Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[C:17]3[CH2:25][OH:26])=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27]O>C(#N)C.Cl>[CH3:27][O:26][CH2:25][C:17]1[N:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:15][CH:14]=2)[C:24]2[C:19]([CH:18]=1)=[CH:20][CH:21]=[CH:22][CH:23]=2
Reactant: OCc1cc2ccccc2n1-c1ccc(OCCCN2CCCC2)cc1
Reactant: CO
Agent: Cl
Solvent: CC#N
Product: COCc1cc2ccccc2n1-c1ccc(OCCCN2CCCC2)cc1
Reaction time: 2 h

Procedure:
{1-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]-1H-indol-2-yl}methanol (15 mg) was dissolved in a mixture of methanol, acetonitrile, and 1 N HCl. After standing at room temperature for 2 hours, the solution was purified by semi-prep LC-MS to give 1.1 mg of the desired product. LC-MS (C23H28N2O2 calc'd 364) m/z 365 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.66-7.61 (m, 1H), 7.33 (d, J=9 Hz, 2H), 7.20-6.75 (m, 5H), 6.66 (s, 1H), 4.40 (s, 2H), 4.10 (t, J=6.3 Hz, 2H), 3.28 (s, 3H), 2.82-2.71 (m, 6H), 2.17-2.08 (m, 2H), 1.87 (m, 4H).
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].Br[CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CCOCC>[C:3]([C:2]1([C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:14][CH2:13]1)(=[O:4])[CH3:5]
Reactant: BrCCBr
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(=O)C1(C(=O)OC(C)(C)C)CC1
Temperature: 55 °C

Procedure:
Step 1 A stirred suspension of tert-butyl acetoacetate (2.1 mL, 12.6 mmol), 1,2-dibromoethane (1.14 mL, 13.3 mmol) and potassium carbonate (3.49 g, 25.3 mmol) in acetone (50.6 mL) was heated to 55° C. over a weekend. Upon cooling the mixture was diluted with Et2O and washed with water (×2). The organic phase was dried (Na2SO4), filtered and concentrated. Biotage column (40+M) eluting with a gradient of 0% Et2O/petrol to 20% Et2O/petrol gave tert-butyl 1-acetylcyclopropane-1-carboxylate, 0.78 g, 29%. 1H NMR (400 MHz, CDCl3): 2.46 (3H, s), 1.51 (9H, s), 1.43-1.38 (4H, m).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:19]([NH:22][NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[CH2:14][CH2:15][C:16]([N:22]([CH:19]([CH3:21])[CH3:20])[NH:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: O=C(O)CCc1cc(F)ccc1OC1CCCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1cc(F)ccc1OC1CCCC1
Yield: 29.9 %

Procedure:
A solution of 3-(2-cyclopentyloxy-5-fluoro-phenyl)-propionic acid (220 mg, 0.87 mmoles) and benzoic acid N′-isopropyl-hydrazide (130 mg, 0.73 mmoles) in DMF (5mL) was treated with diisopropylethylamine (0.32 mL, 1.81 mmoles), and PyBroP (507 mg, 1.09 mmoles) at room temperature for 48 h. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate/hexanes gradient to afford the product as a solid (90 mg, 30%). LC-MS m/e 413.32 (M+H+)
Reaction SMILES: [CH3:1][C:2](=O)[C:3](=O)[CH3:4].[NH2:7][N:8]1[C:12]([NH2:13])=[N:11][N:10]=[C:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1>>[CH3:1][C:2]1[C:3]([CH3:4])=[N:13][C:12]2[N:8]([C:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:10][N:11]=2)[N:7]=1
Reactant: CC(=O)C(C)=O
Reactant: Nc1nnc(Cc2ccc(O)cc2)n1N
Product: Cc1nc2nnc(Cc3ccc(O)cc3)n2nc1C

Procedure:
General procedure A was followed with the reaction of butane-2,3-dione and 4-(4,5-diamino-4H-[1,2,4]triazol-3-ylmethyl)-phenol to provide 4-(6,7-dimethyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-ylmethyl)-phenol (example 8).
Reaction SMILES: [I-].C([N+]1C2C(=CC=CC=2)C=CC=1I)C.[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:23]1([CH2:29][C:30](O)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CCCC)CCCC)CCC>C(Cl)Cl>[C:23]1([CH2:29][C:30]([O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: OCc1ccccc1
Agent: CC[n+]1c(I)ccc2ccccc21
Agent: [I-]
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: O=C(Cc1ccccc1)OCc1ccccc1
Yield: 95 %

