Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][CH2:8][CH2:9][N:10]1C(=O)C2=CC=CC=C2C1=O.O.NN>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][CH2:8][CH2:9][NH2:10]
Reactant: O=C1c2ccccc2C(=O)N1CCSc1ncccn1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCSc1ncccn1
Reaction time: 1 h
Yield: 70.9 %

Procedure:
A mixture of N-[2-(2-pyrimidinylthio)ethyl]phthalimide (17.1 g), hydrazine hydrate (21 g) and ethanol (200 ml) was stirred for one hour under reflux. The crystals separated was filtered off, and the filtrate was concentrated under reduced pressure to obtain 2-(2-pyrimidinylthio)ethylamine (6.6 g 71%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:23][CH2:22]3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:30].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:30])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:23][CH2:22]3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C2CC2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCN(C2CC2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(4-cyclopropylpiperazin-1-yl)quinolin-7-yl]ethanone (0.0611 g, 0.185 mmol) and ammonium acetate (0.143 g, 1.85 mmol) in methanol (0.8 mL) and acetonitrile (0.8 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.46 mL, 0.46 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C18H24ClN4 (M+H)+: m/z=331.2; Found: 331.1.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:24])[CH2:8][O:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH:19]=[CH:18]3)=[N:5]1.Br[CH:26]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:27]([O:29][CH2:30][CH3:31])=[O:28].[Cl-].[NH4+]>C1COCC1>[CH3:3][C:4]1([CH3:24])[CH2:8][O:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH:26]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:19]=[CH:18]3)=[N:5]1
Reactant: CC1(C)COC(c2ccccc2-c2ccc3[nH]ccc3c2)=N1
Reactant: CCCCCCC(Br)C(=O)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCCC(C(=O)OCC)n1ccc2cc(-c3ccccc3C3=NC(C)(C)CO3)ccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86.8 %

Procedure:
Sodium hydride (0.54 mmoles, 22 mg of 60% in mineral oil) was added to 5-[2-(4,4-dimethyloxazolin-2-yl)phenyl]indole (0.43 mmoles, 125 mg) in 2 ml THF. After stirring 20 minutes, the solution was cooled to 0° C. Ethyl 2-bromooctanoate (0.54 mmoles, 0.135 mg) was added. The solution was stirred for 15 minutes, allowed to warm to room temperature, and stirred for 1.5 hours. The solution was poured into saturated ammonium chloride and extracted with ethyl acetate. The organic phase was dried and concentrated. The oil was chromatographed over silica gel eluted with 20 % ether in hexane. The reaction yielded 172 mg of ethyl 2-[5-[2-(4,4-dimethyloxazolin-2-yl)phenyl]indol-1-yl]octanoate. (MS)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].Cl[C:23]1[C:32]2[C:27](=[CH:28][N:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:9]([O:8][C:6]([NH:5][C@@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:23]2[C:32]3[C:27](=[CH:28][N:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][N:24]=2)=[CH:16][CH:15]=1)[C:3]([O:2][CH3:1])=[O:21])=[O:7])([CH3:12])([CH3:10])[CH3:11]
Reactant: Clc1nccc2cnccc12
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(Oc2nccc3cnccc23)cc1)NC(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 78.9 %

Procedure:
To N-(t-butyloxycarbonyl)tyrosine methyl ester (1.42 g, 4.82 mmol) in dry DMF (10 ml) was added 1-chloro-2,6 naphthyridine (0.79 g, 4.82 mmol) and cesium carbonate (1.65 g, 5.06 mmol) and the reaction stirred at 45° under N2 for 2 days. The DMF was evaporated, EtOAc added and washed (3×) with water, dried (MgSO4), and evaporated in vacuo. The residue was chromatographed (SiO2; 40 to 100% EtOAc/isohexane) to afford the title compound as white foam (1.61 g, 82%). δH (CDCl3) 9.29 (1H, s), 8.76 (1H, d, J 5.74 HZ), 8.17 (1H, d, J 5.74 Hz), 8.11 (1H, d, J 5.8 Hz), 7.43 (1H, d, J 5.8 Hz), 7.22-7.18 (3H, m), 5.03 (1H, br s), 4.61 (1H, br s), 3.75 (3H, s), 3.15-3.05 (2H, m), 1.44 (9H, s); m/z (ES+, 70V) MH+424.
Reaction SMILES: [CH3:1][C:2]1([CH2:11][C:12]([O:14]CC)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.CO.[OH-].[Na+]>O1CCCC1.O>[CH3:1][C:2]1([CH2:11][C:12]([OH:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)CC1(C)CCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1(CC(=O)O)CCc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.1 %

