Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]1([CH2:15][NH:16][C:17](=[O:41])[C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[C:28]4[NH:30][C:31](=[O:38])[C:32]5([CH2:37][CH2:36][S:35][CH2:34][CH2:33]5)[C:27]4=[CH:26][CH:25]=3)[C:21]([CH3:39])=[C:20]([F:40])[CH:19]=2)[CH2:14][CH2:13]1.[OH2:42]>ClCCl>[CH:12]1([CH2:15][NH:16][C:17](=[O:41])[C:18]2[CH:19]=[C:20]([F:40])[C:21]([CH3:39])=[C:22]([C:24]3[CH:29]=[C:28]4[NH:30][C:31](=[O:38])[C:32]5([CH2:37][CH2:36][S:35](=[O:9])(=[O:42])[CH2:34][CH2:33]5)[C:27]4=[CH:26][CH:25]=3)[CH:23]=2)[CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O
Reactant: Cc1c(F)cc(C(=O)NCC2CC2)cc1-c1ccc2c(c1)NC(=O)C21CCSCC1
Solvent: ClCCl
Product: Cc1c(F)cc(C(=O)NCC2CC2)cc1-c1ccc2c(c1)NC(=O)C21CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
3-chloroperbenzoic acid (0.04 g, 0.23 mmol) was added portionwise to a solution of N-(cyclopropylmethyl)-3-fluoro-4-methyl-5-(2-oxo-1,2,2′,3′,5′,6′-hexahydrospiro-[indole-3,4′-thiopyran]-6-yl)benzamide (example 28a, 0.10 g, 0.24 mmol) in dichloromethane (4 mL) at 0° C. The mixture was warmed to ambient temperature. After 2 hours, the mixture was cooled to 0° C. and further 3-chloroperbenzoic acid (0.04 g, 0.23 mmol) was added portionwise and the resulting mixture was stirred at room temperature for 1 additional hour. Water and dichloromethane were added, the organic layer was separated and washed with a 4% aqueous sodium hydrogen carbonate solution, dried (MgSO4) and the solvent evaporated under reduced pressure. The residue was triturated with diethyl ether to yield the title compound (0.09 g, 79%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[OH:22])[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[OH:30])[N:10]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH:39](Br)([CH3:41])[CH3:40]>COCCOCCOC>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH:39]([CH3:41])[CH3:40])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:2]([CH3:7])[CH3:3])=[CH:25][C:24]=2[OH:30])[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:5]([CH3:6])[CH3:4])=[CH:17][C:16]=2[OH:22])[N:14]=1
Reactant: CC(C)Br
Reactant: Oc1ccc(-c2nc(-c3ccc(O)cc3O)nc(-c3ccc(O)cc3O)n2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: COCCOCCOC
Product: CC(C)Oc1ccc(-c2nc(-c3ccc(OC(C)C)cc3O)nc(-c3ccc(OC(C)C)cc3O)n2)c(O)c1
Temperature: 140 °C
Reaction time: 24 h

Procedure:
A mixture of 50.0 g (0.123 mol ) of 2,4,6-tris(2′,4′-dihydroxyphenyl)-1,3,5-triazine, 54.6 g (0.395 mol) of potassium carbonate, 1.0 g (0.006 mol) of potassium iodide (Merck, 99.0%) and 50.1 g (0.407 mol) of isopropyl bromide (Fluka, 99.0%) in 200 ml of diethylene glycol dimethyl ether (Diglyme, Merck, >99%) is held with stirring at 140° C. under a pressure of 3.8 bar for 24 h.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH:12]=3)[C:7]([OH:22])=[C:6]([C:23](OCC)=[O:24])[C:5]2=[O:28])[CH2:3][CH2:2]1.[NH2:29][CH2:30][CH2:31][OH:32]>C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH:12]=3)[C:7]([OH:22])=[C:6]([C:23]([NH:29][CH2:30][CH2:31][OH:32])=[O:24])[C:5]2=[O:28])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C2CC2)c1=O
Reactant: NCCO
Solvent: CCO
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C2CC2)c1=O
Yield: 64 %

Procedure:
A solution of ethyl 1-cyclopropyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (24 mg, 0.06 mmol) and 2-aminoethanol (0.05 mL) in ethanol (1 mL) was heated in a microwave for 20 minutes. The reaction mixture was concentrated in vacuo and the residue taken up in water. The solution was acidified with 1 N HCl to a final pH˜4. The precipitate was filtered through a Teflon filter and the solids collected. This material was azeotroped with methanol to provide the title compound (16 mg, 64%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.38 (s, 1 H), 8.54 (s, 1 H), 7.80 (s, 1 H), 7.17 (m, 2 H), 7.03 (m, 2 H), 4.13 (s, 2 H), 3.84 (m, 2 H), 3.62 (m, 2 H), 2.82 (m, 1 H), 1.23 (m, 2 H), 0.76 (m, 2 H); HRMS m/z calcd for C21H21N3O4F (M+H)+ 398.1517, found 398.1512.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[ClH:32]>C1(C)C=CC=CC=1.CCOCC.CCO>[ClH:1].[ClH:32].[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)[CH2:27][CH2:28]2)=[CH:7][CH:8]=1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1ccc(C(CCCN2CCN(c3ccccn3)CC2)c2ccc(F)cc2)cc1
