Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:22]([NH2:24])=[O:23])[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH:25](OCC)(OCC)OCC>>[CH2:15]([N:12]1[CH2:13][CH2:14][C:9]2([N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:25]=[N:24][C:22]2=[O:23])[CH2:10][CH2:11]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(OCC)OCC
Reactant: NC(=O)C1(Nc2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Product: O=C1N=CN(c2ccc(Cl)cc2)C12CCN(Cc1ccccc1)CC2
Temperature: 150 °C
Reaction time: 240 h

Procedure:
4-(4-chloro-phenyl-amino)-1-(phenylmethyl)-4-piperidine-carboxamide (6.47 g) was dissolved in 31 ml triethyl orthoformate and stirred at 150° C. for 10 d. After cooling to 0° C., the reaction mixture was filtered and the light brown powder washed with ether to yield 8-benzyl-1-4-chloro-phenyl-1,3,8-triazaspiro[4,5]dec-2-en-4-one (3.90 g). M.p. 217-219° C.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[S:8][C:9]([C:11]([O-:13])=O)=[N:10][C:4]=2[CH2:3]1.[Li+].[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH:31]([C:35](=[O:41])[NH:36][CH2:37][CH2:38][O:39][CH3:40])[CH2:30]1)(=[O:28])=[O:27])[CH:20]=[CH:19]2>>[ClH:15].[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([S:26]([N:29]1[CH2:34][CH2:33][N:32]([C:11]([C:9]3[S:8][C:5]4[CH2:6][NH:7][CH:2]([CH3:1])[CH2:3][C:4]=4[N:10]=3)=[O:13])[CH:31]([C:35](=[O:41])[NH:36][CH2:37][CH2:38][O:39][CH3:40])[CH2:30]1)(=[O:27])=[O:28])[CH:20]=[CH:19]2
Reactant: CC1Cc2nc(C(=O)[O-])sc2CN1
Reactant: COCCNC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1
Agent: [Li+]
Product: COCCNC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1nc2c(s1)CNC(C)C2
Product: Cl

