Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([Cl:18])=[N:13][C:12]([C:19]([F:22])([F:21])[F:20])=[N:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.CCOCC>C(OCC)(=O)C.CO>[ClH:18].[F:22][C:19]([F:20])([F:21])[C:12]1[N:13]=[CH:14][C:15]2[CH2:16][CH2:17][NH:8][CH2:9][C:10]=2[N:11]=1
Reactant: FC(F)(F)c1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CO
Product: Cl
Product: FC(F)(F)c1ncc2c(n1)CNCC2
Temperature: 25 °C

Procedure:
A flask containing a solution of 23.4 g (71.41 mmol) of 7-benzyl-4-chloro-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine in 285 mL of ethyl acetate and 530 mL of methanol was purged with nitrogen, and 2 g of 10% Pd/C was added. The mixture was stirred under 1 atm of hydrogen until the reaction was judged complete by TLC analysis (about 7.5 h total). The mixture was filtered through Celite, and the Celite washed with methanol. The organics were concentrated in vacuo and the resultant pale yellow oil was triturated with 400 mL of ether. Crystals formed and an additional 400 mL of ether was added. The mixture was stirred overnight. The resultant solid was collected by filtration and dried in vacuo to give off-white crystals that contained an impurity by TLC analysis. The crystals were dissolved in a minimum amount of methanol. Ether was added to turbidity and the mixture was warmed on a steam bath. Crystals formed and the mixture was allowed to cool to ambient temperature and aged for 30 min. It was then filtered. The collected solid was dried in vacuo to give the title compound as a white crystalline solid. LC-MS 204 (M+1).
Reaction SMILES: [CH3:1][C:2](=[CH2:6])[C:3]([OH:5])=[O:4].[CH3:7][O:8][C:9](=[O:52])/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[C:24]([CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])=[CH:30][C:29]=3[O:40][CH3:41])[CH:23]=[C:22]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]Cl)[CH:21]=2)=[C:14]([O:50][CH3:51])[CH:13]=1>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[CH3:51][O:50][C:14]1[CH:13]=[C:12](/[CH:11]=[CH:10]/[C:9]([O:8][CH3:7])=[O:52])[CH:17]=[CH:16][C:15]=1[O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:23]=[C:24]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])=[CH:30][C:29]=2[O:40][CH3:41])[CH:25]=1)[O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][O:4][C:3](=[O:5])[C:2]([CH3:1])=[CH2:6]
Reactant: COC(=O)/C=C/c1ccc(OCc2cc(COc3ccc(/C=C/C(=O)OC)cc3OC)cc(OCCCCCCCl)c2)c(OC)c1
Reactant: C=C(C)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCCCCCCOc1cc(COc2ccc(/C=C/C(=O)OC)cc2OC)cc(COc2ccc(/C=C/C(=O)OC)cc2OC)c1
Temperature: 80 °C
Reaction time: 25 h
Yield: 90.3 %

Procedure:
382 mg (2.5 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5) (DBU) in 4 ml N,N-dimethylformamide were added dropwise to a solution of 200 mg (2.3 mmol) 2-methylacrylic acid in 8 ml N,N-dimethylformamide over a period of 35 minutes. After addition of 4 mg phenothiazine, 1.5 g (2.3 mmol) (E)-3-[4-[[3-[(6-chlorohexyl)oxy]-5-[[2-methoxy-4-[(E)-2-(methoxycarbonyl)vinyl]phenoxy]methyl]benzyl]oxy]-3-methoxyphenyl]acrylic acid methyl ester and 84 mg tetrabutylammonium iodide the resulting mixture was stirred at 80° C. for 25 hours. The reaction mixture was poured into 50 ml of an ice cold 1 M HCl solution. The aqueous phase was extracted three times with 50 ml ethyl acetate. The organic phase was washed with 50 ml of a saturated sodium bicarbonate solution and repeatedly with water, dried over magnesium sulfate, filtered and concentrated by vacuum evaporation. Purification of the residue by column chromatography on 275 g silica gel using hexane:ethyl acetate (1:1) as eluent yielded 1.46 g (90%) of 2-methylacrylic acid 6-[3,5-bis[[2-methoxy-4-[(E)-2-(methoxycarbonyl)vinyl]phenoxy]methyl]phenoxy]hexyl ester as a yellowish oil.
Reaction SMILES: COC(=O)[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[C:13](OC)=[O:14])Br.[OH:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[C:21]#[N:22].C(N(CC)CC)C>CC#N>[Cl:12][C:9]1[CH:8]=[C:7]2[C:6]([C:4]3[O:18][C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=4[C:21]=3[N:22]=[C:13]2[OH:14])=[CH:11][CH:10]=1
Reactant: N#Cc1ccccc1O
Reactant: COC(=O)c1cc(Cl)ccc1C(Br)C(=O)OC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Oc1nc2c3ccccc3oc2c2ccc(Cl)cc12
Temperature: 25 °C
Yield: 56.7 %

