Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P(=O)(OCC)OCC)#N.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:21]([O:25][C:26](=[O:40])[NH:27][C@H:28]1[C:37]2[C:32](=[CH:33][C:34]([CH:38]=O)=[CH:35][CH:36]=2)[CH2:31][CH2:30][CH2:29]1)([CH3:24])([CH3:23])[CH3:22].C[C:42](C)(O)[C:43]#[N:44]>C1COCC1>[C:43](/[CH:42]=[CH:38]/[C:34]1[CH:33]=[C:32]2[C:37](=[CH:36][CH:35]=1)[C@H:28]([NH:27][C:26](=[O:40])[O:25][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:29][CH2:30][CH2:31]2)#[N:44]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCc2cc(C=O)ccc21
Reactant: CC(C)(O)C#N
Agent: CCOP(=O)(C#N)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCc2cc(/C=C/C#N)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 300 mL flame dry 3-neck round bottom flask was added diethyl cyanophosphonate (14.86 g, 83.89 mmol) and THF (100 mL). After cooled to 0° C., sodium bis(trimethyl-silyl)amide (72.0 mL, 71.90 mmol) was added dropwise via the addition funnel. After stirred for 30 min at 0° C., It was cooled to −78° C. followed by adding (R)-tert-butyl-6-formyl-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate (6.6 g, 23.97 mmol) in TBF (60 mL) dropwise via the addition funnel. It was stirred for 18 h. Acetone cyanohydrin (3.1 mL, 33.48 mmol) was then added dropwise via the addition funnel. The resulting mixture was warmed up to rt and continued to stir for 18 h. The reaction mixture was quenched with sat. NH4Cl. Solvent was evaporated in vacuo. The residue was extracted with EtOAc. The organic layer was washed with H2O, brine, dried over MgSO4 and removed solvent. The crude product was purified by chromatography on silica gel. Elution with Hex:EtOAc mixture (70:30) gave final compound. MS m/z: 299.12 (M+H). Calc'd. for C18H22N2O2-298.23. B. (R,E)-3-(5-amino-5,6,7,8-tetrahydronaphthalen-2-yl)acralonitrile The product from the previous step was deprotected using HCl in dioxane to give the title compound in quantitative yield. MS m/z: 199.12 (M+H). Calc'd. for C13H14N2-198.23. C. N-((R)-6-((E)-2-cyanovinyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2-((R)-3-oxo-1-tosylpiperazin-2-yl)acetamide To a 250 mL round bottom flask was added (R)-2-(3-oxo-1-tosylpiperazin-2-yl)acetic acid (2.0 g, 6.40 mmol), followed by (R,E)-3-(5-amino-5,6,7,8-tetrahydronaphthalen-2-yl)acrylonitrile (1.26 g, 6.40 mmol), dry CH2Cl2 (70 mL), HATU (1.2 mg, 3.20 mmol), EDCI (1.4 g, 7.04 mmol) and hunig base (2.2 mL, 12.80 mmol). The resulting mixture was stirred at rt for 20 h. Removed solvent to dryness. The residue was purified by chromatography on silica gel. Elution with CH2Cl2:MeOH mixture (95:5) gave final compound (2.1 g, 66%). MS m/z: 493.3 (M+H). Calc'd. for C26H28N4O4S -492.6. D. N-((R)-6-(3-aminopropyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2-((R)-3-oxo-1-tosylpiperazin-2-yl)acetamide
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH:20]C(=O)C(Cl)(Cl)[Cl:23])[C:11]=2[N:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Cl>CO.C(O)(C)C>[ClH:23].[CH2:1]([C:8]1[S:9][C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:20])[C:11]=2[N:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1nc2ccccc2c2sc(Cc3ccccc3)nc12)C(Cl)(Cl)Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Product: Nc1nc2ccccc2c2sc(Cc3ccccc3)nc12
Temperature: 25 °C

