Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20](O)=[O:21])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.S(Cl)([Cl:29])=O>>[F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20]([Cl:29])=[O:21])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: O=C(O)CCOCCN1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCOCCN1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1
Yield: 100 %

Procedure:
3-(2-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)ethoxy)propionic acid (377 mg, 1.0 mmol) was dissolved in thionyl chloride, raised the temperature to reflux for 3 h, spun dry, residuals were washed by an appropriate amount of ethyl ether, generated 395 mg target product, yield was 100%, directly put to the next reaction step.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O)=[O:16]>>[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:16]
Reactant: O=Cc1ccccc1B(O)O
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1ccccc1C=O

Procedure:
Methyl 2-bromo-5-nitrobenzoate was coupled to 2-formylphenylboronic acid using the procedure described for Example 4, Part A to provide methyl 2-(2′-formylphenyl)-5-nitrobenzoate. 1HNMR (300 MHz, CDCl3) δ 8.91 (s, 1H); 8.42 (d, 1H, J=8.5 Hz); 8.00 (d, 1H, J=8.5 Hz); 7.64 (m, 2H); 7.47 d, 1H, J=8.5 Hz); 7.22 (d, 1H, J=8.5 Hz); 3.71 (s, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:8]2[CH:9]=[N:10][C:11]([NH:13][C:14]([NH:16][C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])=[O:15])=[CH:12][C:7]=2[NH:6][N:5]=1)[CH3:2].CN(C=O)C.C1C(=O)N([Br:37])C(=O)C1>C(#N)C>[Br:37][C:12]1[C:7]2[NH:6][N:5]=[C:4]([NH:3][CH2:1][CH3:2])[C:8]=2[CH:9]=[N:10][C:11]=1[NH:13][C:14]([NH:16][C@@H:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:18])=[O:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCNc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCNc1n[nH]c2c(Br)c(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-1-(3-(Ethylamino)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (Example 2; 316 mg, 0.974 mmol) was dissolved in acetonitrile (10 mL) and DMF (2 mL) then NBS (225 mg, 1.266 mmol) was added. The reaction was stirred at room temperature overnight. The solvents were concentrated in vacuo and the residue was purified by flash chromatography (2-10% MeOH/DCM) to give (R)-1-(7-bromo-3-(ethylamino)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. for C12H19BrN6O [M+1]+ 403. found 403.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:6]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C=O>[CH2:23]([O:2][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[N:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:8]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)n1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)cc(C(=O)OC)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 100 g of dimethyl 4-hydroxypyridine-2,6-dicarboxylate hydrochloride disloved in 500 ml of N,N-dimethylformamide, 122 g of potassium carbonate was added, and the mixture was stirred at room temperature for 1 hour. 52.5 ml of benzyl bromide was added to the resulting reaction mixture, and it was stirred at 50° C. overnight. The reaction mixture was poured into water; and then the resulting white solid was collected after filtration, washed with water, and dried in vacuo to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][NH:14]C(OCC1C=CC=CC=1)=O)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[C].[Pd]>[NH2:14][CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)NC(CNC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CN)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
2-tert-Butoxycarbonylamino-3-benzyloxycarbonylaminopropionic acid (1.06 g) was dissolved in methanol (50 ml). 10% Palladium carbon (100 mg) was added thereto, and the mixture was stirred at room temperature for two hours under hydrogen atmosphere. The resultant mixture was filtered, and the filtrate was concentrated under reduced pressure to thereby obtain 540 mg of 3-amino-2-tert-butoxycarbonylaminopropionic acid, which was dissolved in ethanol (50 ml). Potassium carbonate (365 mg) and 2-fluoronitrobenzene (377 mg) were added thereto, and the mixture was refluxed with heat for 3 hours. The resultant mixture was concentrated under reduced pressure. Water was added to the residue, and the residue was washed with diethyl ether. 1N Hydrochloric acid was added to the aqueous layer to adjust pH to 3. The resultant mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure, to thereby obtain 530 mg of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+]>C(O)C>[ClH:36].[ClH:36].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:41])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 90 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 90% of theory, Rf value: 0.17 (silica gel; dichloromethane/ethanol=4:1) C27H28N6O3 (484.6) ##EQU29##
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16](F)[CH:17]=2)[C:12](=[O:21])[C:11]([C:22]([OH:24])=[O:23])=[CH:10]1.[CH3:25][O:26][N:27]=[C:28]1[C:32]2([CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]2)[CH2:31][NH:30][CH2:29]1.C(#N)C>C(N(CC)CC)C>[C:39]([O:38][C:36]([N:34]1[CH2:35][C:32]2([C:28](=[N:27][O:26][CH3:25])[CH2:29][N:30]([C:16]3[CH:17]=[C:18]4[C:13]([C:12](=[O:21])[C:11]([C:22]([OH:24])=[O:23])=[CH:10][N:9]4[C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])=[CH:14][C:15]=3[F:20])[CH2:31]2)[CH2:33]1)=[O:37])([CH3:42])([CH3:41])[CH3:40]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(F)c(F)cc2c1=O
Reactant: CON=C1CNCC12CN(C(=O)OC(C)(C)C)C2
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON=C1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2F)CC12CN(C(=O)OC(C)(C)C)C2
Reaction time: 4 h
Yield: 67.8 %

