Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(N2C3C=CC(C4NN=NN=4)=CC=3OC3C2=CC=CC=3)CC1)=O)(C)(C)C.[C:66]([OH:72])([C:68]([F:71])([F:70])[F:69])=[O:67].Cl>C(Cl)Cl>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:28]4[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=4)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][CH2:13]1.[C:66]([OH:72])([C:68]([F:71])([F:70])[F:69])=[O:67]
Reactant: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(-c4ccncc4)ccc32)CC1
Agent: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(-c4nnn[nH]4)ccc32)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c(c1)Oc1cc(-c3ccncc3)ccc1N2C1CCNCC1

Procedure:
Using an adaptation of the method described in Procedure 6, substituting 4-(3-pyridin-4-yl-phenoxazin-10-yl)-piperidine-1-carboxylic acid tert-butyl ester, 1k, for 4-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-piperidine-1-carboxylic acid tert-butyl ester, 5a, and a mixture of TFA in methylene chloride for a 4N hydrochloric acid solution, the title compound 10-piperidin-4-yl-3-pyridin-4-yl-10H-phenoxazine, 2k, was obtained as a TFA salt after purification via reverse phase HPLC (eluent gradient: CH3CN in water containing 0.1% TFA). MS m/z (MH+) 344.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:16]([Br:17])=[CH:15][C:8]([C:9](N(OC)C)=[O:10])=[C:7]([Cl:18])[CH:6]=1)[CH:2]=[CH2:3].[CH2:19]([C:21]1[CH:26]=[CH:25][C:24]([Mg]Br)=[CH:23][CH:22]=1)[CH3:20].[NH4+].[Cl-]>C1COCC1>[CH2:1]([O:4][C:5]1[C:16]([Br:17])=[CH:15][C:8]([C:9]([C:24]2[CH:25]=[CH:26][C:21]([CH2:19][CH3:20])=[CH:22][CH:23]=2)=[O:10])=[C:7]([Cl:18])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: CCc1ccc([Mg]Br)cc1
Reactant: C=CCOc1cc(Cl)c(C(=O)N(C)OC)cc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCOc1cc(Cl)c(C(=O)c2ccc(CC)cc2)cc1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.5 %

Procedure:
To solution of Weinreb amide 22 (4.5 g, 13.4 mmol) in THF (100 mL) was added 4-ethylphenylmagnesium bromide (0.5 M in THF, 50.8 mL, 26.9 mmol) at 0° C. The reaction mixture was warmed up to r.t. slowly and stirred at r.t. for 15 hours. To the reaction mixture was added aqueous saturated NH4Cl solution (100 mL). The mixture was extracted with EtOAc (100 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with hexane (100 mL) and stirred at r.t. for 30 min. The solid was precipitated, filtered, washed with hexane (50 mL) and dried under high vacuum to obtain the title product (4.30 g, 73%).
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:11]([O:13][C@@H:14]([CH2:36][C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[CH:38]=2)[C@@H:15]([C@H:17]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][N:18]2CC2C=CC(OC)=CC=2)[OH:16])=[O:12])[C:6]1=[O:53])[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[CH2:1]([C@H:5]1[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:11]([O:13][C@@H:14]([CH2:36][C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[CH:38]=2)[C@H:15]([OH:16])[C@H:17]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][NH:18]2)=[O:12])[C:6]1=[O:53])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H]1CCN([C@@H](CCc2ccccc2)C(=O)O[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2Cc3ccccc3CN2Cc2ccc(OC)cc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CCCC[C@H]1CCN([C@@H](CCc2ccccc2)C(=O)O[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2Cc3ccccc3CN2)C1=O
Reaction time: 8 h

