Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:9][CH2:8][C:5]2([CH2:7][CH2:6]2)[CH:4]=[C:3]1[C:10]#[N:11].N#N>CO.[Pd]>[O:1]=[C:2]1[CH2:9][CH2:8][C:5]2([CH2:6][CH2:7]2)[CH2:4][CH:3]1[C:10]#[N:11]
Reactant: N#CC1=CC2(CCC1=O)CC2
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: N#CC1CC2(CCC1=O)CC2
Reaction time: 16 h

Procedure:
6-Oxospiro[2.5]oct-4-ene-5-carbonitrile (0.16 g, 1.1 mmol) was dissolved in MeOH (11 mL) and combined with 10% palladium on activated carbon (0.12 g, 0.11 mmol). The resulting mixture was subjected to alternating vacuum and H2 gas (4×). The mixture was then stirred under an atmosphere of H2 (50 psi) for 16 hours. The mixture was then subjected to alternating vacuum and N2 gas (4×). The mixture was filtered through celite and rinsed with MeOH. The filtrate was concentrated in vacuo to afford the title compound. The material was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:3]=1[C:4]([NH:6][C@@H:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH2:28][O:29][CH2:30][CH3:31])=[CH:22][C:21]=2[O:32][CH3:33])=[CH:16][CH:15]=1)[C:8]([O:10]CC)=[O:9])=[O:5].Cl>O.O1CCOCC1>[F:1][C:2]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:3]=1[C:4]([NH:6][C@@H:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21]([O:32][CH3:33])=[CH:22][C:23]([CH2:28][O:29][CH2:30][CH3:31])=[CH:24][C:25]=2[O:26][CH3:27])=[CH:18][CH:19]=1)[C:8]([OH:10])=[O:9])=[O:5]
Reactant: CCOCc1cc(OC)c(-c2ccc(C[C@H](NC(=O)c3c(F)cccc3F)C(=O)OCC)cc2)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCOCc1cc(OC)c(-c2ccc(C[C@H](NC(=O)c3c(F)cccc3F)C(=O)O)cc2)c(OC)c1
Temperature: 60 °C
Reaction time: 60 h
Yield: 90 %

Procedure:
To a solution of ethyl (αS)-α-[(2,6-difluorobenzoyl)amino]-4′-ethoxymethyl-2′,6′-dimethoxy(1,1′-biphenyl)-4-propionate (500 mg) in water (12.6 ml) and dioxane (50 ml) was added hydrochloric acid (12.4 g) and the mixture was stirred for 60 hours at 60° C. The organic solvent was removed in vacuo and the aqueous layer was cooled. The crystalline precipitates were collected by filtration and recrystallized from ethanol-water to yield (αS)-α-[(2,6-difluorobenzoyl)amino]-4′-ethoxymethyl-2′,6′-dimethoxy(1,1′-biphenyl)-4-propionic acid (426 mg). The physicochemical data were the same as that obtained in Example 1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26](OC)=[O:27])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>C1COCC1.C(OCC)C>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][OH:27])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: COC(=O)c1ccccc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2CO)CC1
Reaction time: 1 h
Yield: 63.7 %

Procedure:
Lithium aluminium hydride (0.026 g, 0.7 mmol) was suspended in dry THF (1 mL) under a nitrogen atmosphere and cooled in an ice bath. A solution of 4-(2-methoxycarbonyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.27 g, 0.7 mmol) in dry THF (2 mL) was added drop wise and the reaction mixture stirred for 1 hour. The reaction mixture was diluted with diethyl ether (5 mL) and quenched with hydrochloric acid (1 N, 5 mL). The organic solution was separated and washed with saturated aqueous sodium hydrogen carbonate (5 mL) and brine (5 mL), dried over magnesium sulphate, filtered and the solvent removed under vacuum to give the title compound as a colourless gum (0.13 g). LCMS m/z 292.0 [M+H]+. R.T.=4.57 min (Analytical Method 4).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([F:15])([F:14])[F:13])[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][C:7]=2[CH:21]=1)=[O:2].C[Si](C)(C)[C:24]([F:27])([F:26])[F:25].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:2][CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([F:15])([F:14])[F:13])[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][C:7]=2[CH:21]=1)[C:24]([F:27])([F:26])[F:25]
Reactant: CCOC(=O)C1=Cc2cc(C=O)ccc2OC1C(F)(F)F
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CCOC(=O)C1=Cc2cc(C(O)C(F)(F)F)ccc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 21.1 h
Yield: 91.8 %