Procedure:
1-(2,4-difluorophenyl)-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 120 mg of t-butyl 8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate and 400 mg of AmberliteR IRA-420 were added to 10 ml of acetonitrile and thereto 0.5 ml of triethylamine was added by dropping. The resulting mixture was refluxed for 48 hours and thus precipitated solid was filtered off. To the filtrate 5 ml of ethylether was added and the resulting mixture was stirred for 4 hours. The precipitated solid was filtered and dried to give 110 mg of the titled compound (yield: 67.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[Li]CCCC.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C1COCC1>[C:19]([Si:16]([CH3:18])([CH3:17])[N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([Cl:1])=[C:3]2[CH:10]=[CH:9]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Clc1ccnc2[nH]ccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)n1ccc2c(Cl)ccnc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
To a −78° C. solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (prepared as described in WO03/082289, 1.44 g, 9.47 mmol) in THF (75 ml) was slowly added a 1.4 M solution of n-BuLi in THF (7.4 ml). The resulting mixture was stirred for 10 minutes, and then tert-butyl-dimethylsilyl chloride (1.4 g, 9.47 mmol) was added to the mixture. The reaction mixture was warm to RT overnight and partitioned between H2O and EtOAc. The organic layer was separated, washed with brine, dried, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) affording 1-(tert-Butyl-dimethyl-silanyl)-4-chloro-1H-pyrrolo[2,3-b]pyridine as a clear oil (2.0 g, 62% yield).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([F:13])=[CH:8][C:7]=1[Cl:14])(=[O:4])=[O:3].Cl.[N:16]([O-])=O.[Na+].[OH-].[Na+]>O>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([NH:12][NH2:16])[C:9]([F:13])=[CH:8][C:7]=1[Cl:14])(=[O:3])=[O:4]
Reactant: O=N[O-]
Reactant: CS(=O)(=O)Oc1cc(N)c(F)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)Oc1cc(NN)c(F)cc1Cl
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
A mixture of 2-chloro-4-fluoro-5-aminophenyl methanesulfonate (24.0 g), 35% hydrochloric acid (63 g) and water (48 ml) was stirred at 60° C. for 30 minutes. Then, a solution of sodium nitrite (9.1 g) in water (55 ml) was added dropwise to the resulting mixture at -20° C. to effect diazotization reaction. The resulting mixture was added under stirring to a preformed and cooled (-20° C.) solution of 35% hydrochloric acid (52 ml) and stannous chloride hydrate (58 g) in water (100 ml) and the stirring was continued for 30 minutes under cooling. Then, the reaction solution was brought to room temperature and the pH of the solution was adjusted to 8.0 with an aqueous sodium hydroxide solution. Then, the reaction solution was extracted with toluene and tetrahydrofuran and the extract was washed with water, dried over anhydrous sodium sulfate and subjected to distillation under a reduced pressure to remove the solvent used, affording the titled compound (21.9 g) of the formula: ##STR54## as yellow crystals. Recrystallization from cyclohexane gave pale yellow crystals having melting point 75°-77° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:45])[C:5]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH2:43]C)([CH2:41]C)[CH2:33][O:34]C1CCCCO1)([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH2:26]C)([CH2:24]C)[CH2:16][O:17]C1CCCCO1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(O)C>Cl.O>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH3:41])([CH3:43])[CH2:33][OH:34])([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:24])([CH3:26])[CH2:16][OH:17])[C:4]([O:3][CH2:1][CH3:2])=[O:45])[CH3:10]
Reactant: CCOC(=O)C(CCCCC(CC)(CC)COC1CCCCO1)(CCCCC(CC)(CC)COC1CCCCO1)C(=O)OCC
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CCCCC(C)(C)CO)(CCCCC(C)(C)CO)C(=O)OCC
Yield: 0.1 %

