Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]([CH3:21])([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11](O)=[O:12])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:29][OH:30].C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl.C1COCC1.O>[OH:30][NH:29][C:11](=[O:12])[C:10]([S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([CH3:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(SC(C)(Cc2ccccc2)C(=O)O)cc1
Reactant: NO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(SC(C)(Cc2ccccc2)C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid ethyl ester (4.12 g, 12 mmol) dissolved in methanol (50 ml) and 10 N NaOH (20 ml) was added. The reaction was allowed to stir overnight at room temperature. The reaction mixture was concentrated, diluted with 1:1 hexane:diethyl ether and extracted with H2O. The water layer was cooled with ice and acidified to pH 3. The acid was then extracted with chloroform and the organic layer was dried over MgSO4, filtered and concentrated to afford of 2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid as a low melting solid. Yield 580 mg, 16%; MS: 303.2 (M+H)+. To a stirred solution of 2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid (0.5 g, 1.65 mmol) and DMF (2 drops) in CH2Cl2 (100 ml) at 0° C., oxalyl chloride (1.0 gm, 8 mmol) was added in a drop-wise manner. After the addition, the reaction mixture was stirred at room temperature for 1 hour. Simultaneously, in a separate flask a mixture of hydroxylamine hydrochloride (2.0 gm, 29 mmol) and triethylamine (5 ml, excess) was stirred in THF:water (5:1, 30 ml) at 0° C. for 1 hour. At the end of 1 hour, the oxalyl chloride reaction mixture was concentrated and the pale yellow residue was dissolved in 10 ml of CH2Cl2 and added slowly to the hydroxylamine at OC. The reaction mixture was stirred at room temperature for 24 hours and concentrated. The residue obtained was extracted with chloroform and washed well with water. The product obtained was purified by silica gel column chromatography and eluted with ethyl acetate. The N-hydroxy-2-(4-methoxyphenylsulfanyl)-2-methyl-3-phenyl -propionamide was isolated as a colorless solid. mp 88° C.; Yield, 300 mg, 57%; MS: 318 (M+H)+; 1H NMR (300 Mz, CDCl3): δ 1.32 (s, 3H), 3.07 (d, J=11 Hz, 1H), 3.23 (d, J=11 Hz, 1H), 3.79 (s, 3H), 6.83-7.36 (m, 9H).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[N+](C1C=CC(OC(=O)[NH:44][C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:55][CH2:54][CH2:53][CH2:52]3)=[CH:47][CH:46]=2)=CC=1)([O-])=O>>[N:51]1([C:48]2[CH:49]=[CH:50][C:45]([NH:44][C:6]([N:8]3[CH2:13][CH2:12][CH:11]([C:14]4[C:23]5[C:18](=[CH:19][C:20]([N:26]6[CH2:27][CH2:28][O:29][CH2:30][CH2:31]6)=[C:21]([O:24][CH3:25])[CH:22]=5)[N:17]=[CH:16][N:15]=4)[CH2:10][CH2:9]3)=[O:5])=[CH:46][CH:47]=2)[CH2:52][CH2:53][CH2:54][CH2:55]1
Reactant: O=C(Nc1ccc(N2CCCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2c(C3CCN(C(=O)OC(C)(C)C)CC3)ncnc2cc1N1CCOCC1
Agent: Cl
Product: COc1cc2c(C3CCN(C(=O)Nc4ccc(N5CCCC5)cc4)CC3)ncnc2cc1N1CCOCC1

Procedure:
The title compound was prepared from 4-(6-methoxy-7-morpholin-4-yl-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester, prepared as described in Example 211a, and (4-pyrrolidin-1-yl-phenyl)-carbamic acid 4-nitro-phenyl ester hydrochloride, prepared as described in Example 74a, using essentially the protocol given for Example 170c. 1H-NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 7.37 (s, 1H), 7.25 (s, 1H), 7.19 (m, 2H), 6.53 (m, 2H), 6.21 (s, 1H), 4.26 (m, 2H), 4.05 (s, 3H), 3.94 (m, 4H), 3.57 (tt, 1H), 3.31-3.24 (m, 8H), 3.15 (td, 2H), 2.20-2.08 (m, 2H), 2.03-1.94 (m, 6H). LC/MS (ESI): calcd mass 516.3, found 517.3 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[F:10].[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][C@H:14]([CH3:18])[NH:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:13]2[C@@H:14]([CH3:18])[CH2:15][O:16][CH2:17][C@@H:12]2[CH3:11])=[CH:4][C:3]=1[F:10]
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: C[C@H]1COC[C@H](C)N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1COC[C@H](C)N1Cc1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 30.4 %

