Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:17])([O-])[O:2][C:3]1[CH:8]=CC([N+]([O-])=O)=C[C:4]=1C(C)(C)C.[CH2:18]([NH2:21])[CH2:19][NH2:20].[CH3:22]N(C=O)C>>[C:1]([NH:20][CH2:19][CH2:18][NH2:21])([O:2][C:3]([CH3:4])([CH3:8])[CH3:22])=[O:17]
Reactant: CN(C)C=O
Reactant: NCCN
Reactant: CC(C)(C)c1cc([N+](=O)[O-])ccc1OC(=O)[O-]
Product: CC(C)(C)OC(=O)NCCN
Temperature: 0 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
tert-Butyl-4-nitrophenyl carbonate (1) (10.0 g; 0.0418 mol) dissolved in DMF (50 ml) was added dropwise over a period of 30 min to a solution of ethylenediamine (27.9 ml; 0.418 mol) and DMF (50 ml) and stirred overnight. The mixture was evaporated to dryness, in vacuo, and the resulting oil dissolved in water (250 ml). After cooling to 0° C., pH was adjusted to 3.5 with 4 M hydrochloric acid. The solution then was filtered and extracted with chloroform (3×250 ml). The pH was adjusted to 12 at 0° C. with 2 M sodium hydroxide, and the aqueous solution extracted with methylene chloride (3×300 ml). After treatment with sat. aqueous sodium chloride (250 ml), the methylene chloride solution was dried over magnesium sulfate. After filtration, the solution was evaporated to dryness, in vacuo, resulting in 4.22 g (63%) of the product (oil). 1H-NMR (90 MHz; CDCl3): δ1.44 (s, 9H); 2.87 (t, 2H); 3.1 (q, 2H); 5.62 (s, broad).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[CH2:28][OH:29]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[CH2:28][OH:29])=[O:6]
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(O)c1ccccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(c1ccccc1Cl)N1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To 2-chlorobenzoic acid (10 g; 63.9 mmol) in dimethylformamide (100 ml) under nitrogen was added carbonyldiimidazole (10.9 g; 67.1 mmol) and the solution stirred for 1 h at room temperature. (S)-(+)-2-pyrrolidinemethanol (7.56 ml, 76.6 mmol) was added and the mixture stirred at 40° C. for 18 h. The solvent was removed under reduced pressure and the crude product purified by chromatography on silica (eluting with 50% to 75% ethyl acetate in heptane) to afford (S)-1-(2-chlorobenzoyl)-2-pyrrolidinemethanol (10.2 g), which was used directly in the next step.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([C:11]1[CH:31]=[CH:30][C:14]([C:15]([NH:17][C@H:18]([C:20]2[NH:24][C:23]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:22]=3[N:21]=2)[CH3:19])=[O:16])=[CH:13][C:12]=1[Cl:32])=[O:10].[C:33](OC(=O)C)(=[O:35])[CH3:34].[Cl-].[Na+].ClCl>C(O)(=O)C.CO>[C:33]([NH:1][CH2:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([C:11]1[CH:31]=[CH:30][C:14]([C:15]([NH:17][C@H:18]([C:20]2[NH:24][C:23]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:22]=3[N:21]=2)[CH3:19])=[O:16])=[CH:13][C:12]=1[Cl:32])=[O:10])(=[O:35])[CH3:34]
Reactant: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CCN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CC(=O)OC(C)=O
Agent: ClCl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)NCC[C@@H]1CCCN1C(=O)c1ccc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Yield: 67 %

