Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:5][CH2:4]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[CH:2]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:5][CH2:4]1)=[O:1]
Reactant: CCOC(=O)C[C@H]1CC[C@H](CO)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CC[C@H](C=O)CC1
Temperature: 25 °C

Procedure:
To a 0° C. solution of ethyl [trans-4-(hydroxymethyl)cyclohexyl]acetate (102. 8 mg, 0.514 mmol) in CH2Cl2 (6 n-L) was added Dess-Martin periodinane. The reaction was warmed to room temperature and stirred for several hours. The reaction was then diluted with EtOAc (50 mL) and washed with 1N NaOH and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (5 to 25% EtOAc/hexanes) afforded ethyl (trans-4-formylcyclohexyl)acetate. Rf=0.57 (40% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 9.61 (d, J=1.4 Hz, 1H), 4.13 (q, J=7.1 Hz, 2H), 2.13-2.22 (m, 3H), 1.98-2.01 (m, 2H), 1.87-1.91 (m, 2H), 1.77 (m, 1H), 1.31 (qd, J=13.0, 3.4 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H), 1.05 (qd, J=13.0, 3.4 Hz, 2H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([OH:8])=[O:7].OS(O)(=O)=O.[CH2:14](O)[CH3:15]>>[CH2:14]([O:7][C:6](=[O:8])[CH2:5][O:4][CH2:3][CH2:2][Cl:1])[CH3:15]
Reactant: O=C(O)COCCCl
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)COCCCl
Yield: 89 %

Procedure:
54.1 g (390 mmol) M24 obtained from the preceding reaction step was dissolved in 380 ml absolute ethanol and 9 ml conc. H2SO4 was added. The mixture was heated at reflux for 18 hours. Most of the ethanol was evaporated and the residue was dissolved in 400 ml CHCl3/100 ml water and basified with powder NaHCO3. The organic phase was washed with 2×400 ml saturated NaHCO3 and dried over Na2SO4. The solvent was evaporated to afford 58.3 g clear oil (yield: 89%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[C:25]([CH3:27])[CH:26]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:23]3[CH:22]=[C:21]([CH3:20])[CH:26]=[C:25]([CH3:27])[CH:24]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: Cc1cc(C)cc(CC(=O)O)c1
Product: Cc1cc(C)cc(CC(=O)Nn2nc(-c3ccc(Cl)cc3)c3ccccc3c2=O)c1

Procedure:
The product of Example 86A and 2-(3,5-dimethylphenyl)acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.41-8.43 (m, 1H), 7.93-8.04 (m, 2H), 7.72-7.74 (m, 1H), 7.59-7.69 (m, 4H), 6.98-6.99 (bs, 2H), 6.90-6.91 (bs, 1H), 3.60 (s, 2H), 2.26 (s, 6H); MS (ESI−) M/Z 416 (M−H)−.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([CH3:29])([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[NH:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:8])[CH3:5].O.Cl>C1COCC1.[OH-].[Na+].CO>[CH3:29][C:4]([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[NH:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:8])([CH3:5])[C:3]([OH:30])=[O:2]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1NCCCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(NC(=O)c1ccc2ccccc2c1NCCCc1ccccc1)C(=O)O
Yield: 51.8 %

