Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:34])[C:15]2[O:21][C:20]3[C:22]([Cl:30])=[CH:23][C:24]([NH:26][CH2:27][CH2:28]Cl)=[CH:25][C:19]=3[CH2:18][S:17](=[O:32])(=[O:31])[C:16]=2[CH:33]=1)=[O:11].O>CN(C=O)C>[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:34])[C:15]2[O:21][C:20]3[C:22]([Cl:30])=[CH:23][C:24]([NH:26][CH2:27][CH2:28][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:25][C:19]=3[CH2:18][S:17](=[O:32])(=[O:31])[C:16]=2[CH:33]=1)=[O:11]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCN3CCN(C)CC3)cc(Cl)c1O2
Temperature: 110 °C
Reaction time: 2 h

Procedure:
1-Methyl-piperazine (0.191 g, 1.91 mol) was added to a solution of Example 56k (0.5 g, 1.16 mmol) in dry DMF (10 mL) and stirred at 110° C. for 2 h. The reaction mixture was treated with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.350 g, (60.97%); 1H NMR (DMSO-d6): δ 2.2 (s, 3H, CH3), 2.5-2.60 (m, 10H, 5CH2), 2.70 (s, 3H, CH3), 3.10 (d, 2H, CH2), 3.90 (s, 3H, CH3), 5.10 (s, 2H, CH2), 6.7 (s, 2H, Ar), 8.01 (s, 1H, Ar), 8.20 (s, 1H, Ar); MS: m/e (ES+) 495 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].Cl.CN(C)[CH2:15][CH2:16]CN=C=N.O.ON1C2C=CC=CC=2N=N1.C(O)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([O:8][CH2:15][CH3:16])=[O:7]
Reactant: CN(C)CCCN=C=N
Reactant: O=C(O)c1ccc(Cl)cc1O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1ccc(Cl)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
4-Chlorosalicylic acid (344 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (420 mg), 1-hydroxybenzotriazole hydrate (337 mg), and ethanol (2 ml) were dissolved in N,N-dimethylformamide to prepare a solution which was then stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give ethyl 4-chlorosalicylate (174 mg, yield 43%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]=[CH:8]2.[C:15](Cl)(=[O:17])[CH3:16].[Cl-].[Cl-].[Cl-].[Al+3]>>[C:15]([C:6]1[CH2:7][CH2:8][C:9]2[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH:5]=1)(=[O:17])[CH3:16]
Reactant: COc1ccc(OC)c2c1C=CCC2
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(OC)c2c1C=C(C(C)=O)CC2

Procedure:
In spite of the fact that in literature the attempts of acylating the compound II were reported as fruitless or non interesting because of the low yields, the 5,8-dimethoxy-3,4-dihydronaphthalene II is treated with acetyl chloride in the presence of an excess of aluminium trichloride, preferably 5-9 moles of aluminium trichloride for one mole of acyl chloride, at the temperature of −35°+25° C., preferably at 0° C. After the usual work-up and crystallisation with ethyl acetate, the product, 2-acetyl-5,8-dimethoxy-3,4-dihydronaphthalene is obtained in yields higher than 70%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5]1.C(N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(OCC)(=O)C>[C:24]([O:1][CH2:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5]1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: OCCC1CN(Cc2ccccc2)CCO1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)OCCC1CN(Cc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-(2-hydroxyethyl)-4-benzylmorpholine (27.7 g), triethylamine (28 ml), and ethyl acetate (100 ml) is dropwise added acetic anhydride (17.8 ml). The reaction mixture is stirred at 25° C. for 1 hour and evaporated under reduced pressure. The residue is dissolved in chloroform and chromatographed on silica gel. Fractions containing the title compound are pooled and evaporated to give the title compound (29.1 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([CH3:14])=[C:10]([CH3:15])[C:9]2=[O:16])=[C:4]([F:17])[CH:3]=1.[H][H]>C(OCC)(=O)C.[Pt]=O>[F:17][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[N:8]1[C:12](=[O:13])[C@H:11]([CH3:14])[C@H:10]([CH3:15])[C:9]1=[O:16]
Reactant: CC1=C(C)C(=O)N(c2ccc(Cl)cc2F)C1=O
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: C[C@@H]1C(=O)N(c2ccc(Cl)cc2F)C(=O)[C@@H]1C
Reaction time: 5 h

