Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([P:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28](OC(=O)C)(=[O:30])[CH3:29]>ClCCl.CN(C1C=CN=CC=1)C>[C:15]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[N:13]=[C:12]([NH:14][C:28](=[O:30])[CH3:29])[CH:11]=[CH:10][CH:9]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(P(c2ccccc2)c2ccccc2)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(P(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.9 %

Procedure:
0.10 g (0.36 mmol) of 6-(diphenylphosphino)-2-aminopyridine from example 14.3.1 was dissolved in 2.0 ml of dichloromethane and admixed with 0.05 ml (0.04 g, 0.40 mmol) of triethylamine and a spatula-tip of DMAP. After 0.04 ml (0.04 g, 0.40 mmol) of acetic anhydride had been added, the mixture was stirred at room temperature for 2 h and then the solvent was removed under reduced pressure. The residue was purified by column chromatography with cyclohexane/ethyl acetate (1:1). 0.074 g (0.23 mmol, 63.9%) of 6-(diphenylphosphino)-2-acetylaminopyridine was obtained as a beige-colored solid.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:12][C:13]1[N:14]=[CH:15][S:16][C:17]=1[CH2:18]Br.[H-].[Na+].O>CN(C)C=O.ClCCl>[C:1]1([S:7]([N:10]2[CH2:18][C:17]3[S:16][CH:15]=[N:14][C:13]=3[CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: BrCc1ncsc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1ccccc1)N1Cc2ncsc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.7 %

Procedure:
Benzenesulfonamide (638 mg) and 4,5-bis(bromo-methyl)thiazole (1.10 g) were dissolved in dimethylformamide (10 ml), 60% sodium hydride in oil (357 mg) was added at a time, and the mixture was stirred at room temperature for 3 hours. Water and dichloromethane were added to conduct liquid separation. After the resultant oil layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by column chromatography on silica gel (dichloromethane:ethylacetate=9:1) to obtain the title compound (137 mg) as colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][CH:19]=2)=[C:9](\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH2:10][CH3:11])=[CH:4][CH:3]=1.CCN(CC)CC.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[C:40]([O:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:18]2[CH:19]=[CH:20][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])=[CH:22][CH:23]=2)=[C:9](\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH2:10][CH3:11])=[CH:4][CH:3]=1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC/C(=C(/c1ccc(O)cc1)c1ccc(/C=C/C(=O)OC(C)(C)C)cc1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC/C(=C(\c1ccc(/C=C/C(=O)OC(C)(C)C)cc1)c1ccc(OC(=O)c2ccccc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To a solution of 12 (100 mg, 0.23 mmol) in CH2Cl2 (5 mL) was added Et3N (0.13 mL, 0.94 mmol) followed by the addition of benzoyl chloride (35 mg, 0.24 mmol). The reaction mixture was stirred at RT for 2 hr. The solution was washed with H2O (5 mL) and the organic layer dried (Na2SO4), and concentrated to provide a tan solid. This solid was then purified by chromatography (silica, 1:4 ethyl acetate/hexanes) to provide 19 as a white solid (80 mg, 67%). 1HNMR (400 MHz, DMSO-d6): δ 0.86 (t, 3H), 1.47 (s, 9H), 2.40 (q, 2H), 6.50 (d, J=16 Hz, 1H), 6.89 (d, J=8 Hz, 2H), 6.95 (d, J=8 Hz, 2H), 7.12-7.16 (m, 3H), 7.17-7.22 (m, 4H), 7.53 (d, J=8 Hz, 2H), 7.56 (d, J=16 Hz, 1H), 7.62-7.72 (m, 3H), 8.01 (d, J=8 Hz, 2H).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.[CH3:34][C:35]([CH3:37])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(Cl)Cl>[CH:35]([N:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1)([CH3:37])[CH3:34]
Reactant: CC(C)=O
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N1CC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.4 %