Procedure:
4-Bromo-3-fluorobenzaldehyde (0.250 g, 1.23 mmol) and (3S,5S)-3,5-dimethylmorpholine (0.205 g, 1.35 mmol) were dissolved in dichloromethane (10 mL). Sodium triacetoxyborohydride (0.378 g, 1.79 mmol) was added and the mixture was stirred under argon atmosphere at RT for 20 h. The mixture was diluted with dichloromethane and washed with NaHCO3 (aq). The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica eluting with gradients of ammonia in methanol and dichloromethane. The fractions containing product were pooled and evaporated to give (3S,5S)-4-(4-bromo-3-fluorobenzyl)-3,5-dimethylmorpholine (0.113 g, 30%) as a liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][NH:14][CH2:15][CH:7]1[C:6](=[O:16])[NH:5]2.[N:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][N:14]([CH2:23][C:20]3[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=3)[CH2:15][CH:7]1[C:6](=[O:16])[NH:5]2
Reactant: O=C1Nc2cc(F)ccc2N2CCNCC12
Reactant: ClCc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C1Nc2cc(F)ccc2N2CCN(Cc3ccncc3)CC12

Procedure:
A solution of 2 g. (0.008 mole) of 8-fluoro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one and 1.6 g. (0.01 mole) of 4-picolyl chloride, 3.5 g. of potassium carbonate and 0.5 ml. of triethylamine was stirred and refluxed in 100 ml. of acetone for 48 hours, cooled and filtered. The solvent was removed under reduced pressure. The residue was dissolved in ethanol and treated with dry hydrogen chloride saturated ether. The product hydrochloride was filtered and recrystallized from ethanol-water to yield 1.25 g. of the title compound as the dihydrochloride, m.p. 269°-272° C.
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([CH:7]([N:13]2[C:17]3[CH:18]=[CH:19][C:20]([NH:22][S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])=[CH:21][C:16]=3[N:15]=[CH:14]2)[CH2:8][C:9]([O:11]C)=[O:10])=[CH:3][CH:2]=1>Cl>[C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:2]=[CH:3][C:4]([CH:7]([N:13]2[C:17]3[CH:18]=[CH:19][C:20]([NH:22][S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])=[CH:21][C:16]=3[N:15]=[CH:14]2)[CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:6]=1
Reactant: COC(=O)CC(c1ccc(-c2ccccc2)cc1)n1cnc2cc(NS(=O)(=O)c3ccccc3)ccc21
Agent: Cl
Product: O=C(O)CC(c1ccc(-c2ccccc2)cc1)n1cnc2cc(NS(=O)(=O)c3ccccc3)ccc21

Procedure:
A solution of methyl 3-(1,1′-biphenyl)-4-yl-3-{5-[(phenylsulfonyl)amino]-1H-benzimidazol-1-yl}propanoate (12 mg, 23 μmol) in hydrochloric acid (10 mL of a 5N solution) was stirred at room temperature for 120 hours. The solution was evaporated in vacuo to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=5.04 min, MH+ 498].
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@@:4]([NH:27]C(=O)OC(C)(C)C)([CH2:7][C:8]#[C:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=3)[CH:13]=[CH:12][N:11]=2)[C:3]1=[O:35].OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C>[NH2:27][C@@:4]1([CH2:7][C:8]#[C:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=3)[CH:13]=[CH:12][N:11]=2)[CH2:5][CH2:6][N:2]([CH3:1])[C:3]1=[O:35]
Reactant: CN1CC[C@](CC#Cc2cc(-c3cccc(OC(F)(F)F)c3)ccn2)(NC(=O)OC(C)(C)C)C1=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN1CC[C@@](N)(CC#Cc2cc(-c3cccc(OC(F)(F)F)c3)ccn2)C1=O
Reaction time: 0.75 h
Yield: 97.1 %

