Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:5]=[C:4]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>C1COCC1>[C:18]([C:4]1[CH:3]=[C:2]([NH:1][C:29]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:30])[N:6]([C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:5]=1)([CH3:20])([CH3:19])[CH3:21]
Reactant: CCOC(=O)c1cccc(-n2nc(C(C)(C)C)cc2N)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a mixture of ethyl 3-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)benzoate (60 g, 208.8 mmol) and K2CO3 (86.6 g, 626.4 mmol) in THF (1400 mL) was added phenyl chloroformate (98.1 g, 626.4 mmol). The reaction was stirred at room temperature overnight. The solid was removed by filtration and most of the solvent was evaporated under reduced pressure. The residual mixture was dissolved in EtOAc and washed with brine, then water. The organic layer was then dried and concentrated. The crude product was purified by recrystallization from CH2Cl2/hexanes to give the desired product as a white powder (78.5 g, 92%). MS m/z 408.1 (M+H)+; calcd. mass 407. Retention time (LC-MS): 3.92 min. 1H-NMR (DMSO-d6): δ 10.19 (s, broad, 1H); 8.11 (m 1H); 7.97 (d, J=7.6 Hz, 1H); 7.86 (m, 1H); 7.71 (t, 1H); 7.38 (m, 2H); 7.24 (m, 1H); 7.08 (m, 1H); 6.40 (s, 1H); 4.38 (q, 2H); 1.32 (t, 3H); 1.29 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](F)[CH:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:24][CH2:25][CH2:26][C:27]1[N:31]=[CH:30][NH:29][CH:28]=1>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:24][CH2:25][CH2:26][C:27]4[NH:31][CH:30]=[N:29][CH:28]=4)[CH:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: NCCc1c[nH]cn1
Reactant: Fc1ccc(-c2nn3ccccc3c2-c2ccnc(F)c2)cc1
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2nn3ccccc3c2-c2ccnc(NCCc3cnc[nH]3)c2)cc1
Temperature: 140 °C

Procedure:
In a sealed-tube was combined 2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridine (Example 27. 30 mg, 0.10 mmol) and histamine (40 mg, 0.36 mmol), and the reaction was placed in a pre-heated oil bath at 140° C. The reaction was stirred at 140° C. until consumption of starting material was indicated by TLC analysis (50% ethyl acetate in hexanes). The contents of the sealed-tube were transferred to a flask and concentrated to dryness at 50° C. under high vacuum. The residue was purified by silica gel chromatography to yield the title compound, 23 mg (0.06 mmol, 60%). 1H NMR (d6-DMSO) δ 11.8 (brs, 1H), 8.73 (d, 1H, J=6.8 Hz), 7.94 (d, 1H, J=5.3 Hz), 7.63 (d, 1H, J=9.3 Hz), 7.57 (dd, 2H, J=5.3, 8.6 Hz), 7.48 (s, 1H), 7.30 (t, 1H, J=7.6 Hz), 7.23 (t, 2H, J=9.0 Hz), 6.97 (t, 1H, J=6.8 Hz), 6.75 (brs, 1H), 6.57 (br t, 1H, J=5.3 Hz), 6.44 (s, 1H), 6.33 (d, 1H, J=5.3 Hz), 3.41 (q, 2H, J=6.6 Hz), 2.7 (t, 2H, J=6.6 Hz). MS (ES+ve): 399.1 (50, M+), 305.3 (90), 169.4 (100).
Reaction SMILES: [CH:1]12[NH:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH:13][C:14]3[N:19]=[C:18]([NH:20][C@@H:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]4[NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:17]([Cl:32])=[CH:16][N:15]=3)=[CH:3][C:2]2=1.[CH:33]1([CH:36]=O)[CH2:35][CH2:34]1>>[CH:33]([N:12]1[CH:9]2[CH2:10][CH2:11][CH:1]1[C:2]1[CH:3]=[C:4]([NH:13][C:14]3[N:19]=[C:18]([NH:20][C@@H:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]4[NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:17]([Cl:32])=[CH:16][N:15]=3)[CH:5]=[CH:6][C:7]=1[CH2:8]2)([CH2:34][CH3:35])[CH3:36]
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)C2CCC(C3)N2)ncc1Cl
Reactant: O=CC1CC1
Product: CCC(C)N1C2CCC1c1cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)ccc1C2
Yield: 68.1 %

