Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:42])[NH:10][C@@H:11]([CH2:36][C:37]2[N:38]=[CH:39][S:40][CH:41]=2)[C:12](=[O:35])[NH:13][CH2:14][C:15]2[N:16]=[N:17][N:18]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:19]=2)[O:7]1)=[O:5])C.[Li+].[OH-]>>[O:35]=[C:12]([NH:13][CH2:14][C:15]1[N:16]=[N:17][N:18]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH:19]=1)[C@@H:11]([NH:10][C:9]([C@H:8]1[O:7][C@@H:6]1[C:4]([OH:5])=[O:3])=[O:42])[CH2:36][C:37]1[N:38]=[CH:39][S:40][CH:41]=1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cscn1)C(=O)NCc1cn(-c2ccc(S(=O)(=O)N3CCCCC3)cc2)nn1
Agent: [Li+]
Agent: [OH-]
Product: O=C(NCc1cn(-c2ccc(S(=O)(=O)N3CCCCC3)cc2)nn1)[C@H](Cc1cscn1)NC(=O)[C@H]1O[C@@H]1C(=O)O
Yield: 4.8 %

Procedure:
Followed general procedure using: the corresponding peptidomimetic epoxide ethyl ester 40 (26 mg, 0.42 mmol); LiOH (1.0 mg, 0.04 mmol); after extraction afforded the desired product as a white solid (12 mg, 48.3%). 1H NMR (Acetone-d6, 400 MHz): δ8.98 (bs, 1H); 8.48 (s, 1H); 8.16-8.12 (d, 2H, 8.48); 8.02-8.00 (d, 2H, J=8.48 Hz); 7.37 (bs, 1H); 4.81 (bs, 1H); 4.52 (s, 2H); 3.85-3.79 (m, 4H); 3.61 (s, 1H); 3.55 (s, 1H); 1.82-1.60 (m, 6H). 13C NMR (Acetone-d6, 100 MHz): 170.07, 169.01, 165.12, 153.52, 139.36, 136.19, 129.47, 120.84, 120.21, 107.39, 107.25, 66.62, 53.44, 52.80, 52.77, 46.83, 32.52, 30.07, 25.02, 23.13. HRMS-ESI: m/z [M+H+] calculated for C24H27N7O7S2: 590.6440, observed: m/z 590.1050 (M+H+); HPLC Method 2: Rt=21.7 min; purity=96.3%.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14]Br)[CH2:5]1)(=[O:3])[CH3:2].[OH:16][C:17]1([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14][N:20]2[CH2:21][CH2:22][C:17]([OH:16])([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:28]=3)[CH2:18][CH2:19]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(CCBr)c2ccccc21
Reactant: OC1(c2ccc(C(F)(F)F)cc2)CCNCC1
Product: CC(=O)N1CC(CCN2CCC(O)(c3ccc(C(F)(F)F)cc3)CC2)c2ccccc21

