Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[C:8](=[O:15])[N:7]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:6]2=[O:21].C(OCC)(=O)C>CO.C(Cl)Cl.[Pd]>[NH2:12][C:11]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[C:6](=[O:21])[N:7]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:8]2=[O:15]
Reactant: COC(=O)CN1C(=O)c2cc(OC)c([N+](=O)[O-])cc2C1=O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)CN1C(=O)c2cc(N)c(OC)cc2C1=O
Yield: 99.9 %

Procedure:
A mixture of methyl 2-(5-methoxy-6-nitro-1,3-dioxoisoindolin-2-yl)acetate (0.225 g, 0.765 mmol) and 10% w/w Pd/C (a catalytic amount) in MeOH (20 ml) and ethyl acetate (10 ml) was hydrogenated in a Parr apparatus at 15 psi for 1 hour. The mixture was diluted with DCM till complete dissolution of the yellow precipitate, the catalyst was filtered off and the filtrate was evaporate to dryness affording methyl 2-(5-amino-6-methoxy-1,3-dioxoisoindolin-2-yl)acetate (0.202 g, 0.764 mmol, 100% yield). MS/ESI+ 265.0 [MH]+.
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:20][O:19][C:17]([CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][C:6]([OH:21])=[O:5])=[CH:10][CH:11]=1)=[O:18]
Reactant: COC(=O)COc1ccc(CCC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)COc1ccc(CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-(4-Methoxycarbonylmethoxy-phenyl)-propionic acid tert-butyl ester (0.097 g, 0.33 mmol) is added a 90% solution of TFA in DCM (2 ml) and the resulting solution is stirred at room temperature for 1 hour. The solvents are removed in vacuo to yield 3-(4-Methoxycarbonylmethoxy-phenyl)-propionic acid as an off-white powder; [M+H-18]+ 256.0
Reaction SMILES: S=[C:2]1[NH:6][C:5]2=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=[C:4]2[O:3]1.P(Cl)(Cl)(Cl)(Cl)[Cl:16]>P(Cl)(Cl)(Cl)=O>[Cl:16][C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1
Reactant: COC(=O)c1cccc2oc(=S)[nH]c12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc2oc(Cl)nc12
Temperature: 95 °C
Yield: 100.3 %

Procedure:
A mixture of the thione from Step B (0.65 g, 3.11 mmol) and phosphorus pentachloride (0.65 g, 3.11 mmol) in phosphorus oxychloride (6 mL) was heated to 95° C. for 2.5 h. After cooling to room temperature, the reaction mixture was concentrated and dried on vacuum to give methyl 2-chlorobenzoxazole-4-carboxylate (0.66 g, quantitative) as a brown solid: 1H NMR (300 MHz, CDCl3) δ 8.05 (dd, J 8.1, 1.2 Hz, 1H), 7.72 (dd, J 8.1, 1.2 Hz, 1H), 7.45 (t, J=8.1 Hz, 1H), 4.04 (s, 3H); MS (ESI+) m/z 212 (M+H).
Reaction SMILES: C1(SC2C=CC=CC=2)C=CC=CC=1.[O:14]1[C:18]2([CH2:23][CH2:22][C:21](=[CH:24][C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1.[H][H]>CO.[Pd].[C]>[O:14]1[C:18]2([CH2:23][CH2:22][CH:21]([CH2:24][C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:26])[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1
Reactant: [H][H]
Reactant: O=C(C=C1CCC2(CC1)OCCO2)OCc1ccccc1
Agent: [Pd]
Agent: c1ccc(Sc2ccccc2)cc1
Solvent: CO
Product: O=C(CC1CCC2(CC1)OCCO2)OCc1ccccc1
Reaction time: 5 h
Yield: 81.4 %

Procedure:
Diphenyl sulfide (33 mg, 0.18 mmol) and 10% Pd-carbon (1.08 g) were added to a solution of benzyl 2-(1,4-dioxaspiro[4,5]decan-8-ylidene)acetate (5.0 g, 17.34 mmol) in methanol (50 ml) under a nitrogen gas stream, the atmosphere in the system was replaced five times with nitrogen gas, was then filled with hydrogen gas, followed by stirring under a hydrogen gas stream for 5 hr. The catalyst was removed by filtration through Celite pad and was washed with ethanol, and the filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (4.1 g, yield 82%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH2:22])[CH2:13][C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]([N:26]1[CH:30]=[C:29]([CH2:31][CH2:32]OS(C)(=O)=O)[CH:28]=[N:27]1)([CH3:25])[CH3:24]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH:22][CH2:32][CH2:31][C:29]3[CH:28]=[N:27][N:26]([CH:23]([CH3:25])[CH3:24])[CH:30]=3)[CH2:13][C:12]2=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Reactant: CC(C)n1cc(CCOS(C)(=O)=O)cn1
Product: CC(C)n1cc(CCNC2CCc3[nH]c4ccc(OCc5ccccc5)cc4c3C2)cn1
Yield: 63.4 %

