Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][CH:15]=2)[CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)[Cl:34]>>[ClH:34].[NH2:8][C@@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][CH:15]=2)[CH2:10]1
Reactant: ClCCl
Reactant: CCOC(=O)COc1ccc2c(c1)C[C@H](NC(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)COc1ccc2c(c1)C[C@H](N)CC2
Product: Cl
Reaction time: 0.5 h

Procedure:
A solution of 3.5 g of (R)-2-tert-butoxycarbonylamino-7-carbethoxymethoxytetraline, EXAMPLE 3, in 35 ml of methylene chloride is cooled to 0° C. Then, there is added a solution of 7.7 ml of trifluoroacetic acid in 40 ml of methylene chloride and the mixture is left to stand under stirring at first 30 minutes at a temperature of 0°-5° C., then 4 hours at room temperature. After neutralization with a solution of sodium bicarbonate, the organic phase is separated, washed with water, dried and evaporated to dryness. The residue is taken up with 15 ml of ethyl acetate and made acid with a solution of hydrochloric acid in ethanol. The precipitated so obtained is filtered and washed with ether. Thus, 1.1 g of (R)-2-amino-7-carbethoxymethoxytetraline hydrochloride is obtained; m.p. 168°-171° C., /alpha/=+51.14° (methanol, c=1%). (b) To a solution of 5.8 g of (R)-2-tert-butoxycarbonylamino-7-carbethoxymethoxytetraline, EXAMPLE 3, in 135 ml of absolute ethanol there is added at room temperature 82 ml of a 7.2N solution of hydrogen chloride in ethanol. The mixture is left under stirring at room temperature for 150 minutes, then it is evaporated to dryness under reduced pressure. The residue is taken up with ethyl ether and filtered. Thus, 4.6 g of (R)-2-amino-7-carbethoxymethoxytetraline hydrochloride are obtained; m.p. 170°-171° C., /alpha/=+51° (methanol, c=1%). By crystallization from methanol, the melting point remains unchanged (170°-172° C.) and the /alpha/ rises to +51.6° (methanol, c=1%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH2:12]Cl)[N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:7]2=[O:21].[N:22]1[C:30]([NH2:31])=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[N:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:31][C:30]1[N:22]=[CH:23][N:24]=[C:25]2[C:29]=1[N:28]=[CH:27][N:26]2[CH2:12][C:9]1[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:7](=[O:21])[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=c1c2cccc(Cl)c2nc(CCl)n1-c1ccccc1Cl
Reactant: Nc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1nc2c(Cl)cccc2c(=O)n1-c1ccccc1Cl
Yield: 38.8 %

Procedure:
Prepared according to Procedure C using Intermediate 2h (100 mg, 0.294 mmol), adenine (44 mg, 0.324 mmol), K2CO3 (45 mg, 0.324 mmol), and DMF (1 mL). The crude product was chromatographed in MeOH/CH2Cl2 to provide 50 mg of a pale yellow solid (39%), mp 273.3-273.5° C. (discolors). 1H NMR (DMSO-d6) δ: 8.11 (dd, J=1.3, 8.0 Hz, 1H); 8.08 (s, 1H); 8.05 (s, 1H); 8.00 (dd, J=1.3, 7.8 Hz, 1H); 7.79-7.83 (m, 2H); 7.63-7.66 (m, 2H); 7.56 (t, J=7.9 Hz, 1H); 7.21 (br s, 2H); 5.17 (d, J=17 Hz, 1H); 4.97 (d, J=17 Hz, 1H). 13C NMR (DMSO-d6) ppm: 160.2, 156.1, 152.8, 152.2, 150.2, 143.3, 142.0, 135.6, 133.1, 132.3, 131.9, 131.1, 131.0, 130.9, 129.4, 128.4, 126.0, 122.5, 118.4, 45.0. MS (ES): m/z 438.0 (M+). Anal. calcd. for C20H13Cl2N7O.0.1CH4O.0.6H2O (0.15KCl: C, 52.09; H, 3.18; N, 21.15. Found: C, 51.85; H, 2.93; N, 21.01.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])[C:8]=1[NH:23]C)[CH2:4][CH3:5])[CH3:2].[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1.[CH2:32](N(CC)CC)C>C(Cl)Cl>[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:32])[N:10]=[C:9]([O:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])[C:8]=1[NH:23][C:28](=[O:29])[CH2:27][CH2:26][C:25]([OH:30])=[O:31])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1ccnc(Oc2c(C)cc(C)cc2C)c1NC
Reactant: O=C1CCC(=O)O1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1NC(=O)CCC(=O)O
Temperature: 25 °C

