Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Li+].[CH2:3]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:4]([CH3:6])=[O:5].[Cl:15][C:16]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]I>>[C:4]([CH:3]([P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:17]1[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:16]=1[Cl:15])(=[O:5])[CH3:6]
Reactant: CCOP(=O)(CC(C)=O)OCC
Reactant: COc1ccc(OCCCCCI)c(Cl)c1
Agent: [H-]
Agent: [Li+]
Product: CCOP(=O)(OCC)C(CCCCCOc1ccc(OC)cc1Cl)C(C)=O
Yield: 16.9 %

Procedure:
[II; Ar is 2-Cl-4-CH3OC6H3, Y is O(CH2)5, R is C2H5, R' is CH3CO] was prepared from 0.71 g of lithium hydride, 17.2 g of diethyl acetonylphosphonate and 34 g of 5-(2-chloro-4-methoxyphenoxy)pentyl iodide according to the procedure of Example 2(b). The product was chromatographed on Florisil and further purified by preparative TLC on silica gel to give 6.3 g of diethyl [1-acetyl-6-(2-chloro-4-methoxyphenoxy)hexyl]phosphonate as a light yellow oil; MIC vs. herpes simplex type 2=6 mcg/ml. The IR spectrum was consistent with the assigned structure.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][N:4]2[CH:13]=[C:14]([C:16]([OH:18])=O)[CH:15]=[C:3]12.S(Cl)([Cl:21])=O>>[Cl:21][C:16]([C:14]1[CH:15]=[C:3]2[N:4]([CH:13]=1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:2]2=[O:1])=[O:18]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2n(c1)CCc1ccccc1C2=O
Product: O=C(Cl)c1cc2n(c1)CCc1ccccc1C2=O
Yield: 89 %