Procedure:
A solution of 2,2-bis-[5,5-diethyl-6-(tetrahydropyran-2-yloxy)-hexyl]-malonic acid diethyl ester (2.92 g, 5 mol) in concentrated HCl (2.4 mL) and water (1.6 mL) was refluxed for 1 h. Ethanol (8.2 mL) was added and the reaction mixture was heated to reflux for 3 h. The reaction mixture was diluted with water (20 mL) and extracted with diethyl ether (3×20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), and dried over Na2SO4. The solution was concentrated to furnish 2,2-bis(6-hydroxy-5,5-dimethyl-hexyl)-malonic acid diethyl ester (1.74 g, 84%). 1H NMR (300 MHz, CDCl3/TMS): (ppm) 4.13 (q, J=7.2 Hz, 4H), 3.25 (s, 4H), 2.42 (s, 2H), 1.90-1.75 (m, 4H), 1.30-1.12 (m, 18H), 0.84 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): (ppm) 172.0, 71.7, 60.9, 57.4, 38.2, 34.9, 32.1, 24.8, 24.0, 23.7, 14.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=[CH:9]1.C(O[CH2:27][N:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:29][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.ClCCl>[CH2:34]([N:28]1[CH2:29][CH:10]2[CH:9]([C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:13][CH2:12][C:11]2=[O:14])[CH2:27]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CC(c2ccccc2F)(c2ccccc2F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2F)(c2ccccc2F)C2CN(Cc3ccccc3)CC12
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (3 drops) is added to a solution of 4,4-bis(2-fluorophenyl)cyclohexenone (4.3 g) and N-butoxymethyl-N-(trimethylsilylmethyl)benzylamine (5.8 cc) in dry dichloromethane (30 cc). The reaction mixture is brought to reflux and then stirred for 16 hours after the temperature has been allowed to return to 25° C. N-Butoxymethyl-N-(trimethylsilylmethyl)benzylamine (2.5 cc) and trifluoroacetic acid (3 drops) are added and the mixture is stirred for 3 hours under reflux. The reaction mixture is treated with potassium carbonate (3 g) and stirred for 15 minutes. After filtration and concentration to dryness under reduced pressure (2.7 kPa), the residue is chromatographed on a column of silica gel (particle size 0.04-0.063 mm, diameter 4 cm, height 32 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (85:15) and collecting 20-cc fractions. Fractions 13 to 22 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-2-benzyl-7,7-bis(2-fluorophenyl)perhydro-4-isoindolone (2.28 g). M.p. 138° C.
Reaction SMILES: [N:1]1([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][CH2:5][C:4](=O)[CH2:3][C:2]1=[O:8].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[NH:23][CH2:24][C:25](=O)[CH3:26].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N:23]1[C:4]2[CH2:5][CH2:6][N:1]([N:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[C:2](=[O:8])[C:3]=2[C:25]([CH3:26])=[CH:24]1
Reactant: O=C1CCN(N2CCCCC2)C(=O)C1
Reactant: CC(=O)CNc1ccc(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cn(-c2ccc(Cl)cc2Cl)c2c1C(=O)N(N1CCCCC1)CC2
Temperature: 25 °C
Yield: 25 %