Procedure:
A mixture of 4-(1-ethyl-propoxy)-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylamine (100 mg, 0.304 mmol), succinic anhydride 31 mg, 0.304 mmol) and triethylamine in methylene chloride was stirred at rt. overnight. The mixture was quenched with water, and extracted with methylene chloride. The organic layer was separated, dried and concentrated to give a solid. The title compound was isolated as a white crystal after silica gel column chromatography.
Reaction SMILES: C([O-])=O.[CH3:4][C:5]1[N:6]=[C:7]([NH3+:20])[NH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.[C:21]([O:25][C:26]([NH:28][CH2:29][C:30]1[CH:31]=[C:32]([C:39](O)=[O:40])[C:33]([CH:36]([F:38])[F:37])=[N:34][CH:35]=1)=[O:27])([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.O>[F:38][CH:36]([F:37])[C:33]1[N:34]=[CH:35][C:30]([CH2:29][NH:28][C:26](=[O:27])[O:25][C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:31][C:32]=1[C:39](=[O:40])[NH:20][C:7]1[NH:8][C:9]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=2)=[C:5]([CH3:4])[N:6]=1
Reactant: Cc1nc([NH3+])[nH]c1-c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)NCc1cnc(C(F)F)c(C(=O)O)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1nc(NC(=O)c2cc(CNC(=O)OC(C)(C)C)cnc2C(F)F)[nH]c1-c1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 56.5 %

Procedure:
Dissolve [4-methyl-5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]ammonium formate (0.205 g, 0.714 mmol) and 5-[(tert-butoxycarbonylamino)methyl]-2-(difluoromethyl)pyridine-3-carboxylic acid (0.283 g, 0.749 mmol) in DCM (5 mL). Add DIPEA (0.50 mL, 2.855 mmol) followed by BOP (0.350 g, 0.792 mmol). Heat the mixture to 60° C., and stir 16 hours. Add benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.150 g, 0.339 mmol). Stir the mixture for 2 hours. Pour the reaction mixture into water (15 mL). Extract with EtOAc (3×15 mL, and sequentially wash the combined organics with a saturated sodium chloride aqueous solution (4×15 mL) and a saturated sodium bicarbonate aqueous solution (15 mL). Dry the organic extracts over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure. Purify the residue by reverse phase flash chromatography (Analogix® 55 g @ 40 mL/min) eluting with a gradient of 5-75% ACN/water over 30 minutes. Concentrate the appropriate fractions under reduced pressure until only water remains and the product is a suspended solid. Add a saturated NaHCO3 aqueous solution (50 mL), and extract with EtOAc (2×30 mL) to give the title compound (0.212 g, 56%) as a white solid. LCMS (m/z) 526 (M+1) 524 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CCN(CC)CC.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:5][CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc(N)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)C(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 6-methoxy-pyridin-3-amine (Aldrich, 10.0 g, 77 mmol) in anhydrous CH2Cl2 (100 ml) at 0° C. was added Et3N (13.9 ml, 100.1 mmol) and a solution of pivaloyl chloride (10.5 ml, 84.7 mmol) in CH2Cl2 (20 ml). The mixture was stirred at 0° C. for 10 min and at room temperature for 2 h. After quenched with ice, the reaction was diluted with CH2Cl2, washed with 1M NaOH, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound as orange solid.
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-])=[O:2].C1(N=C=O)C=CC=CC=1.[C:15]([Sn:17]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])#[CH:16].CCN(CC)CC>C1C=CC=CC=1>[CH3:5][C:4]1[CH:16]=[C:15]([Sn:17]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:26][CH2:27][CH2:28][CH3:29])[O:2][N:1]=1
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Reactant: CC[N+](=O)[O-]
Solvent: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C)no1
Temperature: 50 °C
Reaction time: 14 h
Yield: 85 %