Procedure:
6 mg 2-methyl-2-{[1-(3-phenyl-propylamino)-naphthalene-2-carbonyl]-amino}-propionic acid methyl ester in 0.2 ml THF, 40 μl of 2 M sodium hydroxide and 0.2 ml methanol were reacted at room temperature for 3 h. To the mixture 0.5 ml of water were added and the pH was adjusted to 3-4 with 2 M hydrochloride acid. The volatiles were then removed by freeze drying, the resultic residue was suspended in methanol and filtrated. Concentration of the filtrate yielded 3 mg of 2-methyl-2-{[1-(3-phenyl-propylamino)-naphthalene-2-carbonyl]-amino}-propionic acid.
Reaction SMILES: F[C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[N:30]=[CH:29][CH:28]=[N:27]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.N[C@H]1CCC[C@@H]1NC(=O)C1C=CC=CC=1N1N=CC=N1.[Cl:53]C1C(F)=NC=C(C(F)(F)F)C=1>>[Cl:53][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[N:30]=[CH:29][CH:28]=[N:27]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F)c1ccccc1-n1nccn1
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Agent: N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Cl)c1ccccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-{ [3-fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 105) from N-[(1S,2S)-2-amino cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 4; 100 mg, 0.33 mmol) and 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine (CAS number 72537-17-8; 71 mg, 0.36 mmol) except this was then further purified using column chromatography (basic silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:18]2[C:9](=[N:10][C:11]3[C:16]([N:17]=2)=[C:15]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:14]2=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=1)=O.[CH3:25][N:26]([CH3:31])[CH2:27][CH:28]([NH2:30])[CH3:29]>>[CH3:25][N:26]([CH3:31])[CH2:27][CH:28]([NH:30][C:3]([C:5]1[C:18]2[C:9](=[N:10][C:11]3[C:16]([N:17]=2)=[C:15]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:14]2=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=1)=[O:2])[CH3:29]
Reactant: CC(N)CN(C)C
Reactant: COC(=O)c1cccc2nc3ccc4c(OC)cccc4c3nc12
Product: COc1cccc2c1ccc1nc3cccc(C(=O)NC(C)CN(C)C)c3nc12
Temperature: 110 °C

Procedure:
A mixture of 4-methoxy-benzo[a]phenazine-11-carboxylic acid methyl ester (IV.1) (350 mg) and 1-dimethylamino-2-propylamine (2 mL)(commercially available) was heated to 110° C. under N2 for 4 hours. The reaction mixture was then cooled and the excess amine was removed in vacuo. The residue was then purified using flash chromatography (silica, ethyl acetate and then 25% methanol in ethyl acetate) to yield the title compound as a yellow solid (164 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[CH2:21]([S:23]([C:26]1[S:30][C:29]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[N:28][CH:27]=1)(=[O:25])=[O:24])[CH3:22]>>[CH2:21]([S:23]([C:26]1[S:30][C:29]([N:31]2[CH2:32][CH2:33][N:34]([C:10]([C:9]3[CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=3[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[O:12])[CH2:35][CH2:36]2)=[N:28][CH:27]=1)(=[O:25])=[O:24])[CH3:22]
Reactant: CS(=O)(=O)c1ccc(OCC(F)(F)F)c(C(=O)O)c1
Reactant: CCS(=O)(=O)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CCS(=O)(=O)c1cnc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OCC(F)(F)F)CC2)s1
Yield: 72 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-ethoxy)-benzoic acid (Example A3) and 1-(5-ethanesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 32(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 72%). MS (m/e): 542.2 (M+H+, 100%), 559.3 (M+NH4+, 60%).
Reaction SMILES: CC1C(C([NH:10][NH2:11])=O)=NC=CC=1.[CH3:12][C:13]1[C:18]([C:19]([O:21]CC)=O)=[CH:17][CH:16]=[CH:15][N:14]=1.CC1N=C(C(OCC)=O)C=CC=1>>[CH3:12][C:13]1[C:18]([C:19]([NH:10][NH2:11])=[O:21])=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: Cc1cccnc1C(=O)NN
Reactant: CCOC(=O)c1cccnc1C
Agent: CCOC(=O)c1cccc(C)n1
Product: Cc1ncccc1C(=O)NN