Procedure:
Prepared analogously to Example 124 from 4-[(2S)-2-(2-aminoethyl)pyrrolidin-1-ylcarbonyl]-3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]benzamide and acetic anhydride in glacial acetic acid. Yield: 67%; Rf value: 0.32 (Reversed phase RP 8; methanol:5% sodium chloride solution=6:4); C25H27Cl2N5O3 (516.43); mass spectrum: (M+H)+=516/518/520 (chlorine isotope).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:12]I>C(OCC)(=O)C>[CH3:12][N:5]1[CH2:6][CH:7]=[C:2]([C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:4]1
Reactant: CCOC(=O)c1ccncc1
Reactant: CI
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=CCN(C)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
To a solution of ethyl isonicotinate (151 g) in ethyl acetate (1000 mL) was added methyl iodide (126 mL), and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was cooled, and the orange precipitate was collected by filtration. The precipitate was suspended in ethanol (1000 mL), sodium borohydride (37.8 g) was added with cooling at −40° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and ethanol was evaporated under reduced pressure. The resultant product was extracted with ethyl acetate-tetrahydrofuran, the organic layer was dried, and the solvent was evaporated under reduced pressure. The residue was distilled under reduced pressure to give ethyl 1-methyl-1,2,3,6-tetrahydropyridine-4-carboxylate (85.8 g, 51%) as a pale yellow oil.
Reaction SMILES: ClC1C(I)=NSN=1.C([Sn](CCCC)(CCCC)C1C=NC=CC=1)CCC.C1C=CC(/C=C/[C:35](/[CH:37]=C/C2C=CC=CC=2)=[O:36])=CC=1.C1C=CC(/C=C/[C:53](/[CH:55]=C/C2C=CC=CC=2)=[O:54])=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=[O:72])=CC=1.[Pd:81].[Pd]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:37][C:35]([O-:54])=[O:36].[CH3:55][C:53]([O-:72])=[O:54].[Pd+2:81]
Reactant: [Pd]
Reactant: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: Clc1nsnc1I
Solvent: Cc1ccccc1
Product: CC(=O)[O-]
Product: [Pd+2]
Yield: 76 %

Procedure:
To a solution of 3-chloro-4-iodo-1,2,5-thiadiazole (62 mg, 0.25 mmol) in toluene (1 ml) under nitrogen is added tributyl-(3-pyridyl)stannane (92 mg, 0.25 mmol) and Pd2dba3 (5.7 mg, 5%mol). The resulting mixture is heated to reflux for 2 hours. A 76% yield was measured by quantitative HPLC, TLC (Hexane8/EtOAc2): only product. Similar results were obtained with 2% of Pd2(dba)3 as catalyst as well with Pd(CH3CN)2Cl2 or Pd(OAc)2.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:36]=[CH:35][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=3)[N:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].[Li+].[OH-].O.Cl>C1COCC1.C(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])[N:15]=[C:14]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=3)[N:13]=2)=[CH:35][CH:36]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCOc1ccc(CNc2nc(Nc3ccc(C(=O)OC)cc3)nc(OCC(F)(F)F)n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCCOc1ccc(CNc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 60 °C
Yield: 101 %

Procedure:
methyl 4-(4-(4-(but-3-enyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (46 mg, 0.091 mmol) was dissolved in THF (2 mL). LiOH (10.94 mg, 0.457 mmol) and Water (2 mL) were added to the solution and the reaction was warmed to 60° C. for 16 h. The reaction was diluted with DCM and acidified with 1 N HCl. The organic layer was collected, dried over sodium sulfate, and concentrated under vacuum to give 4-(4-(4-(but-3-enyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (45 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.O.O.O.O.O.[OH-].C[N+](C)(C)C.Br[CH2:34][CH2:35][CH2:36][OH:37].Cl>CN(C=O)C.O>[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:34][CH2:35][CH2:36][OH:37])=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Reactant: OCCCBr
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCOc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Yield: 144.5 %

Procedure:
To 4-(6-chloro-2,3-dihydro-indol-1-yl)-quinazolin-7-ol (125 mg, 0.42 mmol; from Example 65) in DMF (2 mL) was added H2O (50 μL), K2 CO3 (s) (116 mg, 0.84 mmol) and tetramethylammonium hydroxide pentahydrate (15 mg, 0.08 mmol) followed by 3-bromopropanol (43 μL, 0.46 mmol). The mixture was stirred at 50° C. under N2(g) for 24 hours before another aliquot (11 μL) of 3-bromopropanol was added. After heating another 24 hours, extractive workup and chromatography analogous to that described in Example 1 followed by conversion to the HCl salt as outlined for Example 2 afforded 119 mg (70%) of product. (M.P. 211°-223° C. (dec); LC-MS: 356 (MH+); anal. RP18-HPLC RT: 4.40 min.; M.P. of free-base: 137°-138° C.).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:2]2[C:3]3[CH:4]=[CH:5][C:6]([NH:20][CH2:19][C:17]4[O:18][C:14]([CH3:13])=[CH:15][CH:16]=4)=[N:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:24][CH:23]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1ccc(CN)o1
Reactant: Clc1ccc2c(I)cccc2n1
Product: Cc1ccc(CNc2ccc3c(Nc4ccc(Cl)cc4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=364.3 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-chloroquinoline (CAS 455955-26-7), 5-methyl-2-furanmethanamine and 4-chloroaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl.CCOCC>CO.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCCNc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: O=C(O)c1ccc(OCCNc2ccc(Cl)cc2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 144.4 %