Procedure:
In the manner described in Example 5, reaction of 1-acetyl-3-(2-bromoethyl)indoline with 4-hydroxy-4-(α,α,α-trifluoro-p-tolyl)piperidine gives white crystals, which melt at 141°-143°C., after recrystallization from dilute acetone.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21](O)=[O:22])=[CH:6][N:5]2[C:24]=1[CH3:25].[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.C(N(CC)CC)C.[NH:55]1[CH2:62][CH2:61][CH2:60][C@H:56]1[C:57]([NH2:59])=[O:58]>C(Cl)Cl>[CH2:19]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=1[CH2:11][NH:10][C:9]1[C:4]2[N:5]([C:24]([CH3:25])=[C:2]([CH3:1])[N:3]=2)[CH:6]=[C:7]([C:21]([N:55]2[CH2:62][CH2:61][CH2:60][C@H:56]2[C:57]([NH2:59])=[O:58])=[O:22])[CH:8]=1)[CH3:20]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: CCc1cccc(C)c1CNc1cc(C(=O)O)cn2c(C)c(C)nc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cccc(C)c1CNc1cc(C(=O)N2CCC[C@H]2C(N)=O)cn2c(C)c(C)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid (0.15 g, 0.44 mmol), o-Benzotriazol-1-yl-N,N,N′,N′-Tetramethyluronium tetrafluoroborate (TBTU)(0.14 g, 0.45 mmol) and triethylamine (0.05 g, 0.5 mmol) were added to methylene chloride (10 ml) and the mixture was stirred for 10 min. (S)-prolinamide (0.016 g, 0.45 mmol) was added and the reaction mixture was stirred at ambient temperature for 1 h. The solvent was evaporated under reduced pressure and purification of the residue by column chromatography on silica gel using methylene chloride:methanol (9:1) as eluent and crystallization from diethyl ether gave 0.07 g (36%) of the title compound.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](/[C:18](/[CH3:25])=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=2)=[CH:8][CH:7]=1)\[CH3:5].[CH2:26]([O:28][C@@H:29]([CH2:35][C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:27]>>[CH2:26]([O:28][C@H:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:1][CH2:2]/[CH:3]=[C:4](/[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14](/[C:18](/[CH3:25])=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=3)=[CH:8][CH:7]=2)\[CH3:5])=[CH:38][CH:37]=1)[CH3:27]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: CCOC(=O)/C=C(\C)c1cccc(-c2ccc(/C(C)=C/CO)cc2)c1
Product: CCOC(=O)/C=C(\C)c1cccc(-c2ccc(/C(C)=C/COc3ccc(C[C@H](OCC)C(=O)OCC)cc3)cc2)c1
Yield: 59 %

Procedure:
The title compound (230 mg, 58%) was prepared from (E,E)-ethyl 3-[4′-(3-hydroxy-1-methyl-propenyl)-biphenyl-3-yl]-but-2-enoate (235 mg, 0.70 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (175 mg, 0.73 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]([S:15][CH2:16][CH2:17][S:18][CH3:19])=[O:14]>C(Cl)Cl>[CH3:12][C:13]([S:15][CH2:16][CH2:17][S:18]([CH3:19])=[O:9])=[O:14]
Reactant: CSCCSC(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)SCCS(C)=O
Reaction time: 2 h
Yield: 38 %

Procedure:
m-Chloroperbenzoic acid (2.03 g., 0.01 mole, 85% pure) was added to a solution of 1.5 g (0.01 mole) 2-(methylcarbonylthio)-1-(methylthio)ethane in 40 ml. methylene chloride cooled to -10° C. After stirring at -10° for 2 hr., the solution was washed with two 30 ml. portions of saturated aqueous sodium bicarbonate solution, 30 ml. water and 30 ml. saturated aqueous saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel, eluting with 10:1 ethyl acetate-methanol to yield 680 mg. (38% yield) of the title compound as an amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH:9](=O)[CH3:10].COC(=O)COC1C=C(OC)C(SCCCN(CC)C2C=CC(C3C=CC=CC=3)=CN=2)=CC=1C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH3:10])=[N:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC=O
Agent: CCN(CCCSc1cc(C)c(OCC(=O)OC)cc1OC)c1ccc(-c2ccccc2)cn1
Product: CCNc1ccc(Br)cn1

Procedure:
5-Bromo-pyridin-2-ylamine and acetaldehyde were treated under the conditions of Compound 64C to give the intermediate (5-bromo-pyridin-2-yl)-ethyl-amine. This was then reacted with Compound 64A to give the title product. MS m/z 481 (M+1). Step 2. Preparation of (4-{3-[(5-Bromo-pyridin-2-yl)-ethyl-amino]-propylsulfanyl]-5-methoxy-2-methyl-phenoxy}-acetic acid (Compound 68)
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:11][C:12]#[N:13].[K+].C(=O)([O-])O.[Na+].[NH2:20][C:21]1[CH:42]=[CH:41][C:24]([O:25][C:26]2[CH:27]=[CH:28][C:29]3[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]4[CH2:40][CH2:39]4)=[O:37])[N:34]=3)[CH:31]=2)=[CH:23][CH:22]=1>C(#N)C.C1(C)C=CC=CC=1.C(O)C>[C:1]1([CH2:7][C:8]([NH:13][C:12]([NH:20][C:21]2[CH:42]=[CH:41][C:24]([O:25][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]5[CH2:39][CH2:40]5)=[O:37])[N:34]=4)[CH:31]=3)=[CH:23][CH:22]=2)=[S:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N#C[S-]
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 31.1 %