Procedure:
6,11-Dihydro-11-oxo-pyrrolo[2,1-b][3]benzazepine-2-carboxylic acid (24 g., 99 mmoles) in 100 ml. of thionyl chloride was refluxed for 15 minutes. The volatiles were removed under vacuum and the residue was triturated in ether. Filtration and air-drying yielded 2-chlorocarbonyl-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one (23 g., 89%), m.p. 147°-148.5.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:22][CH2:21][CH2:20][NH:19]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:23]([O:40][C:41]1[CH:50]=[CH:49][CH:48]=[C:47]2[C:42]=1[CH2:43][CH2:44][C:45](=O)[CH2:46]2)([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[BH3-]C#N.[Na+].C(OCC)(=O)C>CO.C(O)(=O)C.O>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:22][CH2:21][CH2:20][N:19]3[CH:45]3[CH2:44][CH2:43][C:42]4[C:47](=[CH:48][CH:49]=[CH:50][C:41]=4[O:40][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:46]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC(=O)C2)(c1ccccc1)c1ccccc1
Reactant: c1ccc(-c2nc(C3CCCN3)oc2-c2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)[Si](Oc1cccc2c1CCC(N1CCCC1c1nc(-c3ccccc3)c(-c3ccccc3)o1)C2)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of 2-(4,5-diphenyloxazol-2-yl)pyrrolidine (0.6 g) and 5-tert-butyldiphenylsilyloxy-2-oxo-1,2,3,4-tetrahydronaphthalene (0.5 g) in a mixture of methanol (10 ml) and acetic acid (2 ml) was added NaBH3CN (250 mg) at room temperature. After being stirred for 2 hours at the same temperature, the mixture was poured into the mixture of ethyl acetate and water. The organic layer was washed with water and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 2-[2-(4,5-diphenyloxazol-2-yl)pyrrolidin-1-yl]-5-tert-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalen (0.84 g). MS (m/z): 676 (M+) IR (Neat): 1580 cm-1NMR (CDCl3, δ): 1.08 (9H, s), 1.5-2.4 (6H, m), 2.6-3.3 (6H, m), 4.42 (1H, m), 6.10 (1H, m), 6.4-6.7 (2H, m), 7.2-7.8 (20H, m)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([C:15]2[CH2:19][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[O:17][N:16]=2)[CH:12]=[C:11]([C:26]([OH:28])=O)[CH:10]=1.Cl.[N:30]1[N:31]=[C:32]([C@@H:35]([NH2:37])[CH3:36])[NH:33][CH:34]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([C:15]2[CH2:19][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[O:17][N:16]=2)[CH:12]=[C:11]([C:26]([NH:37][C@H:35]([C:32]2[NH:33][CH:34]=[N:30][N:31]=2)[CH3:36])=[O:28])[CH:10]=1
Reactant: C[C@H](N)c1nnc[nH]1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C3=NO[C@H](c4ccccn4)C3)c2)c(F)c1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1ccc(-c2cc(C(=O)N[C@@H](C)c3nnc[nH]3)cc(C3=NO[C@H](c4ccccn4)C3)c2)c(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2′-fluoro-4′-methyl-5-[(5S)-5-(2-pyridinyl)-4,5-dihydro-3-isoxazolyl]-3-biphenylcarboxylic acid (125 mg, 0.227 mmol) in N,N-dimethylformamide (1 mL) were added (1S)-1-(4H-1,2,4-triazol-3-yl)ethanamine hydrochloride salt (52 mg, 0.283 mmol), EDC (65 mg, 0.340 mmol), HOAT (9 mg, 0.068 mmol) and triethylamine (95 μL, 0.680 mmol). The reaction mixture was stirred at ambient temperature for 18 h. Water was added. Purification by reverse phase HPLC(C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.05% ammonium hydroxide), and concentration gave the free base. Concentrate was taken up in dichloromethane into which hydrogen chloride gas was bubbled. Concentration gave the title compound as the hydrochloride salt (94.0 mg). HRMS 471.1977 (M+1). 1H NMR (500 MHz, CD 30D): δ 8.94 (s, 1H); 8.78 (d, J=5.6 Hz, 1H); 8.53 (t, J=7.7 Hz, 1H); 8.25 (t, J=1.7 Hz, 1H); 8.16 (t, J=1.6 Hz, 1H); 8.11-8.07 (m, 2H); 7.94 (t, J=6.6 Hz, 1H); 7.46 (t, J=7.9 Hz, 1H); 7.15-7.07 (m, 2H); 6.18 (dd, J=11.4, 6.6 Hz, 1H); 5.50-5.45 (m, 1H); 4.21 (dd, J=17.3, 11.5 Hz, 1H); 3.86 (dd, J=20.8, 7.9 Hz, 1H); 2.41 (s, 3H); 1.74 (d, J=7.1 Hz, 3H).
Reaction SMILES: Cl.C(O)(C)C.[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:15][C@H:16]1[CH2:19][C@H:18]([O:20]CC2C=CC=CC=2)[CH2:17]1.C([O-])(O)=O.[Na+]>CCO.[Pd]>[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:15][C@H:16]1[CH2:17][C@H:18]([OH:20])[CH2:19]1
Reactant: c1ccc(CO[C@H]2C[C@H](Nc3nc4ccccc4s3)C2)cc1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Solvent: CC(C)O
Product: O[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Temperature: 70 °C
Yield: 113.5 %

Procedure:
A mixture of hydrogen chloride (5-6N) in isopropyl alcohol (5 mL, 25 mmol), trans-benzothiazol-2-yl-(3-benzyloxy-cyclobutyl)amine (500 mg, 1.6 mmol), and palladium black (250 mg, 50% wt percent) in EtOH (20 mL) under hydrogen atmosphere (balloon) was heated to 70° C. for 20 h. Then it was cooled to RT and solid NaHCO3 (500 mg) was added. The mixture was stirred until gas evolution ceased. The palladium was filtered off using Celite® and the filtrate was concentrated in vacuo to give an oil (400 mg), which was used to next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](OC)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CCCCCCC>C(Cl)Cl>[CH2:1]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccn1Cc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCCC
Solvent: ClCCl
Product: OCc1cccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.4 %