Procedure:
A solution of tert-butyl N-[(3S)-1-methyl-2-oxo-3-[3-[4-[3-(trifluoromethoxy)phenyl]-2-pyridyl]prop-2-ynyl]pyrrolidin-3-yl]carbamate (8.91 g, 18.19 mmol) (which may be prepared as described in Description 106) in 1,4-dioxane (70 mL) was cooled in an ice bath and treated dropwise with conc. H2SO4 (7.4 mL, 93.22 mmol). The mixture was allowed to reach room temperature and after 45 mins, the mixture was again cooled in an ice bath and treated cautiously with satd. aq. Na2CO3 solution (˜150 ml). The mixture was diluted with ethyl acetate (200 ml) and the product was extracted into ethyl acetate (2×150 ml). The combined organic extracts were dried (Na2SO4) and concentrated to give the title compound (D107) as an orange oil (6.88 g, 97%) consistent spectroscopically with that prepared by Method A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([O:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][S:32][CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:40])([F:39])[F:38])=[CH:23][CH:22]=3)=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]3)=[CH:5][CH:4]=1.I([O-])(=O)(=O)=[O:44].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]([O:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][S:32]([CH2:33][CH2:34][CH2:35][C:36]([F:41])([F:42])[C:37]([F:40])([F:39])[F:38])=[O:44])=[CH:23][CH:22]=3)=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]3)=[CH:7][CH:8]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COc1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCCCSCCCC(F)(F)C(F)(F)F)cc2)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCCCS(=O)CCCC(F)(F)C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
Dissolve 6-(4-methoxy-phenyl)-5-{4-[4-(4,4,5,5,5-pentafluoro-pentylsulfanyl)-butoxy]-phenoxy}-naphthalen-2-ol (0.313 g, 0.516 mmol) in MeOH (15 mL). Add sodium periodate (0.122 g, 0.570 mmol) in H2O (2 mL). Stir overnight at room temperature. Extract with EtOAc (30 mL). Wash with H2O (15 mL), NaHCO3 (saturated solution, 15 mL), brine (20 mL). Dry the organics (Na2SO4), filter and concentrate in vacuo. Purify by radial chromatography (eluting with 50% EtOAc, 48% Hexanes, 2% MeOH) to afford 0.185 mg (58%) of the desired 6-(4-Methoxy-phenyl)-5-{4-[4-(4,4,5,5,5-pentafluoro-pentane-sulfinyl)-butoxy]-phenoxy}-naphthalen-2-ol as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J=8.8 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.47 (m, 3H), 7.19 (m, 1H), 7.02 (m, 1H), 6.82 (d, J=8:8 Hz, 2H), 6.57 (s, 4H), 3.76 (m, 5H), 2.65-2.84 (m, 4H), 2.10-2.25 (m, 4H), 1.79-1.93 (m, 4H). MS (ion spray): ES+: 623 (M+1); ES−: 621 (M−1).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](O)[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC3OCCOC=3C=2)[C:31](F)=[CH:30]N=1.C(C1C=CC(N)=CC=1)C>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:30][CH3:31])=[CH:22][CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: CCc1ccc(N)cc1
