Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=O)[CH2:18][CH:19]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[C:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:40]>C(O)(=O)C.C(OCC)(=O)C>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[NH:40][C:17]([CH:14]3[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[CH2:12][CH2:13]3)=[CH:18][C:19]=2[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[CH:23][CH:24]=1
Reactant: [NH4+]
Reactant: O=C(CC(C(=O)c1ccc(F)cc1)c1ccncc1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1

Procedure:
The product of Step 2 was heated in 5 ml of acetic acid in the presence of 2.0 g ammonium acetate at 110° C. for 1.5 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with water. The combined organic phases were washed with brine and dried over MgSO4. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by MPLC over silica gel eluting with 2% MeOH/CH2Cl2 to give the desired product. H1-NMR (CDCl3, 300 MHz):1.67 (m, 2H); 2.02 (bd, 2h); 2.75-3.0 (m, 3H); 4.29 bd, 2H); 5.12 (s, 2H); 6.19 (d, 1H); 7.03 (t, 2H); 7.18 (dd, 2H); 7.25-7.39 (m, 6H); 8.39 (dd, 2H); 8.52 (bs, 1H). FAB ms: C28H26N3O2F:455; Observed: 456 (M++1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:6][C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[NH:16][C:15]2=[O:25])=[C:4]([F:26])[CH:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:6][C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[N:16]([CH3:27])[C:15]2=[O:25])=[C:4]([F:26])[CH:3]=1
Reactant: CCS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CCS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 1.5 h
Yield: 118.3 %

Procedure:
1.00 g (2.41 mmol) of 3-(4-chloro-5-ethylsulfonylamino-2-fluorophenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione was dissolved in 10 ml of acetone, and 0.17 g (1.20 mmol) of anhydrous potassium carbonate and 0.23 ml (2.41 mmol) of dimethyl sulfate were added thereto and the reaction was continued for 1.5 hours. After acetone was distilled off, the reaction product was dissolved in ethyl acetate, washed with water and saturated saline solution, and dried over anhydrous sodium sulfate. Thereafter the ethyl acetate was distilled off to obtain a crude product. The crude product was recrystallized from chloroformdiethyl ether, thereby obtaining 0.61 g of the objective product (yield: 59%) in the form of light yellow crystals.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9].BrCC1C=CC=CC=1[F:25]>>[F:25][C:14]1[CH:15]=[CH:16][CH:2]=[CH:3][C:4]=1[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]
Reactant: CCOP(=O)(Cc1cccc(F)c1)OCC
Reactant: Fc1ccccc1CBr
Product: CCOP(=O)(Cc1ccccc1F)OCC

Procedure:
Prepared according to the method used to prepare diethyl 3-fluorobenzylphosphonate starting with 1-(bromomethyl)-2-fluorobenzene. 1H NMR (CDCl3) δ: 7.36 (t, J=7.5 Hz, 1H), 7.19-7.25 (m, 1H), 7.07-7.13 (m, 1H), 7.04 (t, J=9.2 Hz, 1H), 3.99-4.08 (m, 4H), 3.15-3.24 (m, 2H), 1.25 (td, J=7.0, 0.9 Hz, 6H).
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[C:6](N[C@H](C2N(C3C=NC=C(F)C=3)C3C=C(F)C=CC=3N=2)C)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-:31].[K+].[K+].OO.O>CS(C)=O>[N:5]1[CH:6]=[C:7]([C:8]([NH2:9])=[O:31])[CH:2]=[N:3][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cncnc1
Reaction time: 2 h

Procedure:
To a solution of (S)-4-amino-6-(1-(6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzo[d]imidazol-2-yl)ethylamino)pyrimidine-5-carbonitrile (0.040 g, 0.10 mmol) in DMSO (1.02 mL) was added potassium carbonate (0.017 g, 0.122 mmol) followed by hydrogen peroxide (31% in water, 0.635 mL, 6.42 mmol). After stirring for 2 h the solution was poured into water and extracted with EtOAc. Organic extracts were concentrated and purified by MPLC (eluted with 0-100% (1:10:90 NH4OH:MeOH:DCM) in DCM) to afford 4-amino-6-4(1S)-1-(6-fluoro-1-(5-fluoro-3-pyridinyl)-1H-benzimidazol-2-yl)ethyl)amino)-5-pyrimidinecarboxamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 (d, J=6.85 Hz, 3H) 5.34 (quin, J=6.94 Hz, 1H) 6.57 (s, 2H) 7.04-7.22 (m, 2H) 7.43 (br. s., 2H) 7.67-7.80 (m, 2H) 7.92 (d, J=7.63 Hz, 1H) 8.21 (dt, J=9.29, 2.10 Hz, 1H) 8.71 (s, 1H) 8.81 (d, J=2.74 Hz, 1H). LC-MS (ESI) m/z 411.0 [M+H]+.
Reaction SMILES: [Si]([O:8][CH:9]1[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)/[C:11](=[CH:19]/[C:20]([NH2:22])=[O:21])/[CH2:10]1)(C(C)(C)C)(C)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[F:18][C:14]1[CH:13]=[C:12]2[C:17]([CH:9]([OH:8])[CH2:10]/[C:11]/2=[CH:19]\[C:20]([NH2:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)OC1C/C(=C\C(N)=O)c2cc(F)ccc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: NC(=O)/C=C1\CC(O)c2ccc(F)cc21
Yield: 62.1 %