Procedure:
The aldehyde (Example 75, Step 1) (0.89 g, 3.0 mmol) was cooled to 0° C. and treated with a 0.5 M solution of trimethyl(trifluoromethyl)silane (8.4 mL, 4.2 mmol) and four drops of a 1.0 M solution of tetrabutylammonium fluoride was added. The reaction was allowed to warm to room temperature and stirred for 21.1 hours. The reaction was quenched with 3 N HCl, extracted with ethyl acetate, washed with water, brine, dried over MgSO4, and concentrated in vacuo to give a brown oil (1.02 g). This oil was purified by flash chromatography over silica gel, eluting with 10% ethyl acetate/hexanes to afford a brown oil (0.77 g, 58%): 1H NMR (CDCl3/300 MHz) 7.72 (d, 1H, J=3.4 Hz), 7.34 (m, 2H), 6.99 (d, 1H, J=8.5 Hz), 5.71 (q, 1H, J=6.8 Hz), 4.83 (q, 1H, J=6.4 Hz), 4.33 (m, 2H), 1.35 (t, 3H, J=7.1 Hz), 0.11 (s, 9H). FABLRMS m/z 443 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[CH:11](O)=O>>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[NH:9][CH:11]=[N:10][C:4]=2[CH:3]=1
Reactant: O=CO
Reactant: Nc1cc(F)c(Br)cc1N
Product: Fc1cc2[nH]cnc2cc1Br

Procedure:
A mixture of 98 (600 mg, 2.93 mmol) in formic acid (5.0 mL) was heated to reflux overnight. The reaction mixture was concentrated in vacuo to afford a brown oil that was partitioned between EtOAc (300 mL) and a sat'd. aq. NaHCO3 (100 mL). The organic layer was separated, dried (MgSO4), filtered and evaporated in vacuo to afford 550 mg (87%) of 5-bromo-6-fluoro-1H-benzo[d]imidazole (100) as white solid (550 mg, 87%): MS (ESI) m/z=215 [M+1]+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[O:29][CH:30]=[CH:31][N:32]=3)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.Cl.O1CCOCC1>>[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[O:29][CH:30]=[CH:31][N:32]=3)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(-c3ncco3)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: c1coc(-c2ccc(Cc3ccc(OC[C@H]4CCCN4)cc3)cc2)n1
Yield: 89.7 %

Procedure:
The title compound (15 mg, 80%) was prepared from the product of step 1 (20 mg, 0.05 mmol) and 4M HCl in dioxane (0.12 ml, 0.5 mmol) using the procedure of Example 146, step 4; 1HNMR (400 MHz, CD3OD) δ 8.0 (s, 1H), 7.93 (d, J=38.4 Hz, 2H), 7.34 (d, s, J=8.4 Hz, 3H), 7.19 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 4.32 (dd, J=10.4, 3.6 Hz, 1H), 4.10 (m, 1H), 4.32 (m, 2H), 4.10 (m, 1H), 3.94 (s, 2H), 3.36 (m, 2H), 2.25 (m, 1H), 2.10 (m, 2H), 1.90 (m, 1H); LC/MS (APCI+) 90%, 335 (M+1, 100).
Reaction SMILES: [N:1]([CH:4]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[N:14]([CH2:17][C@@H:18]([NH:20]C(=O)OCC2C=CC=CC=2)[CH3:19])[N:13]=[CH:12]3)[O:7][CH2:6][CH:5]1Br)=[N+]=[N-].C[OH:33]>[Pd]>[NH2:1][CH:4]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[N:14]([CH2:17][C@@H:18]([NH2:20])[CH3:19])[N:13]=[CH:12]3)[O:7][CH2:6][CH:5]1[OH:33]
Reactant: CO
Reactant: C[C@@H](Cn1ncc2ccc3c(c21)C(N=[N+]=[N-])C(Br)CO3)NC(=O)OCc1ccccc1
Agent: [Pd]
Product: C[C@H](N)Cn1ncc2ccc3c(c21)C(N)C(O)CO3
Reaction time: 18 h
Yield: 96 %