Procedure:
Starting materials: lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate, 4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-[[N-(2-methoxyethyl)]carbamoyl]piperazine
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([CH2:12][C@H:13]([N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH3:24])[CH2:14][O:15]CC1C=CC=CC=1)[CH2:8][CH:9]([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.CC(O)=O.[Pd]>[C:1]([O:5][C:6](=[O:32])[N:7]([CH2:12][C@H:13]([N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH3:24])[CH2:14][OH:15])[CH2:8][CH:9]([F:10])[F:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](COCc1ccccc1)CN(CC(F)F)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C(=O)OC(C)(C)C)[C@H](CO)CN(CC(F)F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
To a solution of [(S)-3-Benzyloxy-2-(tert-butoxycarbonyl-methyl-amino)-propyl]-(2,2-difluoro-ethyl)-carbamic acid tert-butyl ester (2.42 g, 5.28 mmol) in MeOH (20 mL) and AcOH (2.0 mL) was added Pd/C (10%, 1.0 g). The reaction mixture was transferred to an autoclave and charged with hydrogen (50 psi). The mixture was stirred RT for 20 h and filtered. The filtrated was concentrated and the residue was purified on silica gel using a mixture of EtOAc and hexanes to give [(S)-2-(tert-Butoxycarbonyl-methyl-amino)-3-hydroxy-propyl]-(2,2-difluoro-ethyl)-carbamic acid tert-butylester (1.81 g, 93%). LRMS (M+Na+) m/z 391.2.
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[CH:9]1[CH2:15][CH2:14][CH2:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH:11]12[CH:10]=[CH:9][CH:15]([CH2:14][CH2:13][CH2:12]1)[CH:5]1[CH:6]2[C:1](=[O:8])[CH:2]=[CH:3][C:4]1=[O:7]
Reactant: O=C1C=CC(=O)C=C1
Reactant: C1=CCCCC=C1
Solvent: ClCCl
Product: O=C1C=CC(=O)C2C3C=CC(CCC3)C12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 17.2 g of 1,4-benzoquinone in 240 mL DCM were added 7.6 mL of BF3-diethyletherate followed by 17.2 mL of 1,3-cycloheptadiene at −20° C. The cooling bath was removed after 20 min and the mixture furthermore stirred for 30 min at rt. The reaction mixture was then poured into ice cold KOH (30% aq.) solution and it was vigorously stirred for 10 min. After filtration over celite the organic phase was dried over K2CO3 and concentrated in vacuo to obtain 21.7 g of the desired compound as mixture of stereoisomers as brown solid.
Reaction SMILES: [Mg].[Br:2]C(Br)C.[Br:6][C:7]1[C:8]([O:27][CH2:28][CH:29]2[CH2:31][O:30]2)=[CH:9][CH:10]=[C:11]2[C:15]=1[N:14]([CH2:16][C@@H:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH3:18])[N:13]=[CH:12]2>C1COCC1>[Br:2][CH2:31][CH:29]([OH:30])[CH2:28][O:27][C:8]1[C:7]([Br:6])=[C:15]2[C:11]([CH:12]=[N:13][N:14]2[CH2:16][C@@H:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH3:18])=[CH:10][CH:9]=1
Reactant: C[C@@H](Cn1ncc2ccc(OCC3CO3)c(Br)c21)O[Si](C)(C)C(C)(C)C
Reactant: CC(Br)Br
Agent: [Mg]
Solvent: C1CCOC1
Product: C[C@@H](Cn1ncc2ccc(OCC(O)CBr)c(Br)c21)O[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a suspension of magnesium powder (0.73 g, 30.2 mmol) in anhydrous THF (50 mL) under nitrogen was added dibromoethane (2.13 g, 0.98 mL, 11.3 mmol) in portions over about 30 min. During this period the mixture was heated at about 50° C. until gas evolution was observed. The mixture was stirred for an additional 1 h, placed in an ice bath, and a solution of the product from Step D (3.33 g, 7.55 mmol) in THF (10 mL) was added. After stirring for 1 h at ambient temperature, the mixture was quenched with a saturated aqueous solution of ammonium chloride (100 mL) and extracted with EtOAc (3×100 mL). Evaporation of the extracts gave a crude oil (3.76 g, 95%): LC/MS (+APCI) m/z 441, 443 (M+H−HBr).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:13]2[CH2:17][NH:16][C:15](=[O:18])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[F:23][C:24]1([F:33])[CH2:27][N:26]([C:28](=[O:32])/[CH:29]=[CH:30]\I)[CH2:25]1.O>CN(C=O)C>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([CH:13]2[CH2:17][N:16](/[CH:30]=[CH:29]/[C:28]([N:26]3[CH2:27][C:24]([F:33])([F:23])[CH2:25]3)=[O:32])[C:15](=[O:18])[CH2:14]2)[CH:4]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:8]=1
Reactant: O=C1CC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1
Reactant: O=C(/C=C\I)N1CC(F)(F)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1/C=C/C(=O)N1CC(F)(F)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 4 %

