57 mmol) in MeOH (20 mL) was added 2N NaOH (5 mL). The reaction mixture was stirred at room temperature for 20 h and was heated under reflux for 3 h. The-volatiles were removed in vacuo and the residue was diluted with CH2Cl2 and 1N HCl. The aqueous solution was extracted with CH2Cl2 (2×) and the combined organic extracts were washed with brine. The organic solution was dried (MgSO4), filtered and concentrated to yield the title compound (2.03 g). 1H NMR (CDCl3) δ7.98 (d, 2H), 7.34-7.18 (m, 7H), 3.80 (m, 1H), 3.67 (m, 1H), 3.58 (m, 1H), 2.97 (m, 1H), 2.81 (m, 1H), 2.68 (m, 3H), 2.45-2.27 (m, 2H), 2.13-1.30 (m, 9H); MS 396.3 (M+1), 394.2 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.C[O-].[Na+].CO.Cl.C(Cl)(=O)C(Cl)=O.Cl.[NH:26]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:27].C(O)C.[O-]CC.[Na+]>O1CCCC1.CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6]([OH:8])=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:26]([CH3:27])[C:9]2=[O:10])=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Reactant: CCOC(=O)CNC
Agent: CC[O-]
Agent: C[O-]
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CO
Product: CCOC(=O)c1c(O)c2ccc(Cl)cc2c(=O)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.9 %

Procedure:
To a solution of 4-chlorophthalic anhydride (9.13 g, 50 mmol) in tetrahydrofuran (50 ml) was added 28% sodium methoxide-methanol solution (11.6 ml, 60 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water, and, after making the mixture acidic with 1N hydrochloric acid, extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (100 ml) and oxalyl chloride (5.2 ml, 60 mmol) and N,N-dimethylformamide (3 drops) were added thereto. The mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (100 ml). To the obtained solution was added ethyl sarcosinate hydrochloride (9.22 g, 60 mmol). The obtained mixture was stirred at room temperature for 2 h. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (100 ml) and 20% sodium ethoxide ethanol solution (27.2 g, 80 mmol) was added. The mixture was stirred at room temperature for 1 h. The reaction mixture was poured into 1N hydrochloric acid (100 ml) and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the component eluted earlier was concentrated to give ethyl 7-chloro-4-hydroxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (2.24 g, 20.9%) as crystals.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].S([O-])(=O)(=O)C.S(O[CH:15]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1)(C)(=O)=O>O>[N:1]([CH:19]1[CH2:15][CH2:16][CH:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)C1CCC(OS(C)(=O)=O)C1
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)C1CCC(N=[N+]=[N-])C1

Procedure:
Sodium azide (156 mg) was added to the mesylate [prepared in (1) ]dissolved in hexamethylphosphamide (3 ml). The mixture was poured into water. The mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and then evaporated to obtain the title compound having the following physical data.