Procedure:
The product from step B (0.26 g, 0.30 mmol) and Pd/C (10%, 0.026 g) were mixed with methanol (5 mL) and placed under a hydrogen atmosphere for 18 h. The mixture was filtered and evaporated to give a yellowish solid (0.155 g, 96%): mp 84-88° C.; LC/MS (+APCI) m/z 263 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[NH2:18][C@@H:19]([CH3:35])[CH2:20][N:21]1[CH:25]=[CH:24][C:23]([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([Cl:34])[CH:27]=2)=[N:22]1>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:18][C@@H:19]([CH3:35])[CH2:20][N:21]2[CH:25]=[CH:24][C:23]([C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([Cl:34])[CH:27]=3)=[N:22]2)=[O:9])=[N:6][CH:7]=1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(Cl)c1cnc(Cl)cn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cnc(Cl)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.4 %

Procedure:
5-Chloropyrazine-2-carbonyl chloride (3.28 mmol, 580 mg) was dissolved in dry THF (40 ml). Triethylamine (9.83 mmol, 995 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (3.28 mmol, 854 mg) were added and the resulting mixture was stirred for one day at RT. The crude product was purified by recrystallization from DCM. 900 mg of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.25 (d, 3H), 4.29 (dd, 1H), 4.47 (dd, 1H), 4.59-4.71 (m, 1H), 6.66 (d, 1H), 7.51 (d, 1H), 7.68-7.73 (m, 1H), 7.75-7.80 (m, 1H), 8.12 (d, 1H), 8.64 (d, 1H), 8.77 (d, 1H), 9.17 (d, 1H).
Reaction SMILES: [CH2:1]1[CH2:5]O[CH2:3][CH2:2]1.[OH:6][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([N:10]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:8]1)[CH2:14]2.[H-].[K+].C1(CBr)CC1>CCOC(C)=O>[CH:1]1([CH2:5][O:6][C:7]23[CH2:8][CH:9]4[CH2:15][CH:13]([CH2:12][CH:11]([N:10]4[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16]2)[CH2:14]3)[CH2:3][CH2:2]1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1C2CC3CC1CC(O)(C3)C2
Agent: BrCC1CC1
Agent: [H-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C2CC3CC1CC(OCC1CC1)(C3)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A 15 mL seal tube fitted with magnetic stirrer was charged with 5 mL of THF, tert-butyl 5-hydroxy-2-azatricyclo[3.3.1.13,7]decane-2-carboxylate, Intermediate-6 (50 mg, 0.2 mmol). To the tube, potassium hydride (20 mg, 0.5 mmol) was added at 0° C., under N2 atm. The reaction mass was stirred at room temperature for 30 minutes. To this mixture, cyclopropyl methyl bromide (40 mg, 0.3 mmol) was slowly added at 0° C. and the resulting reaction mass was refluxed at 60° C. under sealed condition for 12 hrs. After completion of the reaction (reaction was monitored by TLC), reaction mixture was quenched with cold water and extracted with ethyl acetate (25 ml×3). The organic layer was washed with sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give crude Intermediate-17, which was subjected to column chromatogram (18% EtOAc in PE) to obtain an oily mass (50 mg, yield=80%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([N:15]=[C:14]([CH3:16])[C:13](=S)[NH:12]3)[CH2:10][CH2:9][O:8][C:5]2=[CH:6][CH:7]=1.[NH3:18]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([N:12]=[C:13]([NH2:18])[C:14]([CH3:16])=[N:15]3)[CH2:10][CH2:9][O:8][C:5]2=[CH:6][CH:7]=1
Reactant: N
Reactant: CC1=NC2(CCOc3ccc(Br)cc32)NC1=S
Solvent: CO
Product: CC1=NC2(CCOc3ccc(Br)cc32)N=C1N
Temperature: 60 °C
Yield: 77 %

