Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:6]([S:13]C#N)=[CH:7][C:8]([CH3:12])=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].SC[C@H]([C@@H](CS)O)O.OP([O-])(O)=O.[K+]>CCO>[C:1]([C:5]1[C:6]([SH:13])=[CH:7][C:8]([CH3:12])=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(SC#N)c(C(C)(C)C)cc1O
Agent: O=P([O-])(O)O
Agent: O[C@H](CS)[C@H](O)CS
Agent: [K+]
Solvent: CCO
Product: Cc1cc(S)c(C(C)(C)C)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a round bottom flask equipped with a magnetic stirrer and condenser were added 35 g (158 mmol) of 5-tert-butyl-2-methyl-4-thiocyanato-phenol prepared in Example GGG, dithiothreitol (25.61 g, 166 mmol), EtOH (250 mL), and 0.02 M KH2PO4 buffer solution (25 mL), respectively. The reaction was heated to reflux; after 2 hours, additional dithiothreitol (5.0 g, 32.4 mmol) and 0.02 M KH2PO4 buffer solution (25 mL) were added. After 2 hours at reflux, the solution was cooled to room temperature and concentrated. The reaction was quenched with brine and extracted with 1:1 Et2O:hexanes. The organic layer was washed with brine, dried (MgSO4), and concentrated. The residue was submitted to column chromatography (100% CHCl3, silica gel) to yield the title compound. 1H NMR (CDCl3) δ 1.45 (s, 9 H), 2.15 (s, 3 H), 3.43 (s, 1 H), 4.56 (br s, 1 H), 6.82 (s, 1 H), 7.05 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][N:10]=[C:9]2[NH:14][CH2:15][C:16]1[CH:17]=[C:18]([NH:22]C(=O)OC(C)(C)C)[CH:19]=[CH:20][CH:21]=1)=[O:3].Cl.CCOCC>C(Cl)Cl>[NH2:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][NH:14][C:9]1[C:8]2[C:13](=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=[CH:6][CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CNc2ncnc3c(C(N)=O)cccc23)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Yield: 97 %

Procedure:
The title compound was prepared as light yellow solid in 97% yield by treating tert-butyl [3-({[8-(aminocarbonyl)quinazolin-4-yl]amino}methyl)phenyl]carbamate with 2N HCl/ether in DCM overnight. The precipitate was filtered, washed with ether and dried. Mass: M+H+: 294.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]=[CH:6]2.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[NH:1]([C:2]1[CH:3]=[N:4][N:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]=[CH:6]2)[C:15]([CH3:16])=[O:17]
Reactant: Nc1cnn2cnc3ccccc3c12
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cnn2cnc3ccccc3c12
Yield: 90 %

Procedure:
19.8 g (0.1 mole) of 1-aminopyrazolo[1,5-c]quinazoline are boiled with 100 ml of acetic anhydride for 1 hour. On cooling the product separates. After filtration, washing and drying, 22.0 g (90%) of 1-acetaminopyrazolo[1,5-c]quinazoline are obtained. M.p.: 256°-258° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]=1[C:8]#[N:9].C[O-].[Na+].B.C1C[O:34][CH2:33]C1.Cl>CO.O1CCOCC1.O>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[C:6]1[C:7]([CH2:8][NH2:9])=[C:2]([O:34][CH3:33])[C:3]2[N:4]([C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:19][N:20]=2)[CH:5]=1
Reactant: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2c(N3CCOCC3)cnc2c1Cl
Reactant: C1CCOC1
Agent: B
Agent: C[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: COc1c(CN)c(-c2ccc(Cl)cc2Cl)cn2c(N3CCOCC3)cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
A mixture of 8-chloro-6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-imidazo[1,2-a]pyridine-7-carbonitrile (20 mg, 0.05 mmol, prepared according to Example 30, Step 16.1) and NaOMe (8.2 mg, 0.15 mmol) in MeOH (0.5 mL) was refluxed and stirred for 1 h. The reaction mixture was cooled to RT, poured into water (20 ml) and extracted with DCM (3×10 mL). The combined organic fractions were dried over Na2SO4, filtered, and evaporated. The remaining residue was dissolved in THF and a BH3.THF complex (1.0 M solution in THF, 0.2 mL, 0.2 mmol) followed by a 4M HCl solution in dioxane (2 drops) were added. The reaction mixture was stirred and refluxed for 2 h30, then cooled to 0° C. (ice bath) and poured into MeOH. The resulting solution was evaporated to dryness and the remaining residue was purified by reverse phase prep-HPLC (Waters system) to give the title compound (2TFA salt, 3.3 mg, 0.005 mmol, 9% for 2 steps). MS: 407 [M+1]+; HPLC: AtRet=1.09.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[F:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=O)=[CH:10][CH:9]=1>CCOCC.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=[CH2:1])=[CH:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1cccc(Oc2ccc(F)cc2)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: C=Cc1cccc(Oc2ccc(F)cc2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86 %

