Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22]Cl)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]2=[O:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCCCl)NC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(N2CCCCC2=O)CC1
Reaction time: 8 h
Yield: 107.2 %

Procedure:
4-(5-Chloro-pentanoylamino)-piperidine-1-carboxylic acid benzyl ester (15.6 g) was added to a suspension of sodium hydride (2.12 g) in tetrahydrofuran (175 mL). After being stirred overnight, the reaction was quenched with water, then the tetrahydrofuran was removed under reduced pressure. The aqueous solution was diluted with water and extracted with methylene chloride (4×50 mL). The organic extracts were dried and evaporated to give the title compound (15 g). Rf=0.30 in ethyl acetate. MS: m/z=317 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6](=[O:13])[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[N:9]=2)[CH2:3][CH2:2]1.[Cl:14][O-].[Na+].S(=O)(O)[O-].[Na+]>O>[Cl:14][C:7]1[C:6](=[O:13])[NH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[N:9][C:8]=1[C:10]([OH:12])=[O:11]
Reactant: [O-]Cl
Reactant: O=C(O)c1cc(=O)[nH]c(C2CC2)n1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1nc(C2CC2)[nH]c(=O)c1Cl
Temperature: 9 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-cyclopropyl-1,6-dihydro-6-oxo-4-pyrimidinecarboxylic acid (i.e. the product of Step A1 or A2) (184 g, 1.02 mol) in water (45 mL) and concentrated hydrochloric, acid (292 g, 3 mol) at 8-12° C. was added dropwise aqueous sodium hypochlorite solution, (8.4%, 1.02 kg, 1.15 mol) over 2 h so that with cooling the reaction mixture was maintained at 8-10° C. The mixture was then held at 10-12° C. for 1 h and the conversion was monitored by HPLC. When less than 5% of the starting material remained solid sodium bisulfite was added until a negative KI starch paper test was obtained. The mixture was cooled to 5° C., and the suspended product was isolated by filtration and washed with a minimum amount of cold water. The product was then dried to constant weight in vacuum-oven at 50° C. to afford the title compound (194 g); m.p. 189-190° C.
Reaction SMILES: CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)[N:4]2[C@H]1C(O)=O.C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](NC(N)=N)[C@@H](O)[C@@H]2NC(N)=N)[C@H]([O:49][C@@H:50]2[O:55][C@@H:54]([CH2:56]O)[C@H:53](O)[C@@H:52](O)[C@@H:51]2[NH:60]C)[C@@]1(O)C=O.C([O-])(=O)CCCCCCC/C=C\CCCCCCCC.[Na+]>OCC(CO)O>[NH2:60][C@H:51]([C:50]([OH:55])=[O:49])[CH2:52][CH2:53][CH2:54][CH2:56][NH2:4]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Agent: [Na+]
Solvent: OCC(O)CO
Product: NCCCC[C@H](N)C(=O)O
Reaction time: 24 h

Procedure:
Glycerol stocks of the strains prepared in of Example 7 were thawed. 100 μL of each was evenly spread on an LB agar medium plate containing 40 mg/L ampicillin and 25 mg/L streptomycin and incubated at 37° C. for 24 hours. About ¼ volume of bacterial cells on the plate were inoculated into 40 mL of fermentation medium described below containing 40 mg/L ampicillin and 25 mg/L streptomycin in a 500 mL-Erlenmeyer flask equipped with baffles, and cultured using a reciprocal shaking culture apparatus at 37° C. for 48 hours. As a carbon source in a main culture, sodium oleate added with polyoxyethylene sorbitan monooleic acid ester (Tween 80: manufactured by NACALAI TESQUE, INC.) as an emulsification promoter to a final concentration of 0.5% (w/v) was used. As for a total amount of carbon sources, sodium oleate was 10 g/L. The medium composition used for the culture is shown below.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][N:14]=1>>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)=[O:18])=[CH:15][N:14]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: Nc1ccc2cccnc2c1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(Cl)nc1

Procedure:
Using the procedure outlined in Example 45, the title compound was prepared from 7-aminoquinoline (D55) (213 mg, 1.48 mmol) and 6-chloronicotinic acid (279 mg, 1.77 mmol) as a cream solid (405 mg). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.94 (m, 2H), 8.24 (m, 2H), 8.16 (d, 1H), 8.14 (br.s, 1H), 8.01 (dd, 1H), 7.87 (d, 1H), 7.51 (d, 1H), 7.39 (dd, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=O.[NH2:14][NH2:15].C(OCC)(OCC)(OCC)C>C1(C)C(C)=CC=CC=1>[CH3:13][C:12]1[CH:11]=[CH:10][C:4]([C:5]2[O:7][C:8]([CH3:9])=[N:14][N:15]=2)=[CH:3][C:2]=1[OH:1]
Reactant: CCOC(=O)c1ccc(C)c(O)c1
Reactant: NN
Agent: CCOC(C)(OCC)OCC
Solvent: Cc1ccccc1C
Product: Cc1nnc(-c2ccc(C)c(O)c2)o1
Temperature: 150 °C