Procedure:
To a solution of phenylacetyl chloride (422 mg, 2.59 mmol) in acetonitrile (8 mL) was added potassium thiocyanate (317 mg, 3.24 mmol), and the mixture was stirred at 50° C. for 1 hr. The reaction solution was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was dissolved in toluene (2 mL)/ethanol (2 mL), N-[6-(4-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 649 μmol) was added, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethanol/water to give the title compound (98 mg, 31%) as a pale-yellow powder.
Reaction SMILES: C(Cl)CCl.[NH2:5][CH2:6][C:7]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:8]=1[CH2:9][CH:10]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH:11]([F:13])[F:12].[C:28]([N:35]1[CH2:42][CH2:41][CH2:40][C@H:36]1[C:37](O)=[O:38])([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:27][C:25]1[CH:24]=[CH:23][C:8]([CH2:9][CH:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:11]([F:13])[F:12])=[C:7]([CH:26]=1)[CH2:6][NH:5][C:37](=[O:38])[C@@H:36]1[CH2:40][CH2:41][CH2:42][N:35]1[C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29]
Reactant: COc1ccc(NC(Cc2ccc(Cl)cc2CN)C(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(NC(Cc2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)C(F)F)cc1
Yield: 72.3 %

Procedure:
EDC (0.402 g, 2.10 mmol) was added to a stirred mixture of N-{1-[2-(aminomethyl)-4-chlorobenzyl]-2,2-difluoroethyl}-N-(4-methoxyphenyl)amine (0.550 g, 1.61 mmol), N-Boc-L-proline (0.347 g, 1.61 mmol) and HOAT (0.286 g, 2.10 mmol) in DMF (2.8 mL). After 18 h the mixture was partitioned between EtOAc and water. The organic phase was washed with 1 M citric acid, saturated aqueous NaHCO3 and brine, dried (Na2SO4) and evaporated in vacuo to give N-(5-Chloro-2-{3,3-difluoro-2-[(4-methoxyphenyl)amino]propyl}benzyl)-1-tert-butoxycarbonyl-L-prolinamide (0.626 g) as an oil; MS m/z=538.4.
Reaction SMILES: Cl.O[CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].O.[NH2:15][NH2:16]>CO>[NH2:5][C@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[CH:3]=[N:15][NH2:16]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CO
Product: NN=C[C@H](N)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 8 h

Procedure:
A mixture of 2.0 g of glucosamine hydrochloride, 5 ml of methanol and 5 ml of hydrazine hydrate was stirred overnight and then evaporated to dryness giving 2-amino-2-deoxy-D-glucose hydrazone.
Reaction SMILES: [NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[NH2:25][C@H:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:28](=[O:30])[NH2:29]>>[NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:12]([NH:25][C@H:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:28](=[O:30])[NH2:29])=[O:14])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CC(N)=O
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(N)=O)C(=O)OC(C)(C)C

Procedure:
Fragment I was prepared by stepwise chain elongation using the mixed anhydride procedure at -15° C. with careful temperature control. As seen in the scheme of FIG. 2 mixed anhydride (M.A.) coupling (isobutylchloroformate) of Z-Glu(OtBu)-OH with H-Asn-OtBu provided Z-Glu(OtBu)-Asn-OtBu. Catalytic hydrogenation (10% Pd-C) of this compound cleaved the N-terminal protective group and the dipeptide was coupled to Z-Ala-OH using mixed anhydride coupling to give Z-Ala-Glu (OtBu)-Asn-OtBu. The N-terminal was again deprotected by catalytic hydrogenation and the tripeptide coupled with Z-Glu(OtBu)-OH to give the protected tetrapeptide Z-Glu(OtBu)-Ala-Glu(OtBu)-Asn-OtBu which is deblocked by catalytic hydrogenation to provide the desired protected tetrapeptide (1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[OH:26][CH2:27][CH2:28][CH2:29][NH:30][CH:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1>CN(C=O)C.CCN(C(C)C)C(C)C>[F:24][CH:23]([F:25])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([N:30]([CH2:29][CH2:28][CH2:27][OH:26])[CH:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH2:33][CH2:32]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NCCCO)CC1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N(CCCO)c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Yield: 83 %