Procedure:
To a suspension of potassium tert-butoxide (2.61 g, 23.3 mmol) in ether (100 mL) was added methyltriphenylphosphonium bromide (8.34 g, 23.3 mmol) and the solution was brought to reflux for 15 min. It was then cooled to 0° C. and 3-(4-fluorophenoxy)benzaldehyde (4.80 g, 22.2 mmol) was added. The reaction was stirred for 5 min at 0° C., the cooling bath was withdrawn and the reaction allowed to warm to ambient temperature and stir for 45 min. It was then filtered through Celite and concentrated. The resulting residue was chromatographed (silica gel; hexanes, ether 96:4) to afford 4.09 g (86%) of 3-(4-fluorophenoxy)styrene as a colorless oil.
Reaction SMILES: C([O:8][C:9](=[O:49])[C@H:10]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[NH:11][C:12](=[O:41])[C@H:13]([CH2:30][C:31](=[O:40])[O:32]CC1C=CC=CC=1)[NH:14][C:15](=[O:29])[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[N:26]1[CH:27]=[CH:28][C:23]([N:20]2[CH2:19][CH2:18][N:17]([CH2:16][C:15]([NH:14][C@H:13]([C:12]([NH:11][C@H:10]([C:9]([OH:49])=[O:8])[CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)=[O:41])[CH2:30][C:31](=[O:32])[OH:40])=[O:29])[CH2:22][CH2:21]2)=[CH:24][CH:25]=1
Reactant: [H][H]
Reactant: O=C(CN1CCN(c2ccncc2)CC1)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)C[C@H](NC(=O)CN1CCN(c2ccncc2)CC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
To a solution of O-benzyl-N-[O-benzyl-N-[2-[4-(4-pyridyl)piperazin-1-yl]acetyl]-L-aspartyl]-L-phenylalanine (0.92 g) in methanol (125 ml) under argon was added 10% Pd on C (0.45 g). The mixture was covered with a blanket of hydrogen and stirred at room temperature until deprotection was complete. The catalyst was filtered off through a pad of kieselguhr and the filtrate was evaporated to dryness. The resultant white solid was dissolved in water and lyophilised overnight to yield the title compound (274 mg) as a white solid: m.p. 153° C. (dec.); NMR (d6DMSO+CD3CO2D) δ2.65 (6H, m), 3.02 (4H, m), 3.63 (4H, m), 4.44 (1H, m), 4.67 (1H, m), 7.13 (2H, d), 7.23 (5H, m), 8.22 (2H, d); m/Z 484 (M+H)+ ; calculated for C24H29N5O6. m/Z 484 (M+H)+ ; amino acid analysis: found; Asp, 1.00; Phe 0.99; requires; Asp, 1.00; Phe, 1.00.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[CH:9]=[CH:10][CH:11]=1.[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[Br:5][C:6]1[CH:11]=[CH:10][C:9]2[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:8]=2[CH:7]=1
Reactant: O=C(O)CCCCCc1cccc(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: S=C=S
Product: O=C1CCCCCc2cc(Br)ccc21
Temperature: 60 °C
Reaction time: 20 h
Yield: 67.4 %