Procedure:
4-(3,5-bis(trifluoromethyl)phenyl)pyrrolidin-2-one (0.5 g, 1.0 eq.) was dissolved in DMF (5 mL) and cooled to 0° C. A solution of NaH in DMF (0.133 g, 2.0 eq.) was added at 0° C. (Z)-1-(3,3-difluoroazetidin-1-yl)-3-iodoprop-2-en-1-one (0.689 g, 1.5 eq.) was then introduced. The reaction mixture was stirred for 30 min at room temp. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (3×50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 0.502 g of crude product, which was purified by chromatography (1% Methanol in DCM) to give 0.030 g of (E)-4-(3,5-bis(trifluoromethyl)phenyl)-1-(3-(3,3-difluoroazetidin-1-yl)-3-oxoprop-1-enyl)pyrrolidin-2-one (Yield 4.03%). 1H NMR (400 MHz, CDCl3) δ 8.15-8.19 (d, J=14 Hz, 1H), 7.69-7.87 (m, 3H), 5.27-5.31 (d, J=14 Hz, 1H), 4.05-4.47 (m, 4H), 3.89-3.93 (s, 1H), 3.73-3.77 (s, 1H), 3.60-3.62 (s, 1H), 3.08-3.13 (s, 1H), 2.78-2.90 (s, 1H); LCMS calcd. for C18H14F8N2O2 [M+H]+. found 443.44 at retention time 2.97 min.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][O:11][C:12](=[O:27])[C@H:13]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH2:17].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O.Cl.COC(=O)[C@H](CC1C=CC=CC=1)N>>[CH3:10][O:11][C:12](=[O:27])[C@H:13]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH:17][C:7](=[O:9])[CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Reactant: O=C(O)CC1CCCC1
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)CC1CCCC1

Procedure:
Following General Procedure U and using cyclopentylacetic acid (Aldrich) and N-(L-alaninyl)-L-phenylalanine methyl ester (prepared by coupling N-BOC-L-alanine (Bachem) with L-phenylalanine methyl ester hydrochloride (Bachem) using General Procedure U, followed by removal of the BOC-group using General Procedure Y), the title compound was prepared as a solid (mp=137-139° C.). The reaction was monitored by tlc (Rf=0.23 in 1:1 EtOAc/hexanes).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]([CH3:17])C(OCC)=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.O1CCC[CH2:19]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH2:29]>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]([OH:29])[CH2:17][CH3:19])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O
Reactant: C1CCOC1
Reactant: CCOC(=O)C(C)c1c(C)[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCC(O)c1c(C)[nH]c2ccccc12
Yield: 68.8 %

Procedure:
A solution of 27.3 g of ethyl (2-methylindol-3-yl)propionate and 100 ml of tetrahydrofuran was added slowly to a suspension of 4.3 g of lithium aluminum hydride and 120 ml of tetrahydrofuran, with stirring. After the addition was complete, the reaction mixture was heated under reflux for 2 hrs, and cooled in an ice bath. Water (17 ml) was added cautiously at ice-bath temperature. The mixture was filtered and the filtrated was concentrated. Distillation of the residue at 0.2 mm gave 15.6 g (68.8%) of product, bp 180°.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.Cl.[NH2:12][OH:13].[OH-].[Na+].C(=O)C1C=CC=CC=1>O.CO>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[N:12][OH:13]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=Cc1ccccc1
Solvent: O
Product: ON=Cc1c(Cl)cccc1Cl
Reaction time: 8 h