Procedure:
A mixture of 19A (crude, 20.29 mmol) and 2-hydroxy-benzonitrile (20.29 mmol) in MeCN (100 mL) was stirred at room temperature. To the solution was added triethylamine (TEA, 20.44 g, 202.9 mmol) dropwise. After addition completed, the reaction was refluxed for 24 hours, then cooled. The precipitated solids were collected by filtration, washed with a small amount of MeCN, then washed with water several times until there was no TEA salt, dried to give pure product 19B (3.1 g).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([O:12][C:13]([N:15]1[CH2:25][CH2:24][CH:18]([C:19](OCC)=[O:20])[CH2:17][CH2:16]1)=[O:14])[CH3:11].[H-].[Na+]>C1(C)C=CC=CC=1>[CH2:10]([O:12][C:13]([N:15]1[CH2:25][CH2:24][CH:18]([C:19]([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]#[N:9])=[O:20])[CH2:17][CH2:16]1)=[O:14])[CH3:11]
Reactant: CCOC(=O)C1CCN(C(=O)OCC)CC1
Reactant: N#CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(C(=O)C(C#N)c2ccccc2)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 61.9 %

Procedure:
Phenylacetonitrile (5.8 g), ethyl 1-ethoxycarbonylisonipecotate (11.5 g), sodium hydride (purity 60%, 2.0 g) and toluene (25 mL) were mixed, and the mixture was stirred at 80° C. for 3 hrs. After the completion of the reaction, the reaction mixture was cooled to room temperature, and the insoluble material was washed by decantation. The insoluble material was dissolved in water, and acetic acid was added to acidify the mixture, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was evaporated. The obtained residue was subjected to silica gel column chromatography, and the fraction eluted with hexane:ethyl acetate=2:1 was concentrated to give α-(1-ethoxycarbonylpiperidin-4-yl)carbonylphenylacetonitrile (9.2 g) as an oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][NH:21][CH2:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32]>>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][N:21]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH2:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNCC3)cc1
Reactant: CC(C)OC(=O)Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)OC(C)C)CC3)cc1

Procedure:
Compound et was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)phenyl)urea with isopropyl chloroformate. LC-MS: m/z=+483 (M+H)+.
Reaction SMILES: C[C:2]1[O:3][C:4](=O)[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.FC(F)(F)[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>CCOC(C)=O.CCCCCC>[C:17]1([N:18]2[CH:4]=[C:5]3[C:6]([CH:8]=[CH:9][CH:10]=[CH:11]3)=[N:7][C:2]2=[O:3])[CH:19]=[CH:20][CH:21]=[CH:15][CH:16]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1nc2ccccc2c(=O)o1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=c1nc2ccccc2cn1-c1ccccc1
Temperature: 160 °C
Yield: 56 %