Procedure:
To a solution of methyl 1-benzyl-1H-pyrrole-2-carboxylate (3.00 g, 13.9 mmol) in DCM (70 mL) at −78° C. was added a 1M solution of diisobutylaluminum hydride (DIBAL-H) in heptane (35.0 mL, 34.8 mmol). After 45 min the reaction was quenched with saturated aqueous solution of NH4Cl (20 mL) and Rochell's salt (100 g). The mixture was allowed to warm to rt and was stirred for 2.5 h. The reaction mixture was extracted with EtOAc (3×). The combined organic layers were washed with H2O, saturated aq NaCl, dried over MgSO4, filtered and concentrated in vacuo to give a pale yellow oil. The crude product was chromatographed over silica gel (0 to 20% EtOAc in heptane over 20 min) to give (1-benzyl-1H-pyrrol-2-yl)-methanol as a colorless oil (2.30 g, 88%). Rf=0.47 (1:1 heptane/EtOAc); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.27-7.35 (m, 4H) 7.08-7.10 (m, 1H) 7.06-7.08 (m, 1H) 6.73 (dd, J=2.7, 1.8 Hz, 1H) 6.19 (dd, J=3.5, 1.8 Hz, 1H) 6.12-6.16 (m, 1H) 5.21-5.23 (s, 2H) 4.53 (d, J=5.1 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15](O)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:60]1([NH2:66])[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1>CN(C=O)C.CCOC(C)=O.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:66][CH:60]3[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: NC1CCCCC1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC[C@H](C(=O)NC2CCCCC2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.8 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (415 mg, 1.128 mmol) and HATU (533 mg, 1.401 mmol) in DMF (3 mL) into a 10 mL round-bottomed flask was added Hunig's base (0.408 mL, 2.34 mmol), and the resulting mixture was stirred at room temperature for 15 minutes. Cyclohexylamine (0.16 mL, 1.401 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured into water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic layer solution was concentrated, and the formed solid was recrystallized in CH3CN to afford the title compound (245 mg) as a light yellow solid. LC-MS (ES) m/z=437 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[C:6]2[C:7]([CH:13]=[O:14])=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[N:5]2[N:4]=1.[CH2:18]([Mg]Br)[CH2:19][CH3:20].O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[OH:14][CH:13]([C:7]1[C:6]2[N:5]([N:4]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:15]=2)[C:10]([O:11][CH3:12])=[CH:9][CH:8]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCC[Mg]Br
Reactant: COc1ccc(C=O)c2cc(C(F)(F)F)nn12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(OC)n2nc(C(F)(F)F)cc12
Temperature: -40 °C
Reaction time: 3 h

Procedure:
The compound of Example 115 (300 mg) was dissolved in tetrahydrofuran (12.0 mL) in an argon atmosphere. While this solution was kept at −78° C., 1.04 mol/L n-propyl magnesium bromide/tetrahydrofuran solution (1.40 mL) was added dropwise and the mixture was stirred for 3 hours as it was allowed to gradually warm to −40° C. Subsequently, a saturated aqueous solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. Evaporation of the solvent and subsequent purification of the residue by silica gel column chromatography (hexane:ethyl acetate=1:1) afforded the title compound as a yellow oil (265 mg).
Reaction SMILES: [Si:1]([O:8][CH:9]([C:19]([F:22])([F:21])[F:20])[CH:10]([NH:14][C:15](=[O:18])[CH2:16]Cl)[CH:11]([CH3:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Na+].[I-:24].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O.O>[Si:1]([O:8][CH:9]([C:19]([F:22])([F:21])[F:20])[CH:10]([NH:14][C:15](=[O:18])[CH2:16][I:24])[CH:11]([CH3:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)C(NC(=O)CCl)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Reactant: [I-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)C(NC(=O)CI)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Reaction time: 8 h
Yield: 91.9 %

Procedure:
N-(2-tert-Butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)-2-chloroacetamide (15.56 g) was added to a solution of NaI (19.3 g) in acetone (130 mL). The mixture was stirred overnight and the yellow reaction mixture was diluted with water (180 mL). The resulting precipitate was filtered; washed with water and saturated aqueous sodium thiosulfate; and dried under vacuum at 40° C. overnight. After spectral data indicated the presence of starting material, the product was subjected to another iteration of the above reaction conditions. The subsequent work-up was identical except that no sodium thiosulfate wash was performed. Purification by chromatography, eluting with hexane:ethyl acetate (gradient, 80:20 and 50:50), and drying under vacuum afforded N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)-2-iodoacetamide (17.91 g); TLC: Rf =0.30, hexane:ethyl acetate (9:1); MS: m/z=454(M+1).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:10]1[CH2:9][CH:8]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH2:7][C:6]2[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1ccncc1)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1ccncc1)C2
Yield: 93.6 %