Yield: 67 %

Procedure:
3.3 g (0.01 mole) of 1-chloro-4,4-bis(p-fluorophenyl)butane, 3.3 g (0.02 mole) of 1-(2-pyridyl)-piperazine and 0.05 g of KI were refluxed in 15 ml of toluene for 48 h. After cooling and addition of ether (30 ml) 1-(2-pyridyl)-piperazine hydrochloride precipitated and was filtered off. After subsequent washing several times with H2O the organic layer was dried with K2CO3. Evaporation of the solvent yielded the crude base. This was dissolved in ether and HCl in EtOH was added to precipitate the hydrochloride. Recrystallization from EtOAc/EtOH yielded 3.2 g (67%) of the title compound (2:1), m.p. 224°-27° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:34]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH:34]1([NH:39][C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: NC1CCCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(NC4CCCC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and cyclopentylamine. ES-MS m/e (%): 454 (M+H+, 100).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([NH:18][CH2:19][CH3:20])=[N:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])C.C([CH:23]([C:27](Cl)=[O:28])[C:24](Cl)=[O:25])C.[Na].[C:31](O)(=[O:33])[CH3:32]>C(OCC)C.C(O)C.O>[CH2:31]([O:33][C:27]([C:23]1[C:24](=[O:25])[N:18]([CH2:19][CH3:20])[C:7]2[N:8]=[C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:10]=[CH:11][C:6]=2[C:4]=1[OH:5])=[O:28])[CH3:32]
Reactant: CCNc1nc(-c2ccccc2)ncc1C(=O)OCC
Reactant: CC(=O)O
Reactant: CCC(C(=O)Cl)C(=O)Cl
Agent: [Na]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(O)c2cnc(-c3ccccc3)nc2n(CC)c1=O

Procedure:
To 9.2 g. (0.034 mole) of 4-ethylamino-2-phenyl-5-pyrimidine-carboxylic acid ethyl ester in diethyl ether was added to 2.6 g. (0.017 mole) of ethyl malonyl chloride and then stirred 3 hours at room temperature. The reaction was then filtered and the filtrate stripped to dryness. This residue was dissolved in ethanol and added to a solution of 0.78 g. of sodium (0.034 mole) in ethanol and stirred at room temperature for 10 minutes. Acidification with acetic acid followed by the slow addition of water resulted in the formation of a precipitate. The crude product was removed by filtration and recrystallized from hexane m.p. 175°-177° C.--to give 1.0 g. of the title product.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)=[CH:26][CH:25]=1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Nc1ccc(F)cc1
Product: Cc1nc(NCc2ccccn2)nc(Nc2ccc(F)cc2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (4-fluorophenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.07 (s, 3H), 2.34 (s, 3H), 4.69 (d, J=5.9 Hz, 2H), 5.98 (bs, 1H), 6.32 (s, 1H), 6.94 (t, J=8.3 Hz, 1H), 7.16 (t, J=7.5 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.36-7.42 (m, 2H), 7.61 (t, J=7.5 Hz, 1H), 8.58 (d, J=5.4 Hz, 1H); MS (ESI) m/z 324.0 (M+1)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.CCN(CC)CC.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
To a stirring solution of benzyl 4-hydroxy-1-piperidinecarboxylate (3.55 mL, 23.4 mmol, Aldrich) and Et3N (7.18 mL, 51.5 mmol, Aldrich) in CH2Cl2 (25 mL) at room temperature was added a solution of methanesulfonyl chloride (1.99 mL, 25.8 mmol, Acros) in CH2Cl2 (25 mL) dropwise. The reaction mixture was stirred at room temperature for 1 h and washed with 1N HCl aqueous solution, H2O and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to yield 7.43 g of the desired product as a yellow oil. MS (ESI) 314 (M+H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.C(Cl)(=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[N:36]1[S:37][N:38]=[C:39]2[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:40]=12>>[N:36]1[S:37][N:38]=[C:39]2[C:44]([NH:45][C:24]([C@@H:9]3[CH2:10][C:11](=[N:13][O:14][CH2:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)[CH2:12][N:8]3[C:6](=[O:7])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:26])=[CH:43][CH:42]=[CH:41][C:40]=12