Procedure:
To a solution of the compound of Step (A) in MeOH was added 10% Pd/C. The mixture was shaken under H2 in a Parr shaker, and after 3 pump/flush cycles, the reaction was allowed to shake overnight. The reaction was filtered through a 0.45 μm filter, and solvents removed in vacuo. The residue was injected onto a reverse-phase HPLC column (XTERRA S5 19×100 mm, gradient from 10% MeOH/H2O to 90% MeOH/H2O, containing 0.1% TFA) to afford, after solvent removal, pure product. 1H NMR (500 MHz, CD3OD) δ ppm 0.93 (t, J=7.02 Hz, 3H) 1.08-1.22 (m, 1H) 1.24-1.46 (m, 5H) 1.64-1.78 (m, 1H) 1.78-1.99 (m, 2H) 1.99-2.12 (m, 1H) 2.20-2.44 (m, 3H) 2.77 (dd, J=14.04, 11.29 Hz, 1H) 2.98-3.09 (m, 1H) 3.11-3.23 (m, 2H) 3.23-3.43 (m, 2H) 3.51-3.60 (m, 1H) 4.03 (dd, J=9.77, 2.14 Hz, 1H) 4.17-4.48 (m, 4H) 6.73-6.82 (m, 1H) 6.82-6.92 (m, 4H) 7.06-7.32 (m, 7H). HPLC retention time: 1.84 min (method C). MS (ESI) (M+H)+ 604.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH3:15])[CH2:3][CH2:2]1.[N:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[N:16]1([NH:22][C:12]([C:10]2[CH:9]=[CH:8][C:7]([CH3:15])=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1ccc(C(=O)O)nc1OCC1CC1
Reactant: NN1CCCCC1
Product: Cc1ccc(C(=O)NN2CCCCC2)nc1OCC1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid (Example 36 d) and 1-piperidinamine (CAN 2213-43-6) as starting materials, MS (EI): m/e 290.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([S:14]([CH3:16])=[O:15])[S:13][C:6]=12.C1C=C(Cl)C=C(C(OO)=[O:32])C=1.O>C(Cl)Cl>[F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([S:14]([CH3:16])(=[O:32])=[O:15])[S:13][C:6]=12
Reactant: CS(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of 233 (50 mg, 0.142 mmol) in DCM (2 mL), was added mCPBA (77%, 33 mg, 0.142 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour, water was added and the phases were separated. The organic layer was collected, washed with a 1% sodium hydroxide solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford title compound 236 (46 mg, 88% yield, crude) as a yellow solid which was used in the next step without additional purification. MS (m/z): 369.0 (M+1).
Reaction SMILES: Br[C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:12].C([Li])CCC.CN([CH:21]=[O:22])C.Cl>C1COCC1>[CH:21]([C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:12])=[O:22]
Reactant: Cc1cc(C(=O)O)cc(C)c1Br
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cc(C)c1C=O
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-bromo-3,5-dimethylbenzoic acid (0.92 g, 4 mmol) in THF (10 mL) was cooled down to −100° C. with N2(I)-Et2O bath and added n-butyllithium (1.6 M in hexanes, 5 mL, 8 mmol) slowly. After completion of addition, the reaction mixture was warmed to −78° C. and DMF (0.74 mL, 8 mmol) was added dropwise. The resulting mixture was stirred at −78° C. for 1.5 h and allowed to warm to −20° C., followed by the addition of 2N aqueous HCl (30 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc, the combined organic phases were dried over MgSO4. The solvent was removed and the resulting residue was purified by flash column chromatography (eluent: EtOAc-hexanes-1:1) to yield 4-formyl-3,5-dimethyl-benzoic acid (10c).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[F:19])[CH:8]=[C:9](I)[CH:10]=1)=[O:4].[CH:20]([N:23]1[C:27](B(O)O)=[CH:26][CH:25]=[N:24]1)([CH3:22])[CH3:21].CC([O-])=O.[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[F:19])[CH:8]=[C:9]([C:27]2[N:23]([CH:20]([CH3:22])[CH3:21])[N:24]=[CH:25][CH:26]=2)[CH:10]=1)=[O:4]
Reactant: CC(C)n1nccc1B(O)O
Reactant: COC(=O)c1cc(I)cc(-c2ccc(C)cc2F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(C)cc2F)cc(-c2ccnn2C(C)C)c1
Temperature: 130 °C
Yield: 52.5 %

Procedure:
To a microwave vessel was added 2′-fluoro-5-iodo-4′-methyl-biphenyl-3-carboxylic acid methyl ester (1.91 g, 5.4 mmol), 2-isopropyl-2H-pyrazole-3-boronic acid (1.08 g, 7.02 mmol), KOAc (1.59 g, 16.2 mmol), Pd(PPh3)4 (0.187 g, 0.16 mmol), dimethylglycol (15 mL) and water (3 mL). The mixture was flushed with N2 before submitting to microwave heating at 130° C. for 1 hour. After cooling down to room temperature, the reaction mixture was extracted with EtOAc and the combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column to afford 2′-fluoro-5-(2-isopropyl-2H-pyrazol-3-yl)-4′-methyl-biphenyl-3-carboxylic acid methyl ester as a viscous oil (1.0 g, 55.2%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[C:10]=1[CH:17]([OH:22])[C:18]([F:21])([F:20])[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[C:10]=1[CH:17]([O:22][S:31]([CH3:30])(=[O:33])=[O:32])[C:18]([F:20])([F:21])[F:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ccc(=O)c(OCc2ccccc2)c1C(O)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ccc(=O)c(OCc2ccccc2)c1C(OS(C)(=O)=O)C(F)(F)F
Reaction time: 3 h
Yield: 19.4 %