Procedure:
A mixture of 7.5 g (0.03 mol) of N-(4-chloro-2-fluorophenyl)-2,3-dimethylmaleic acid imide and 400 mg of platinum oxide (PtO2) is hydrogenated with hydrogen in 75 ml of ethyl acetate at room temperature under normal pressure. After about 5 hours, the reduction is complete. The catalyst is then filtered off and the filtrate is concentrated in vacuo. 7.6 g (99% of the theoretical yield) of cis-N-(2-fluoro-4-chlorophenyl)-2,3-dimethylsuccinimide in the form of a yellowish oil which is uniform in a thin-layer chromatogram remain as residue.
Reaction SMILES: CS[C:3]1[S:4][C:5]([C:9]#[N:10])=[C:6]([NH2:8])[N:7]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>CS(C)=O>[N:11]1([C:3]2[S:4][C:5]([C:9]#[N:10])=[C:6]([NH2:8])[N:7]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCNC1
Reactant: CSc1nc(N)c(C#N)s1
Solvent: CS(C)=O
Product: N#Cc1sc(N2CCCC2)nc1N
Temperature: 60 °C
Yield: 91 %

Procedure:
40 parts of 2-methylmercapto-4-amino-5-cyanothiazole are dissolved in 200 parts of dimethylsulfoxide and 45 parts of pyrrolidine are added. The mixture is heated for 6 hours at 60° C. and the product is filtered off. 41.5 parts of 2-pyrrolidino-4-amino-5-cyano-thiazole (91% of theory) of melting point 305°-308° C. are obtained.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[C:25]1([NH:31]N)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([N:31]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NNc1ccccc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Yield: 10 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-3) and phenylhydrazine according to the method described for Example 1 in 10% yield. MS: M=383.4 (M+H)+
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][CH:5]1[O:28][C:9]2([CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([CH3:27])[CH:18]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:8][NH:7][CH2:6]1.C([O-])(O)=O.[Na+].FC(F)(F)S(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O>C(O)C>[OH:2][CH2:3][CH2:4][CH:5]1[O:28][C:9]2([CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([CH3:27])[CH:18]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:8][N:7]([CH2:40][C:41]([F:44])([F:43])[F:42])[CH2:6]1
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CNCC(CCO)O3)ccc1OC(C)C
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(CC(F)(F)F)CC(CCO)O3)ccc1OC(C)C
Temperature: 80 °C
Yield: 69.8 %

Procedure:
To [10-(2-hydroxyethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone hydrochloride salt (20 mg, 0.05 mmol) and NaHCO3 (16 mg, 0.19 mmol) in ethanol (0.5 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (11 μL, 0.07 mmol) and the reaction mixture heated in a sealed vial at 80° C. for 5 hours. The reaction mixture was microfiltered and purified by prep LCMS (10-99% ACN/Water, 5 mM HCl modifier) to give [10-(2-hydroxyethyl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (16 mg, 87%) as a colorless oil ESI-MS m/z calc. 458.2. Found 459.7 (M+1)+; Retention time: 1.78 minutes (3 min run).
Reaction SMILES: C(O)[C@@H](O)[C@H:3]1[O:8][C:6](=[O:7])[C:5]([OH:9])=[C:4]1[OH:10].[CH:13](P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:15])[CH3:14].C([Li])CCC.O=C[C@@H]([C@@H](CO)O)O>O1CCCC1.C(OCC)(=O)C>[CH3:14][C:13]1([CH3:15])[O:9][C@@H:5]2[C@@H:4]([CH2:3][O:8][CH:6]2[OH:7])[O:10]1
Reactant: CC(C)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1O[C@H]([C@H](O)CO)C(O)=C1O
Agent: O=C[C@H](O)[C@H](O)CO
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2COC(O)[C@@H]2O1
Temperature: -40 °C
Reaction time: 20 h

