Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:7]([C:17](=[O:32])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:6]1.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>CN(C)C=O>[CH3:3][O:4][C@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11])[C@@H:7]([C:17](=[O:32])[N:18]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:6]1
Reactant: CO[C@@H]1C[C@H](C(=O)Nc2ccc(N3CCOCC3=O)cc2)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN(C(=O)[C@H]1C[C@@H](OC)CN1C(=O)OC(C)(C)C)c1ccc(N2CCOCC2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
61 mg (2.54 mmol) of sodium hydride are added to the solution of 1 g (2.31 mmol) of tert-butyl (2R,4R)-4-methoxy-2-[4-(3-oxomorpholin-4-yl)-phenylcarbamoyl]pyrrolidine-1-carboxylate (prepared analogously to Example 7.1) in 20 ml of dimethylformamide, and the mixture is stirred at room temperature for 30 minutes. 0.22 mg (2.31 mmol) of methyl bromoacetate is subsequently added to the reaction mixture, which is then left to stir at room temperature for 12 hours. The reaction mixture is then evaporated under reduced pressure, the residue is taken up in 20 ml of water, and the aqueous solution is extracted three times with 20 ml of methylene chloride each time. Drying of the combined organic phases over sodium sulfate and stripping-off of the solvent gives 1.1 g of tert-butyl (2R,4R)-4-methoxy-2-{methoxycarbonylmethyl-[4-(3-oxomorpholin-4-yl)phenyl]-carbamoyl}pyrrolidine-1-carboxylate as a yellow oil; ESI (M-BOC) 392.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[CH3:42][S:43]([NH2:46])(=[O:45])=[O:44]>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[CH:28][CH:27]=[C:23]([C:24](=[O:25])[NH:46][S:43]([CH3:42])(=[O:45])=[O:44])[CH:22]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NS(C)(=O)=O)c3)cc12
Yield: 71.5 %

Procedure:
In a 1 dram vial with stir bar were combined 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (35 mg, 0.090 mmol), DMAP (33 mg, 0.27 mmol), EDC hydrochloride (26 mg, 0.14 mmol), and methanesulfonamide (25 mg, 0.26 mmol). DMF (0.5 mL) was added, the vial was capped, and the reaction was stirred at r.t. overnight. The reaction was filtered, purified by prep HPLC, and concentrated to give 30 mg (72% yield) of the title compound as a white powder. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.36 (br. s., 1H) 8.53 (d, J=4.58 Hz, 1H) 8.27 (s, 1H) 7.97-8.05 (m, 2H) 7.84-7.96 (m, 3H) 7.77-7.82 (m, 1H) 7.71-7.76 (m, 1H) 7.56 (t, J=7.78 Hz, 1H) 7.40 (t, J=8.85 Hz, 2H) 3.17 (s, 3H) 2.86 (d, J=4.58 Hz, 3H). LC/MS was performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=1.56 min, (ES+) m/z (MH+)=467. Analytical HPLC were performed using a Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: solvent A=5% CH3OH/95% H2O/10 mM NH4HCO3, solvent B=95% CH3OH/5% H2O/10 mM NH4HCO3, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: Phenomenex Gemini C18, 4.6 mm, 3 μm, Rt=11.93 min, purity=100%; column: Waters Xbridge Phenyl 4.6×150 mm, 3.5 μm, Rt=13.97 min, purity=99%.
Reaction SMILES: [C:1]([C:3]1[CH:54]=[CH:53][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH2:16][O:17][C:18]4[CH:50]=[CH:49][C:21]([CH2:22][CH:23]5[S:27][C:26](=[O:28])[N:25](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[C:24]5=[O:48])=[CH:20][CH:19]=4)[N:13]([CH3:51])[C:12]=3[CH:52]=2)=[CH:5][CH:4]=1)#[N:2]>C(O)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH2:16][O:17][C:18]4[CH:50]=[CH:49][C:21]([CH2:22][CH:23]5[S:27][C:26](=[O:28])[NH:25][C:24]5=[O:48])=[CH:20][CH:19]=4)[N:13]([CH3:51])[C:12]=3[CH:52]=2)=[CH:53][CH:54]=1)#[N:2]
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ccc(Oc3ccc(C#N)cc3)cc21
Solvent: CC(=O)O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(C#N)cc3)cc21
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 5-{4-[6-(4-cyanophenoxy)-1-methyl-1H-benzimidazole-2-ylmethoxy]benzyl}-3-triphenylmethylthiazolidine-2,4-dione (0.69 g) and aqueous acetic acid solution (80%, 25 ml) was stirred at 70° C. for 3 hours. The reaction mixture was concentrated and an aqueous solution of sodium bicarbonate (10%, 250 ml) was added to the residue. The mixture was stirred at ambient temperature for several hours. The insoluble product was isolated by filtration and dried in the air to afford 5-{4-[6-(4-cyanophenoxy)-1-methyl-1H-benzimidazole-2-ylmethoxy]benzyl}thiazolidine-2,4-dione. A mixture of the product and 4N hydrogen chloride/dioxane was stirred at ambient temperature for 2 hours. Insoluble product was isolated by filtration and washed with ethyl acetate to give the title compound (0.41 g).
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@H:17]([C:28]#[CH:29])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C=C1C2[C@](C)(CCC(=[O:49])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1>>[C:28]([C@@H:17]1[CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:49])[CH2:19]2)[C@@H:25]2[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:2])[CH2:8][CH2:7]3)[CH2:16]1)#[CH:29]
Reactant: C#C[C@H]1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Product: C#C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Yield: 46 %

