Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[CH:4]=[CH2:5].[C:7]([NH:10][C@@H:11]1[C@H:16]([OH:17])[CH2:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][C@H:12]1[O:22][CH:23]([CH3:25])[CH3:24])(=[O:9])[CH3:8]>C1COCC1>[C:7]([NH:10][C@@H:11]1[C@H:16]([O:17][CH2:5][CH:4]=[CH2:3])[CH2:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][C@H:12]1[O:22][CH:23]([CH3:25])[CH3:24])(=[O:9])[CH3:8]
Reactant: COC(=O)C1=C[C@@H](OC(C)C)[C@H](NC(C)=O)[C@H](O)C1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCO[C@@H]1CC(C(=O)OC)=C[C@@H](OC(C)C)[C@@H]1NC(C)=O
Reaction time: 5 h
Yield: 90.4 %

Procedure:
Sodium hydride (60%, 35 mg, 0.875 mmol) and allyl bromide (0.051 mL, 0.589 mmol) were added to a 0° C. solution of Example 13L (80 mg, 0.295 mmol) in THF (15 mL). After stirring for 5 hours, the reaction mixture was quenched with saturated NH4Cl, and then extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by flash chromatography using ethyl acetate to afford 83 mg (90%) of the desired product as a white solid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[C@H:31]([OH:32])[CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[C@H:31]([OH:32])[CH2:30][N:29]([C:36](=[O:37])[CH2:35][O:34][CH3:33])[CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CNC[C@H]1O
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1C[C@@H](O)[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f10) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:17]=[C:16](F)[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@@H:32]([CH2:38][CH3:39])[CH:33]([OH:37])[CH:34]([CH3:36])[CH3:35]>CCCCO.CS(C)=O>[CH2:1]([NH:8][C:9]1[N:17]=[C:16]([NH:31][C@@H:32]([CH2:38][CH3:39])[CH:33]([OH:37])[CH:34]([CH3:36])[CH3:35])[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)n1cnc2c(NCc3ccccc3)nc(F)nc21
Reactant: CC[C@H](N)C(O)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CS(C)=O
Product: CC[C@H](Nc1nc(NCc2ccccc2)c2ncn(C(C)C)c2n1)C(O)C(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of benzyl-(2-fluoro-9-isopropyl-9H-purin-6-yl)-amine (40 mg, 1 eq, 0.14 mmol) in n-BuOH/DMSO (2.5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.24 mL, 4.9 eq, 1.38 mmol) followed by (3RS,4S)-4-amino-2-methyl-hexan-3-ol (39 mg, 2.12 eq, 0.30 mmol). The reaction mixture-was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×50 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with hexane:ether:MeOH (50:50:0→50:50:2) to afford the title compound as a white solid; Yield: 6.7 mg (12%). (50% de 45,3S: 50% de 4S,3R). 1H-NMR (d-CDCl3, 250 MHz): δ 0.95-1.04 (m, 9H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 1.57 (d, 6H, J=6.79 Hz, —CH(CH3)2), 1.62-1.88 (m, 4H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 3.26-3.32 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 3.87-4.00 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 4.57-4.70 (m, 1H, —CH(CH3)2), 4.76-4.90 (m, 2H, —HNCH2-Bz), 5.25-5.55 (m, 1H NHCH(CH2CH3)CH(CH(CH3)2)OH), 7.26-7.45 (m, 6H, 5×Bz-H+HNCH2-Bz), 7.53 (s, 1H, —N═CH—N). FABMS m/z (relative intensity): 397 ([M+H]+, 95), 385 (20), 323 (100). Accurate Mass (M+H): Actual: 397.2716, Measured: 393.2724.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][C@@H:11]([CH3:28])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:25]=[C:24]([F:26])[C:21]([C:22]#[N:23])=[C:20]([Cl:27])[CH:19]=2)=[N:14]1>>[Cl:27][C:20]1[CH:19]=[C:18]([C:15]2[CH:16]=[CH:17][N:13]([CH2:12][C@@H:11]([NH:10][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[NH:3][CH:4]=3)=[O:9])[CH3:28])[N:14]=2)[CH:25]=[C:24]([F:26])[C:21]=1[C:22]#[N:23]
Reactant: Cc1nc(C(=O)O)c[nH]1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)c[nH]1