Product: CCc1ccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 4-ethylaniline were reacted to yield N4-(3,4-ethylenedioxyphenyl)-N2-(4-ethylphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.87 (bs, 1H), 7.42 (d, 2H, J=8.7 Hz), 7.26 (d, 1H, J=3.0 Hz), 7.13-7.08 (m, 3H), 6.95 (dd, 1H, J=2.4 and 8.7 Hz), 6.82 (d, 1H, J=9.0 Hz), 6.60 (bs, 1H), 4.23 (s, 4H), 2.59 (q, 2H, J=7.5 Hz), 1.20 (t, 3H, J=7.5 Hz); 19F NMR (CDCl3): −47549; LCMS: ret. time: 25.31 min.; purity: 99%; MS (m/e): 367 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[NH2:5][CH2:4][C:3]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:2]=1[NH2:1]
Reactant: N#Cc1cc(Cl)ccc1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCc1cc(Cl)ccc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
2-Amino-5-chloro-benzonitrile (9.0 g, 59 mmol) in tetrahydrofuran (100 ml) was added dropwise to an ice cooled 1 molar solution of lithium aluminium hydride (100 ml) in tetrahydrofuran and the reaction mixture was stirred at room temperature for 18 hours. Water (10 ml) was added dropwise. The resulting emulsion was dried over magnesium sulphate, filtered and evaporated under reduced pressure to give the title compound as a white solid (4.56 g).
Reaction SMILES: CO[C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:16]([S:17][CH3:18])=[C:15]3[C:10]([N:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:12](=[O:21])[N:13]([CH3:20])[C:14]3=[O:19])=[N:9]2)=[CH:5][CH:4]=1.BrCC1C=C[C:34]([S:37](C)(=[O:39])=[O:38])=CC=1>>[CH3:20][N:13]1[C:14](=[O:19])[C:15]2=[C:16]([S:17][CH3:18])[N:8]([CH2:7][C:6]3[CH:27]=[CH:28][C:3]([S:37]([CH3:34])(=[O:39])=[O:38])=[CH:4][CH:5]=3)[N:9]=[C:10]2[N:11]([CH2:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:12]1=[O:21]
Reactant: COc1ccc(Cn2nc3c(c2SC)c(=O)n(C)c(=O)n3CC(C)(C)C)cc1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Product: CSc1c2c(=O)n(C)c(=O)n(CC(C)(C)C)c2nn1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
The synthetic procedure of this compound is analogous to EXAMPLE 5 wherein 2-(4-methoxybenzyl)-5-methyl-3-(methylthio)-7-neopentyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione is used instead of 2-(4-methoxybenzyl)-5-methyl-7-neopentyl-3-(phenylthio)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione, and 1-(bromomethyl)-4-(methylsulfonyl)benzene is used instead of 1-(4-(bromomethyl)phenyl)-1H-1,2,4-triazole. MS (ESI) m/z 451.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[C:27]([F:32])=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:21]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1>CO>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C@:4]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[C:27]([F:32])=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:21]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:18])([F:17])[F:19])=[CH:11][CH:10]=2)[N:3]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)(F)F)cc2)(c2cccc(-c3cccnc3F)c2)N=C1N
Solvent: CO
Product: CN1C(=O)[C@@](c2ccc(OC(F)(F)F)cc2)(c2cccc(-c3cccnc3F)c2)N=C1N