Procedure:
Trichloroacetyl isocyanate (1.2 mL, 10.3 mmol) was added to a solution of 2-benzylthiazolo[4,5-c]quinoline-5N-oxide (2.0 g, 6.8 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated to provide crude N-(2-benzylthiazolo[4,5-c]quinolin-4-yl)trichloroacetamide. The amide was dissolved in methanol. Sodium methoxide (1 equivalent) was added. The reaction mixture was heated on a steam bath for 30 minutes and then allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration and then suspended in a mixture of methanol and isopropanol. Hydrochloric acid (1 equivalent) was added and all of the solid dissolved initially. A white solid crystallized out. This material was isolated by filtration, washed with isopropanol and then dried to provide 1.5 g of 2-benzylthiazolo[4,5-c]quinolin-4-amine hydrochloride, m.p. 152-155° C. Analysis: Calculated for: C17H13N3S.HCl: %C, 62.28; %H, 4.30; %N, 12.82; Found: %C, 62.05; %H, 4.23; %N, 12.82.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:14]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[CH:21]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.C([Li])CCC.[B:27](OC(C)C)([O:32]C(C)C)[O:28]C(C)C.Cl>CCCCCC.C1(C)C=CC=CC=1.C1COCC1>[CH:19]1[C:20]2[CH:21]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([B:27]([OH:32])[OH:28])=[CH:3][CH:4]=3)[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc(-c2cc3ccccc3c3ccccc23)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2cc3ccccc3c3ccccc23)cc1
Temperature: -60 °C
Yield: 72 %

Procedure:
In argon atmosphere, a liquid mixture of 21.3 (63.9 mmol) of 9-(4-bromophenyl)phenanthrene and 200 ml of dry THF was cooled to −60° C. under argon atmosphere, and 49.2 ml (76.7 mmol) of a 1.55 M hexane solution of n-butyllithium was added dropwise under stirring. Further, the reaction mixture was stirred at −60° C. for 2 h. The reaction solution was cooled again to −60° C., and 36.1 g (192 mol) of triisopropyl borate was added dropwise. The reaction mixture was heated up to room temperature and stirred for 17 h. The reaction mixture was cooled to 0° C., added with hydrochloric acid, and stirred at room temperature for one hour. After the reaction, toluene was added to the reaction mixture and the aqueous phase was removed. The organic phase was dried over magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The residue was recrystallized from toluene and then from hexane to obtain 13.8 g (yield: 72%) of 4-(9-phenanthrenyl)phenylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[N:27]1[CH:32]=[C:31]([NH2:33])[CH:30]=[CH:29][C:28]=1[NH2:34]>>[NH2:34][C:28]1[N:27]=[CH:32][C:31]([NH:33][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([C:11]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH:14]=3)=[O:26])=[C:2]([Cl:1])[CH:3]=2)=[CH:30][CH:29]=1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: Nc1ccc(N)nc1
Product: Nc1ccc(NC(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)c(Cl)c2)cn1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to pyridine-2,5-diamine via Procedure G. The crude product was purified on reverse phase HPLC to yield N4-(6-aminopyridin-3-yl)-2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide. MS (Q1) 478 (M)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1.O.[N-:10]=[N+:11]=[N-:12].[Na+]>O1CCOCC1>[N:10]([CH2:2][C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1)=[N+:11]=[N-:12]
Reactant: Nc1nc(CCl)cs1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: [N-]=[N+]=NCc1csc(N)n1
Yield: 70 %

Procedure:
To a solution of 4-chloromethyl-thiazol-2-ylamine (7.45 g, 50.0 mmol) in dioxane:water mixture (8:2) was added sodium azide (4.87 g, 75.0 mmol) and the reaction mixture was refluxed for 2-3 h. The mixture was concentrated in vacuo to remove all dioxane and the residue was dissolved in EtOAc (200 mL). The organic layer was washed with water (2×200 mL), brine (2×200 mL), dried over (Na2SO4) and concentrated in vacuo to give 4-azidomethyl-thiazol-2-ylamine in 70-90% yield.
Reaction SMILES: [CH2:1]1[NH:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4][NH:3][CH2:2]1.[CH2:10]1[CH2:21][NH:20][CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1.[P:22](O)([OH:24])[OH:23]>>[CH2:1]1[NH:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4][NH:3][CH2:2]1.[CH2:7]([O:24][PH:22]([CH2:19][CH:18]=[CH2:17])=[O:23])[CH3:8].[CH2:18]1[CH2:17][NH:16][CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][CH2:21][NH:20][CH2:19]1
Reactant: OP(O)O
Agent: C1CNCCCNCCCNC1
Agent: C1CNCCNCCN1
Product: C=CC[PH](=O)OCC