Reactant: Nc1cccc2nsnc12
Reactant: COc1ccc(CON=C2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: O=C(Cl)c1ccccc1
Product: COc1ccc(CON=C2C[C@@H](C(=O)Nc3cccc4nsnc34)N(C(=O)c3ccccc3)C2)cc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, benzoyl chloride, and 2,1,3-benzothiadiazol-4-amine the title compound was obtained in 61% purity by LC/MS. MS(ESI+): m/z=502.4.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5]1)[CH3:2].C([Li])CCC.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1.CCCCCC>[C:15]1([S:21]([N:8]2[CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][C:7]2=[O:9])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC1CCC(=O)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC1CCC(=O)N1S(=O)(=O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 29.9 %

Procedure:
To 4.5 g of 5-ethoxypyrrolidin-2-one dissolved in 140 cm3 of anhydrous tetrahydrofuran, 21.8 cm3 of butyl-lithium in hexane (1.6M) is added drop by drop under an inert atmosphere, while cooling to about -10° C. After 45 minutes, 6.15 g of benzenesulphonyl chloride in tetrahydrofuran is added, and the whole is kept at -10° C. under agitation for 2 hours. It is then returned to ambient temperature, and the residue, after concentrating under reduced pressure, is taken up in 100° ethanol. By cooling and under agitation, the product precipitates, and is then filtered, washed abundantly with water, dried, and 2.8 g of the expected product is obtained after crystallizing from isopropanol, m.p. 112°-113° C.
Reaction SMILES: CN(C=O)C.[CH2:6]([C:9]1[C:17]2[O:16][N:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=2[CH:12]=[CH:11][C:10]=1[O:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31])[CH2:7][CH3:8].[H-].[Na+].Br[CH:35]([CH3:40])[C:36]([O:38][CH3:39])=[O:37]>C(OCC)(=O)C>[O:31]=[C:27]1[N:26]([CH2:25][CH2:24][CH2:23][O:22][C:10]2[CH:11]=[CH:12][C:13]3[C:14]([C:18]([F:21])([F:19])[F:20])=[N:15][O:16][C:17]=3[C:9]=2[CH2:6][CH2:7][CH3:8])[CH2:30][CH2:29][N:28]1[CH:35]([CH3:40])[C:36]([O:38][CH3:39])=[O:37]
Reactant: CCCc1c(OCCCN2CCNC2=O)ccc2c(C(F)(F)F)noc12
Reactant: COC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCN2CCN(C(C)C(=O)OC)C2=O)ccc2c(C(F)(F)F)noc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a DMF solution (2 mL) of 1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-2-one as prepared in Example 39 (10 mg, 0.027 mmol), was added NaH (4.3 mg, 1.08 mmol) and stirred at room temperature for 30 minutes. Methyl 2-bromopropionate (27 mg, 0.16 mmol) was added and the mixture stirred for another 3 hour. After aqueous work-up and silica gel chromatography (hexanes:70% ethyl acetate), the title compound was obtained.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[F:26][C:27]([F:36])([F:35])[C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31].[C:37]1(=O)[CH2:42][CH2:41][CH2:40][C:39](=[O:43])[CH2:38]1.CO>O>[F:26][C:27]([F:35])([F:36])[C:28]1[CH:29]=[C:30]([NH:31][C:37]2[CH2:42][CH2:41][CH2:40][C:39](=[O:43])[CH:38]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: O=C1CCCC(=O)C1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CO
Solvent: O
Product: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ytterbiumtriflate (138 mg; 0.223 mmol) is added to a solution of m-trifluoromethylaniline (5.55 mL; 44.6 mmol) and 1,3-cyclohexanedione (5.0 g; 44.6 mmol) and the mixture is stirred at room temperature for 1 h. Methanol is added to the suspension until everything is dissolved. Water is added and the precipitate is filtered off, washed with water and dried. Yield: 10.35 g. ESI mass spectrum: [M+H]+=256; Retention time HPLC: 0.47 min (X012_S01).