Procedure:
Following a procedure analogous to 80a, N-{(1R,2R)-2-[2-(12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (90 mg, 0.19 mmol) and cyclopropanecarbaldehyde (0.056 mL, 0.75 mmol), were converted to the title compound as an off-white solid (69 mg, 69%): 1:1 mixture of diastereomers. 1HNMR (400 MHz, DMSO-d6) δ 9.1 (s, 1H), 7.9 (s, 1H), 7.6 (s, 0.5H), 7.5 (s, 0.5H), 7.3 (m, 1H), 7.2 (d, 0.5H, J=8.6 Hz), 7.1 (d, 0.5H, J=8.3 Hz), 6.9 (d, 1H, J=8.3 Hz), 6.7 (d, 1H, J=8.3 Hz), 4.0 (m, 1H), 3.9-3.8 (m, 1H), 3.5 (m, 1H), 3.4-3.3 (m, 1H), 3.0-2.9 (m, 4H), 2.5-2.4 (m, 1H), 2.3 (d, 1H, J=16.9 Hz), 2.2-2.0 (m, 5H), 1.9 (m, 3H), 1.6-1.2 (m, 6H), 0.9-0.8 (m, 2H), 0.4 (m, 2H); MS (m/e) 531 (M+1); mp 120-124° C.
Reaction SMILES: [N:1]1([C:7](=[O:29])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:25]3[C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:18]=[CH:17][C:16]=3[N:15]=[C:14]2[CH2:26][CH2:27][CH3:28])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:42].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[N:1]1([C:7](=[O:29])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:25]3[C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:18]=[C:17]([NH2:42])[C:16]=3[N:15]=[C:14]2[CH2:26][CH2:27][CH3:28])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)N1CCOCC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCCC(=O)N1CCOCC1
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, a solution of 1-(6-morpholin-4-yl-6-oxohexyl)-2-propyl-1H-imidazo[4,5-c]quinoline (3.6 g, 9.1 mmol) in chloroform (100 mL) was treated with mCPBA (6.29 g, 36.5 mmol). The reaction was stirred for two hours, washed sequentially with saturated aqueous sodium bicarbonate (3×) and brine, dried over magnesium sulfate, and filtered. Concentrated ammonium hydroxide (40 mL) and p-toluenesulfonyl chloride (2.60 g, 13.7 mmol) were added sequentially to the filtrate. The reaction was stirred vigorously for two hours, and then the organic layer was separated and washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 95:5 dichloromethane:methanol) followed by recrystallization from ethyl acetate:hexane to provide 0.84 g of 1-(6-morpholin-4-yl-6-oxohexyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as brown needles, mp 149-151° C.
Reaction SMILES: C=[O:2].S(=O)(=O)(O)O.O.[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=NO)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:2])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(CCCCCCl)=NO
Reactant: C=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C(=O)CCCCCCl

Procedure:
The solution of ethyl 7-chloro-2-hydroxyiminoheptanoate [III-1] in toluene obtained in Example 9 (without being concentrated) is added dropwise into 36 % aqueous formalin solution, and thereto is added sulfuric acid. The mixture is warmed, and further thereto is added water. The organic layer is separated, neutralized, washed with water, and concentrated under reduced pressure to give ethyl 7-chloro-2-oxoheptanoate [I-1].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[N:21]=[C:22]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[S:23][CH:24]=2)[CH2:15][CH2:14]1)([O-])=O.C(O)C.[Cl-].[NH4+]>O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:20]2[N:21]=[C:22]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[S:23][CH:24]=2)[CH2:17][CH2:18]1
Reactant: CCC(=O)Nc1nc(CN2CCC(c3c[nH]c4ccc([N+](=O)[O-])cc34)CC2)cs1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCC(=O)Nc1nc(CN2CCC(c3c[nH]c4ccc(N)cc34)CC2)cs1
Temperature: 80 °C
Yield: 71.4 %

