Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[CH2:7]([NH2:11])[CH2:8][C:9]#[CH:10]>C(OCC)C>[CH2:7]([NH:11][C:5]([NH:4][CH2:3][CH2:2][Cl:1])=[O:6])[CH2:8][C:9]#[CH:10]
Reactant: C#CCCN
Reactant: O=C=NCCCl
Solvent: CCOCC
Product: C#CCCNC(=O)NCCCl
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
Add chloroethyl isocyanate (5.25 g, 50 mmol) dropwise to a solution of but3-ynyl-amine (3.4 g, 50 mmol) (prepared by following the procedure described in Tetrahedron Lett. 1987, 43, 5145) in ethyl ether (100 mL). Stir the suspension for 30 min and filter the solid to obtain the desired intermediate (8.7 g, 100%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:27])/[CH:17]=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)[CH2:12][CH2:11]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16](=[O:27])/[CH:17]=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)NCCC1CCN(C(=O)/C=C/c2cc(Cl)cc(Cl)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCC1CCN(C(=O)/C=C/c2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (E)-tert-butyl(2-(1-(3-(3,5-dichlorophenyl)acryloyl)piperidin-4-yl)ethyl)carbamate (step 3) (400 mg, 0.936 mmol) in DCM (5 ml) was added TFA (0.865 ml, 11.23 mmol) and the mixture was stirred at RT for 1 h. The solvent was removed under reduced pressure and the crude material was dissolved in MeOH and loaded on to an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with excess MeOH. The product was eluted using 2.0 M ammonia in MeOH and the solvent removed under reduced pressure to afford the title compound as a white solid;
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C@@H:12]1[CH:25]=[CH2:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1C2CCCC1CCC2.C1C[O:40]CC1>>[CH2:1]([O:8][C:9](=[O:27])[NH:10][C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:13][C@@H:12]1[CH2:25][CH2:26][OH:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: C=C[C@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: B1C2CCCC1CCC2
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@@H](CCO)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The compound [(1S,2R,4R)-[4-tert-butoxycarbonylamino-2-(vinyl)-cyclohexyl]-carbamic acid benzyl ester (0.82 g, 2.2 mmol) was dissolved in THF (15 mL). The resultant solution was cooled to 0° C. and charged with 9-BBN (11 mL of a 0.5 M solution in THF). The mixture was stirred for 20 h at RT and then quenched sequentially with aqueous sodium acetate (0.6 g in 1.5 mL water) and 30% hydrogen peroxide (1.5 mL). This was stirred at RT for 14 h and partitioned between EtOAc and sat. NaHCO3. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to afford [(1S,2R,4R)-[4-tert-butoxycarbonylamino-2-(hydroxyethyl)-cyclohexyl]-carbamic acid benzyl ester (0.42 g) as a white foam. MS found: (M+H)+=393.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:4][C:3]=1[F:15].Cl[CH:17]([C:20]1([C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[N:29]=[CH:28][CH:27]=[CH:26]3)[CH2:22][CH2:21]1)[CH:18]=O>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][C:11]3[N:10]([C:17]([C:20]4([C:23]5[CH:24]=[C:25]6[C:30](=[CH:31][CH:32]=5)[N:29]=[CH:28][CH:27]=[CH:26]6)[CH2:22][CH2:21]4)=[CH:18][N:14]=3)[CH:9]=2)=[CH:4][C:3]=1[F:15]
Reactant: Nc1ncc(-c2ccc(Br)c(F)c2)cn1
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Solvent: CCO
Product: Fc1cc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)ccc1Br
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(4-bromo-3-fluorophenyl)pyrimidin-2-amine (0.50 g, 1.9 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.463 g, 1.88 mol) in ethanol (20 mL) was stirred at 100° C. overnight. The solution was concentrated and the residue was purified by chromatography on silica gel with MeOH in CH2Cl2 (0-6%) to afford the desired compound. LCMS: (M+H)=458.9.
Reaction SMILES: [C:1]1([N:7]2[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][NH:9][C:8]2=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18]N(C)C=O.[H-].[Na+].P(OC)(OC)(OC)=O>O>[C:1]1([N:7]2[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][N:9]([CH3:18])[C:8]2=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: O=C1NCc2cccnc2N1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COP(=O)(OC)OC
Product: CN1Cc2cccnc2N(c2ccccc2)C1=O
Reaction time: 0.5 h