Procedure:
A solution of nitroethane and phenyl isocynate in 8 ml of benzene was stirred at 50° C. for 5 minutes before ethynyltri-n-butyltin in 8 ml of benzene containing one droplet of Et3N was added. The mixture was stirred at 50° C. for 14 hours. The reaction mixture was then quenched with water and filtered through celite. The filtrate was extracted with EtOAc, dried with Na2SO4. Silica Chromatography using Hexance/EtOAc afforded 3-methyl-5-(tributylstannyl)isoxazole, 6.30 g, 85% yield.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][CH2:11][N:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4]1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22](Cl)=[O:23])=[CH:14]1>>[CH2:4]1[CH:5]2[N:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:11][CH2:12][CH:3]1[CH2:2][O:1][C:22]([C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:13][CH:14]=1)=[O:23]
Reactant: O=C(Cl)c1c[nH]c2ccccc12
Reactant: OCC1CCN2CCCCC2C1
Product: O=C(OCC1CCN2CCCCC2C1)c1c[nH]c2ccccc12

Procedure:
The title compound was prepared from ax-2-hydroxymethylquinolizidine (D4) and indole-3-carboxylic acid chloride using the method of Example 1. The product was purified by chromatography on neutral alumina eluting with ethyl acetate, followed by crystallisation from ether/pentane, to give the title compound (E9a) as a white solid mp 156°-157° C.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[CH2:4][CH2:5][CH3:6].[H-].[Na+].CO[C:12](=O)[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][Si](C(C)(C)C)(C)C)=[C:17]([O:29][Si](C(C)(C)C)(C)C)[CH:16]=1>O1CCCC1>[CH2:4]([C:3]1[N:7]=[C:12]([CH:13]=[CH:14][C:15]2[CH:16]=[C:17]([OH:29])[C:18]([OH:21])=[CH:19][CH:20]=2)[O:1][N:2]=1)[CH2:5][CH3:6]
Reactant: COC(=O)C=Cc1ccc(O[Si](C)(C)C(C)(C)C)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CCCC(=N)NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1noc(C=Cc2ccc(O)c(O)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-hydroxy-butyramidine (0.24 g, 2.34 mmol) in tetrahydrofuran (5 mL) was added slowly into the suspension of 60% sodium hydride (0.14 g, 3.5 mmol) in dry tetrahydrofuran (5 mL) under nitrogen atmosphere at 0° C. to 10° C. The mixture was stirred for 30 min at room temperature. 3-[3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-phenyl]-acrylic acid methyl ester (compound of Example 1, Step 1; 0.5 g, 1.18 mmol) in dry tetrahydrofuran (5 mL) was added into the reaction mixture and heated at 60° C. for 8 h. The reaction mixture was cooled at 0° C. and quenched with methanol (2 mL) to destroy excess sodium hydride. The reaction mixture was extracted with ethyl acetate (2×10 mL) and the combined organic layers were washed with water (2×10 mL) followed by brine (10 mL). The organic phase obtained was dried over anhydrous sodium sulphate and concentrated to dryness. The crude product obtained was purified by column chromatography (silica gel, chloroform-methanol) to afford the title compound.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH:26]=[CH:25]3)=[CH:18][C:17]=1[CH:31]=O.[NH2:33][CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.C(=O)(O)[O-].[Na+]>ClCCCl.ClCCl.C(O)(=O)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH:26]=[CH:25]3)=[CH:18][C:17]=1[CH2:31][NH:33][CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=Cc1cc(-c2ccc3[nH]ccc3c2)ccc1F
Reactant: NCCN1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: Fc1ccc(-c2ccc3[nH]ccc3c2)cc1CNCCN1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.8 %