Procedure:
Beginning with 0.698 gm (2.39 mMol) 6-benzyloxy-3-amino-1,2,3,4-tetrahydro-9H-carbazole and 0.787 gm (3.39 mMol) 2-(1-isopropyl-1H-pyrazol-4-yl)-1-mesyloxyethane, 0.649 gm (63.4%) of the desired compound were prepared by the procedure described in detail in Example 72.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]([C:25]([F:28])([F:27])[F:26])=[CH:19][C:20](OCC)=[O:21])=[S:16])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C.CN(C)C=O>[Cl:1][C:2]1[CH:13]=[CH:12][C:11]([N:14]2[C:20](=[O:21])[CH:19]=[C:18]([C:25]([F:28])([F:27])[F:26])[NH:17][C:15]2=[S:16])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)C=C(NC(=S)Nc1ccc(Cl)c(C(=O)OC(C)C)c1)C(F)(F)F
Agent: [Na]
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=S)ccc1Cl

Procedure:
using isopropyl 2-chloro-5-{3-[2-(ethoxycarbonyl)-1-trifluoromethylvinyl]thioureido}-benzoate with sodium isopropylate is an isopropanol/dimethylformamide mixture there is obtained isopropyl 2-chloro-5-[3,6-dihydro-4-trifluoromethyl-6-oxo-2-thioxo-1(2H)-pyrimidinyl]benzoate,
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:28])[C@@H:15]([NH2:27])[CH:16]([CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:17][C:18]([F:21])([F:20])[F:19].N1C=CC=CC=1>C(Cl)Cl.Cl>[CH3:12][O:13][C:14](=[O:28])[C@@H:15]([NH:27][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:16]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:22][C:23]([F:25])([F:26])[F:24]
Reactant: COC(=O)[C@@H](N)C(CC(F)(F)F)CC(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(CC(F)(F)F)CC(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
A solution of 4-chlorobenzenesulfonyl chloride (2.66 g, 12.2 mmol, 97% pure) in CH2Cl2 (7 mL) was added to a solution of (2S)-2-amino-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)pentanoic acid methyl ester (2.173 g, 8.14 mmol) and pyridine (1.97 mL, 24.4 mmol) in CH2Cl2 (15 mL). The reaction mixture was stirred at 25° C. for 4 hours, then cooled to 0° C. IN HCl (15 mL) was added followed by dichloromethane (10 mL) and the phases were separated. The organic phase was washed with 1N HCl (15 mL) and brine, dried over Na2SO4, and concentrated to afford 4.1 g of crude mixture as a yellow solid. The solids were recrystallized from heptane (14 mL) to afford 3.035 g of the title product (84% yield). Mass Spectrum (+ESI): 442 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:14][O:15][C:16]([C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1)=[O:17].C(N(C(C)C)CC)(C)C>C(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:14][O:15][C:16]([C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:12])=[O:17]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(CCl)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of chloroacetic benzyl ester (1.8 g, 9.75 mmol) in DCM (50 mL) is added (S)-pyrrolidine-2-carboxylic acid methyl ester hydrochloride (1.51 g, 11.70 mmol), diisopropylethylamine (4.09 mL, 23.40 mmol) and tetrabutylammonium iodide (3.60 g, 9.75 mmol) and the resulting mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure and the residue purified by column chromatography using a gradient of 2-45% EtOAc/heptane to give (S)-1-benzyloxycarbonylmethyl-pyrrolidine-2-carboxylic acid methyl ester; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.81-2.05 (m, 3H), 2.13-2.24 (m, 1H), 2.78-2.84 (m, 1H), 3.15-3.20 (m, 1H), 3.57-3.69 (m, 3H), 3.70 (s, 3H), 5.15 (s, 2H), 7.36 (m, 5H).
Reaction SMILES: [OH:1][CH:2]([CH3:39])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:22]2[CH2:26][CH2:25][C@H:24]([C:27]3[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=3)[O:23]2)[CH:10]=[C:11]([O:17][CH2:18][CH2:19][CH2:20]Br)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].[NH:40]1[CH:44]=[CH:43][N:42]=[CH:41]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:1][CH:2]([CH3:39])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:22]2[CH2:26][CH2:25][C@H:24]([C:27]3[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=3)[O:23]2)[CH:10]=[C:11]([O:17][CH2:18][CH2:19][CH2:20][N:40]2[CH:44]=[CH:43][N:42]=[CH:41]2)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5]
Reactant: CCCOc1c(OCCCBr)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1c(OCCCn2ccnc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Temperature: 55 °C
Reaction time: 28 h

