Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH:10]([C:17]#[N:18])[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20]C1C=CC(C(Cl)=O)=CC=1>>[CH3:19][O:20][C:5]1[CH:4]=[CH:3][C:2]([C:1]([O:9][CH:10]([C:17]#[N:18])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:8])=[CH:7][CH:6]=1
Reactant: N#CC(OC(=O)c1ccccc1)c1ccncc1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)OC(C#N)c2ccncc2)cc1

Procedure:
The title compound was prepared using the same procedure Lantos, I. et al. (J. Med. Chem. 1984, 27, 72-75) employed to prepare 1-cyano-1(4-pyridyl)-methyl benzoate, except using 4-methoxybenzoyl chloride: 1H NMR (CDCl3): d 8.81 (d, 2H); 8.10 (d, 2H); 7.57 (d, 2H); 7.01 (d, 2H); 6.74 (s, 1H); 3.93 (s, 3H).
Reaction SMILES: CC([O-])(C)C.[K+].[N+:7]([CH3:10])([O-:9])=[O:8].[O:11]=[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][N:13]1[CH:22]([C:35](=[O:37])C)[CH:23]([NH:31][C:32]([CH3:34])=[O:33])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C)C=O>[O:11]=[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][N:13]1[CH:22]([CH:35]([OH:37])[CH2:10][N+:7]([O-:9])=[O:8])[CH:23]([NH:31][C:32]([CH3:34])=[O:33])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: CC(=O)NC(C(=O)OC(C)(C)C)C(C(C)=O)N1CCc2ccccc2C1=O
Reactant: C[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)NC(C(=O)OC(C)(C)C)C(C(O)C[N+](=O)[O-])N1CCc2ccccc2C1=O
Yield: 64.1 %

Procedure:
To 1.15 g (10.0 mMol) of KOtBu (potassium tertbutoxide) in dimethylformamide (30 mL) at 0° C. under nitrogen and nitromethane (1.75 mL, 32.5 mMol) was added 3-(1,2,3,4-tetrahydro-1-oxo-isoquinoline-2-yl)-acetamino-4-oxo-pentanoic acid, tert-butyl ester (3.6 g, 10.0 mMol). After 3 hours at 0° C. the reaction was quenched by addition of 1.5 mL of acetic acid and partitioned between ethyl acetate (200 mL) and water (20 mL). The organic phase was washed with saturated aqueous sodium hydrogen carbonate and water, dried over sodium sulfate, and concentrated under reduced pressure. Purification of the residue over silica (elution with dichloromethane/methanol 20:1) gave 2.7 g of 3-(1, 2, 3, 4-tetrahydro-1-oxo-isoquinoline-2-yl)-acetamino-4-hydroxy-5-nitro-pentanoic acid, tert-butyl ester as 1:1 mixture of diastereomers.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[S:11]([N:21]([CH2:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][C@H:27]1[CH2:28][OH:29])=[O:25])[CH3:22])([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[S:11]([N:21]([CH2:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][C@H:27]1[CH:28]=[O:29])=[O:25])[CH3:22])([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:12])=[O:13]
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)N2CCC[C@H]2CO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)N(C)CC(=O)N2CCC[C@H]2C=O)cc1
Reaction time: 0.08 h
Yield: 62.3 %

