Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:27])[N:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[C:14]([C:19](O)=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:4](=[O:22])[C:3]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:2]12.[CH2:28]([NH2:33])[CH2:29][CH:30]([CH3:32])[CH3:31].C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>>[CH2:28]([NH:33][C:19]([C:14]1[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]2[C:4](=[O:22])[C:3]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:2]3[C:1]2=[O:27])=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:20])[CH2:29][CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)CCN
Reactant: O=C(O)c1ccccc1-c1ccccc1CN1C(=O)c2ccccc2C1=O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Product: CC(C)CCNC(=O)c1ccccc1-c1ccccc1CN1C(=O)c2ccccc2C1=O

Procedure:
From 3 g (8.4 mmol) of 2′-phthalimidomethylbiphenyl-2-carboxylic acid (precursor 2), by reaction with isopentylamine in the presence of HOBT and DIC, 3.2 g of 2′-phthalimidomethylbiphenyl-2-carboxylic acid isopentylamide were obtained; m.p. 169° C. The product was dissolved in 100 ml of methanol and treated with 5 ml of hydrazine hydrate. After stirring at 40° C. for 1 h, the cooled reaction mixture was filtered. The filtrate was concentrated and the residue was taken up in methylene chloride. After washing with water, drying and concentrating, 1.8 g of 2′-amino-methylbiphenyl-2-carboxylic acid isopentylamide were obtained.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[CH:16][CH2:17][CH2:18][OH:19])C1C=CC=CC=1>C(O)C>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][CH2:18][OH:19]
Reactant: OCCC=Cc1ccccc1OCc1ccccc1
Solvent: CCO
Product: OCCCCc1ccccc1O

Procedure:
4-(2-Benzyloxyphenyl)-3-buten-1-ol was hydrogenated in ethanol using the same method as in Example 20b.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:18]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:21]2[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:20]=2[N:19]=1)[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:11]([O:10][CH2:9][C@H:8]([NH2:7])[C:18]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:21]2[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:20]=2[N:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)c1nc2ccc(F)cc2n1-c1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](COCc1ccccc1)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [(R)-2-benzyloxy-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (420 mg, 0.91 mmol) in DCM (6 mL) was added TFA (3 mL) and the mixture stirred at RT for 2 h. The volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The crude material was used in the following step without further purification. Yellow oil (284 mg, 86%). LCMS (Method B): RT 2.16 min [M+H]+ 363.20.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].C(=O)([O-])[O-].[K+].[K+].Br[CH2:58][C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:60]>>[CH2:62]([O:61][C:59](=[O:60])[CH2:58][O:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1c(C)cc2c(c1OCC(=O)OCc1ccccc1)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Yield: 52 %

Procedure:
Following General Procedure: Method A using (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (35 mg, 0.050 mmol), potassium carbonate (21 mg, 0.15 mmol) and benzyl bromoacetate (24 μL, 0.15 mmol), the product was purified by preparative TLC (silica gel, 95:5 dichloromethane/methanol) to afford (6R,6aS,14aR)-methyl 1-(2-(benzyloxy)-2-oxoethoxy)-6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (22 mg, 51%) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 14.18 (s, 1H), 8.29 (s, 1H), 7.44-7.31 (m, 5H), 6.88 (d, J=8.7 Hz, 1H), 6.85 (s, 1H), 5.87 (s, 1H), 5.40 (d, J=12.2 Hz, 1H), 5.31 (d, J=12.2 Hz, 1H), 5.00 (s, 1H), 4.95 (dd, J=9.9, 7.3 Hz, 1H), 4.68 (d, J=8.7 Hz, 1H), 4.54 (d, J=15.2 Hz, 1H), 4.48 (br s, 1H), 4.45 (br s, 1H), 3.78 (s, 3H), 3.76-3.71 (m, 1H), 3.69 (d, J=1.6 Hz, 1H), 3.60-3.54 (m, 2H), 3.60 (s, 6H), 3.39 (s, 3H), 3.36-3.32 (m, 1H), 3.13 (t, J=9.2 Hz, 1H), 2.47 (d, J=4.5 Hz, 1H), 2.18 (s, 3H), 1.36 (d, J=6.2 Hz, 3H); MS (ESI+) m/z 846 (M+H); HPLC 94.4% (AUC), tR 18.76 min.
Reaction SMILES: C(O)(C)C.[F:5][C:6]1[CH:7]=[C:8]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH:19]3[CH2:24][CH2:23][Si:22](OC(C)C)(OC(C)C)[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:9]=[CH:10][C:11]=1[F:12].C(C1C=CC=CC=1)(=O)C>C(N(CC)CC)C>[F:5][C:6]1[CH:7]=[C:8]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH:19]3[CH2:24][CH2:23][SiH2:22][CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: CC(C)O[Si]1(OC(C)C)CCC([C@H]2CC[C@H](c3ccc(F)c(F)c3)CC2)CC1
Solvent: CC(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Fc1ccc([C@H]2CC[C@H](C3CC[SiH2]CC3)CC2)cc1F

