Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22]C=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1.CC1[O:40][N:39]=C(CO)C=1>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][CH2:20][C:25]4[CH:24]=[C:23]([CH3:22])[O:40][N:39]=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)Oc1ccccc1
Reactant: Cc1cc(CO)no1
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)OCc1cc(C)on1
Temperature: 100 °C

Procedure:
Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (30 mg, 0.065 mmol) was mixed with (5-methyl-3-isoxazolyl)methanol (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100° C. overnight. The solvent was removed and the residue was purified by preparative reverse phase LC/MS to give (5-methyl-3-isoxazolyl)methyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (18 mg, 0.038 mmol). 1H NMR (CDCl-d) δ 2.06(m, 4H), 2.44 (s, 3H), 3.64 (m, 2H), 3.91 (s, 3H), 4.13 (m, 2H), 4.96 (m, 1H), 5.26 (s, 2H), 6.12(s, 1H), 6.95 (s, 1H), 7.06 (m, 2H), 7.39 (s, 1H), 8.17 (bs, 1H), 8.21(s, 1H). LC/MS: MH+479.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.[CH:15]([NH:18][C:19]1[CH:23]=[CH:22][NH:21][N:20]=1)([CH3:17])[CH3:16]>ClCCl>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=[C:2]([N:21]2[CH:22]=[CH:23][C:19]([NH:18][CH:15]([CH3:17])[CH3:16])=[N:20]2)[CH:11]=1
Reactant: COc1ccc2c(Cl)cc(Cl)nc2c1
Reactant: CC(C)Nc1cc[nH]n1
Solvent: ClCCl
Product: COc1ccc2c(Cl)cc(-n3ccc(NC(C)C)n3)nc2c1
Temperature: 115 °C
Yield: 82.1 %