Procedure:
The title compound II-am was prepared in 46% yield from 3,3:17,17-bis(ethylendioxy)-6α-ethynylandrostane by the procedure described for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, cyclohexane/CH2Cl2/acetone 80/10/10). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 2.69-0.78 (22H, m), 1.12 (3H, s), 0.87 (3H, s).
Reaction SMILES: C1(C[O:8][C:9](=[O:33])[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]([C:22](=[O:31])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:19](=[O:32])[CH2:18][CH2:17]3)C=CC=CC=1>[Pd]>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([N:20]2[C:21]3[C:16](=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11][CH2:10][C:9]([OH:33])=[O:8])[CH2:17][CH2:18][C:19]2=[O:32])=[O:31])=[CH:28][CH:27]=1
Reactant: COc1ccc(C(=O)N2C(=O)CCc3cccc(CCC(=O)OCc4ccccc4)c32)cc1
Agent: [Pd]
Product: COc1ccc(C(=O)N2C(=O)CCc3cccc(CCC(=O)O)c32)cc1

Procedure:
A solution of 1-(4-methoxybenzoyl)-1,2,3,4-tetrahydro-2-oxo-8-quinolinepropanoic acid phenylmethyl ester (10 g, 0.023 mole) is dissolved in tetrahydroferan (250 ml) and 1 g of 20% Pd/C is added. The mixture is shaken under an atmosphere of H2 gas until H2 absorption is complete. The mixture is filtered and concentrated at reduced pressure to yield after trituration with anhydrous diethylether and drying, 1-(4-methoxybenzoyl)-1,2,3, 4-tetrahydro-2-oxo-8-quinolinepropanoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH2:24][CH:25]=[CH2:26])=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:11]=3[N:12]=2)[CH:7]=1.[CH:27]1[C:32]([C:33]([OH:35])=[O:34])=[CH:31][C:30]2[C:36]([O:38][C:39](=O)[C:29]=2[CH:28]=1)=[O:37]>>[CH2:24]([O:23][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[C:36](=[O:37])[C:30]3[C:29](=[CH:28][CH:27]=[C:32]([C:33]([OH:35])=[O:34])[CH:31]=3)[C:39]2=[O:38])=[CH:7][C:6]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][C:11]=2[N:12]=1)[CH:25]=[CH2:26]
Reactant: C=CCOc1ccc(N)cc1-c1nc2cc(-c3ccccc3)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: C=CCOc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 1b), from 2-(5-amino-2-allyloxyphenyl)-5-phenylbenzoxazole (190 mg, 0.55 mmol) and 1,2,4-benzenetricarboxylic anhydride (106 mg, 0.55 mmol) the title compound was obtained (102 mg, 36%). 1H NMR (DMSO) δ 8.57(m, 1H), 8.35(dd, 1H), 8.37(s, 1H), 8.13(d, 1H), 7.94(m, 3H), 7.77(d, 1H), 7.63(m, 3H), 7.35(m, 4H), 6.04(m, 1H), 5.49(dd, 1H), 5.33(dd, 1H), 4.77(d, 2H). MS 517 m/z (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[NH:16][C:10]3[N:11]=[CH:12][N:13]=[C:14](O)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:14]1[C:9]2[CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:16][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2[nH]c(-c3ccccc3)cc12
Product: Clc1ncnc2[nH]c(-c3ccccc3)cc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
With the exclusion of moisture, 1.795 g (8.5 mmol) of 6-phenyl-7H-pyrrolo[2,3-d]-pyrimidin-4-ol and 27 ml of phosphorus oxychloride are heated at boiling for 3 hours. Pouring the reaction mixture into ice-water, filtering and washing with hot isopropanol and hexane yield the title compound; FAB-MS: (M+H)+ =230.
Reaction SMILES: [P:1]([CH2:5][C@H:6]1[CH2:11][CH2:10][NH:9][C@@H:8]([C:12]([OH:14])=[O:13])[CH2:7]1)([OH:4])([OH:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.[OH-].[Na+]>[C:21]([N:9]1[CH2:10][CH2:11][C@H:6]([CH2:5][P:1]([OH:3])([OH:4])=[O:2])[CH2:7][C@@H:8]1[C:12]([OH:14])=[O:13])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(O)[C@H]1C[C@@H](CP(=O)(O)O)CCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@H]1C[C@@H](CP(=O)(O)O)CCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 200 mg of cis-4-phosphonomethyl-2-piperidinecarboxylic acid, 96 mg of sodium carbonate in 5 ml of water and 2.31 ml of 1N aqueous sodium hydroxide is added 119 mg of benzoyl chloride. The reaction mixture is stirred at room temperature for 16 hours and the solvent is removed in vacuo. The residue is dissolved in ethanol, the solution is filtered and evaporated to dryness. Crystallization from ethanol/ethyl acetate affords cis-1-benzoyl-4-phosphonomethyl-2-piperidinecarboxylic acid, m.p. 135°-145° dec.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH3:12])=[N:8][CH:9]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH3:12])=[N:8][CH:9]=1
Reactant: [H][H]
Reactant: CCCc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: CCCc1ccc(N)cn1