Procedure:
A solution, in 100 ml of dichloromethane, of 42.0 g of 4-(trans-4-(3,4-difluorophenyl)cyclohexyl)-1,1-diphenyl-1-silacyclohexane obtained in Preparatory Example 1 was added to 250 ml of a dichloromethane solution of 1.0 mol/liter of iodine monochloride at room temperature, followed by agitation for 1 hour to obtain 4-(trans-4-(3,4-difluorophenyl)cyclohexyl)-1,1-dichloro-1-silacyclohexane. Subsequently, a mixture of 50.0 g of isopropyl alcohol and 300 g of triethylamine was added to the solution at room temperature, followed by agitation under reflux for 1 hour. The resultant solution was concentrated, after which 200 ml of hexane was added thereby permitting secondarily produced hydrochloride to be settled down. The hydrochloride was removed by filtration and the resultant filtrate was concentrated to obtain a mixture of 4-(trans-4-(3,4-difluorophenyl)cyclohexyl)-1,1-diisopropoxy-1-silacyclohexane and acetophenone. This mixture was subjected to distillation under reduced pressure to remove the acetophenone therefrom, and the residue was dissolved in 100 ml of THF and added to a solution of 10.0 g of lithium aluminium hydride in 100 ml of THF. The reaction mixture was agitated under reflux for 1 hour, after which the mixture was poured into 200 ml of 5% hydrochloric acid and extracted with ethyl acetate. The resultant extract was washed with brine, dried and concentrated by a usual manner, followed by purification through silica gel chromatography to obtain 26.2 g of 4-(trans-4-(3,4-difluorophenyl)cyclohexyl)-1-silacyclohexane. The results of IR analysis of the product are shown below.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[N:9][N:10]=[C:6]2[C:5]([N+:11]([O-])=O)=[C:4]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[C:3]=1[CH3:20]>[Pt].C(#N)C>[NH2:11][C:5]1[C:6]2[N:7]([N:8]=[N:9][N:10]=2)[C:2]([CH3:1])=[C:3]([CH3:20])[C:4]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19]
Reactant: Cc1c(NCCCCO)c([N+](=O)[O-])c2nnnn2c1C
Agent: [Pt]
Solvent: CC#N
Product: Cc1c(NCCCCO)c(N)c2nnnn2c1C

