Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[N:6](C2C=CC=C(I)C=2)[C:5]2[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:4]=2[N:3]=1.S1C=CC=C1B(O)O>>[F:21][C:18]([F:19])([F:20])[C:16]1[CH:15]=[CH:14][C:5]2[N:6]=[CH:2][NH:3][C:4]=2[CH:17]=1
Reactant: Nc1nc2cc(C(F)(F)F)ccc2n1-c1cccc(I)c1
Agent: OB(O)c1cccs1
Product: FC(F)(F)c1ccc2nc[nH]c2c1

Procedure:
2-Amino-1-]3(2-thienyl)phenyl]-5-trifluoromethylbenzimidazole was prepared from 1-(2-amino-5-trifluoromethyl-1-benzimidazolyl)-3-iodobenzene and 2-thienylboronic acid according method B. mp 89°-91° C.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]([CH3:18])[CH2:12][C:13](=[O:17])[O:14]2)=[CH:9][CH:8]=1.C(Cl)(Cl)Cl.[C:23]([O-])(O)=[O:24].[Na+]>CO>[OH:14][C:15]1[CH:16]=[C:7]([OH:6])[CH:8]=[CH:9][C:10]=1[CH:11]([CH3:18])[CH2:12][C:13]([O:24][CH3:23])=[O:17]
Reactant: CC1CC(=O)Oc2cc(O)ccc21
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)CC(C)c1ccc(O)cc1O
Reaction time: 16 h

Procedure:
Concentrated sulfuric acid (1.2 mL, 43 mmol) was added to a solution of 7-hydroxy-3,4-dihydro-4-methylcoumarin (B1) (75.8 g, 430 mmol) in methanol (1 L) at room temperature and the solution stirred for about 16 hours. At this time, TLC (8% methanol:chloroform) showed the clean formation of product at the expense of starting material. The solution was neutralized with 7% NaHCO3 solution (50 ml) and the majority of the solvent (750 ml) removed under reduced pressure. The solution was diluted with ethyl acetate (1 L), washed successively with saturated NaHCO3: saturated NaCl (1:1, 200 ml), saturated NaCl (2×200 ml), dried (Na2SO4), filtered and the solvent removed to give an orange oil. Further purification by filtering through a short pad of silica gel and eluting with 5% methanol in chloroform afforded pure product as a pale orange gel (87 g, 98%): 1H NMR (DMSO-d6) d 1.13 (d, JJ=7.0, 3H), 2.42 (dd, JJ=15.0, 8.9, 1H), 2.58 (dd, JJ=15.0, 5.8, 1H), 3.37 (m, 1H), 3.55 (s, 3H), 6.15 (dd, JJ=8.6, 2.4, 1H), 6.28 (d, JJ=2.4, 1H), 6.84 (d, JJ=8.2, 1H), 8.93 (s, 1H), 9.11 (s, 1H); 13C NMR (DMSO-d6) d 20.16, 29.09, 40.77, 51.00, 102.55, 106.02, 122.09, 127.04, 155.18, 156.27, 172.55; m/z (EI; TMS derivatized; M+) 354; IR (neat; cm−1) 3384.5, 2969.3, 1708.9, 1621.0, 1606.3, 1518.4, 1454.9, 1367.0, 1303.5, 1220.4, 1166.7, 1108.1, 976.2, 839.4, 810.1.
Reaction SMILES: C([O:8][C:9]1[C:10]([O:37][CH3:38])=[CH:11][C:12]2[CH2:21][CH2:20][N:19]3[CH:14]([CH2:15][C:16]4[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[C:22]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][OH:35])[C:17]=4[CH2:18]3)[C:13]=2[CH:36]=1)C1C=CC=CC=1>[Ni]>[OH:8][C:9]1[C:10]([O:37][CH3:38])=[CH:11][C:12]2[CH2:21][CH2:20][N:19]3[CH:14]([CH2:15][C:16]4[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[C:22]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][OH:35])[C:17]=4[CH2:18]3)[C:13]=2[CH:36]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)C1Cc3c(Cl)cc(OC)c(OCCOCCO)c3CN1CC2
Agent: [Ni]
Product: COc1cc2c(cc1O)C1Cc3c(Cl)cc(OC)c(OCCOCCO)c3CN1CC2