Procedure:
A solution of (E)-2-(3-((tert-butyldimethylsilyl)oxy)-6-fluoro-1-indanylidene) acetamide (1.80 g, 5.6 mmoles) and pyridinium p-toluenesulfonate (0.85 g, 3.4 mmoles, Aldrich) in ethanol (65 mL) was heated at 55-68° C. for 3.5 hours under a nitrogen atmosphere and evaporated in vacuo. The residue was dissolved in ethyl acetate (150 mL) and washed successively with water (2×150 mL) and brine (150 mL), dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate. gradually increasing the polarity to ethyl acetate:ethanol (95:5). The fractions containing the major spot were combined and evaporated in vacuo, and the residue was dried in a vacuum at 80° C. for 18 hours to give 0.72 g (62%) of (E)-2-(6-fluoro-3-hydroxy-1-indanylidene)acetamide as a white solid, mp 166-168° C.;
Reaction SMILES: C[N:2]([CH3:12])[CH:3]=[CH:4][C:5]([C:7]1[CH:11]=[CH:10][O:9][CH:8]=1)=O.N[C:14]1[C:18]([C:19]#[N:20])=C[NH:16][N:15]=1>C(O)(=O)C>[O:9]1[CH:10]=[CH:11][C:7]([C:5]2[N:16]3[N:15]=[CH:14][C:18]([C:19]#[N:20])=[C:12]3[N:2]=[CH:3][CH:4]=2)=[CH:8]1
Reactant: CN(C)C=CC(=O)c1ccoc1
Reactant: N#Cc1c[nH]nc1N
Solvent: CC(=O)O
Product: N#Cc1cnn2c(-c3ccoc3)ccnc12

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-1-(3-furyl)-2-propen-1-one and 0.01 mole of 3-aminopyrazole-4-carbonitrile in glacial acetic acid is heated at reflux temperature for 6 hours. The solvent is removed in vacuo and the residue purified as described for Example 1 to give the product of the example.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:6][CH:7]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:8]O.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:20][CH2:8][CH:7]([CH2:6][C:5]1[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCC(CO)Cc1ccc(OC)c(OC)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCC(CBr)Cc1ccc(OC)c(OC)c1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
Part E. The alcohol compound from Part D above (3.39 g, 13.4 mmol) and carbon tetrabromide (5.78 g, 17.4 mmol) were dissolved in methylene chloride (30 mL). This solution was cooled to 0° C. and treated with a 20 mL methylene chloride solution of triphenylphosphine (4.57 g, 17.4 mmol). The solution was allowed to stir for 14 hours, then evaporated. The residual oil was separated by flash chromatography (1:9 ethyl acetate-hexane) to afford the product, 1-bromo-2-(3,4-dimethoxybenzyl)hexane, as an oil (4.01 g, 12.7 mmol, 95%). 1H NMR (CDCl3): δ 6.81-6.71 (3H, m); 3.88 (3H, s); 3.87 (3H, s); 3.41 (1H, dd, J=9.9, 4,4 Hz); 3.33 (1H, dd, J=9.9, 4.0 Hz); 2.64 (1H, dd, J=13.5, 6.2 Hz); 2.58 (1H, dd, J=13.5, 8.0 Hz); 1.90-1.80 (1H, m); 1.48-1.24 (6H, m); 0.91 (3H, t, J=6.8 Hz). Mass spectrum (NH3 -CI/DDIP): m/z 334 (98%); 332 (100%); 317 (33%); 315 (34%); 252 (3%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]2=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](B2OC(C)(C)C(C)(C)O2)=[N:23]1>>[NH:22]1[C:30]2[C:25](=[C:26]([C:2]3[N:7]=[C:6]4[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]4=[C:4]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=4)[N:3]=3)[CH:27]=[CH:28][CH:29]=2)[CH:24]=[N:23]1
Reactant: COc1cccc(Nc2nc(Cl)nc3c2c(C)nn3C)c1
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Product: COc1cccc(Nc2nc(-c3cccc4[nH]ncc34)nc3c2c(C)nn3C)c1