Procedure:
Reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (WO 2006/095906) with tert-butyl 4-[(3-hydroxypropyl)amino]-1-piperidinecarboxylate in DMF and DIPEA as in Example 21 gave tert-butyl 4-[[4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl](3-hydroxypropyl)amino]-1-piperidinecarboxylate in 83% yield: mp (CH2Cl2/hexanes) 188-190° C.; 1H NMR (DMSO-d6) (rotamers) δ 8.45 and 8.35 (2d, J=7.9, 8.3 Hz, 1H), 7.83 and 7.75 (2t, JHF=52.9 Hz, 1H), 7.85 (2d, J=8.0 Hz, 1H), 7.54-7.41 (m, 2H), 4.72-4.65 and 4.56-4.51 (2m, 1H), 4.58 and 4.48 (2t, J=4.8, 5.0 Hz, 1H), 4.15-4.07 (m, 2H), 3.83-3.78 (m, 4H), 3.70 (m, 4H), 3.62-3.47 (m, 4H), 2.81 (m, 2H), 1.78-1.65 (m, 6H), 1.42 (s, 9H); Anal Calcd. for C28H38F2N8O4: C, 57.1; H, 6.5; N, 19.0. Found: C, 57.4; H, 6.3; N, 19.1%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[NH:12][C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH:22]2[C:27](O)=[O:28])=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].CCN=C=NCCCN(C)C.Cl.C1C=NC2[N:53]([OH:56])N=NC=2C=1.CCN(C(C)C)C(C)C.[Si](ON)(C(C)(C)C)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@H:22]2[C:27](=[O:28])[NH:53][OH:56])[NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[N:14]1
Reactant: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: On1nnc2cccnc21
Agent: CC(C)(C)[Si](C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)NO)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 6.5 %

Procedure:
A solution of (3S)-4-(((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (0.74 g, 1.36 mmol), EDC.HCl (0.31 g, 1.62 mmol), HOAt (185 mg, 1.36 mmol) and DIPEA (210 mg, 1.62 mmol) in DCM (20 mL) was stirred at −10° C. for 30 minutes. Then to the mixture was added a solution of O-(tert-butyldimethylsilyl)hydroxylamine (0.2 g, 1.36 mmol) in DCM (2.0 mL) slowly at −10° C. Then the mixture was warmed to 25° C. and stirred for 12 hours. The mixture was concentrated in vacuo and the residue was dissolved in a solution of HCl in EtOAc (6 mol/L, 10 mL), then the mixture was stirred at 25° C. for 2 hours. The reaction mixture was diluted with EtOAc (200 mL) and water (100 mL), and the mixture was adjusted to pH 7 with aqueous ammonia. The organic layer was dried over Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=30/1) to give the title compound as a yellow solid (0.05 g, 6.5%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:42])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:32][C@H:31]([CH2:33][O:34]CC4C=CC=CC=4)[C@@H:22]([O:23]CC4C=CC=CC=4)[C@@H:13]3[O:14]CC3C=CC=CC=3)[C:6]=2[N:7]=1.B(Cl)(Cl)Cl>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([Cl:42])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:32][C@H:31]([CH2:33][OH:34])[C@@H:22]([OH:23])[C@@H:13]3[OH:14])[C:6]=2[N:7]=1
Reactant: Cc1cn([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)c2nc(N)nc(Cl)c12
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c2nc(N)nc(Cl)c12
Temperature: -78 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a precooled (−78° C.) solution of the compound from Step A (0.99 g, 1.7 mmol) in dichloromethane (30 mL) was added borontrichloride (1M in dichloromethane) (17 mL, 17.0 mmol) over a 10 min. The resulting solution was stirred at −78° C. for 1 h, allowed to warm to −15° C. and stirred for another 3 h. The reaction was quenched by addition of methanol/dichloromethane (1:1) (15 mL), stirred at −15° C. for 30 min, and pH adjusted to 7.0 by addition of NH4OH. The mixture was evaporated in vacuo and the resulting oil purified on silica using methanol/dichloromethane (1:9) as eluent. Fractions containing the product were pooled and evaporated in vacuo to give the desired product (257 mg) as a colorless foam.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:17])[CH3:16])[C:6]=2[C:5](=[O:18])[NH:4][C:3]1=[O:19].[OH-].[Na+].[CH3:22][CH2:23][CH2:24]Br.S(=O)(=O)(O)O>O.CO>[CH2:22]([N:4]1[C:5](=[O:18])[C:6]2[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:17])[CH3:16])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:19])[CH2:23][CH3:24]
Reactant: CC(=O)CCCCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CCCBr
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCn1c(=O)c2c(ncn2CCCCC(C)=O)n(C)c1=O
Yield: 85 %