Procedure:
The title compound was prepared according to the method of Example 247 starting from 2-methyl-1H-imidazole-4-carboxylic acid and (S)-4-[1-(2-aminopropyl)-1H-pyrazol-3-yl]-2-chloro-6-fluorobenzonitrile (which can be prepared according to Example 34(c)). The crude product was purified by flash chromatography on silica gel by using CH2Cl2-MeOH as a gradient eluent (100:0-98:2) to give the product, which was triturated in diethyl ether at RT to afford the title compound. 1H NMR (400 MHz, DMSO-d6): 1.06 (3H, d), 2.31 (3H, s), 4.28 (1H, distorted dd), 4.35-4.45 (2H, m), 7.02 (1H, d), 7.42 (1H, s), 7.86 (1H, d), 7.93 (1H, dd), 8.00 (1H, d), 8.07 (1H, d), 12.11 (1H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]2[CH2:17][CH2:18][CH2:19][CH:12]1[CH:13]([O:31]C)[N:14]([CH2:21][CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:15]2=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH:16]2[CH2:17][CH2:18][CH2:19][CH:12]1[C:13](=[O:31])[N:14]([CH2:21][CH2:22][O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:15]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1C2CCCC(C(=O)N1CCOCc1ccccc1)N2C(=O)OCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: O=C1C2CCCC(CN1CCOCc1ccccc1)N2C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 87 %

Procedure:
3-(2-Benzyloxyethyl)-2-methoxy-4-oxo-3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (Compound 4, 0.34 g, 0.76 mmol) was dissolved in CH2Cl2 (5 mL) in a 25-ml flask under argon. BF3OEt2 (0.18 ml, 1.52 mmol) was added dropwise to the reaction flask (fumes were released) followed by triethylsilane (0.24 g, 1.52 mmol), and the solution was stirred overnight. The CH2Cl2 was evaporated and the residue was dissolved in EtOAc and washed with saturated NaHCO3 (2×10 mL). The mixture was extracted with EtOAc (3×10 mL). The organic layer was dried over Na2SO4 and concentrated. Purification of the residue by flash column chromatography with 20% EtOAc/hexanes gave Compound 5 (0.27 g, 89%, 1:1 mixture of enantiomers) as a clear oil. Rf=0.42 (50% EtOAc/hexanes); 1H NMR (major rotamer): δ 1.62-1.72 (m, 6H), 3.25-3.50 (m, 2H), 3.68-3.90 (m, 5H), 4.49 (s, 2H), 4.75 (s, 1H), 5.14 (s, 2H), 7.26-7.34 (m, 10 H).
Reaction SMILES: [CH3:1][C:2](=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[CH2:3]O.P(Br)(Br)[Br:14].O>C(OC(C)C)(C)C>[Br:14][CH2:3][C:2]([CH3:1])=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1
Reactant: BrP(Br)Br
Reactant: CC(=Cc1ccc(C)cc1)CO
Solvent: O
Solvent: CC(C)OC(C)C
Product: CC(=Cc1ccc(C)cc1)CBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 119.2 %

Procedure:
To a solution of 2-methyl-3-(4-methylphenyl)-2-propen-1-ol (11.40 g, 70.27 mmol) in isopropyl ether (100 ml) was added under ice cooling phosphorus tribromide (12.83 g, 47.38 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. Water was added into the reaction solution and the product was extracted with isopropyl ether. The organic layer was washed with water and an aqueous saturated solution of sodium hydrogen carbonate, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain 12.71 g (80% yield) of the oily title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12][C:13]3[CH:14]=[C:15]([C:19]4([C:25]#[N:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:10]=2)[N:5]2[CH:27]=[N:28][N:29]=[C:4]2[CH:3]=1.[C:30]1([CH3:39])[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.[F-].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:30]1([CH3:39])[CH:35]=[CH:34][CH:33]=[C:32]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12][C:13]4[CH:14]=[C:15]([C:19]5([C:25]#[N:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)[CH:16]=[CH:17][CH:18]=4)=[CH:9][CH:10]=3)[N:5]3[CH:27]=[N:28][N:29]=[C:4]3[CH:3]=2)[CH:31]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: N#CC1(c2cccc(Sc3ccc4c(Cl)cc5nncn5c4c3)c2)CCOCC1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Cc1cccc(-c2cc3nncn3c3cc(Sc4cccc(C5(C#N)CCOCC5)c4)ccc23)c1
Temperature: 80 °C