Procedure:
To a solution of 2.2 g of 1-phenyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine and 20 ml of dimethylformamide was added 0.5 g of approximately 50% sodium hydride, and the mixture was allowed to stand at room temperature for 30 minutes. To this was further added dropwise 4.2 g of trimethyl phosphate and the resulting mixture was heated at a temperature of 170° - 180° C in a sealed-tube for 7 hours. After the reaction was complete, the solvent was removed from the reaction mixture by distillation under reduced pressure. The residue thus obtained was diluted with water, extracted with ether and dehydrated. The ether was removed by evaporation to leave a residue. This residue was recrystallized from a mixture of ether and petroleum ether to yield 1.7 g of 1-phenyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as colorless prisms, melting at 172° - 173° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[C:13]1[NH:14][C:15](=[O:23])[C:16]2[N:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)[CH3:2].C(O)C.[OH-].[Na+].ClCCl>O>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:13]2[NH:14][C:15](=[O:23])[C:16]3[N:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:6]=1
Reactant: CCOc1ccc([N+](=O)[O-])cc1-c1nc2cccnc2c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CCOc1ccc(N)cc1-c1nc2cccnc2c(=O)[nH]1
Yield: 72.3 %

Procedure:
A stirred mixture of 2-(2-ethoxy-5-nitrophenyl)-pyrido(3,2-d]pyrimidin-4(3H)-one (Example 19; 1.1 g, 0.00353 mol), stannous chloride dihydrate (4.0 g, 0.0177 mol) and ethanol (15 ml) was heated under reflux for 4 hours. The resulting mixture was allowed to cool, diluted with water (15 ml), adjusted to pH 8 with 2N aqueous sodium hydroxide solution, vigorously shaken with dichloromethane (30 ml), and then this mixture filtered. The aqueous phase was separated and extracted further with dichloromethane (2×30 ml), and the organic extracts were then combined, dried (MgSO4) and evaporated under vacuum. Crystallization of the product from acetonitrile gave the title compound as a hydrated yellow solid (0.72 g, 72%), m.p. 208-210° C.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:13]=[N:14][C:15]2[C:20]([CH:21]=1)=[N:19][CH:18]=[C:17](Br)[CH:16]=2>CN(C=O)C>[CH2:1]([O:8][C:17]1[CH:18]=[N:19][C:20]2[C:15]([CH:16]=1)=[N:14][CH:13]=[C:12]([Br:11])[CH:21]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Brc1cnc2cc(Br)cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cnc2cc(OCc3ccccc3)cnc2c1
Temperature: 60 °C
Yield: 36.5 %

Procedure:
To a solution of benzyl alcohol (2.25 g, 20.8 mmol) in DMF (25 mL) was added NaH (60% in mineral oil, 0.83 g, 20.8 mmol). The resulting mixture was heated to 60° C. for 10 minutes and was added to 3,7-dibromo-1,5-naphthyridine (Intermediate 3, 5.0 g, 17.4 mmol) in DMF (25.0 mL) at 100° C. The resulting mixture was stirred over night at 100° C., cooled, and concentrated under reduced pressure. Water (50 mL) was added and the aqueous layer was washed with DCM (3×50 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification (FCC, SiO2, DCM/petroleum ether, 1:1) afforded the title compound as a white solid (2.0 g, 36.7%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:39]([CH3:40])=[N:38][N:37](C4CCCCO4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28]CC4C=CC=CC=4)=[CH:24][C:23]=3[F:36])[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)(C)(C)C>CO>[NH2:7][C:8]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[F:36])[N:19]=[C:18]3[NH:37][N:38]=[C:39]([CH3:40])[C:17]=23)=[O:15])[CH2:10][CH2:9]1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)N3CCC(NC(=O)OC(C)(C)C)(c4ccccc4)CC3)c12
Solvent: CO
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3F)cc(C(=O)N3CCC(N)(c4ccccc4)CC3)c12
Temperature: 38 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
{1-[6-(4-Benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-4-phenyl-piperidin-4-yl}-carbamic acid tert-butyl ester (90 mg) was dissolved in methanol (2 mL) and purged with argon, then hydrogen. Palladium (10% on charcoal, 13 mg) was added and the mixture was stirred at 38° C. for 2 h. The catalyst was filtered off, the solvent was evaporated and the residue was dissolved in THF (5 mL) containing HCl (4N in dioxane, 0.14 mL). The solution was stirred at r.t. over night, the precipitate formed was filtered off. The filtrate was concentrated, the residue was re-dissolved in methanol/water (v/v=1/1, 4 mL), and concentrated hydrochloric acid (1 mL) was added. The precipitate formed was filtered off, washed with ethyl acetate and acetone and dried in air. The two filtration solids were combined yielding 45 mg (75%) of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[N:14]=[C:13]([S:17][CH3:18])[N:12]=[CH:11][C:10]=3[CH2:9][CH2:8][C:7]=2[C:6]([C:19]([NH2:21])=[O:20])=[N:5]1.CN1CCNCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO>[CH:3]([N:4]1[C:16]2[C:15]3[N:14]=[C:13]([S:17][CH3:18])[N:12]=[CH:11][C:10]=3[CH2:9][CH2:8][C:7]=2[C:6]([C:19]([NH2:21])=[O:20])=[N:5]1)=[CH2:2]
Reactant: CSc1ncc2c(n1)-c1c(c(C(N)=O)nn1CCCl)CC2
Agent: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: C=Cn1nc(C(N)=O)c2c1-c1nc(SC)ncc1CC2
Temperature: 60 °C
Yield: 35 %