Procedure:
A mixture of 4-[4-(5-nitro-3-indolyl)piperidinomethyl]-2-propionylaminothiazole (1.39 g) and ethanol (60 ml) was added to a solution of ammonium chloride (1.08 g) in water (20 ml), followed by stirring at 80° C. Iron (1.13 g) was added thereto and the mixture was refluxed for 2 hours, after which it was filtered. The residue was washed with hot ethanol and the filtrate and washings were combined and concentrated under reduced pressure. The residue was made alkaline to litmus paper with 2N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and elution was carried out with a mixture of chloroform and methanol to give 4-[4-(5-amino-3-indolyl)piperidinomethyl]-2-propionylaminothiazole (0.92 g).
Reaction SMILES: [N:1]([CH:4]([CH2:13][CH2:14][CH3:15])[CH:5]([OH:12])[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7])=[N+]=[N-]>[Pd].CO>[NH2:1][CH:4]([CH2:13][CH2:14][CH3:15])[CH:5]([OH:12])[C:6]([NH:8][CH:9]1[CH2:10][CH2:11]1)=[O:7]
Reactant: CCCC(N=[N+]=[N-])C(O)C(=O)NC1CC1
Agent: [Pd]
Solvent: CO
Product: CCCC(N)C(O)C(=O)NC1CC1
Temperature: 25 °C
Yield: 63.9 %

Procedure:
Compound 40 (15.1 g, 71.3 mmol), Pd/C (1.5 g, 5 wt %, 50% wet) and MeOH (150 mL) was charged to a pressure vessel then purged with nitrogen gas for 5 min. The vessel was sealed, pressurized to 1 bar with nitrogen gas then released three times. The same was repeated with hydrogen gas. After the third purge with hydrogen the vessel was charged with 3 hydrogen at a pressure of 3 bars. The reaction was agitated and a temperature of 25±5° C. was maintained for 14 hours after which time the reaction mixture was filtered through a pad of Celite 545 and the solvent removed to provide crude compound 41 (8.48 g) as a yellow solid. To this material was added acetonitrile (ACN; 150 mL) and the reaction heated to reflux at which time all of the solids dissolved. The mixture was then cooled to 25±5° C. and the white needles formed were collected, washed with cold ACN and dried to provide purified compound 41. 1H NMR (500 MHz, d6-DMSO): 8.05 (br s, 3H), 4.20 (d, J=3.2, 1H), 3.42-3.34 (m, 1H), 2.71-2.65 (m, 1H), 1.51-1.20 (m, 4H), 1.17 (d, J=6.5 Hz, 1H), 0.83 (t, J=7.6 Hz, 3H), 0.64-0.60 (m, 2H), 0.54-0.49 (m, 2H).
Reaction SMILES: [CH3:1][C@@H:2]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[C:3]#[CH:4].Cl/[C:14](=[N:20]\[OH:21])/[C:15]([O:17][CH2:18][CH3:19])=[O:16].CCN(CC)CC>CN(C=O)C>[C:8]([O:7][C:6]([NH:5][C@@H:2]([C:3]1[O:21][N:20]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:4]=1)[CH3:1])=[O:12])([CH3:11])([CH3:10])[CH3:9]
Reactant: C#C[C@@H](C)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)/C(Cl)=N/O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc([C@@H](C)NC(=O)OC(C)(C)C)on1
Reaction time: 5 h