Procedure:
A mixture of 4-methyl-7-(4-pyridyl)-5,6,7,8-tetrahydroquinolin-5-one (0.1 g), aminoguanidine hydrochloride (0.049 g), concentrated hydrochloric acid (0.15 ml), water (0.15 ml) and ethanol (10 ml) was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol-water to give 5-guanidinoimino-4-methyl-7-(4-pyridyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 76) (0.13 g) as colorless crystals.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:2]2[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[CH2:19][CH2:18]1
Reactant: CN1CCC(N)CC1
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCC(Nc2ccc(C(=O)O)cc2[N+](=O)[O-])CC1

Procedure:
To a solution of ethyl 4-fluoro-3-nitrobenzoate (2.13 g) and 1-methylpiperidin-4-amine (1.14 g) in tetrahydrofuran (40 mL) was added N,N-diisopropylethylamine (5 mL). The mixture was then stirred at reflux overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate (300 mL) and washed with aqueous NaHCO3, water and brine. After evaporation of the solvent, the residue was dissolved in tetrahydrofuran (20 mL), methanol (10 mL) and water (10 mL). Then, LiOH H2O (2 g) was added. The mixture was stirred at room temperature overnight. The mixture was then concentrated and the residue was neutralized with 5% aqueous HCl. The precipitate was filtered, washed with brine, and dried under vacuum to give the product.
Reaction SMILES: S(O)(O)(=O)=O.[CH:6]1[C:22]2[CH2:21][C@H:20]3[N:23]([CH2:25][CH2:26][C@@:12]45[C@H:19]3[CH:18]=[CH:17][C@H:15]([OH:16])[C@@H:13]4[O:14][C:10]([C:11]=25)=[C:8]([OH:9])[CH:7]=1)[CH3:24].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([OH:37])=[O:36].[ClH:38]>C(O)C>[ClH:38].[C:35]([CH2:34][O:9][C:8]1[CH:7]=[CH:6][C:22]2[CH2:21][C@H:20]3[N:23]([CH3:24])[CH2:25][CH2:26][C@:12]45[C:11]=2[C:10]=1[O:14][C@H:13]4[C@@H:15]([OH:16])[CH:17]=[CH:18][C@@H:19]35)([OH:37])=[O:36]
Reactant: O=C(O)CBr
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CN1CC[C@]23c4c5ccc(OCC(=O)O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5

Procedure:
Morphine sulfate (1.67 g, 5×10-3 mol) was dissolved with potassium carbonate (2.07 g, 1.5×10-2 mol) in 80 ml ethanol. The solution was heated to reflux while stirring and a solution containing bromoacetic acid (0.7 g, 5×10-3 mol) added in 2 ml ethanol. This was refluxed for 2 hr, then the flask was cooled in an ice-water bath. The pH was adjusted to 3 with 12N hydrochloric acid and precipitates were filtered. Solvents were evaporated under vacuum and 10 ml ethanol was added to the residue. Precipitates were filtered and solvents evaporated under vacuum. The residue was recrystallized from water/acetone (10:90). Approximately 300 mg of the desired product was recovered.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[O:14][C:15]4[C:20]([C:21](=[O:29])[C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:9]=[C:10](I)[C:3]=12.C([N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43](B3OC(C)(C)C(C)(C)O3)[CH:44]=2)[C:39]([CH3:55])=[N:38]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[O:14][C:15]4[C:20]([C:21](=[O:29])[C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:9]=[C:10]([C:43]3[CH:44]=[C:45]4[C:40]([C:39]([CH3:55])=[N:38][NH:37]4)=[CH:41][CH:42]=3)[C:3]=12
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Reactant: Nc1ncnc2c1c(I)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: Cc1n[nH]c2cc(-c3nn(Cc4oc5ccccc5c(=O)c4-c4ccccc4)c4ncnc(N)c34)ccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 25.8 %