Procedure:
To a solution of the product from Example 131A (0.47 g, 2.1 mmol) in tetrahydrofuran (6 mL), water (3 mL), and methanol (6 mL) was added 5N NaOH aqueous solution (2.1 mL, 10.8 mmol). After stirring at room temperature for 4 hours, the reaction mixture was concentrated to half the volume, diluted with water (10 mL), washed with methylene chloride (10 mL), acidified to pH˜2 with aqueous 3N HCl solution, and extracted with methylene chloride (3×15 mL). The combined organic extracts were washed with H2O (50 mL), brine (50 mL), dried over MgSO4, filtered, and concentrates under reduced pressure to obtain 0.32 g of the title compound. MS (DCI/NH3) m/z 208 (M+NH4)+
Reaction SMILES: C1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.N[C:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=CS[C:25]=1C(OC)=O.C(OCC)(OCC)OCC.NC1CC2C(C=1)=CC=CC=2>C(O)(=O)C>[CH2:28]1[C:29]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:25][CH:24]1[N:7]1[C:12](=[O:13])[C:11]2[S:14][CH:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:10]=2[N:9]=[CH:8]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Agent: NC1=Cc2ccccc2C1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3)c2ncn1C1Cc2ccccc2C1
Yield: 58 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (55.8 mg, 0.24 mmol), triethyl orthoformate (0.53 ml), 2-aminoindene (59.25 mg, 0.45 mmol), and acetic acid (0.06 ml) were used to give 48 mg (0.14 mmol, 58% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13].[CH3:17]OS([O-])(=O)=O.C[S+](C)C.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O.CCOCC.[Cl-].[Na+].O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:12]2[CH2:17][O:13]2)[CH:14]=[CH:15][CH:16]=1
Reactant: COS(=O)(=O)[O-]
Reactant: COCCOCCOc1cccc(C=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[S+](C)C
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: COCCOCCOc1cccc(C2CO2)c1
Yield: 126.9 %

Procedure:
To a stirred solution of 1.32 g of 3-[2-(2-methoxyethoxy)ethoxy]benzaldehyde and 15 mg of tetra-n-butylammonium bromide in 15 ml of CH2Cl2 is added a solution of 2.4 g of trimethylsulfonium methylsulfate in 4 ml of water, followed by 10 ml of 50% NaOH. The mixture is stirred and refluxed for 4 h, then cooled, diluted with ether and brine, and filtered. The organic phase is washed with brine, dried (MgSO4), and concentrated under reduced pressure to provide 1.78 g of the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[CH3:5][C:6]1([CH3:18])[CH2:10][N:9]([CH2:11][CH2:12][N+:13]([CH3:16])([CH3:15])[CH3:14])[C:8](=[O:17])[NH:7]1.C(O[Cl:24])(C)(C)C>CO>[C:1]([O-:4])(=[O:3])[CH3:2].[Cl:24][N:7]1[C:6]([CH3:18])([CH3:5])[CH2:10][N:9]([CH2:11][CH2:12][N+:13]([CH3:16])([CH3:15])[CH3:14])[C:8]1=[O:17]
Reactant: CC1(C)CN(CC[N+](C)(C)C)C(=O)N1
Reactant: CC(C)(C)OCl
Agent: CC(=O)[O-]
Solvent: CO
Product: CC1(C)CN(CC[N+](C)(C)C)C(=O)N1Cl
Reaction time: 0.25 h
Yield: 64.5 %