Procedure:
In the next step, a solution of dimethyl sulfoxide (DMSO) (35.3 ml, 0.491 mol) in methylene chloride (970 ml) is added dropwise, over a period of 2.5 hours at -60° C. under an atmosphere of nitrogen, to a solution of oxalyl chloride (44.7 ml, 0.491 mol) in methylene chloride (970 ml), and the mixture is stirred for a further five minutes. A solution of N-tosylsarcosyl-L-prolinol (80 g, 0.245 mol) in methylene chloride (950 ml) is then added dropwise to the mixture over a period of 75 minutes, and the mixture is stirred for a further thirty minutes. Triethylamine (348 ml, 2.45 mol) is then added dropwise thereto over a period of ten minutes, and the mixture is stirred for a further ten minutes. After brought back to room temperature, the mixture is washed with water (2 l×2) and the organic layer is concentrated to dryness under reduced pressure. The residue is dissolved in ethanol (320 ml), and the solution is vigorously stirred for 15 minutes after addition of a saturated aqueous solution of sodium hydrogen carbonate (250 ml) and water (438 ml). The ethanol is then distilled off under reduced pressure, and water (600 ml) is added to the residue. The mixture is extracted with chloroform (300 ml) and ether (500 ml×2) and the organic layers are discarded. The aqueous layers are adjusted with potassium carbonate to a pH higher than 10 and extracted with chloroform. The organic layer is separated, washed successively with water (500 ml×2), 1N hydrochloric acid (500 ml) and water (500 ml), dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give N-tosylsarcosyl-L-prolinal (49.5 g, 62.3%).
Reaction SMILES: [O:1]=[C:2]1[NH:10]/[C:9](=[N:11]\[N:12]=[CH:13]/[CH2:14][CH2:15][NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)/[N:8]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:7]2[N:6]=[CH:5][NH:4][C:3]1=2>C(O)(=O)C>[CH2:19]([O:18][C:17](=[O:26])[NH:16][CH2:15][CH2:14][C:13]1[N:10]2[C:2](=[O:1])[C:3]3[NH:4][CH:5]=[N:6][C:7]=3[N:8]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:9]2=[N:11][N:12]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCCCCn1/c(=N/N=C\CCNC(=O)OCc2ccccc2)[nH]c(=O)c2[nH]cnc21
Solvent: CC(=O)O
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(CCNC(=O)OCc3ccccc3)nnc12
Yield: 54.8 %

Procedure:
A mixture of benzyl (3Z)-3-[(2E)-(6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene)hydrazono]propylcarbamate (4.0 g, 5.6 mmol) in acetic acid (50 mL) was refluxed in the air overnight. The mixture was concentrated and purified by preparative LCMS to give the desired product (1.3 g, 54% yield) as a white solid. LCMS calculated for C21H26N7O3 (M+H): 424.2. found: 424.2.
Reaction SMILES: [CH3:1][CH:2]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20]C)=[O:19])[CH2:3][C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:7](=[O:14])[NH:6][N:5]=1.O[Li].O>O1CCCC1.O>[CH3:1][CH:2]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([OH:20])=[O:19])[CH2:3][C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:7](=[O:14])[NH:6][N:5]=1
Reactant: COC(=O)c1cccc(C(C)Cc2n[nH]c(=O)c3c2CCCC3)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(Cc1n[nH]c(=O)c2c1CCCC2)c1cccc(C(=O)O)c1

Procedure:
A solution of EXAMPLE 266 (50 mg, 0.16 mmol) in tetrahydrofuran (10 ml) was treated with a solution of LiOH.H2O (100 mg, 4 mmol) in water (4 ml) at 50° C. overnight. The mixture was concentrated, and the residue was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound. MS (DCI/NH3) m/z 313 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:12])[C:9]([OH:11])=O.[CH2:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:13]([N:20]1[CH2:25][CH2:24][N:23]([C:9](=[O:11])[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH3:12])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CC(C(=O)O)c1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C(=O)N1CCN(Cc2ccccc2)CC1)c1ccccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.7 %

Procedure:
2-(2-Fluorophenyl)propanoic acid (7.7 g, 0.046 mol), 1-benzylpiperazine (8.0 g, 0.045 mol), triethylamine (4.6 g, 0.046 mol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (9.6 g, 0.050 mol) were dissolved in dichloromethane (150 ml) and stirred at room temperature for 18 h. The solution was evaporated and the residue diluted with water and extracted with brine, dried and evaporated. Chromatography on silica gel with dichloromethane-methanol (97:3) yielded 4-benzyl-1-[2-(2-fluorophenyl)propanoyl]piperazine (5.54 g, 38%) as an oil.
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5]([CH3:13])([C:7]1[N:8]=[CH:9][N:10]([CH3:12])[CH:11]=1)[CH3:6])C.[OH-].[Na+]>CO>[CH3:13][C:5]([C:7]1[N:8]=[CH:9][N:10]([CH3:12])[CH:11]=1)([CH3:6])[C:4]([OH:14])=[O:3]
Reactant: CCOC(=O)C(C)(C)c1cn(C)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cnc(C(C)(C)C(=O)O)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
1.96 g of 2-methyl-2-(1-methyl-1H-imidazol-4-yl)-propionic acid ethyl ester is taken up in 10 ml of methanol and the mixture is admixed with 10 ml of 3M NaOH. The mixture is then stirred at 60° C. for 16 hours. The methanol is removed in vacuo and the aqueous residue acidified with 2M HCl to pH 7. The mixture is concentrated under reduced pressure. The residue is taken up in 10 ml of ethanol and the insoluble salts removed by filtration. Concentration of the filtrate under reduced pressure provides the title compound which can be used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](S)=[N:10][C:9]=2[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[Fe]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[S:12][CH:11]=[N:10][C:9]=2[CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2sc(S)nc2c1
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc2scnc2c1