Procedure:
A mixture of 2,4-dichloro-7-methoxy-quinoline (1.34 g, 5.88 mmol) and isopropyl-(1H-pyrazol-3-yl)-amine (1.10 g, 8.80 mmol) was heated at 115° C. for 3 h while stirring in a sealed tube. After ˜20 min. of heating, the pressure built up in the tube was released by using a needle. The mixture was then dissolved in dichloromethane and loaded onto a silica gel column. Elution with dichloromethane and methanol afforded [1-(4-chloro-7-methoxy-quinolin-2-yl)-1H-pyrazol-3-yl]-isopropyl-amine (1.53 g, 82%). LC/MS=317.2 (M++1).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[CH:8]1([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[CH:28]=[N:27][CH:26]=[CH:25][C:21]=3[C:22](O)=[O:23])=[O:18])[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1>>[CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:22]([C:21]2[CH:25]=[CH:26][N:27]=[CH:28][C:20]=2[NH:19][C:17]([C:15]2[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=[C:11]([CH:8]3[CH2:10][CH2:9]3)[N:16]=2)=[O:18])=[O:23])[CH2:4]1
Reactant: COC1CCNC1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: COC1CCN(C(=O)c2ccncc2NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)C1
Yield: 18 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 3-methoxy-pyrrolidine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (18%) as off-white powder.
Reaction SMILES: O[C:2]1([C:8]([CH3:20])([CH3:19])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][O:3]1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>>[CH3:20][C:8]([CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][O:3]1)([CH3:19])[C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10]
Reactant: CC(C)(C(=O)OCc1ccccc1)C1(O)CCCCO1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C(=O)OCc1ccccc1)C1CCCCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred suspension of benzyl 2-bromo-2-methylpropanoate (0.748 g, 2.91 mmol), tetrahydro-2H-pyran-2-one (0.260 g, 2.60 mmol) and indium (0.341 g, 2.97 mmol) in THF (3 mL) was sonicated for 6 h. The reaction was quenched with sat. NaHCO3 and extracted with ether, then concentrated. The residue was purified by silica gel flash chromatography to afford benzyl 2-(2-hydroxytetrahydro-2H-pyran-2-yl)-2-methylpropanoate. 1H NMR (500 MHz, CDCl3) δ ppm 7.30-7.43 (5H, m), 5.18 (2H, s), 3.51-3.61 (2H, m), 2.41 (2H, t, J=7.10 Hz), 1.56-1.66 (2H, m), 1.35-1.47 (8H, m). Benzyl 2-(2-hydroxytetrahydro-2H-pyran-2-yl)-2-methylpropanoate was dissolved in triethylsilane (0.415 mL, 2.60 mmol) and treated with TFA (0.200 mL, 2.60 mmol) and the reaction mixture was stirred at rt for 16 h, then evaporated to dryness to yield benzyl 2-methyl-2-(tetrahydro-2H-pyran-2-yl)propanoate. 1H NMR (500 MHz, CDCl3) δ ppm 7.30-7.41 (5H, m), 5.22 (1H, d, J=12.66 Hz), 5.10 (1H, d, J=12.51 Hz), 3.91-4.01 (1H, m), 3.53 (1H, dd, J=11.22, 1.75 Hz), 3.39 (1H, td, J=11.56, 2.37 Hz), 1.82-1.92 (1H, m), 1.44-1.59 (4H, m), 1.30-1.41 (1H, m), 1.19-1.25 (3H, m), 1.11-1.19 (3H, m). A stirred suspension of 10% Pd—C (16.63 mg) and benzyl 2-methyl-2-(tetrahydro-2H-pyran-2-yl)propanoate (82 mg, 0.313 mmol) in EtOAc (5 mL) was stirred under H2 for 6 h, and then filtered and concentrated to yield Cap P-23 (54 mg). 1H NMR (500 MHz, CDCl3) δ ppm 4.09-4.19 (1H, m), 3.48-3.57 (1H, m), 3.33-3.42 (1H, m), 1.88-1.97 (1H, m), 1.71 (1H, d, J=13.12 Hz), 1.47-1.65 (3H, m), 1.29-1.40 (1H, m), 1.23-1.27 (3H, m), 1.14-1.20 (3H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[N+:14]([O-])([OH:16])=[O:15].C(O)(=O)C>C(OC(=O)C)(=O)C.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:14]([O-:16])=[O:15])[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COc1cc2c(cc1[N+](=O)[O-])C(=O)CCC2
Yield: 24 %

