Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:24]([O:30][CH2:31]I)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>>[CH3:26][C:25]([CH3:28])([CH3:27])[C:24]([O:30][CH2:31][O:19][CH2:18][CH2:17][O:16][CH2:15][N:14]1[C:10]([S:9][C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]=[C:13]1[CH3:20])=[O:29]
Reactant: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1COCCO
Reactant: CC(C)(C)C(=O)OCI
Product: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1COCCOCOC(=O)C(C)(C)C
Yield: 32.3 %

Procedure:
The compound 8 (375 mg, 1 mmol) was alkylated with the pivaloyloxymethyl iodide (1.21 g, 5 mmol) under potassium carbonate (415 mg, 3 mmol) in the same manner as the example 61 to give the compound 77 (158 mg, 32%) as oil. Rf 0.26 (1:1 EtOAc - hexane).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH2:10][O:11][C@H:12]2[CH2:17][CH2:16][CH2:15][NH:14][C@H:13]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[C:7]([CH3:9])[CH:8]=1.[C:24](O)(=O)C.C([BH3-])#N.[Na+].C=O>CO>[CH3:9][C:7]1[CH:6]=[C:5]([CH2:10][O:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH3:24])[C@H:13]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:4]=[C:3]([CH3:2])[CH:8]=1
Reactant: CC(=O)O
Reactant: Cc1cc(C)cc(CO[C@H]2CCCN[C@H]2c2ccccc2)c1
Agent: C=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: Cc1cc(C)cc(CO[C@H]2CCCN(C)[C@H]2c2ccccc2)c1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
A solution of cis-3-((3,5-dimethylphenyl)methyloxy)-2-phenylpiperidine (220 mg, 0.75 mmol, Example 2) and acetic acid (0.212 ml) in dry methanol (6 ml) was cooled to 0° C. and sodium cyanoborohydride (96 mg, 1.5 mmol) was added followed by formaldehyde (38% aq. solution, 0.15 ml). The reaction mixture was stirred at 23° C. for 18 h, then the solvent was removed in-vacuo and the residue partitioned between dichloromethane and 2M sodium hydroxide. The layers were separated, and the aqueous phase extracted with dichloromethane (2×20 ml). The combined organic extracts were washed with water then brine, then dried (K2CO3) and concentrated to leave a clear oil. Purification on silica-gel (CH2Cl2 /MeOH/NH3 97:3:0.5 then CH2Cl2 /MeOH 90:10) provided the title compound as a clear, colourless oil. 1H NMR (CDCl3) 7.42 (m), 7.30 (m), 6.77 (s), 6.54 (s), 4.27 (d, J=12.2 Hz), 4.04 (d, J=12.2 Hz), 3.42 (s), 3.07 (m), 2.91 (d, J=1.9 Hz), 2.17 (s), 2.10 (m) 2.04 (s), 1.56 (m), 1.39 (m). MS (CI) m/z 310 (MH).
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:16][F:17])([CH3:15])[C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[Br:18]Br>C(Cl)Cl>[F:1][CH2:2][C:3]([CH2:16][F:17])([CH3:15])[C:4](=[O:14])[CH:5]([Br:18])[O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: BrBr
Reactant: CC(CF)(CF)C(=O)COc1ccc(Cl)cc1
Solvent: ClCCl
Product: CC(CF)(CF)C(=O)C(Br)Oc1ccc(Cl)cc1
Yield: 89 %

Procedure:
166 g (0.632 mol) of 3,3-bisfluoromethyl-1-(4-chlorophenoxy)-butan-2-one were dissolved in 500 ml of methylene chloride, and 100 g (0.625 mol) of bromine were added dropwise at 20° to 30° C., while stirring and cooling. The mixture was subsequently stirred at 20° C. for 2 hours. After distilling off the solvent in vacuo, the residue was crystallized from petroleum ether. 190 g (88% of theory) of 3,3-bisfluoromethyl-1-bromo-1-(4-chlorophenoxy)-butan-2-one of melting point 54°-55° C. were obtained. ##STR75##
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:36])[NH:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)=[O:24])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:17]=1)=[O:15])[C:10]([OH:12])=O)(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:77][C:78]1[CH:79]=[C:80]([CH:89]=[CH:90][CH:91]=1)[C:81]([CH:83]1[CH2:88][CH2:87][NH:86][CH2:85][CH2:84]1)=[O:82].C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:77][C:78]1[CH:79]=[C:80]([CH:89]=[CH:90][CH:91]=1)[C:81]([CH:83]1[CH2:84][CH2:85][N:86]([C:10](=[O:12])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30](=[O:36])[NH:31][CH:32]3[CH2:33][CH2:34][CH2:35]3)=[O:24])[N:18]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([OH:5])=[O:43])[CH2:87][CH2:88]1)=[O:82]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Reactant: O=C(c1cccc(Cl)c1)C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)N1CCC(C(=O)c2cccc(Cl)c2)CC1