Procedure:
Thionyl chloride (13.2 mL, 181 mmol) was added (neat) to Example 2a, 6-(3-bromophenyl)hexanoic acid (16 g, 59.2 mmol) in a 1 L round-bottomed flask under a nitrogen atmosphere. The mixture was warmed to 60° C. for 2 h, excess reagent was removed in vacuo, and the residue was subjected to azeotropic conditions (benzene 3×). The acid chloride was dissolved in carbon disulfide (550 mL) and cannulated into a solution of aluminum trichloride (26.3 g, 198 mmol) in carbon disulfide (1315 mL) heated at reflux. The reaction was stirred 20 h, cooled, decanted, concentrated, and the resultant solids were stirred in diethyl ether/THF (1:1, 1 L), and 1N HCl (500 mL) for 1.5 hours. The organic layer was filtered, washed with water, and brine to give Example 3c, 2-bromo-7,8,9,10-tetrahydrobenzo[8]annulen-5(6H)-one 10.1 g (66%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.55 (d, J=8.4 Hz, 1H), 7.38 (dd, J=8.4 Hz, 1.8 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H), 2.99 (t, J=6.6 Hz, 2H), 2.89 (t, J=6.6 Hz, 2H), 1.85-1.73 (m, 4H), 1.52-1.44 (m, 2H). RT=2.8 minutes (condition 2); LRMS: Anal. Calcd. for C12H13BrO: 253.02. found: 253.15 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[CH3:22][C:23]1[N:24]=[N:25][S:26][C:27]=1[C:28](O)=[O:29].C(N(CC)CC)C.C(OCC)C>CN(C)C=O>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:28]([C:27]3[S:26][N:25]=[N:24][C:23]=3[CH3:22])=[O:29])[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: Cc1nnsc1C(=O)O
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nnsc1C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 31.5 %

Procedure:
Preparation of example 16 from the title compound of Example 7 (15 mg, 0.054 mmol), 4-methyl-[1,2,3]thiadiazole-5-carboxylic acid (8 mg, 0.062 mmol), triethylamine (0.030 mL, 0.22 mmol), and O-7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) in N,N-dimethylformamide (1.0 mL) was carried out analogously to Example 11. Additional 4-methyl-[1,2,3]thiadiazole-5-carboxylic acid (1.0 mg, 0.006 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (2.0 mg, 0.006 mmol) were added after c.a. 18 hours to drive the reaction to completion. Silica gel chromatography, also in an analogous manner, followed by diethyl ether trituration afforded the title compound (7 mg, 0.017 mmol) as a yellow powder in 32% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:21]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[NH:33][C:34]([CH:38]=O)=[C:35]([CH3:37])[CH:36]=2)=[O:31])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>N1CCCCC1.C(O)C.CN(C=O)C.O>[N:21]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[NH:33][C:34]([CH:38]=[C:18]3[C:11]4[C:10]([NH:9][C:4]5[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=5)=[N:15][CH:14]=[N:13][C:12]=4[N:16]([CH3:20])[C:17]3=[O:19])=[C:35]([CH3:37])[CH:36]=2)=[O:31])[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=O
Reactant: CN1C(=O)Cc2c(Nc3ccc(F)c(Cl)c3)ncnc21
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: O
Product: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=C1C(=O)N(C)c2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 90 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-7-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (244 mg, 0.83 mmol), 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (1.2 equiv.) and piperidine (1 drop) in ethanol and DMF (2 mL) was stirred at 90° C. for 2 hours. The reaction was diluted with water and the precipitate was collected by vacuum filtration, washed with water, ethyl acetate and hexane and dried to give 138.5 mg (31%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 13.39 (br s, 1H, NH), 9.29 (br s, 1H), 8.38 (m, 2H), 7.72 (m 1H), 7.39 (s, 1H, H-vinyl), 7.34 (m, 2H), 6.81 (s, 1H), 3.56 (m, 4H, 2×CH2), 3.35 (m, 2H, CH2), 3.31 (s, 3H, CH3), 2.45 (m, 2H, CH2), 2.41 (m, 4H, 2×CH2), 2.20 (s, 3H, CH3). MS 540 [M+1].
Reaction SMILES: [OH:1][CH:2]([CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:16][CH3:17].[C:26](OC(=O)C)(=[O:28])[CH3:27].O>CCOCC>[C:26]([O:1][CH:2]([CH2:18][N:19]1[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:16][CH3:17])(=[O:28])[CH3:27]
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCC(O)CN1CCN(C)CC1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CCOCC
Product: COc1cc2c(=O)[nH]cnc2cc1OCC(CN1CCN(C)CC1)OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A solution of 7-[2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy]-6-methoxyquinazolin-4-one (1.2 g, 3.3 mmol) and acetic anhydride (670 μl) in ether (2 ml) was stirred 10 minutes at ambient temperature. Ether (2 ml) was further added, followed by acetic anhydride (670 μl). After stirring 1 hour at ambient temperature, water (305 μl) was added and stirring was continued for 1.5 hours. The mixture was partitioned between methylene chloride and saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was further extracted with methylene chloride. The organic layers were combined, dried (MgSO4) and evaporated. The solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 7-[2-acetoxy-3-(4-methylpiperazin-1-yl)propoxy]-6-methoxyquinazolin-4-one (0.93 g, 72%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([Br:12])=[CH:4][N:3]=1.[C:13]1([CH:19]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:12][C:5]1[C:6]([N:24]2[CH2:25][CH2:26][N:21]([CH:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:20])[CH2:22][CH2:23]2)=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: CC(c1ccccc1)N1CCNCC1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(c1ccccc1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Temperature: 45 °C
Reaction time: 20 h