Procedure:
6-Methoxy-1-tetralone (12.0 g, 68.1 mmol) was dissolved in acetic anhydride (60 ml), a fuming nitric acid (4.8 ml)-acetic acid (4.2 ml) mixed solvent was slowly added dropwise under ice-cooling with stirring, and thereafter the mixture was stirred at the same temperature for 2 hr. The reaction mixture was diluted with ether, and the precipitated solid was collected by filtration and dried under reduced pressure. The obtained solid was recrystallized from benzene (100 ml), and the precipitated solid was filtered, dried under reduced pressure to give the title compound (3.62 g, yield 24%) as a colorless solid.
Reaction SMILES: CSC.B.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.[CH2:26]([C:28]1[C:46]([C:47]([F:50])([F:49])[F:48])=[CH:45][C:31]2[N:32]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33][CH2:34][CH2:35][C:36](=[O:37])[C:30]=2[CH:29]=1)[CH3:27].CO>ClCCl>[C:41]([O:40][C:38]([N:32]1[CH2:33][CH2:34][CH2:35][C@@H:36]([OH:37])[C:30]2[CH:29]=[C:28]([CH2:26][CH3:27])[C:46]([C:47]([F:50])([F:48])[F:49])=[CH:45][C:31]1=2)=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCCC2=O
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: CO
Solvent: CSC
Solvent: ClCCl
Product: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@H]2O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
Add a solution of borane dimethylsulfide complex (16.0 mL, 16.0 mmol, 1M in tetrahydrofuran) dropwise to a solution of (S)-2-methyl-CBS-oxazaborolidine (7.50 mL, 7.50 mmol, 1M in toluene) in dichloromethane (100 mL) at −30° C. under nitrogen. Stir the mixture for 30 min and add a solution of tert-butyl 7-ethyl-5-oxo-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (8.60 g, 24.0 mmol) in dichloromethane (50 mL) dropwise and warm the mixture slowly to 0° C. over a period of 6 h. Pour the mixture into methanol (200 mL) at −20° C. and slowly warm the stirring mixture to room temperature over 1 h. Remove the solvents under reduced pressure and purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (0 to 15%), to provide the title compound as a colorless oil (7.62 g, 88%): TLC Rf 0.49 (3:1 hexanes/ethyl acetate); 1H NMR (CDCl3, 300 MHz) δ 1.21-2.30 (m, 19H), 2.83-2.89 (m, 2H), 4.78-4.80 (m, 1H), 7.31-7.45 (m, 2H); Chiral HPLC (OD Column) 91.6% ee; APCI MS m/z 360 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)[CH:4]=[N:3]1.[CH:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([CH3:14])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH:12]([N:15]1[CH2:20][CH2:19][N:18]([C:9](=[O:11])/[CH:8]=[CH:7]/[C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[CH2:17][CH2:16]1)([CH3:14])[CH3:13]
Reactant: Cn1cc(/C=C/C(=O)O)cn1
Reactant: CC(C)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)/C=C/c2cnn(C)c2)CC1
Temperature: 25 °C
Yield: 48.3 %

Procedure:
(E)-3-(1-methyl-1H-pyrazol-4-yl)acrylic acid (913 mg, 6.00 mmol) and 1-isopropylpiperazine (1539 mg, 12.00 mmol) were dissolved in anhydrous DMF (12 mL) then HATU (2282 mg, 6.00 mmol) was added and the resulting reaction mixture was stirred over night at RT. The reaction mixture was diluted with concentrated aq. NaHCO3 and extracted with EtOAc (4×80 ml). The organic phases were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 760 mg 45A (48.3% yield) as a yellow oil residue. 45A was used directly in the next step with out further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97 (d, J=6.64 Hz, 6H) 2.42 (br. s., 4H) 2.63-2.75 (m, 1H) 3.60 (br. s., 5H) 3.82 (s, 4H) 6.92 (d, J=15.23 Hz, 1H) 7.36 (d, J=15.23 Hz, 1H) 7.84 (s, 1H) 8.03 (s, 1H), ES[M+H]+=263.26
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C[O-].[Na+].[O:8]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19]/[C:18]/2=[N:31]/[C:32]#[N:33])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO>[CH3:2][N:3]1[C:32]([NH2:33])=[N:31][C:18]2([C:17]3[C:22](=[CH:23][CH:24]=[C:15]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:16]=3)[O:21][CH:20]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:19]2)[O:4]1
Reactant: N#C/N=C1/CC(c2ccccc2)Oc2ccc(Oc3ccccc3)cc21
Reactant: CNO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1OC2(CC(c3ccccc3)Oc3ccc(Oc4ccccc4)cc32)N=C1N
Reaction time: 0.17 h
Yield: 51.6 %