Procedure:
A product obtained in Example 18 (0.116 g, 0.21 mmol) was hydrogenated in the present of Raney-Ni. The desired product was obtained following the synthetic procedure described in Example 1, 4 or 7. The crude product was purified by silica chromatography (ethyl acetate/petroleum ether/methanol) to give yellow solid (0.035 g, 36.2%). 1HNMR (CDCl3) δ: 2.61˜2.68 (3H, m, CH2), 3.18˜3.70 (1H, m, CH2 and N—CH), 3.81 (3H, s, Ar—OCH3), 3.84 (3H, s, Ar—OCH3), 4.21 (2H, m, OCH2), 4.40 (1H, d, CH2), 6.57 (1H, s, ArH), 6.83 (1H, s, ArH), 6.85 (1H, s, ArH).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][C@H:18]2[C:31]([O:33][CH3:34])=[O:32])[C:13]1=[O:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][C@@H:18]2[C:31]([O:33][CH3:34])=[O:32])[C:13]1=[O:35])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.3 %

Procedure:
To a solution of (1R,2S,5R)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)-cyclohexanecarboxylate (281 mg, 0.573 mmol, see Example 12a, Step 3) in anhydrous DMF was added cesium carbonate (747 mg, 2.29 mmol), and the mixture was stirred for 16 h at rt. At the end of the stirring the mixture was poured into water, and extracted with EtOAc (3×). The combined extracts were washed with water, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with elution by EtOAc to afford pure trans isomer, (1S,2S,5R)-methyl 2-((S)-3-(benzyloxycarbonyl)amino-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonyl)amino-cyclohexanecarboxylate (214 mg) as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]([O:27]C(C)(C)C)=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[C:10]2[CH:32]=[CH:33][CH:34]=[CH:35][C:9]=2[N:8]=1.FC(F)(F)C(O)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:20]([C:25]([OH:27])=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:17][CH:18]=2)[C:10]2[CH:32]=[CH:33][CH:34]=[CH:35][C:9]=2[N:8]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(Cn2c(-c3ccccn3)nc3ccccc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccccc1-c1ccc(Cn2c(-c3ccccn3)nc3ccccc32)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-(2-pyridyl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH2:7][CH2:8][NH:9][CH2:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1>[Pd]>[F:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c3c([nH]c2c1)CNCC3
Agent: [Pd]
Product: Fc1ccc2c(c1)[nH]c1cnccc12
Yield: 87.5 %

Procedure:
7-fluoro-2,3,4,9-tetrahydro-1H-β-carboline (3.5 g, 18.42 mmol) was suspended in xylenes (60 ml) in a 250 ml round-bottom flask equipped with a condenser that was open to the atmosphere, and heated. To this hot reaction mixture was added Pd/C (10 wt %, 0.2 eq, 700 mg) and the mixture refluxed in xylenes overnight (12-14 hours). The solution was then filtered through a pad of celite and the collected filtrate was then evaporated on a rotary evaporator to give the desired product as a brown/tan solid (3.0 g, 88% yield).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[CH2:23][CH:22]([C:25]3[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:33])[CH:21]3[C:34](=[O:38])[NH:35][C:36](=[O:37])[CH:20]3[C:19]=2[C:18]2[CH:17]=[C:16]([O:39][CH3:40])[CH:15]=[CH:14][C:13]1=2)(C(C)(C)C)(C)C.[Si](OCCCN1C2CC(C3C=CC=CC=3OC)C3C(=O)NC(=O)C3C=2C2C=C(OC)C=CC1=2)(C(C)(C)C)(C)C.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.Cl>C1COCC1.CO>[Cl:33][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:25]=1[C:22]1[C:21]2[C:34](=[O:38])[NH:35][C:36](=[O:37])[C:20]=2[C:19]2[C:18]3[CH:17]=[C:16]([O:39][CH3:40])[CH:15]=[CH:14][C:13]=3[N:12]([CH2:11][CH2:10][CH2:9][OH:8])[C:24]=2[CH:23]=1
Reactant: COc1ccc2c(c1)c1c(n2CCCO[Si](C)(C)C(C)(C)C)CC(c2c(Cl)cccc2OC)C2C(=O)NC(=O)C12
Agent: COc1ccc2c(c1)c1c(n2CCCO[Si](C)(C)C(C)(C)C)CC(c2ccccc2OC)C2C(=O)NC(=O)C12
Agent: Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)c1c3c(c(-c4c(Cl)cccc4OC)cc1n2CCCO)C(=O)NC3=O
Yield: 76 %