Procedure:
2,3-O-Isopropylidene-D-erythrose was prepared by literature procedures (Cohen, N. et al, J. Am. Chem. Soc. 1983, 105, 3661) from D-isoascorbic acid. To a suspension of isopropyltriphenylphosphine (121 g, 2.4 equiv, 0.314 mol) in tetrahydrofuran (1.5 L) at -40° C. under nitrogen was added n-butyllithium (1.6 M solution in hexanes) (197 mL, 2.4 equiv) dropwise. The erythrose (21 g, 1 equiv, 0.131 mol) in tetrahydrofuran (231 mL) was also added dropwise maintaining the temperature at -40° C. The mixture was then allowed to warm to room temperature and stirred under nitrogen for 20 hours and then quenched by the addition of ammonium chloride (77 g). The insoluble material was removed by filtration through Celite and the filtrate concentrated at reduced pressure to afford a residue which was extracted (4x) with ether. The combined ether extracts were washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo to afford a yellow oil. Chromatography on silica gel eluting with 20% ethyl acetate in hexanes afforded the title compound (13.0 g, 53%). 1H NMR (CDCl3, 300 MHz) δ 1.4 (s, 3H), 1.50 (s, 3H), 1.73 (s, 3H), 1,78 (s, 3H), 3,57 (t of d, J=1.5Hz, J=6 Hz, 2H), 4.20 (q, J=6Hz, 8Hz, 1H), 4.44 (q, J=9Hz, 9Hz, 1H), and 5.75 (d, J=9Hz, 1H). MS(DCI/NH3) m/e 204 (M+H+NH3)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:14]([O-])=O)[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1>[Pd].C(O)C>[NH2:14][C:7]1[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:17]([F:18])([F:19])[F:20])[CH:3]=[CH:2]2
Reactant: COc1cc([N+](=O)[O-])c2nc(C(F)(F)F)cc(Cl)c2c1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)c2nc(C(F)(F)F)ccc2c1
Reaction time: 4.5 h
Yield: 51.6 %

Procedure:
A mixture of 3.1 g of (0.01 mole) of 4-chloro-6-methoxy-8-nitro-2-trifluoromethylquinoline, 75 ml of ethanol and 1 g of 5% Pd on CaCO3 was shaken on a Parr apparatus for 4.5 hr, at 50°-60°, under a hydrogen pressure of 70 psig. The yellow mixture was filtered and concentrated to dryness in vacuo. The residue was extracted with boiling ligroine (bp 90°-120° ) and the solvent was removed from the extract under reduced pressure. The residue was distilled to give 1.25 g (52%) of 8-amino-6-methoxy-2-trifluoromethylquinoline as a yellow oil, bp 127°-128° /1 mm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[F:32][C@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH2:28][N:35]4[CH2:36][CH2:37][C@@H:33]([F:32])[CH2:34]4)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: F[C@H]1CCNC1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Product: Fc1ccccc1-n1nnc(-c2nc(-c3ccc(CN4CC[C@@H](F)C4)cc3)no2)c1-c1ccncc1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (200 mg; 0.48 mmol) and (S)-3-fluoropyrrolidine (121 mg; 0.97 mmol) to give Example 160 as a white solid. 1H NMR: (CDCl3, 400 MHz) δ 8.73-8.70 (2H, m), 8.05 (2H, d, J=8.03 Hz), 7.63-7.52 (2H, m), 7.47 (2H, d, J=8.0 Hz), 7.39-7.34 (3H, m), 7.18 (1H, t, J=9.1 Hz), 5.27-5.08 (1H, m), 3.72 (2H, s), 2.92-2.70 (3H, m), 2.49 (1H, q, J=7.4 Hz), 2.22-2.02 (2H, m). LC/MS (Method C): 486 (M+H)+. HPLC (Method F) Rt 3.99 min (Purity: 99.5%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[O:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH2:22])[CH2:17][CH2:16]1.O1CCOCC1>CCOC(C)=O>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:22]([CH2:21][CH:18]1[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1)[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: NCC1CCOCC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=c1c2cccc([N+](=O)[O-])c2ccn1CC1CCOCC1

Procedure:
5-Nitro-isochromen-1-one (1.0 g, 0.0052 mol) and C-(tetrahydro-pyran-4-yl)-methylamine (0.72 g, 0.0063 mol) were stirred in 1,4-dioxane (3 mL, 0.04 mol) at 120° C. for 18 hours. The mixture was diluted with EtOAc (200 mL), washed with 1 N HCl (30 mL×2), brine (30 mL) and dried over Na2SO4. After the filtration the solvent was removed and the residue was purified via flash chromatography (40 g of silica gel, 40% EtOAc/Hexanes) to give a yellow oil. MS m/z (M+H) 289.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[C:18][CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[OH:8].N1C2C(=CC=CC=2)C=CC=1>C(O)C.[Pd]>[OH:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: OCC#CCCCCCCC#Cc1ccc(O)c(O)c1
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: CCO
Product: OC/C=C\CCCCCC/C=C\c1ccc(O)c(O)c1
Yield: 75.2 %

