Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([OH:33])[C:5]2[CH2:11][CH:10]([CH2:12][CH2:13][C:14]3[CH:15]=[C:16]([C:19]([NH:21][C@H:22]([C:29]([O:31]C)=[O:30])[CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[O:20])[NH:17][CH:18]=3)[CH2:9][NH:8][C:6]=2[N:7]=1.C(O)(=O)C>[OH-].[Na+]>[NH2:1][C:2]1[N:3]=[C:4]([OH:33])[C:5]2[CH2:11][CH:10]([CH2:12][CH2:13][C:14]3[CH:15]=[C:16]([C:19]([NH:21][C@H:22]([C:29]([OH:31])=[O:30])[CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:20])[NH:17][CH:18]=3)[CH2:9][NH:8][C:6]=2[N:7]=1
Reactant: COC(=O)CC[C@H](NC(=O)c1cc(CCC2CNc3nc(N)nc(O)c3C2)c[nH]1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1nc(O)c2c(n1)NCC(CCc1c[nH]c(C(=O)N[C@@H](CCC(=O)O)C(=O)O)c1)C2
Yield: 78.6 %

Procedure:
A solution of dimethyl N-{4-[2-(amino-4-hydroxy-5,6,7,8-tetrahydropyrido-[2,3-d]pyrimidin-6-yl)ethyl]pyrrol-2-ylcarbonyl}-L-glutamate (92 mg, 0.2 mmol) in 1N sodium hydroxide (1 mL) was stirred at room temperature for 3 days, then acidified to pH 5 by addition of glacial acetic acid. The white solid was collected by filtration, washed with water, and dried in vacuo to give N-{4-[2-(amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]pyrrol-2-ylcarbonyl}-L-glutamic acid (68 mg, 79%) as a white solid: 1H NMR (DMSO-d6) δ 11.44 (s, 1H), 9.84 (br s, 1H), 7.79 (d, 1H, J=7.7 Hz), 6.64 (s, 2H), 6.23 (s, 1H), 5.97 (s, 2H), 4.27 (s, 1H), 3.16 (brd, 1H, J=9.6 Hz), 2.74 (brt, 1H, J=10.2 Hz), 2.45-2.18 (m, 5H), 1.95-1.75 (m, 3H), 1.65-1.40 (m, 3H). HR FAB MS calcd for C19H25N6O6 433.1836 (M+ +H), found 433.1866.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11]=1[OH:20])=[O:9])([CH3:6])[CH3:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[I-].[Na+]>CN(C)C=O.O.C(OCC)C>[CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:6])([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11]=1[O:20][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:9])[CH3:5]
Reactant: BrCCc1ccccc1
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2c(c1O)CCCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)NC(=O)c1ccc2c(c1OCCc1ccccc1)CCCC2
Temperature: 80 °C
Reaction time: 6 h
Yield: 63.5 %

Procedure:
80 mg 2-[(1-hydroxy-5,6,7,8-tetrahydro-naphthalene-2-carbonyl)-amino]-2-methyl-pro-pionic acid methyl ester, 224 mg cesium carbonate, 61 mg of (2-bromoethyl)-benzene and 4 mg sodium iodide were dissolved in 5 ml of N,N-dimethylformamide and stirred at 80° C. for 6 h. 10 ml of diethyl ether and 10 ml of water were added to the reaction. The organic layer was separated and washed again with 10 ml of water. It was then dried over magnesium sulphate, filtered and concentrated in vacuo. Purification by flash chromatography (silica, heptanes/ethyl acetate) afforded 69 mg of 2-methyl-2-[(1-phenethyloxy-5,6,7,8-tetrahydro-naphthalene-2-carbonyl)-amino]-propionic acid methyl ester.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13](O)([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=2[NH:17][C:18]([C:20]2[NH:21][CH:22]=[C:23]([C:25]#[N:26])[N:24]=2)=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[N-:27]=[N+:28]=[N-:29].[Na+].C(O)(C(F)(F)F)=O.CCOC(C)=O>C(Cl)(Cl)Cl>[N:27]([C:13]([C:11]1[CH:10]=[CH:9][C:8]([NH:17][C:18]([C:20]2[NH:21][CH:22]=[C:23]([C:25]#[N:26])[N:24]=2)=[O:19])=[C:7]([C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)[CH:12]=1)([CH3:15])[CH3:14])=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(O)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N=[N+]=[N-])c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a mixture of 4-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-amide (as prepared in example 1, step (h), 15.0 mg, 0.0428 mmol) and NaN3 (27.8 mg, 0.428 mmol) in 1 mL of chloroform at 0° C. under Ar was added TFA (49 μL, 0.64 mmol). The resulting mixture was stirred at 0° C. for 1 h under Ar. Treated with 30 mL of EtOAc, the mixture was washed with saturated aqueous NaHCO3 (10 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (0-5% EtOAc/DCM) gave 13.6 mg (84%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C20H21N7O, 376.2 (M+H). found 376.0.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7]([CH2:11][CH2:12][CH2:13][OH:14])(O)[CH2:6][CH2:5]2)[O:3]C1.C(N(C(C)C)CC)(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O>C(Cl)Cl>[O:14]1[C:7]2([CH2:6][CH2:5][C:4](=[O:3])[CH2:9][CH2:8]2)[CH2:11][CH2:12][CH2:13]1
Reactant: OCCCC1(O)CCC2(CC1)OCCO2
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCC2(CCCO2)CC1