Procedure:
Following the same procedure as in step 2 of Example 337 using 5-tert-butyl-1,3-benzothiazole-2-thiol (1.2 g, 5.36 mmol, 1.00 equiv), and iron powder (3.0 g, 53.57 mmol, 10.00 equiv) in acetic acid (60 mL). 1.12 g (crude) of the title compound was obtained as a yellow liquid, which was used directly for next step without further purification. 1H-NMR (400 MHz, DMSO-d6): δ ppm δ 1.459(s, 9H), 7.544(dd, J=1.6 Hz, J=8.8 Hz, 1H), 7.897(d, J=8.8 Hz, 1H), 8.187(d, J=1.6 Hz, 1H), 9.00(s, 1H).
Reaction SMILES: N[CH:2]1[CH2:7]C[CH:5]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][C@@H:13]([NH2:16])[CH2:12]2)=[O:10])[CH2:4][CH2:3]1.C(OC(=O)[NH:23]C1CCNCC1)(C)(C)C>>[NH2:23][CH:3]1[CH2:2][CH2:7][N:8]([C:9]([N:11]2[CH2:15][CH2:14][C@@H:13]([NH2:16])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: NC1CCC(NC(=O)N2CC[C@@H](N)C2)CC1
Product: NC1CCN(C(=O)N2CC[C@@H](N)C2)CC1

Procedure:
(4-Amino-piperidin-1-yl)-((R)-3-amino-pyrrolidin-1-yl)-methanone is prepared analogously to (R)-3-amino-pyrrolidine-1-carboxylic acid (4-amino-cyclohexyl)-amide (Intermediate IF) by replacing (4-amino-cyclohexyl)-carbamic acid tert-butyl ester with piperidin-4-yl-carbamic acid tert-butyl ester.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([F:17])[C:11]=1[F:18])(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.Cl>C1COCC1>[F:18][C:11]1[C:12]([F:17])=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]=1[CH2:9][OH:8]
Reactant: Cc1ccc(CO[Si](C)(C)C(C)(C)C)c(F)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(CO)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl-(2,3-difluoro-4-methyl-benzyloxy)-dimethyl-silane (6.5 g, 24 mmol) in THF (24 mL) was added tetrabutylammonium fluoride (24 mL of a 1M solution in THF, 24 mmol). After stirring at ambient temperature for 1 hour, the mixture was poured into water, acidified with 1M aqueous HCl, extracted 3× with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (10:1 to 2:1 hexane-ethyl acetate), affording (2,3-Difluoro-4-methyl-phenyl)-methanol as a light yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:7]1[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1
Reactant: Brc1ccccn1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: O=C(O)c1ccc(-c2ccccn2)cc1

Procedure:
Production Example 14 was repeated except that 4-carboxyphenylboronic acid and 2-bromopyridine were used, to provide the title compound as white solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]#[CH:15])(=O)=O)=CC=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CCO>[CH2:12]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH2:13][C:14]#[CH:15]
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: C1CNCCN1
Solvent: CCO
Product: C#CCCN1CCNCC1