Procedure:
To a suspended CH2Cl2 (2 ml) solution of 1-ethyl-2-iodoquinolinium iodide (493 mg, 1.2 mmol) was added a mixture of benzyl alcohol (108 mg, 1.0 mmol), phenylacetic acid (136 mg, 1.0 mmol) and tri-n-butylamine (444 mg, 2.4 mmol) in CH2Cl2 (2 ml), and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and benzyl phenylacetate was isolated in 95% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:22]([NH2:32])[C:23]1[CH:31]=[CH:30][C:29]2[O:28][CH2:27][O:26][C:25]=2[CH:24]=1>>[O:28]1[C:29]2[CH:30]=[CH:31][C:23]([CH2:22][N:32]3[C:6]([C:13]([OH:15])=[O:14])=[C:5]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=4)[C:8]3=[O:12])=[CH:24][C:25]=2[O:26][CH2:27]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: O=C(O)c1oc(=O)c2ccc(Cl)cc2c1-c1ccccc1
Product: O=C(O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc2c(c1)OCO2

Procedure:
The present compound was synthesized by a method similar to that in Example 226 and using 6-chloro-1-oxo-4-phenyl-1H-isochromen-3-carboxylic acid (400 mg) and piperonylamine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH2:28]([C@@H:30]1[CH2:34][O:33][C:32](=[O:35])[NH:31]1)[CH3:29]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:31]4[C@H:30]([CH2:28][CH3:29])[CH2:34][O:33][C:32]4=[O:35])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: CC[C@@H]1COC(=O)N1
Product: CC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(S(C)(=O)=O)c1
Yield: 42.4 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (874 mg) described in Preparation Example 61 and (R)-4-ethyloxazolidin-2-one (300 mg) described in Preparation Example 26, the title compound (399 mg) was obtained.
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]([CH2:8][C:9]2[C:10]([CH3:22])=[C:11]([CH3:21])[C:12]([CH:19]=C)=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:5]=1.CC(C)=[O:28].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[F:25][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:10]([CH3:22])=[C:11]([CH3:21])[C:12]([CH:19]=[O:28])=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:23][CH:24]=1
Reactant: CC(C)=O
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(OC(F)F)cc2)c(C)c1C
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Cc2ccc(OC(F)F)cc2)c(C)c(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(4-(difluoromethoxy)benzyl)-3,4-dimethyl-2-vinylbenzoate (0.16 g) in a mixed solvent of acetone (3.00 mL)-acetonitrile (3.00 mL)-water (3.00 mL) were added osmium oxide (fixed catalyst I) (0.06 g) and sodium periodate (0.49 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.04 g).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][C@@H:15]([CH3:18])[CH2:16][OH:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].[NH2:33][C@@H](C)CO>>[NH2:33][C:16]([C@H:15]([NH:14][C:12](=[O:13])[C:11]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:9]([N:6]2[C:7](=[O:8])[C:2]([Br:1])=[C:3]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[N:4]=[CH:5]2)[CH:10]=1)[CH3:18])=[O:17]
Reactant: Cc1ccc(C(=O)N[C@@H](C)CO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Reactant: C[C@H](N)CO
Product: Cc1ccc(C(=O)N[C@H](C)C(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 2 of the synthesis of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[(1S)-2-hydroxy-1-methylethyl]-4-methylbenzamide by substituting D-alanine amide HCl for (S)-(+)-2-amino-1-propanol. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.96 (m, 1H), 7.82 (m, 1H), 7.62 (q, 1H, J=8.0 Hz), 7.53 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.5.9 (m, 2H), 4.54 (q, 1H, J=6.0 Hz), 2.20 (s, 3H), 1.45 (d, 3H, J=6.0 Hz). ESHRMS m/z 521.0593 (M+H calculated for C22H20BrF2N4O4 requires 521.0630).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=1.C(C1C=C(B(O)O)C=CC=1)=O.BrC1C=CC=CN=1>>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)=[N:14][CH:15]=1)([O-:21])=[O:20]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Agent: Brc1ccccn1
Agent: O=Cc1cccc(B(O)O)c1
Product: O=Cc1ccc(-c2ccc([N+](=O)[O-])cn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 11 by substituting 4-formylphenylboronic acid and 2-bromo-5-nitropyridine for the 3-formylphenylboronic acid and 2-bromopyridine, respectively, of Reference Example 11. MS 229 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3](=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[C:3]([CH:2]=[P:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC(=O)CCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CCCCCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 24 h
Yield: 20.4 %