Procedure:
A suspension of 79.2 g of 3-methyl-7-(5-oxohexyl)-xanthine in a mixture of 120 g of water and 72 g of methanol is brought into solution by the addition of 18 g of sodium hydroxide at about 60° C. 55.5 g of n-propyl bromide are then added. After boiling under reflux for 24 hours, the reaction mixture is treated with 1 ml of concentrated sulphuric acid and cooled. Unreacted 3-methyl-7-(5-oxohexyl)-xanthine is filtered off and the alcohol is distilled off in vacuo. The remaining solution is made alkaline with 4 ml of 50% sodium hydroxide solution and extracted with 350 ml of methylene chloride. 1-n-Propyl-3-methyl-7-(5-oxohexyl)-xanthine with a melting point of 76°-78° C. is obtained in 85% yield from the residue of the methylene chloride solution by recrystallisation from isopropanol. The solubility of the product in ethanol, dimethyl sulphoxide and dimethylformamide is over 10%.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]([N:12]([CH2:17][CH3:18])[S:13]([CH3:16])(=[O:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:19])[CH:8]=2)[O:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:27]([O:29][CH2:30][CH2:31][CH2:32]Br)[CH3:28]>CC(N(C)C)=O>[CH2:27]([O:29][CH2:30][CH2:31][CH2:32][O:19][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:1])([CH3:20])[CH2:11][CH:10]2[N:12]([CH2:17][CH3:18])[S:13]([CH3:16])(=[O:15])=[O:14])[CH3:28]
Reactant: CCOCCCBr
Reactant: CCN(C1CC(C)(C)Oc2ccc(O)cc21)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOCCCOc1ccc2c(c1)C(N(CC)S(C)(=O)=O)CC(C)(C)O2
Temperature: 110 °C