Procedure:
2,6-Dichloro-benzaldehyde (7.0 g, 40 mmol) and hydroxylamine hydrochloride (2.16 g, 44 mmol) are added to 10 mL of water and 30 mL of methanol. Sodium hydroxide (4.0 g, 100 mmol) is dissolved in 8 mL of water slowly. The sodium hydroxide solution is added to the benzaldehyde solution. The reaction is stirred overnight. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is washed with brine and dried over solid sodium sulfate. The organic layer is filtered and the solvent is removed under reduced pressure to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18](O)=[O:19])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].ON1C2N=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.ClC(Cl)C.[CH2:50]([NH:57][CH:58]1[C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH2:61][CH2:60][CH:59]1[CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([O:75][CH3:76])[CH:70]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C)C1C=CN=CC=1.ClCCl.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18](=[O:19])[N:57]([CH2:50][C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH:58]3[C:67]4[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=4)[CH2:61][CH2:60][CH:59]3[CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[C:71]([O:75][CH3:76])[CH:70]=3)[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cccc(-c2cccc(CC(=O)O)c2)c1
Reactant: COc1cccc(CC2CCc3ccccc3C2NCc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2cccnc21
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2cccc(CC(=O)N(Cc3ccccc3)C3c4ccccc4CCC3Cc3cccc(OC)c3)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
3′-Carboxymethyl-biphenyl-3-carboxylic acid methyl ester (77 mg) is combined with 76 mg 1-hydroxy-7-azabenzotriazole, 234 mg polymer-bound DCC, and 4 mg 4-dimethylaminopyridine in 4 ml 3:1 dichloroethane:DMF. The slurry is shaken 30 minutes at ambient temperature before adding 100 mg Benzyl-[2-(3-methoxy-benzyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-amine (prepared in a similar fashion to Preparation C). The mixture is shaken at ambient temperature 18 hours. The resin is filtered off and washed with dichloromethane and methanol. The solvent is evaporated to give a yellow oil. The oil is dissolved in dichloromethane, the insoluble material is filtered off, and the filtrate is separated by radial chromatography (4 mm plate, 3:1 hexanes:ethyl acetate). Product fractions are combined and evaporated to give 76 mg of the title compound as a colorless oil, 42%.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][C:45]=3[Cl:48])[C:40]2=[O:49])[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:50][C:51]1[CH:56]=[N:55][CH:54]=[CH:53][N:52]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][C:45]=3[Cl:48])[C:40]2=[O:49])[C:36]([NH:50][C:51]2[CH:56]=[N:55][CH:54]=[CH:53][N:52]=2)=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2c(Cl)cccc2C1=O
Reactant: Nc1cnccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: O=C(Nc1cnccn1)[C@H](CC1CCCCC1)N1Cc2c(Cl)cccc2C1=O
Yield: 17.5 %

Procedure:
BOP coupling of (S)-3-cyclohexyl-2-(4-Chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (ca. 1:1 mixture of regioisomers, prepared in Example 36, Step C; 243 mg; 0.76 mmol) and 2-aminopyrazine(1 70 mg; 1.77 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide as outlined in Example 9, Step B) provided after chromatography (Biotage 40M column, eluent: 20% ethyl acetate/hexanes) 53 mg of (S)-3-Cyclohexyl-2-(4-Chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2-yl-propionamide: EI-HRMS m/e calcd for C21H23ClN4O2 (M+) 398.1510, found 398.1520; and 41 mg of regioisomeric (S)-3-Cyclohexyl-2-(7-Chloro-1-oxo-1,3dihydro-isoindol-2-yl)-N-pyrazin-2-yl-propionamide: EI-HRMS m/e calcd for C21H23ClN4O2 (M+) 398.1510, found 398.1507.
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@@H:32]([CH2:39][CH3:40])[CH:33]([OH:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@@H:32]([CH2:39][CH3:40])[CH:33]([OH:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)([CH3:13])[CH3:12]
Reactant: CC[C@H](N)C(O)C(C)(C)C
Reactant: CC(C)n1cnc2c(NCc3ccccn3)nc(F)nc21
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC[C@H](Nc1nc(NCc2ccccn2)c2ncn(C(C)C)c2n1)C(O)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-2-ylmethyl-amine (30 mg, 1 eq, 0.10 mmol) in n-BuOH/DMSO (5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.10 mL, 5.5 eq, 0.57 mmol) followed by (3RS,4S)-4-amino-2,2-dimethyl-hexan-3-ol (43 mg, 2.81 eq, 0.29 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine-(50 mL), dried,(NgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 5.9 mg (14%).(53% de 4S,3R: 47% de 4S,3S). 1H-NMR (d-CDCl3, 250 MHz): δ 1.00-1.04 (m, 12H, —NHCH(CH2CH3)CH(C(CH3OH), 1.56 & 1.58 (2×d, 6H, J=6.63 & 6.63 Hz, —CH(CH3)2), 1.67-1.90 (m, 2H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 3.56 (d, 1H, J=1.89 Hz, —NHCH(CH2CH3)CH(C(CH3)3)OH), 3.70-3.83 (m, 1H, —NHCH(CH2CH3)CH (C(CH3)3) OH), 4.58-4.69 (m, 1H, —CH(CH3)2), 4.88-4.98 (m, 2H, —HNCH2-Pyr), 5.23-5.39 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 6.71-6.80 (m, 1H, —HNCH2-Pyr), 7.17-7.24 (m, 1H, Pyr-H), 7.38 (d, 1H, J=7.90, Pyr-H), 7.57 (s, 1H, —N═CH—N—), 7.63-7.70 (m, 1H, Pyr-H), 8.61 (d, 1H, J=4.90 Hz, Pyr-H). FABMS m/z (relative intensity): 412 ([M+H]+, 100), 324 (75). Accurate Mass (M+H): Actual: 412.2825, Measured: 412.2835.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.ON1C(=O)N(O)C(=O)N(O)[C:11]1=[O:20].[O:21]=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]([OH:20])=[O:21])=[CH:4][CH:3]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1
Reactant: O=O
Reactant: O=c1n(O)c(=O)n(O)c(=O)n1O
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccc(Cl)cc1
Solvent: CC(=O)O
Product: O=C(O)c1ccc(Cl)cc1