Reaction SMILES: C[O:2][C:3]1([CH2:9][N:10]2[C:14]([CH3:15])=[CH:13][CH:12]=[N:11]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Br:16]N1C(=O)CCC1=O>CN(C)C(=O)C.C(OCC)(=O)C>[Br:16][C:13]1[CH:12]=[N:11][N:10]([CH2:9][C:3]2([OH:2])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[C:14]=1[CH3:15]
Reactant: COC1(Cn2nccc2C)CCCCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1c(Br)cnn1CC1(O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 165B (10.6 g) in N,N-dimethylacetamide (30 mL) was added N-bromosuccinimide (9.72 g). The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (400 mL) and washed with aqueous sodium bisulfite, water, and brine. Evaporation of the solvent gave the crude product which was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([N:5]([CH2:21][C:22]1[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([O:30]CC)=[O:29])=[C:24]([CH3:35])[CH:23]=1)[C:6]1[C:11]([CH3:12])=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([N:5]([CH2:21][C:22]1[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[C:24]([CH3:35])[CH:23]=1)[C:6]1[C:11]([CH3:12])=[C:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[N:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1ncnc(-c2ccc(OC)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1ncnc(-c2ccc(OC)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of ethyl [4-({butyl[6-(4-methoxyphenyl)-5-methylpyrimidin-4-yl]amino}methyl)-2-methylphenoxy]acetate (62 mg, 0.13 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL), was added 2M sodium hydroxide (1 mL). After shaking for 1 h at room temperature the solvent was removed. The residue was then acidified with 0.5M HCl aq. (20 mL), before extraction into EtOAc (2×25 mL). The organic solution was washed with brine, dried (MgSO4) and the solvents removed in vacuo to afford the title compound as a pale yellow solid (58 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[F:21][C:22]1[C:27]([F:28])=[C:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:22]1[C:27]([F:28])=[C:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:25]=[CH:24][C:23]=1[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: CCCCCCCCc1ccc(B(O)O)c(F)c1F
Reactant: CCCCCCOc1ccc(-c2ncc(Br)cn2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCCCCc1ccc(-c2cnc(-c3ccc(OCCCCCC)nc3)nc2)c(F)c1F
Yield: 79.9 %

Procedure:
The reaction of 2 mmol of 5-bromo2-(6-hexyloxypyridin-3-yl)pyrimidine, 2.2 mmol of 2,3-difluoro-4-octylphenylboronic acid, 4 mmol of sodium carbonate and 0.02 mmol of tetrakis(triphenylphosphine)palladium(0) in 14 ml of toluene, 7 ml of ethanol and 7 ml of water is carried out Analogously to the procedure indicated for Example 1a). The crude product is separated off by column chromatography on silica gel 60 using n-heptane/ethyl acetate 9:1 (v/v) as eluent and is recrystallized from acetonitrile, giving 0.77 g (80%) of colorless crystals, X 104 SC 94 SA 129 I.
Reaction SMILES: [NH:1]1[C:6]2N=CC=[CH:10][C:5]=2[C:4](=[O:11])[O:3][C:2]1=[O:12].Br[CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17].[CH2:19](Br)CCC.N>>[CH3:19][C:6]1[N:1]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:2](=[O:12])[O:3][C:4](=[O:11])[C:5]=1[CH3:10]
Reactant: CC(C)CCBr
Reactant: CCCCBr
Reactant: O=c1[nH]c2ncccc2c(=O)o1
Agent: N
Product: Cc1c(C)n(CCC(C)C)c(=O)oc1=O

Procedure:
The title compound was prepared according to the procedure of Example 1B substituting the product of Example 123A for the product of Example 1A and substituting 1-bromo-3-methyl butane for n-butyl bromide (0.224 g, 60%). MS (DCI/NH3) m/z 255 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 0.92 (d, J=6.62 Hz, 6 H) 1.46 (m, 2 H) 1.59 (dt, J=13.14, 6.48 Hz, 1 H) 1.85 (s, 3 H) 2.26 (s, 3 H) 3.77 (m, 2 H).