Procedure:
It appears however that the HI3 salts of the monomethylenesulfonic acids of [9]aneN3 and [12]aneN3 can be used directly. When these trilodide salts are added to melted phosphorous acid at 80° C., at 25° C., HP(=O)Et(OEt), or HP(=O)(OEt)2, a very exothermic reaction occurs whereby the respective monomethylenephosphonate, the monomethylene(ethyl)-phosphinate ethyl ester and the monomethylenephosphonate diethyl ester of [9]aneN3 (FIGS. 31A, 31B, and 31C) and the monomethylenephosphonate diethyl ester and the monomethylene(ethyl)-phosphinate ethyl ester of [12]aneN3 (FIGS. 32A and 32B) are formed almost quantitatively within a few seconds.
Reaction SMILES: CCN(CC)CC.CC(C)(C)C(Cl)=O.[CH2:15]([C@H:22]1[CH2:26][O:25][C:24](=[O:27])[NH:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Li].C([O-])(O)=O.[Na+]>CCOC(C)=O.C1COCC1>[CH2:15]([CH:22]1[CH2:26][O:25][C:24](=[O:27])[NH:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Li]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1NC(Cc2ccccc2)CO1
Temperature: 0 °C

Procedure:
To a suspension of 13-5 (5.6 g, 19 mmol), THF (97 mL), and NEt3 (3.2 mL, 23 mmol) at −78° C. was added trimethylacetyl chloride (2.6 mL, 21 mmol) dropwise. After addition was complete, the reaction mixture was warmed to 0° C. for 2 h then recooled to −78° C. and treated with lithium (S)-(−)-4-benzyl-2-oxazolidinone (18 mL, 29 mmol; 1.6M solution in THF). The reaction mixture was then warmed to 0° C. for 1 h and poured into EtOAc (300 mL) and sat. NaHCO3 (30 mL). The organic phase was washed with sat. NaHCO3, H2O, and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, EtOAc) gave 13-6 as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=2)[CH2:11][N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:4][N:3]=1.[NH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[OH:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][NH:27][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=3)[CH2:11][N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:4][N:3]=2)=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)N(Cc1cccc(-c2ccnc(Cl)n2)c1)Cc1ccccn1
Reactant: NCCc1ccc(O)cc1
Product: CS(=O)(=O)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1)Cc1ccccn1

Procedure:
Intermediate 11 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 490. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.6 (d, 1H) 8.3 (d, 1H) 7.9 (s, 2H) 7.6 (m, 1H) 7.4 (m, 2H) 7.3 (m, 2H) 7.2 (m, 1H) 7.0 (d, 2H) 6.9 (d, 1H) 6.7 (d, 2H) 5.5 (m, 1H) 4.5 (d, 4H) 3.7 (m, 2H) 3.0 (s, 3H) 2.9 (m, 2H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](Cl)([Cl:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:1]1([O:7][C:8]([Cl:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(Cl)Oc1ccccc1
Yield: 90.6 %

Procedure:
The distillation residue is re-used with 500 g of phenol and 540 g of phosgene, without the use of fresh triphenylphosphine. After a phosgenation time of 10 hours, 754 g of distilled chloroformic acid phenyl ester are obtained (purity 99.8%; yield 90.4% of the theoretical yield).
Reaction SMILES: [CH2:1]([N:8](C(OC(C)(C)C)=O)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.ClCCl>[CH2:1]([NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)[CH2:13][CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)COc1ccc([C@H]2CC[C@H](N(Cc3ccccc3)C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)COc1ccc([C@H]2CC[C@H](NCc3ccccc3)CC2)cc1
Reaction time: 2 h

Procedure:
A solution of 4.5 g of ethyl trans-(4-{4-[benzyl(tert-butoxycarbonyl)amino]cyclohexyl}-phenoxy)acetate (9.6 mmol) in a mixture of trifluoroacetic acid (30 ml) and dichloromethane (90 ml) is stirred for 2 h. The solvents are evaporated under reduced pressure and then water, ethyl acetate and a saturated aqueous sodium carbonate solution are added. The organic phase is washed once with water and dried over sodium sulfate. Ethyl trans-{4-[4-(benzylamino)cyclohexyl]phenoxy}acetate is obtained in the form of an oil (3.22 g, 88%) after evaporation of the solvents under reduced pressure. [M+H+]=368.3
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[Cl-].[NH4+]>O1CCCC1>[OH:18][CH:17]([C:16]1[CH:19]=[CH:20][C:13]([CH3:12])=[CH:14][CH:15]=1)[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: Cc1ccc(C=O)cc1
Reactant: C#CC(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C#CC(O)c1ccc(C)cc1
Reaction time: 0.17 h