Procedure:
A solution of 0.545 g of the product obtained in Example 7 in 20 ml of absolute ethanol containing 0.1 ml of freshly distilled quinoline was hydrogenated at room temperature and normal pressure using as catalyst 0.136 g of palladium on calcium carbonate (5% Pd; poisoned with lead "Lindlar-catalyst"). After consumption of the theoretical amount of hydrogen, the catalyst was filtered off and the filtrate evaporated in a vacuum. The residue was purified by HPLC with methanol/water (6:4) to yield 0.416 g of the title compound.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C@@H:10]([CH3:27])[CH2:11][N:12]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[C:18]=3[CH3:26])=[N:13]2)=[O:8])[N:6]=1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>N1C=CC=CC=1>[Cl:25][C:19]1[C:18]([CH3:26])=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@@H:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([NH:32][CH2:31][CH2:30][O:29][CH3:28])[S:3][CH:4]=3)=[O:8])[CH3:27])[N:13]=2)[CH:22]=[CH:21][C:20]=1[C:23]#[N:24]
Reactant: COCCN
Reactant: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3csc(Br)n3)n2)ccc(C#N)c1Cl
Solvent: c1ccncc1
Product: COCCNc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3C)n2)cs1
Temperature: 120 °C
Yield: 38.5 %

Procedure:
(S)-2-bromo-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)thiazole-4-carboxamide (0.2 g, 0.430 mmol) was added into a microwave vial with dry pyridine as a solvent under nitrogen atmosphere. 2-methoxyethylamine (0.187 ml, 2.152 mmol) was added and the mixture was heated with microwaves at 120° C. Next day a total of 0.187 ml of 2-methoxyethylamine was added and the reaction mixture was heated for additional 3 h. The reaction mixture was evaporated and the crude product dissolved in DCM, washed with Na2CO3, water and brine. The product was purified by Flash-chromatography. Yield 38.5%. 1H-NMR (400 MHz; MeOD): δ 1.25 (d, 3H), 2.50 (s, 3H), 3.35 (s, 3H), 3.40-3.43 (m, 2H), 3.46-3.49 (m, 2H), 4.34 (dd, 1H), 4.41 (dd, 1H), 4.47-4.56 (m, 1H), 6.49 (d, 1H), 7.19 (s, 1H), 7.55 (d, 1H), 7.64 (dd, 1H), 7.73 (d, 1H).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=O)=[CH:9]1)=O)(C)(C)C.[BH-](O[C:29]([CH3:31])=[O:30])(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:12]1([CH3:13])[CH:11]=[CH:10][CH:9]=[CH:31][C:29]=1[O:30][C:14]1[CH:15]=[C:16]2[C:11]([CH2:17][CH2:10][CH2:9][NH:8]2)=[CH:12][CH:13]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)n1cc(C=O)c2ccccc21
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccccc1Oc1ccc2c(c1)NCCC2
Reaction time: 48 h

Procedure:
A mixture of 3-formyl-indole-1-carboxylic acid t-butyl ester, Compound 9, where R1 is 4-tolyl, R2 is H, R3 is 2-methylprop-1-yl, and R4 is CH3 (9 mg (0.0609 mmol) and NaBH(OAc)3 (17 mg, 0.0812 mmol) in 1 mL of anhydrous CH2Cl2 was vigorously stirred for 2 days, during which the the initially cloudy solution turned clear. The mixture was partitioned between 5 mL of EtOAc and 3 mL of saturated-NH4Cl solution and extracted three times. The combined EtOAc layer was washed with brine, dried over Na2SO4 and evaporated to dryness under vacuum. The product was purified by a silica gel column with Hexane/EtOAc (4/1-2/1) to afford 15 mg of 7-tolyloxy-3,4-dihydro-2H-quinoline-1-(3-methyl-indole-3-yl-1-carboxylic acid t-butyl ester)-4-spiro-5′-3′-1(2-methylpropy-1-yl)-1′ methyl-imidazolidine-2′,4′-dione as a light brown oil (71% yield).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:45])[C@@H:15]([NH:37]C(OC(C)(C)C)=O)[CH2:16][CH2:17][CH2:18][O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[ClH:46]>O1CCOCC1>[ClH:46].[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:45])[C@@H:15]([NH2:37])[CH2:16][CH2:17][CH2:18][O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Reaction time: 2.5 h