Procedure:
A mixture of 4-(3-Hydroxypropyl)-4-hydroxy-cyclohexanone ethylene ketal (1.4 g) and diisopropylethylamine (3.37 mL) in methylene chloride (100 mL) at -78° C. was treated with triflic anhydride (1.64 mL). After 30 min the reaction mixture was washed with water, the solvent was dried over magnesium sulfate and removed in vacuo. The residue was dissolved in 30 mL of tetrahydrofuran and 15 mL of 3% HCl. After 5 h at room temperature the reaction mixture was diluted with water and the product was extracted with ether. After drying over magnesium sulfate the solvent was removed in vacuo to afford 1-Oxaspiro[4.5]decan-8-one as an oil.
Reaction SMILES: CO[C:3]([CH:5]([CH:12]1[NH:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=O.ClC1C=CC=C[N:20]=1.C1(CC#N)C=CC=CC=1>>[N:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:3]#[N:20]
Reactant: Clc1ccccn1
Reactant: COC(=O)C(c1ccccc1)C1CCCCN1
Solvent: N#CCc1ccccc1
Product: N#CC(c1ccccc1)c1ccccn1

Procedure:
U.S. Pat. Nos. 2,507,631 and 2,957,880 disclose synthetic procedures wherein methylphenidate, alternatively known as methyl α-piperid-2-ylphenylacetate, is prepared through a multi-step process in which 2-chloropyridine and phenylacetonitrile initially are coupled to form α-pyrid-2-ylphenylacetonitrile. The resulting α-pyrid-2-ylphenylacetonitrile then is hydrated in the presence of acid to yield α-pyrid-2-ylphenylacetamide which, in turn, is either: (a) catalytically hydrogenated to yield α-piperid-2-ylphenylacetamide and then converted to methyl α-piperid-2-ylphenylacetate, or (b) converted to methyl α-pyrid-2-ylphenylacetate which, in turn, is hydrogenated to yield methyl α-piperid-2-ylphenylacetate.
Reaction SMILES: [ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Br[CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Reactant: BrC1CCCC1
Agent: Cl
Product: O=C1N(C2CCCC2)CN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2

Procedure:
The title compound, white solid, m. p. 221° C. and MS: m/e=438.3 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and bromocyclopentane.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][C:5]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24].[Li+].[OH-]>CO>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[C:5]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[CH:6]=2)[CH:13]=1
Reactant: COC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1-c1cc(COc2cccnc2)ccc1C(=O)O
Yield: 85.5 %