Procedure:
A solution of 8.4 ml (0.1 mol) of methyl propiolate in 100 ml of tetrahydrofuran was treated at -78° under argon with 68.8 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 11.8 ml (0.1 mol) of 4-methylbenzaldehyde in 100 ml of tetrahydrofuran was added within 40 minutes. The reaction mixture was stirred at -78° for a further 20 minutes, then brought to room temperature and treated with 100 ml of saturated ammonium chloride solution The aqueous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 1000 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained methyl 4-hydroxy-4-(4-methylphenyl)-2-butynoate as a yellow oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[C:10]([C:11]2[CH:20]=[C:19]3[C:14]([C:15](=[O:21])[CH:16]=[CH:17][NH:18]3)=[CH:13][C:12]=2[O:22][CH3:23])=[C:9]([CH3:24])[O:8][N:7]=1>C(O)(=O)CC>[CH3:5][C:6]1[C:10]([C:11]2[CH:20]=[C:19]3[C:14]([C:15]([OH:21])=[C:16]([N+:1]([O-:4])=[O:2])[CH:17]=[N:18]3)=[CH:13][C:12]=2[O:22][CH3:23])=[C:9]([CH3:24])[O:8][N:7]=1
Reactant: COc1cc2c(=O)cc[nH]c2cc1-c1c(C)noc1C
Reactant: O=[N+]([O-])O
Solvent: CCC(=O)O
Product: COc1cc2c(O)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Temperature: 100 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
Nitric acid (1.86 g, 1.32 ml, 29.5 mmol) was added dropwise to a stirred solution of 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4(1H)-quinolinone (for a preparation see Intermediate 6) (6.9 g, 25.6 mmol) in propionic acid (70 ml). After complete addition the reaction mixture was stirred at 100° C. for 1 h. The reaction mixture was cooled to room temperature, the solid was filtered off, washed with diethyl ether and dried to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-nitro-4-quinolinol (5.0 g, 15.86 mmol, 62.1% yield) as a bright yellow solid. LCMS (formate) Rt 1.15 min, MH+ 316
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH2:3][CH2:4][O:5][C:6](=[O:12])[CH2:7][CH2:8][C:9](O)=[O:10].N1C=CC=CC=1.S(Cl)([Cl:27])=O>CCOCC>[CH3:1][CH:2]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH2:3][CH2:4][O:5][C:6](=[O:12])[CH2:7][CH2:8][C:9]([Cl:27])=[O:10]
Reactant: CC(C)=CCCC(C)CCOC(=O)CCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)=CCCC(C)CCOC(=O)CCC(=O)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
A solution of 35.5 g succinic acid mono-(3,7-dimethyl-oct-6-enyl) ester and 12.3 g pyridine in 200 ml of ether was cooled in an ice bath. Then a solution of 18.0 g thionyl chloride in 100 ml of ether was added dropwise at 5-10° C. during 90 min. The resulting solution was stirred overnight at room temperature, then it was filtered and evaporated to dryness. The residue was not further purified to yield 31.5 g of a yellow liquid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:40])[CH3:39])=[CH:33][CH:32]=1>C(O)C>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([CH2:21][O:20][C:18]2[CH:17]=[CH:16][C:15]([S:30][C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:40])[CH3:39])=[CH:33][CH:32]=3)=[C:14]([NH:13][C:2]3[C:3]4[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=4)[N:9]=[CH:10][CH:11]=3)[CH:19]=2)=[CH:27][CH:26]=1)#[N:29]
Reactant: CC(=O)Nc1ccc(Sc2ccc(OCc3ccc(C#N)cc3)cc2N)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc(OCc3ccc(C#N)cc3)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 ml) with the product from Example 156a (33 mg, 0.085 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (12 mg, 21%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.69-1.92 (m, 2 H) 2.02 (s, 3 H) 2.99 (t, J=7.54 Hz, 2 H) 5.27 (s, 2 H) 6.30 (d, J=6.99 Hz, 1 H) 7.14 (d, J=8.82 Hz, 2 H) 7.17-7.27 (m, 2 H) 7.37 (d, J=8.46 Hz, 1 H) 7.42 (d, J=8.82 Hz, 2 H) 7.64 (d, J=8.09 Hz, 2 H) 7.81 (d, J=8.82 Hz, 1 H) 7.89 (d, J=8.46 Hz, 2 H) 8.38 (d, J=6.99 Hz, 1 H) 8.97 (d, J=8.82 Hz, 1 H) 9.98 (s, 1 H) 11.01 (s, 1 H) 14.38 (s, 1 H); MS (ESI+) m/z 560 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:3]=1.[CH:31]([C:34]1[NH:38][C:37]2[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=2[N:35]=1)([CH3:33])[CH3:32].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.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]>[CH:31]([C:34]1[N:35]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([CH:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)[CH2:17][CH2:18]4)[N:8]3[CH3:11])=[C:4]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:3]=2)[C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1)([CH3:33])[CH3:32]
Reactant: CC(C)c1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCN(C3CCOCC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C4CCOCC4)CC3)n(C)c2n1
Yield: 37 %