Procedure:
To a suspension of 3-benzyloxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (4 g) in CH2Cl2 (80 mL) was added Et3N (2.40 mL, 17.5 mmol), followed by methanesulfonyl chloride (1.25 mL, 16.2 mmol) at ice-water bath temperature. The resulting mixture was then stirred for 3 h. The reaction mixture was quenched with water and extracted twice with CH2Cl2 (2×50 mL). The combined organic fractions were washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography on silica gel using a mixture of CH2Cl2 and MeOH (95/5, v/v) as eluant, thereby affording the product, methanesulfonic acid 1-(3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridin-2-yl)-2,2,2-trifluoro-ethyl ester (0.97 g, 19.4% yield). MS-ESI (m/z): 391.9 [M+1]+, 206, 91.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[CH:6]=1)[CH3:2].CC1C=C(C=CC=1)N>>[CH2:1]([N:3]([CH2:4][C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)[CH2:14][CH3:15])[CH3:2]
Reactant: CCN(CC)Cc1cccc([N+](=O)[O-])c1
Solvent: Cc1cccc(N)c1
Product: CCN(CC)Cc1cccc(N)c1

Procedure:
The title compound is prepared as described in Example 149B but using diethyl-(3-nitrobenzyl)-amine. The title compound contains 30% of 3-methyl-aniline and is used as a crude impure material.
Reaction SMILES: C(Cl)Cl.O[CH:5]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:6][N:7]1[C:15]2[C:10](=[C:11]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.C(N(S(F)(F)[F:36])CC)C.CO>O>[F:36][CH:5]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:6][N:7]1[C:15]2[C:10](=[C:11]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1NC(=O)C(Cc2cccc3c2ccn3CC(O)c2ccccc2)S1
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: O=C1NC(=O)C(Cc2cccc3c2ccn3CC(F)c2ccccc2)S1
Temperature: -34 °C
Reaction time: 0.08 h
Yield: 72.7 %

Procedure:
To 10 ml of methylene chloride, there was dissolved 134 mg of 5-[1-(2-hydroxy-2-phenylethyl)indol-4-yl]methyl-2,4-thiazolidinedione prepared in Example 323 under an argon gas atmosphere and the resulting solution was then cooled to -34° C. After addition of 88 mg of diethylaminosulfur trifluoride to the solution and stirring it for 5 minutes and the solution was then stirred at room temperature for additional 30 minutes. After addition of 10 ml of methanol, the solution was poured into 50 ml of water and extracted with ethyl acetate. The resulting extract was dried over anhydrous sodium sulfate and the solvent was removed through evaporation under reduced pressure to give a crude product. The product was purified by preparatory silica gel thin layer chromatography (hexane:ethyl acetate=10:1) to give 98 mg of 5-[1-(2-fluoro-2-phenylethyl)indol-4-yl]methyl-2,4-thiazolidinedione as a yellow amorphous substance. The yield thereof was found to be 73%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][CH:23]=[C:24]([CH2:26][C:27](O)=[O:28])[N:25]=2)=[N:10]1.[CH:30]([NH2:33])([CH3:32])[CH3:31]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][CH:23]=[C:24]([CH2:26][C:27]([NH:33][CH:30]([CH3:32])[CH3:31])=[O:28])[N:25]=2)=[N:10]1
Reactant: CC(C)N
Reactant: CCOC(=O)C1=C(C)NC(c2nc(CC(=O)O)cs2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(C)NC(c2nc(CC(=O)NC(C)C)cs2)=NC1c1ccc(F)cc1Br
Yield: 45 %