Procedure:
A suspension of ethyl 3-hydroxy-4-methylbenzoate (3.60 g, 20 mmol) in anhydrous hydrazine (10 mL, 318 mmol) (Aldrich) was heated at reflux (150° C. bath temperature) for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a dry solid. This was suspended in xylene (50 mL) and concentrated under reduced pressure. The resulting solid was suspended in triethyl ortho-acetate (35 mL, 191 mmol) (Aldrich) and heated at reflux (150° C. bath temperature) for 20 hours with removal of ethanol. After cooling, dichloromethane was added and the solid was collected by filtration to give 2-methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenol as an off-white crystalline material. (Yield 2.28 g).
Reaction SMILES: [Br:1]Br.[C:3]1([C:9]2[N:10]=[C:11](N)[NH:12][N:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N([O-])=O.[Na+].C(OC([O-])=O)([O-])=O.[Na+].[Na+]>>[Br:1][C:11]1[NH:12][N:13]=[C:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:10]=1
Reactant: BrBr
Reactant: Nc1nc(-c2ccccc2)n[nH]1
Agent: O=C([O-])OC(=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Product: Brc1nc(-c2ccccc2)n[nH]1
Temperature: 25 °C

Procedure:
115 mL bromine hydro acid was added to 9.5 g 5-phenyl-2H-(1,2,4)triazol-3-ylamine and 12.3 g sodiumnitrite at −5° C. The reaction was warmed to RT and refluxed for 20 min. Then the mixture was cooled and basicfied with sodiumdicarbonate and extracted with ethyl acetate. The organic layer was dried and evaporated to give 11 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=2)=[CH:4][C:3]=1[C:18]12[CH2:26][O:25][CH2:24][CH:23]1[CH2:22][S:21][C:20]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[N:19]2.CO.C(=O)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=2)=[CH:4][C:3]=1[C@:18]12[CH2:26][O:25][CH2:24][C@H:23]1[CH2:22][S:21][C:20]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[N:19]2
Reactant: CC(C)(C)OC(=O)NC1=NC2(c3cc(NC(=O)c4ccc(F)cn4)ccc3F)COCC2CS1
Agent: O=C=O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(NC(=O)c4ccc(F)cn4)ccc3F)COC[C@H]2CS1
Yield: 40.8 %

Procedure:
Racemic tert-butyl (4aSR,7aSR)-7a-(2-fluoro-5-(5-fluoropicolinamido)phenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-ylcarbamate (0.226 g, 0.460 mmol) is purified by chiral HPLC: 2.1×25 cm Chiralcel OD-H, 5 micron column, 30% methanol/CO2, flow rate: 70 mL/min, UV: 230 nm. The second eluting isomer is isolated to provide the enantiomerically enriched title compound (0.092 g, 41%). ES/MS (m/e): 491 (M+1).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)CCOC[N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH:29]=O.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:29][C:21]2[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: C[Si](C)(C)CCOCn1c(C=O)nc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: c1ccc(CC2CCN(Cc3nc4ccccc4[nH]3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 144.8 %