Procedure:
To a solution of 1-(2-chloroethyl)-8-(methylsulfanyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (50 mg 0.15 mmol) in methanol (3 ml), N-methylpiperazine (62 μl, 0.61 mmol) and cesium carbonate (97 mg, 0.3 mmol), were added. The resulting mixture was heated at 60° C. for 48 hours. The volatiles were removed under vacuum, the crude solid was dissolved with ethyl acetate and water, the organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude was purified by silica gel chromatography (DCM/EtOAc 8/2) to give the compound 1-ethenyl-8-(methylsulfanyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide as a yellow solid (15 mg 35% yield). LC/MS (254 nm) HPLC method 2 Rt 5.34 min. 1H NMR (401 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.35 (dd, J=8.73, 15.44 Hz, 1H), 7.71 (s, 1H), 7.46 (br. s., 1H), 5.96 (d, J=15.38 Hz, 1H), 5.15 (d, J=8.67 Hz, 1H), 3.00-3.09 (m, 2H), 2.86-2.94 (m, 2H), 2.56 (s, 3H). HRMS (ESI) calcd for C13H13N5OS [M+H]+ 288.0914 found 288.0913.
Reaction SMILES: [BH4-].[Li+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[I:21])[C:14](OC)=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH2:14][OH:15])[CH:18]=[CH:19][C:20]=1[I:21])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(I)c(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(I)c(OCc2ccccc2)c1
Temperature: 60 °C

Procedure:
1.18 g (54 mmol, 3 eq) of lithium borohydride are added to a solution of 6.9 g of methyl 3-benzyloxy-4-iodobenzoate in 30 ml of tetrahydrofuran. The reaction medium is heated at 60° C. for 12 hours and then hydrolyzed with ammonium chloride solution and extracted with ethyl acetate. The organic phases are combined and the solvents are evaporated off. 6.5 g of (3-benzyloxy-4-iodophenyl)methanol in oil form are used in the following reaction without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[O:15]=[C:16]1[CH:20]([C:21](O)=[O:22])[CH2:19][CH2:18][N:17]1[C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([CH:20]1[CH2:19][CH2:18][N:17]([C:24]2[CH:25]=[CH:26][C:27]([O:30][C:31]([F:34])([F:32])[F:33])=[CH:28][CH:29]=2)[C:16]1=[O:15])=[O:22]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)C1CCN(c2ccc(OC(F)(F)F)cc2)C1=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2ccc(OC(F)(F)F)cc2)C1=O
Yield: 37.2 %

Procedure:
This compound was prepared according to method E with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), 2-oxo-1-(4-(trifluoromethoxy)phenyl)pyrrolidine-3-carboxylic acid (0.125; 0.433 mmol), PyBOP (0.225 g; 0.433 mmol), N,N diisopropylethylamine (0.186 mL; 1.08 mmol) in DMF (3 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.075 g (37%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-oxo-1-(4-(trifluoromethoxy)phenyl)pyrrolidine-3-carboxamide as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[N:21][C:22](Cl)=[CH:23][C:24]=2[C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)=[CH:4][C:5]([F:17])=[C:6]([S:8]([NH:11][C:12]2[N:13]=[CH:14][S:15][CH:16]=2)(=[O:10])=[O:9])[CH:7]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[N:21][C:22]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=3)=[CH:23][C:24]=2[C:25]2[CH:29]=[N:28][NH:27][CH:26]=2)=[CH:4][C:5]([F:17])=[C:6]([S:8]([NH:11][C:12]2[N:13]=[CH:14][S:15][CH:16]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2cnc(Cl)cc2-c2cn[nH]c2)cc1F
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2cnc(-c3cccc(F)c3)cc2-c2cn[nH]c2)cc1F
Reaction time: 0.33 h
Yield: 19.5 %