Procedure:
A suspension of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 (215 mg, 0.45 mmol) in dry DCE (4.5 mL) under argon was treated with acetone (49 μL, 0.67 mmol) followed by sodium triacetoxyborohydride (190 mg, 0.89 mmol). The reaction mixture was stirred at RT for 18 hours. Aqueous saturated sodium bicarbonate solution and DCM were added and the phases were separated. The aqueous phase was extracted with DCM (×2) and the combined organic phase was washed with water followed by brine, dried (Na2SO4) and concentrated in vacuo. The resultant solid was triturated with ether, to give 423 as an off-white solid (115 mg, 63%). LCMS: RT=7.44 min, [M+H]+=410. 1H NMR δ (ppm) (CDCl3): 8.30 (1H, d, J=8.17 Hz), 7.89 (1H, s), 7.07 (1H, dd, J=8.20, 1.83 Hz), 6.96 (1H, d, J=1.81 Hz), 5.93-5.84 (1H, m), 4.38 (2H, t, J=5.05 Hz), 3.79 (2H, t, J=7.00 Hz), 3.74-3.63 (1H, m), 3.39 (2H, t, J=5.06 Hz), 3.12 (2H, m), 2.38 (1H, m), 1.60 (6H, d, J=6.63 Hz), 0.97 (6H, d, J=6.21 Hz)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:37]2[CH:42]=[CH:41][C:40]([C:43]3([OH:47])[CH2:46][CH2:45][CH2:44]3)=[C:39]([O:48]C)[N:38]=2)=[CH:19][CH:20]2[N:24](CC3C=CC(OC)=CC=3OC)[C:23](=[O:36])[CH2:22][CH2:21]2)=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]>C1(OC)C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:12]1[CH:13]=[CH:14][C:15]([C:18]([C:37]2[NH:38][C:39](=[O:48])[C:40]([C:43]3([OH:47])[CH2:44][CH2:45][CH2:46]3)=[CH:41][CH:42]=2)=[CH:19][C@H:20]2[CH2:21][CH2:22][C:23](=[O:36])[NH:24]2)=[CH:16][CH:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: COc1ccc(CN2C(=O)CCC2C=C(c2ccc(C(C)(C)C)cc2)c2ccc(C3(O)CCC3)c(OC)n2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(C)(C)c1ccc(C(=C[C@H]2CCC(=O)N2)c2ccc(C3(O)CCC3)c(=O)[nH]2)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of 5-{2-(4-tert-butylphenyl)-2-[5-(1-hydroxycyclobutyl)-6-methoxypyridin-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (EZ mixture) (35 mg) in anisole (1 mL), and the mixture was stirred at 85° C. overnight. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→1:5). The resulting compound was dissolved in 1,4-dioxane (1 mL) and 48% hydrobromic acid (1 mL) was added, after which the mixture was stirred at 65° C. for one hour. Aqueous sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire 19×150 mm 5 μm, rate: 20 mL/min, eluent: A=acetonitrile, B=0.1% trifluoroacetic acid solution, gradient: 10 to 90%) to give one isomer (A) of the title compound (1 mg, 8%) and the other isomer (B) of the title compound (1.0 mg, 8%) as colorless powders.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[NH:21][C:20](=[O:23])[CH:19]=[CH:18]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:24]O>>[C:1]1([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[NH:21][C:20](=[O:23])[CH:19]=[CH:18]3)=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1ccc2cccc(OCCCCSc3ccccc3)c2[nH]1
Reactant: OO
Product: O=c1ccc2cccc(OCCCCS(=O)c3ccccc3)c2[nH]1