Procedure:
Sodium triacetoxyborohydride (530 g, 2.51 mmol) and then enough acetic acid to bring the pH to 5 were added to a solution of 5-(4-fluoro-3-formylphenyl)-1H-indole (200 mg, 0.84 mmol) and 1-(2-aminoethyl)pyrrolidine (191 mg, 1.67 mmol) in 15 mL of 1,2-dichloroethane. The mixture was stirred at ambient temperature overnight, and then it was diluted with dichloromethane, and neutralized with the careful addition of saturated sodium bicarbonate solution. The layers were separated and the aqueous phase extracted into dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to leave the crude product. Chromatography (elution with methanol/dichloromethane) provided 90 mg of the title compound. LC/MS: Retention time, 0.34 min.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][C@H:10]2[C@@H:12]([C@:13]([C:18]3[CH:23]=[C:22]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=4)(=[O:27])=[O:26])[CH:21]=[CH:20][C:19]=3[F:35])([CH:15]([F:17])[F:16])[N:14]=1)[CH2:11]2)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C:8]1[O:9][C@H:10]2[C@@H:12]([C@:13]([C:18]3[CH:23]=[C:22]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=4)(=[O:26])=[O:27])[CH:21]=[CH:20][C:19]=3[F:35])([CH:15]([F:16])[F:17])[N:14]=1)[CH2:11]2
Reactant: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(NS(=O)(=O)c3ccc(Cl)cn3)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1=N[C@@](c2cc(NS(=O)(=O)c3ccc(Cl)cn3)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
To a solution of tert-butyl((1R,5S,6R)-5-(5-(5-chloropyridine-2-sulfonamido)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate (0.061 g, 0.11 mmol) in DCM (2 mL) at room temperature was added trifluoroacetic acid (2.0 mL). The reaction mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. The residue was partitioned between saturated NaHCO3 and EtOAc. The aqueous phase was extracted with EtOAc (2×). The combined organic extracts were washed with brine and dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (30% to 70% EtOAc in heptane) to give the title compound (0.045 g, 0.10 mmol, 90% yield) as a white solid. MS m/z=446.9 [M+H]+. Calculated for C17H14ClF3N4O3S 446.0. 1H NMR (400 MHz, CDCl3) δ 0.80-0.90 (m, 1H), 1.33 (t, J=6.85 Hz, 1H), 1.69-1.78 (m, 2H), 3.65-3.70 (m, 1H), 5.70 (s br, 2H), 6.06 (t, J=56.10 Hz, 1H), 6.95 (dd, J=6.75, 2.64 Hz, 1H), 7.06 (dd, J=11.44, 8.71 Hz, 1H), 7.45 (ddd, J=8.56, 4.25, 2.84 Hz, 1H), 7.72 (s, 2H), 8.33 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][NH2:16])=[N:13][CH:14]=2)[O:3]1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19].C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH2:18]([NH:20][C:21]([NH:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([B:4]2[O:3][C:2]([CH3:17])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:14][N:13]=1)=[O:22])[CH3:19]
Reactant: CCN=C=O
Reactant: CC1(C)OB(c2ccc(CN)nc2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCNC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
Into a 50 mL round bottom flask was added C-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-methylamine (I-161, 1 g, crude), pyridine (10 mL), and ethyl isocyanate (0.5 mL, 6.5 mmol). The reaction was stirred at room temperature for 30 minutes and then NaHCO3 (sat) was added. The product was extracted with 3×10 mL EtOAc and the combined organics were dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography eluting with 50% acetone/dichloromethane—100% MeOH to afford 289 mg of I-162 as a brown oil in 22% yield.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][N:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: Brc1ccccn1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccccn1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 130 °C
Reaction time: 36 h
Yield: 24 %

Procedure:
A mixture of tert-butyl 4-(methylamino)piperidine-1-carboxylate (WO 03/089412, p22), (2 g, 9.33 mmol), 2-bromopyridine (1.35 mL, 13.99 mmol) and N,N-diisopropylethylamine (2.5 mL, 13.99 mmol) was heated at 130° C. for 3 hours. Potassium carbonate (2 g, 14 mmol) was added and the reaction mixture was heated at 130° C. for a further 8 hours. 2-Bromopyridine (1 mL, 10.36 mmol) was then added to the mixture and heating continued at 130° C. for 36 hours. The reaction mixture was then cooled and partitioned between ethyl acetate (30 mL) and water (15 mL). The organic layer was separated and extracted with saturated citric acid solution (2×15 mL), and the combined aqueous solution was basified with sodium hydrogen carbonate and extracted with dichloromethane (2×30 mL). The combined organic solution was dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate:pentane, 0:100 to 50:50, to afford the title compound in 24% yield, 646 mg. 1H NMR(CDCl3, 400 MHz) δ: 1.45(s, 9H), 1.55-1.70(m, 4H), 2.78-2.90(m, 5H), 4.10-4.30(m, 2H), 4.65-4.80(m, 1H), 6.45-6.55(m, 2H), 7.40-7.45(m, 1H), 8.10-8.15(m, 1H); LRMS APCI m/z 292 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:3]=1[O:4][CH2:5][C@H:6]([OH:35])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:21][N:22]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[C:23](=[O:28])[C:24]=3[CH:25]=2)[N:17]=1.[CH3:41][C:42]([CH3:44])=O.[BH4-].[Na+]>CO>[CH3:1][C:2]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:3]=1[O:4][CH2:5][CH:6]([OH:35])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:21][N:22]([CH:29]4[CH2:30][CH2:31][N:32]([CH:42]([CH3:44])[CH3:41])[CH2:33][CH2:34]4)[C:23](=[O:28])[C:24]=3[CH:25]=2)[N:17]=1
Reactant: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCNCC2)C4)c(C)c1
Reactant: CC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(OCC(O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCN(C(C)C)CC2)C4)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7 %