Procedure:
A solution of but-3-ynyl 4-methylbenzenesulfonate (2.0 mL) and piperazine (2.0 g) in EtOH (6 mL) was heated to reflux for 30 min. The mixture was concentrated, diluted with NaOH 2 M (8 mL) and extracted with Et2O (50 mL). Evaporation of the organic layer gave a 2:1 mixture of mono and bis-alkylated piperazine (450 mg) which was discarded. The aqueous layer was further extracted with DCM (100 mL) to give of 1-(but-3-ynyl)piperazine (640 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[CH3:16].[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][CH:24]=2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[NH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([CH:20]2[CH2:21][CH2:22][N:17]([CH2:2][CH2:3][C:4]3[C:9](=[O:10])[N:8]4[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:7]4=[N:6][C:5]=3[CH3:16])[CH2:18][CH2:19]2)=[CH:24]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: Cc1nc2cccc(C)n2c(=O)c1CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: Cc1nc2cccc(C)n2c(=O)c1CCN1CCC(c2c[nH]c3ccccc23)CC1
Yield: 31 %

Procedure:
A mixture of 4.8 parts of 3-(2-chloroethyl)-2,6-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one, 4 parts of 3-(4-piperidinyl)-1H-indole, 8.5 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone is stirred and refluxed overnight using a water-separator. The reaction mixture is cooled, water is added and the precipitated product is filtered off. It is dissolved in a mixture of trichloromethane and methanol (90:10 by volume). The solution is filtered over silica gel and the filtrate is evaporated. The residue is crystallized from 2-propanol, yielding 2.5 parts (31%) of 3-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-2,6-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 224.9° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]([C:23]2[CH:36]=[CH:35][C:26]([O:27][CH2:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[C:25]([CH3:37])[CH:24]=2)([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]([OH:21])[CH2:19][OH:20])=[C:12]([CH3:22])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[OH:21][C@@H:18]([CH2:19][OH:20])[CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2([C:23]3[CH:36]=[CH:35][C:26]([O:27][CH2:28][CH:29]([OH:34])[C:30]([CH3:31])([CH3:32])[CH3:33])=[C:25]([CH3:37])[CH:24]=3)[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]2)=[CH:11][C:12]=1[CH3:22]
Reactant: CC(=O)N1CCC(c2ccc(OCC(=O)C(C)(C)C)c(C)c2)(c2ccc(OCC(O)CO)c(C)c2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)N1CCC(c2ccc(OCC(O)C(C)(C)C)c(C)c2)(c2ccc(OC[C@@H](O)CO)c(C)c2)CC1
Yield: 69.5 %

Procedure:
To a solution of 1-(4-{1-acetyl-4-[4-(2,3-dihydroxypropoxy)-3-methylphenyl]-piperidin-4-yl}-2-methylphenoxy)-3,3-dimethylbutan-2-one (0.14 g, 0.28 mmol) in anhyd MeOH (3 mL) cooled to 0° C. was added sodium borohydride (11 mg, 0.29 mmol). After 8 h the reaction was quenched with water and extracted with EtOAc (2×20 mL). The combined extracts were washed with brine, dried (anhyd Na2SO4), concentrated under reduced pressure and purified by reverse-phase HPLC (C18 column), eluting with 0.05% TFA in MeCN—H2O (1:9 to 9:1) to provide the title compound (0.10 g, 73%) as a white solid: 1H-NMR (CDCl3) δ 6.96-7.01 (4H, m), 6.74 (2H, d, J=8.3), 4.05-4.14 (2H, m), 4.03 (2H, m), 3.82-3.88 (2H, m), 3.74-3.80 (1H, dd, J=5.3, 11.4), 3.67-3.71 (1H, dd, J=2.8, 8.6), 3.64 (2H, m), 3.47 (2H, m), 2.27-2.36 (4H, m), 2.19 (3H, s), 2.18 (3H, s), 2.08 (3H, s), 1.00 (9H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:27])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]([CH3:26])=[CH2:25])[C:5]2=[CH:4][CH:3]=1.[CH3:28][O:29][CH:30]([Si:32]([CH3:35])([CH3:34])[CH3:33])[CH3:31].Br[CH2:37][C:38]([NH2:40])=[O:39].C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[NH2:40][C:38]([CH2:37][N:12]1[C:13](=[O:23])[CH2:14][CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:10]2([C:5]3[C:6](=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[NH:8][C:9]2=[O:27])[CH:11]1[C:24]([CH3:26])=[CH2:25])=[O:39].[CH3:28][O:29][CH:30]([Si:32]([CH3:35])([CH3:34])[CH3:33])[CH3:31]
Reactant: C=C(C)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12
Reactant: NC(=O)CBr
Agent: COC(C)[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(C)C1N(CC(N)=O)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
To a mixture of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (100 mg, 0.17 mmol) and 2-bromo-acetamide (72 mg, 0.52 mmol) in DMF (1 mL) was added Cs2CO3 (332 mg, 1.01 mmol). The mixture was stirred at room temperature for overnight. Then additional 2-bromo-acetamide (72 mg, 0.52 mmol) and Cs2CO3 (332 mg, 1.01 mmol) were added to the reaction mixture. The resulting mixture was heated at 50° C. for 2 h, then poured into ethyl acetate (20 mL). The organic layer was washed with water 3 times, dried over Na2SO4, purified by column chromatography to give title compound 60 mg.
Reaction SMILES: [F:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N1CC[C@H](O)C1)(OC(C)(C)C)=O.COCCN(S(F)(F)F)CCOC>ClCCl>[F:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](F)C1
Agent: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](F)C1