Procedure:
6-Bromo-4′-methylspiro[chroman-4,2′-imidazole]-5′(1′H)-thione (0.10 g, 0.32 mmol, Intermediate 3) was dissolved in MeOH (1 mL) and 7M ammonia in MeOH (4 mL, 28 mmol) was added. The solution was heated at 60° C. for 12 h in a sealed vial. The solution was evaporated in vacuo. The treatment with 7M ammonia was repeated in the same way one more time. Evaporation in vacuo gave the title compound (73 mg, 77% yield) which was used without further purification in the following step. 1H NMR (400 MHz, CDCl3) δ ppm 2.11 (m, 2 H), 2.35 (s, 3 H), 4.53 (m, 2 H), 4.98 (br s, 2 H), 6.66 (m, 1 H), 6.78 (d, 1 H), 7.22 (m, 1 H); MS (ES+) m/z 294 [M+H]+.
Reaction SMILES: [CH3:1]C1C=C(O)C=CC=1O.CC1C(C)=C(C=CC=1O)O.[CH3:20][C:21]1[C:22]([OH:30])=[C:23]([CH3:29])[C:24]([CH3:28])=[C:25]([CH:27]=1)[OH:26]>[Fe].CO>[CH3:20][C:21]1[C:22]([OH:30])=[C:23]([CH3:29])[C:24]([CH3:28])=[C:25]([OH:26])[C:27]=1[CH3:1]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: Cc1cc(O)ccc1O
Agent: [Fe]
Agent: Cc1c(O)ccc(O)c1C
Solvent: CO
Product: Cc1c(C)c(O)c(C)c(C)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into an autoclave (inner volume: 9 ml, made of SUS 316, equipped with a manometer) were charged 0.104 g of methylhydroquinone, 3.4078 g of methanol and 8.3 mg of iron powders (manufactured by Wako Pure Chemical Ind., Ltd.). The reaction was started by elevating the temperature up to 350° C. with sand bath. The pressure during the reaction was 20 MPa. After 2 hours, the autoclave was quickly cooled and the reaction solution was taken out from the autoclave when the temperature was cooled back to the room temperature. The measurement according to the process described above revealed that the conversion of methylhydroquinone was 16% by mole, the selectivity of dimethylhydroquinone was 82% by mole and the selectivity of trimethylhydroquinone was 3% by mole. No tetramethylhydroquinone was produced.
Reaction SMILES: Cl[C:2]1[C:3]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[CH3:17][OH:18].[OH-].[K+]>CS(C)=O>[CH3:17][O:18][C:2]1[C:3]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1
Reactant: Nc1cc(Cl)c(-n2cccc2)cc1[N+](=O)[O-]
Reactant: CO
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(N)c([N+](=O)[O-])cc1-n1cccc1

Procedure:
The title compound was prepared from 5-chloro-2-nitro-4-pyrrol-1-yl-phenylamine (Example F3) (5.94 g, 25 mmol), methanol (25 mL) and KOH (1.98 g, 30 mmol) in DMSO (25 mL) according to the general procedure E. Obtained as an orange solid (5.88 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:19])=[C:6]([C:8](=[O:18])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH:7]=1.[OH-].[Na+]>O.CCO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:19][CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:9][C:8]2=[O:18]
Reactant: O=C(C=Cc1cccc(Cl)c1)c1cc(Br)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1CC(c2cccc(Cl)c2)Oc2ccc(Br)cc21
Reaction time: 8 h
Yield: 82 %

Procedure:
1-(5-Bromo-2-hydroxyphenyl)-3-(3-chlorophenyl)prop-2-en-1-one (23 g, 68 mmol) was dissolved in H2O (513 mL) and EtOH (171 mL). Then NaOH (2.74 g, 68 mmol) was added. The mixture was stirred overnight and filtered. The solid was dissolved in EtOAc and washed with H2O twice. The organic layer was dried and filtered. The filtrate was concentrated to give 6-bromo-2-(3-chlorophenyl)chroman-4-one (18.82 g, 82%). 1H-NMR (CDCl3): 2.87 (m, 1H), 3.02 (m, 1H), 5.44 (m, 1H), 6.96 (d, 1H), 7.31 (m, 1H), 7.37 (m, 2H), 7.48 (s, 1H), 7.58 (m, 1H), 8.02 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C:17](=O)[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:14]=3)[C:9]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:8]2[CH2:32][C:33]([CH3:39])([CH3:38])[C:34]([O:36]C)=[O:35])=[CH:4][CH:3]=1.ClC1C=C[C:46]([CH2:47][N:48]2C3C(=CC(OC(=O)C4C=CC=CC=4)=CC=3)C(C(=O)C3C=CC=CC=3)=C2CC(C)(C)C(OC)=O)=[CH:45]C=1>>[Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]5[C:47](=[CH:46][CH:45]=[CH:19][CH:20]=5)[N:48]=4)=[CH:13][CH:14]=3)[C:9]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:8]2[CH2:32][C:33]([CH3:39])([CH3:38])[C:34]([OH:36])=[O:35])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Cc1c(Cc2ccccc2)c2cc(OC(=O)c3ccccc3)ccc2n1Cc1ccc(Cl)cc1
Reactant: COC(=O)C(C)(C)Cc1c(C(=O)c2ccccc2)c2cc(OC(=O)c3ccccc3)ccc2n1Cc1ccc(Cl)cc1
Product: CC(C)(Cc1c(Cc2ccccc2)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)O