Procedure:
Methyl 4-[2-[N-(4-chlorophenyl)amino]ethoxy]benzoate (0.4 g) was suspended in methanol (20 ml), and thereto a solution of sodium hydroxide (0.16 g) in water (5 ml) was added, and the mixture was heated with stirring at 60° C. for 3 hours. The reaction mixture was cooled, and neutralized with hydrochloric acid and concentrated under reduced pressure. After adding water thereto, the resulting residue was crushed, then, collected by filtration to give crude crystal. An equivalent amount of hydrochloric acid was added to the crude crystal in methanol, and the mixture was dried under reduced pressure to give a salt. The salt was suspended in a mixed solvent of methanol and ether, and collected by filtration to give the desired product (0.31 g). mp. 190°-193° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][NH:10][C:11]([CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14]2)=O)=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.[NH4+:34].O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:34]=[C:11]([CH:13]3[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:14]3)[NH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(CNC(=O)C1CN(Cc2ccccc2)CCO1)c1ccc(Cl)cc1
Reactant: [NH4+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Clc1ccc(-c2c[nH]c(C3CN(Cc4ccccc4)CCO3)n2)cc1
Temperature: 150 °C
Yield: 89.4 %

Procedure:
A mixture of N-[2-(4-chlorophenyl)-2-oxoethyl]-4-(phenylmethyl)-2-morpholinecarboxamide (3.3 g, 8.85 mmol) and ammonium trifluoroacetate (5.27 g, 44.3 mmol) was heated at 150° C. for 20 minutes. After cooling, to the resulting mixture was added water (50 mL) and CH2Cl2 (50 mL). The organic layer was separated and washed with brine, dried (MgSO4), and concentrated to afford the crude title compound (2.8 g). LC-MS (ES) m/z=354 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:31].[CH:32]([NH2:35])([CH3:34])[CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:35][CH:32]([CH3:34])[CH3:33])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:31]
Reactant: CC(C)N
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CSc1nc(-c2cc(C(=O)NC(C)C)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 97322.8 %

Procedure:
To the solution of 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoic acid (150 mg, 0.34 mmol) in CH2Cl2 (10 mL) were added isopropylamine (0.087 mL, 1.02 mmol), HATU (135 mg, 0.355 mmol) and diisopropyl ethyl amine (0.2 mL, 1.15 mmol). The reaction mixture was stirred over night. The reaction mixture was diluted with CH2Cl2 (50 mL) and water (50 mL) and shaked. The layers were separated and the organic layer was washed with brine (75 mL), dried over Na2SO4, filtered and concentrated. Flash chromatography then provided the title compound as a white solid 160 g (97%). LC-MS m/z 484 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][C:10]2=O)=[CH:5][C:4]=1[CH3:16].C[Mg+].[Br-].[CH2:20](OCC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](=[CH:5][C:4]=1[CH3:16])[C:7]([CH3:15])([CH3:14])[CH2:8][CH:9]=[C:10]2[CH3:20]
Reactant: CCOCC
Reactant: COc1cc2c(cc1C)C(C)(C)CCC2=O
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cc2c(cc1C)C(C)(C)CC=C2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
General Procedure A CeCl3 7 H2O (1.28 g, 3.4 mmol) was heated in an oil bath to 140-150° C. under high vacuum without stirring for 2 h, and then with stirring for 2 h. Argon was then introduced, and the flask was cooled to room temperature. Tetrahydrofuran (10 mL) was added, and the resulting slurry solution was stirred at room temperature under the argon atmosphere for 3 h. A solution of 7-methoxy-4,4,6-trimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 6, 0.53 g, 2.3 mmol) and 5 mL of tetrahydrofuran was added, and the reaction mixture was stirred for 1 h, then cooled to 0° C. A solution of 3 M MeMgBr in diethyl ether (1.2 mL, 3.4 mmol) was added, and the ice bath was removed. After 1 h, the reaction was poured into concentrated sulfuric acid in ice, extracted with ethyl acetate, washed with IN NaHCO3, brine, dried over MgSO4, and filtered. The solvent was removed to give 0.42 g (80%) of the title compound as an orange oil.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na].[Cl:9][C:10]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[CH2:15][C:14]([CH3:22])([CH3:21])[CH2:13][C:12]=2[N:11]=1.O>C(OCC)C>[ClH:9].[CH:1]1([O:7][C:10]2[CH:19]=[CH:18][C:17]3[C:16](=[O:20])[CH2:15][C:14]([CH3:22])([CH3:21])[CH2:13][C:12]=3[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: CC1(C)CC(=O)c2ccc(Cl)nc2C1
Agent: [Na]
Solvent: O
Solvent: CCOCC
Product: CC1(C)CC(=O)c2ccc(OC3CCCCC3)nc2C1
Product: Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.4 %