Procedure:
A solution of 1-chloroheptan-2-one (33 g.) and triphenylphosphine (60 g.) in chloroform (50 ml.) was saturated with nitrogen and refluxed under nitrogen overnight. The chloroform was removed in vacuo and the residue was dissolved in dichloromethane (150 ml.). Dry diethyl ether (600 ml.) was added to precipitate 2-oxoheptyltriphenylphosphonium chloride (60 g.), m.p. 165°-168° C. This compound (23 g.) was added portionwise to a solution of sodium carbonate (25 g.) in water (250 ml.) and the mixture was stirred vigorously for 24 hours. The solution was extracted with diethyl ether, and the ethereal extracts were dried over magnesium sulphate. The solvent was removed by evaporation and the residue was cooled and triturated with petroleum ether (b.p. 40°-60° C). The solid thus obtained was recrystallised from petroleum ether (b.p. 60°-80° C.) to give hexanoylmethylenetriphenylphosphorane (17 g.), m.p. 73°-74° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([NH:10]C(OC(C)(C)C)=O)=[N:7][C:6]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:29])[NH:25][CH:26]2[CH2:28][CH2:27]2)=[CH:20][CH:19]=1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([NH2:10])=[N:7][C:6]=1[C:18]1[CH:19]=[CH:20][C:21]([C:24](=[O:29])[NH:25][CH:26]2[CH2:28][CH2:27]2)=[CH:22][CH:23]=1)=[O:4]
Reactant: COC(=O)c1sc(NC(=O)OC(C)(C)C)nc1-c1ccc(C(=O)NC2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1sc(N)nc1-c1ccc(C(=O)NC2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-tert-Butoxycarbonylamino-4-(4-cyclopropylcarbamoyl-phenyl)-thiazole-5-carboxylic acid methyl ester (0.28 g, 6.71 mmol) and TFA (5 mL) in dichloromethane (5 mL) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo to give 2-Amino-4-(4-cyclopropylcarbamoyl-phenyl)-thiazole-5-carboxylic acid methyl ester; MS: 417.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:25]3[CH2:28][CH2:27][CH2:26]3)=[N:9][C:10]=2[C:11]2[CH2:12][CH2:13][N:14]([C:17](C3C=CC=CC=3)=[O:18])[CH2:15][CH:16]=2)[CH:5]=[CH:6][N:7]=1.[C:29]1([CH2:35]C(O)=O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:25]3[CH2:28][CH2:27][CH2:26]3)=[N:9][C:10]=2[C:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:18])[CH2:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:15][CH:16]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: Nc1nccn2c(C3CCC3)nc(C3=CCN(C(=O)c4ccccc4)CC3)c12
Product: Nc1nccn2c(C3CCC3)nc(C3=CCN(C(=O)Cc4ccccc4)CC3)c12