Procedure:
A solution of 2-(4,4-dimethyl-2-oxoimidazolidin-1-yl)-N,N,N-trimethylethanaminium acetate (0.428 mmol) in MeOH (2 ml) was cooled to 0° C. tert-Butylhypochlorite (100 ul, 0.84 mmol) was added, causing a white precipitate to form. The solution was stirred for 15 min, and another portion of tert-butylhypochlorite (100 ul, 0.84 mmol) was added. The solution was stirred for an additional 15 min, then concentrated in vacuo. The residue was purified by RP-HPLC (H2O/CH3CN) to afford the title compound as a white powder (74.7 mg, 0.276 mmol, 65%). 1H NMR (D2O, 400 MHz) δ 1.24 (s, 6H), 1.85 (s, 3H), 3.11 (s, 9H), 3.37 (s, 2H), 3.50 (m, 2H), 3.68 (m, 2H). 13C NMR (D2O, 100 MHz) δ 22.32, 27.01, 39.24, 55.38, 57.82, 62.40, 161.31, 180.46. ESI/APCI (pos) expected for C10H21ClN3O+: 234.14. Found: 234.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([S:14]([CH:17]3[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)(=[O:16])=[O:15])=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30].Cl[Si](C)(C)C>CO>[NH:19]1[CH2:20][CH:17]([S:14]([C:12]2[CH:11]=[CH:10][C:9]3[N:5]([CH2:4][CH2:3][N:2]([CH3:33])[CH3:1])[C:6]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[N:7][C:8]=3[CH:13]=2)(=[O:15])=[O:16])[CH2:18]1
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)C3CN(C(=O)OC(C)(C)C)C3)ccc21
Agent: C[Si](C)(C)Cl
Solvent: CO
Product: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)C3CNC3)ccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 104.4 %

Procedure:
To a solution of tert-butyl 3-(1-(2-(dimethylamino)ethyl)-2-neopentyl-1H-benzo[d]imidazol-5-ylsulfonyl)azetidine-1-carboxylate (prepared in STEP F of Example 1, 327 mg, 0.683 mmol) in methanol (4 mL) was added chlorotrimethylsilane (873 microL, 6.80 mmol). After stirring for 20 h at room temperature, the mixture was concentrated in vacuo. The residue was diluted with methanol (10 mL) and filtered through SCX column. The column was washed with 1 mol/L ammonia in methanol solution to wash out the product. The filtrated was concentrated to give the title compound (270 mg, 97%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:7][NH:8][C:9]2=O)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=2)[C:6]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:7][N:8]=1
Reactant: O=c1[nH]nc(-c2ccc(F)cc2)c2ccc(F)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc(-c2nnc(Cl)c3cc(F)ccc23)cc1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 7-fluoro-4-(4-fluorophenyl)-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: OC(C(F)(F)F)=O.Br[C:9]1[CH:10]=[C:11]2[C:18]3([O:22][N:21]([CH3:23])[C:20]([NH2:24])=[N:19]3)[CH2:17][CH:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:15][C:12]2=[CH:13][CH:14]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][N:21]1[C:20]([NH2:24])=[N:19][C:18]2([C:11]3[C:12](=[CH:13][CH:14]=[C:9]([C:33]4[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=4)[CH:10]=3)[O:15][CH:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:17]2)[O:22]1
Reactant: OB(O)c1cccnc1
Reactant: CN1OC2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CN1OC2(CC(c3ccccc3)Oc3ccc(-c4cccnc4)cc32)N=C1N
Temperature: 100 °C
Yield: 35.1 %