Procedure:
13.9 mg (0.03 mmol) of 5-chloro-4-((6-chloro-4-(1H-pyrazol-4-yl)pyridin-3-yl)oxy)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide was dissolved in 1 mL of 1,4-dioxane, and 6.3 mg (0.05 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 3.5 mg (10 mol %) of Pd(PPh3)4, 12.4 mg (0.09 mmol) of Na2CO3, and 0.2 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 20 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, dimethylchloride:ethanol=15:1) to obtain 3.2 mg (19.7% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C@H:10]3[C:16](=O)[N:15](COCC[Si](C)(C)C)[C:14]4[CH:26]=[C:27]([O:32][CH2:33][CH2:34][CH2:35][O:36][C:37]5[C:38]([O:64][CH3:65])=[CH:39][C:40]6[C:46](=[O:47])[N:45]7[CH:48]=[C:49]([CH:51]8[CH2:53][CH2:52]8)[CH2:50][C@H:44]7[C:43](=O)[N:42](COCC[Si](C)(C)C)[C:41]=6[CH:63]=5)[C:28]([O:30][CH3:31])=[CH:29][C:13]=4[C:12](=[O:66])[N:11]3[CH:67]=2)=[CH:4][CH:3]=1.[Li+].[B-](CC)(CC)CC>C1COCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][C@H:10]3[CH:16]=[N:15][C:14]4[CH:26]=[C:27]([O:32][CH2:33][CH2:34][CH2:35][O:36][C:37]5[C:38]([O:64][CH3:65])=[CH:39][C:40]6[C:46](=[O:47])[N:45]7[CH:48]=[C:49]([CH:51]8[CH2:53][CH2:52]8)[CH2:50][C@H:44]7[CH:43]=[N:42][C:41]=6[CH:63]=5)[C:28]([O:30][CH3:31])=[CH:29][C:13]=4[C:12](=[O:66])[N:11]3[CH:67]=2)=[CH:6][CH:7]=1
Reactant: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(C4CC4)C[C@H]1C(=O)N3COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)[C@@H]1CC(c3ccc(N)cc3)=CN1C2=O
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(C4CC4)C[C@H]1C=N3)N=C[C@@H]1CC(c3ccc(N)cc3)=CN1C2=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 66.3 %

Procedure:
SEM dilactam 14 (0.66 g, 0.69 mmol) was dissolved in THF (23 mL) and cooled to −78° C. under an argon atmosphere. Super-Hydride® solution (1.7 mL, 1 M in THF) was added drop wise over 5 minutes while monitoring the temperature. After 20 minutes a small sample was taken and washed with water for LC/MS analysis. Water (50 mL) was added and the cold bath was removed. The organic layer was extracted and washed with brine (60 mL). The combined aqueous layers were washed with CH2Cl2/MeOH (90/10 v/v) (2×50 mL). The combined organic layers were dried with MgSO4, filtered and the solvent removed in vacuo. The crude product was dissolved in MeOH (48 mL), CH2Cl2 (18 mL) and water (6 mL) and sufficient silica gel was added to afford a thick suspension. After 5 days stirring, the suspension was filtered through a sintered funnel and washed with CH2Cl2/MeOH (9:1) (˜200 mL) until product ceased to be eluted. The organic layer was washed with brine (2×70 mL), dried with MgSO4, filtered and the solvent removed in vacuo. Purification by silica gel column chromatography (100% CHCl3 to 96/4 v/v CHCl3/MeOH) afforded the product 15 as a yellow solid (302 mg, 66%). Method 1, LC/MS (2.42 min (ES+) m/z (relative intensity) 660.74 ([M+H]+, 30). 1H NMR (400 MHz, CDCl3) d 7.86 (d, 1H, J=3.6 Hz), 7.78 (d, 1H, J=3.6 Hz), 7.58-7.44 (m, 3H), 7.34-7.20 (m, 3H), 6.88-6.66 (m, 4H), 4.35-4.15 (m, 6H), 3.95-3.75 (m, 7H), 3.39-3.22 (m, 1H), 3.14-3.04 (m, 1H), 2.93-2.85 (m, 1H), 2.46-2.36 (m, 2H), 1.49-1.41 (m, 1H), 0.80-0.72 (m, 2H), 0.58-0.51 (app. s, 2H) ppm.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=3)=[CH:11][C:10]([S:27]([NH2:30])(=[O:29])=[O:28])=[C:9]2[CH3:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].O>CN(C=O)C>[CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:20])[CH3:21])[CH:16]=[C:15]([C:23]([CH3:24])([CH3:25])[CH3:26])[CH:14]=3)=[CH:11][C:10]([S:27]([NH:30][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])(=[O:29])=[O:28])=[C:9]2[CH3:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CBr
Reactant: Cc1c(S(N)(=O)=O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNS(=O)(=O)c1cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n(CC2CCCCC2)c1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 20.8 %

