Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.O1CCCC1.C(O)(=O)C.[C:12]([O:16][C:17]([CH2:19][O:20][N:21]=[C:22]([C:49]1[N:50]=[C:51]([NH:54][CH:55]=[O:56])[S:52][CH:53]=1)[C:23]([NH:25][CH:26]1[C:47](=[O:48])[N:28]2[C:29]([C:34]([O:36]CC3C=CC([N+]([O-])=O)=CC=3)=[O:35])=[C:30]([Cl:33])[CH2:31][S:32][C@H:27]12)=[O:24])=[O:18])([CH3:15])([CH3:14])[CH3:13]>[C].[Pd].O>[C:12]([O:16][C:17]([CH2:19][O:20][N:21]=[C:22]([C:49]1[N:50]=[C:51]([NH:54][CH:55]=[O:56])[S:52][CH:53]=1)[C:23]([NH:25][CH:26]1[C:47](=[O:48])[N:28]2[C:29]([C:34]([OH:36])=[O:35])=[C:30]([Cl:33])[CH2:31][S:32][C@H:27]12)=[O:24])=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Reaction time: 4 h
Yield: 75.8 %

Procedure:
Methanol (40 ml), tetrahydrofuran (20 ml) and acetic acid (0.3 ml) were added to 4-nitrobenzyl 7-[2-(tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 3.8 g). 10% Palladium carbon (1.9 g) containing water (3 ml) was added to the solution, and subjected to catalytic reduction for 4 hours. After removal of palladium carbon by filtration, the filtrate was concentrated in vacuo. To the residue were added ethyl acetate and water, and the solution was adjusted to pH 7.5 with a saturated solution of sodium bicarbonate. After the aqueous layer was separated, ethyl acetate was added to the aqueous layer, and adjusted to pH 2.0 with 10% hydrochloric acid. The ethyl acetate layer was separated. The organic solution was washed with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diisopropyl ether, and then the precipitates were collected by filtration and dried to give 7-[2-(tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol- 4-yl)acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 2.31 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([O:12][C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH:16]=[CH:17][N+:18]([O-])=O)[CH2:11][CH2:10][CH2:9][CH2:8]1>CCOCC.O1CCCC1>[CH:7]1([O:12][C:13]2[CH:14]=[C:15]([CH2:16][CH2:17][NH2:18])[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1OC1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CCN)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a suspension of lithium aluminum hydride (10.83 g, 28.5 mmol) in ether (250 mL) at 0° C. under an argon atmosphere was added dropwise a solution of 3-cyclopentyloxy-4-methoxy-β-nitrostyrene (15.00 g, 57.0 mmol) in tetrahydrofuran (85 mL). The resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was cooled to 0° C. and quenched by the successive dropwise addition of water (11 mL), 15% sodium hydroxide (11 mL) and water (33 mL). The mixture was filtered through a pad of Celite™ and the filtrate was washed successively with water, 10% hydrochloric acid and water. The aqueous washes were combined, made basic with saturated aqueous potassium carbonate and extracted three times with ether and twice with methylene chloride. The organic layers were combined and dried (potassium carbonate). Removal of the solvent in vacuo provided the amine (10.80 g, 81%). A portion of the crude amine was purified by flash chromatography, eluting with 1:10:90 water/methanol/chloroform.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:21][CH:20]=3)[CH:18]=2)=[O:12])[CH2:7][C@H:6]1[O:36][CH3:37])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C@H:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]4)=[CH:21][CH:20]=3)[CH:18]=2)=[O:12])[CH2:7][C@H:6]1[O:36][CH3:37]
Reactant: CCCCc1nnc(C(=O)N2CC[C@H](CN=[N+]=[N-])[C@H](OC)C2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: [Pd]
Solvent: CO
Product: CCCCc1nnc(C(=O)N2CC[C@H](CN)[C@H](OC)C2)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 2.5 h