Procedure:
A mixture of 0.380 g of 4-chlorotoluene, 0.027 g of hexahydro-1,3,5-trihydroxy-1,3,5-triazine-2,4,6-trione (5% by mole relative to 4-chlorotoluene), 5 g of acetic acid and 0.004 g of cobalt(II) acetate.4H2O was stirred at 100° C. in an atmosphere of oxygene gas (1 atm=0.1 MPa) for 14 hours. The resulting product in the reaction mixture was analyzed by gas chromatography and was found to yield 4-chlorobenzoic acid in 99% yield at 100% conversion of 4-chlorotoluene.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3]([NH2:6])(=[O:5])=[O:4].Cl.CN(C)CCCN=C=NCC.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]3[CH:37]=[C:38]([C:42](O)=[O:43])[O:39][C:40]=3[CH3:41])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][C:36]3[CH:37]=[C:38]([C:42]([NH:6][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])=[O:43])[O:39][C:40]=3[CH3:41])=[CH:32][CH:33]=2)=[CH:26][CH:27]=1
Reactant: CN(C)S(N)(=O)=O
Reactant: COc1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(-c2ccc(OCc3cc(C(=O)NS(=O)(=O)N(C)C)oc3C)cc2)cc1
Reaction time: 18 h
Yield: 35.7 %

Procedure:
N,N-Dimethylsulphamide (73 mg, 0.59 mmoles), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (31 mg, 0.162 mmoles) and dimethyl-pyridin-4-yl-amine (1 mg) were added to a stirred solution of 4-(4′-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (4)(50 mg, 0.148 mmoles) in dichloromethane (20 ml). The mixture was stirred under an argon atmosphere for 18 hours. After evaporation of the solvent, the residue was partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined extracts were washed with 1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, brine and dried (MgSO4). Evaporation of the solvent afforded the crude product, which was purified by HPLC (gradient: 30% acetonitrile/70% water containing 0.1% trifluoroacetic acid to 98% acetonitrile/2% water at a rate of 1%/min) to afford compound 122(23.5 mg) as a white solid. LC/MS System C: Rt=3.67 mins, m/z (ES−)=443 ((M−H) for C22H24N2O6S).
Reaction SMILES: [CH2:1]([S:3]([NH2:6])(=[O:5])=[O:4])[CH3:2].[H-].[Na+].Cl[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([C:19]([F:22])([F:21])[F:20])=[CH:12][N:11]=1.O>O1CCCC1>[N+:16]([C:15]1[C:10]([NH:6][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[N:11][CH:12]=[C:13]([C:19]([F:22])([F:20])[F:21])[CH:14]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Reactant: CCS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCS(=O)(=O)Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 54.5 %