Procedure:
To a solution of 6-bromo-2′-methyl-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine TFA salt (65 mg, 0.13 mmol), 3-pyridineboronic acid (64 mg, 0.52 mmol) and Cs2CO3 (127 mg, 0.39 mmol) in 1,4-dioxane (3 mL) and H2O (0.5 mL) in a 10 mL CEM microwave test tube was added PdCl2(PPh3)2 (10 mg). After degassing by purging with N2, the mixture was heated to 100° C. for 5 min in a CEM microwave reactor. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 2′-methyl-2-phenyl-6-(pyridin-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (17 mg) as a TFA salt. MS ESI +ve m/z 393 (M+H)+. 1H-NMR (400 MHz, CD3OD): 9.19 (br s, 1H), 8.87 (d, J=7.6 Hz, 1H), 8.78 (br s, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.11 (t, J=6.4 Hz, 1H), 7.91 (dd, J=8.8, 2.4 Hz, 1H), 7.54-7.38 (m, 5H), 7.21 (d, J=8.8 Hz, 1H), 5.37 (d, 12.8 Hz, 1H), 3.43 (s, 3H), 2.88 (dd, J=14.4, 2.0 Hz, 1H), 2.42 (dd, J=14.4, 12.8 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][NH:9][CH:8]([CH3:21])[CH2:7][C:6]=2[CH:22]=1>C(OC(=O)CC)(=O)CC.O>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][N:9]([C:3](=[O:23])[CH2:2][CH3:22])[C:8]([CH3:21])=[CH:7][C:6]=2[CH:22]=1
Reactant: COc1cc2c(cc1Br)CC(C)NN=C2c1ccc([N+](=O)[O-])cc1
Agent: CCC(=O)OC(=O)CC
Solvent: O
Product: CCC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc(OC)c(Br)cc2C=C1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 140.3 %

Procedure:
0.67 g (1.7 mmol) of 7-bromo-8-methoxy-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (Example 4, Step A) is suspended in 3.35 ml of propionic acid anhydride and stirred for 3 hours at room temperature. The mixture is diluted with water, and the product is filtered. After washing with water and drying by column chromatography, the crude product is purified (silica gel, eluant benzene:ethyl acetate: 4:0.2). 0.53 g (70%) of 7-bromo-8-methoxy-4-methyl-1-(4-nitrophenyl)-3-propionyl-3H-2,3-benzodiazepine is obtained as a thick oil.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15](I)[CH:16]=3)[CH2:11][C@@H:10]2[OH:19])=[O:7])=[CH:4][CH:3]=1.[C:22]([N:29]1[CH2:34][CH2:33][NH:32][C:31](=[O:35])[CH2:30]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].CNCCNC>CN1CCCC1=O.C(OCC)(=O)C.[Cu]I>[F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N:32]4[CH2:33][CH2:34][N:29]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:30][C:31]4=[O:35])[CH:16]=3)[CH2:11][C@@H:10]2[OH:19])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1c2cc(I)ccc2C[C@@H]1O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)[C@H](NC(=O)c2ccc(F)cc2)[C@@H](O)C3)C(=O)C1
Temperature: 100 °C
Reaction time: 6 h
Yield: 74.2 %