Procedure:
To a solution of Example 57a (0.462 g, 0.930 mmoles) in DMF (6 ml), ethanol (3 ml) and water (3 ml), N-Boc-3-methylindazole-6-boronic acid pinacol ester 98 (0.500 g, 1.39 mmoles) and sodium carbonate (0.295 g, 2.79 mmoles) were added and the system is degassed for 30 min. Tetrakistriphenylphosphine Palladium (0.057 g, 0.046 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as off-white solid (0.120 g, 26% yield). MP: 2924-295° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 12.74(s,1H), 8.24(s,2H), 8.06(dd, J=7.9,1.5 Hz, 1H), 7.84(d, J=8.3 Hz, 1H), 7.75(m,1H), 7.63(s,1H), 7.49(t, J=7.3 Hz, 1H), 7.45(d, J=8.3 Hz, 1H), 7.38-7.32(m, 6H), 5.53(s, 2H), 2.51(s, 3H). Mass: 499.90(M+).
Reaction SMILES: C(Cl)(Cl)=O.[CH3:5][O:6][N:7]=[C:8]([C:12]1[N:13]=[C:14]([NH:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:15][CH:16]=1)[C:9](O)=[O:10].[CH2:37]([C:41]1[CH2:48][S:47][CH:46]2[N:43]([C:44](=[O:50])[CH:45]2[NH2:49])[C:42]=1[C:51]([O:53][CH:54]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52])[C:38]([CH3:40])=[O:39].Cl>C1C=CC=CC=1.C(Cl)Cl.CN(C)C(=O)C.C(N(CC)CC)C>[CH2:37]([C:41]1[CH2:48][S:47][CH:46]2[N:43]([C:44](=[O:50])[CH:45]2[NH:49][C:9](=[O:10])[C:8](=[N:7][O:6][CH3:5])[C:12]2[N:13]=[C:14]([NH:17][C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[S:15][CH:16]=2)[C:42]=1[C:51]([O:53][CH:54]([C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)=[O:52])[C:38]([CH3:40])=[O:39]
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(=O)CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)C2SC1
Agent: Cl
Agent: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC(C)=O)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -10 °C
Reaction time: 16 h
Yield: 35.8 %

Procedure:
A 2.5M solution of phosgene in benzene (6.47 cc) is added, in the course of 20 minutes, to a suspension of 2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetic acid (syn isomer) (5.84 g) in a mixture of methylene chloride (50 cc) and N,N-dimethylacetamide (1.23 cc) at -10° C. The reaction is left to proceed for 16 hours at -10° C. and a solution of 3-acetonyl-7-amino-2-benzhydryloxycarbonyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (5.57 g) in a mixture of methylene chloride (50 cc) and triethylamine (5.6 cc) is then added in the course of 20 minutes. The mixture is stirred for 2 hours at -10° C. 0.5N hydrochloric acid (100 cc) is added and the organic phase is separated off by decantation. It is dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. The residue is chromatographed on a column of Merck silica gel (0.06-0.2) (130 g) (diameter of the column: 3 cm; height: 37 cm). Elution is carried out with a 40/60 (by volume) ethyl acetate/cyclohexane mixture (2 liters), 100 cc fractions being collected. Fractions 8 to 14 are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. This yields the syn isomer of 3-acetonyl-2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (4 g), which is identical to the product prepared above under A.
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][N:16]([CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[S:17]([CH3:20])(=[O:19])=[O:18])[CH:9]=1)(C)(C)C>Cl.O1CCOCC1>[Cl:30][C:26]1[CH:25]=[C:24]([CH2:23][CH2:22][CH2:21][N:16]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:15][CH2:14][C:10]2[CH:9]=[C:8]([CH2:7][C:6]([OH:31])=[O:5])[CH:13]=[CH:12][CH:11]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)Cc1cccc(CCN(CCCc2cccc(Cl)c2)S(C)(=O)=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)N(CCCc1cccc(Cl)c1)CCc1cccc(CC(=O)O)c1
Yield: 13.6 %

Procedure:
A solution of [3-(2-{[3-(3-chloro-phenyl)-propyl]-methanesulfonyl-amino}ethyl)-phenyl]-acetic acid tert-butyl ester (170 mg, 0.36 mmol) in HCl/dioxane (5 mL) was stirred for 48 h at room temperature. The reaction was concentrated and the residue was taken up in dilute aqueous NaOH (10 mL, pH=9.3). The aqueous solution was washed with EtOAc (10 mL) and the layers were separated. The aqueous layer after extraction with EtOAc (10 mL) was acidified with dilute aqueous HCl to a pH of 2.5. After extraction of the acidic aqueous layer with EtOAc (10 mL) the organic solution was dried over MgSO4, filtered, and concentrated to afford the title compound as an oil (20 mg). 1H NMR (400 MHz, CDCl3) δ 6.90–7.50 (m, 8H), 3.00–3.30 (m, 4H), 2.95 (s, 3H), 2.45–2.85 (m, 4H), 1.80 (m, 2H); MS 408 (M−1).