Procedure:
5s (70 mg, 0.17 mmol), m-tolylboronic acid (34 mg, 0.25 mmol), Pd2dba3 (4 mg, 0.01 mmol), potassium fluoride (29 mg, 0.50 mmol), and 2-(di-tert-butylphosphino)biphenyl (5 mg, 0.02 mmol) were dissolved in THF (5 mL) and degassed with N2 for 5 minutes. The reaction was heated to 80° C. for 5 hours, then cooled to room temperature and concentrated. The residue was purified by preparative HPLC to give the desired product, 5t.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]1([S:18][CH2:19][C:20]2[O:24][N:23]=[C:22]([C:25]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)=[O:26])[N:21]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[O-]S([O-])(=S)=O.[Na+].[Na+].CCOCC>C(Cl)Cl>[C:12]1([S:18]([CH2:19][C:20]2[O:24][N:23]=[C:22]([C:25]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)=[O:26])[N:21]=2)=[O:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(C(=O)c2noc(CSc3ccccc3)n2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(C(=O)c2noc(CS(=O)c3ccccc3)n2)cc1
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
A solution of 5.14 g of m-chloroperoxybenzoic acid (85%) in 125 ml CH2Cl2 was added dropwise to a solution of 7.5 g of 5-phenylthiomethyl-3-(4-toluoyl)-1,2,4-oxadiazole in 150 ml CH2Cl2 at -70° under N2. The temperature was maintained below -65° during the addition by controlling the addition rate and stirring was continued for 30 minutes after the addition while maintaining the temperature below -65°. The resulting mixture was poured directly into a separatory funnel containing 250 ml of 10% Na2S2O3 and 500 ml of Et2O. The organics were washed with saturated NaHCO3 and dried over MgSO4. Concentration gave an oil which solidified on standing. Recrystallization from acetone/hexane gave 5.3 g (64%) of needles, m.p. 97°-99°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=[O:18])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])([CH3:9])[CH3:8])[CH3:2].[F:20][C:21]([Si](C)(C)C)([F:26])[C:22]([F:25])([F:24])[F:23].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:3][C:4](=[O:19])[C:5]([OH:18])([C:21]([F:26])([F:20])[C:22]([F:25])([F:24])[F:23])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])([CH3:9])[CH3:8])[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)C(F)(F)F
Reactant: CCOC(=O)C(=O)CC(C)(C)c1ccccc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(CC(C)(C)c1ccccc1OC)C(F)(F)C(F)(F)F

Procedure:
Analogously to Example 7, 687 mg of ethyl-4-(2-methoxyphenyl)-4-methyl-2-oxopentanoate (WO 00/32584) is reacted with 1 g of (pentafluoroethyl)trimethylsilane and 0.5 ml of (tetrabutylammonium fluoride solution (1 M in THF)) in 18 ml of THF to form g of ethyl-4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)-pentanoate. 450 mg of the obtained ester in 12 ml of diethyl ester is mixed in portions at 0° C. with 66 mg of lithium aluminum hydride. After stirring for 11 hours, it is added to saturated bicarbonate solution and filtered through diatomaceous earth. The phases are separated, and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated by evaporation. 420 mg of diol is obtained as a yellow oil. 400 mg of the diol is oxidized to the corresponding aldehyde with 0.11 ml of oxalyl chloride, 0.21 ml of DMSO and 1 ml of triethylamine. It is washed with water and brine, dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 0->5%), 268 mg of the title compound is obtained as a yellow oil.
Reaction SMILES: [NH2:1]/[C:2](/[CH2:10][F:11])=[C:3](/[F:9])\[C:4](OCC)=[O:5].[Cl:12][C:13]1[C:18]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:17][C:16]([N:23]=[C:24]=[O:25])=[C:15]([F:26])[CH:14]=1>>[Cl:12][C:13]1[C:18]([O:19][CH:20]([CH3:21])[CH3:22])=[CH:17][C:16]([N:23]2[C:4](=[O:5])[C:3]([F:9])=[C:2]([CH2:10][F:11])[NH:1][C:24]2=[O:25])=[C:15]([F:26])[CH:14]=1
Reactant: CCOC(=O)/C(F)=C(\N)CF
Reactant: CC(C)Oc1cc(N=C=O)c(F)cc1Cl
Product: CC(C)Oc1cc(-n2c(=O)[nH]c(CF)c(F)c2=O)c(F)cc1Cl