Procedure:
To a mixture of 2-amino-5-bromo-4-chloro-3-nitropyridine (0.252 g, 1.00 mmol) and isopropanol (18 ml) was added 1-(1-phenylethyl)piperazine (0.209 g, 1.10 mmol) followed by diisopropylethylamine (0.20 ml, 1.15 mmol). The reaction mixture was stirred at 45° C. for 20 h, then allowed to cool to room temperature and diluted with isopropanol (10 ml). The resulting precipitate was collected by filtration, washed with isopropanol (3×5 ml), diethyl ether (3×5 ml), and dried. The title compound was obtained as a yellow solid (0.300 g, 74%). 1H-NMR (500 MHz, DMSO-d6) 1.30 (d, J=6.7 Hz, 3H, CHCH3), 2.42 (m, 2H) and 2.54 (m, 2H) (piperazine N(CH2)2), 3.03 (br s, 4H, piperazine N(CH2)2), 3.45 (q, J=6.7 Hz, 1H, CHCH3), 6.95 (s, 2H, NH2), 7.23 (m, 1H) and 7.32 (m, 4H) (PhH), 8.13 (s, 1H, pyridine 6-H);
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5](O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2].[C:32]1([SH:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([S:38][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCCCCCCN(CCc1ccc(CC(O)C(=O)OCC)cc1)C(=O)OC(C)(C)C
Reactant: Sc1ccccc1
Product: CCCCCCCN(CCc1ccc(CC(Sc2ccccc2)C(=O)OCC)cc1)C(=O)OC(C)(C)C

Procedure:
Synthesized from 3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-2-hydroxy-propionic acid ethyl ester using a procedure analogous to that used for Example 50 and substituting benzenethiol as the nucleophile to give an approximate 1:1 mixture of ethyl and methyl ester as a clear film (51 mg, 87%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7](Cl)[C:8]2[N:9]([C:17](=[O:20])[NH:18][N:19]=2)[C:10]=1[CH:11]([OH:16])[CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][NH2:30])[CH:23]=1.O>CN1CCCC1=O>[C:1]([C:5]1[N:6]=[C:7]([NH:30][CH2:29][CH2:28][C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)[C:8]2[N:9]([C:17](=[O:20])[NH:18][N:19]=2)[C:10]=1[CH:11]([OH:16])[CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CC(O)c1c(C(C)(C)C)nc(Cl)c2n[nH]c(=O)n12
Reactant: NCCc1cccnc1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)CC(O)c1c(C(C)(C)C)nc(NCCc2cccnc2)c2n[nH]c(=O)n12