Procedure:
To a solution of 150 mg (S)-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 7 ml DMF were added 62 μl DIPEA, 95 mg HATU and 56 mg 4-(3-chlorobenzoyl)-piperidine. After stirring for 12 h saturated NaHCO3 solution was added and the mixture loaded on a Chem Elut® cartridge, the crude product being eluted with dichloromethane. The solution was concentrated to a volume of 1 ml and stirred in the presence of 100 μl TFA. After stirring for 4 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 135 mg MS (ES+): m/e=747.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.CCCCCC.[CH3:19][C:20]([CH3:28])([CH2:25][O:26][CH3:27])[C:21](OC)=[O:22]>C1COCC1.O.C(O)(=O)C>[CH3:19][C:20]([CH3:28])([CH2:25][O:26][CH3:27])[C:21](=[O:22])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: COCC(C)(C)C(=O)OC
Agent: [Li]CCCC
Solvent: O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COCC(C)(C)C(=O)CP(=O)(OC)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a solution of dimethyl methylphosphonate (9.62 g, 77.0 mmol) in anhydrous THF (130 ml) was added under argon atmosphere a solution of n-butyl lithium in hexane (1.62N, 47.5 ml, 77.0 mmol) at -78° C. The reaction mixture was stirred for 30 min. and a solution of methyl 2,2-dimethyl-4-oxapentanoate (4.50 g, 30.8 mmol) in anhydrous THF (15 ml) was added at -78° C. This mixture was stirred for 30 min., allowed to warm to room temperature and stirred for 30 min. The resulting solution was neutralized with acetic acid, water (20 ml) was added, and the mixture was then concentrated. Ethyl acetate (120 ml) and water (20 ml) were added to the residue. The organic layer was separated from the aqueous layer, washed with water (50 ml), and with brine (50 ml), dried over anhydrous magnesium sulfate, and concentrated. Distillation of the residue (b.p. 104°-107° C./0.4 mmHg) gave dimethyl 3,3-dimethyl-2-oxo-5-oxahexylphosphonate (5.96 g, 25.0 mmol, 81.2%) as an oily material. The product was assigned the structure by the following data.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2/[CH:24]=[CH:25]/[CH2:26][CH2:27][CH3:28])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH3:23][C:19]1[C:18](/[CH:24]=[CH:25]/[CH2:26][CH2:27][CH3:28])=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:29]
Reactant: CCC/C=C/c1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC/C=C/c1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.4 %

Procedure:
The mixture 2-[3-methyl-2-((E)-pent-1-enyl)-benzoylamino]-indan-2-carboxylic acid ethyl ester (145) (170 mg, 0.43 mmol) and KOH (60 mg, 10.7 mmol) is dissolved in EtOH (8 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more precipitate came out of the water. The precipitate is filtered to give a pure product (146) as white solid (160 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:22]=[C:21]4[C:17]([CH:18]=[C:19]([C:23]5[C:28]([CH3:29])=[CH:27][C:26]([CH2:30][CH2:31][C:32]([O:34]C)=[O:33])=[CH:25][C:24]=5[CH3:36])[NH:20]4)=[CH:16][CH:15]=3)=[N:11][N:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+].C1COCC1>O.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:22]=[C:21]4[C:17]([CH:18]=[C:19]([C:23]5[C:28]([CH3:29])=[CH:27][C:26]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:25][C:24]=5[CH3:36])[NH:20]4)=[CH:16][CH:15]=3)=[N:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)CCc1cc(C)c(-c2cc3ccc(-c4nnc(-c5ccc(OC)cc5)o4)cc3[nH]2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2nnc(-c3ccc4cc(-c5c(C)cc(CCC(=O)O)cc5C)[nH]c4c3)o2)cc1