Procedure:
Prepared analogous to Example 88 from 8-(4-phenylmercapto-butoxy)-carbostyril by oxidation with hydrogen peroxide.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[C:14]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:13]3[CH3:28])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].C([O-])(=O)C.[Na+].[ClH:38]>C(O)(=O)C.O>[Cl:38][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[C:14]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:13]3[CH3:28])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cl
Reactant: COC(=O)Cc1c(C)n(-c2ncnc3cc(N)ccc23)c2ccc(OC)cc12
Agent: CC(=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)Cc1c(C)n(-c2ncnc3cc(Cl)ccc23)c2ccc(OC)cc12
Reaction time: 1 h

Procedure:
A solution of methyl 1-(7-aminoquinazolin-4-yl)-5-methoxy-2-methylindol-3-ylacetate (0.5g.) in acetic acid (12 ml.) was treated with concentrated hydrochloric acid (1.5 ml.). The solution obtained was stirred at 0°-5° C during the addition, over 15 minutes, of a solution of sodium nitrite (0.15g.) in water (2 ml.). The dark red solution was added dropwise to a solution of cuprous chloride (0.2g.) in concentrated hydrochloric acid (5ml.) kept at room temperature. The mixture was then stirred for 1 hr. before addition of sufficient sodium acetate to adjust the pH of the mixture to 4-5. The mixture was then concentrated in vacuo and the residue treated with water (100ml.) and ethyl acetate (50ml.). The aqueous layer was extracted with ethyl acetate (2 × 30ml.) and the extracts washed with saturated sodium hydrogen carbonate solution (2 × 30ml.). After being washed with water (30ml.) and dried(Na2SO4), evaporation of the extracts in vacuo gave an oil, which slowly solidified to give methyl 1-(7-chloroquinazolin-4-yl)-5-methoxy-2-methyl-indol-3-ylacetate as a yellow solid, m.p. 111°-114° C.
Reaction SMILES: OC(C)(C)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])=[CH:7][N:6]=1.[H-].[Na+]>C1(C)C=CC=CC=1>[C:4]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])=[CH:7][N:6]=1)#[CH:3]
Reactant: CN1CCC[C@H]1c1ccc(C#CC(C)(C)O)nc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C#Cc1ccc([C@@H]2CCCN2C)cn1
Yield: 67 %

Procedure:
Compound 8 (0.12 g, 0.5 mmol) and NaH as a 60% dispersion in mineral oil (0.005 g, 0.13 mmol) were dissolved in dry toluene (10 mL). The stirred solution was slowly distilled until the boiling point of the distillate reached 110° C. The rest of the toluene was evaporated in vacuo. The residue was chromatographed [SiO2, CHCl3/MeOH, (10:1)] to give 0.062 g, (67%) of 9 as a yellow oil.
Reaction SMILES: [C:1]([C:6]1[C:13]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:12][C:9]([CH:10]=O)=[CH:8][C:7]=1[C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:5])[CH2:2][CH2:3][CH3:4].[C:22]([NH:26][OH:27])([CH3:25])([CH3:24])[CH3:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([C:6]1[C:13]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:12][C:9]([CH:10]=[N+:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[O-:27])=[CH:8][C:7]=1[C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Reactant: CC(C)(C)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCC(=O)c1c(C(C)(C)C)cc(C=[N+]([O-])C(C)(C)C)cc1C(C)(C)C
Yield: 50.2 %

Procedure:
To a solution of 4-n-butanoyl-3,5-di-tert-butylbenzaldehyde (9.63 g, 0.032 mol) in benzene (200 mL) was added tert-butylhydroxylamine (3.52 g, 0.040 mol) and p-toluenesulfonic acid (0.100 g). Using a Dean-Stark trap, the resulting solution was refluxed until no more aldehyde was detected by TLC (Rf=0.30 for product and 0.91 for starting material using 3:1 hexanes/EtOAc). The solvent was removed in vacuo and the residue was crystallized from EtOAc and hexanes to afford the titled compound (50.2% yield) as a white solid, m.p. 216.9-236.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([CH3:8])=[CH2:7])=[CH:4][CH:3]=1.[C:11]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:19]2[CH:20]=[C:15]([C:11]([CH3:13])([CH3:12])[CH3:14])[CH:16]=[CH:17][C:18]=2[OH:21])([CH3:8])[CH3:7])=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: C=C(C)c1ccc(Cl)cc1
Product: CC(C)(C)c1ccc(O)c(C(C)(C)c2ccc(Cl)cc2)c1