Procedure:
A mixture of 0.5 g of 4-benzyl-piperidine, 0.5 g of 1-(2-trimethylsilylethoxymethyl)-1H-benzoimidazole-2-carbaldehyde, 5 mL of 1,2-dichloroethane and 0.5 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was diluted with 50 mL chloroform and 10 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×25 mL of chloroform and the combined organic layers dried over magnesium sulfate and concentrated under reduced pressure. The crude SEM ether was heated to reflux in 50 mL of ethanol containing 5 mL of 3N HCl for 2 h, cooled, concentrated and partitioned between 10 mL of saturated aqueous sodium carbonate and 3×25 mL of chloroform. The chloroform extracts were dried over magnesium sulfate and concentrated. Purification by chromatography eluting with 90:10 CHCl3: MeOH gave 0.8 g of 2-[4-benzyl-piperidin-1-ylmethyl]-1H-benzimidazole: MS (m+1)=: 1H NMR (400MHz, CDCl3).
Reaction SMILES: N1C2C(=CC=CC=2)C(=O)C1=O.[CH3:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2=[O:23].BrCCC1CC1.Br[CH:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:32]1([CH:31]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:18]2[C:19]3[C:15](=[CH:14][C:13]([CH3:12])=[CH:21][CH:20]=3)[C:16](=[O:23])[C:17]2=[O:22])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: BrCCC1CC1
Agent: O=C1Nc2ccccc2C1=O
Product: Cc1ccc2c(c1)C(=O)C(=O)N2C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 2A, and making non-critical variations to replace isatin with 5-methylisatin, and (2-bromoethyl)cyclopropane with 1,1′-(bromomethylene)dibenzene, the title compound was obtained (74%) as a bright orange solid: 1H NMR (300 MHz, CDCl3) δ 7.42-7.26 (m, 11H), 7.09 (d, 1H), 6.95 (s, 1H), 6.37 (d, 1H), 2.24 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21](OCC)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[N:27]1([CH2:32][CH2:33][CH2:34][NH2:35])[CH2:31][CH2:30][CH2:29][CH2:28]1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:35][CH2:34][CH2:33][CH2:32][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Reactant: NCCCN1CCCC1
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)c(C(=O)NCCCN2CCCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 60 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (25 mg, 0.070 mmol) described in example 92 and [3-(1-pyrrolidinyl)propyl]amine (0.08 mL of a 4.68 M solution in chloroform, 0.0364 mmol), was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-N-[3-(1-pyrrolidinyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxamide (18 mg, 60% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.32 (br s, 1 H), 8.56 (s, 1 H), 8.51 (s, 1 H), 7.40 (s, 1 H), 7.17-7.14 (m, 2 H), 7.04-7.00 (m, 2 H), 4.13 (s, 2 H), 3.58 (s, 2 H), 3.54-3.52 (m, 2 H), 3.13 (br s, 4 H), 3.03-2.98 (m, 2 H), 2.19-2.06 (m, 2 H), 2.01 (br s, 4 H); HRMS m/z calcd for C24H28N4O3F: 439.2145 Found: 439.2141.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][C:11]([CH:17]=O)=[CH:10][CH:9]=2)=[O:4].[OH:19][CH2:20][C@H:21]([NH:28][C:29]1[S:30][CH2:31][C:32](=[O:34])[N:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][C:11](/[CH:17]=[C:31]1/[C:32](=[O:34])[N:33]=[C:29]([NH:28][C@H:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][OH:19])[S:30]/1)=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1cnc2ccc(C=O)cc2c1OC
Reactant: O=C1CSC(N[C@@H](CO)c2ccccc2)=N1
Product: COC(=O)c1cnc2ccc(/C=C3\SC(N[C@@H](CO)c4ccccc4)=NC3=O)cc2c1OC

Procedure:
Similar procedure as described in example 1g was used, starting from 6-formyl-4-methoxy-quinoline-3-carboxylic acid methyl ester (example 1e) and 2-((R)-2-hydroxy-1-phenyl-ethylamino)-thiazol-4-one (example 3a) to give 6-[2-((R)-2-hydroxy-1-phenyl-ethylamino)-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-methoxy-quinoline-3-carboxylic acid methyl ester. LC-MS m/e 464 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=O.C1C=CC=CC=1>C(O)(=O)C>[CH2:19]([O:18][C:12](=[O:17])[CH:13]=[C:14]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=1)[CH3:16])[CH3:20]
Reactant: COc1ccc(N)cc1OC
Reactant: CCOC(=O)CC(C)=O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C=C(C)Nc1ccc(OC)c(OC)c1