Procedure:
A mixture of trans-2-[3-(2-hydroxy-n-propylsulfonyl)-4-n-propoxy-5-(3-bromopropoxy)phenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (87 mg, 0.14 mmol) (Example 19B), imidazole (47 mg, 0.69 mmol) and potassium carbonate (95 mg, 0.69 mmol) in acetone (2 mL) was heated with stirring at 55° C. under nitrogen for 28 h. The reaction mixture was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was washed with water and brine, dried, and evaporated to a residue. Purification by preparative TLC (CH2Cl2 -MeOH; 9:1, v/v) gave the title compound: Rf 0.6; MS, m/z 618 M+. ; NMR (CDCl3) δ 1.28 (bd, CH2CHOHCH3), 6.94 and 7.08 (bs, NCH=CHN), 7.54 (NCH=N).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]3[CH2:17][CH:18]([CH2:23][C:24]([OH:26])=[O:25])[C:19](=[O:22])[NH:20][CH2:21][C:15]=3[CH:14]=2)[CH:3]=1.Cl.O1CCO[CH2:32][CH2:31]1.[CH2:36](N(CC)CC)C>C(O)C>[N:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]2[CH2:17][CH:18]([CH2:23][C:24]([O:26][CH2:31][CH3:32])=[O:25])[C:19](=[O:22])[N:20]([CH3:36])[CH2:21][C:15]=2[CH:14]=1
Reactant: CCN(CC)CC
Reactant: C1COCCO1
Reactant: Nc1ccnc(NCCCOc2ccc3c(c2)CNC(=O)C(CC(=O)O)C3)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC1Cc2ccc(OCCCNc3ccccn3)cc2CN(C)C1=O
Reaction time: 72 h
Yield: 69.4 %

Procedure:
A solution of (±)-8-[3-[(4-amino-2-pyridyl)amino]-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid (0.27 g, 0.7 mmol) and 4 M HCl in dioxane (0.2 mL, 0.8 mmol) in ethanol (10 mL) was heated to reflux. After 72 hr, the reaction was concentrated and the residue was partitioned between EtOAc and aqueous K2CO3. The organic phase was washed with brine, dried (MgSO4), and concentrated. The residue was dissolved in toluene (5 mL) and triethylamine (0.35 mL, 2.5 mmol). and the resulting solution was heated to reflux. After 18 hr, the reaction was concentrated under vacuum to give the title compound (0.20 g, 69%) as a tan foam: MS (ES) m/e 413.4 (M+H)+. Anal. Calcd for C22H28N4O4.0.25 H2O: C, 63.37; H, 6.89; N,13.44. Found: C, 63.32; H, 7.17; N, 13.05.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([NH:11][CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=1>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)=[CH:4][C:3]=1[C:9]([NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=1)=[O:10]
Reactant: COc1cccc(CBr)c1
Reactant: COC(=O)c1ccc(CNC(=O)c2cc(O)ccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CNC(=O)c2cc(OCc3cccc(OC)c3)ccc2Cl)cc1