Procedure:
using ethyl 3-amino-2,4-difluorocrotonate and 4-chloro-2-fluoro-5-isopropoxyphenyl isocyanate there is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5-fluoro-6-fluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 152°-154° C.;
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1>>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=3)[C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1ccccc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: Cc1nc(N2CCCC(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 47 %

Procedure:
Following the procedure as described in Example 2, making variation as required to use N-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide to react with 1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound was obtained as a white solid in 47% yield: mp 217-218° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J=8.1 Hz, 2H), 7.38-7.21 (m, 7H), 6.02 (t, J=5.6 Hz, 1H), 4.57 (d, J=5.6 Hz, 2H), 4.35-4.24 (m, 1H), 3.98-3.89 (m, 1H), 3.49-3.41 (m, 1H), 2.93-2.74 (m, 2H), 2.63 (s, 3H), 2.12-1.68 (m, 3H), 1.62-1.42 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 171.6, 162.6, 156.9, 152.1, 143.2, 137.9, 129.6, 128.8, 127.9, 127.7, 125.9, 125.5, 125.4, 119.9, 47.9, 44.1, 43.9, 37.3, 24.9, 21.3, 17.4; MS (ES+) m/z 488.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(#N)C>[C:9]1([C:2]2[CH:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: c1ccc(-c2cc(-c3ccccc3)ncn2)cc1
Yield: 38 %

Procedure:
First, 5.02 g of 4,6-dichloropyrimidine, 8.29 g of phenylboronic acid, 7.19 g of sodium carbonate, 0.29 g of bis(triphenylphosphine)palladium(II) dichloride (abbreviation: Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile were put into a recovery flask equipped with a reflux pipe, and the air in the flask was replaced with argon. This reaction container was heated by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. Here, there were further put 2.08 g of phenylboronic acid, 1.79 g of sodium carbonate, 0.070 g of Pd(PPh3)2Cl2, 5 mL of water, and 5 mL of acetonitrile into the flask, and the mixture was heated again by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. After that, water was added to this solution and an organic layer was extracted with dichloromethane. The obtained solution of the extract was washed with water and dried with magnesium sulfate. The solution after drying was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by silica gel column chromatography using dichloromethane as a developing solvent, so that a pyrimidine derivative Hdppm (yellow white powder, 38% in yield) was obtained. Note that for the irradiation with microwaves, a microwave synthesis system (Discover, manufactured by CEM Corporation) was used. A synthesis scheme (a-1) of Step 1 is shown below.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23]OS(C4C=CC(C)=CC=4)(=O)=O)=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:36])([CH3:35])[NH:3]1.[NH3:38]>CO>[NH2:38][CH2:23][CH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:8][CH:6]3[CH2:5][C:4]([CH3:36])([CH3:35])[NH:3][C:2]([CH3:37])([CH3:1])[CH2:7]3)[N:14]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)cc2)cc1
Reactant: N
Solvent: CO
Product: CC1(C)CC(Nc2nccc(-c3ccc(CCCN)cc3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared from toluene-4-sulfonic acid 3-{4-[2-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-phenyl}-propyl ester and ammonia in MeOH.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:11]1[S:15][C:14]([S:16]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)(=[O:18])=[O:17])=[CH:13][CH:12]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: CN1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)NC3CCN(C)CC3)s2)s1
Reaction time: 3 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step 1 of Example 9 (110 mg; 0.33 mmol; 1 eq.), is dissolved in a mixture of DCM/DMF(1/1, 10 ml). 4-Amino-1-methylpiperidine (188 mg; 1.65 mmol; 5 eq.) and DIEA (0.17 ml; 0.98 mmol; 3 eq.) are added. After 3 hours, the solvents are evaporated. The crude product is dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, crude material is dissolved in DCM (3 ml) and title compound precipitated with Et2O affording after filtration, compound (4) as a white powder (120 mg; 90%). 1H NMR (DMSO-d6) δ 1.25 (m, 2H), 1.55 (m, 2H), 1.80 (m, 2H), 2.05 (m, 2H), 2.25 (s, 6H), 2.40 (s, 3H), 3.05 (m, 1H), 6.95 (d, J=3 Hz, 1H), 7.52 (d, J=3 Hz, 1H), 12.23 (m, 1H). M− (ESI): 413.30; M+ (ESI): 415.30. HPLC, Rt: 2.08 min (purity: 99.33%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29]C)[CH:24]=2)=[C:6]([NH:8][S:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[CH:16]=2)(=[O:11])=[O:10])[CH:7]=1.B(Br)(Br)Br>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[C:6]([NH:8][S:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[CH:16]=2)(=[O:11])=[O:10])[CH:7]=1
Reactant: COc1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(Cl)ccc1SCc1cccc(O)c1)c1cc2ccccc2o1
Reaction time: 2 h
Yield: 63.7 %