Procedure:
To a stirred solution of (±)-cis-(4-azidomethyl-3-methoxy-piperidin-1-yl)-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yl]-methanone (0.23 mmol, 120 mg) in methanol (1 mL) was added Pd—C (20% by wt., 25 mg). The reaction was hydrogenated at room temperature under balloon pressure for 2.5 h. The reaction was filtered through celite, and the solvent removed under reduced pressure to provide (±)-cis-(4-aminomethyl-3-methoxy-piperidin-1-yl)-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yl]-methanone.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]2[C:20]([C:24]([F:27])([F:26])[F:25])=[N:21][C:22](Br)=[C:16]2[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].ClC[C:30]([O:32][CH3:33])=[O:31]>CO.[CH-]=O.[CH-]=O.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Co].[Co+2]>[CH3:33][O:32][C:30]([C:22]1[N:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:17]2[CH2:18][CH2:19][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])[CH2:15][C:16]=12)=[O:31]
Reactant: COC(=O)CCl
Reactant: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(Br)c2C1
Agent: [Co+2]
Agent: [Co]
Agent: O=C([O-])[O-]
Solvent: CO
Product: COC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Yield: 67.8 %

Procedure:
Octacarbonyldicobalt (5.54 g, 16.2 mmol) and potassium carbonate (11.2 g, 81.1 mmol) was dissolved in 100 mL of methanol under stirring. The reaction mixture was stirred for 15 minutes at 60° C., and 1-bromo-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester 27b (3 g, 8.11 mmol) and methyl chloroacetate (5.25 g, 48.6 mmol) were then added to the solution. The reaction mixture was reacted for 6 hours under a carbon monoxide atmosphere and monitored by thin layer chromatography until the disappearance of the starting materials. After cooling to room temperature, the reaction mixture was filtered through a pad of silica gel, rinsed with methanol. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-1,7-dicarboxylic acid 7-tert-butyl ester 1-methyl ester 27c (1.92 g, yield 67%) as a white solid. (Reference: J. Organomet. Chem, 1985, 293)
Reaction SMILES: [CH:1]([Si:4]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[N:5]1[C:9]2=[N:10][C:11]([S:14]([Cl:17])(=[O:16])=[O:15])=[CH:12][CH:13]=[C:8]2[CH:7]=[CH:6]1)([CH3:3])[CH3:2].C1C(=O)N([Br:31])C(=O)C1>C(Cl)Cl>[Br:31][C:7]1[C:8]2[C:9](=[N:10][C:11]([S:14]([Cl:17])(=[O:16])=[O:15])=[CH:12][CH:13]=2)[N:5]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:18]([CH3:20])[CH3:19])[CH:21]([CH3:23])[CH3:22])[CH:6]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(S(=O)(=O)Cl)nc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(Br)c2ccc(S(=O)(=O)Cl)nc21
Reaction time: 4 h
Yield: 83.7 %

Procedure:
A 100-mL recovery flask was charged with 1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-6-sulfonyl chloride (2.11 g, 5.66 mmol) and DCM (28 ml) to give a clear solution. n-Bromosuccinimide (1.108 g, 6.22 mmol) was added in one portion. The resulting mixture was stirred in the dark for 4 h, then an additional portion of n-bromosuccinimide (1.108 g, 6.22 mmol) was added. The mixture was stirred overnight. In the morning, silica gel was added, and the mixture was concentrated. The impregnated silica gel was loaded onto a column, and the column was eluted onto a silica gel column with 0 to 15% EtOAc/Heptane to give 3-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-6-sulfonyl chloride (2.14 g, 4.74 mmol, 84% yield) as a light-yellow solid. 1H NMR (400 MHz, CDCl3) δ=8.08 (d, J=8.3 Hz, 1 H), 7.95 (d, J=8.3 Hz, 1 H), 7.63 (s, 1 H), 1.88 (spt, J=7.5 Hz, 4 H), 1.15 (d, J=7.5 Hz, 18 H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57]/[CH:58]=[CH:59]/[C:60]([CH2:71][CH3:72])([O:63][Si:64]([CH2:69][CH3:70])([CH2:67][CH3:68])[CH2:65][CH3:66])[CH2:61][CH3:62]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:57]/[CH:58]=[CH:59]/[C:60]([CH2:71][CH3:72])([O:63][Si:64]([CH2:69][CH3:70])([CH2:65][CH3:66])[CH2:67][CH3:68])[CH2:61][CH3:62])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCC(/C=C/CBr)(CC)O[Si](CC)(CC)CC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(/C=C/CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Yield: 100.5 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5 (10 μl) and (E)-1-bromo-4-ethyl-4-triethylsilyloxy-2-hexene (134 mg, 0.420 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) to give the title compound as a colorless oil (86.0 mg, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:7]=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([O-:3])=[O:2].Br[CH2:22][CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Si:26]([O:25][CH2:24][CH2:23][CH2:22][N:14]1[CH2:15][CH2:16][CH:11]([NH:10][C:9]2[CH:8]=[CH:7][C:6]([S:17]([NH2:20])(=[O:18])=[O:19])=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:12][CH2:13]1)([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: NS(=O)(=O)c1ccc(NC2CCNCC2)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCN1CCC(Nc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CC1
Temperature: 70 °C