Procedure:
Crude 4-[(5,6-dimethyl-8-nitrotetraazolo[1,5-a]pyridin-7-yl)amino]butan-1-ol was combined in a pressure vessel with catalyst (1.3 g of 5% platinum on carbon), and acetonitrile (222 mL). The reaction mixture was placed under hydrogen pressure (30 psi, 2.1×105 Pa) for 3 hours, filtered through a layer of CELITE filter aid, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure to provide 11.15 g of 4-[(8-amino-5,6-dimethyl-tetrazolo[1,5-a]pyridin-7-yl)amino]butan-1-ol.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:33]2[C:32]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([C:42](O)=[O:43])=[CH:38][CH:37]=3)=[CH:31][S:30][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=O)C.Cl.[NH2:46][CH2:47][C:48]([NH2:50])=[O:49].OCCN1CCNCC1>>[C:48]([CH2:47][NH:46][C:42]([C:39]1[CH:38]=[CH:37][C:36]([CH2:35][CH2:34][C:32]2[C:33]3[C:25]([O:24][C@@H:6]4[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]4[OH:4])=[CH:26][CH:27]=[CH:28][C:29]=3[S:30][CH:31]=2)=[CH:41][CH:40]=1)=[O:43])(=[O:49])[NH2:50]
Reactant: NCC(N)=O
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3scc(CCc4ccc(C(=O)O)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: OCCN1CCNCC1
Product: NC(=O)CNC(=O)c1ccc(CCc2csc3cccc(O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c23)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 90 using 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-[2-(4-carboxyphenyl)ethyl]-benzo[b]thiophene and glycinamide hydrochloride instead of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-[2-(4-{2-[1-carboxy-1-(methyl)ethylcarbamoyl]ethyl}phenyl)ethyl]-benzofuran and 1-(2-hydroxyethyl)piperazine, respectively.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=O)C.[N:28]1([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=2)[CH:32]=[CH:31][N:30]=[CH:29]1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[N:28]1([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH:40][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=4[F:22])=[CH:14][CH:15]=3)=[O:3])=[N:38][CH:39]=2)[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: Nc1ccc(Cn2ccnc2)cn1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(Cn4ccnc4)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 3 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), 5-imidazol-1-ylmethyl-pyridin-2-ylamine (Step 120.1), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 3 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. The title compound: ESI-MS: 503.1 [M+H]+; tR=3.76 min (System 1); TLC: Rf=0.47 (DCM/MeOH, 9:1).
Reaction SMILES: OC1C(O)CCN(C(C)[CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]3[NH:21][C:22]4[C:27]([CH:28]=3)=[C:26]([O:29][CH2:30][C:31]3[C:35]5[CH:36]=[C:37]([Cl:40])[CH:38]=[CH:39][C:34]=5[O:33][CH:32]=3)[CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:13][CH2:12]2)C1.[CH2:42]1[CH:47]2[CH:48](CO)[CH2:49][CH2:50][CH2:51][N:46]2[CH2:45][CH2:44][O:43]1>>[CH2:42]1[C@@H:47]2[C@H:48]([CH2:10][N:11]3[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]4[NH:21][C:22]5[C:27]([CH:28]=4)=[C:26]([O:29][CH2:30][C:31]4[C:35]6[CH:36]=[C:37]([Cl:40])[CH:38]=[CH:39][C:34]=6[O:33][CH:32]=4)[CH:25]=[CH:24][CH:23]=5)=[O:19])[CH2:13][CH2:12]3)[CH2:49][CH2:50][CH2:51][N:46]2[CH2:45][CH2:44][O:43]1
Reactant: CC(CN1CCC(NC(=O)c2cc3c(OCc4coc5ccc(Cl)cc45)cccc3[nH]2)CC1)N1CCC(O)C(O)C1
Reactant: OCC1CCCN2CCOCC12
Product: O=C(NC1CCN(C[C@@H]2CCCN3CCOC[C@H]23)CC1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1

Procedure:
This compound is synthesized from the compound 176 (see example 138) and (9RS,9aSR)-1-(octahydro-pyrido[2,1-c][1,4]oxazin-9-yl)-methanol (63) analogously to the method described in example 127.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[N:25]=[C:24](C(=O)C)[C:23]([O:29][N:30]=[C:31]([CH3:33])C)=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>CCO.CCOC(C)=O>[Cl:34][C:22]1[C:21]([N:35]2[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]2)=[C:20]([CH2:19][OH:18])[N:25]=[C:24]2[C:31]([CH3:33])=[N:30][O:29][C:23]=12
Reactant: CC(=O)c1nc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(Cl)c1ON=C(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO)nc12
Temperature: 75 °C
Reaction time: 1 h

Procedure:
1-(6-((tert-Butyldiphenylsilyloxy)methyl)-4-chloro-5-((2R,6S)-2,6-dimethylmorpholino)-3-(propan-2-ylideneaminooxy)pyridin-2-yl)ethanone (Intermediate 336, 821 mg, 1.35 mmol) was dissolved in 13 ml of EtOH. Aqueous 1M HCl, (4.33 ml, 4.33 mmol) was added to give an immediate precipitate, which dissolved to give a hazy yellow solution. The mixture was heated at 75° C. After 1 hour, 15 minutes, the reaction was cooled and diluted with EtOAc. Added saturated NaHCO3 to quench was followed by extraction 2× with EtOAc. The combined organic phase was dried over MgSO4 and concentrated. The crude was purified on SiO2 using 15-40% EtOAc/hexanes. Recovered 389 mg (88%) of the title compound as white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][O:14][CH3:15])[O:10][C:9]2=[O:16])=[N:6][CH:7]=1.C[Sn](C)(C)[C:19]1[CH2:28][CH2:27][C:22]2([O:26][CH2:25][CH2:24][O:23]2)[CH2:21][CH:20]=1.C(OCC)(=O)C.[F-].[K+]>O1CCCC1.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>[O:23]1[C:22]2([CH2:27][CH2:28][C:19]([C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:12][CH:11]([CH2:13][O:14][CH3:15])[O:10][C:9]4=[O:16])=[N:6][CH:7]=3)=[CH:20][CH2:21]2)[O:26][CH2:25][CH2:24]1
Reactant: COCC1CN(c2ccc(Br)cn2)C(=O)O1
Reactant: C[Sn](C)(C)C1=CCC2(CC1)OCCO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCC1CN(c2ccc(C3=CCC4(CC3)OCCO4)cn2)C(=O)O1
Reaction time: 18 h
Yield: 37.5 %