Procedure:
The reaction of 6-(3-{[tert-Butyl(dimethyl)silyl]oxy}propyl)-4-(2-chloro-6-methoxyphenyl)-9-methoxy-4,5,6,10c-tetrahydropyrrolo[3,4-c]carbazole-1,3(2H,3aH)-dione (IV; Ar=2-chloro-6-methoxyphenyl, R10═CH2CH2CH2OSiMe2t-Bu) (104) prepared as described in example 57 with DDQ using the procedure described in example 70 followed by reaction with 2N HCl in THF/methanol gave 4-(2-Chloro-6-methoxyphenyl)-6-(3-hydroxypropyl)-9-methoxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (V; Ar=2-chloro-6-methoxyphenyl, R10═CH2CH2CH2OH) (105) in a 76% yield as an orange powder; mp 224–227° C. 1H NMR δ [(CD3)2SO] 11.05 (br, 1H), 8.51 (d, J=2.6 Hz, 1H), 7.75 (s, 1H), 7.69 (d, J=8.9 Hz, 1H), 7.44 (dd, J=8.2, 8.2 Hz, 1H), 7.31 (dd, J=8.9, 2.6 Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 7.13 (d, J=8.2 Hz, 1H), 4.63 (t, J=4.9 Hz, 1H), 4.51 (t, J=6.8 Hz, 2H), 3.91 (s, 3H), 3.68 (s, 3H), 3.41 (m, 2H), 1.89 (m, 2H). Found: C, 69.71; H, 4.53; N, 6.43. C25H22N2O5 requires C, 69.76; H, 5.15; N, 6.51.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16]2[C:17]3[O:18][CH:19]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[CH2:20][CH2:21][C:22]=3[C:23]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:24][C:15]=2[N:14]=[C:13]1[CH3:37])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH:19]2[CH2:20][CH2:21][C:22]3[C:23]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:24][C:15]4[N:14]=[C:13]([CH3:37])[N:12]([CH2:11][CH2:10][CH2:9][OH:8])[C:16]=4[C:17]=3[O:18]2)=[CH:31][CH:32]=1
Reactant: Cc1nc2cc(C(=O)N(C)C)c3c(c2n1CCCO[Si](C)(C)C(C)(C)C)OC(c1ccc(F)cc1)CC3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc2cc(C(=O)N(C)C)c3c(c2n1CCCO)OC(c1ccc(F)cc1)CC3
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 31.2 %