Procedure:
To a solution of 900 mg 4-[(S)-2-tert-Butoxycarbonylamino-5-(tert-butyl-diphenyl-silanyloxy)-pentanoyl]-piperazine-1-carboxylic acid butyl ester in 5 ml dioxane were added 5 ml HCl in dioxane (4 M). After 2.5 h conversion was complete and the reaction mixture was neutralized with basic ion exchange resin III (Merck), filtered and concentrated. Yield: 760 mg.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([CH:42]2[CH2:47][CH2:46][CH:45]([N:48]([CH3:50])[CH3:49])[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([CH:42]4[CH2:43][CH2:44][CH:45]([N:48]([CH3:49])[CH3:50])[CH2:46][CH2:47]4)=[C:35]4[C:39]=3[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH3:29])[CH:15]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: CN1Cc2c(C3CCC(N(C)C)CC3)ccc(N)c2C1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C4CCC(N(C)C)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-amino-4-[4-(dimethylamino)cyclohexyl]-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 233A). 1H NMR (CD3OD, 400 MHz): δ=1.30 (t, J=7.07 Hz, 6H), 1.75-1.85 (m, 2H), 1.85-2.02 (m, 4H), 2.39 (d, J=14.15 Hz, 2H), 2.77-2.88 (m, 1H), 3.04 (s, 6H), 3.18 (s, 3H), 3.38-3.50 (m, 3H), 3.86 (s, 3H), 4.07-4.20 (m, 4H), 4.51 (s, 2H), 7.01-7.07 (m, 1H), 7.12 (t, J=2.15 Hz, 1H), 7.62 (d, J=8.59 Hz, 2H), 8.32-8.42 (m, 2H). MS (ES+): m/z 705.26 [MH+] (TOF, polar).
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:18])=O>CN(C)C=O.C(Cl)Cl>[C:1]1([CH2:11][C:12]([Cl:18])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1cccc2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1cccc2ccccc12
Reaction time: 0.5 h

Procedure:
Into 20 mL of methylene chloride, 0.250 g of the naphthyl acetic acid prepared as in Example 2 above, was dissolved. After cooling the solution in an ice bath, 0.090 mL of oxalyl chloride and a few drops of dimethylformamide were added. After 30 minutes, the ice bath was removed, and the reaction was allowed to come to room temperature over 30 minutes. The solvent of the reaction mixture was removed under vacuum, and product was redissolved in 50 mL of methylene chloride, followed by evaporation under vacuum, giving the napthylacetyl chloride as an oil. This product was redissolved in 40 mL of methylene chloride, and excess ammonia was bubbled in over 15 minutes at room temperature. After stirring overnight, the solvent of the reaction mixture was removed under vacuum. The reaction product was redissolved in ethyl acetate and washed with brine and dilute potassium carbonate. The organic solution was dried over sodium sulfate, and filtered. The solvent was removed under vacuum, and the product was redissolved in a minimum of methylene chloride. On dilution to cloudiness with hexane and after cooling, 130 mg (55%) of 4-phenoxynaphth-1-yl-acetamide was obtained.
Reaction SMILES: I[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[CH:18]#[C:19][CH2:20][CH2:21][CH3:22].CO.C(=O)(O)[O-]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I.C(Cl)Cl>[C:18]([C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1)#[C:19][CH2:20][CH2:21][CH3:22]
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Reactant: C#CCCC
Agent: [Cu]I
Agent: [Pd]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CO
Product: CCCC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 26 h
Yield: 81.9 %

Procedure:
This compound was prepared by the same procedure that Hobbs, F. W. J., J Org Chem (1989) 54:3420-3422, used for the preparation of other alkynyl substituted nucleosides. A mixture of 30.0 g (84.7 mmol) of 5-iodo-2'deoxyuridine (purchased from Sigma), 23.6 mL of 1-pentyne (Aldrich), 9.79 g of tetrakis (triphenylphosphine) palladium (0) (Aldrich), and 3.23 g of copper (I) iodide were stirred at room temperature for 26 h. To the reaction was added 250 mL of MeOH and 250 mL of CH2Cl2. The mixture was neutralized with Dowex 1×8-200 (bicarbonate form) ion exchange resin. The mixture was filtered and concentrated. The residue was partitioned between H2O and CH2 Cl2. The aqueous layer was extracted three times with CH2 Cl2 and then concentrated. Purification of the crude product by column chromatography afforded 20.4 g (81.9% yield) of product.