Procedure:
A mixture of 2-methyl-4H-Benzo[d][1,3]oxazin-4-one (12; 1.0 g, 6.2 mmol) and 3-trifluoromethylaniline (13, R═H, 0.77 mL, 6.2 mmol, 1.0 eq) were heated at 160° C. (oil bath) for 12 hours. The reaction was cooled to room temperature and the resulting solid was subjected to chromatography on silica gel with 20-50% EtOAc/hexane. Product-containing fractions were pooled and evaporated to yield 1.08 g mg (56%) of 14 as a yellow solid: 1H NMR (CDCl3): 8.27 (d, 1H), 7.29-7.28 (m, 7H), 2.25 (s, 3H).
Reaction SMILES: O.O1CCCC1.[Cl:7][C:8]1[S:12][C:11]([NH:13]C(=O)CCl)=[N:10][C:9]=1/[C:18](=[N:42]/[O:43][CH3:44])/[C:19]([NH:21][C@@H:22]1[C:40](=[O:41])[N:24]2[C:25]([C:37]([OH:39])=[O:38])=[C:26]([CH2:29][O:30][C:31](=[O:36])[CH2:32][C:33](=[O:35])[CH3:34])[CH2:27][S:28][C@H:23]12)=[O:20].CNC(=S)[S-].[Na+]>C(OCC)(=O)C>[NH2:13][C:11]1[S:12][C:8]([Cl:7])=[C:9](/[C:18](=[N:42]/[O:43][CH3:44])/[C:19]([NH:21][C@@H:22]2[C:40](=[O:41])[N:24]3[C:25]([C:37]([OH:39])=[O:38])=[C:26]([CH2:29][O:30][C:31](=[O:36])[CH2:32][C:33](=[O:35])[CH3:34])[CH2:27][S:28][C@H:23]23)=[O:20])[N:10]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)CC(C)=O)CS[C@H]12)c1nc(NC(=O)CCl)sc1Cl
Agent: CNC(=S)[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)CC(C)=O)CS[C@H]12)c1nc(N)sc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
To a mixture of 13 ml of water and 13 ml of tetrahydrofuran is dissolved 2.94 g of 7β-[2-(5-chloro-2-chloroacetamidothiazol-4-yl)-2(Z)-methoxyiminoacetamido]-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid. To the mixture is added 1.15 g of sodium N-methyldithiocarbamate in 3 portions with stirring at room temperature for 3 hours. Ethyl acetate is added to the reaction mixture and the ethyl acetate layer is separated and discarded. The aqueous layer is acidified with concentrated hydrochloric acid and extracted with 200 ml of methyl ethyl ketone. The extract is washed with aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is then evaporated off to give 2.28 g of the above-identified compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:11][CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][N:14]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCNCCCCO
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCN(CCCCO)c1ccc(C=O)cc1
Temperature: 95 °C

Procedure:
To a three neck flask fitted with a mechanical stirrer, a thermometer, and a condenser, is added 124 g (1 mole) of 4-fluorobenzaldehyde, 145.3 g (1 mole) of N-butyl-N-4-hydroxybutylamine, 138.2 g (1 mole) of anhydrous potassium carbonate, and dimethylsulfoxide. The mixture is then heated at 95° C. until the reaction is complete. After cooling to room temperature, the solution is poured into a four-fold excess of ice water, and the solid product is collected by filtration and purified by recrystallization from tetrahydrofuran/benzene.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:19]3[C:14]([C:15](=[O:29])[NH:16][C:17]([C:20]4[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=4)=[N:18]3)=[C:13]([CH2:30][CH3:31])[N:12]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCCC1.[Pd]>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[NH:16][C:15](=[O:29])[C:14]3=[C:13]([CH2:30][CH3:31])[N:12]=[C:11]([C@H:8]4[CH2:9][CH2:10][C@@H:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:6][CH2:7]4)[N:19]3[N:18]=2)=[CH:21][CH:22]=1
Reactant: CCc1nc([C@H]2CC[C@@H](C(C)(C)C)CC2)n2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c(=O)c12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCc1nc([C@H]2CC[C@@H](C(C)(C)C)CC2)n2nc(-c3ccc(N)cc3)[nH]c(=O)c12

Procedure:
580 mg (1.37 mmol) cis-7-(4-tert-butylcyclohexyl)-5-ethyl-2-(4-nitrophenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one (Example 36A) are dissolved in 50 ml tetrahydrofuran and catalytic amounts of palladium (10% on charcoal) are added. The mixture is stirred for 18 hour at room temperature in a 3 bar hydrogen atmosphere. Then the mixture is filtrated and the organic phase evaporated to dryness in vacuo.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([S:10](Cl)(=[O:12])=[O:11])[CH3:9].[CH2:14]([O:18][C:19]1[CH:20]=[C:21]([CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH:22]=[CH:23][C:24]=1[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([O:35][CH3:36])[CH:29]=1)[CH2:15][CH2:16][CH3:17].[Cl-].[Na+]>ClCCl>[CH2:14]([O:18][C:19]1[CH:20]=[C:21]([CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH:22]=[CH:23][C:24]=1[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][S:10]([CH2:8][CH3:9])(=[O:12])=[O:11])=[C:30]([O:35][CH3:36])[CH:29]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCOc1cc(CCC(=O)OC)ccc1CCCc1ccc(O)c(OC)c1
Reactant: CCS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOc1cc(CCC(=O)OC)ccc1CCCc1ccc(OS(=O)(=O)CC)c(OC)c1
Temperature: -20 °C
Reaction time: 3 h
Yield: 100.4 %

Procedure:
0.2 ml (1.6 mmol) of triethylamine and then 0.15 ml (1.7 mmol) of ethanesulfonyl chloride are added to a solution of 0.5 g (1.25 mmol) of methyl 3-{3-butoxy-4-[3-(4-hydroxy-3-methoxyphenyl)propyl]phenyl}propanoate (prepared according to Example 1d) in 3 ml of dichloromethane, cooled beforehand to −20° C. The reaction medium is stirred at room temperature for 3 hours and is then treated by addition of saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phases are combined, dried over sodium sulfate, filtered and evaporated. The residue is purified by chromatography on a column of silica eluted with a 90/10 heptane/ethyl acetate mixture. 618 mg (99%) of methyl 3-{3-butoxy-4-[3-(4-ethanesulfonyloxy-3-methoxyphenyl)propyl]phenyl}propanoate are obtained in the form of a colorless oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[F:7][C:8]([F:12])([F:11])[CH2:9]I>CN(C=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:9][C:8]([F:12])([F:11])[F:7])[CH:6]=1
Reactant: Ic1cn[nH]c1
Reactant: FC(F)(F)CI
Solvent: CN(C)C=O
Product: FC(F)(F)Cn1cc(I)cn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 4-iodo-1H-pyrazole (960 mg, 5 mmol), 2,2,2-trifluoroethyl iodide (3.13 g, 15 mmol) and CS2CO3 (2.4 g, 7.7 mmol) in DMF (5 ml) is heated at 60° C. with stirring overnight. After cooling, the reaction mixture is partitioned between water (50 ml) and ether (20 ml). The organic layer is separated, dried (MgSO4) and concentrated to afford the title compound as an oil which solidified upon standing 1.0 g (72%). 1HNMR (CDCl3): δ (ppm) 4.70 (m, 2H), 7.56 (s, 1H), 7.59 (s, 1H).
Reaction SMILES: C([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([C:25](=[O:37])[NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33](F)(F)F)[CH:28]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1)(C)(C)C.[NH2:39]C1C=C(C)C=C(C)N=1>>[NH2:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([C:25](=[O:37])[NH:26][C:27]4[CH:28]=[C:29]([CH3:33])[CH:30]=[C:31]([CH3:32])[N:39]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1cccc2c(NC(C)(C)C)nccc12
Reactant: Cc1cc(C)nc(N)c1
Product: Cc1cc(C)nc(NC(=O)c2ccc(C)c(NC(=O)c3cccc4c(N)nccc34)c2)c1
Yield: 8 %

Procedure:
The procedures of Steps (1), (2) and (3) of Example 2 and Step (4) of Example 1 were repeated step by step, except for using 2-amino-4,6-dimethylpyridine instead of aniline in Step (1) of Example 2 to obtain the title compound (2.8 mg, 8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:18])=[N:5][CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=1.FC(F)(F)S(O[C:25]1[N:26]=[C:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[O:28][CH:29]=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[F:36][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[O:28][CH:29]=[C:25]([C:7]3[CH:8]=[C:3]([O:2][CH3:1])[C:4]([NH2:18])=[N:5][CH:6]=3)[N:26]=2)=[CH:35][CH:34]=1
Reactant: O=S(=O)(Oc1coc(-c2ccc(F)cc2)n1)C(F)(F)F
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2coc(-c3ccc(F)cc3)n2)cnc1N
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A mixture of 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (200 mg, 0.8 mmol) and 2-(4-fluorophenyl)oxazol-4-yl trifluoromethanesulfonate (250 mg, 0.8 mmol), and 2.0 M aqueous Na2CO3 (1.2 mL, 2.4 mmol) in DME (2.0 mL) was sparged with Ar. Dichlorobis(triphenylphosphine)palladium(0) (281 mg, 0.4 mmol) was added and the reaction mixture was irradiated at 150° C. for 15 min in a microwave reactor. After cooling to rt, the reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography over (SiO2, 100:0-0:100 hexanes-EtOAc) to provide 145 mg of 5-(2-(4-fluorophenyl)oxazol-4-yl)-3-methoxypyridin-2-amine: LCMS (m/z): 286.1 (MH+), tR=0.68 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.C(O)(=O)C.O.[BrH:16]>C(Cl)Cl>[Br:16][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=1
Reactant: Br
Reactant: O=Cc1ccc(CO)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1ccc(CBr)cc1
Reaction time: 8 h
Yield: 95 %

Procedure:
Alcohol 2 (6.46 g, 47.5) was dissolved in DCM (100 ml) before HBr in acetic acid (33 wt %, 42 ml, 243, 5 eq) was added and stirred overnight. Water (100 ml) was added to the reaction mixture and the phases were separated and the organic phase obtained was washed with a NaOH solution (2 M, 2×100 ml), dried over Na2SO4, and evaporated. The residue was washed through a silica plug to yield 3 as a white solid (9.04 g, 45.4 mmol, 95%). Rf=0.77 (DCM); m.p.=100° C. (recrystallised from hexane); νmax=1682, 1604, 1209, 1200, 830, 770, 726 cm−1; 1H NMR (300 MHz, CDCl3) δ=10.02 (s, 1H, CHO), 7.87 (d, 3J(H,H)=8.2 Hz, 2H, ArCH α to CHO), 7.56 (d, 3J(H,H)=8.2 Hz, 2H, ArCH α to CH2Br), 4.52 (s, 21-1, CH2Br); 13C NMR (75 MHz, CDCl3) δ=191.5 (CHO), 144.2 (ArCCBr), 136.2 (ArCCHO), 130.2 (ArCH α to ArCCHO), 129.7 (ArCH α to ArCCH2Br), 31.9 (CH2Br); HRMS (ESI−): m/z calculated for C8H6BrO [M−H]−: 196.9602, found 196.9602; elemental analysis calcd (%) for C8H7BrO (199.04): C, 48.27; H, 3.54. found: C, 47.40; H, 3.53.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:21])[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.Cl[C:23]1[C:32]2[C:27](=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:29]=[CH:30][CH:31]=2)[N:26]=[CH:25][C:24]=1[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:38]>>[C:37]([C:24]1[CH:25]=[N:26][C:27]2[C:32]([C:23]=1[C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:10][C:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:21])=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:34])[F:35])(=[O:38])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(NCc1ccc(B(O)O)cc1)Nc1ccccc1F
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1Cl
Product: O=C(NCc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)Nc1ccccc1F

Procedure:
The title compound was prepared from 4-[3-(2-Fluoro-phenyl)-ureidomethyl]phenylboronic acid and [4-chloro-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone according to the procedure of Example 1. MS (ES) m/z 541.9.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([OH:29])=O)[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:50]([O:52][C:53]([N:55]1[CH2:60][CH2:59][N:58]([C:61](=[O:76])[C@@H:62]([NH2:75])[CH2:63][CH2:64][CH2:65][CH2:66][O:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH2:57][CH2:56]1)=[O:54])[CH3:51]>CN(C=O)C.C(Cl)CCl>[CH2:50]([O:52][C:53]([N:55]1[CH2:60][CH2:59][N:58]([C:61](=[O:76])[C@@H:62]([NH:75][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:30])[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=2)=[O:29])[CH2:63][CH2:64][CH2:65][CH2:66][O:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH2:57][CH2:56]1)=[O:54])[CH3:51]
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCCCOCc2ccccc2)CC1
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCCCOCc2ccccc2)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 448 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 10 ml DMF were added 216 mg HOBt, 271 mg EDC and 0.45 ml DIPEA. After 5 minutes 410 mg (S)-4-(2-Amino-6-benzyloxy-hexanoyl)-piperazine-1-carboxylic acid ethyl ester were added and the mixture stirred for 12 h. The reaction mixture was concentrated, diluted with ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO3. The crude product was obtained by evaporation of the solvent. An aliquot (70 mg) was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound. Yield: 31 mg MS (ES+): m/e=772.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.C=CC1C=CC=CC=1>>[CH:7]#[C:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: C=Cc1ccc(O)cc1
Solvent: C=Cc1ccccc1
Product: C#Cc1ccc(O)cc1

Procedure:
(C-2) Copolymer of p-hydroxystyrene and styrene (copolymerization molar ratio=8:2, Mw=4,000)
Reaction SMILES: CC1(C)CO[CH:5]([C:8]2[C:13]([O:14]COC)=[C:12]([O:18][CH3:19])[CH:11]=[CH:10][C:9]=2[NH:20][CH2:21][C@@H:22]([OH:33])[CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[CH3:32])OC1.Cl.[NH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][C:45]=1[NH2:46])[C:42](=[O:47])[N:41]([CH:48]1[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]1)[CH2:40]2.CC(O)=O>C1COCC1.CCO>[CH3:32][C:26]1[CH:27]=[C:28]([CH3:31])[CH:29]=[CH:30][C:25]=1[O:24][CH2:23][C@H:22]([OH:33])[CH2:21][NH:20][C:9]1[C:8]([C:5]2[NH:46][C:45]3[C:37](=[CH:38][C:39]4[CH2:40][N:41]([CH:48]5[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]5)[C:42](=[O:47])[C:43]=4[CH:44]=3)[N:36]=2)=[C:13]([OH:14])[C:12]([O:18][CH3:19])=[CH:11][CH:10]=1
Reactant: COCOc1c(OC)ccc(NC[C@@H](O)COc2ccc(C)cc2C)c1C1OCC(C)(C)CO1
Reactant: CN1CCC(N2Cc3cc(N)c(N)cc3C2=O)CC1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(NC[C@@H](O)COc2ccc(C)cc2C)c(-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCN(C)CC2)C4)c1O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 10.6 %

Procedure:
To a solution of (R)-1-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-4-methoxy-3-methoxymethoxy-phenylamino]-3-(2,4-dimethyl-phenoxy)-propan-2-ol (102 mg, 0.21 mmol) in THF (5.0 mL) was added 36% aqueous HCl (1.0 mL). After it was heated at 50° C. for 1.5 h, the reaction mixture was evaporated and the residue was mixed with 5,6-diamino-2-(1-methyl-piperidin-4-yl)-2,3-dihydro-isoindol-1-one (76 mg, 0.21 mmol) and AcOH (0.4 mL) in EtOH (8 mL). The mixture was stirred at the room temperature for 30 min, heated at 80° C. for 1.5 h, and evaporated to dryness. Chromatography of the residual crude with CH2Cl2/MeOH/28% aqueous NH4OH (40:10:1) afforded the title compound (13 mg, 10%). ESI-MS m/z 586.5 (MH+).
Reaction SMILES: Cl.[CH2:2]=[C:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:9][O:10][C:11]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>ClCCl>[CH3:9][O:10][C:11]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:12]=1[C:13]([N:6]1[CH2:7][CH2:8][C:3](=[CH2:2])[CH2:4][CH2:5]1)=[O:14]
Reactant: C=C1CCNCC1
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Agent: Cl
Solvent: ClCCl
Product: C=C1CCN(C(=O)c2ccc(OC)cc2OC)CC1
Reaction time: 16 h

Procedure:
To a stirring solution of 4-methylene-piperidine hydrochloride (1.00 g, 8.12 mmol, JOC 66,2487-2492,2001) in 10 mL anhydrous dichloromethane at room temperature is added 2,4-dimethoxybenzoyl chloride (1.63 g, 8.12 mmol) and TEA (4 g, 40 mmol). The reaction mixture is allowed to stir for 16 hours. Dichloromethane is removed in vacuo, and the resultant residue is purified through silica gel chromatography (95% DCM, 5% MeOH) to give (2,4-dimethoxy-phenyl)-(4-methylene-piperidin-1-yl)-methanone. Yield: 1.62 g, 6.23 mmol. m/z (MS) M+1 261.01.