Procedure:
To the solution of 1-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-8-(4-fluorophenyl)-N,N,2-trimethyl-1,6,7,8-tetrahydrochromeno[7,8-d]imidazole-5-carboxamide (35 mg, 0.067 mmol, Step 9) in tetrahydrofuran was added 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.1 mL). The mixture was stirred at room temperature for 2.5 hours. The reaction was quenched by saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative TLC eluting with dichloromethane/methanol (20:1). The obtained product was triturated in hexane to afford the title compound as a pale yellow solid (8.6 mg, 31%)
Reaction SMILES: [NH2:1][C:2]([CH3:33])([CH3:32])[CH2:3][NH:4][C:5]1[N:10]=[C:9]([O:11][C:12]2[C:17]3[N:18]=[C:19]([NH2:21])[S:20][C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH:8]=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:6]=1.[CH2:34]([CH2:38][CH:39]=O)[CH2:35][CH:36]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:32][C:2]([N:1]1[CH2:39][CH2:38][CH2:34][CH2:35][CH2:36]1)([CH3:33])[CH2:3][NH:4][C:5]1[N:10]=[C:9]([O:11][C:12]2[C:17]3[N:18]=[C:19]([NH2:21])[S:20][C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH:8]=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)[N:6]=1
Reactant: CC(C)(N)CNc1nc(Oc2cccc3sc(N)nc23)cc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: O=CCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(CNc1nc(Oc2cccc3sc(N)nc23)cc(-c2ccc(C(F)(F)F)cc2)n1)N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-(2-(2-amino-2-methylpropylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-amine (47 mg, 1.0 mmol, Example 80) and 50% aqueous solution of glutaric dialdehyde (40 mg, 0.2 mmol, Aldrich) in 1,2-dichloroethane (2 mL) was added sodium triacetoxyborohydride (212 mg, 1.0 mmol, Aldrich) and the mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was treated with sat. aqueous solution of NaHCO3 (5 mL), and extracted with EtOAc (2×20 mL). The combined EtOAc extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (10% MeOH/DCM) to afford the title compound as a white amorphous solid. MS (ESI, pos. ion.) m/z: 543 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH2:11][CH2:12][O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)=[CH:17][C:15]=3[CH:16]=2)=[O:9])[CH2:3][CH2:2]1.[CH:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:28]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[CH2:11][CH2:12][O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=4)=[CH:17][C:15]=3[CH:16]=2)=[O:9])[CH2:5][CH2:6]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCNCC2)CCO3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCN(Cc4ccccc4)CC2)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To N-(4-piperidinyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (0.15 g) and benzaldehyde (0.05 g) dissolved in 1,2-dichloroethane (10 ml) was added under ice cooling sodium triacetoxyborohydride (0.12 g), and the resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was evaporated to remove the solvent, was neutralized with a 1 N aqueous solution of sodium hydroxide and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and then was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate/hexane to obtain N-(1-benzylpiperidin-4-yl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 58) (0.17 g) as colorless prisms.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16](Br)[CH:15]=1)([CH3:13])([CH3:12])[CH3:11].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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]>[C:10]([C:14]1[CH:15]=[C:16]([NH:8][C:6]2[C:5]([CH3:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:17]=[CH:18][CH:19]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1cnc(Cl)nc1N
Reactant: CC(C)(C)c1cccc(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cnc(Cl)nc1Nc1cccc(C(C)(C)C)c1
Yield: 92.6 %

Procedure:
A mixture of 2-chloro-5-methylpyrimidin-4-amine (670 mg, 4.7 mmol), 1-tert-butyl-3-bromobenzene (1.5 g, 7 mmol), Pd2(dba)3 (366 mg, 0.4 mmol), Xantphos (695 mg, 1.2 mmol) and cesium carbonate (6.2 g, 19 mmol) was suspended in dioxane (150 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in EtOAc (10 mL) and added hexanes (100 mL). The solid was collected by filtration and washed with hexanes to afford the crude title compound (1.2 g, 99%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][CH:23]=[C:24]([CH2:26][C:27]([NH:29][CH3:30])=[O:28])[N:25]=2)=[N:10]1.C1C(=O)N([Br:38])C(=O)C1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:38])[NH:12][C:11]([C:21]2[S:22][CH:23]=[C:24]([CH2:26][C:27]([NH:29][CH3:30])=[O:28])[N:25]=2)=[N:10]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2nc(CC(=O)NC)cs2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CBr)NC(c2nc(CC(=O)NC)cs2)=NC1c1ccc(F)cc1Br
Yield: 54.9 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(4-(2-(methylamino)-2-oxoethyl)thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with NBS (0.39 g, 2.2 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.63 g, 55%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[O:5][CH2:4]1.C([O-])(=O)C.[Na+].[CH2:31]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([CH2:47][CH2:48][CH2:49][CH2:50][C:51](=O)[C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:43][CH2:42]1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH2:31]([O:38][C:39]([N:41]1[CH2:42][CH2:43][CH:44]([CH2:47][CH2:48][CH2:49][CH2:50][C@@H:51]([NH:2][C@@H:3]2[C:9](=[O:10])[N:8]([CH2:11][C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[C:7]3[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=3[O:5][CH2:4]2)[C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:45][CH2:46]1)=[O:40])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: N[C@H]1COc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Reactant: CCOC(=O)C(=O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1COc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5.4 %