Procedure:
A mixture of methyl 3-(4-{6-[5-(4-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]-1H-indol-2-yl}-3,5-dimethylphenyl)-propionate (35 mg, 73 pmol) and IN NaOH (174 μL, 174 μmol) in 5 mL of 2:1 water/methanol and 5 mL THF was heated at 50° C. for 4 h. The solvent was removed under reduced pressure and the residue was stirred with water, and neutralized with 174 μL of 1N HCl. The precipitate was filtered, washed with water, and dried to the title compound. H1-NMR (DMSO-d6): δ ppm 12.17 (s, broad, 1H), 11.62 (s, 1H), 8.08 (m, 3H), 7.76 (m, 2H), 7.19 (d, J=8.8 Hz, 2H), 7.06 (s, 2H), 6.46 (s, 1H), 3.88 (s, 3H), 2.82 (t, J=7.4 Hz, 2H), 2.58 (t, J=7.6 Hz, 2H), 2.12 (s, 6H). MS: m/z 468.2 (M+1); Retention time=1.33 min (Method 10). High Res MS (M+H): theory 468.1923, measured 468.1918.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]([CH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18][CH2:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:23]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C([BH3-])#N.[Na+]>C1COCC1.CO>[CH:23]1([NH:22][C@H:19]2[CH2:20][CH2:21][C@H:16]([CH2:15][O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:17][CH2:18]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: N[C@H]1CC[C@H](COc2ccccc2)CC1
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: c1ccc(OC[C@H]2CC[C@H](NC3CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Trans-4-phenoxymethylcyclohexylamine trifluoroacetate (1.2 mmol) is dissolved in a mixture of 4 ml of THF and 4 mL of MeOH in a 20 ml glass vial equipped with a magnetic stirrer and a screw cap. 117 mg of cyclohexanone and 3 g of 3 Å molecular sieves are added. The mixture is stirred for 10 min. after which 2.4 mL of 1N sodiumcyanoborohydride in tetrahydrofuran is added. The reaction stirred 4 days at room temperature then filtered through celite washing through with 30 mL of dichloromethane. The organic phase is washed with 10 mL of water, 10 mL of brine, dried (MgSO4), filtered and concentrated in vacuo to give 300 mg of cyclohexyl-(trans-4-phenoxymethyl-cyclohexyl)-amine.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25])=[C:19]([Cl:30])[CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].[SH:39][C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1.O>CN(C)C=O>[Cl:30][C:19]1[CH:18]=[C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][S:39][C:40]4[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=4)=[C:7]([O:31][CH3:32])[CH:8]=3)[N:13]=[CH:12][N:11]=2)[CH:22]=[CH:21][C:20]=1[NH:23][C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25]
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OCCCBr)c(OC)cc23)cc1Cl
Reactant: Sc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OCCCSc4ccncc4)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
A starting compound (N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)-N′-propyl-urea, 80 mg), potassium carbonate (138 mg), and 4-mercaptopyridine (22 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 60 mg (yield 72%) of the title compound.
Reaction SMILES: [OH:1][C:2]12[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[C:6]1([NH:15][C:16](=[O:18])[CH3:17])[C:5]1[CH:19]=[CH:20][C:21]([CH:23]([CH3:25])[CH3:24])=[CH:22][C:4]=1[O:3]2.CN(C)C>C1COCC1>[C:16]([N:15]([C:6]1([C:5]2[CH:19]=[CH:20][C:21]([CH:23]([CH3:24])[CH3:25])=[CH:22][C:4]=2[OH:3])[C:2](=[O:1])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:14])[C:2](=[O:1])[O:3][CH2:4][CH3:5])(=[O:18])[CH3:17]
Reactant: CC(=O)NC12C(=O)c3ccccc3C1(O)Oc1cc(C(C)C)ccc12
Agent: CN(C)C
Solvent: C1CCOC1
Product: CCOC(=O)N(C(C)=O)C1(c2ccc(C(C)C)cc2O)C(=O)c2ccccc2C1=O
Reaction time: 4 h
Yield: 151 %