Procedure:
A suspension of 5-nitro-2-n-propylpyridine (8.31 g, 50 mmol) and 400 mg 5% palladium on charcoal in 200 ml of ethanol was stirred in a hydrogen atmosphere until no more hydrogen was absorbed. The reaction mixture was filtered twice and the solvent was evaporated. The resulting oil was purified by kugelrohr destillation at 150° C. and high vacuum pressure. This gave 6.72 g (98%) of 5-amino-2-n-propylpyridine as a colourless oil. MS(GC): m/z 136 (M+). 1H-NMR (CDCl3, 200 MHz) δ: 0.83 (t, 3H); 1.60 (sext, 2H); 2.54 (t, 2H); 3.67 (br s, 2H); 6.81 (d, 2H); 7.91 (d, 1H).
Reaction SMILES: [O:1]=[S:2]1(=[O:22])[CH2:6][CH2:5][CH2:4][N:3]1[C@@H:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9].[OH-].[Na+].[CH2:25](I)[CH2:26][CH3:27]>CS(C)=O.O>[C:16]1([C@H:7]([N:3]2[CH2:4][CH2:5][CH2:6][S:2]2(=[O:22])=[O:1])[C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:9][CH2:25][CH2:26][CH3:27])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S1(=O)CCCN1[C@@H](c1ccccc1)[C@H](O)c1ccccc1
Reactant: CCCI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCO[C@H](c1ccccc1)[C@H](c1ccccc1)N1CCCS1(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The product obtained from stage b) (70 mg, 0.221 mmol) was dissolved in 1 ml of DMSO, and 110 mg of powdered NaOH and then 169 mg (0.995 mmol) of n-propyl iodide were added. The reaction mixture was stirred at room temperature for 1.5 hours and then diluted with water. The crystalline precipitate obtained thereby was filtered off with suction. After drying, the material was stirred several times with n-heptane. 14.5 mg of (1S,2R)-2-(1,2-diphenyl-2-propoxyethyl)isothiazolidine 1,1-dioxide were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]O.C(Br)(Br)(Br)[Br:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:15]
Reactant: COC(=O)CCCCCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)CCCCCCCCBr
Temperature: 4 °C
Reaction time: 10 h