Procedure:
A suspension of 1.4 g of 3-(5-bromo-pyridin-2-yl)-5-methoxymethyl-oxazolidin-2-one, 1.4 g of 8-trimethylstannyl-1,4-dioxa-spiro[4,5]dec-7-ene and 0.3 of bis(triphenylphosphine)palladium(II) dichloride in 20 ml of tetrahydrofuran was stirred at 70° under argon for 18 h. Then, the mixture was cooled, treated with 150 ml of ethyl acetate and 150 ml of saturated potassium fluoride solution and stirred for 30 minutes. The mixture was filtered over a Celite® pad, the phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried with magnesium sulfate, concentrated and chromatographed over silica gel 60 with diethyl ether as the eluent. There was obtained 0.6 g of (RS)-3-[5-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-pyridin-2-yl]-5-methoxymethyl-oxazolidin-2-one. 1H-nmr(CDCl3) ppm: 8.41 (s, 1H), 8.03 (d, 1H), 7.89 (d, 1H), 6.08 (t, 1H), 4.82 (m, 1H), 4.21 (t, 1H), 3.91 (t, 1H), 3.92 (s, 4H), 3.60 (m, 2H), 3.32 (s, 3H), 2.54 (m, 2H), 2.38 (m, 2H), 1.82 (t, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[N:23]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[N:22]=[N:21][CH:20]=4)=[CH:13][CH:12]=3)=[C:9](Br)[N:8]([C@@H:33]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:45]B(O)O.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[N:23]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[N:22]=[N:21][CH:20]=4)=[CH:13][CH:12]=3)=[C:9]([CH3:45])[N:8]([C@@H:33]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CB(O)O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2c(Br)c(-c3ccc(OCc4cnnn4COC(=O)C(C)(C)C)cc3)c3c(N)ncnc32)C1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(OCc3cnnn3COC(=O)C(C)(C)C)cc2)c2c(N)ncnc2n1[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 120 °C
Yield: 61 %

Procedure:
To a solution of (R)-tert-butyl 3-(4-amino-6-bromo-5-(4-((1-(pivaloyloxymethyl)-1H-1,2,3-triazol-5-yl)methoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (82) (344 mg, 0.51 mmol) in toluene (10 mL) were added methylboronic acid (306 mg, 5.1 mmol), Pd2(dba)3 (23.3 mg, 0.0255 mmol), PCy3 (14.3 mg, 0.051 mmol) and K3PO4.3H2O (407 mg, 1.53 mmol). The resulting mixture was purged with N2 for three times before heated to 120° C. overnight. The solvents were removed under vacuum and the residue was purified by flash chromatography (silica gel, 0 to 15% MeOH in DCM, with 0.5% TEA) to provide (R)-tert-butyl 3-(4-amino-6-methyl-5-(4-((1-(pivaloyloxymethyl)-1H-1,2,3-triazol-5-yl)methoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (83) (188 mg, 61%). LC-MS (ESI): m/z (M+1) 605.0.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:23]=2[C:24](N)=[O:25])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[CH3:32][CH:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:47]=[CH:46][C:44]([NH2:45])=[C:43]([O:48][CH3:49])[CH:42]=2)[CH2:37][CH2:36]1)[CH3:34].[I-].[K+].Cl.C(=O)(O)[O-].[Na+]>ClCCl>[F:31][C:28]1[CH:27]=[C:23]2[C:22](=[CH:30][CH:29]=1)[N:21]=[C:4]1[C:5]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)(=[O:12])=[O:13])[C:6]=3[N:7]=[C:2]([NH:45][C:44]3[CH:46]=[CH:47][C:41]([N:38]4[CH2:39][CH2:40][N:35]([CH:33]([CH3:32])[CH3:34])[CH2:36][CH2:37]4)=[CH:42][C:43]=3[O:48][CH3:49])[N:3]1[C:24]2=[O:25]
Reactant: COc1cc(N2CCN(C(C)C)CC2)ccc1N
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc(F)cc4C(N)=O)nc(Cl)nc32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: ClCCl
Product: COc1cc(N2CCN(C(C)C)CC2)ccc1Nc1nc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c2nc3ccc(F)cc3c(=O)n12
Yield: 76.2 %