Procedure:
Prepare using the method of Intermediate 48 with N-Boc-(S)-(+)-3-pyrrolidinol (0.50 g, 2.67 mmol), [bis(2-methoxyethyl)amino]sulfur trifluoride (0.59 mL, 3.20 mmol) and anhydrous dichloromethane (4 mL) to give the title compound as a colourless oil (0.36 g): MS (m/e): 212 (M+23).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[CH2:29][OH:30])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([NH:19]C)(=[O:18])=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(S(Cl)(=O)=O)CCCC.[CH3:40][NH:41][CH3:42]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[CH2:29][OH:30])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([NH:19][N:41]([CH3:42])[CH3:40])(=[O:17])=[O:18])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CNS(=O)(=O)CCC[C@@H](C)N(c1cc(Cl)ccc1CO)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CNC
Agent: CCCCCS(=O)(=O)Cl
Product: C[C@H](CCCS(=O)(=O)NN(C)C)N(c1cc(Cl)ccc1CO)S(=O)(=O)c1ccc(Cl)cc1
Yield: 73 %

Procedure:
4-chloro-N-[5-chloro-2-(hydroxymethyl)phenyl]-N-[4-(dimethylaminoaminosulfonyl)-1(R)-methylbutyl]-benzenesulfonamide was prepared analogous to 4-chloro-N-[5-chloro-2-(hydroxymethyl)phenyl]-N-[4-[(methylamino)sulfonyl]-1(R)-methylbutyl]benzenesulfonamide by reacting (4R)-4-[5-chloro-2-(acetoxymethyl)phenyl][4-chlorophenyl)sulfonyl]-amino]pentylsulfonyl chloride with dimethylamine. Yield=73%; MS (ESI+), 509 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:8]([NH:18]C(=O)OC(C)(C)C)[C@@H:9]([OH:17])[C@H:10]([OH:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>>[NH2:18][C@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([OH:17])[C@H:10]([C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[OH:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)[C@H](O)[C@@H]1CCCN1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](Cc1ccccc1)[C@@H](O)[C@@H](O)[C@@H]1CCCN1