Procedure:
Prepared according to a procedure analogous to that described for synthesis of [4-(8-amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-3,6-dihydro-2H-pyridin-1-yl]-phenylmethanone except using phenyl-acetic acid. 1H NMR (400 MHz, CDCl3): δ 2.03 (dd, J=8.08, 3.03 Hz, 1H) 2.11-2.25 (m, 1H) 2.41-2.60 (m, 5H) 2.74 (br. s., 1H) 3.68-3.78 (m, 2H) 3.84 (s, 2H) 3.93 (t, J=5.68 Hz, 1H) 4.17 (d, J=2.53 Hz, 1H) 4.35 (d, J=2.53 Hz, 1H) 5.78-6.08 (m, 1H) 6.81 (t, J=6.06 Hz, 1H) 6.99 (d, J=5.56 Hz, 1H) 7.22-7.40 (m, 5H). MS (ES+): m/z 388.00 (100) [MH+]. HPLC: tR=2.19 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH:5]([NH2:10])[C:6]([F:9])([F:8])[F:7])[CH3:2].[C:12]1([CH3:24])[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[S:20](Cl)(=[O:22])=[O:21].S(Cl)(Cl)(=O)=O>N1C=CC=CC=1.Cl>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([NH:10][S:20]([C:13]1[C:14]([CH3:19])=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[CH3:24])(=[O:22])=[O:21])[C:6]([F:7])([F:8])[F:9])[CH3:2]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CCOC(=O)C(N)C(F)(F)F
Agent: Cl
Solvent: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(NS(=O)(=O)c1c(C)cc(C)cc1C)C(F)(F)F
Temperature: 70 °C
Reaction time: 3 h
Yield: 25.3 %

Procedure:
A mixture of 2.10 g (12.3 mmol) of 2-amino-3,3,3-trifluoropropionic acid ethyl ester and 2.80 g (12.8 mmol) of 2-mesitylenesulfonyl chloride in 10 mL of pyridine was warmed at 70° C. After 3 hours, TLC (ethyl acetate-hexanes (2:8)) indicated a new product (PMA stain) that was more polar then sulfonyl chloride. The mixture was then diluted with 1 N aqueous HCl and extracted with three 30 mL portions of ethyl acetate. The combined organic layers were washed with three 30 mL portions of 1 N aqueous HCl, 20 mL of brine, and three 20 mL portions of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate-hexanes (2-6% gradient) to afford 1.1 g (25%) of 3,3,3-trifluoro-2-(2,4,6-trimethylbenzenesulfonylamino)propionic acid ethyl ester.
Reaction SMILES: [C:1]1([C@H:11]([N:13]([CH2:21][C@@H:22]2[C@@H:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][N:24](C(=O)C(F)(F)F)[CH2:23]2)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1.CO>[C:1]1([C@H:11]([N:13]([CH2:21][C@@H:22]2[C@@H:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:25][NH:24][CH2:23]2)[C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)C(F)(F)F)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A 9.27 g portion of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenyl-1-(trifluoroacetyl)pyrrolidin-3-yl]methyl}carbamate was dissolved in 105 ml of THF-methanol (2:1), mixed with 35 ml of 1 M sodium hydroxide aqueous solution and stirred at room temperature for 1Hour. The reaction solution was concentrated under a reduced pressure, the residue was mixed with water and extracted with chloroform, and the organic layer was dried with anhydrous sodium sulfate. This was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol-aqueous ammonia) to obtain 6.97 g of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate as a colorless oily substance. FP: 431, NMR 1 (80° C.): 1.42 (9H, s), 1.45-1.55 (1H, m), 1.48 (3H, d, J=6.8 Hz), 2.23-2.30 (1H, m), 2.30-2.38 (1H, m), 2.48-2.57 (2H, m), 2.82-2.88 (1H, m), 2.87-2.92 (1H, m), 2.96-3.03 (1H, m), 5.95 (1H, q, J=6.8 Hz), 6.70-6.76 (2H, m), 7.04-7.17 (3H, m), 7.37 (1H, t, J=7.6 Hz), 7.39 (1H, m), 7.47-7.54 (2H, m), 7.81 (1H, m), 7.88-7.94 (1H, m), 8.02-8.09 (1H, m).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[C:12]([CH:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:1][CH2:2]1)([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:18]
Reactant: O=C1CCOc2ccccc21
Reactant: CCOC(=O)C(=O)OCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(=O)C1COc2ccccc2C1=O
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
A solution of 4-chromanone (11.2 g) and diethyl oxalate (13.3 g) in anhydrous dioxane (75 ml) is added under stirring at room temperature to a suspension of 50% sodium hydride (4 g) in anhydrous dioxane (150 ml). The mixture is allowed to react under stirring at 80° C. for 3.5 hours. After cooling, the reaction mixture is diluted with ice water and acidified to pH 4 with 40% citric acid aqueous solution. The oily precipitate is extracted with ethyl acetate, then the organic solution is washed with 40% citric acid and water until neutral. After evaporation of the solvent in vacuo the residue is purified over a SiO2 column using hexane/ethyl acetate 80:20 as eluent. Crystallization from isopropyl alcohol gives 3-ethoxalylchroman-4-one, m.p. 73°-75° C. (7.7 g), which is reacted with phenylhydrazine (3.68 g) in acetic acid (80 ml) at a temperature varying between 25° C. and about 40° C. for 30 minutes. The reaction mixture is diluted with ice water and then neutralized with 30% ammonium hydroxide. The precipitate is filtered and washed with water. Crystallization from isopropyl alcohol gives 1,4-dihydro-1-phenyl-[1]-benzopyrano[4,3-c]pyrazole-3-carboxylic acid, ethyl ester, m.p. 154°-156° C. (7.4 g), which is reacted with acetonitrile (74 ml) in dioxane (45 ml) in the presence of 50% sodium hydride (2.2 g) under stirring at 60° C. for 30 minutes. After cooling the reaction mixture is diluted with ice water and acidified to pH 4 with citric acid. The precipitate is filtered and washed with water and purified over a SiO2 column, using chloroform as eluent.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH:25]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]2=[O:32])[CH2:24][N:11]2[CH2:12][CH2:13][C:14]3[C:19]([CH:10]2[CH2:9]1)=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)(C)(C)C>C(O)C.CCCCCCC>[NH2:7][C@H:8]1[C@H:25]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]2=[O:32])[CH2:24][N:11]2[CH2:12][CH2:13][C:14]3[C:19]([C@H:10]2[CH2:9]1)=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3
Reactant: COc1cc2c(cc1OC)C1CC(NC(=O)OC(C)(C)C)C(N3CCCCC3=O)CN1CC2
Solvent: CCCCCCC
Solvent: CCO
Product: COc1cc2c(cc1OC)[C@H]1C[C@@H](N)[C@H](N3CCCCC3=O)CN1CC2