Procedure:
Purge a mixture of 4-fluoro-N-[(1S,2S)-2-hydroxy-6-iodo-indan-1-yl]benzamide (8.70 g, 21.9 mmol), 4-N-boc-2-oxo-piperazine (4.61 g, 22.3 mmol), and potassium carbonate (6.12 g, 43.8) in N-methylpyrrolidone (100 mL) with nitrogen gas. Add copper (I) iodide (2.11 g, 11.0 mmol) and sym-dimethylethylene diamine (2.34 mL, 21.9 mmol). Seal the flask with a septum and stir at 100° C. for 6 hr. Cool the mixture to room temperature and dilute with ethyl acetate (100 mL). Wash the organic portion with water (3×100 mL), then brine, and then dry over sodium sulfate, filter, and concentrate to dryness. Purify the residue by column chromatography (120 g silica, 2 to 5% methanol/chloroform) to obtain the title compound (7.63 g, 74%). LC-ES/MS m/z 470 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:14](Cl)(=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:14](=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: COc1ccc(C)cc1
Reactant: CCCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCC(=O)c1cc(C)ccc1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
4-Methoxytoluene (100 ml, 0.793 mol) and methylene chloride (300 ml) were mixed, and this solution was cooled to 0° C. To this solution was added aluminum chloride (190.3 g, 1.44 mol), and then heptanoyl chloride (123 ml, 0.8 mol) was added dropwise to this solution over 2 hours. The reaction mixture was heated to room temperature, and stirred for 2 hours. The reaction mixture was poured onto ice (400 g) to stop the reaction. The aqueous layer was extracted with chloroform (300 ml). The organic layers were combined, washed successively with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine (100 ml each), and dried over anhydrous magnesium sulfate. The drying agent was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by distillation (120 pa, 125-140° C.) to give 1-(2-hydroxy-5-methylphenyl)heptan-1-one (127.8 g, 77%/) as a colorless oil.
Reaction SMILES: [C:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:20]([C:21](=[O:23])[CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C@H:13]([CH2:14][CH:15]=[CH:16][CH2:17]1)[CH2:12][CH2:11]3)(=O)[NH2:2]>C(Cl)(Cl)Cl>[C:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:20]([C:21](=[O:23])[CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C@H:13]([CH2:14][CH:15]=[CH:16][CH2:17]1)[CH2:12][CH2:11]3)#[N:2]
Reactant: C[C@]12CC=CC[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(N)=O)[C@@]3(C)CC(=O)[C@@H]12
Solvent: ClC(Cl)Cl
Product: C[C@]12CC=CC[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C#N)[C@@]3(C)CC(=O)[C@@H]12
Yield: 56.1 %

Procedure:
17β-Carbamoyl-5α-androst-2-en-11-one (4.0g., 13 mmole) and polyphosphate ester (20g.) were refluxed in chloroform (200 ml.) for 20 hr. The chloroform was removed by evaporation and the residue stirred with aqueous 10% sodium carbonate (150 ml.) for an hour. The mixture was extracted with ether and the extract washed (H2O), dried filtered and evaporated to give a solid which, after recrystallisation from chloroform/cyclohexane, gave the title compound (2.17g); m.p. 189°-191°; [α]D + 152°, (c 0.9).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:15][CH2:16][CH:17]1[O:21][C:20](=[O:22])[N:19]([CH3:23])[CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC.CC(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH:17]3[O:21][C:20](=[O:22])[N:19]([CH3:23])[CH2:18]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(N2CCNCC2)cc1
Reactant: CN1CC(CCCl)OC1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Solvent: CC(C)O
Product: CN1CC(CCN2CCN(c3ccc(Br)cc3)CC2)OC1=O
Yield: 76 %

Procedure:
This compound was prepared according to the procedure of Example 2. A mixture of 3.6 g (0.015 mol) of 1-(4-bromophenyl)piperazine, 2.5 g (0.015 mol) of 5-(2-chloroethyl)-3-methyl-2-oxazolidinone, 4.8 g (0.045 mol) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol heated at reflux for 22 h gave 4.2 g (76%) of white solid, mp 125°-127° C. (2-propanol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:9][CH:8]=[N:7][C:6]=1[N:10]1[C:14](=[O:15])[NH:13][C:12]([CH:16]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[C:43]([CH2:49][NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH:42]=2)[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH2:26][CH2:27][O:28][Si](C(C)C)(C(C)C)C(C)C)[C:18]=2[F:39])=[N:11]1)=[O:4].C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O>[CH3:1][O:2][C:3]([C:5]1[O:9][CH:8]=[N:7][C:6]=1[N:10]1[C:14](=[O:15])[NH:13][C:12]([CH:16]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[C:43]([CH2:49][NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH:42]=2)[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH2:26][CH2:27][OH:28])[C:18]=2[F:39])=[N:11]1)=[O:4]
Reactant: COC(=O)c1ocnc1-n1nc(C(Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)c2cc(OC)cc(OCCO[Si](C(C)C)(C(C)C)C(C)C)c2F)[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ocnc1-n1nc(C(Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)c2cc(OC)cc(OCCO)c2F)[nH]c1=O
Reaction time: 3 h
Yield: 117.9 %