Reaction SMILES: BrCC(O)C.Br[CH:7]([CH3:10])[CH2:8][OH:9].[F:11][C:12]1[CH:13]=[C:14]([OH:22])[CH:15]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:11][C:12]1[CH:13]=[C:14]([CH:15]=[C:16]([S:18]([CH3:21])(=[O:19])=[O:20])[CH:17]=1)[O:22][CH:7]([CH3:10])[CH2:8][OH:9]
Reactant: CS(=O)(=O)c1cc(O)cc(F)c1
Reactant: CC(Br)CO
Agent: CC(O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CO)Oc1cc(F)cc(S(C)(=O)=O)c1
Temperature: 120 °C

Procedure:
A mixture of 1-bromo-2-propanol (70%) and 2-bromo-1-propanol (30%) (5.81 g, 41.8 mmol) was added to a solution of 3-fluoro-5-methylsulfonyl-phenol (1.59 g, 8.36 mmol) and potassium carbonate (2.37 g, 16.71 mmol) in dry dimethyl formamide (10 ml), the mixture was heated to 120° C. for 20 hours, the mixture was allowed to cool to ambient temperature and water (100 ml) was added. The aqueous phase was extracted with ethyl acetate (3×100 ml), the combined organic phase was washed with LiCl (5% aqueous solution, 4×50 ml), brine (50 ml) and dried with Na2SO4 and evaporated. Purification flash chromatography (isooctane:ethyl acetate 1:0 to 3:2). 0.65 g (mixture of 1-(3-fluoro-5-methylsulfonyl-phenoxy)propan-2-ol and 2-(3-fluoro-5-methylsulfonyl-phenoxy)propan-1-ol), 31%. MS m/z (relative intensity, 70 eV) 248 (M+, 14), 204 (54), 203 (bp), 191 (37), 190 (44).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[NH2:17].Cl.[C:19]([C:22]1([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]1)(O)=[O:20].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[NH:17][C:19]([C:22]1([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]1)=[O:20]
Reactant: NC(=O)C1(C(=O)O)CC1
Reactant: Nc1ccc(OCc2ccc(F)cc2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)C1(C(=O)Nc2ccc(OCc3ccc(F)cc3)cc2F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
A mixture of 2-fluoro-4-(4-fluoro-benzyloxy)-phenylamine (1:1) hydrochloride (272 mg, 1 mmol), 1-carboxycyclopropanecarboxamide (129 mg, 1 mmol), N-(3-dimethylaminopropyl)-N′ethylcarbodiimide hydrochloride (EDCI, 211 mg, 1.1 mmol) and triethylamine (111 mg, 1.1 mmol) in DCM (7 mL) was stirred at rt for 2 h. Then the mixture was poured into water and the mixture extracted with DCM. The combined organic extracts were then dried and evaporated to afford the title compound (130 mg, 38%) as a light brown solid after purification by chromatography on silica gel eluting with ethyl acetate: heptane (1:1 to 3:1). MS: m/e=347.0 (M++H).
Reaction SMILES: Cl.[CH:2]([NH:5][NH2:6])([CH3:4])[CH3:3].[CH2:7]([O:14][C:15](=[O:21])[NH:16][CH2:17][CH2:18][CH:19]=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCN(CC)CC>C(O)(C)C>[CH2:7]([O:14][C:15](=[O:21])[NH:16][CH2:17][CH2:18][CH:19]=[N:6][NH:5][CH:2]([CH3:4])[CH3:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=CCCNC(=O)OCc1ccccc1
Reactant: CC(C)NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)NN=CCCNC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of isopropylhydrazine hydrochloride (92.4 g, 0.84 mol) and (3-oxo-propyl)-carbamic acid benzyl ester (173 g, 0.84 mol) in isopropyl alcohol (1.7 L) was added Et3N (140 mL, 1.0 mol) over 20 min. The resulting slurry was heated at reflux for 3 h, and then was cooled to rt and concentrated. The residue was partitioned between EtOAc (700 mL) and water (700 mL). The organic layer was washed with water (3×500 mL), satd. aq. NaCl (300 mL), dried (MgSO4), and concentrated to afford the title compound. The crude product was used in next reaction without purification. MS (ESI): exact mass calcd. for C14H21N3O2, 263.16; m/z found, 264.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.36-7.25 (m, 5H), 7.02 (t, J=4.5, 1H), 5.10 (br s, 1H), 5.09 (s, 2H), 3.45-3.34 (m, 3H), 2.40-2.34 (m, 2H), 1.11 (d, J=6.4, 6H).