Procedure:
To a stirred solution of (R)-tert-butyl but-3-yn-2-ylcarbamate (262.5 g, 1.56 mol) and (Z)-ethyl 2-chloro-2-(hydroxyimino)acetate (78.2 g, 0.52 mol) in DMF (1 L) was added dropwise Et3N (216 mL, 1.56 mol) at 90° C. The mixture was stirred for 5 hr, and then concentrated in vacuo. The residue was re-dissolved in ethyl acetate. The ethyl acetate solution was washed with water, dried over Na2SO4, and evaporated to provide the crude compound (R)-ethyl 5-(1-(tert-butoxycarbonylamino)ethyl)isoxazole-3-carboxylate. To a solution of (R)-ethyl 5-(1-(tert-butoxycarbonylamino)ethyl)isoxazole-3-carboxylate in THF (2 L) was added aqueous 2.5 N LiOH (1 L) at RT. The mixture was stirred for 1 hr, and then evaporated under reduced pressure to remove THF. The residue was partitioned between water (1 L) and ethyl acetate (0.5 L). The organic layer was separated and the aqueous layer was extracted with ethyl acetate twice. The aqueous layer was adjusted to pH 2 with 10% HCl and extracted with ethyl acetate (2×1 L). All the organic layers were combined, washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dried under vacuum to give the crude product N.4, (R)-5-(1-(tert-butoxycarbonylamino)ethyl)isoxazole-3-carboxylic acid (55.2 g, 44.8%), which was used without further purification. 1H NMR (CDCl3) δ 6.57 (s, 1H), 4.12 (q, 1H), 1.56 (d, 3 H), 1.37 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2]
Reactant: CN1CCNCC1
Reactant: N#Cc1cc(C(=O)c2ccc(F)cc2)n2c1ccc1ccccc12
Product: CN1CCN(c2ccc(C(=O)c3cc(C#N)c4ccc5ccccc5n34)cc2)CC1

Procedure:
The title compound was prepared as described for the Example 21, using 3-cyano (4-fluoro-benzoyl)-pyrrolo[1,2-a]quinoline (31 mg, 0.0986 mmol) and 4-methyl piperazine (212 mg, 0.212 mmol), and yielded 12.1 mg (68%). 1H NMR (CDCl3): 8.01 (m, 3H), 7.82 (dd, J=7.8, 1.8 Hz, 1H), 7.66 (s, 2H), 7.53 (m, 2H), 7.35 (s, 1H), 6.98 (m 2H), 3.70 (t, J=5.1 Hz, 4H), 3.00 (m, 4H), 2.66 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:4]([O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.S(=O)(=O)([OH:31])N.Cl([O-])=O.[Na+]>CC(C)=O.O>[CH3:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:4]([O:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]([OH:31])=[O:20])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccccc3)c(C)cc2c1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc2c(Oc3ccc(C(=O)O)cc3)c(-c3ccccc3)c(C)cc2c1
Reaction time: 0.08 h
Yield: 94.6 %