Procedure:
To a solution of compound 1 (600 mg, 1.36 mmol) in dry DMF (10 mL) was added NaH (60%, 60 mg, 1.50 mmol) at 0° C. and the mixture was stirred at 0° C. for 10 min. Ethyl 2-bromoacetate (225 mg, 1.36 mmol) was added and then this mixture was stirred at rt for 5 h. Water was added for quench and the solution was extracted with EA. The organic layer was washed with brine twice, concentrated and purified by CC (PE/EA=5/1) to give compound 42 (150 mg, 21%) as a white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+].[I-].[BH4-].[Na+]>C(#N)C.CO.O>[CH2:11]([N:7]1[CH2:8][CH2:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: c1cnc2ccncc2c1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: c1ccc(CN2CCc3ncccc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution 1,6-naphthyridine (2.09 g, 16.05 mmol) in acetonitrile (50.0 ml) is added benzylbromide (3.30 g, 19.27 mmol, 1.2 eq.) and NaI (50.0 mg). The resulting mixture is refluxed under nitrogen overnight. Acetonitrile is evaporated, and the residue is washed with ether (20 ml), and dried in vacuo to give the quaternary salt, which is dissolved in a mixture of MeOH (90 ml) and water (30 ml). To the solution at 0° C. is added sodium borohydride (2.28 g, 96.5 mmol, about 6.0 eq.). The resulting mixture is warmed to rt, and stirred overnight. The organic solvent is evaporated, and the residue is taken up in water (50 ml), extracted with EtOAc (50 ml×3). The combined organic phase is washed with brine, dried over sodium sulfate, and concentrated. The crude product is purified by silica gel chromatography (Hexane/EtOAc 1:1 plus 4% TEA) to give the title compound. MS (+VE) m/z 225.1 (M++1).
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:24]([Cl:25])=[CH:23][C:10]3[NH:11][C:12]([C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=4)=[O:15])=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.C([SiH](CC)CC)C.[CH:46]([O:49][P:50]([O-:55])[O:51][CH:52]([CH3:54])[CH3:53])([CH3:48])[CH3:47]>CCOC(C)=O.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].C1(C)C=CC=CC=1>[CH:46]([O:49][P:50]([C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([C:14]([C:12]2[NH:11][C:10]3[CH:23]=[C:24]([Cl:25])[C:7]([C:4]4[CH:5]=[CH:6][C:1]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:2][CH:3]=4)=[CH:8][C:9]=3[N:13]=2)=[O:15])[CH:21]=1)(=[O:55])[O:51][CH:52]([CH3:54])[CH3:53])([CH3:48])[CH3:47]
Reactant: O=C(c1cccc(Br)c1)c1nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Reactant: CC(C)OP([O-])OC(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC[SiH](CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)OP(=O)(OC(C)C)c1cccc(C(=O)c2nc3cc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3[nH]2)c1
Reaction time: 0.33 h

Procedure:
To a microwave reactor vial was added compound 14-2 (150 mg, 0.31 mmol), PdCl2(dppf) (50 mg, 0.061 mmol), triethylamine (0.13 mL, 0.93 mmol), triethylsilane (19 μL, 0.12 mmol), diisopropylphosphite (62 μL, 0.37 mmol) and 3 mL of toluene. The reaction was run in a microwave reactor for 20 min at 140° C. The reaction mixture was then diluted with EtOAc (50 mL) and washed three times with 50 mL portions of saturated aqueous ammonium chloride. The combined organic layers were dried over MgSO4, filtered, concentrated in vacuo, and then purified on ISCO (EtOAc/Hexanes=1/1) to yield title compound 14-3 as a brown oil.
Reaction SMILES: C(OCC)C.O.[BH4-].[Na+].[OH-].[CH:10]1([Sn+:16]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(OCC)C>[CH:23]1([SnH:16]([CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: C1CCC([Sn+](C2CCCCC2)C2CCCCC2)CC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: C1CCC([SnH](C2CCCCC2)C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture (400 mL) of diethyl oxide:water 1:1 was cooled at 0° C. under nitrogen in a three-necked flask of 1 L. Sodium borohydride (3 g, 79.4 mmol) and then tricyclohexyltin hydroxide (30 g, 62.2 mmol) were successively and carefully added. After addition of 100 mL of diethyl oxide, the mixture was stirred 2 days at room temperature. After separation, the organic layer was dried over magnesium sulphate and evaporated under reduced pressure. The crude product was distilled under high vacuum to afford, a colourless oil (23.23 g; 63 mmol).