Procedure:
The title compound was prepared under the conditions described in Step B and Step C of Example 9 but substituting the ester from Example 10 (Step A) for the ester of Example 9 (Step A), m.p. 178° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15]CC2C=CC=CC=2)=[CH:6][CH:5]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(OCCCCOCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(OCCCCO)cc1
Yield: 92.8 %

Procedure:
2.7 g (8.6 mmol) of 4-(4-benzyloxy-butoxy)-benzoic acid methyl ester were dissolved in 15.0 ml of methanol. 0.3 g palladium on charcoal (10%) were added and the reaction mixture hydrogenated at normal pressure until the consumption of hydrogen came to an end. Then, it was filtered over celite and evaporated giving 1.79 g (93%) of 4-(4-hydroxy-butoxy)-benzoic acid methyl ester as colorless solid, MS: 224 (M+).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[C:5]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)(=[O:8])[CH2:6][CH3:7]>C1(C)C=CC=CC=1>[Cl:4][C:1]([N:12]1[CH2:13][CH2:14][N:9]([C:5](=[O:8])[CH2:6][CH3:7])[CH2:10][CH2:11]1)=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CCC(=O)N1CCNCC1
Solvent: Cc1ccccc1
Product: CCC(=O)N1CCN(C(=O)Cl)CC1
Temperature: -5 °C
Yield: 98.8 %

Procedure:
A solution of phosgene (45.0 g.) in anhydrous toluene (500 cm3) and 1-propionylpiperazine (129.0 g.) are added simultaneously to anhydrous toluene (500 cm3), while the temperature is maintained at about -5° C. 1-Chlorocarbonyl-4-propionylpiperazine (92.0 g.), m.p. about 45° C., is thus obtained. After one hour's stirring at 2° C., the 1-propionylpiperazine hydrochloride formed is separated by filtration and, after evaporation of the filtrate under reduced pressure (20 mm.Hg) 1-chlorocarbonyl-4-propionyl-piperazine is obtained.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[N:14]=2)[CH2:7]1)(=O)=O.[C:23]([O-:26])(=[S:25])[CH3:24].[K+]>CN(C)C=O>[C:23]([S:25][CH:6]1[CH2:7][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)=[O:16])[N:14]=2)[CH2:9]1)(=[O:26])[CH3:24]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CCCCC3)cs2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N3CCCCC3)cs2)C1
Temperature: 90 °C
Reaction time: 4 h
Yield: 84.8 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-(4-piperidinocarbonyl-1,3-thiazol-2-yl)azetidine (346 mg, 1.00 mmol) (obtained as described in Reference Example 27(3)) in dimethylformamide (15 ml) was added potassium thioacetate (687 g, 6.01 mmol) at room temperature. The reaction mixture was stirred in an oil bath (90° C.) for 4 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-acetylthio-1-(4-piperidinocarbonyl-1,3-thiazol-2-yl)azetidine (276 mg, yield 85%) as a pale brown solid.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:7][CH2:6]1.[CH2:28]([NH:31][CH3:32])[CH:29]=[CH2:30]>CN(C)C(=O)C>[CH2:28]([N:31]([CH3:32])[CH2:2]/[CH:3]=[CH:4]/[C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:7][CH2:6]1)[CH:29]=[CH2:30]
Reactant: C=CCNC
Reactant: CN(CC[C@H]1CC[C@H](/C=C/CCl)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)N(C)C
Product: C=CCN(C)C/C=C/[C@H]1CC[C@H](CCN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-N-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with N-allyl-methyl-amine in N,N-dimethylacetamide at room temperature to yield trans-N-(2-{4-[3-(allyl-methyl-amino)-(E)-propenyl]-cyclohexyl}-ethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless viscous oil, MS: 459 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[Br:13]Br>C(Cl)Cl>[Br:13][C:9]1[CH:10]=[C:11]([CH3:12])[C:2]([OH:1])=[CH:3][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: BrBr
Reactant: COC(=O)c1ccc(C)c(O)c1
Solvent: ClCCl
Product: COC(=O)c1cc(O)c(C)cc1Br
Reaction time: 8 h