Procedure:
A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-8-[4-(tetrahydropyran-4-yl)piperazin-1-ylmethyl]-9H-purine (180 mg, 0.41 mmol), 2-isopropyl-1H-benzoimidazole (80 mg, 0.50 mmol), Pd2dba3 (11 mg, 0.012 mmol), Xphos (22 mg, 0.046 mmol) and cesium carbonate (201 mg, 0.62 mmol) in DMF (4 mL) was purged with argon gas then subjected to microwave irradiation at 145° C. for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g), which was washed with MeOH/DCM before the desired product was eluted with 2 M NH3 in MeOH/DCM. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH 100:0 to 95:5) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 60:40 to 10:90) to afford 564 as a white solid (85 mg, 37%). LCMS (method I): RT=2.61 min, M+H+=560. 1H NMR (CDCl3, 400 MHz) δ 7.89 (d, J=7.6 Hz, 1 H), 7.78 (d, J=7.5 Hz, 1 H), 7.26 (m, 2 H), 4.34 (m, 4 H), 4.03 (d, J=10.1 Hz, 2 H), 3.95 (m, 1 H), 3.86 (m, 7 H), 3.77 (s, 2 H), 3.38 (t, J=11.7 Hz, 2 H), 2.63 (m, 9 H), 1.79 (m, 2 H), 1.60 (m, 2 H), 1.48 (s, 3 H) and 1.46 (s, 3 H)
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[CH:29]=[CH:30][C:31](O)=[O:32].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:25][C:26]1[CH:27]=[C:28]([CH:29]=[CH:30][C:31]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:32])[CH:34]=[CH:35][CH:36]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(O)C=Cc1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1cccc(F)c1
Yield: 73 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (4.0 g), triethylamine (2.3 mL), 3-fluorocinnamic acid (2.7 g), WSC.HCl (3.2 g), and methylene chloride (100 mL), to give the captioned compound (4.2 g, 74%) as an oily product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][NH:30][CH3:31])=[CH:27][CH:26]=1.C1CCN2C(=NCCC2)CC1>CN1C(=O)CCC1>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][N:30]([CH3:31])[C:13]2[CH:12]=[C:11]3[C:16]([CH:17]=[C:8]([C:6]4[CH:7]=[C:2]([NH2:1])[C:3]([F:22])=[CH:4][C:5]=4[CH3:21])[C:9](=[O:20])[N:10]3[CH3:19])=[CH:15][N:14]=2)=[CH:27][CH:26]=1
Reactant: Cc1cc(F)c(N)cc1-c1cc2cnc(Cl)cc2n(C)c1=O
Reactant: CNCc1ccc(OC)cc1
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2cc(N)c(F)cc2C)c(=O)n3C)cc1
Temperature: 180 °C
Yield: 100.5 %

Procedure:
3-(5-amino-4-fluoro-2-methylphenyl)-7-chloro-1-methyl-1,6-naphthyridin-2(1H)-one (1.36 g, 4.28 mmol, 1.00 eq), 4-methoxy-N-methylbenzylamine (0.971 g, 6.42 mmol, 1.50 eq) and DBU (0.960 mL, 6.42 mmol, 1.50 eq) were combined in NMP (20 mL) and heated at 180° C. under Ar overnight. The mixture was cooled to RT and poured onto H2O (200 mL). The resulting solids were collected by filtration, rinsed very well with H2O, dried on the filter to dampness and then dissolved in EtOAc. The solution was dried (MgSO4), filtered and evaporated to afford 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-4-fluoro-2-methylphenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (1.86 g, 100% yield) as a brittle brown foam which was used as is in the next reaction. 1H NMR (400 MHz, DMSO-d6): δ 8.45 (s, 1H), 7.63 (s, 1H), 7.16 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 6.86-6.82 (m, 1H), 6.57 (d, J=9.6 Hz, 1H), 6.29 (s, 1H), 4.88 (br s, 2H), 4.85 (s, 2H), 3.69 (s, 3H), 3.52 (s, 3H), 3.07 (s, 3H), 1.94 (s, 3H); MS (ESI) m/z: 433.3 [M+H]+.