Procedure:
(RS,RS,RS)-[9,10-Dimethoxy-3-(2-oxo-piperidin-1-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester (580 mg, 1.61 mmol) was dissolved in ethanol/heptane 3:2 (5 mL) and subjected to preparative HPLC (Chiralpak® AD column, heptane/ethanol 80:20).
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=[O:7])(C)(C)C.[F:44][C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=1)C(Cl)=O>>[F:44][C:45]1[CH:53]=[C:52]([C:6]([NH:8][C@@H:9]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@@H:11]([CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]3)[CH2:10]2)=[O:7])[CH:51]=[CH:47][CH:46]=1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: O=C(Cl)c1cccc(F)c1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)c3cccc(F)c3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 34 in Step A and 3-fluorobenzoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([O:15][C:16](=[O:23])[NH:17][CH:18]1[CH2:21][C:20](=O)[CH2:19]1)([CH3:14])([CH3:13])[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCOC(C)=O>[C:11]([O:15][C:16](=[O:23])[NH:17][CH:18]1[CH2:21][C:20](=[CH2:1])[CH2:19]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1CC(=O)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C1CC(NC(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a three necked flask equipped with additional funnel which was cooled to −78° C. was added a solution of methyl(triphenyl)phosphonium bromide (43 g, 121 mmol) in anhydrous tetrahydrofuran (200 mL) under nitrogen protection. 1 M KHMDS in tetrahydrofuran (105 mL, 105 mmol) was then introduced dropwise over 40 minutes while the internal temperature was kept below −60° C. After addition, the mixture was stirred at −78° C. for 15 minutes. Then a solution of tert-butyl(3-oxocyclobutyl)carbamate (14 g, 81 mmol) in 100 mL of tetrahydrofuran was added slowly while the internal temperature was kept below −60° C. The resulting mixture was then warmed naturally to room temperature and stirred overnight. The resulting reaction mixture was diluted with EtOAc, and then washed with saturated aqueous solution of ammonium chloride and brine, then dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was purified by flash chromatography (EA:PE=1:10 to 1:2) to afford tert-butyl(3-methylidenecyclobutyl)carbamate (7.5 g).