Procedure:
To a solution of cyclohexanol (0.2 g, 2.0 mmol) in diethyl ether (10 ml) was added sodium (0.035 g, 1.5 mmol) and it was stirred at room temperature for 2.5 h. Then 2-chloro-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one (0.21 g, 1.0 mmol) was added and the resulting mixture was stirred at 30° C. for 24 h. Water (12 ml) was added and the mixture was extracted with ethyl acetate (2×10 ml). The organic phase was washed with water (10 ml) and dried over magnesium sulphate, then it was filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (petroleum ether-ethyl acetate, 10:1) followed by treatment with a dry 0.5M HCl solution in diethyl ether to give the title compound (0.28 g, 47%) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].Cl.[CH2:11]([O:18][C:19](=[O:25])[C@@H:20]1[CH2:24][CH2:23][CH2:22][NH:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>C(O)(C)(C)C>[CH2:11]([O:18][C:19]([C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[CH2:3][CH2:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:25])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCN1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 80 °C
Yield: 79 %

Procedure:
Tert-butyl acrylate (5.00 mL) was added to a solution of L-proline benzyl ester hydrochloride salt (1.10 g, 4.54 mmol) and Et3N (632 μL, 4.54 mmol) in tert-butanol (5.00 mL). The reaction was heated to 80° C. for 3 h then and evaporated in vacuo. The residue was purified by FCC, using 0-50% EtOAc in cyclohexane, to give the title compound (1.20 g, 79%). 1H NMR (300 MHz, CDCl3): 1.43 (9H, s), 1.72-2.00 (3H, m), 2.08 (1H, m), 2.39-2.48 (3H, m), 2.72 (1H, ddd, J 12.2, 8.4, 6.7), 3.00 (1H, dt, J 12.3, 7.8), 3.13 (1H, m), 3.28 (1H, dd, J 8.6, 5.4), 5.13 (1H, d, J 12.3), 5.18 (1H, d, J 12.3), 7.29-7.39 (5H, m).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH2:12][CH2:13][CH2:14][CH3:15])=[N:8][O:9][C:10]=1[CH3:11])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:12]([C:7]1[C:6]([CH2:4][OH:3])=[C:10]([CH3:11])[O:9][N:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1noc(C)c1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCc1noc(C)c1CO
Yield: 95.7 %