Procedure:
N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (0.70 g, 2.07 mmol) was dissolved in anhydrous THF (15 ml). This solution was added with Ethyl chroloformate (0.32 g, 3.11 mmol) and Trimethylamine (0.25 g, 2.48 mmol). The reaction mixture was stirred for 4 hrs. After concentrating in a vacuum to remove THF, and the remainder was diluted with Methylene chrolide and washed with water many times. After drying and filtrating, the organic layer was purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (0.64 g, 71%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][OH:22])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][OH:22])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2n1)c1ccccc1CO
Reactant: OB(O)c1ccc(F)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: O=S(=O)(c1ccc2cc(-c3ccc(F)cc3F)ccc2n1)c1ccccc1CO
Temperature: 90 °C
Yield: 17.1 %

Procedure:
A mixture of {2-[(6-chloroquinolin-2-yl)sulfonyl]phenyl}methanol (Step 2, 157 mg, 0.47 mmol), 2,4-difluorobenzeneboronic acid (173 mg, 1.09 mmol), palladium acetate (6 mg, 0.023 mmol), 2-dicyclohexylphosphino-2′-methylbiphenyl (18 mg, 0.05 mmol) and potassium phosphate (313 mg, 1.47 mmol) was degassed. Toluene (2 mL) was added and the mixture degassed again then heated to 90° C. under nitrogen for 1 hour. The cooled reaction mixture was poured into 1M sodium hydroxide solution and extracted with ethyl acetate (x2). The combined organic layers were washed with brine, dried over MgSO4 and evaporated. The residue was purified by flash column chromatography on silica, eluting with 5-10% ethyl acetate/isohexane, followed by recrystallisation from ethyl acetate/isohexane to give the title compound (33 mg, 17%). 1H NMR (500 MHz, CDCl3) δ 8.46 (1H, d, J=8.5 Hz), 8.27 (1H, d, J=8.5 Hz), 8.20 (1H, d, J=7.9 Hz), 8.16 (1H, d, J=8.9 Hz), 8.02 (1H, s), 7.94 (1H, d, J=8.8 Hz), 7.65-7.59 (2H, m), 7.53-7.47 (2H, m), 7.04-6.96 (2H, m), 5.12 (2H, d, J=7.0 Hz), 4.18 (1H, t, J=7.1 Hz); m/z (ES+) 412 [MH+].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(Cl)(=O)C([Cl:20])=O>ClCCl.CN(C)C=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([Cl:20])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 50 mL round bottom flask, dissolved 4-(4-methylpiperazin-1-yl)benzoic acid (1.00 g, 4.50 mmol) in dichloromethane (5.0 mL). Added oxalyl chloride (1.2 mL, 9.1 mmol) and N,N-dimethylformamide (2 drops). Stirred at RT for 2 hours. Concentrated and isolated 4-(4-methylpiperazin-1-yl)benzoyl chloride as an off-white solid. LC/MS of methyl ester (quenched with methanol) revealed an MS (M+H)+ of 235; Calc'd 234.29 for C13H18N2O2 (methyl ester).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9]C.B(Br)(Br)Br.CO>C(Cl)Cl>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([OH:9])[CH:4]=1
Reactant: COc1cc(N)ccc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc(F)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a mixture of 4-fluoro-3-methoxyaniline (2.0 g, 14.2 mmol) in CH2Cl2 (20 mL) at 0° C. was added 1.0 M solution of BBr3 in CH2Cl2 (40 mL). It was stirred overnight, at which time the temperature was raised to room temperature. To it was added MeOH and the solvents were removed under reduced pressure. To the residue was added water, basified with saturated NaHCO3, and extracted with EtOAc. Extracts were washed with brine, dried over MgSO4, and concentrated under reduced pressure to afford 5-amino-2-fluorophenol as solid (1.3 g, 73%). 1H NMR (300 MHz, DMSO-d6) δ 9.26 (s, 1H), 6.81 (dd, 1H), 6.34 (dd, 1H), 6.04 (dd, 1H), 4.63 (br, 2H).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([NH2:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl>C(OCC)(=O)C>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:18]([NH2:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Yield: 74 %