Procedure:
2-Methyl-3-pyridinecarbohydrazide was prepared in a manner analogous to that described above for 3-methyl-2-pyridinecarbohydrazide (I22) but using ethyl 2-methyl-3-pyridinecarboxylate (CAS [1721-26-2], commercially available e.g. from Sigma-Aldirch or Alfa Aesar) in the place of ethyl 6-methyl-2-pyridylcarboxylate.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1.[C:21]([NH:24][C@H:25]([C:28]([OH:30])=[O:29])[CH2:26][SH:27])(=[O:23])[CH3:22]>>[C:21]([NH:24][CH:25]([CH2:26][S:27][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:2](=[O:1])[NH:3][C:11]1[CH:16]=[CH:15][C:14]([S:17](=[O:19])(=[O:18])[NH2:20])=[CH:13][CH:12]=1)[C:28]([OH:30])=[O:29])(=[O:23])[CH3:22]
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Reactant: NS(=O)(=O)c1ccc(-n2sc3ccccc3c2=O)cc1
Product: CC(=O)NC(CSSc1ccccc1C(=O)Nc1ccc(S(N)(=O)=O)cc1)C(=O)O
Yield: 81.6 %

Procedure:
This compound was prepared according to the method of Example 132 using 0.8 g (2.4 mmol) of 4-(3-oxo-3H-benzo[d]isothiazol-2-yl)benzenesulfonamide and 0.39 g (2.4 mmol) of N-acetyl-L-cysteine. The product was washed with ether and dried in vacuo to give 0.92 g of the title compound, mp 218-220° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]1[O:23][N:22]=[C:21]([CH:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25])[N:20]=1.CO>CCCCCCC>[CH3:28][CH:27]([CH3:29])[CH2:26][CH:24]([NH:25][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:21]1[N:20]=[C:19]([CH3:18])[O:23][N:22]=1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: Cc1nc(C(N)CC(C)C)no1
Solvent: CCCCCCC
Solvent: CO
Product: Cc1nc(C(CC(C)C)NC(=O)c2ccc(C3CC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 5-methyl-α-(2-methylpropyl)-1,2,4-oxadiazole-3-methanamine (CAN 1155538-06-9) as starting materials. The product was isolated by chiral chromatography on Chiralpak AD using heptane/8% ethanol as eluent. The (+)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 385.2234 (M+H)+, αD20 (MeOH)=+22.5°.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH:19](=[C:26]1/[C:27]2[CH:28]=[C:29]([C:43]([O:45][CH3:46])=[O:44])[N:30](COCC[Si](C)(C)C)[C:31]=2[CH2:32][CH2:33][CH2:34]/1)\[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH:19](=[C:26]1/[C:27]2[CH:28]=[C:29]([C:43]([O:45][CH3:46])=[O:44])[NH:30][C:31]=2[CH2:32][CH2:33][CH2:34]/1)\[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1cc2c(n1COCC[Si](C)(C)C)CCC/C2=C\c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1cc2c([nH]1)CCC/C2=C\c1ccccc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 13.2 %

Procedure:
Tetrabutylammonium fluoride (TBAF) (23 mL, 1M in THF, 23 mmol) was added over 5 min to a solution of (E)-methyl 4-benzylidene-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (900 mg, 2.26 mmol) in cooled THF (0° C.). The reaction mixture was then heated for 4 h at 80° C. After 48 h at rt, the reaction mixture was partitioned between ether and water. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (cyclohexane/EtOAc:80/20) to afford the (E)-methyl 4-benzylidene-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (80 mg). LC/MS: 76%, m/z=267.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:14][N:13]([C:15](OC(C)(C)C)=O)[CH2:12]1)[CH2:10][C:9]2=[O:26].[F:28][C:29]1[CH:36]=[CH:35][C:32](C=O)=[CH:31][CH:30]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:12][N:13]([CH2:15][C:32]3[CH:35]=[CH:36][C:29]([F:28])=[CH:30][CH:31]=3)[CH2:14]1)[CH2:10][C:9]2=[O:26]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)OC(C)(C)C)C1)O2
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3ccc(F)cc3)C1)O2