Procedure:
A solution of 1 g (6 mmoles) of the ester from step a. dissolved in 10 ml of dry CH2Cl2 and cooled in an ice bath was treated dropwise with 0.96 g (6 mmoles) of Br2 in 2 ml CH2Cl2. The reaction flask was sealed and stored at -15° overnight. Gentle swirling of the reaction solution induced crystallization of fine white needles that were collected by filtration and washed with cold CH2Cl2 /hexanes.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:37])[C@:4]1([OH:36])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@:18]([F:24])([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:25])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH2:29].ClC1C=CC=C(C(OO)=[O:46])C=1>ClCCl>[Cl:1][CH2:2][C:3](=[O:37])[C@:4]1([OH:36])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@:18]([F:24])([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:25])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:26][CH2:27][C:28]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:29][O:46]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CCl)c1ccccc1
Solvent: ClCCl
Product: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](OCC4(c5ccccc5)CO4)[C@](O)(C(=O)CCl)[C@@]3(C)C[C@H](O)[C@@]12F
Yield: 116.5 %

Procedure:
A solution of 4.0 g of 21-chloro-9-fluoro-11β,17-dihydroxy-16α-[(2-phenyl-2-propenyl)oxy]pregna-1,4-diene-3,20-dione in 100 ml of dichloromethane is stirred with 1.6 g of m-chloroperbenzoic acid for 1 hour at room temperature. The resulting solution is washed with a mixture of 100 ml each of 5% sodium sulfite solution and 5% sodium bicarbonate solution, dried, and evaporated in vacuo to give 4.8 g of crude 21-chloro-9-fluoro-11β,17-dihydroxy-16α-[(2-phenyloxiranyl)methoxy]pregna-1,4-diene-3,20-dione.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25]OS(C)(=O)=O)[O:22][C:21]3=[O:31])=[CH:16][C:15]=2[F:32])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:33]=[N+:34]=[N-:35])[O:22][C:21]3=[O:31])=[CH:16][C:15]=2[F:32])[CH2:12][CH2:13]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of (R)-(−)-4-[4-[5-[[(methylsulfonyl)oxy]methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 20, Step 6, 13.83 g) and sodium azide (7.62 g) in dry dimethylformamide (117 mL) under N2 is stirred at 60° C. for five hours and at ambient temperature for 16 hours. The mixture is then diluted with ethyl acetate (200 mL), washed with water (8×100 mL) and saline (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound, mp 109-110° C.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[CH:4][C:3]=1Cl.NC1C=CC(O)=CC=1[Cl:27]>>[NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[C:4]([Cl:27])[CH:3]=1
Reactant: Nc1ccc(O)cc1Cl
Reactant: NC(=O)c1cc(Oc2ccc(N)c(Cl)c2)ccn1
Product: NC(=O)c1cc(Oc2ccc(N)cc2Cl)ccn1

Procedure:
The title compound was prepared in the same manner described for 4-(4-amino-3-chloro-phenoxy)pyridine-2-carboxamide, substituting 4-aminophenol for 4-amino-3-chlorophenol. 1H-NMR (DMSO-d6) δ 8.43 (d, J=5.7 Hz, 1H), 8.07 (broad s, 1H), 7.66 (broad s, 1H), 7.31 (d, J=2.7 Hz, 1H), 7.07 (dd, J=5.7 Hz, 2.7 Hz, 1H), 6.85 (d, J=9.0 Hz, 2H), 6.62 (d, J=8.7 Hz, 2H), 5.17 (broad s, 2H).