Procedure:
The 4-(3-pyridyloxymethyl)-2-(2-methylphenyl)benzoic acid methyl ester prepared in Example 204D (160 mg, 0.48 mmol) was dissolved in 5 mL of methanol and 1 mL of saturated aqueous LiOH was added. The reaction was heated to reflux for 1 hour. The reaction was then evaporated and 1 mL of formic acid was added to acidify the crude product 1 to pH=3. The reaction was evaporated again to remove formic acid and 5 mL of ethyl acetate and 1 mL of H2O were added to completely solubilize the reaction mixture. The aqueous layer was extracted with ethyl acetate (3×5 mL) and all the ethyl acetate layers were combined and dried over Na2SO4, filtered and evaporated to give 4-(3-pyridyloxymethyl)-2-(2-methylphenyl)benzoic acid (131 mg, 86%) as an oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]1(=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.Cl>C(O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:13]3[C:14]4[C:19]([CH2:11][C:12]=3[C:5]=2[CH:4]=1)=[CH:18][CH:17]=[CH:16][CH:15]=4
Reactant: O=C1CCc2ccccc21
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: Fc1ccc2[nH]c3c(c2c1)Cc1ccccc1-3
Reaction time: 5 h

Procedure:
A mixture of 4-fluorophenylhydrazine hydrochloride (1.83 g, 11.25 mM) and 1-indanone (1.49 g) in ethanol (20 cm3) was heated to reflux, and conc. hydrochloric acid was (1 cm3) added. Heating was continued for 5 hours, and the reaction mixture was cooled. The product which crystallised out from the cold solution as coloured platelets, was collected by filtration and dried (1.90 g, 75%). M.p. 225°-227° C. (from ethyl acetate/petrol [60°-80 ]). 1H NMR (CDCl3) δ: 8.3 (1H, br, s), 7.6-6.9 (7H, m), 3.70 (2H, s).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=3[F:29])[C@:20]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[F:39])([C:30]#[N:31])[C@H:19]([CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])[NH:18]2)=[O:16])[CH2:10][CH2:9]1.C(OC(=O)C)(=O)C.C(N(CC)CC)C>C(Cl)Cl>[CH3:13][N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]([CH:17]2[CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=3[F:29])[C:20]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[F:39])([C:30]#[N:31])[CH:19]([CH2:40][C:41]([CH3:42])([CH3:44])[CH3:43])[NH:18]2)=[O:16])[CH2:12][C:2]1=[C:3]=[O:5]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NC2CCNCC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CN1CCC(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)CC1=C=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid piperidin-4-ylamide trifluoroacetic acid (80 mg, 0.10 mmol) in methylene chloride (10 mL), acetic anhydride (18 uL, 0.18 mmol) and triethylamine (84 uL, 0.61 mmol) were added and the mixture was stirred at rt for 1.5 hr. The reaction was quenched with water and the organic layer was separated and dried with sodium sulfate. Removal of solvent gave the crude which was chromatographed on an ISCO machine (0-10% EtOAc/CH2Cl2) to give a white solid. 58 mg.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[O:12][CH:13]=[C:14]([C:16]([O:18]CC)=[O:17])[N:15]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[OH-].[Li+]>C1COCC1.CO.O>[CH3:1][S:2]([N:5]1[CH2:6][CH2:7][CH:8]([C:11]2[O:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: CCOC(=O)c1coc(C2CCN(S(C)(=O)=O)CC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)N1CCC(c2nc(C(=O)O)co2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
Ethyl 2-(1-(methylsulfonyl)piperidin-4-yl)oxazole-4-carboxylate (590 mg, 1.951 mmol) was dissolved in THF/methanol mixture (9:1) and 1M lithium hydroxide (3.90 ml, 3.90 mmol) was added slowly. The reaction mixture was stirred at RT for 1 h, diluted with water and pH was adjusted to 1.5. The mixture was extracted three times with ethyl acetate. Ethyl acetate phases were combined and evaporated to yield the title compound (74.7%). 1H-NMR (400 MHz; DMSO): δ 1.68-1.81 (m, 2H), 2.06-2.15 (m, 2H), 2.85-2.96 (m, 5H), 2.99-3.10 (m, 1H), 3.51-3.59 (m, 2H), 8.67 (s, 1H), 13.02 (bs, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[C:17]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18]1.O>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCCC1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc(C(=C2CCCC2)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
To a stirred suspension of zinc powder (0.71 g, 10.9 mmoL) in anhydrous THF (15 mL) was slowly added, via syringe, TiCl4 (0.58 mL, 1.0 g, 5.3 mmoL) at RT under a nitrogen atmosphere. The stirred reaction mixture was heated at reflux under a nitrogen atmosphere for 2.5 h. To the refluxing reaction mixture was added a solution of (4-bromophenyl)(4-hydroxyphenyl)methanone (2) (0.408 g, 1.47 mmol) and cyclopentanone (0.38 mL, 0.36 g, 4.3 mmol) in THF (15 mL) and heating continued an additional 2 h. The reaction mixture was allowed to cool to room temperature and water (10 mL) slowly added. The reaction mixture was then filtered through a pad of Celite and the Celite pad washed with EtOAc. The filtrate was transferred to a separatory funnel and the organic layer was separated. The organic phase was washed with brine, dried (MgSO4), filtered, and the filtrate concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography on silica gel with hexanes:EtOAc (100:0 to 60:40) to give 0.391 g (81%) of compound 3 as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.59 (m, 4H), 2.27 (m, 4H), 6.66 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 7.04 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 9.32 (s, 1H). HRMS (EI) Calcd for C18H17BrO: 328.0463 (M+.). Found: 328.0469.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](I)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:12].C(N(CC)CC)C.[CH3:20][CH:21]([OH:24])[C:22]#[CH:23]>O1CCOCC1.[Cu]I>[Cl:1][C:2]1[N:10]=[C:9]([C:23]#[C:22][CH:21]([OH:24])[CH3:20])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:12]
Reactant: Cn1cnc2c(Cl)nc(I)nc21
Reactant: C#CC(C)O
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(O)C#Cc1nc(Cl)c2ncn(C)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-chloro-2-iodo-9-methyl-9H-purine (6.8 g, 23.3 mmol), CuI (454 mg, 2.23 mmol) and bis-triphenylphosphine palladium dichloride (811 mg, 1.15 mmol) in dioxane (93 ml) were added triethylamine (4.9 ml, 34.5 mmol) and but-3-yn-2-ol (1.1 ml, 25.63 mmol). The reaction mixture was stirred at RT for 1 h. The volatiles were removed under reduced pressure. Water (50 ml) was added to the dark residue obtained. The aqueous phase was extracted with DCM (3×100 ml). The combined organic phases were dried over anhydrous sodium sulphate and evaporated under reduced pressure. The combined organic phases were dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by flash chromatography (DCM/MeOH: 94/6).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=O)=[C:6]([C:8]2[C:9]([C:14](OC)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:18]([OH:20])[C:14](=[O:15])[C:9]3[C:8](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[CH:7]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccccc1-c1cc(F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: O=c1c2ccccc2c2cc(F)ccc2n1O
Yield: 98.1 %