Procedure:
To a solution of methylhydroxylamine HCl salt (83.6 mg, 1 mmol) in anhydrous MeOH (11 mL) was added NaOMe (25% in MeOH (Wt. %), 0.2 mL, 0.9 mmol), followed by (Z)—N-(6-phenoxy-2-phenylchroman-4-ylidene)cyanamide (340 mg, 1 mmol). After stirring for 10 min, the solvent was removed in vacuo. The residue was redissolved in DCM (30 mL) The mixture was filter, and the solvent was removed to give the residue, which was purified by column chromatography to give 2′-methyl-6-phenoxy-2-phenyl-2′H-spiro[chroman-4,5′-[1, 2, 4]oxadiazol]-3′-amine (200 mg, 52%). 1H-NMR (CDCl3): 2.41-2.66 (m, 1H), 2.65 (m, 1H), 2.75 (m, 1H), 3.32 (m, 3H), 5.35 (m, 1H), 6.95 (m, 2H), 7.06 (m, 1H), 7.20 (m, 2H), 7.42 (m, 3H), 7.48 (m, 3H), 7.51 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=5[F:38])[CH:33]=O)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:50]([N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)[CH3:51]>>[CH2:50]([N:52]1[CH2:57][CH2:56][N:55]([CH2:33][C:32]2[CH:35]=[CH:36][C:37]([F:38])=[C:30]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:20]=[C:15]([C:12]5[CH:13]=[N:14][C:9]([N:8]([CH2:39][C:40]6[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=6)[CH2:7][C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:49][CH:48]=6)=[N:10][CH:11]=5)[C:16]=4[CH2:29][CH2:28]3)[CH:31]=2)[CH2:54][CH2:53]1)[CH3:51]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cc(C=O)ccc3F)cn2)cc1
Reactant: CCN1CCNCC1
Product: CCN1CCN(Cc2ccc(F)c(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)c2)CC1

Procedure:
In the same manner as Step A in Example 1-D-26, using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (215 mg) and 4-fluoro-3-bromo-benzaldehyde (113 mg) instead of 2-(4-bromo-phenyl)-[1,3]dioxolane, a crude product of 3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-4-fluoro-benzaldehyde was obtained as a colorless solid (260 mg). Using a crude product (130 mg) of 3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-4-fluoro-benzaldehyde, in the same manner as Step B in Example 1-D-26, using 1-ethylpiperazine (0.05 ml) instead of 1-methylpiperazine, a crude product of 5-{7-[5-(4-ethyl-piperazin-1-ylmethyl)-2-fluoro-phenyl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine was obtained as a colorless solid (57 mg). Using a crude product (57 mg) of 5-{7-[5-(4-ethyl-piperazin-1-ylmethyl)-2-fluoro-phenyl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine, according to the above Deprotection method 2, 5-{7-[5-(4-ethyl-piperazin-1-ylmethyl)-2-fluoro-phenyl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-ylamine was obtained as a colorless powder (26 mg, 68%).
Reaction SMILES: C(OC(C1C=[CH:37][CH:36]=[CH:35][C:7]=1[O:8][C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1)=O)C.[F:39][CH:40]([F:49])[O:41][C:42]1C(O)=CC=C[N:43]=1>>[F:39][CH:40]([F:49])[O:41][C:42]1[C:7]([O:8][C:9]2[C:23]([O:24][C:25]3[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:29][CH:30]=3)=[CH:22][C:12]3[NH:13][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[N:15][C:11]=3[CH:10]=2)=[CH:35][CH:36]=[CH:37][N:43]=1
Reactant: CCOC(=O)c1ccccc1Oc1cc2nc(-c3ccccn3)[nH]c2cc1Oc1ccc(S(C)(=O)=O)cc1
Reactant: Oc1cccnc1OC(F)F
Product: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2cccnc2OC(F)F)cc1

Procedure:
The entitled compound was obtained as a pale yellow solid in the same method as in Example 14 or in accordance with the method or by combining it with an ordinary method but using 5-fluoro-4-(4-methanesulfonyl-phenoxy)-2-nitro-phenylamine obtained in Example 14 and 2-difluoromethoxy-pyridin-3-ol.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[C:20]1([CH:26]2[CH2:30][O:29][C:28](=[O:31])[NH:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:27]3[CH:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:30][O:29][C:28]3=[O:31])[CH2:6][CH2:7]2)=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: O=C1NC(c2ccccc2)CO1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)CN3C(=O)OCC3c3ccccc3)CC2)ccc1Cl