Procedure:
A racemic mixture of 2-amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[4-(trifluoromethoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one was separated by chiral HPLC using Chiralcel AD, 2×25 cm (column) with mobile phase 9% EtOH in hexanes (0.1% diethtylamine) to give the title R-isomer: [α]25=−13.4 (1% in MeOH); 1H NMR (DMSOd6 300 MHz) δ 2.95 (s, 3H), 6.65 (brs, 2H), 7.28 (d, 2H), 7.4-7.45 (m, 3H), 7.5 (m, 1H), 7.55 (d, 2H), 7.65 (d, 1H), 7.95-8.0 (m, 1H), 8.2 (m, 1H); MS m/e (M+H)+ 445.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13]C(OCC3C=CC=CC=3)=O)[C:9]2=[O:24])=[CH:4][CH:3]=1>C(O)C.C1CCCCC=1.[OH-].[Pd+2].[OH-]>[NH2:13][C@@H:10]1[CH2:11][CH2:12][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]1=[O:24]
Reactant: O=C(N[C@@H]1CCN(c2ccc(Cl)cc2)C1=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: N[C@@H]1CCN(c2ccc(Cl)cc2)C1=O

Procedure:
To a solution of N-[(3R)-1-(4-chlorophenyl)-2-oxopyrrolidin-3-yl](phenylmethoxy)carboxamide (0.2 g, 0.58 mmol) in ethanol (10 ml) and cyclohexene (4 ml) was added palladium hydroxide (40 mg). The reaction was refluxed vigorously overnight. Palladium was removed by filtration and the filtrate was concentrated to yield (3R)-3-amino-1-(4-chlorophenyl)pyrrolidin-2-one.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH:22]([NH2:25])([CH3:24])[CH3:23]>>[CH:22]([NH:25][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])([CH3:24])[CH3:23]
Reactant: CC(C)N
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CC(C)Nc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Yield: 58 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with isopropylamine according to the GPA affording 19.6 mg (58%) of a red powder. Rt=4.44 min.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11](=[O:37])[C@@H:12]([NH:28][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:13][CH2:14][CH2:15][CH2:16][NH:17]C(OCC1C=CC=CC=1)=O)([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[H][H]>C(O)C.[Pd]>[CH3:9][C:2]([NH:10][C:11](=[O:37])[C@@H:12]([NH:28][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])([CH3:1])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)(NC(=O)[C@H](CCCCN)NC(=O)c1ccccc1)c1ccccc1
Yield: 106.5 %

Procedure:
1.73 g of (2S)-N-(α,α-dimethylbenzyl)-2-benzoylamino-6-(benzyloxycarbonylamino)hexanamide (prepared as described in Example 8) dissolved in 80 ml of ethanol and 4 ml of 1N hydrochloric acid was catalytically reduced by hydrogen gas in the presence of 0.33 g of 10% w/w palladium-on-carbon at room temperature. After filtering off the catalyst, the filtrate was concentrated by evaporation under reduced pressure to afford 1.35 g of the title compound as an amorphous substance melting at 94°-101° C. (with decomposition)
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].N1C=CC=CC=1.[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][C:7]1[CH:8]=[C:2]([F:1])[C:3]([NH2:4])=[C:5]([F:9])[CH:6]=1
Reactant: Nc1c(F)cccc1F
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Nc1c(F)cc(Br)cc1F
Yield: 83.6 %

Procedure:
252 g (1.95 mol) of 2,6-difluoroaniline and 170 g (2.15 mol) of anhydrous pyridine were dissolved in 780 cm3 of chloroform, and a solution of 328 g (2.05 mol) of bromine dissolved in 390 cm3 of chloroform was added dropwise for 2 hours on an ice water bath while stirring, after which it was stirred for 2 hours at room temperature. After washing the reaction solution with water, the chloroform was removed, the residue was distilled under reduced pressure (b. p. 100° C./30 mmHg), and the crystals obtained were recrystallized from hexane to obtain 340 g (1.63 mol) of 4-bromo-2,6-difluoroaniline.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].Br[C:21]1[CH:26]=[CH:25][C:24]([C:27]2([C:38]([F:41])([F:40])[F:39])[N:29]([Si](C)(C)C)[N:28]2[Si](C)(C)C)=[CH:23][CH:22]=1.C([Li])CCC>>[F:41][C:38]([F:39])([F:40])[C:27]1([C:24]2[CH:25]=[CH:26][C:21]([C:4]([C:3]3[CH:10]=[C:11]([C:14]#[C:15][Si:16]([CH3:17])([CH3:18])[CH3:19])[CH:12]=[CH:13][C:2]=3[NH2:1])=[O:5])=[CH:22][CH:23]=2)[NH:28][NH:29]1
Reactant: CON(C)C(=O)c1cc(C#C[Si](C)(C)C)ccc1N
Reactant: C[Si](C)(C)N1N([Si](C)(C)C)C1(c1ccc(Br)cc1)C(F)(F)F
Agent: [Li]CCCC
Product: C[Si](C)(C)C#Cc1ccc(N)c(C(=O)c2ccc(C3(C(F)(F)F)NN3)cc2)c1
Temperature: 25 °C
Yield: 58 %