Procedure:
A solution of methyl 4-({[(2-chloro-5-hydroxyphenyl)carbonyl]amino}methyl)benzoate (95 mg, 0.3 mol), potassium carbonate (2 eq, 83 mg, 0.6 mmol) and 1-(bromomethyl)-3-(methyloxy)benzene (1.2 eq, 50 ul, 0.36 mmol) in DMF (2 ml) was stirred at room temperature for 2 hours. The mixture was then diluted with ethyl acetate (100 ml) and H2O (80 ml). Layers separated, organic layer washed with brine (80 ml) then dried and evaporated in vacuo. Residue purified by column chromatography (Biotage SP4) eluting with 0-40% ethylacetate in hexanes to give the title compound as a clear oil. MS (ES+) m/z 440 [M+H]+ (C24H2235ClNO5). 1H-NMR (400 MHz, d6-DMSO) δ 3.76 (3H, s), 3.85 (3H, s), 4.51 (2H, d, J 6), 5.12 (2H, s), 6.89-7.96 (11H, m), 7.46 (2H, d, J 8.4), 7.92 (2H, m), 9.05 (1H, J 6).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:23][CH2:24][C@@:25]([OH:31])([CH3:30])[C:26]([O:28]C)=[O:27])=[O:22])[N:4]=1)#[N:2].O.CCOC(C)=O.Cl>CO.[OH-].[Na+]>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:23][CH2:24][C@@:25]([OH:31])([CH3:30])[C:26]([OH:28])=[O:27])=[O:22])[N:4]=1)#[N:2]
Reactant: COC(=O)[C@@](C)(O)CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: C[C@](O)(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-Methyl 3-(1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxamido)-2-hydroxy-2-methylpropanoate (9 mg, 0.02 mmol) was dissolved in MeOH (0.4 mL) and 2 N NaOH (0.4 mL). After stirring for 16 hours at room temperature, H2O (15 mL) and EtOAc (15 mL) were added. To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% MeOH/CH2Cl2) to give the title compound in 6 mg. MS: (−) m/z 406.13 (M−1).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:11][N:12]1C(=O)C2=CC=CC=C2C1=O.[N+]([O-])=[O:24].[N]=O>C(O)(=O)C.C(#N)C1C=CC=CC=1>[N+:12]([C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2)([O-:11])=[O:24].[C:1]12([OH:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=[N+][O-]
Reactant: C1C2CC3CC1CC(C2)C3
Agent: [N]=O
Solvent: N#Cc1ccccc1
Solvent: CC(=O)O
Product: O=[N+]([O-])C12CC3CC(CC(C3)C1)C2
Product: OC12CC3CC(CC(C3)C1)C2
Yield: 6 %
Yield: 68 %

Procedure:
Into a flask, 1 mmole of adamantane, 0.1 mmole of N-hydroxyphthalimide, 2 ml of nitrogen dioxide (N2O), 6 ml of benzonitrile (6 ml) and 1.2 ml of acetic acid were added and stirred for 12 hours at 60° C. in an atmosphere of nitrogen monoxide (NO). The reaction products were analyzed by gas chromatography, and, as a result, the conversion of adamantane was 98%, nitroadamantane (yield 68%), adamantanol (yield 6%) and acetyloxyadamantane (yield 4%) were formed.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][O:5][C:4](=[O:7])[NH:3]1.[H-].[Na+].I[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].OS(O)(=O)=O>C1COCC1.CCCCCC>[CH3:1][CH:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCI
Reactant: CC1COC(=O)N1
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCN1C(=O)OCC1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
4-Methyl-oxazolidin-2-one (18.0 g, 178 mmol) in THF (100 ml) was added slowly via dropping funnel to a slurry of hexane-washed NaH (60% in mineral oil, 7.12 g, 178 mmol, 1.0 quiv.) in THF (400 ml) upon which H2-evolution was observed. Neat iodopentane (70.51 g, 356 mmol, 2.0 equiv.) was added rapidly and the mixture stirred for 1 h at room temperature, then heated to reflux for 60 h. After cooling to 5° C., 2N H2SO4 (180 ml) was slowly added. The mixture was extracted with MTBE and worked up as usual. Distillation over a Widmer-column at 115° C./0.08 mbar afforded the product as a slightly yellow liquid (20.54 g, 73%).
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9]([O:11][CH2:12][CH:13]([O:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:14][O:15][C:16](=[O:32])[C@H:17]([CH:29]([CH3:31])[CH3:30])[NH:18]C(OCC2C=CC=CC=2)=O)=[O:10])[O:5][C@@H:4]([N:53]2[C:63]3[N:62]=[C:60]([NH2:61])[NH:59][C:57](=[O:58])[C:56]=3[N:55]=[CH:54]2)[CH2:3]1>CO.C(OCC)(=O)C.C(O)(=O)C.[Pd]>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9]([O:11][CH2:12][CH:13]([O:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:14][O:15][C:16](=[O:32])[C@H:17]([CH:29]([CH3:31])[CH3:30])[NH2:18])=[O:10])[O:5][C@@H:4]([N:53]2[C:63]3[N:62]=[C:60]([NH2:61])[NH:59][C:57](=[O:58])[C:56]=3[N:55]=[CH:54]2)[CH2:3]1
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F)COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F)COC(=O)[C@@H](N)C(C)C
Reaction time: 2 h