Procedure:
To a pressurized vessel was added 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-5-fluorobenzamide (3.0 g, 6.54 mmol), 4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)aniline (2.11 g, 8.5 mmol), potassium iodide (<10 mg) and hydrochloric acid as a 4.0M solution in dioxanes (ca 10 mL). The resulting suspension was stirred until all solids had completely dissolved (24 hr.) The reaction was poured into into saturated sodium bicarbonate and diluted with dichloromethane. The organic layer was dried over sodium sulfate, volatiles removed under reduced pressure, and the solids triturated with diethyl ether to afford 9-fluoro-5-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (3.27 g, 76% yield) of sufficient purity for use in subsequent transformations. ESIMS (M+H)=656.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH3:17])[C:13](SC)=[N:12]3)[CH2:10][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=3[F:27])[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:28].[I-].N.CCO>>[NH2:28][C:13]1[N:14]([CH3:17])[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=3[F:27])[CH2:10]2)[N:12]=1
Reactant: CSC1=NC2(CC(c3cccc(F)c3F)Oc3ccc(Br)cc32)C(=O)N1C
Reactant: [NH4+]
Agent: N
Agent: [I-]
Solvent: CCO
Product: CN1C(=O)C2(CC(c3cccc(F)c3F)Oc3ccc(Br)cc32)N=C1N
Yield: 59.2 %

Procedure:
A solution of 6-bromo-2-(2,3-difluorophenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (63 mg, 0.14 mmol), NH4I (60.6 mg, 0.42 mmol) in a solution of NH3/EtOH (3 mL, 1.5 N) was heated at 110° C. in a tube under microwave reactor for 3 hrs. After cooling, the mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-2-(2,3-difluorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (35 mg, 60%). 1H-NMR (CDCl3): 2.31 (d, 1H), 2.45 (t, 1H), 3.27 (s, 3H), 6.12 (d, 1H), 6.87 (m, 1H), 7.09 (m, 3H), 7.34 (m, 2H), 7.45 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][O:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[C].[Pd].C(O)C.O1CCCC1>[O:13]1[CH:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[N:11]=[CH:12]1
Reactant: O=[N+]([O-])c1ccc(-c2cocn2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(-c2cocn2)cc1

Procedure:
5% Palladium-carbon powder was added to an ethanol-tetrahydrofuran mixed suspension of 4-(4-nitrophenyl)-1,3-oxazol and stirred for 12 hours at room temperature in a hydrogen atmosphere. The reaction solution was filtered through Celite and the filtrate was evaporated under reduced pressure. The resulting crude product is purified with a silica gel column chromatography to obtain [4-(1,3-oxazol-4-yl)phenyl]amine (pale yellow solid). Electron Impact-MS(M)+: 160.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[C:13]([F:34])=[CH:14][C:15]([F:33])=[C:16]([NH:18][C:19](=[O:32])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4([C:29]#[N:30])[CH2:28][CH2:27]4)[C:21]=3[Cl:31])[CH:17]=1)[N:5]=2.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1.O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Cl:31][C:21]1[C:22]([C:26]2([C:29]#[N:30])[CH2:28][CH2:27]2)=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([NH:18][C:16]1[CH:17]=[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:38]([CH:35]4[CH2:37][CH2:36]4)=[O:39])=[N:10][C:9]3=[CH:8][CH:7]=2)[C:13]([F:34])=[CH:14][C:15]=1[F:33])=[O:32]
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(N)sc5n4)c(F)cc3F)c2Cl)CC1
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(NC(=O)C6CC6)sc5n4)c(F)cc3F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2,4-difluorophenyl}-2-chloro-3-(1-cyanocyclopropyl)benzamide (0.17 g, 0.33 mmol) and N,N-dimethylpyridine-4-amine (0.12 g, 1.00 mmol) in pyridine (2 mL) was added dropwise cyclopropanecarbonyl chloride (0.11 g, 1.00 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The ethyl acetate layers were combined, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (5 mL), 8N aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (88 mg, 47%) as white crystals.