Procedure:
A mixture of 2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one (27.1 mg, 0.05 mmol), acetone (200 μL) and Ti(i-PrO)4 (300 μL) was stirred at the room temperature for 2 h and diluted with MeOH (5 mL). NaBH4 (190 mg, 5 mmol) was added into the reaction mixture and the mixture was stirred at the room temperature for 16 h and concentrated. Chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (490:10:1) afforded the title compound (2.06 mg, 7%). 1H NMR (DMSO-d6) δ 1.22 (s, 3H, CH3), 1.24 (s, 3H, CH3), 1.25-1.45 (4H), 1.80-2.30 (6H), 3.33-3.60 (2H), 3.70 (m, 1H), 3.90-4.19 (2H), 4.35-4.50 (2H), 5.47 (m, 1H, NH), 6.22 (m, 1H), 6.81 (m, 1H), 6.89-6.99 (2H), 7.32-7.38 (1.5H), 7.68 (s, 0.5H), 7.80 (s, 0.5H), 7.94 (s, 0.5H), 11.18 (br s, 1H, NH), 11.22 (d, J=6 Hz, 1H, NH); ESI-MS m/z 585.5 (MH+).
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:8][N:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]2[N:17]=[C:18]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=3[O:31][CH3:32])[N:19]=[CH:20][C:5]=2[N:4]([CH3:33])[C:3]1=[O:34].C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47][CH2:46]1>CN(C)C=O>[F:35][C:2]1([F:1])[CH2:8][N:7]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:6]2[N:17]=[C:18]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:51][CH:48]4[CH2:49][CH2:50][O:45][CH2:46][CH2:47]4)=[O:28])=[CH:24][C:23]=3[O:31][CH3:32])[N:19]=[CH:20][C:5]=2[N:4]([CH3:33])[C:3]1=[O:34]
Reactant: NC1CCOCC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(CCc1ccccc1)CC(F)(F)C(=O)N2C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCOCC2)ccc1Nc1ncc2c(n1)N(CCc1ccccc1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a mixture of 0.08 g (0.17 mmole) of 4-(7,7-difluoro-5-methyl-6-oxo-9-phenethyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-275), 0.12 mL (0.64 mmole) of ethyldiisopropyl amine and 0.018 g (0.19 mmole) of tetrahydro-pyran-4-ylamine in 2.0 mL of dimethylformamide was added 0.079 g (0.19 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted with dichloromethane 3 times. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-95:5) gave 0.070 g of 4-(7,7-difluoro-5-methyl-6-oxo-9-phenethyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(tetrahydro-pyran-4-yl)-benzamide (I-280) as a white solid.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]([C@H:16]1[CH2:20][O:19][C:18](=[O:21])[N:17]1[C:22](=[O:31])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:15])[CH3:14].Br[CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH2:24]([C@H:23]([CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C:22]([N:17]1[C@@H:16]([CH:13]([CH3:15])[CH3:14])[CH2:20][O:19][C:18]1=[O:21])=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)CCc1ccccc1
Reactant: O=C(CBr)OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](CC(=O)OCc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
22.50 ml (36.0 mmole) of butyllithium (as a 1.6M solution in hexane) were added dropwise, at -78° C. and under an atmosphere of nitrogen, to a solution of 5.05 ml (36.0 mmole) of diisopropylamine in 100 ml of anhydrous tetrahydrofuran, and the mixture was stirred for 30 minutes. At the end of this time, a solution of 7.84 g (30.0 mmole) of 4(S)-isopropyl-3-(3-phenyl-1-oxopropyl)-2-oxazolidinone (prepared as described in Preparation 12) in 50 ml of anhydrous tetrahydrofuran was added dropwise to the mixture. The mixture was then stirred for 1 hour, after which 14.26 ml (90.0 mmole) of benzyl bromoacetate were added to it. The mixture was stirred for 6 hours while the temperature of the reaction mixture was permitted to revert to room temperature. At the end of this time, the reaction mixture was mixed with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was stripped from it by distillation under reduced pressure. The residue was purified by medium pressure column chromatography through silica gel (using a 1:3 by volume mixture of ethyl acetate and hexane as the eluent), followed by recrystallization from diisopropyl ether, to afford 9.05 g (yield 74%) of the title compound as white crystals, melting at 118°-120° C.