Procedure:
A mixture of benzyl 3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate hydrochloride (3.4 g), ethanol (30 ml), sodium acetate (0.77 g), acetic acid (0.56 g), ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-oxohexanoate (4.4 g) and molecular sieves 3A (10 g) is stirred for 10 minutes at room temperature. To the stirred mixture is added dropwise a solution of sodium cyanoborohydride (0.6 g) in ethanol (50 ml) for 3 hours. After standing overnight at room temperature, the mixture is concentrated in vacuo and diluted with a mixture of water (100 ml) and ethyl acetate (200 ml). The resulting mixture is agitated thoroughly and filtered. The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is dissolved in a mixture of ethyl acetate (20 ml) and oxalic acid (3 g). This solution is diluted with petroleum ether (100 ml), and the supernatant layer is removed by decantation. To the precipitate are added water (50 ml), ethyl acetate (200 ml) and excess sodium bicarbonate. The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and evaporated in vacuo. The oily residue is subjected to silica gel column chromatography using hexame-ethyl acetate (2:1) as an eluent. Evaporation of the first fraction gives benzyl 3(S)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][C:13]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22]C(=O)C(C)(C)C)=[CH:18][CH:17]=3)=[C:8]2[C:7]([O:29][C@@H:30]2[O:38][C@H:37]([CH:39](C(=O)C(C)(C)C)[OH:40])[C@@:35](C(=O)C(C)(C)C)([OH:36])[C@:33](C(=O)C(C)(C)C)([OH:34])[C@@:31]2(C(=O)C(C)(C)C)[OH:32])=[N:6]1.C[O-].[Na+]>CO>[C@@H:30]1([O:29][C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)[N:5]([CH2:4][CH2:3][CH2:2][OH:1])[N:6]=2)[O:38][C@H:37]([CH2:39][OH:40])[C@@H:35]([OH:36])[C@H:33]([OH:34])[C@H:31]1[OH:32]
Reactant: CC(C)(C)C(=O)Oc1ccc(CCc2ccnc3c2c(O[C@@H]2O[C@H](C(O)C(=O)C(C)(C)C)[C@](O)(C(=O)C(C)(C)C)[C@@](O)(C(=O)C(C)(C)C)[C@]2(O)C(=O)C(C)(C)C)nn3CCCO)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OCCCn1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2c(CCc3ccc(O)cc3)ccnc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of 1-(3-hydroxypropyl)-3-(2,3,4,6-tetra-pivaloyl-β-D-glucopyranosyloxy)-4-[2-(4-pivaloyloxy-phenyl) ethyl]-1H-pyrazolo [3, 4-b]pyridine (40 mg) in methanol (2 mL) was added sodium methoxide (28% methanol solution, 0.04 mL), and the mixture was stirred at 60° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (18 mg).
Reaction SMILES: [CH3:1][Si:2]1([CH3:18])[CH2:6][CH:5]([CH3:7])[CH2:4][N:3]1[CH2:8][CH2:9][CH2:10][Si:11]([CH3:17])([CH3:16])[O:12][SiH:13]([CH3:15])[CH3:14].[CH:19]([Si:21]([O:26][CH3:27])([O:24][CH3:25])[O:22][CH3:23])=[CH2:20]>>[CH3:18][Si:2]1([CH3:1])[CH2:6][CH:5]([CH3:7])[CH2:4][N:3]1[CH2:8][CH2:9][CH2:10][Si:11]([CH3:16])([CH3:17])[O:12][Si:13]([CH2:20][CH2:19][Si:21]([O:26][CH3:27])([O:24][CH3:25])[O:22][CH3:23])([CH3:14])[CH3:15]
Reactant: CC1CN(CCC[Si](C)(C)O[SiH](C)C)[Si](C)(C)C1
Reactant: C=C[Si](OC)(OC)OC
Product: CO[Si](CC[Si](C)(C)O[Si](C)(C)CCCN1CC(C)C[Si]1(C)C)(OC)OC
Temperature: 120 °C