Procedure:
A mixture of EXAMPLE 157B (300 mg), (3-bromopropoxy)(tert-butyl)dimethylsilane (304 mg) and cesium carbonate (967 mg) was suspended in anhydrous N,N-dimethylformamide (5 mL). The reaction mixture was heated at 70° C. overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with water, brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified using flash column purification with 3-10% methanol/dichloromethane to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([NH2:28])=[S:27])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][C:30](OC(C)=O)=O.ClCC=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:20]3[CH:21]=[CH:22][C:23]([C:26]4[S:27][CH:29]=[CH:30][N:28]=4)=[CH:24][CH:25]=3)[CH2:18][CH2:19]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3ccc(C(N)=S)cc3)CC2)CC1
Agent: O=CCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3ccc(-c4nccs4)cc3)CC2)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A solution of the product of Example 12.24, Step 1 above (151 mg; 0.374 mmol) in DMF (3 ml) was treated with Ac2O (1 ml) and chloroacetaldehyde (587 mg; 50% aq. solution; 3.74 mmol). The solution was stirred at 80° C. for 1 hr. The reaction was partitioned between iPrOAc (50 mL) and aq. sodium bicarbonate (20 mL). The organic was washed three more times with aq. sodium bicarbonate (3×10 mL). The organic was dried over magnesium sulfate, filtered and evaporated to a brown semi-solid. The solid was digested (refluxing MTBE). The nearly homogenous solution was allowed to stand at −10° C. for 1 hr, causing the deposition of a tan solid. The supernatant was drawn off and the solid rinsed with MTBE. All volatiles were removed and light tan solid was chromatographed (PTLC; 40:1 CH2Cl2/MeOH), affording the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([CH3:30])=[C:17]([S:19]([NH:22][Si](C(C)(C)C)(C)C)(=[O:21])=[O:20])[CH:18]=3)=[O:12])=[CH:8][CH:9]=2)[N:4]([Si](C(C)(C)C)(C)C)[CH:3]=1.C(Cl)Cl.CO.[OH-].[NH4+:44]>>[CH3:30][C:16]1[CH:15]=[CH:14][C:13]([C:11]([C:7]2[CH:6]=[C:5]3[C:10]([C:2]([C:5]4[CH:10]=[CH:9][N:44]=[C:7]([CH3:8])[CH:6]=4)=[CH:3][NH:4]3)=[CH:9][CH:8]=2)=[O:12])=[CH:18][C:17]=1[S:19]([NH2:22])(=[O:21])=[O:20]
Reactant: Cc1ccc(C(=O)c2ccc3c(Br)cn([Si](C)(C)C(C)(C)C)c3c2)cc1S(=O)(=O)N[Si](C)(C)C(C)(C)C
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(-c2c[nH]c3cc(C(=O)c4ccc(C)c(S(N)(=O)=O)c4)ccc23)ccn1

Procedure:
2-Methyl-5-[3-(2-methyl-pyridin-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamide is prepared from 0.25 g of 5-[3-bromo-1-(tert-butyl-dimethyl-silyl)-1H-indole-6-carbonyl]-N-(tert-butyl-dimethyl-silyl)-2-methyl-benzenesulfonamide according to the procedure described in Example 6 (microwave irradiation at 150° C. for 5 min). MS (m/z): 404 (M−1); Rf 0.19 (90:10:1 methylene chloride/methanol/ammonium hydroxide).
Reaction SMILES: C([O:3][P:4]([CH2:24][NH:25][C:26](=[O:62])[C@H:27]([CH2:58][CH:59]([CH3:61])[CH3:60])[NH:28][C:29](=[O:57])[C@@H:30]([NH:46][C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45])([CH2:6][CH:7]([C:12](=[O:23])[NH:13][C@H:14]([C:19](=[O:22])[NH:20][CH3:21])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:5])C.Br.ClC(OCC1C=CC=CC=1)=O>C(O)(=O)C.C(=O)([O-])O.[K+]>[CH2:50]([O:49][C:47]([NH:46][C@@H:30]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[C:36](=[O:45])[C:37]2=[CH:44][CH:43]=[CH:42][CH:41]=[C:38]2[C:39]1=[O:40])[C:29]([NH:28][C@H:27]([C:26]([NH:25][CH2:24][P:4]([CH2:6][CH:7]([C:12](=[O:23])[NH:13][C@H:14]([C:19](=[O:22])[NH:20][CH3:21])[CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:8][CH:9]([CH3:10])[CH3:11])(=[O:3])[OH:5])=[O:62])[CH2:58][CH:59]([CH3:61])[CH3:60])=[O:57])=[O:48])[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: CCOP(=O)(CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN1C(=O)c2ccccc2C1=O)NC(=O)OCc1ccccc1)CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC
Agent: Br
Agent: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Solvent: CC(=O)O
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN1C(=O)c2ccccc2C1=O)NC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 91.2 %