Procedure:
4-Aminoveratrole (62.0 g.), ethyl acetoacetate (63.0 g.), benzene (375 ml.), and acetic acid (2.1 ml.) are combined and refluxed in a flask equipped with a Dean-Stark strap to remove water until thin layer chromatography indicated the reaction is complete. The solvent is removed under reduced pressure to give a dark oil which crystallized upon standing. Recrystallization from hexane gives 79.0 g. of a tan powder, m.p. 59°-60° ; a second drop afforded 6.7 g., m.p. 54°-56° . A sample is recrystallized from ethanol/water to give an analytical sample, m.p. 57°-58°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]23[CH2:22][CH2:21][C:18]([CH2:23][CH:24]=[O:25])([CH2:19][CH2:20]2)[CH2:17][O:16]3)[CH:5]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:7]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:15]23[CH2:20][CH2:19][C:18]([CH2:23][CH2:24][OH:25])([CH2:21][CH2:22]2)[CH2:17][O:16]3)[CH:5]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:7]=1
Reactant: O=CCC12CCC(c3cc(F)cc(OC4CCCCO4)c3)(CC1)OC2
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OCCC12CCC(c3cc(F)cc(OC4CCCCO4)c3)(CC1)OC2
Temperature: -78 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a −78° C. solution of 2-(1-(3-fluoro-5-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl) acetaldehyde (424 mg, 1.22 mmol) in DCM (5 mL) under N2 was added DIBAL-H (1.34 mL of a 1.0 M solution in DCM, 1.34 mmol) dropwise. The reaction mixture was stirred at −78° C. for 2 h; CELITE® (500 mg) was then added and the reaction was quenched with sat. aq. NH4Cl (0.5 mL). The mixture was stirred at rt for 30 min, MgSO4 (500 mg) was added, and the mixture was stirred at rt for 30 min. The mixture was filtered and the residual solid was washed with DCM (3×). The combined filtrates were concentrated in vacuo. The crude oil was purified by flash chromatography (SiO2) using a gradient of 0% to 50% EtOAc/hexane (10 min) to give the title compound (350 mg, 1.00 mmol, 82% yield) as a clear oil. 1H NMR (CDCl3) δ: 6.85 (t, J=1.7 Hz, 1H), 6.73 (ddd, J=10.1, 2.3, 1.5 Hz, 1H), 6.66 (dt, J=10.6, 2.3 Hz, 1H), 5.38 (t, J=3.1 Hz, 1H), 3.94-3.81 (m, 3H), 3.70 (td, J=7.2, 4.1 Hz, 2H), 3.60 (dtd, J=11.3, 4.0, 1.2 Hz, 1H), 2.04-1.92 (m, 5H), 1.90-1.77 (m, 2H), 1.76-1.52 (m, 8H), 1.45 (t, J=7.3 Hz, 2H); 19F NMR (CDCl3) δ: −112.1 (s).
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[O:7][CH2:6][CH2:5][NH:4][CH2:3]1.[C:9]([O:13][C:14]([N:16]1[CH2:19][C:18](=O)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[C:9]([O:13][C:14]([N:16]1[CH2:19][CH:18]([N:4]2[CH2:5][CH2:6][O:7][C:2]([CH3:8])([CH3:1])[CH2:3]2)[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CC1(C)CNCCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(N2CCOC(C)(C)C2)C1
Reaction time: 16 h
Yield: 80.5 %

Procedure:
A mixture of 2,2-dimethylmorpholine (260 mg, 2.26 mmol) and 3-oxoazetidine-1-carboxylic acid tert-butyl ester (464 mg, 2.71 mmol) in DCE (15 mL) was stirred at room temperature for 2 h before the addition of sodium triacetoxyborohydride (957 mg, 4.52 mmol). The resulting mixture was stirred for 16 h, then diluted with DCM and washed with H2O. The organic phase was dried (phase separator) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 0-40%) affording the title compound as an oil (492 mg, 81%). 1H NMR (CDCl3, 300 MHz): δ 3.95-3.85 (m, 2H); 3.80-3.71 (m, 4H); 3.07-2.88 (m, 1H); 2.32-2.22 (m, 2H); 2.14-2.06 (m, 2H); 1.44 (s, 9H); 1.25 (s, 6H).
Reaction SMILES: C(=O)([O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([Br:14])=[CH:7][C:6]=1[C:15]([CH3:18])([CH3:17])[CH3:16])OC.[OH-].[K+].Cl>CO>[C:15]([C:6]1[CH:7]=[C:8]([Br:14])[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=1[OH:4])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(Br)cc1C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1cc(Br)c([N+](=O)[O-])cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a solution of methyl (2-tert-butyl-4-bromo-5-nitrophenyl) carbonate (121.5 g, 0.366 mol) in methanol (1000 mL) was added potassium hydroxide (30.75 g, 0.549 mol) in portions. After addition, the mixture was stirred at room temperature for 3 h and acidified with 1N HCl to pH 7. Methanol was removed and water was added. The mixture was extracted with ethyl acetate and the organic layer was separated, dried over Na2SO4 and concentrated to give 2-tert-butyl-4-bromo-5-nitro-phenol (C-14-a) (100 g, 99%).
Reaction SMILES: [CH2:1]([CH:8]([C:22]#[N:23])[CH2:9][P:10]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:14])[O:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N.[H][H]>C(O)C.[Ni]>[NH2:23][CH2:22][CH:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][P:10]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:14])[O:11][CH2:12][CH3:13]
Reactant: CCOC(OCC)P(=O)(CC(C#N)Cc1ccccc1)OCC
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC(CN)Cc1ccccc1)OCC