Procedure:
A solution of 70 mg of the product of Step A, 34 mg of TEA and 33 mg of 2-pyridin-3-yl-ethylamine in 1-methyl-2-pyrrolidinone (1.5 mL) was heated to 80° C. After six h, the reaction mixture was cooled, poured into water and extracted with EtOAc and then 15% IPA/chloroform. The organic extracts were washed dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in EtOAc and washed with water and sat. sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, concentrated, and the residue was recrystallized from ether/hexanes to provide the title compound as a white solid. MS (M+H+)=397.4.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([C:11]#[N:12])=[CH:9][CH:10]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:11]([C:8]1[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][CH:9]=1)#[N:12]
Reactant: CCOC(=O)c1ccc(C#N)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1ccc(C(=O)O)[nH]1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
To 260 mg of 5-cyano-1H-pyrrole-2-carboxylic acid ethyl ester (as prepared in the previous step) (1.59 mmol) in ethanol (6 mL) was added 1M aq sodium hydroxide (3.00 mL, 3.00 mmol) and the mixture was stirred at 80° C. for 2.5 h. The solvent was removed in vacuo, and the resulting solution was acidified to pH 3 with concentrated hydrochloric acid. The solid was collected on a filter and washed with water (1 mL) and dried under high vacuum to yield the title compound as a light tan solid which was used without further purification in the following step.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[I:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([I:28])[C:26]=1[OH:27])[C:21](Cl)=[O:22].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[I:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([I:28])[C:26]=1[OH:27])[C:21]([C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][C:2]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:22]
Reactant: O=C(Cl)c1cc(I)c(O)c(I)c1
Reactant: CCOC(=O)CCc1cc2ccccc2o1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)CCc1oc2ccccc2c1C(=O)c1cc(I)c(O)c(I)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
218 g of compound 4 and 409 g of 3,5-diiodo-4-hydroxybenzoyl chloride are dissolved in 2L of anhydrous methylene chloride. Slowly add 287 g of tin(IV) chloride. Stir at room temperature for 12 hours and pour into 3L of ice-water. Wash the organic phase with 5% sodium bicarbonate solution and then with 2N HCl. Dry over sodium sulfate. Evaporate. The product is crystallized from ethanol.
Reaction SMILES: C([O:5][C:6](=[O:52])[C:7]([O:10]/[N:11]=[C:12](/[C:39]1[N:40]=[C:41]([NH:44]C(OC(C)(C)C)=O)[S:42][CH:43]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([O-:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][N+:34]([CH3:37])=[CH:33][C:32]=2[CH3:38])[N:28]=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:44][C:41]1[S:42][CH:43]=[C:39](/[C:12](=[N:11]/[O:10][C:7]([C:6]([OH:52])=[O:5])([CH3:9])[CH3:8])/[C:13]([NH:15][C@@H:16]2[C:19](=[O:20])[N:18]([S:21]([O-:24])(=[O:22])=[O:23])[C@@H:17]2[CH2:25][N:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][N+:34]([CH3:37])=[CH:33][C:32]=3[CH3:38])[N:28]=[N:27]2)=[O:14])[N:40]=1
Reactant: Cc1c[n+](C)ccc1-c1cn(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)[O-])nn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c[n+](C)ccc1-c1cn(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c3csc(N)n3)C(=O)N2S(=O)(=O)[O-])nn1
Yield: 61.7 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(1,3-dimethylpyridin-1-ium-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-4-oxoazetidine-1-sulfonate (24 mg, 0.032 mmol), DCM (1.2 mL) and TFA (0.3 mL, 3.9 mmol). The crude residue was purified by reverse phase prep HPLC (T3, 30×150 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 1 mL/min), affording the title compound (12 mg, 62%) as a white solid. LCMS: m/z=606.1 (M−1); 1H NMR (400 MHz, D2O): δ 8.65 (s, 1H), 8.57 (s, 1H), 8.49 (d, J=5.6 Hz, 1H), 8.27 (d, J=6.8 Hz, 1H), 6.74 (br s, 1H), 5.47 (d, J=5.2 Hz, 1H), 4.97-4.88 (m, 3H), 4.21 (s, 3H), 2.46 (s, 3H), 1.30 (s, 3H), 1.28 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.Cl.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:34]=1>O1CCCC1.[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:39]([C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)(=[O:41])=[O:40])[CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: O=Cc1c[nH]c(-c2ccccc2F)c1
Agent: C1COCCOCCOCCOCCO1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccnc2)c1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution (96 mL) of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (475 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 503 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (2.77 g) was added dropwise and the mixture was stirred for 30 min, pyridine-3-sulfonyl chloride hydrochloride (1.35 g) was added, and the mixture was further stirred for 3 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3→2:3), and crystallized from diisopropyl ether-ethyl acetate (4:1) to give the title compound as colorless crystals (yield 680 mg, 82%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:18]([O:20]CC)=[O:19])[CH2:13][C:12]([F:15])([F:14])[C:11]2([F:17])[F:16])=[CH:6][CH:5]=1)[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:18]([OH:20])=[O:19])[CH2:13][C:12]([F:15])([F:14])[C:11]2([F:16])[F:17])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(OCC)cc2)CC(F)(F)C1(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1ccc(C2(C(=O)O)CC(F)(F)C2(F)F)cc1
Temperature: 0 °C

Procedure:
Ethyl 1-(4-ethoxyphenyl)-2,2,3,3-tetrafluorocyclobutane carboxylate (14.5 g) was dissolved in ethanol (100 ml) and a 10% w/w solution of sodium hydroxide in water (100 ml) was added and the mixture refluxed for 2.5 hours. The mixture was cooled, added to ice water and extracted with diethyl ether. The aqueous layer was acidified and the precipitate was filtered off, washed with water, dried and crystallised from 60°-80° petroleum ether to give the acid mp 112°-3° C. Yield 11.2 g (85%).