Procedure:
A solution of methyl-9-hydroxy-nonanoate (1.1 g, 5.85 mmol, 1.0 equiv) in CH2Cl2 (30 mL, 0.2 M) at 0° C. was treated successively with CBr4 (2.5 g, 7.54 mmol, 1.3 equiv) and PPh3 (2.15 g, 8.19 mmol, 1.4 equiv) and the reaction mixture was stirred at 4° C. for 10 h. The reaction mixture was then concenctrated under reduced pressure and washed repeatedly with Et2O (8×10 mL washes). The Et2O washes were combined and concentrated under reduced pressure. Chromatography (SiO2,5 cm×15 cm, hexanes) afforded the intermediate as a clear, colorless oil (1.02 g, 1.47 g theorectical, 69.5 %): 1H NMR (CDCl3,250 MHz) d 3.64 (s, 3H, C(O)OCH3), 3.38 (t, 2H, J=6.8 Hz, CH2Br), 2.29 (t, 2H, J=7.4 Hz CH2C(O)OCH3), 1.83 (p, 2H, cH2CH2Br), 1.63 (m, 2H, CH2CH2C(O)OCH3) 1.47-1.28 (m, 8H, alkyl protons).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[N:24]1[C:29]2[NH:30][CH:31]=[CH:32][C:28]=2[CH:27]=[N:26][CH:25]=1.[OH-].[K+].O>CO>[F:1][C:2]1[C:7]([CH:8]([OH:9])[C:32]2[C:28]3[CH:27]=[N:26][CH:25]=[N:24][C:29]=3[NH:30][CH:31]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: O=Cc1cccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F
Reactant: c1ncc2cc[nH]c2n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=S(=O)(Nc1cccc(C(O)c2c[nH]c3ncncc23)c1F)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.3 %

Procedure:
To N-(2-fluoro-3-formyl-phenyl)-4-trifluoromethyl-benzenesulfonamide (34, 172 mg, 0.50 mmol) in 1 mL of methanol, 7H-pyrrolo[2,3-d]pyrimidine (6, 71 mg, 0.60 mmol) and potassium hydroxide (84 mg, 1.5 mmol) were added under an atmosphere of nitrogen. The reaction was stirred at room temperature for 24 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was purified by silica gel column chromatography eluting with 5% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a solid (P-0034, 101 mg, 44%). MS(ESI) [M+H+]−=467.8.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])=[CH:4][CH:3]=1.F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Cc1ccc(-c2ccccc2O)cc1
Product: Cc1ccc(-c2ccccc2Oc2ccccc2[N+](=O)[O-])cc1

Procedure:
Prepared from 4-methyl-2'-hydroxy-1,1'-biphenyl (Example 12, Step C) and 1-fluoro-2-nitrobenzene by the procedure described in Example 27, Step A. 1H NMR (200 MHz,CDCl3): δ 2.30 (s,3H), 6.74 (dd;2,8 Hz;1H), 6.9-7.5 (m,10H), 7.84 (dd;2,8 Hz;1H).
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].[N:46]#[C:47]Br.C(=O)(O)[O-].[Na+]>O>[NH2:46][C:47]1[NH:45][C:44]2[CH:43]=[CH:42][CH:41]=[C:3]([C:4]([NH:6][C:7]3[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=4[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[O:28])=[O:12])=[CH:9][C:8]=3[O:39][CH3:40])=[O:5])[C:2]=2[N:1]=1
Reactant: N#CBr
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(N)nc12
Reaction time: 2 h
Yield: 26.6 %

Procedure:
To a suspension of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (242 mg) in water (3 ml) was added cyanogen bromide (46 mg) at ambient temperature. The mixture was stirred at the same temperature for 2 hours and then allowed to stand at the same temperature overnight. To the reaction mixture was added saturated aqueous sodium bicarbonate solution and the solution was extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform-methanol=10:1) to give 4-(2-amino-1H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (67 mg) as a powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:22]([O:25][C:26]([F:39])([F:38])[C:27]([F:37])([F:36])[O:28][C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])([F:24])[F:23])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:40]([O:44][CH2:45][CH2:46][CH2:47][CH2:48]Cl)[CH2:41][CH2:42][CH3:43]>>[CH2:40]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][O:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:22]([O:25][C:26]([F:39])([F:38])[C:27]([F:36])([F:37])[O:28][C:29]([F:34])([F:35])[C:30]([F:31])([F:32])[F:33])([F:24])[F:23])=[CH:12][CH:13]=2)=[N:4][CH:3]=1)[CH2:41][CH2:42][CH3:43]
Reactant: Oc1cnc(-c2ccc(OCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F)cc2)nc1
Reactant: CCCCOCCCCCl
Product: CCCCOCCCCOc1cnc(-c2ccc(OCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 12 by combining 5-hydroxy-2-[4-(5-(2-(2-(pentafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)pentoxy)phenyl]pyrimidine (3.0 g, 5.1 mmol) with 4-butoxybutyl chloride (1.0 g, 6.1 mmol). The reaction mixture was quenched with water, and the crude product was further purified by recrystallization from ethanol, followed by Kugelrohr distillation (230-40° C. at 0.5 torr), to provide a yield of 2.4 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([CH:17]=[O:18])=[C:9]2[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11][C:10]=12)=[O:4].[O-:19]Cl=O.[Na+]>C(O)(C)(C)C.O>[CH3:1][O:2][C:3]([C:5]1[C:10]2[O:11][C:12]([CH3:16])([CH3:15])[O:13][CH2:14][C:9]=2[C:8]([C:17]([OH:19])=[O:18])=[CH:7][N:6]=1)=[O:4]
Reactant: [O-][Cl+][O-]
Reactant: COC(=O)c1ncc(C=O)c2c1OC(C)(C)OC2
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COC(=O)c1ncc(C(=O)O)c2c1OC(C)(C)OC2