Procedure:
Compound 42 was prepared according to the procedure described in Example 2 using 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (0.1 mmol), 4-phenyl-oxazolidin-2-one and Cs2CO3 in DMF: HPLC retention time, 2.30 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 430.2, found, 430.3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[N:5]=[C:4]([CH2:12][CH3:13])[N:3]=1.CCOC(C)=O>CO.[Ni]>[NH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([CH2:12][CH3:13])=[N:5][C:6]=1[Cl:11]
Reactant: CCc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Agent: [Ni]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1nc(Cl)c(N)c(Cl)n1
Yield: 100 %

Procedure:
4,6-Dichloro-5-nitro-2-ethylpyrimidine (185 g, 0.83 mol) was dissolved in methanol (1.5 L) and reduced under 15 p.s.i. H2 in the presence of Raney nickel (30 g) for 5 hr. The mixture was filtered through Celite (washing well with MeOH) and the filtrate was evaporated to dryness to give 159.1 g (0.83 mol, quantitative yield) of the title compound as a chromatographically pure (silica gel plates, developed with EtOAc:hexanes, 3:1) dark liquid which was used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[C:20]1([CH3:31])[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29]Br)=[CH:22][CH:21]=1>O1CCCC1>[CH2:9]([O:8][C:6](=[O:7])[C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH2:29][CH2:28][CH2:27][CH2:26][C:23]1[CH:22]=[CH:21][C:20]([CH3:31])=[CH:25][CH:24]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:17])[CH3:10]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: Cc1ccc(CCCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCCc1ccc(C)cc1)(C(=O)OCC)c1ccccc1
Yield: 55 %

Procedure:
Phenylmalonic acid diethyl ester (8.8 mmol) dissolved in 5 ml absolute tetrahydrofuran is added dropwise to 20 ml absolute tetrahydrofuran and sodium hydride (9.7 mmol). Then 4-p-tolylbutyl bromide (8.8 mmol) dissolved in 10 ml absolute tetrahydrofuran is added after 15 minutes. It is heated for 3 days under reflux. The solvent is concentrated in a vacuum. The residue is taken up in 50 ml acette and extracted with 2×50 ml water. The organic phase is dried over magnesium sulfate, filtered and concentrated by evaporation. It is purified by chromatography on silica gel (heptane/ethyl acetate 9:1). Yield 55% colouriess oil.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=4)[CH2:14][CH2:13]3)[C:7](=[O:22])[CH:6]3[CH2:23][O:24][CH2:25][CH2:26][N:5]3[C:4]=2[N:3]=1.[CH3:27][NH:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1)=[O:30]>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:21][C:18]1[CH:19]=[C:20]2[C:15]([CH2:14][CH2:13][CH:12]2[N:8]2[C:7](=[O:22])[CH:6]3[CH2:23][O:24][CH2:25][CH2:26][N:5]3[C:4]3[N:3]=[C:2]([C:35]4[CH:34]=[CH:33][C:32]([NH:31][C:29]([NH:28][CH3:27])=[O:30])=[CH:37][CH:36]=4)[N:11]=[CH:10][C:9]2=3)=[CH:16][CH:17]=1
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=C1C2COCCN2c2nc(Cl)ncc2N1C1CCc2ccc(Cl)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CNC(=O)Nc1ccc(-c2ncc3c(n2)N2CCOCC2C(=O)N3C2CCc3ccc(Cl)cc32)cc1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 84 using 2-chloro-5-(6-chloro-2,3-dihydro-1H-inden-1-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (PREPARATION x41, 90 mg, 0.230 mmol), 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (127 mg, 0.460 mmol) and PdCl2(dppf) (8.42 mg, 0.012 mmol) in dioxane (2 mL) and aqueous saturated NaHCO3 (0.4 mL). 1H NMR (400 MHz, DMSO-d6) δ 2.36-2.45 (m, 2H), 2.62-2.66 (d, 3H), 3.08-3.22 (m, 3H), 3.55-3.67 (m, 3H), 3.95-4.10 (m, 1H), 4.13-4.30 (m, 1H), 4.38-4.66 (m, 2H), 6.03-6.16 (m, 1H), 7.14-7.43 (m, 4H), 7.43-7.52 (d, 2H), 8.03-8.16 (d, 2H), 8.72-8.82 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C26H25ClN6O3, 505.17. found 505.4.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][N:4]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[C:22]1[NH:23][C:24]2[CH:30]=[C:29]([C:31]([NH:33][NH2:34])=O)[CH:28]=[CH:27][C:25]=2[N:26]=1.CCOP(O)N(C(C)C)C(C)C.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.CCOC(C)=O>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[C:22]1[NH:23][C:24]2[CH:30]=[C:29]([C:31]3[O:8][C:7]([C:6]4[CH:5]=[N:4][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:11][CH:10]=4)=[N:34][N:33]=3)[CH:28]=[CH:27][C:25]=2[N:26]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: CCOP(O)N(C(C)C)C(C)C
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(-c2nnc(-c3ccc4nc(-c5c(Cl)cccc5Cl)[nH]c4c3)o2)cn1
Temperature: 150 °C
Reaction time: 17 h
Yield: 57.8 %