Procedure:
2′,3′-dideoxy-3′-fluoro-5′-O-[1-(N-CBz-L-valyloxy)-2-stearoyloxy-3-propyloxy carbonyl]guanosine (190 mg), was dissolved in a mixed solvent of methanol (6 ml), ethyl acetate (2 ml) and acetic acid (1 ml). To the solution was added palladium black (30 mg), and the reaction mixture was kept under hydrogen for 2 h. It was then filtered and the filtrate was evaporated and the titled product was isolated by silica gel column. 110 mg.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]5[CH:36]=[C:35]([Cl:37])[C:34]([OH:38])=[C:33]([Cl:39])[CH:32]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:40](=[O:42])[CH3:41])=[CH:16][N:15]=2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>>[ClH:37].[ClH:37].[ClH:37].[NH2:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[N:15]=[CH:16][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]5[CH:32]=[C:33]([Cl:39])[C:34]([OH:38])=[C:35]([Cl:37])[CH:36]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:40](=[O:42])[CH3:41])=[CH:18][CH:19]=2)[CH2:9]1
Reactant: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@H](N)C2)nc1
Product: Cl
Yield: 134.8 %

Procedure:
Following general procedure IV-2, (S)-tert-butyl[1-(5-{[3-acetyl-6-(3,5-dichloro-4-hydroxy-phenyl)-1,5-naphthyridin-4-yl]amino}pyridin-2-yl)piperidin-3-yl]carbamate (0.197 mmol) was reacted with TFA (2 mL) followed by formation of the trihydrochloride salt to afford the desired product (42 mg, 33% over two steps) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.39 (s, 1H), 8.49 (d, J=9.0 Hz, 1H), 8.41 (d, J=9.0 Hz, 1H), 8.25 (d, J=2.6 Hz, 1H), 7.92 (dd, J=9.5, 2.6 Hz, 1H), 7.57 (s, 2H), 7.27 (d, J=9.5 Hz, 1H), 4.37 (d, J=10.9 Hz, 1H), 4.02-3.99 (m, 1H), 3.52-3.32 (m, 3H), 2.84 (s, 3H), 2.24-2.22 (m, 1H), 2.07-1.95 (m, 1H), 1.82-1.77 (m, 2H); ESI MS m/z 523 [M+H]+; HPLC 97.5% (AUC), tR=9.56 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11](O)[CH2:10][CH:9]1[CH3:19])=[O:7].[NH:23]1[C:32]2[C:27](=[CH:28][C:29]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:30][CH:31]=3)[CH2:26][CH2:25][CH2:24]2)[CH2:10][CH:9]1[CH3:19])=[O:7]
Reactant: COc1cccc(C(=O)N2c3ccccc3C(O)CC2C)c1
Reactant: CCOC(=O)CCCCOc1ccc2c(c1)CCCN2
Product: CCOC(=O)CCCCOc1ccc2c(c1)CCCN2C1CC(C)N(C(=O)c2cccc(OC)c2)c2ccccc21
Yield: 25.6 %

Procedure:
Starting with 1-(3-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (1.0 g, 3.36 mmol) prepared in Reference Example 21 and ethyl 5-[(1,2,3,4-tetrahydro-6-quinolinyl)oxy]pentanoate (2.14 g, 7.73 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (479 mg, yield: 26%) as a colorless oil. (cis:trans=1:3.5)
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[Br:5][CH2:6][C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9]>CC(C)=O>[BrH:5].[CH2:11]([O:10][C:8]([C:7]1[N:1]=[C:2]([NH2:4])[S:3][CH:6]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(N)=S
Solvent: CC(C)=O
Product: Br
Product: CCOC(=O)c1csc(N)n1
Yield: 52 %

Procedure:
Thiourea (1.5 g, 20 mmol) and ethyl bromopyruvate (2.8 ml, 22 mmol) were heated at 100° C. for 1 h. The reaction was cooled and acetone (10 ml) was added. The mixture was then filtered to give a yellow/brown solid and the crude material was crystallised from hot ethanol (20 ml) to give the title compound as the HBr salt (2.63 g). The liquor was concentrated and recrystallised from hot EtOH (5 ml) to give further product (0.63 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Li]CCCC.[C:17](=[O:19])=[O:18].O>CCOCC>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:17]([OH:19])=[O:18]
Reactant: Cc1cccc2c1ccn2C
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: Cc1cccc2c1cc(C(=O)O)n2C
Reaction time: 1 h
Yield: 26.4 %

Procedure:
A solution of 1,4-dimethyl-1H-indole (0.9 g, 6.2 mmole) in anhydrous Et2O (20 mL) was treated with 2.5 M n-BuLi in hexanes (5.0 mL, 12 mmole) and the reaction was heated at reflux for 15 hr. The dark reaction mixture was poured into a slurry of excess crushed dry ice in Et2O, and the mixture was allowed to stand for 1 hr. Water (10 mL) was added, the layers separated, and the aqueous layer was filtered through Celite®. The clear filtrate was acidified with 2.0 N HCl to pH 2, and the precipitate was collected and dried to afford the title compound (0.29 g, 26.4%) as an off-white solid: MS (ES) m/e 190.2 (M+H)+.