Procedure:
To a mixture of 4-(3-{[3-(t-butoxycarbonylaminomethyl)-4-cyanophenylamino]-[2-fluoro-5-methoxy-3-(2-triisopropylsilanyloxyethoxy)phenyl]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)oxazole-5-carboxylic acid methyl ester (41.1 mg) and THF (2 mL) there was added a 1M THF solution of tetrabutylammonium fluoride (0.100 mL). The mixture was stirred for 3 hours, and then ethyl acetate (30 mL) and water (15 mL) were added. The mixture was sufficiently shaken, and then the organic layer was separated off, washed with water (15 mL) and saturated aqueous sodium chloride (15 mL) in that order, and dried over anhydrous magnesium sulfate. The mixture was filtered to obtain a filtrate and the solvent in the filtrate was distilled off under reduced pressure to obtain the target compound (39.1 mg) as a colorless oil.
Reaction SMILES: C(OC(N1CCC(N)(CN)CC1)=O)(C)(C)C.C(OC(N1CCC(N)(C#N)CC1)=O)(C)(C)C.[NH2:33][C:34]1([C:48]#[N:49])[CH2:39][CH2:38][N:37]([CH:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH3:41])[CH2:36][CH2:35]1>>[NH2:49][CH2:48][C:34]1([NH2:33])[CH2:39][CH2:38][N:37]([CH:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH3:41])[CH2:36][CH2:35]1
Reactant: CC(c1ccccc1)N1CCC(N)(C#N)CC1
Agent: CC(C)(C)OC(=O)N1CCC(N)(C#N)CC1
Agent: CC(C)(C)OC(=O)N1CCC(N)(CN)CC1
Product: CC(c1ccccc1)N1CCC(N)(CN)CC1

Procedure:
4-Aminomethyl-1-(1-phenyl-ethyl)-piperidin-4-ylamine is prepared analogously to Intermediate U by replacing 4-amino-4-cyano-piperidine-1-carboxylic acid tert-butyl ester in Step 1 with 4-amino-1-(1-phenyl-ethyl)-piperidine-4-carbonitrile; [M+H]+ 234.
Reaction SMILES: C(OC([N:8]1[C:13](=[O:14])[CH:12]2[CH:10]([CH:11]2[C:15]([O-:17])=[O:16])[CH:9]1[C:18]([O-:20])=[O:19])=O)(C)(C)C.Cl.[CH2:22]([O:29][NH2:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C1COCC1.[C-]#N.[K+]>[C:15]([CH:11]1[CH:12]([C:13]([NH:30][O:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:14])[CH:10]1[CH:9]([C:18]([OH:20])=[O:19])[NH2:8])([OH:17])=[O:16]
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C(C(=O)[O-])C2C1C(=O)[O-]
Reactant: NOCc1ccccc1
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(C(=O)O)C1C(C(=O)O)C1C(=O)NOCc1ccccc1
Reaction time: 8 h
Yield: 134.2 %

Procedure:
To a solution of ethyl (1SR, 2 SR, 5RS, 6RS) 3-tert -butoxycarbonyl-4-oxo-3-azabicyclo[3.1.0]hexane-2,6-dicarboxylate (150 mg, 0.44 mmol) in dry THF (3 mL) under argon was added O-benzylhydroxylamine hydrochloride (421.5 mg, 2.64 mmol), potassium cyanide (1.43 mg, 0.02 mmol) and triethylamine (0.36 mL, 2.64 mmol). After stirring overnight in an ultrasonic bath, the solvent was removed under reduced pressure. The residue was directly purified by flash chromatography (hexane/ethyl acetate 1.5/1) to give 182 mg of the desired compound (89% yield).