Procedure:
6-Trifluoromethyl-nicotinoyl chloride (119 uL, 0.817 mmol) was added to a solution of 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (250 mg, 0.778 mmol) in THF (10 mL) and EDIPA (149 uL, 0.856 mmol). The reaction was stirred for 17 hr. The reaction was diluted with EtOAc (75 mL) and extracted with water (20 mL). The organic phase was dried over Na2SO4 and concentrated. The concentrate was taken up in DMF (3 mL) and transferred to a microwave vial charged with Burgess reagent (555 mg, 2.33 mmol). The reaction was heated to 150° C. for 15 min by microwave irradiation. The reaction was diluted with EtOAc (75 mL) and extracted with water (15 mL). The organic phase was dried over Na2SO4 and concentrated. The concentrate was purified by silica gel column chromatography (15-40% ACN/DCM) and the resulting colorless film triturated with MeOH/DCM to afford the title compound (214 mg): 1H NMR (400 MHz, DMSO-d6) δ ppm 7.64-7.68 (m, 1H) 7.71 (s, 1H) 7.73 (d, J=2.02 Hz, 1H) 7.83 (tautomer, d, J=8.46 Hz, 1H) 7.97 (tautomer, d, J=8.59 Hz, 1H) 8.12 (dd, J=14.15, 8.72 Hz, 1H) 8.21 (d, J=8.34 Hz, 1H) 8.41 (tautomer, s, 1H) 8.60 (tautomer, s, 1H) 8.85 (d, J=8.34 Hz, 1H) 9.54 (s, 1H) 13.41 (d, J=14.15 Hz, 1H); LCMS tR=1.53 min, MS (m/z) 476.7.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:7][CH2:6]2)#N.C(O)=[O:18]>[Ni]>[CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:7][CH2:6]2)=[O:18]
Reactant: CCC(=O)NC1CCc2cc(C#N)ccc21
Reactant: O=CO
Agent: [Ni]
Product: CCC(=O)NC1CCc2cc(C=O)ccc21
Yield: 80 %

Procedure:
1.46 g of N-(5-cyanoindan-1-yl)propionic acid amide were dissolved in 20 ml of a 75% aqueous formic acid solution. 1.1 g of Rainey nickel were added to this solution followed by heating and refluxing for 2 hours. After returning the reaction solution to room temperature and filtering with CELITE, the solvent was distilled off under reduced pressure. The resulting residue was added to water, and extracted with ethyl acetate. After washing the organic layer with saturated aqueous sodium bicarbonate and saturated brine, the organic layer was dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.18 g of the target compound. Yield: 80%