Procedure:
2-(2-(4-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-6-methyl-1,4-dihydropyrimidin-2-yl)thiazol-4-yl)acetic acid (3 g, 6.2 mmol) was reacted with isopropylamine (0.55 g, 9.3 mmol) according to the procedure as described in Example 62, Step B to give the title compound as a yellow solid (1.46 g, 45%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C([O:45][C:46](=[O:53])[CH2:47]CCCCBr)C.COC(C)(C)C>[Cl-].C[N+](C)(C)C.C(OCOCC)C>[CH2:1]([O:8][C@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:12][CH:10]1[O:11][CH2:47][C:46]([OH:53])=[O:45])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: CCOC(=O)CCCCCBr
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CCOCOCC
Product: O=C(O)COC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 10 °C

Procedure:
A mixture that consists of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl-mannopyranose, 0.55 g (5 mmol) of tetramethylammonium chloride and 33.7 g (600 mmol) of fine-powder potassium hydroxide in 350 ml of diethoxymethane is cooled to 10° C. At 10° C., 35.7 g (160 mmol) of 6-bromohexanoic acid ethyl ester is added in drops over 10 minutes while being stirred vigorously. It is stirred for 2 hours at 10° C. 250 ml of MTB (methyl-tert-butyl ether) is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of ethanol/50 ml of water. 60 ml of 50% aqueous sodium hydroxide solution is added, and it is refluxed for four hours. It is cooled to 0° C., set at pH 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water, 500 ml of ethyl acetate is added, and the pH of the aqueous phase is set at 2 while being stirred (10% aqueous hydrochloric acid). The organic phase is separated, and the aqueous phase is extracted once more with 200 ml of ethyl acetate. The combined organic phases are dried on magnesium sulfate, the solvent is distilled off in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/n=hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate, and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6])#[N:2].S(Cl)([Cl:14])=O>>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:14])=[O:6])#[N:2]
Reactant: N#Cc1ccccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: N#Cc1ccccc1C(=O)Cl

Procedure:
A mixture of 2-cyanobenzoic acid (2 g, 13.6 mmol) and 15 ml of thionyl chloride was refluxed overnight. Excess thionyl chloride was removed in vacuo and the resultant 2-cyanobenzoyl chloride obtained as such as an off white solid was used in the above acylation.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:16]3[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]3)=[C:10]([C:17]#[N:18])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:19]N1C(=O)CCC1=O>>[Br:19][C:9]1[C:10]([C:17]#[N:18])=[C:11]2[N:16]([C:8]=1[C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[CH2:15][CH2:14][CH2:13][CH2:12]2
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1cc(-c2cccnc2F)n2c1CCCC2
Product: N#Cc1c(Br)c(-c2cccnc2F)n2c1CCCC2
Yield: 84.8 %

Procedure:
2-Bromo-3-(2-fluoro-3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile is prepared as described in Example 9, from 1.6 g of 3-(2-fluoro-3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile and 1.3 g of N-bromosuccinimide. 1.8 g of 2-bromo-3-(2-fluoro-3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile are thus obtained in the form of beige powder melting at 172° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:10][C:11]([NH2:13])=O)=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].C(Cl)(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCCl>[C:11]([CH2:10][N:9]([CH2:14][C:15]([F:16])([F:18])[F:17])[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:19]([F:21])([F:22])[F:20])[CH:5]=1)#[N:13]
Reactant: N#Cc1ccc(N(CC(N)=O)CC(F)(F)F)cc1C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Solvent: ClC(Cl)(Cl)Cl
Product: N#CCN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 87 °C
Yield: 54.3 %

Procedure:
A mixture of N2-[4-cyano-3-(trifluoromethyl)phenyl]-N2-(2,2,2-trifluoroethyl)glycinamide (0.060 g, 0.18 mmol), CCl4 (0.5 mL), DCE (4.5 mL) and polymer-supported triphenyl phosphine (3 mmol/g, 0.123 g, 0.36 mmol) was heated at 87° C. for 3 h. Upon cooling, the resin was filtered off, washed thoroughly with CHCl3 and the filtrate concentrated in vacuo. The residue was purified by silica gel chromatography (5-40% EtOAc-hexane gradient) and the product was crystallized from CH2Cl2-hexanes to give the title compound as a white solid (0.030 g, 55% yield): 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J=8.6 Hz, 1H), 7.20 (d, J=2.6 Hz, 1H), 7.09 (dd, J=8.6, 2.6 Hz, 1H), 4.38 (s, 2H), 4.06 (q, J=8.2 Hz, 2H); MS (ES) m/z 308 (M+1).
Reaction SMILES: C1NC2N([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)C=NC=2C(=O)N=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1.[CH:44]1([CH2:49][O:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[OH:57])[CH2:48][CH2:47][CH2:46][CH2:45]1.[CH2:58]([O:60][C:61](=[O:66])[C:62](Br)([CH3:64])[CH3:63])[CH3:59].CS(C)=O>O>[CH2:58]([O:60][C:61](=[O:66])[C:62]([O:57][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=1[O:50][CH2:49][CH:44]1[CH2:45][CH2:46][CH2:47][CH2:48]1)([CH3:64])[CH3:63])[CH3:59]
Reactant: Oc1ccccc1OCC1CCCC1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=c1nc[nH]c2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccccc1OCC1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.8 %