Procedure:
To a solution of N-{5-chloro-2-[(3-methoxybenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide (315 mg, 0.69 mmol) in CH2Cl2 (5 ml) at room temperature was added BBr3 (1M solution in CH2Cl2, 2.1 ml, 2.1 mmol) and the reation was stirred for 2 h, diluted with EtOAc, washed with brine, dried over Na2SO4, concentrated in vacuo. The crude product was purified by column chromatography on silica gel (25% ethyl acetate in hexane) to give the title compound (196 mg, 64%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15]C(F)(F)F)[C:11](C(F)(F)F)=[CH:10][C:9]=1[NH:24][C:25](=[O:46])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH:35]=2)[CH:29]=1)(C)(C)C.C(O)([C:50]([F:53])([F:52])[F:51])=O>C(Cl)Cl>[N:40]1([C:36]2[CH:35]=[C:34]([C:30]3[CH:29]=[C:28]([C:27]4[CH2:26][C:25](=[O:46])[NH:24][C:9]5[CH:10]=[C:11]([C:50]([F:53])([F:52])[F:51])[C:12]([O:14][CH2:15][C:50]([F:53])([F:52])[F:51])=[CH:13][C:8]=5[N:7]=4)[CH:33]=[CH:32][CH:31]=3)[CH:39]=[CH:38][N:37]=2)[CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(N3CCCC3)c2)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccnc(N4CCCC4)c3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from [2-{3-oxo-3-[3-(2-pyrrolidin-1-yl-pyridin-4-yl)-phenyl]-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M293) (376 mg, 0.61 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (111 mg, 33%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:20][CH:19]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=c1[nH]c2nccc(-c3ccc(Cl)cc3)c2c2ccccc12
Yield: 8.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 153 using Compound 83 (50 mg, 0.22 mmol) and 4-chlorophenylboronic acid (44 mg, 0.33 mmol) to provide 154 (6 mg, 9% yield) as a white solid. LC-MS (M+H=307, obsd.=307).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12]([OH:15])(=[O:14])=O)[N:6]=1)=[O:4].S(Cl)(Cl)=O.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)(=[O:14])=[O:15])[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C)c(S(=O)(=O)O)n1
Reactant: C1CCNCC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(S(=O)(=O)N2CCCCC2)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 12.1 %

Procedure:
5-Methyl-6-sulfo-pyridine-2-carboxylic acid methyl ester (340 mg, 1.47 mmol), thionyl chloride (CAN 7719-09-7, 1 mL) and 1 drop of DMF were added to methylene chloride (10 mL), and the mixture was stirred for 2 h at 40° C. The mixture was cooled to room temperature, and piperidine (CAN 110-89-4, 1.0 g, 12 mmol) in methylene chloride (10 mL) was added to the above mixture. The solvent was removed in vacuo, and the crude product was purified by prep-HPLC (eluting with 50% ethyl acetate in petroleum ether) to give the product (53 mg, 12%); MS (EI): m/e=299.1 [M+H]+.