Procedure:
(E)-3-[1′-(4-Fluoro-benzyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid methyl ester was synthesized starting from Intermediate 4 (350 mg, 1.13 mmol), according to the procedure described in Example 31, Step A, using 4-fluorobenzaldehyde (0.24 ml, 2.26 mmol) and NaBH(OAc)3 (360 mg, 1.69 mmol). The product was obtained as a yellow solid (390 mg).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[C:12]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH:7](=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]([O:20][CH2:21][CH3:22])=[O:19])[C:6]1[CH:1]=[CH:2][C:3]2[O:11][CH2:10][O:9][C:4]=2[CH:5]=1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=Cc1ccc2c(c1)OCO2)C(=O)OCC

Procedure:
Into a one-liter three-necked conical flask are introduced 50 g (333.04 mmol) of piperonal, 53.34 g (333.04 mmol) of diethyl malonate, 2.26 g (26.59 mmol) of piperidine, 110 ml of toluene and 1.6 g (26.66 mmol) of acetic acid.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[CH:10]([Si:12]([Cl:15])(Cl)[Cl:13])=[CH2:11]>>[Cl:13][Si:12]([Cl:15])([CH:10]=[CH2:11])[NH:3][Si:2]([CH3:9])([CH3:8])[CH3:1]
Reactant: C=C[Si](Cl)(Cl)Cl
Reactant: C[Si](C)(C)N[Si](C)(C)C
Product: C=C[Si](Cl)(Cl)N[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
In a 250 ml three-neck flask, 50 ml of hexamethyldisilazane (38.7 g, 0.24 mol) are admixed with 70 ml of vinyltrichlorosilane (88.9 g, 0.55 mol) and stirred overnight at room temperature. The mixture is fractionated under reduced pressure. After trimethylchlorosilane and excess vinyltrichlorosilane have been distilled off, (1,1-dichloro-1-vinyl)trimethyldisilazane goes over as a clear, colorless liquid. The boiling point is 40° C. at 11 mbar, and the yield is 80%.
Reaction SMILES: CC[Mg+].[Br-:4].C1C=CC(C(C2NC=CC=2)C2NC=CC=2)=CC=1.C[C:23]1[CH:37]=[CH:36][C:26]([C:27](=[O:35])[S:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:25][CH:24]=1>C1COCC1>[Br:4][C:23]1[CH:37]=[CH:36][C:26]([C:27](=[O:35])[S:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:25][CH:24]=1
Reactant: [Br-]
Reactant: Cc1ccc(C(=O)Sc2ccccn2)cc1
Agent: CC[Mg+]
Agent: c1ccc(C(c2ccc[nH]2)c2ccc[nH]2)cc1
Solvent: C1CCOC1
Product: O=C(Sc1ccccn1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
Exemplified for 1-(4-Methylbenzoyl)-5-phenyldipyrromethane (2a). A solution of EtMgBr (50.0 mL, 50.0 mmol, 1.0 M in THF) was added via syringe to a stirred solution of 1a (4.44 g, 20.0 mmol) in THF (20 mL) under argon. The mixture was stirred for 10 min at room temperature and then cooled to −78° C. A solution of 6a (4.58 g, 20.0 mmol) in THF (20 mL) was added. The mixture was stirred for 10 min at −78° C. Then the cooling bath was removed, the mixture was stirred for 20 min, and then the reaction was quenched with saturated aqueous NH4Cl (150 mL). The mixture was diluted with THF (10 mL), washed with water (100 mL), and then dried (Na2SO4). Removal of solvents and chromatography [silica (6×24 cm), CH2Cl2 (2300 mL)] afforded a golden amorphous solid (5.82 g, 86%): mp 69-70° C.; 1H NMR δ 2.43 (s, 3H), 5.55 (s, 1H), 5.95-6.01 (m, 1H), 6.05-6.09 (m, 1H), 6.14-6.18 (m, 1H), 6.67-6.71 (m, 1H), 6.79-6.82 (m, 1H), 7.20-7.35 (m, 7H), 7.72-7.76 (m, 2H), 8.05-8.22 (brs, 1H), 9.50-9.68 (brs, 1H); Anal. Calcd for C23H20N2O: C, 81.15; H, 5.92; N, 8.23. Found: C, 80.74; H, 5.74; N, 8.25.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][CH:8]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9]([NH:11][NH:12][C:13]([C@@H:15]1[CH2:21][CH2:20][C@@H:19]2[CH2:22][N:16]1[C:17](=[O:31])[N:18]2[O:23]CC1C=CC=CC=1)=[O:14])=[O:10])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:38])[NH:7][CH:8]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9]([NH:11][NH:12][C:13]([C@@H:15]1[CH2:21][CH2:20][C@@H:19]2[CH2:22][N:16]1[C:17](=[O:31])[N:18]2[OH:23])=[O:14])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O)c1ccccc1
Reaction time: 3 h
Yield: 103.2 %