Procedure:
The configuration inversion at C-7 of the methyl (5E,7R,8S)-8-[(tert-butoxycarbonyl)amino]-7-hydroxy-9-phenyl-non-5-enoate (4) is obtained in three steps. Initially the amino alcohol (4) is converted to oxazolidinone by treating with methanesulfonyl chloride (Benedetti, F.; Norbedo, S. Tetrahedron Lett. 2000, 39, 10071); thus methyl (5E)-6-[(4S,5S)-4-benzyl-2-oxo-1,3-oxazolidin-5-yl]hex-5-enoate (14) is obtained. The oxazolidinone is reprotected at the nitrogen with di-tert-butyl dicarbonate to give (4S,5S)-tert-butyl 5-[(E)-5-(methoxycarbonyl)pent-1-enyl]-4-benzyl-2-oxooxazolidin-3-carboxylate (15) which is then hydrolysed under controlled conditions (two equivalents of K2CO3, or Cs2CO3) in aqueous methanol. The methyl (5E,7S,8S)-8-[(tert-butoxycarbonyl)amino]-7-hydroxy-9-phenyl-non-5-enoate (16) with (S) configuration at the C7 thus obtained is then converted, by applying the aforedescribed method for the synthesis of benzyl 3-((2R,3R)-3-{[(1S,2S)-1-hydroxy-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}oxiran-2-yl)propylcarbamate (9), to benzyl 3-((2S,3S)-3-{[(1R,2S)-1-hydoxy-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}oxiran-2-yl)propylcarbamate (17). By deprotecting this epoxyamine by catalytic hydrogenation, tert-butyl (1S,2R,3R)-1-benzyl-2,3-dihydroxy-3-[(2R)-pyrrolidin-2-yl]propylcarbamate (18) is thus obtained which is converted into the corresponding [(1S,2R,3R)-3-amino-4-phenyl-1-[(2R)-pyrrolidin-2-yl]butan-1,2-diol] (13) by treating with TFA. Opening the epoxide ring of benzyl 3-((2S,3S)-3-{[(1R,2S)-1-hydoxy-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}oxiran-2-yl)propylcarbamate (17) with lithium bromide and Amberlist 15 (Bonini, C. et al. Synth. Commun. 1992, 22, 1863; Bonini, C., Righi, G. Synthesis 1994, 225) gives the bromoalcohol benzyl (4R,5R,6R,7S)-4-bromo-7-[(tert-butoxycarbonyl)amino]-5,6-dihydroxy-8-phenyl-octylcarbamate (19) which, by catalytic hydrogenation, cyclizes to give tert-butyl (1S,2R,3R)-1-benzyl-2,3-dihydroxy-3-[(2S)-pyrrolidin-2-yl]propylcarbamate (20); finally, deprotecting the primary amino group with TFA gives [(1S,2R,3R)-3-amino-4-phenyl-1-[(2S)-pyrrolidin-2-yl]butan-1,2-diol] (12).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH:24]1[CH2:29][C:28](=[O:30])[CH:27]=[CH:26][CH2:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.[C-:37]#[N:38].[K+].[Cl-].[Na+]>CCOCC.C(O)C.O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:22])([CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[C@H:24]1[CH2:25][C@H:26]([C:37]#[N:38])[CH2:27][C:28](=[O:30])[CH2:29]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: CCCCCCC(C)(C)c1ccc(C2CC=CC(=O)C2)c(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCCCC(C)(C)c1ccc([C@@H]2CC(=O)C[C@@H](C#N)C2)c(OCc2ccccc2)c1
Yield: 71 %

Procedure:
To a refluxing solution of 3.99 g. (9.87 mmole) of 5-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-cyclohexen-1-one in 6.65 ml. of ethyl acetate was added a hot solution of 800 mg. (11.9 mmole) of potassium cyanide in 2 ml. water and 2.3 ml. ethanol. The reaction was refluxed 2 hours and then another 2.74 mmole of potassium cyanide added. The reaction was refluxed one hour longer and then cooled and added to 400 ml. saturated sodium chloride-400 ml. ether. The ether extract was dried over magnesium sulfate and evaporated to yield an oil. The crude oil was purified via column chromatography on 160 g. of silica gel eluted with 10% acetone-hexane to yield 3.02 g. (71%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[C:6]([CH:11]=1)[N:7]([CH3:10])[CH:8]=O.CCCCCC>N1C=CC=CC=1>[F:1][C:2]1[CH:11]=[C:6]2[C:5]([C:12](=[O:18])[C:13]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][N:7]2[CH3:10])=[CH:4][CH:3]=1
Reactant: CN(C=O)c1cc(F)ccc1C(=O)CS(C)(=O)=O
Solvent: CCCCCC
Solvent: c1ccncc1
Product: Cn1cc(S(C)(=O)=O)c(=O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 5'-fluoro-N-methyl-2'-methylsulphonylacetylformanilide (0.85 g), prepared in a similar manner to that described in Example 11, in pyridine (85 ml) was stirred at ambient temperature for 3 days. The mixture was added to hexane (180 ml) and the solid collected by filtration was dried at 50° in vacuo to give 7-fluoro-1-methyl-3-methylsulphonyl-4-quinolone, m.p.234°-235° (0.49 g).