Procedure:
8-(methoxycarbonyl)-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-5-carboxylic acid (23a) was synthesized from 5-Formyl-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxylic acid methyl ester [J. Org. Chem. 1999, 64, 4537] 1 mmol and 1.5 mmol NaClO2 in t-butanol/water
Reaction SMILES: [I-].[Li+].[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:24]2[CH2:29][CH2:28][S:27][C:26]([CH3:31])([CH3:30])[C@@H:25]2[C:32]([O:34]C(C)(C)C)=[O:33])(=[O:23])=[O:22])=[CH:17][CH:16]=1)(=[O:5])[CH3:4]>>[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([N:24]2[CH2:29][CH2:28][S:27][C:26]([CH3:30])([CH3:31])[C@@H:25]2[C:32]([OH:34])=[O:33])(=[O:22])=[O:23])=[CH:19][CH:20]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)OCCCCC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)OC(C)(C)C)cc1
Agent: [I-]
Agent: [Li+]
Product: CC(=O)OCCCCC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)O)cc1
Yield: 100.1 %

Procedure:
According to the procedure of Example 251, lithium iodide mediated ester cleavage of 0.456 g (0.845 mmol) of tert-butyl(3S)-4-[(4-{[7-(acetyloxy)-2-heptynyl]-oxy}phenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholinecarboxylate provided 0.409 g (100%) of (3S)-4-[(4-{[7-(acetyloxy)-2-heptynyl]oxy)phenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholinecarboxylic acid as a colorless oil. Electrospray Mass Spec: 446.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:33])[C:30](O)=[O:31])=[CH:25][CH:24]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[NH2:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[N:39]1([CH2:38][CH2:37][NH:36][C:30](=[O:31])[CH:29]([C:26]2[CH:27]=[CH:28][C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:35])([F:34])[F:1])=[O:6])[CH:9]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)=[CH:24][CH:25]=2)[CH3:33])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: CC(C(=O)O)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1
Reactant: NCCN1CCOCC1
Product: CC(C(=O)NCCN1CCOCC1)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1

Procedure:
This compound was prepared by using procedure analogous to those described for the synthesis of Example 98, Step 9 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}phenyl)propanoic acid and N-(2-aminoethyl)morpholine. LCMS (M+H)+: m/z=596.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH:10](O)[CH3:11])=[CH:4][CH:3]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH:10]([N:17]2[C:13](=[O:23])[C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16]2=[O:18])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(O)C#Cc1ccc(Cl)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C#Cc1ccc(Cl)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-but-3-yn-2-ol (3 g, 16.6 mmol), phthalimide (3.7 g, 25.2 mmol, 1.5 eq.) and PPh3 (4.8 g, 18.3 mmol, 1.1 eq.) in 100 mL of THF cooled to 0° C. with an ice bath was added dropwise DEAD (i.e., diethyl azodicarboxylate) (3.1 mL, 19.9 mmol, 1.2 eq.). The ice-bath was removed and the mixture was stirred overnight at room temperature. The THF was evaporated and the residue was stirred with 200 mL of 1:1 ether-hexane mixture for 1 hr. The precipitate was filtered off and the filtrate was concentrated and chromatographed with 15% ethyl acetate-hexane to provide 4.1 g of 2-[3-(4-chloro-phenyl)-1-methyl-prop-2-ynyl]-isoindole-1,3-dione.