Procedure:
A mixture of tert-butyl[2-(2-{[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-2-oxo-1-phenylethyl]carbamate 250 (0.40 g, 0.76 mmol) and Pd/C (0.20 g) in methanol (15 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to provide 251 (0.34 g, quant. yield) as a white foam.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:22])[CH:7]([CH2:13][CH2:14][C:15]([F:21])([F:20])[C:16]([Br:19])([F:18])[F:17])C(OCC)=O)C.Cl>>[Br:19][C:16]([F:17])([F:18])[C:15]([F:20])([F:21])[CH2:14][CH2:13][CH2:7][C:6]([OH:22])=[O:5]
Reactant: CCOC(=O)C(CCC(F)(F)C(F)(F)Br)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCC(F)(F)C(F)(F)Br
Temperature: 25 °C
Yield: 94.7 %

Procedure:
7000 g (26.4 mol) of 15% of sodium hydroxide aqueous solution was added to 1940 g (5.29 mol) of the objective 2-(4-bromo-3,3,4,4-tetrafluorobutyl)-malonic acid diethyl ester obtained as discussed above, followed by refluxing it for 2 hours. Upon cooling it to room temperature, 2900 g (29.1 mol) of concentrated hydrochloric acid (36%) is added in an iced bath, followed by extraction with diisopropyl ether. A residue obtained by distilling a solvent off was heated to 170° C. thereby obtaining 1338 g of the objective 6-bromo-5,5,6,6-tetrafluorohexanoic acid (95% yield) in the form of a brown liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][NH2:11])([O-:3])=[O:2].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=O)[CH3:19].S(=O)(=O)(O)O.C(O)C>O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][N:11]=[C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1)[CH3:19])([O-:3])=[O:2]
Reactant: NNc1ccccc1[N+](=O)[O-]
Reactant: CC(=O)c1ccccn1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CC(=NNc1ccccc1[N+](=O)[O-])c1ccccn1
Yield: 84.9 %

Procedure:
A mixture of (2-nitrophenyl)hydrazine (2.00 g), 1-(pyridin-2-yl)ethanone (1.67 g), sulfuric acid (0.73 mL) and ethanol (50 mL) was heated under reflux for 1 hr. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried to give the title compound (2.84 g, 85%) as brown crystals. melting point 145-146° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([OH:8])[CH3:7].Br[CH2:10][C:11]([OH:13])=[O:12]>O>[C:11]([CH2:10][N:3]1[CH:4]=[CH:5][S:1][CH:2]1[CH:6]([OH:8])[CH3:7])([OH:13])=[O:12]
Reactant: CC(O)c1nccs1
Reactant: O=C(O)CBr
Solvent: O
Product: CC(O)C1SC=CN1CC(=O)O
Temperature: 25 °C
Reaction time: 96 h
Yield: 107.9 %