Procedure:
A mixture of the 20.67 g (68.1 mmol) of 1-(3-(2,2,4-trimethyl-1-aza-2-silacyclopentyl)propyl-1,1,3,3-tetramethyldisiloxane, 10.6 g (71.5 mmol) of vinyltrimethoxysilane which had been distilled from sodium, and 0.03 g of a chloroplatinic acid-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex having about 0.7 weight percent platinum was heated for one hour at 120° C. The resulting product was distilled and the distillate was collected at 152° C. and 0.1 mm Hg. The amount of distillate collected was 28.2 g of 1-(3-(2,2,4-trimethyl-1-aza-2-silacyclopentyl)propyl)-3-(2-trimethoxysilylethyl)-1,1,3,3-tetramethyldisiloxane which was identified by 13C and 29Si NMR (nuclear magnetic resonance) and GC-MS.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].C(N(CC)CC)C.[C:13]([O:17][C:18]([N:20]1[CH2:32][C:31]2[S:30][C:29]3[N:28]=[CH:27][NH:26][C:25](=O)[C:24]=3[C:23]=2[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)(O)[O-].[Na+]>O>[C:13]([O:17][C:18]([N:20]1[CH2:32][C:31]2[S:30][C:29]3[N:28]=[CH:27][N:26]=[C:25]([Cl:3])[C:24]=3[C:23]=2[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3nc[nH]c(=O)c23)C1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Temperature: 60 °C
Yield: 25 %

Procedure:
To a of mixture of POCl3 (30 mL) and triethylamine (50 mL) at 0° C. was added 4-oxo-3,5,6,8-tetrahydro-4H-9-thia-1,3,7-triaza-fluorene-7-carboxylic acid tert-butyl ester (10.0 g). The reaction mixture was heated at 60° C. for 3 h. Water was then added, followed by sodium bicarbonate to neutralize the reaction mixture. The resulting mixture was extracted with dichloromethane. The organic layer was concentrated and the crude compound was purified by silica gel column chromatography using a mixture of hexanes:ethyl acetate (10:1) to give the title compound (3.1 g, 25%). 1H NMR (400 MHz, CDCl3): δ 8.70 (s, 1H), 4.69 (s, 2H), 3.74 (t, 2H, J=5.6 Hz), 3.14-3.18 (brs, 2H), 1.46 (s, 9H). LC-MS (ESI) m/z 326.0 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:16][CH2:15]2)=[CH:10][C:9]=1[NH:17][C:18](=[O:30])[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]#[N:29])[CH:23]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:14]1([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:20]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28]#[N:29])[CH:23]=4)[CH2:19][C:18](=[O:30])[NH:17][C:9]=3[CH:10]=2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CC2)cc1NC(=O)CC(=O)c1ccnc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(C2=Nc3ccc(C4CC4)cc3NC(=O)C2)ccn1

Procedure:
Prepared from {2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-4-cyclopropyl-phenyl}-carbamic acid tert.-butyl ester (Example K79) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light brown solid (88 mg).