Procedure:
4-Chloro-α-methylstyrene (50 g) and 45 g of 4-tert-butylphenol are reacted according to the procedure of Example 3 to afford the title compound in a yield of 66.6 g as a colorless oil. The structure is confirmed by 1Hnmr and mass spectroscopy.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1.Cl>C1COCC1>[NH2:11][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([O:5][CH2:4][CH2:3][C:2]([CH3:15])([CH3:14])[CH3:1])=[N:7][CH:8]=1
Reactant: CC(C)(C)CCOc1ccc(C#N)cn1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)CCOc1ccc(CN)cn1
Reaction time: 8 h

Procedure:
Dissolve 6-(3,3-dimethyl-butoxy)-nicotinonitrile (1.4 g, 6.86 mmol) in anhydrous THF (10 mL) under nitrogen and add 1M BH3-THF complex in THF (20.6 mL, 20.6 mmol). Stir the mixture overnight under nitrogen and then pour the reaction carefully into 5N aqueous HCl (20 mL). Stir the resulting suspension for 6 h at room temperature. Then basify by adding 2N aqueous
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[O:10][CH:11]=[CH:12][C:4]=2[CH2:3]1.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1F>>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[O:9][CH:6]1[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]2[CH:12]=[CH:11][O:10][C:5]1=2
Reactant: Fc1cccc(Cl)c1Cl
Reactant: CN1CCC(O)c2occc2C1
Product: CN1CCC(Oc2cccc(Cl)c2Cl)c2occc2C1

Procedure:
The same method as in Example 1 was conducted using 5-methyl-5,6,7,8-tetrahydro-4H-furo[3,2-c]azepin-8-ol (Reference Example 21) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,3-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: Cl[C:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH:14]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:11])[CH2:6][CH2:5]1)=[O:3].[Si]([CH:31]=[N+:32]=[N-:33])(C)(C)C>C1(C)C=CC=CC=1>[N+:32](=[CH:31][C:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH:14]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:11])[CH2:6][CH2:5]1)=[O:3])=[N-:33]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(Cl)C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=CC(=O)C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a stirred solution of (9H-fluoren-9-yl)methyl 4-(chlorocarbonyl)piperidine-1-carboxylate (5 g, 13.6 mmol) in toluene at 0° C. was added TMS-diazomethane (30 mL). This reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure to afford of (9H-fluoren-9-yl)methyl 4-(diazoacetyl)piperidine-1-carboxylate (5 g, 98%) as dark brown liquid.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:27]1[CH2:30][CH:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:28]1>CN(C1C=CN=CC=1)C.CC#N>[C:34]([O:33][C:32](=[O:38])[NH:31][CH:29]1[CH2:30][N:27]([S:23]([C:21]2[CH:20]=[CH:19][C:8]3[N:9]([CH2:10][CH:11]4[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]4)[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][C:7]=3[CH:22]=2)(=[O:25])=[O:24])[CH2:28]1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCC(F)(F)CC2)C1
Yield: 74 %