Procedure:
To a solution of [1,1′]bipiperidinyl-2,4-dione (520 mg, 2.65 mmol) from Example 1 step 4 in dry toluene (25 ml) at room temperature were added 1-(2,4-dichlorophenylamino)-propan-2-one (576 mg, 2.64 mmol) from Step 1 above followed by a catalytic amount of p-TSA. The reaction mixture was boiled under reflux with a Dean-Stark trap, and 10 ml toluene was collected in the trap. One molar equivalent of p-TSA (250 mg) was added and the reaction mixture was boiled under reflux for 5.5 hours. After cooling to room temperature, the reaction mixture was evaporated and purified by flash chromatography (heptane:EtOAc gradient) to give 250 mg (25%) of the title compound as a brown solid. A parallel experiment with 1.51 g 1-(2,4-dichlorophenylamino)propan-2-one afforded 0.68 g (26%) of the product.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:16]=2)=[CH:9][C:8]=1[NH:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([NH2:36])[CH:31]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[CH:16]=2)=[CH:9][C:8]=1[NH:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][S:2]([CH3:1])(=[O:4])=[O:3])[CH:31]=1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(NS(C)(=O)=O)c1

Procedure:
Methanesulphonyl chloride (0.16 ml) was added to a stirred mixture of N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-3-aminobenzamide (0.765 g), pyridine (0.29 ml) and methylene chloride (30 ml) and the resultant mixture was stirred at ambient temperature for 18 hours. A second portion (0.158 ml) of methanesulphonyl chloride was added and the resultant mixture was stirred at ambient temperature for a further 18 hours. The reaction mixture was washed with water, dried (MgSO4) and evaporated. The residue was triturated under diethyl ether. The solid so obtained was dried under vacuum at 60° C. There was thus obtained the title compound (0.97 g); NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 3.03 (s, 3H), 3.2 (t, 4H), 3.74 (t, 4H), 7.17 (m, 1H), 7.23 (d, 1H), 7.4 (m, 5H), 7.59 (m, 1H), 7.7 (d, 1H), 7.8 (m, 2H), 9.93 (d, 2H), 10.14 (s, 1H); Mass Spectrum: M+H+ 509.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-:24].[K+].[K+].OO>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:24])[NH2:22])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cc2)CC1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 4-(4-cyano-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester Example 9, step 1, 215 mg, 0.71 mmol) and potassium carbonate (49 mg, 0.36 mmol) in DMSO (35 mL) at 0° C. Then add dropwise hydrogen peroxide (213 μL). Then stir at room temperature for 1 h. Quench the reaction with water (10 mL) and extract with EtOAc/hexanes (2/1, 3×20 mL). Combine the organic layers, dry over magnesium sulfate, filter and concentrate to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:15])=[CH:11][C:12](Cl)=[O:13].C(N(CC)CC)C>C(OC(C)C)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12](=[O:13])[CH:11]=[C:10]([CH3:15])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)=CC(=O)Cl
Reactant: Oc1ccc(F)cc1
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: CC(C)=CC(=O)Oc1ccc(F)cc1
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of the 4-fluorophenol (25.3 g) and dimethylacryloyl chloride (25.9 g) in diisopropyl ether (500 mL) cooled in an ice bath was added triethylamine (35 mL) dropwise over a period of 20 minutes. After 1 hour, the reaction mixture was washed with water and brine, dried over sodium sulfate, and the organic solvent was evaporated in vacuo to give crude ester. Distillation under vacuum gave dimethylacrylate 4-fluorophenyl ester (38.20 g, 87%).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[C:13]1([N:12]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Product: O=C1c2ccccc2C(=O)N1c1ccccc1
Yield: 97.8 %