Procedure:
2-amino-N-methoxy-N-methyl-5-[2-(trimethylsilyl)ethynyl]benzamide (403 mg, 1.5 mmol, 1 eq.) and 3-(4-bromophenyl)-3-(trifluoromethyl)-1,2-bis(trimethylsilyl)diaziridine (synthesized by a 5-step process: Bender et al., 2007, 599 mg, 1.5 mmol, 1 eq.) were added together in a round-bottom flask and purged with nitrogen. THF was added, and the reaction was stirred at room temperature until all solids dissolved. The reaction was then cooled to −80° C. in a diethyl ether/dry ice bath, and 2.5 M n-butyllithium in hexanes (1.0 mL, 2.6 mmol, 1.8 eq.) was added, causing the reaction to turn a dark red color. The reaction was stirred at −80° C. for 2 hours and then quenched with saturated ammonium chloride solution (20 mL). The quenched reaction was extracted three times with ethyl acetate (50 mL each). The organic layer was then dried over sodium sulfate, and the solvent was evaporated. Purification on silica column (hexanes/ethyl acetate, 3:1→1:1) resulted in 342 mg (58%) of the title compound as a yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.69 (dd, J=8.2, 37.0, 4H, Ar—H), 7.50 (d, J=1.8, 1H, Ar—H), 7.37 (dd, J=1.9, 8.6, 1H, Ar—H), 6.65 (d, J=8.6, 1H, Ar—H), 6.32 (s, 2H, NH2), 2.88 (d, J=8.6, 1H, CNH), 2.32 (d, J=8.8, 1H, CNH), 0.18 (s, 9H, Si(CH3)3). 13C NMR (126 MHz, CDCl3) δ 197.58 (CO), 151.25 (C—Ar), 141.43 (C—Ar), 138.23 (C—Ar), 138.06 (C—Ar), 134.66 (C—Ar), 129.57 (C—Ar), 128.37 (q, C—Ar, J=0.57), 123.55 (q, J=278.40, CF3), 117.35 (C—Ar), 117.19 (C—Ar), 110.28 (C—Ar), 104.90 (CSi(CH3)3), 92.18 (CCSi(CH3)3), 58.05 (q, J=36.3, C(NH)2), 0.25 (Si(CH3)3). Exact Mass, 403.13. 402.1046 [M−H]−, 404.1982 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:22])=[C:7]([C:14]([NH:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:15])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][CH:3]=1.[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])#[CH:24].C(N(C(C)C)C(C)C)C.O1CCCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:21][O:20][C:18](=[O:19])[CH2:17][NH:16][C:14]([C:7]1[C:8](=[O:13])[N:9]([CH3:12])[C:10]2[C:5]([C:6]=1[OH:22])=[CH:4][CH:3]=[C:2]([C:24]#[C:23][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:11]=2)=[O:15]
Reactant: COC(=O)CNC(=O)c1c(O)c2ccc(Br)cc2n(C)c1=O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)CNC(=O)c1c(O)c2ccc(C#C[Si](C)(C)C)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.3 %

Procedure:
In a sealed tube was combined methyl 2-(7-bromo-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (0.75 g, 2.0 mmol), Dichlorobis(triphenylphosphine)palladium(II) (0.14 g, 0.20 mmol), copper(I) iodide (0.077 g, 0.41 mmol), ethynyltrimethylsilane (1.4 ml, 10 mmol), and N-ethyl-N-isopropylpropan-2-amine (2.8 ml, 16 mmol) in tetrahydrofuran (20.0 ml, 2.0 mmol). The tube was flushed with Ar, sealed, and placed in an oil bath at 100° C. for 5 hours. The dark mixture was cooled to rt, filtered and washed with ethyl acetate (2×30 mL). The crude mixture was concentrated, adsorbed onto silica and purified by flash chromatography (15% to 40% EtOAc:Hex gradient) to afford the product as a solid (0.59 g, 75% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1OC
Solvent: CC(=O)O
Product: COc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1OC
Yield: 89.6 %

Procedure:
To acetic acid (130 ml) was added 1-benzyl-4-(3,4-dimethoxyphenyl)piperidine-4-ol (26.0 g, 79.4 mmol) obtained in Reference Example 14. The mixture was refluxed for 3 hours. The reaction mixture was concentrated, and the residue was made to basic with a solution of potassium carbonate and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residual crystals were washed with hexane to obtain 22.0 g (yield 90%) of the title compound. mp. 94–96° C.