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (0.41 g, 1.0 mmol), tert-butyl azetidin-3-ylcarbamate (0.17 g, 1.0 mmol) and DMAP (0.37 g, 3.0 mmol) in MeCN (20 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 0.40 g (74%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.33 (s, 9 H), 1.48-1.62 (m, 2 H), 1.64 (s, 9 H), 1.67-1.87 (m, 4 H), 1.98-2.15 (m, 2 H), 2.19-2.35 (m, 1 H), 3.62 (t, J=7.03 Hz, 2 H), 3.96 (t, J=8.11 Hz, 2 H), 4.05-4.16 (m, 1 H), 4.51 (d, J=7.42 Hz, 2 H), 7.86 (dd, J=9.18, 1.17 Hz, 1 H), 7.98 (d, J=8.79 Hz, 1 H), 8.14 (d, J=1.56 Hz, 1 H); MS (ESI) (M+H)+=541.3; Anal. Calcd for C26H38F2N4O4S+1.00 TFA+0.20 EtOAc (674.72): C, 51.62; H, 6.07; N, 8.30. Found: C, 51.73; H, 5.94; N, 8.27.
Reaction SMILES: [F:1][C:2]([F:25])([C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3]([NH2:5])=[O:4].[CH3:26][Si:27]([CH3:30])([CH3:29])Cl.CCCCCCCCCCCCCCCC>CCCCCC>[CH3:26][Si:27]([CH3:30])([CH3:29])[N:5]([Si:27]([CH3:30])([CH3:29])[CH3:26])[C:3](=[O:4])[C:2]([F:25])([F:1])[C:6]([F:23])([F:24])[C:7]([F:21])([F:22])[C:8]([F:19])([F:20])[C:9]([F:17])([F:18])[C:10]([F:15])([F:16])[C:11]([F:14])([F:13])[F:12]
Reactant: C[Si](C)(C)Cl
Reactant: NC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCCCCC
Solvent: CCCCCCCCCCCCCCCC
Product: C[Si](C)(C)N(C(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)[Si](C)(C)C

Procedure:
First, perfluorooctaneamide (CF3(CF2)7CONH2) (46 g) was dissolved in n-hexane (300 ml). Thereafter, trimethylchlorosilane (15 ml) was dropped gradually into the solution obtained above, in a dry nitrogen atmosphere. Then this was allowed to react for two hours while being stirred. After the reaction was completed, hexadecane contained in the reaction solution was removed with the evaporator. Thus, N,N-bis(trimethylsilyl)perfluorooctaneamide was obtained.
Reaction SMILES: [CH2:1]([C:7]1[CH:20]=[CH:19][C:10]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][C:8]=1[N+:21]([O-])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.NN>C(O)C.[Pd]>[NH2:21][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:7]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:11]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[O:12]
Reactant: CCCCCCc1ccc(C(=O)N2CCOCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CCCCCCc1ccc(C(=O)N2CCOCC2)cc1N
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
The compound ([5]-(54)-75) (700 mg) prepared in Example 62 was dissolved in ethanol (35 ml). After the solution was heated to 50° C., a suspension of 10% Pd/C (70 mg) in ethanol was added, and hydrazine monohydrate (0.35 ml) was added to the solution. The solution was stirred at 50° C. for 30 minutes. After the reaction was completed, the solution was filtered through celite 545 to remove the catalyst. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Kieselgel 60=20 g, ethyl acetate) to obtain the above-captioned compound ([5]-(55)-75) (631 mg) as colorless oil.
Reaction SMILES: C([O-])C.[Na+].OC1C=C(C=C([N+]([O-])=O)C=1C1C=CC=CC=1)C(OCC)=O.C(I)C.[CH2:29]([O:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([N+:47]([O-:49])=[O:48])[C:40]=1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]([O-:37])=[O:36])[CH3:30].[Na+]>C(O)C>[CH2:29]([O:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([N+:47]([O-:49])=[O:48])[C:40]=1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]([OH:37])=[O:36])[CH3:30]
Reactant: CCOc1cc(C(=O)[O-])cc([N+](=O)[O-])c1-c1ccccc1
Agent: CCOC(=O)c1cc(O)c(-c2ccccc2)c([N+](=O)[O-])c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCI
Solvent: CCO
Product: CCOc1cc(C(=O)O)cc([N+](=O)[O-])c1-c1ccccc1