Procedure:
De-(1,1-dimethylethoxy)carbonylation of Boc-Leu-Phe-NH2 (24.0 g.) was carried out using hydrogen chloride in ethyl acetate (4.4N, 200 ml.) for 2 hr. at room temperature. Upon attempted extraction with ethyl acetate the product unexpectedly entered the saturated aqueous sodium bicarbonate wash solution, which was subjected in its entirety to reverse phase HPLC on octadecylsilated silica gel. The column was washed with water. The product was eluted with methanol and crystallized from ethanol-ether-hexane affording H-Leu-Phe-NH2 as a tan solid (13.0 g., 74% yield, m.r. 127°-131° C.).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32](O)=[O:33])[C:15]=3[N:16]=[C:17]([CH3:19])[N:18]=2)[CH2:3][CH2:2]1.[NH2:35][CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][CH:36]4[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]4)=[O:33])[C:15]=3[N:16]=[C:17]([CH3:19])[N:18]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: Cc1ccc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-2,6-dimethyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c16) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH:14](O)[C@@H:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@@:16]3([C:37]#[N:38])[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]1([CH3:41])[CH3:40])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(C(OS(OC(C(F)(F)F)(C(F)(F)F)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C(F)(F)F)C(F)(F)F)=CC=1>ClCCl>[C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH:13]=[CH:14][C@@H:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@@:16]3([C:37]#[N:38])[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]1([CH3:41])[CH3:40])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@@]2(C#N)[C@@H]3C(O)C[C@H]4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: FC(F)(F)C(OS(OC(c1ccccc1)(C(F)(F)F)C(F)(F)F)(c1ccccc1)c1ccccc1)(c1ccccc1)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@@]2(C#N)[C@@H]3C=C[C@H]4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.7 %

Procedure:
To a solution of 3β-benzoyloxy-14α-cyano-4,4-di-methyl-5α-cholestan-7-ol (100 mg, 0.18 mmole) prepared as in Example 13(iv), in dichloromethane (2.5 mL) held at -78° C. was added Martin sulfurane dehydrating agent (bis [α,α-bis(trifluoromethyl)benzenemethanolato]-diphenyl-sulfur) (240 mg, 0.36 mmole) in dichloromethane (2.5 mL). The mixture was warmed to ambient temperature, stirred for an additional 6 hours, concentrated in vacuo and the residue was triturated with methanol to give 3β-benzoyloxy-14α-cyano-4,4-dimethyl-5α-cholest-6-ene (80 mg, 82%); mp 232°-233° C. (from CH2Cl2/MeOH).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:2]1.I[C:15]1[CH:16]=[C:17]([Cl:21])[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1CCCC1.CCOC(C)=O.Cl[Cu]>[Cl:21][C:17]1[CH:16]=[C:15]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:2]2)[CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cccc2cc[nH]c12
Reactant: Clc1cccc(I)c1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: CN1CCCC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2ccn(-c3cccc(Cl)c3)c12
Temperature: 120 °C
Yield: 35 %

Procedure:
A mixture of methyl 1H-indole-7-carboxylate (0.175 g), 3-iodo-chlorobenzene (0.358 g), Cs2CO3 (0.490 g), CuCl (0.099 g), and 2,2,6,6-tetramethyl-3,5-heptanedione (0.04 mL) in 5 mL of N-methylpyrrolidine was heated at 120° C. for 3 days. The mixture was then diluted with 50 mL of EtOAc and filtered through a pad of silica gel. The filtrate was washed with 3×15 mL of water and dried over Na2SO4. After filtration and concentration, the residue was purified by Combiflash eluted with a gradient of EtOAc/hexane to give 0.1 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:16]=3[N:17]=[C:18]([C:20](O)=[O:21])[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)([N:30]1C=CN=C1)=O.N>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:16]=3[N:17]=[C:18]([C:20](=[O:21])[NH2:30])[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCc1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)nc(C(=O)O)nc2s1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Product: CCc1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)nc(C(N)=O)nc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
4-(4-tert-Butoxycarbonyl-piperazin-1-yl)-6-ethyl-thieno[2,3-d]pyrimidine-2-carboxylic acid (102.3 mg) was dissolved in tetrahydrofuran (0.50 mL) and 1,1′-carbonyl-diimidazole (42.3 mg) was added. The reaction was stirred at room temperature for 30 minutes and ammonia (0.5 M in dioxane, 1.57 mL) was added. The reaction was stirred at room temperature for 8 days and concentrated to dryness. The residue was purified on silica gel (0% to 10% ethyl acetate/hexane over 30 minutes) giving the desired product. Yield=47%, ES-MS: (M+H)+ 392.