Procedure:
To a round-bottomed flask containing 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzaldehyde (8) (0.157 g, 0.426 mmol) was added 6 mL of an acetone:water (2:1) solution. The slightly turbid solution was cooled in an ice-water bath and sulfamic acid (0.097 g, 0.999 mmol, 2.3 eq) was added portionwise over five minutes. The reaction mixture was stirred for 5 min and sodium chlorite (80% tech. Grade) (0.059 g, 0.52 mmol, 1.23 eq) was added portionwise. The reaction mixture was stirred for 40 min. The acetone was removed in vacuo and the crude product was partitioned between water and CH2Cl2. The organic phase was separated, washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated to give 0.155 g of crude 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzoic acid as an amorphous solid. Flash chromatography over SiO2 with CH2Cl2:MeOH (96:4) gave the impure 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzoic acid. Attempted precipitation of the impurity from a solution of 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzoic acid in MeOH had failed to purify the compound. Therefore, the impure 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzoic acid (0.105 g) was dissolved in CH2Cl2 (6 mL) and the stirred solution was cooled in an ice-water bath. To the cold solution was slowly added BBr3 (1 M in CH2Cl2) (0.82 mL, 0.82 mmol) and the reaction mixture was stirred under N2 with cooling for 3 h. The reaction mixture was partitioned between CH2Cl2 and water. The organic phase was separated, washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated to give 0.115 g of the crude title compound. The crude title compound was purified by reverse phase preparative HPLC using an CH3CN:H2O gradient (25:75 to 100:0) with 0.05% TFA as a modifier to give 0.013 g (8% from FN1, Step 5) of the title compound (19) as an off-white solid. 1H NMR (400 MHz; DMSO-d6): δ 2.14 (s, 3H), 6.64 (d, J=8.8 Hz, 2H), 6.98 (dd, J=2.2 Hz, 8.9 Hz, 1H), 7.15 (m, 3H), 7.21 (m, 1H), 7.27 (m, 2H), 7.48 (d, J=9.1 Hz, 1H), 7.58 (s, 1H), 7.70 (d, J=8.8 Hz, 2H), 9.86 (s, 1H), 12.58 (br s, 1H). HRMS (ESI) Calcd for C24H17O4: 369.1127 (M−H)−. Found: 369.1148.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]3[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1>CN(C=O)C>[Cl:47][C:44]1[CH:43]=[CH:42][C:41]([C:34]2[CH:35]=[CH:36][C:37]([O:39][CH3:40])=[CH:38][C:33]=2[CH2:32][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:12]([CH:13]4[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]4)[C:11]4[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:10]=4[N:9]=3)=[CH:4][CH:3]=2)=[CH:46][CH:45]=1
Reactant: N#Cc1ccc2c(c1)nc(-c1ccc(O)cc1)n2C1CCCCC1
Reactant: COc1ccc(-c2ccc(Cl)cc2)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(Cl)cc2)c(COc2ccc(-c3nc4cc(C#N)ccc4n3C3CCCCC3)cc2)c1
Temperature: 40 °C
Reaction time: 18 h
Yield: 96.5 %

Procedure:
A suspension of compound 6 (0.330 g, 1.04 mmol) in DMF (2.4 mL) and cesium carbonate (339 mg, 1.04 mmol) was heated at 40° C. until almost clear. Compound 14 (356 mg, 1.14 mmol) was added in portions. The reaction mixture was stirred at rt for 18 h. The mixture was concentrated on a rotary evaporator. The residue was washed with water and collected by filtration. This material was purified by column chromatography (silica gel, 50% to 100% hexane/ethyl acetate (v/v) to give compound 15 (0.55 g, 100% yield). ESI-MS m/e 548 (M=1).
Reaction SMILES: [P:1]([O-:14])([O:8][CH2:9][CH:10]([OH:13])[CH2:11]Cl)([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:2].[Na+:15].C(O)C.[OH-].[Na+]>C(O)C>[P:1]([O-:14])([O:8][CH2:9][CH:10]1[O:13][CH2:11]1)([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:2].[Na+:15]
Reactant: CCCCOP(=O)([O-])OCC(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCOP(=O)([O-])OCC1CO1
Temperature: 70 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
50 g (0.19 mol) of sodium butyl 2-hydroxy-3chloropropyl phosphate was charged into a reactor, to which 1000 ml of ethanol was added, followed by agitation and heating to 70° C. to obtain a uniform mixture. Thereafter, the reaction system was cooled down to room temperature, to which was gradually added 88.6 g (0.19 mol) of a 0.0021 mol/g sodium hydroxide ethanol solution, followed by agitation for 3 hours while keeping the temperature. The HPLC analysis revealed the disappearance of a peak of the starting material with a peak for the resultant new product appearing. The resultant NaCl precipitate was removed by filtration and the ethanol was distilled off under reduced pressure to obtain 43 g (yield: 100%) of sodium butyl glycidyl phosphate.
Reaction SMILES: Br[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([OH:5])=[O:4].[Cl-:16].[Ca+2].[Cl-]>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C>[Cl:16][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([OH:5])=[O:4]
Reactant: [Cl-]
Reactant: CCCCCCCCCCC(Br)C(=O)O
Agent: CC[N+](CC)(CC)CC
Agent: [Ca+2]
Solvent: CC#N
Product: CCCCCCCCCCC(Cl)C(=O)O