Procedure:
A mixture of phthalic anhydride (19 g) and aniline (14 g) is heated at 140° to 145° C. for 50 minutes, and to the reaction mixture is added water (50 ml). The resulting powder is collected by filtration, washed with 10% aqueous potassium carbonate solution (50 ml) and water (100 ml), and dried to give colorless powder (28 g, 97%). Recrystallization from acetic acid gives colorless needles.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[CH2:9][N:8](C(=O)C(F)(F)F)[CH2:7][CH2:6][N:5]1[C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>O>[O:3]=[C:4]1[CH2:9][NH:8][CH2:7][CH2:6][N:5]1[C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)(=[O:24])=[O:23])=[CH:20][CH:21]=1
Reactant: O=C1CN(C(=O)C(F)(F)F)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1CNCCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
To a stirring solution of sodium hydroxide (1.38 g, 34.5 mmol), and H2O (5.0 mL), at 0° C., was added 4-(2-oxo-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (5.0 g, 11.5 mmol) portionwise over 10 minutes. The mixture was stirred at ambient temperature for 30 minutes. The solution was cooled to 0° C. followed by the addition of 1.0 N HCl aqueous solution (34.5 mL, 34.5 mmol). The light yellow solution was azeotroped with MeOH (4×100 mL) at <30° C. The obtained solid was suspended in 50% MeOH in CH2Cl2 (200 mL) and stirred for 5 minutes. The mixture was filtered and the filtrate was evaporated to give the desired amine as light yellow solid (2.5 g, 7.4 mmol, 64% yield). LC/MS (10%/99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=339.3; tR=0.51 min.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1.C(O)C.[OH-].[Na+]>CCCCCC>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: OC(CCl)CCc1cccnc1
Reactant: COc1cccc(-c2ccc(O)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCO
Product: COc1cccc(-c2ccc(OCC(O)CCc3cccnc3)cc2)c1

Procedure:
Prepared according to the method described in Example 24b) from (±)-α-(chloromethyl)-3-pyridinepropanol (1.90 g), 3'-methoxybiphenyl-4-ol (2.05 g), ethanol (40 ml) and aqueous sodium hydroxide (2.1 M, 5 ml). After the reaction was complete it was concentrated under reduced pressure and the residue partitioned between ethyl acetate and water. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was twice purified by column chromatography over silica eluting with dichloromethane:ethyl acetate as an oil (1.35 g). A white solid was obtained after trituration with ether:hexane.
Reaction SMILES: COC1C=CC(COC([NH:11][NH:12][C:13]([C:15]2[CH:24]=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[C:16]=2[CH3:25])=[O:14])=O)=CC=1.Cl>O1CCOCC1>[CH3:25][C:16]1[C:17]2[O:22][CH2:21][CH2:20][O:19][C:18]=2[CH:23]=[CH:24][C:15]=1[C:13]([NH:12][NH2:11])=[O:14]
Reactant: COc1ccc(COC(=O)NNC(=O)c2ccc3c(c2C)OCCO3)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(C(=O)NN)ccc2c1OCCO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.3 %

Procedure:
In a 500 mL volume flask, was combined 18.6 g (0.0499 moles) of N′-(5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)-hydrazinecarboxylic acid 4-methoxy-benzyl ester, 72 mL of concentrated HCl, and 108 mL of dioxane. The flask was placed into an 80° C. oil bath and mechanically stirred for 2 hours. The reaction mixture was cooled with ice water, then poured onto ice water and transferred to a separatory funnel. The reaction mixture —H2O solution was then extracted twice with 150 mL of CH2Cl2 to remove the acids and neutrals (the starting material). The aqueous phase was made basic (pH 12) with a 20% NaOH solution and extracted 4 times with 150 mL of ethyl acetate. The ethyl acetate extract was dried over MgSO4 and concentrated to yield 4.5 g of 5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid hydrazide. 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.0 (s, 1H), 6.85 (d, 1H), 6.74 (d, 1H), 4.28 (m, 4H), 2.781 (s, 3H).