Procedure:
3.1 g of ethanesulfonamide was dissolved in 50 ml of dry tetrahydrofuran, and 1.2 g of 60% sodium hydride was added thereto under cooling with ice. After completion of the addition, the mixture was reacted for one hour under reflux. After cooling, 5.0 g of 2-chloro-3-nitro-5-trifluoromethylpyridine was added thereto, and then the mixture was reacted for 7 hours under reflux. After completion of the reaction, the reaction product was poured into 200 ml of water. Undissolved materials in water were extracted with ethyl ether and removed. Then, the aqueous layer was weakly acidified with dilute hydrochloric acid. Precipitated crystals were collected by filtration and dried to obtain 3.6 g of N-(3-nitro-5-trifluoromethyl-2-pyridyl)ethanesulfonamide having a melting point of from 160° to 163° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]([NH:29]C(=O)OC(C)(C)C)[CH2:21][O:22]C1CCCCO1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:29][C@@H:20]([CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:21][OH:22]
Reactant: CC(C)(C)OC(=O)N[C@H](COC1CCCCO1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@H](N)CO)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 2 L three neck flask fitted with a thermometer, mechanical stirrer, under argon was added 4 (46 g, 0.089 mol) and CH2Cl2 (1 L). The clear colorless solution was cooled to 0° C. with an ice/methanol bath. The TFA (132 g, 1.16 mol) was added in one portion. After stirring for 3 hr 30 min and allowing to warm to 20° C., the reaction was complete by HPLC. The reddish brown solution was concentrated under reduced pressure. Toluene (1×100 mL and 1×50 mL) was added to the residue and twice concentrated to remove excess TFA. To the resulting red oil was added methanol (600 mL) and water (200 mL). Potassium carbonate (110 g) was added to the resulting solution and stirred vigorously for 2 hr and 15 min. Dichloromethane (1.2 L) was added to the stirring solution. The aqueous layer was separated and extracted with CH2Cl2 (1 L). The organic layers were combined and dried over MgSO4 (20 g), filtered and concentrated under reduced pressure to 44 g of a cloudy orange oil. The oil was dissolved in CH2Cl2 (200 mL) and dried again over MgSO4 (6 g), filtered and concentrated under reduced pressure to 39 g of product 5 as an orange oil. HPLC analysis showed a purity of 54% at a retention time of 2.8 min at 215 nm (Hewlett Packard series 1100 HPLC instrument, using an Alltech Alltima column (C18, 5μ, 250×4.6 mm), with a flow rate of 1.0 mL/min at 40° C., conditions 0:5:95; Water:Al:MeOH, Al consists of 700 mL of water, 300 mL of methanol, and 3 mL of triethylamine adjusted to pH 3.4 with phosphoric acid). There were three major impurities by HPLC at retention times of 3.1 min (21%), 3.4 min (15%) and 3.8 min (9%). The product 5 was carried on without further purification 1H NMR (60 MHz, CDCl3) δ 7.0-7.7 (m, 10H), 3.4-3.9 (m, 5H), 1.8-2.2 (br s, 1H), 1.1 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][O:9][C:10]2=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][NH:15][CH3:16]>C(O)C>[OH:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:12]=1[C:10]([N:15]([CH3:16])[CH3:14])=[O:11]
Reactant: O=C1OCc2ccc([N+](=O)[O-])cc21
Reactant: CNC
Solvent: CCO
Product: CN(C)C(=O)c1cc([N+](=O)[O-])ccc1CO
Reaction time: 5 h

Procedure:
To a stirred solution of 6-nitrophthalide (2 g.) in ethanol (120 ml.) at room temperature was added dimethylamine (in ethanol 33.3% solution: 50 ml.). After stirring for 5 hours the solvent was evaporated off. The resulting gum was dissolved in ethyl acetate. On addition of petrol 60° - 80° a white solid crystallised out.