Procedure:
0.6 g of [[[N-[(S)-2-[1-(benzyloxy)formamido]-6-phthalimidohexanoyl]-L-leucyl]amino]methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester was dissolved in 2 ml of acetic acid and 2 ml of 45% hydrogen bromide in acetic acid and left to stand at room temperature overnight. The solvent was removed by evaporation and the residue was re-evaporated with toluene until a solid was obtained. This solid was dissolved in aqueous potassium hydrogen carbonate solution, 0.14 ml of benzyl chloroformate was added and the mixture was stirred for 4 hours. The solution was extracted twice with diethyl ether and acidified with hydrochloric acid. The solid was separated and dissolved by extraction with hot chloroform. The organic solution was dried over anhydrous magnesium sulfate and evaporated to yield 0.53 g of [[[N-[(S)-2-[1-(benzyloxy)formamido]-6-phthalimidohexanoyl]-L-leucyl]amino]methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid in the form of an amorphous cream powder.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([CH2:22]OS(C)(=O)=O)[O:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Br-:28].[Li+]>CC(C)=O>[CH2:1]([S:17][CH2:18][CH:19]([O:20][CH3:21])[CH2:22][Br:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCC(COS(C)(=O)=O)OC
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCSCC(CBr)OC
Temperature: 25 °C
Yield: 87.2 %