Procedure:
1.5 g (5 mmol) of N-[2,2-dimethyl-6-hydroxychroman-4-yl]-N-ethyl-methanesulfonamide were heated to 80° C. for 30 min with 1.38 g (10 mmol) of powdered potassium carbonate in 60 ml of DMA. 4 ml of 3-ethoxy-1-bromopropane were then added dropwise at 50-60° C., the mixture was heated to 110° C. for 2 h and concentrated in vac. after cooling, the residue was treated with water and aqueous hydrochloric acid, the mixture was extracted with EA, the organic phase was dried and concentrated, and the oily residue was chromatographed on silica gel using n-heptane/EA (2:1). 0.9 g of N-[6-(3-ethoxypropoxy)-2,2-dimethylchroman-4-yl]-N-ethyl-methanesulfonamide was crystallized from appropriate fractions using petroleum ether, m.p. 72-74° C.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:39])[C@H:7]([CH:36]([CH3:38])[CH3:37])[CH2:8][C@H:9]([OH:35])[C@@H:10]([N:32]=[N+]=[N-])[CH2:11][C@@H:12]([CH:29]([CH3:31])[CH3:30])[CH:13]([OH:28])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH2:22][CH:23](OC)[O:24][CH3:25])[CH:15]=1)[CH2:2][CH2:3][CH3:4].C([C@H]1[C@@H]([C@@H](N=[N+]=[N-])C[C@@H](C(C)C)C(O)C2C=CC(OC)=C(CCOCOC)C=2)C[O:45][C:44]1=O)(C)C.C(N)CCC>>[CH2:1]([NH:5][C:6](=[O:39])[C@H:7]([CH:36]([CH3:38])[CH3:37])[CH2:8][C@H:9]([OH:35])[C@@H:10]([NH2:32])[CH2:11][C@@H:12]([CH:29]([CH3:30])[CH3:31])[CH:13]([OH:28])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH2:22][CH2:23][O:24][CH2:25][O:45][CH3:44])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](C[C@@H](C(C)C)C(O)c1ccc(OC)c(CC(OC)OC)c1)N=[N+]=[N-])C(C)C
Reactant: COCOCCc1cc(C(O)[C@@H](C[C@H](N=[N+]=[N-])[C@H]2COC(=O)[C@H]2C(C)C)C(C)C)ccc1OC
Solvent: CCCCN
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@@H](N)C[C@@H](C(C)C)C(O)c1ccc(OC)c(CCOCOC)c1)C(C)C

Procedure:
5(S)-Azido-4(S),8(R,S)-dihydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(2-methoxy-methoxyethyl)-phenyl]-octanoic acid (N-butyl)-amide A solution of 400 mg of 3(S)-isopropyl-4(S)-{1(S)-azido-4(R,S)-hydroxy-3(S)-isopropyl -4-[4-methoxy-3-(2-methoxymethoxyethyl)-phenyl]-butyl}-tetrahydrofuran-2-one (Example 81d) and 3.8 ml of n-butylamine is stirred for 16 hours at 50° C. and then concentrated by evaporation. Purification of the residue by FC (50 g of silica gel, hexane/ethyl acetate=1:1) yields the title compound: Rf (hexane/ethyl acetate=1:1)=0.44; HPLC Rt =16.13 and 17.03 minutes (diastereoisomeric mixture).
Reaction SMILES: [OH-].[Na+].O1CCOCC1.[CH2:9]([O:11][C:12](=[O:44])[C:13]([NH:37][C:38]([O:40][CH2:41][CH:42]=[CH2:43])=[O:39])([CH2:19][C:20]1[O:24][N:23]=[C:22]([CH:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:21]=1)[C:14]([O:16]CC)=[O:15])[CH3:10]>C(OCC)(=O)C.S(=O)(=O)(O)O>[CH2:9]([O:11][C:12](=[O:44])[C:13]([NH:37][C:38]([O:40][CH2:41][CH:42]=[CH2:43])=[O:39])([CH2:19][C:20]1[O:24][N:23]=[C:22]([CH:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30]([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31])[CH:21]=1)[C:14]([OH:16])=[O:15])[CH3:10]
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)OC(C)(C)C)no1)(C(=O)OCC)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)OC(C)(C)C)no1)(C(=O)O)C(=O)OCC
Reaction time: 8 h

Procedure:
Sodium hydroxide, 1M, (21.5 mL, 21.5 mmol) was added in portions over 30 minutes to a dioxane (22 mL) solution of 2-allyloxycarbonylamino-2-[3-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-isoxazol-5-ylmethyl]-malonic acid diethyl ester (10.95 g, 21.5 mmol). After stirring overnight, the reaction had not gone to completion. An additional 0.2 equivalents of 1 M sodium hydroxide (4.2 mL, 4.2 mmol) was added and stirring continued for 3 hours. The reaction was diluted with ethyl acetate (50 mL) and 1M sulfuric acid (23 mL) was added dropwise at 0° C. The aqueous portion was extracted twice with ethyl acetate. The combined organic portions were dried over magnesium sulfate and concentrated in vacuo to give a the title compound. The crude product was used directly in the next step without separation of the unreacted diester. MS (Cl) m/z 382.2 (M-99).