Procedure:
To a stirred solution of 3-butyl-5-methyl-isoxazole-4-carboxylic acid ethyl ester (9.8 g, 46.3 mmol) in THF (100 mL) under argon and at 0° C. was added lithium aluminium hydride (2.03 g, 53.4 mmol) in five portions. After 1 h the reaction mixture was quenched dropwise with Seignette's salt solution. The reaction mixture was filtered and the filtrate extracted with ethyl acetate. The combined organic extracts were washed with Seignette's salt solution then dried, filtered and concentrated. Purification by chromatography (silica, heptane:ethyl acetate=100:0 to 4:6) afforded the title compound (7.5 g, 95%) as a yellow liquid. MS: m/e=170.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:10]=1)[C:5]([OH:7])=[O:6].C(Cl)(=O)C(Cl)=O.[CH2:25](O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl.CN(C)C=O.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14])[CH:10]=1)[C:5]([O:7][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:6]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(C(=O)O)c1
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of the acid 14 (3.80 g, 13.3 mmol) and oxalyl chloride (5.8 mL, 66 mmol) in methylene chloride (60 mL) was added ca. 0.05 mL of N,N-dimethylformamide as a catalyst. After stirring 1 hr at ambient temperature, the reaction was evaporated in vacuo, diluted with methylene chloride, and reacted with benzyl alcohol (1.38 mL, 13.3 mmol) and 4-(N,N-dimethylamino)pyridine (1.60 g, 13.3 mmol). After stirring 16 hrs at ambient temperature, the solution was washed with dilute aqueous HCl, dilute aqueous NaHCO3, and brine, dried over Na2SO4, and filtered. The filtrate was then evaporated in vacuo giving a quantitative yield of gold oil. 1H NMR (300 MHz, CDCl3) δ 7.64 (t, 1H, J=1.5 Hz), 7.45-7.28 (m, 6H), 7.02 (m, 1H), 5.35 (s, 2H), 0.98 (s, 9H), 0.22 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](CC)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O-:12][C:13]#[N:14].[K+].[C:16](O)(=O)[CH3:17]>O>[C:4]([C:3]1[CH:6]=[C:7]([CH2:16][CH3:17])[CH:8]=[CH:9][C:2]=1[NH:1][C:13]([NH2:14])=[O:12])#[N:5]
Reactant: CCc1ccc(C#N)c(N)c1
Reactant: N#C[O-]
Reactant: CC(=O)O
Agent: [K+]
Solvent: O
Product: CCc1ccc(NC(N)=O)c(C#N)c1

Procedure:
To a solution of 2-amino-4-ethylbenzonitrile (39.9 g) in acetic acid (200 ml) was added potassium cyanate (24.4 g) under ice-cooling in the course of 15 minutes and stirred overnight in water bath. To the resultant mixture was added water to give precipitates, which were separated by filtration, washed with water and dried at ambient temperature. The resultant crude crystals were recrystallized from ethanol to give crystalline (2-cyano-4-ethylphenyl)urea (29.0 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:20](Cl)(=O)[CH:21]([CH3:23])[CH3:22].O.[NH2:27][NH2:28]>C1(C)C=CC=CC=1>[CH:21]([C:20]1[NH:28][N:27]=[C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:2]=1)([CH3:22])[CH3:23]
Reactant: CC(C)C(=O)Cl
Reactant: NN
Reactant: CC(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1cc(-c2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 37.3 %

Procedure:
To a solution of acetophenone (1.21 g, 10.07 mmol) in dry toluene (5 mL) was added LiHMDS (11.0 mL, 1.0 M in THF, 11.0 mmol) via syringe at 0° C. under argon. After 5 min, isobutyryl chloride (1.073 g, 10.07 mmol) was added in one portion via syringe. The ice bath was removed and AcOH (2 mL), EtOH (50 mL) and THF (5 mL) were added to form a homogeneous mixture. Hydrazine hydrate (2 mL, 10.07 mmol) was added and the reaction was refluxed for 2 h. After cooled to room temperature, the reaction was concentrated and extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as colorless oil (0.70 g). LCMS m/z=187.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.33 (d, J=6.82 Hz, 6H), 2.94-3.13 (m, 1H), 6.38 (s, 1H), 7.17-7.45 (m, 5H), 10.14 (bs, 1H).
Reaction SMILES: [S:1]=[C:2]1[NH:14][C:5]2[CH:6]=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[N:12][C:13]=3[C:4]=2[N:3]1[CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].[OH-].[NH4+].I[CH3:28]>O.C(O)C>[CH3:28][S:1][C:2]1[N:3]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[C:4]2[C:13]3[N:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1
Reactant: CC(C)(C)OC(=O)NCCn1c(=S)[nH]c2cnc3cccnc3c21
Reactant: CI
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1nc2cnc3cccnc3c2n1CCNC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
tert-Butyl 2-(2-thioxo-2,3-dihydro-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethylcarbamate (31 g, 89.8 mmol) in water (150 mL) and ethanol (150 mL) was treated with ammonium hydroxide (30 mL) and iodomethane (25.5 g, 180 mmol) according to the general method of Part E of Example 22. After three hours, most of the ethanol was removed under reduced pressure, and water (500 mL) was added to the resulting suspension. The mixture was allowed to stand for 30 minutes. A solid was present and was isolated by filtration, washed with water and diethyl ether, and dried under vacuum for three hours to provide tert-butyl 2-[2-(methylthio)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]ethylcarbamate as a white solid.