Procedure:
To a solution of the product of Example 37a (methyl 5′-fluoro-2′-nitrobiphenyl-2-carboxylate, 56.79 mg, 0.206 mmol) in methanol (9 mL) was added 10% palladium on carbon (15.6 mg, 0.015 mmol). The flask was fitted with a hydrogen balloon and de-gassed three times with hydrogen. The reaction mixture was stirred, diluted with dimethylformamide, and filtered. The filtrate was concentrated to provide 2-fluoro-5-hydroxyphenanthridin-6(5H)-one (37b, 46.36 mg, 0.202 mmol, 98% yield).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][OH:25])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[C:27]1(=[O:34])[O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28]1.C(N(CC)CC)C.S(=O)(=O)(O)O>CN(C)C=O>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:25][C:27]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:34])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: O=C1CCCC(=O)O1
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CO
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)CCCC(=O)O
Yield: 56.2 %

Procedure:
In 10 ml of dimethylformamide is dissolved 0.5 g of 16β-ethyl-17β-glycoloyloxy-4-estren-3-one, and 0.2 g of glutaric anhydride and then 0.3 ml of triethylamine are added to the above solution. The mixture is allowed to stand at room temperature (15°-25° C.) for 3 hours and poured into 20 ml of 10% aqueous sulfuric acid, followed by extraction with 100 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography, elution being carried out with 200 ml of ethyl acetate. The eluate is evaporated under reduced pressure to remove the solvent, giving a colorless oil, which is allowed to stand to give 0.37 g of the above-identified compound as a solid.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[SH:16][C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>CCO>[S:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[S:16][CH2:3][C@@H:2]([OH:1])[CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15]
Reactant: Sc1nc2ccccc2s1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1C[C@H](O)CSc1nc2ccccc2s1
Yield: 76 %