Procedure:
To a solution of catacol (0.5 g, 4.54 mmol), triphenylphosphine (1.79 g, 6.8 mmol) and cyclopenylmethanol (0.68 g, 6.8 mmol) in THF (5 ml) DIAD (1.37 g, 6.8 mmol) is added drop wise over a period of 10-15 min at 0° C. The reaction mixture stirred at r.t. for 18 h, quenched with brine (5 ml), extracted in EtOAc (2×20 ml), and dried over Na2SO4. Solvent was evaporated under reduced pressure and crude product. To a solution of 2-Cyclopentylmethoxy-phenol (0.1 g, 0.52 mmol) and 2-bromoisobutyrate ethyl ester (0.15 g, 0.78 mmol) in DMSO (2 ml) Cs2CO3 (0.25 g, 0.78 mmol) was added and heated at 60° C. for 4 h. The reaction mixture was cooled to r.t. and poured on 10 ml of water, extracted in EtOAc (2×20 ml) dried over Na2SO4. Solvent was removed under reduced pressure to yield 2-(2-Cyclopentylmethoxy-phenoxy)-2-methyl-propionic acid ethyl ester (0.1 g, 63%) which was hydrolysed to give 2-(2-Cyclopentylmethoxy-phenoxy)-2-methyl-propionic acid using method Typical Example (A1-II).
Reaction SMILES: C([CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O)C>[Pd].CO>[N:4]1([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])[CH2:5][CH2:6][CH2:7][CH2:3]1
Reactant: CCC1CCCN1Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1CN1CCCC1
Yield: 115.4 %

Procedure:
A mixture of ethyl 1-(2-nitrobenzyl)pyrrolidine (1.90 g) and 10% palladium on carbon (200 mg) in methanol (40 mL) was hydrogenated at ambient temperature. After completion of the reaction, the catalyst in the reaction mixture was removed by filtration. The solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol=20/1 v/v) to give [2-(1-pyrrolidinylmethyl)phenyl]amine (1.65 g) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][C:6]1([CH2:16][CH:17]=O)[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)=[O:4].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([NH2:30])[CH3:29])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([NH:30][CH2:17][CH2:16][C:6]2([NH:5][C:3](=[O:4])[C:2]([F:19])([F:20])[F:1])[CH2:15][CH2:14][C:9]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:8][CH2:7]2)[CH3:29])=[CH:24][CH:23]=1
Reactant: O=CCC1(NC(=O)C(F)(F)F)CCC2(CC1)OCCO2
Reactant: C[C@H](N)c1ccc(Cl)cc1
Product: C[C@H](NCCC1(NC(=O)C(F)(F)F)CCC2(CC1)OCCO2)c1ccc(Cl)cc1
Yield: 75 %

Procedure:
The title compound is prepared from 2,2,2-trifluoro-N-[8-(2-oxo-ethyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-acetamide and (S)-1-(4-chloro-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 75% of theory; LC (method 8): tR=1.10 min; Mass spectrum (ESI+): m/z=435/437 (Cl) [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:8]([CH3:13])=[C:9]([F:12])[C:10]=1[F:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:18])=O>>[Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:8]([CH3:13])=[C:9]([F:12])[C:10]=1[F:11])[C:5]([Cl:18])=[O:6]
Reactant: Cc1c(F)c(F)c(Cl)c(F)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Product: Cc1c(F)c(F)c(Cl)c(F)c1C(=O)Cl

Procedure:
The title compound was prepared from 3-chloro-2,4,5-trifluoro-6-methylbenzoic acid and oxalyl chloride following the same procedure used in Example F.