Procedure:
Into a flask equipped with a magnetic stir bar, drying tube, and a reflux condenser, a solution of 3.0 grams (0.007 mole) (±)-1-S-hexadecyl-2-O-methyl-3-O-mesylthioglycerol and 2.5 grams (0.029 mole) of lithium bromide in 150 milliliters of acetone was refluxed for 24 hours with continuous stirring. The reaction was cooled to room temperature, the sodium mesylate filtered and the solvent evaporated in vacuo. The residue was dissolved in 300 milliliters of ether and extracted three times with 500 milliliter portions of sodium thiosulfate, twice with 500 milliliter portions of water, and the organic layer dried over anhydrous sodium sulfate. Filtration of the drying agent, evaporation of the ether in vacuo and subsequent silica gel chromatography (hexane:ether 9:1 as eluent) afforded 2.5 grams (87%) of an oily product. 1H-NMR (CDCl3): delta, 0.87 (t, 3H, terminal methyl), 1.2-1.6 [m, 28H, (CH2)14 ], 2.58 (m, 2H, S--CH2), 2.62 (m, 2H, CH--CH2 --S), 3.38(S, 3H, O--CH3), 3.48 (m, 3H, CH--CH2Br).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Si:11]([CH3:14])([CH3:13])[CH3:12])[CH3:2].[N+:16]([O-])([OH:18])=[O:17].S(=O)(=O)(O)O>ClCl>[CH2:1]([NH:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=[CH:7][C:6]=1[Si:11]([CH3:14])([CH3:13])[CH3:12])[CH3:2]
Reactant: CCNC(=O)c1ccccc1[Si](C)(C)C
Reactant: O=[N+]([O-])O
Agent: ClCl
Agent: O=S(=O)(O)O
Product: CCNC(=O)c1cc([N+](=O)[O-])ccc1[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a solution of the amide of example 49 (1.10 g, 5 mmol) in CH2 Cl2 (50 mL) at 0° C. was added dropwise over 2 min, a cold mixture of 70% nitric acid (0.95 mL, 15 mmol) and concentrated sulfuric acid (5 mL) dropwise. The mixture was stirred at 0° C. for 10 min and was poured onto ice. The mixture was extracted with ethyl acetate, the combined organic layers washed with brine, sat NaHCO3, brine, dried (MgSo4) and concentrated to a solid (2.68 g, 101%) consisting of a 2:1 ratio of 5-nitro and 3-nitro isomers. The title compound was obtained by RC (ethyl acetate/hexanes) in 60% yield as a white solid. m.p. 100°-102° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=S)[CH2:24][C:25](=O)[CH3:26])=[O:4].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][NH2:36])[N:30]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:21])([F:22])[F:20])(=[O:11])=[O:12])[CH2:7][N:6]1[C:23]1[N:35]([C:31]2[N:30]=[N:29][CH:34]=[CH:33][CH:32]=2)[N:36]=[C:25]([CH3:26])[CH:24]=1)=[O:4]
Reactant: NNc1cccnn1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1-c1cccnn1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 g) was reacted with pyridazin-3-yl-hydrazine (CAS Reg. No. 40972-16-5) to give the title compound as colorless oil. MS (ESI): m/z=496.3 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][CH:6]=[C:7]([F:9])[CH:8]=1)#[CH:2].[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[N:27][OH:28])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:10])=[N:5][CH:6]=[C:7]([F:9])[CH:8]=3)[O:28][N:27]=2)=[CH:21][CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C#Cc1cc(F)cnc1N
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncc(F)cc1-c1cc(Cc2ccc(OCc3ccccc3)cc2)no1
Temperature: 55 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
To a tetrahydrofuran (10 mL) mixture of 3-ethynyl-5-fluoro-pyridin-2-ylamine (129 mg, 0.95 mmol) described in Manufacturing Example 173-1-2 and 4-benzyloxy-phenyl-acetohydroximoyl chloride (314 mg, 1.14 mmol) described in Manufacturing Example 1-1-3 was added triethylamine (264 μL, 1.90 mmol) at room temperature, which was stirred for 1 hour at 55° C., and then for another hour at 60° C. This reaction mixture was cooled to room temperature, and then partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue thus obtained was purified by NH silica gel column chromatography (heptane:ethyl acetate=3:1) to obtain the title compound (212 mg, 60%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:51][CH2:52][CH3:53])[N:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:9]=1[C:10]([O:12][CH3:13])=[O:11])=O.CC(C[AlH]CC(C)C)C.C(OCC)(=O)C.[NH4+].[Cl-]>C1COCC1>[CH3:13][O:12][C:10]([C:9]1[N:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[N:29][N:28]=3)=[CH:19][CH:20]=2)[C:7]([CH2:51][CH2:52][CH3:53])=[N:6][C:5]=1[CH2:3][OH:2])=[O:11]
Reactant: CCCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1nc(CO)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: -75 °C
Reaction time: 2.5 h
Yield: 93.4 %

Procedure:
To a solution of 7.03 g (10.0 mmole) of 4,5-bis (methoxycarbonyl)-2-propyl-1-[(2'-(N-trityltetrazol-5-yl)biphen-4-yl)methyl]-imidazole in 80 mL anhydrous THF was added 20.0 mL 1.0 M DIBAL-H (20.0 mmole, in THF) at -75° C. The mixture was stirred at -75° C. for 2.5 hours and then warmed to room temperature. After stirring overnight at room temperature, TLC (ethyl acetate) showed no starting material. The mixture was poured into 100 mL saturated aqueous NH4Cl solution and stirred for 20 min.; the product was extracted with 4×200 mL ethyl acetate, and the combined organic layer was washed with brine, dried over MgSO4, and filtered. Solvents were then removed under reduced pressure to yield 6.30 g (89.4%) of the title compound as a white foam. 1H NMR (300 MHz, DMSO-d6): δ 0.77 (t, J=7.3 Hz, 3H); 1.55 (m, 2H); 2.44 (t, J=7.7 Hz, 3H); 3.66 (s, 3H); 4.59 (d, J=6.2 Hz, 2H); 4.82 (t, J=6.2 Hz, 1H); 5.49 (s, 2H); 6.80-7.80 (m, 23H). MS (NH3 -CI/DDIP): m/z 675 (M+H, 26%); 619 (M+H-N4, 100%); 243 (Tr, 19%). Calculated mass for C42H39N6O3 (M+H): 675.308365; found: 675.308581.