Procedure:
1-(2-Thiazolyl)ethanol (0.5 g, 3.87 mmole) and bromoacetic acid (0.538 g, 3.87 mmole) were warmed to melt the bromoacetic acid, then were allowed to cool and were stirred 4 days at room temp. The mixture was dissolved in 15–20 mL water and extracted with 4×10 mL ether. The water layer was evaporated in vacuo to give 0.79 g of residue, which was stored under 30 mL acetonitrile at room temp. overnight to effect crystalization. Filtration and washing with 30% ether/acetonitrile gave 0.335 g of the title compound, mp 160–161 C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[N:11]([CH3:25])[C:12]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20](Cl)=[CH:19][CH:18]=2)=[C:13]([CH3:15])[CH:14]=1)[NH2:5].C([O-])(=O)C.[Na+]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[N:11]([CH3:25])[C:12]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:13]([CH3:15])[CH:14]=1)[NH2:5]
Reactant: Cc1cc(Cc2ccc(N)cc2F)n(C)c1C(=O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Cc2ccc(N)cc2F)n(C)c1C(=O)c1ccccc1
Reaction time: 8 h
Yield: 55.2 %

Procedure:
3-Fluoro-4-[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]aniline (5.0 g, 14.0 mmol), sodium acetate (1.15 g, 14 mmol) and 10% Pd/C (475 mg) were suspended in ethanol (230 ml). The reaction mixture was shaken in a Parr apparatus under hydrogen atmosphere at 30 psi overnight. The mixture was filtered through Celite® and the filtrate was evaporated to dryness. The crude product was purified on a silica gel column (methylene chloride-methanol, 99:1) and then crystallized from ethyl acetate/hexane/cyclohexane to give 3-fluoro-4-[5-benzoyl-1,4-dimethyl-1H-pyrrol-2-yl-methyl]aniline (2.49 g, 55%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][C:3]=1[C:22]([F:25])([F:23])[F:24]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)c(C(F)(F)F)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCNCC1

Procedure:
According to Preparation 2: Tert-butyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxypiperidine-1-carboxylate (4.3 g, 11.3 mmol, methylen chloride (30 ml), trifluoroacetic acid (4.5 ml). Yield: 1.4 g. MS m/z (rel. intensity, 70 eV) 279 (M+, 28), 263 (38), 262 (30), 261 (bp), 260 (52).
Reaction SMILES: [CH2:1]([C:3]#[CH:4])[CH3:2].C([Li])CCC.[CH3:10][O:11][C:12]([CH:14]1[CH2:18][C:17](=[O:19])[CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:13]>C1COCC1>[CH3:10][O:11][C:12]([CH:14]1[CH2:18][C:17]([CH2:2][CH2:1][CH2:3][CH3:4])([OH:19])[CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:13]
Reactant: C#CCC
Reactant: COC(=O)C1CC(=O)CN1C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC1(O)CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To ethyl acetylene (140 mg, 2.6 mmol) in THF (5 mL) at −78° C., n-butyllithium (1.1 mL, 2.6 mmol) was added with stirring at −78° C. for 1 hour. Then 4-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (prepared as described in the example 56) (570 mg, 2.3 mmol) in THF (5 mL) was added at −78° C. with stirring for 2 h, the reaction mixture was then allowed to warm to −40° C. over 1 hour. The reaction mixture was extracted with EtOAc (20 mL), washed with saturated NH4Cl (5 mL) and dried over sodium sulfate. Purification of the crude product was carried out by silica gel chromatography using 50% EtOAc in hexane to obtain the 4-butyl4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (520 mg, 73%). To the DAST (556 mg, 3.4 mmol) in DCM (5 mL) at −78° C., was added a solution of the above ester (520 mg, 1.7 mmol) in DCM (5 mL) at −78° C. and stirred for 1 hour. The reaction mixture was extracted with DCM (50 mL) and washed with NaHCO3 (30 mL, 10%). The product obtained after removal of solvent was purified by silica gel chromatography using 5% EtOAc in hexanes to obtain 4-butyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (276 mg, 52%).