Procedure:
A suspension of N-[(2S)-oxiran-2-ylmethyl]-phthalimide (18.4 g, 90.6 mmol) and 2-mercaptobenzothiazole (15.8 g, 94.5 mmol) in EtOH (530 mL) was heated to reflux for 14.5 h. The reaction was then cooled and concentrated under reduced pressure. The crude mixture was crystallized from ethanol and filtered to provide N-[(2S)-3-(1,3-benzothiazol-2-ylthio)-2-hydroxypropyl]-phthalimide (25.5 g, 76%) as a solid. Data for N-[(2S)-3-(1,3-benzothiazol-2-ylthio)-2-hydroxypropyl]-phthalimide: 1H NMR (300 MHz, CDCl3) δ 7.88 (m, 2H), 7.75 (m, 4H), 7.45-7.26 (m, 2H), 5.15 (m, 1H), 4.42 (m, 1H), 4.08-3.88 (m,2H, 3.61 (m, 1H), 3.42 (m, 1H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]([F:27])([F:26])[S:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1.I[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCCC1.CN1CCCN(C)C1=O>[CH:30]1([CH2:29][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([S:15][C:14]([F:26])([F:13])[F:27])=[CH:21][CH:20]=2)[C:23]([OH:25])=[O:24])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=C(O)Cc1ccc(SC(F)(F)F)cc1
Reactant: ICC1CCCC1
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(SC(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
A solution of diisopropylamine (2.4 mL, 16.80 mmol) in dry tetrahydrofuran (7.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL) was cooled to −78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (6.7 mL, 16.80 mmol). The resulting reaction mixture was stirred at −78° C. for 30 min and then treated dropwise with a solution of 4-(trifluoromethylthio)phenylacetic acid (1.89 g, 8.00 mmol) in dry tetrahydrofuran (7.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL). The reaction mixture was allowed to stir at −78° C. for 55 min, at which time, a solution of iodomethylcyclopentane (1.85 g, 8.80 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C. where it was stirred for 41 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (1×300 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (1.47 g, 58%) as a cream solid: mp 69-71° C.; EI-HRMS m/e calcd for C15H17F3O2S (M+) 318.0901, found 318.0912.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.C1N2CCN(CC2)C1.C1C(=O)N(Cl)C(=O)C1.[Cl:30][CH2:31][CH2:32][CH2:33][OH:34].CS(O)(=O)=O>C(Cl)Cl>[Cl:30][CH2:31][CH2:32][CH2:33][O:34][C:2]1[NH:1][C:9]2[C:4]([C:3]=1[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: OCCCCl
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: C1CN2CCN1CC2
Agent: CS(=O)(=O)O
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: COC(=O)c1c(OCCCCl)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
A suspension of methyl indole-3-carboxylate (5.25 g, 30.0 mmol) and DABCO (1.84 g, 16.4 mmol) in dry CH2Cl2 (25 ml) was cooled to 0° C. under argon atmosphere, treated in one portion with NCS (4.41 g, 33.0 mmol) and the mixture stirred for 10 min. The resulting solution was added to a solution of 3-chloropropan-1-ol (3.12 g, 33.0 mmol) in dry CH2Cl2 (25 ml) containing anhydrous methane sulphonic acid (0.23 ml). The resulting suspension was stirred for 30 min and then washed with 10% aqueous Na2CO3 solution (3×25 ml). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The resulting oil was triturated with toluene (10 ml) at 0° C. for 1 h and the solid precipitate filtered, washed with a small amount of toluene and dried in vacuo to leave the product as an off-white solid (5.22 g, 65.0%).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:22])=[CH:6][C:7]([O:20][CH3:21])=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[CH:9]=1)(=[O:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>>[C:1]([C:4]1[C:5]([CH3:22])=[CH:6][C:7]([O:20][CH3:21])=[C:8]([NH:10][C:11]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=3)[CH2:38][CH2:37]2)=[O:19])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: COc1cc(C)c(C(C)=O)cc1NC(=O)Oc1ccccc1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C(C)=O)c(C)cc3OC)CC2)c1
Yield: 91 %

Procedure:
Phenyl N-(5-acetyl-2-methoxy-4-methylphenyl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound.