Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1.C(O)=O>C(O)C.[OH-].[Pd+2].[OH-]>[CH3:16][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1
Reactant: CN(C)CCCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O=CO
Product: CN(C)CCCOc1ccc(N)cc1
Temperature: 60 °C

Procedure:
Palladium(II) hydroxide (20% on carbon; 0.4 g) was added to a solution of dimethyl-[3-(4-nitrophenoxy)propyl]amine (3.75 g) in ethanol (75 ml) under argon. Then formic acid (4 ml) was added dropwise, during which the reaction mixture heated to 60° C. while evolving much gas. After a reaction time of 90 minutes, the catalyst was filtered off and the filtrate was concentrated. The residue was partitioned between methyl tert-butyl ether and sodium hydroxide solution (2N). The organic phase was dried and concentrated. The product with the molecular weight of 194.28 (C11H18N2O); MS (ESI):195 ([M+H]+), was obtained in this way.
Reaction SMILES: O[C:2]1([CH2:26][O:27][CH2:28][CH3:29])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.CCN(S(F)(F)[F:36])CC>ClCCl>[F:36][C:2]1([CH2:26][O:27][CH2:28][CH3:29])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOCC1(O)CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Solvent: ClCCl
Product: CCOCC1(F)CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Yield: 65 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(4-hydroxy-4-ethoxymethylpiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.37 mmol) with DAST (4.10 mmol) in dichloromethane (10 ml) at a temperature 0° C. for one hour and by purifying the compound by silica gel column chromatography in 65% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[C@@H:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH:21](O)=O.N>Cl>[NH:1]1[C:2]2[CH:3]=[C:4]([N:9]3[C@@H:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:12][O:11][C:10]3=[O:20])[CH:5]=[CH:6][C:7]=2[N:8]=[CH:21]1
Reactant: Nc1ccc(N2C(=O)OC[C@@H]2c2ccccc2)cc1N
Reactant: O=CO
Agent: Cl
Agent: N
Product: O=C1OC[C@H](c2ccccc2)N1c1ccc2nc[nH]c2c1
Temperature: 0 °C

Procedure:
The (S)-3-(3,4-diaminophenyl)-4-phenyloxazolidin-2-one was dissolved in 2.5 mL of 5N aqueous hydrochloric acid and 0.25 mL of formic acid was added to the solution. The reaction was stirred at reflux for 1 h before the reaction was cooled down to 0° C. and the reaction mixture was neutralized with buffer (pH7) and conc. ammonia. The aqueous layer was than extracted by means of 25 mL dichloromethane three times. The organic layers were combined, dried, filtered and the solvent was removed under reduced pressure. The final product was purified by means of FPLC using chloroform-methanol gradient (0→10%). The product elutes at about 5% methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH:14]=O)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C1(P(=[CH:35][CH:36]=[O:37])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:35]/[CH:36]=[O:37])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2cccc(F)c2)cn1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=C/C=C/c1ccc(-c2cccc(F)c2)cn1

Procedure:
584 mg of 5-(3-fluorophenyl)pyridine-2-carbaldehyde and 883 mg of (triphenylphosphoranylidene)acetaldehyde are stirred at RT overnight. The solvents are evaporated and the residue is purified by column chromatography (silica gel, MeOH:DCM=99.5:0.5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[C:44]([O:50][CH3:51])[C:4]=1[CH:5]=[CH:6][CH:7]([S:17]([CH:20]([CH:30]=[CH:31][C:32]1[C:37]([O:38][CH3:39])=[CH:36][C:35]([O:40][CH3:41])=[CH:34][C:33]=1[O:42][CH3:43])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([NH2:29])[CH:22]=1)(=[O:19])=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH2:16])[CH:9]=1.[N+:52]([C:55]1[CH:62]=[CH:61][C:58](C=O)=[CH:57][CH:56]=1)([O-:54])=[O:53]>CO.O>[CH3:51][O:50][C:44]1[CH:45]=[C:46]([O:48][CH3:49])[CH:47]=[C:3]([O:2][CH3:1])[C:4]=1[CH:5]=[CH:6][CH:7]([S:17]([CH:20]([CH:30]=[CH:31][C:32]1[C:33]([O:42][CH3:43])=[CH:34][C:35]([O:40][CH3:41])=[CH:36][C:37]=1[O:38][CH3:39])[C:21]1[CH2:22]/[C:23](=[N:29]\[C:58]2[CH:57]=[CH:56][C:55]([N+:52]([O-:54])=[O:53])=[CH:62][CH:61]=2)/[C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)(=[O:19])=[O:18])[C:8]1[CH2:9]/[C:10](=[N:16]\[C:58]2[CH:61]=[CH:62][C:55]([N+:52]([O-:54])=[O:53])=[CH:56][CH:57]=2)/[C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc(OC)c(C=CC(c2ccc(OC)c(N)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Solvent: O
Solvent: CO
Product: COC1=CC=C(C(C=Cc2c(OC)cc(OC)cc2OC)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)C2=CC=C(OC)/C(=N/c3ccc([N+](=O)[O-])cc3)C2)C/C1=N\c1ccc([N+](=O)[O-])cc1
Reaction time: 5 h

Procedure:
To a solution of 2,4,6-trimethoxystyryl-3-amino-4-methoxybenzylsulfone (10 mmol) in methanol (40 mL) is added 4-nitrobenzaldehyde (10 mmol). The solution is refluxed with vigorous stirring for 5 h. The reaction mixture is cooled, diluted with water and the aqueous mixture is then extracted twice with dichloromethane and organic layer is dried over anhydrous magnesium sulfate. The dried organic solution is evaporated and the residue is recrystallized to give (E)-2,4,6-trimethoxystyryl-3-(4-nitrophenylimino)-4-methoxybenzylsulfone.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=2)[CH:3]=1.C([Mg]Cl)(C)C.[CH3:29][C:30]1([CH3:33])[CH2:32][O:31]1.B(F)(F)F.CCOCC.[Li]C(C)(C)C>C1COCC1>[C:18]1([C:4]2[CH:3]=[C:2]([CH2:29][C:30]([OH:31])([CH3:33])[CH3:32])[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: CC1(C)CO1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(Br)cc2C2=CCCCC2)n1
Agent: CC(C)[Mg]Cl
Agent: FB(F)F
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(O)Cc1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 15.2 %

Procedure:
To a solution of 4-cyano-1H-imidazole-2-carboxylic acid (4-bromo-2-cyclohex-1-enyl-phenyl)-amide (prepared in Example 11, step (g)) (0.10 g, 0.27 mmol) in 1.5 mL of THF at −40° C. was added 0.15 mL of i-PrMgCl (0.30 mmol, 2 M solution in THF) and the solution was stirred at this temperature for 15 min. The mixture was then cooled to −78° C. and 2,2-dimethyl-oxirane (0.12 mL, 1.3 mmol) was added followed by boron trifluoride etherate (0.044 mL, 0.35 mmol) and t-BuLi (0.41 mL, 0.69 mmol, 1.7 M solution in pentane). After stirring for 30 min at −78° C. the mixture was quenched with satd NH4Cl (10 mL), extracted with EtOAc (2×10 mL) and the organic layer was dried over Na2SO4 and concentrated. The title compound was eluted from a 20-g SPE column with 50% EtOAc/hexanes to give 0.015 g (15%) of a white solid: 1H-NMR (DMSO-d6, 400 MHz): δ 14.25 (s, 1H), 9.71 (s, 1H), 8.33 (s, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.14 (dd, J=8.2, 1.9 Hz, 1H), 7.06 (d, J=1.9 Hz, 1H), 5.74 (s, 1H), 4.63 (t, J=5.2 Hz, 1H), 3.61 (m, 2H), 2.70 (t, J=7.0 Hz, 2H), 2.23-2.11 (m, 4H), 1.76-1.62 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C21H24N4O2, 365.2 (M+H), found 365.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([CH2:15][CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH2:26])[CH:24]=2)[NH:19][C:18]=1[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:36](Cl)(=[O:41])[CH2:37][CH2:38][CH2:39][CH3:40]>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:35])[N:7]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:15][CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:36](=[O:41])[CH2:37][CH2:38][CH2:39][CH3:40])[CH:24]=2)[NH:19][C:18]=1[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(N)cc3c2CCN(Cc2ccccc2)C(=O)OC(C)(C)C)c1
Reactant: CCCCC(=O)Cl
Solvent: CCN(CC)CC
Product: CCCCC(=O)Nc1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(Cc3ccccc3)C(=O)OC(C)(C)C)c2c1
Reaction time: 0.28 h

Procedure:
To a solution of {2-[5-amino-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}benzylcarbamic acid tert-butyl ester (200 mg in 10 mL dry methylene chloride) at 0° C. was added 0.18 mL triethylamine followed by the dropwise addition of 0.06 mL valeryl chloride and the mixture stirred at low temperature. After 17 minutes, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic portion was washed successively with saturated sodium bicarbonate and saturated ammonium chloride then dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 3:2) gave the title compound (230 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.CN(C)[CH:12]=[O:13].P(Cl)(Cl)(Cl)=O>O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:12]=[O:13])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: c1ccc2c(c1)CCO2
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1ccc2c(c1)CCO2
Temperature: 85 °C
Reaction time: 7.5 h
Yield: 94 %

Procedure:
To a solution of 2,3-dihydrobenzofuran (100.0 g, 832 mmols) in N,N-dimethylformamide (134.0 g, 1.83 mols) was added dropwise phosphorus oxychloride (255.1 g, 1.66 mols), then the mixture was stirred at 80-90° C. for 7.5 hours. The mixture was cooled to room temperature, poured into water (1 L) and stirred for 15 hours. The product was extracted with toluene (1.5 L). The extract was washed with water (500 mL) followed by a saturated aqueous solution of sodium bicarbonate (500 mL) and concentrated under reduced pressure to obtain 115.9 g (yield: 94%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:31])[CH3:9])=[CH:4][CH:3]=1.[O:32]=[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][NH:34]1>>[CH3:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH3:25])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:31])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:36]3[CH:37]=[CH:38][C:33](=[O:32])[NH:34][CH:35]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: O=c1ccc(B(O)O)c[nH]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)NS(C)(=O)=O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CC(C)(C)NS(C)(=O)=O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from N-(1-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2-methylpropan-2-yl)methanesulfonamide and 2-oxo-1,2-dihydropyridin-5-ylboronic acid following a procedure analogous to that described in Example 4. LC-MS Method 1 tR=1.3 min, m/z=524 (M+1); 1H NMR (CDCl3) 7.81 (d, 1H, J=9 Hz), 7.63 (br s, 1H), 7.39-7.31 (m, 5H), 7.18 (d, 2H, J=8Hz), 7.03 (d, 2H, J=7Hz), 6.79 (d, 1H, J=9Hz), 5.67 (q, 1H, J=6Hz), 2.93 (s, 3H), 2.90 (m, 1H), 2.49 (d, 1H, J=15 Hz), 2.32 (d, 1H, J=15 Hz), 2.28-2.18 (m, 3H), 1.54 (d, 3H, J=7Hz), 1.36 (s, 3H), 1.25 (s, 3H).
Reaction SMILES: C([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:19]1[C:24]([Br:25])=[CH:23][CH:22]=[CH:21][N:20]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)(C)(C)C.CCN(C(C)C)C(C)C.ClC(O[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=O>C(Cl)Cl>[CH2:40]([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:19]1[C:24]([Br:25])=[CH:23][CH:22]=[CH:21][N:20]=1)[C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:13][CH:14]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1Br)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an ice bath cooled solution of (S)-(3-bromopyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamine hydrochloride (Intermediate 40) (1.20 g, 2.2 mmol), DIPEA (1.50 mL, 8.6 mmol), and DCM (20 mL) was added benzyl chloroformate (0.40 mL, 2.8 mmol). The resulting mixture was allowed to warm to rt as the bath warmed. After 16 h, the reaction was eluted through a cartridge of silica gel (25 g) with DCM. The filtrate was concentrated in vacuo to give the title compound as a light yellow oil. MS (ESI pos. ion) m/z: 464.9, 466.9 (M+H).
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[CH3:9][O:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][N:16]2[C:20]3[N:21]=[CH:22][CH:23]=[C:24]([OH:25])[C:19]=3[CH:18]=[N:17]2)=[CH:13][CH:12]=1.O>CN(C=O)C>[Cl:8][C:23]1[CH:22]=[N:21][C:20]2[N:16]([CH2:15][C:14]3[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:27][CH:26]=3)[N:17]=[CH:18][C:19]=2[C:24]=1[OH:25]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(Cn2ncc3c(O)ccnc32)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ncc3c(O)c(Cl)cnc32)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
NCS (1.57 g, 11.8 mmol) was added in one portion to a solution of 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (3.00 g, 11.8 mmol) in DMF (30 mL) at room temperature. The mixture was stirred at 60° C. for 1 hour and then cooled to room temperature. After 18 hours, an additional lot of NCS (0.5 eq.) was added to the reaction mixture and stirred at room temperature for an additional 48 hours. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed once with water (50 mL), dried (MgSO4), filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (Biotage Flash 40M+) eluting with 2% MeOH/CH2Cl2 to provide 5-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (466 mg, 1.61 mmol, 13.7% yield). LCMS (APCI+) m/z 290 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([CH:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:16][C:17]1[C:18]([F:28])=[C:19]([O:26][CH3:27])[CH:20]=[C:21]2[C:25]=1[NH:24][CH2:23][CH2:22]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:26][CH3:27])=[C:18]([F:28])[C:17]=3[Cl:16])[CH2:22][CH2:23]2)[C:3](=[O:15])[N:4]([CH:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: COc1cc2c(c(Cl)c1F)NCC2
Reactant: CCC(COC)n1cc(Cl)nc(Cl)c1=O
Product: CCC(COC)n1cc(Cl)nc(N2CCc3cc(OC)c(F)c(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 7-chloro-6-fluoro-5-methoxyindoline as the starting materials. mp 140-142° C.; 1H NMR (300 MHz, CDCl3): δ 7.00 (s, 1 H), 6.79 (d, J=7.3 Hz, 1 H), 4.97-4.85 (m, 1 H), 4.34 (t, J=7.6 Hz, 2 H), 3.86 (s, 3 H), 3.65 (dd, J=10.6, 5.8 Hz, 1 H), 3.54 (dd, J=10.6, 3.7 Hz, 1 H), 3.33 (s, 3 H), 3.07 (t, J=7.5 Hz, 2 H), 1.90-1.72 (m, 2 H), 0.92 (t, J=7.5 Hz, 3 H); HRMS (ESI) calcd for C18H21N3O3Cl2F (M+H)+: 416.0944; found m/z 416.0955.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C@@H:21]([OH:23])[CH3:22])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C@@H:21]([OH:23])[CH3:22])(=[O:14])=[O:13])[CH:6]=[CH:5]3)=[CH:27][CH:26]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: C[C@H](O)c1ccccc1S(=O)(=O)c1ccc2cc(Br)ccc2c1
Product: C[C@H](O)c1ccccc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Yield: 83.5 %

Procedure:
The title compound was prepared from (1S)-1-{2-[(6-bromo-2-naphthyl)sulfonyl]phenyl}ethanol (2.0 g, 5.1 mmol) and 4-fluorobenzeneboronic acid (1.1 g, 7.6 mmol) according to the methods of Example 2 Step 1. Crude product was first purified by flash column chromatography eluting with a 20-80% diethyl ether/isohexane gradient then a second flash column chromatography eluting with 10% diethyl ether/dichloromethane. Crystallisation from methanol/H2O gave (1S)-1-(2-{[6-(4-fluorophenyl)-2-naphthyl]sulfonyl}phenyl)ethanol (1.73 g, 83%). 1H NMR (500 MHz, CDCl3) δ 8.55 (1H, s), 8.17 (1H, d, J 8.0 Hz), 8.05 (1H, d, J 8.6 Hz), 8.02 (1H, s), 7.97 (1H, d, J 8.7 Hz), 7.84 (1H, dd, J 1.5, 8.5 Hz), 7.76 (2H, d, J 8.4 Hz), 7.69-7.63 (3H, m), 7.49 (1H, t, J 7.2 Hz), 7.19 (2H, t, 8.6 Hz), 5.68-5.62 (1H, m), 2.49 (1H, d, J 3.1 Hz), 1.35 (3H, d, J 6.3 Hz); m/z (ES+) 389 [(M-OH)+].
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:17])[NH:9][C:10]2[S:11][CH:12]=[C:13]([CH:15]=O)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:18]1[CH2:22][C:21](=[O:23])[NH:20][C:19]1=[O:24].[Cl-].[NH4+].N>C(O)C>[C:1]1([NH:7][C:8](=[O:17])[NH:9][C:10]2[S:11][CH:12]=[C:13]([CH:15]=[C:22]3[S:18][C:19](=[O:24])[NH:20][C:21]3=[O:23])[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1csc(NC(=O)Nc2ccccc2)n1
Reactant: O=C1CSC(=O)N1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(Nc1ccccc1)Nc1nc(C=C2SC(=O)NC2=O)cs1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 1.1 g of 2-(3-phenylureido)thiazole-4-carbaldehyde, 0.52 g of 2,4-thiazolidinedione, 0.6 g of ammonium chloride, 0.6 ml of 28% v/v aqueous ammonia and 20 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: C1C2C(COC(=O)N[C@H](C([N:25]3[C:29]4=[N:30][CH:31]=[C:32](Br)[CH:33]=[C:28]4[C:27]([C@@H:35]([C:37]4[C:42]([Cl:43])=[CH:41][CH:40]=[C:39]([F:44])[C:38]=4[Cl:45])[CH3:36])=[CH:26]3)=O)CC(C)C)C3C(=CC=CC=3)C=2C=CC=1.CC1(C)C(C)(C)OB([C:55]2[CH:60]=[CH:59][N:58]=[CH:57][CH:56]=2)O1>>[Cl:45][C:38]1[C:39]([F:44])=[CH:40][CH:41]=[C:42]([Cl:43])[C:37]=1[C@H:35]([C:27]1[C:28]2[C:29](=[N:30][CH:31]=[C:32]([C:55]3[CH:60]=[CH:59][N:58]=[CH:57][CH:56]=3)[CH:33]=2)[NH:25][CH:26]=1)[CH3:36]
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)n1cc([C@H](C)c2c(Cl)ccc(F)c2Cl)c2cc(Br)cnc21
Product: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3ccncc3)cc12

Procedure:
Example 68 was synthesized according to the Suzuki coupling method described above for the synthesis of example 66, using ((S)-1-{5-Bromo-3-[(S)-1-(2,6-dichloro-3-fluorophenyl)ethyl]pyrrolo[2,3-b]pyridine-1-carbonyl}-3-methyl-butyl)-carbamic acid 9H-fluoren-9-ylmethyl ester and 4-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)pyridine, except that the crude product was purified by HPLC. 1H NMR (400 MHz, CD3OD): δ 8.48-8.59 (m, 3 H), 7.61 (d, J=2.0 Hz, 1H), 7.52 (dd, J=4.5, 1.5 Hz, 2H), 7.46-7.49 (m, 2 H), 7.20 (t, J=8.7 Hz, 1H), 5.34 (q, J=7.3 Hz, 1H), 1.91 (d, J=7.3 Hz, 3H). MS (ES+): m/z=386.19, 388.17 (100, 88) [MH+]. HPLC: tR=0.94 min (HPLC-ACQUITY, Purity).
Reaction SMILES: I[C:2]1[C:3](=[O:21])[N:4]([CH3:20])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCCC1.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>[CH3:20][N:4]1[C:3](=[O:21])[C:2]([C:24]2[CH:25]=[CH:26][S:22][CH:23]=2)=[C:7]([CH3:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:5]1=[O:19]
Reactant: Cc1c(I)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: OB(O)c1cccs1
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: C1CCOC1
Product: Cc1c(-c2ccsc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Yield: 50.9 %

Procedure:
To a solution of 5-iodo-3,6-dimethyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 60) (60.0 mg), 2-thiophen boronic acid (84.6 mg), sodium carbonate (84.6 mg) in tetrahydrofuran (2.0 ml)/water (0.3 ml) was added tetrakis(triphenylphosphine)palladium (25.2 mg) and the resulting mixture was stirred with heating under reflux for five hours. The reaction mixture was filtered through Celite (trade mark) and thereto was added water (10 ml), and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) and further purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 3,6-dimethyl-5-(thiophen-3-yl)-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (27.3 mg).
Reaction SMILES: CN([CH:4]=[C:5]1[C:9](=O)[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)C.[O-]CC.[Na+].[F:22][C:23]([F:28])([F:27])[C:24]([NH2:26])=[NH:25]>C(O)C.C(OCC)(=O)C.Cl>[F:22][C:23]([F:28])([F:27])[C:24]1[N:26]=[CH:4][C:5]2[CH2:6][NH:7][CH2:8][C:9]=2[N:25]=1
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CC1=O
Reactant: N=C(N)C(F)(F)F
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: FC(F)(F)c1ncc2c(n1)CNC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of the product from Step A (500 mg) in anhydrous ethanol (25 mL) was added sodium ethoxide (2.33 mL, 21% in ethanol). After stirring for 5 min, trifluoroacetamidine (700 mg) was added and the resulting mixture was heated to reflux for 1 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed sequentially with 5% aqueous citric acid solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product which was deprotected by dissolving in 1N methanolic hydrogen chloride for 1 h. The resulting solution was concentrated and chromatographed on a Biotage® system (silica gel cartridge, gradient from 10% to 18% of 10% concentrated aqueous ammonium hydroxide in methanol/dichloromethane) to yield the title compound. LC-MS=190.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: COc1ccc(/C=C/C(=O)O)cc1
Product: COc1ccc(/C=C/C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)c2)cc1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(4-methoxy-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=0.89 min; [M+H]+=366.19.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:12]([OH:17])[CH2:13][CH2:14][C:15]#[CH:16]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:16]#[C:15][CH2:14][CH2:13][CH2:12][OH:17])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: C#CCCCO
Product: CS(=O)(=O)c1ccc(C#CCCCO)cc1

Procedure:
Preparation of the title compound with 4-bromophenyl methyl sulphone (5.87 g, 25 mmol) and 4-pentyn-1-ol (2.1 g, 25 mmol) according to the procedure in Example 18 yielded 5.12 g (87%) of yellow oil which was characterized as 5-(4-Methanesulfonylphenyl)pent-4-yn-1-ol: NMR (CDCl3) δ 1.88-1.93 (m, 2H), 2.56-2.60 (t, J=6.99, 2H ), 3.04 (s, 3H), 3.80-3.84 (t, J=6.15, 2H), 7.56 (d, J=5.1, 2H), 7.85 (d, J=4.8, 2H). MS m/Z 239 (M+H cald. for C12H14O3S 238.3).