Procedure:
To 2-bromododecanoic acid (1 g), after having been dissolved in acetonitrile (50 ml), were added calcium chloride (2 g) and tetraethylammonium chloride (1 g), and the mixture was heated under reflux for 4 hours. The reaction mixture was filtered, concentrated and distributed into ethyl acetate and water, and the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give 2-chlorododecanoic acid.
Reaction SMILES: [NH2:1][NH2:2].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[S:13](Cl)(=[O:15])=[O:14])[CH:6]=[CH:5][CH:4]=1>CO>[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[S:13]([NH:1][NH2:2])(=[O:15])=[O:14])[CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: NN
Solvent: CO
Product: NNS(=O)(=O)c1cccc2cccnc12
Temperature: 5 °C
Yield: 71.7 %

Procedure:
A 500 ml Erlenmeyer flask equipped with a magnetic stirrer and a thermometer is charged with 200 ml of methanol and 3.40 g (0.10 mol) of 95% hydrazine. The solution is cooled to 5° C, and 11.38 g (0.05 mol) of 8-quinolinesulfonyl chloride is added in small portions at a rate such that the reaction temperature does not exceed 15° C. After the reaction is complete, the solution is allowed to warm slowly to room temperature. The precipitating solid is filtered off to give 8.00 g of 8-quinolinesulfonyl hydrazine (C9H9N3O2S), m.p. 135°-137° C.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8](=[O:18])[C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([F:16])=[CH:11][C:10]=2[OH:17])=[C:4]([F:21])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:28]([O:30][C:31](=[O:34])[CH2:32]Br)[CH3:29]>CC(C)=O>[CH2:28]([O:30][C:31](=[O:34])[CH2:32][O:17][C:10]1[CH:11]=[C:12]([F:16])[C:13]([CH3:15])=[CH:14][C:9]=1[C:8](=[O:18])[NH:7][CH2:6][C:5]1[CH:19]=[CH:20][C:2]([Br:1])=[CH:3][C:4]=1[F:21])[CH3:29]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(C(=O)NCc2ccc(Br)cc2F)c(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(F)c(C)cc1C(=O)NCc1ccc(Br)cc1F
Temperature: 50 °C
Yield: 93 %

Procedure:
A stirring solution of N-(4-bromo-2-fluoro-benzyl)-4-fluoro-2-hydroxy-5-methyl-benzamide (1.69 g, 4.76 mmol) in acetone (24 mL, 0.2 M) was treated with an aq K2CO3 solution (3.6 mL, 2 M, 7.12 mmol) and ethylbromoacetate (0.63 mL, 5.69 mmol) in acetone (24 mL, 0.2 M) and heated to 50° C. for 2.5 h. After cooling to room temperature, the solution was concentrated, acidified to pH 1 with 2 N HCl, and diluted with ethyl acetate (100 mL) and washed with 50 mL of saturated aq NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated to provide [2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid ethyl ester (1.95, 93%) as a white solid: mp 128–129° C.; Rf 0.42 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 8.79 (bd t, J=4.5 Hz, 1 H), 8.10 (d, J=9.0 Hz, 1 H), 7.34 (t, J=8.3 Hz, 1 H), 7.26–7.23 (m, 1 H), 7.21 (t, J=2.3 Hz, 1 H), 6.53 (d, J=10.5 Hz, 1 H), 4.66 (d, J=3.9 Hz, 1 H), 4.65 (s, 2 H), 4.28 (q, J=7.2 Hz, 2 H), 2.23 (bd d, J=1.5 Hz, 3 H), 1.30 (t, J=7.2 Hz, 3H); Anal. calcd for C19H18BrFNO4: C, 51.60; H, 4.10; N, 3.17. Found C, 51.65; H, 4.19; N, 3.10.