Procedure:
To a solution of sodium ethanolate (prepared from 0.5 g of sodium) in dry ethanol (40 ml), ethyl 3-hydroxy-5-nitro-4-phenylbenzoate (4.4 g) is added followed by ethyl iodide (2.5 ml), and the resulting solution is refluxed for 20 hours. After about 6 hours an additional amount of sodium ethanolate (prepared from 0.25 g of sodiumn) in dry ethanol (10 ml) is added followed by ethyl iodide (1.3 ml). The mixture is evaporated in vacuo, 2 N sodium hydroxide (25 ml) is added to the residue, and the mixture is heated on a steam bath for 30 minutes to form a clear solution. On cooling, sodium 3-ethoxy-5-nitro-4-phenylbenzoate separates. It is collected by filtration, and washed with a small amount of icecold water. After drying, the sodium salt is dissolved in hot water (50 ml), and the 3-ethoxy-5-nitro-4-phenylbenzoic acid is precipitated by addition of 4 N hydrochloric acid (5 ml). After cooling, the acid is collected by filtration, washed with water and dried. After recrystallization from aqueous ethanol, it is obtained with a melting point of 174°-176° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:25][CH3:26])[C:15]2[C:20]([CH:21]=[C:22](C)[CH3:23])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:44]([OH:46])=O>[OH-].[OH-].[Pd+2]>[NH:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:44]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:25][CH3:26])[C:15]2[C:20]([CH2:21][CH2:22][CH3:23])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:46]
Reactant: CCN(c1ncccc1C=C(C)C)C1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1ccc[nH]1
Agent: [Pd+2]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [OH-]
Product: CCCc1cccnc1N(CC)C1CCN(C(=O)c2ccc[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 20 and making non-critical variations but starting with 1-benzyl-4-[N-ethyl-N-(3-(1-propenyl)-2-pyridinyl)amino]piperidine (XXII, EXAMPLE 19, 0.40 g, 1.20 mmol), Pearlman's catalyst (0.1 g), CDI (0.39 g, 2.4 mmol), and pyrrole-2-carboxylic acid (0.27 g, 2.4 mmol), the title compound is obtained, mp 115°-116°.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[N:6][NH:5][C:4](=[O:11])[C:3]=1[C:12]([O:14]CC)=O.[Na+].[NH2:18][CH2:19][C:20]([O-:22])=[O:21].Cl>COCCO.O>[OH:1][C:2]1[C:7]([CH:8]([CH3:9])[CH3:10])=[N:6][NH:5][C:4](=[O:11])[C:3]=1[C:12]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:14]
Reactant: NCC(=O)[O-]
Reactant: CCOC(=O)c1c(O)c(C(C)C)n[nH]c1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: COCCO
Product: CC(C)c1n[nH]c(=O)c(C(=O)NCC(=O)O)c1O
Temperature: 130 °C
Yield: 72 %

Procedure:
To a 100 mL round bottom flask was added ethyl 5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate (example 14(a), 55 mg, 0.243 mmol) and Glycine Sodium Salt (59.0 mg, 0.608 mmol) in 2-methoxyethanol (10 ml) and the mixture was refluxed at 130° C. for 2 hours. The mixture was diluted with water (10 ml) and acidified with 1N HCl. The aqueous solution was then extracted with ethyl acetate (40 mL), organics dried over MgSO4, filtered and solvents removed by evaporation. The crude oil was purified by HPLC chromatography (ODS silica, gradient 25-95% acetonitrile/water (0.1% TFA)) to afford the title compound, N-{[5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (45 mg, 0.175 mmol, 71.8% yield), as a white solid. 1H NMR (400 MHz, DMSO-d6) d ppm 15.74 (br. s., 1H), 13.07 (s, 1H), 10.19 (t, J=5.68 Hz, 1H), 4.11 (d, J=5.81 Hz, 2H), 3.14 (sept, J=6.82 Hz, 1H), 1.17 (d, J=6.82 Hz, 6H). MS (ES+) m/e 256 [M+H]+.