Procedure:
A solution of 3.5 g of ethyl 2-benzyl-2-cyanoethyl(diethoxymethyl)phosphinate in 50 ml of ethanol is added to 25 g of an 8% solution of ammonia in ethanol. To this are added 2 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered and the filtrate is concentrated under reduced pressure to give ethyl 3-amino-2-benzylpropyl(diethoxymethyl)phosphinate as a viscous oil, 31P=+46.3 ppm (CDCl3).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:38])[C@H:7]([CH3:37])[CH2:8][C@H:9]([OH:36])[C@@H:10]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:11][C@@H:12]([CH:25]([CH3:27])[CH3:26])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([OH:24])[CH:15]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:45]([O:47][C:48](=[O:51])[CH2:49]I)[CH3:46]>CC(C)=O>[CH2:1]([NH:5][C:6](=[O:38])[C@H:7]([CH3:37])[CH2:8][C@H:9]([OH:36])[C@@H:10]([NH:28][C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:11][C@@H:12]([CH:25]([CH3:26])[CH3:27])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([O:24][CH2:49][C:48]([O:47][CH2:45][CH3:46])=[O:51])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)CI
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)c(O)c1)C(C)C)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)c(OCC(=O)OCC)c1)C(C)C)NC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
A mixture of 52 mg of N-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoic acid (N-butyl)amide (Example 5a), 47.5 mg of caesium carbonate, 0.012 ml of iodoacetic acid ethyl ester and 5 ml of acetone is stirred for 3 hours under reflux and then concentrated by evaporation. The residue is partitioned between diethyl ether and water. The organic phases are dried and combined and then concentrated by evaporation, yielding the title compound in the form of the crude product: Rf (dichloromethane/diethyl ether=8:2)=0.28.
Reaction SMILES: O[N:2]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.C(N(CC)C(C)C)(C)C.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([C:44]2[CH:49]=[CH:48][C:47]([NH:50][C:51]3[N:56]=[C:55]([CH2:57][CH2:58][C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=4[CH2:65][C:66]([O-:68])=O)[C:54]([C:69]([F:72])([F:71])[F:70])=[CH:53][N:52]=3)=[CH:46][CH:45]=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].[Li+].C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[NH2:2][C:66](=[O:68])[CH2:65][C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][C:59]=1[CH2:58][CH2:57][C:55]1[C:54]([C:69]([F:72])([F:71])[F:70])=[CH:53][N:52]=[C:51]([NH:50][C:47]2[CH:48]=[CH:49][C:44]([CH:41]3[CH2:40][CH2:39][N:38]([C:36]([O:35][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:37])[CH2:43][CH2:42]3)=[CH:45][CH:46]=2)[N:56]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)[O-])n3)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-Hydroxybenzotriazole (32.8 mg, 0.243 mmol), EDCI (46.6 mg, 0.243 mmol) and N,N-diisopropylethylamine (84.6 μL, 0.486 mmol) were added to a solution of lithium 2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I48) (0.130 g, 0.221 mmol) in dry THF (6 mL) and dry DMF (1 mL) under an atmosphere of nitrogen. Ammonium carbonate (84.8 mg, 0.883 mmol) was added in one portion to the stirred reaction mixture after 10 minutes. The reaction was left stirred at room temperature for 18 hours. The volatiles were removed in vacuo and the residual solution was diluted with EtOAc (50 mL), transferred to a separating funnel and washed with saturated NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (50 mL) and brine (2×50 mL) and dried over Na2SO4. After filtration the solvent was removed in vacuo to afford a pale yellow solid. The crude material was purified by column chromatography on silica gel (0-80% EtOAc in petroleum benzine 40-60° C.) to afford the title compound (I49) (90.8 mg, 70%) as a white foamy solid; 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.53 (m, 3H), 7.31-7.23 (m, peaks obscured by CDCl3), 7.20 (d, J=8.5 Hz, 2H), 5.37 (s, 1H), 5.29 (s, 1H), 4.25 (b s, 2H), 3.72 (s, 2H), 3.15-3.03 (m, 4H), 2.80 (t, J=12.4 Hz, 2H), 2.69-2.59 (m, 1H), 1.83 (d, J=12.6 Hz, 2H), 1.68-1.55 (m, peaks obscured by water peak), 1.49 (s, 9H). LCMS Method C: rt 6.48 min; m/z 606 [M+Na]+, 584 [M+H]+, 528 [M−tButyl+2H]+, 484 [M-Boc+2H]+.