Procedure:
(6-Chloro-1,3-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(3-methoxyphenyl)-amine was reacted with indazole boronic acid pinacol ester using General Procedure A to give 141. NMR (CDCl3): 2.78 (3H, s), 3.89 (3H, s), 4.14 (3H, s), 6.79 (1H, dd), 7.02 (1H, br. s), 7.25 (1H, m), 7.37 (1H, t), 7.54 (1H, t), 7.63-7.68 (2H, m), 8.45 (1H, d), 9.10 (1H, s), 10.11 (1H, br). MS: MH+ 386.20 (100%)
Reaction SMILES: [Na].C([O:4][C:5](=O)[CH2:6][C:7]#[N:8])C.[CH3:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[CH2:14][NH:15][NH2:16].N#N>C(O)C.O>[NH2:8][C:7]1[NH:16][N:15]([CH2:14][C:13]2[CH:17]=[CH:18][CH:19]=[C:11]([CH3:10])[CH:12]=2)[C:5](=[O:4])[CH:6]=1
Reactant: CCOC(=O)CC#N
Reactant: Cc1cccc(CNN)c1
Agent: N#N
Agent: [Na]
Solvent: O
Solvent: CCO
Product: Cc1cccc(Cn2[nH]c(N)cc2=O)c1

Procedure:
4.6 g of sodium are dissolved in 100 ml of ethanol. A mixture of 12 g of cyanoacetic acid ethyl ester and 13.6 g of 3-methylbenzylhydrazine is added to this solution. The mixture is heated to the boil for 5 hours while stirring and passing N2 into it. After driving off the solvent, taking up the residue in water, extracting with ether and clarifying with animal charcoal, acidification with acetic acid yields colorless crystals which after again being recrystallised from ethanol melt at 92°. The yield is 10.3 g of the compound identified above, corresponding to 51% of theory.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=O.[NH2:13][C:14]([NH2:16])=[S:15]>C(O)C>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:13]=[C:14]([NH2:16])[S:15][CH:2]=1
Reactant: COc1ccccc1C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: COc1ccccc1-c1csc(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
2-Bromo-1-(2-methoxy-phenyl)-ethanone (0.6388 g, 2.789 mmol) and thiourea (0.2289 g, 3.007 mmol) were dissolved in a 20 mL of ethanol. The reaction mixture was allowed to stir overnight at room temperature. The ethanol was evaporated to dryness and the crude product was dissolved in a minimum of dichloromethane. The crude product was then extracted twice with 1M sodium hydroxide and once with a saturated aqueous solution of sodium chloride. The organic layer was then dried over sodium sulfate, filtered, and evaporated to dryness to yield the pure product (0.529 g, 2.56 mmol, 92.0%). ESI-MS m/z calc. 206.3. found 207.1 (M+1)+ Retention time 1.86 minutes. 1H NMR (400 MHz, CD3CN) δ 3.91 (s, 3H), 5.54 (s, 2H), 6.97-7.02 (m, 1H), 7.03-7.06 (m, 1H), 7.23 (s, 1H), 7.24-7.29 (m, 1H), 8.06 (dd, J=7.8, 1.8 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18]C)=[O:17])=[C:11]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[C:11]([O:20][CH2:21][C:22]([F:23])([F:24])[F:25])[CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccc(NC(=O)OC(C)(C)C)cc1OCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(CC(=O)O)c(OCC(F)(F)F)c1

Procedure:
To a stirred solution of methyl 4-(tert-butyloxycarbonylamino)-2-(2,2,2-trifluoroethoxy)phenylacetate (0.90 g, 2.5 mmol) in MeOH (15 mL) was added aqueous NaOH (2.5 mL of a 3 N solution, 7.5 mmol). The mixture was refluxed for 1 h. The solvents were removed under reduced pressure and the residue was partitioned between EtOAc (100 mL) and 0.25 M aqueous citric acid (25 mL). The organic phase was separated, washed with water (25 mL), dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give 4-(tert-butyloxycarbonylamino)-2-(2,2,2-trifluoroethoxy)-phenylacetic acid as an amorphous solid (HPLC retention time=8.8 min (method A)).
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:39][C:40]1[CH:45]=[C:44]([S:46]([CH3:49])(=[O:48])=[O:47])[CH:43]=[CH:42][C:41]=1[N:50]1[C:54]2=[N:55][CH:56]=[N:57][C:58]([O:59][CH:60]3[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]3)=[C:53]2[CH:52]=[N:51]1.C(N(CC)CC)C>CN(C=O)C>[F:13][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:63]2[CH2:64][CH2:65][CH:60]([O:59][C:58]3[N:57]=[CH:56][N:55]=[C:54]4[N:50]([C:41]5[CH:42]=[CH:43][C:44]([S:46]([CH3:49])(=[O:48])=[O:47])=[CH:45][C:40]=5[F:39])[N:51]=[CH:52][C:53]=34)[CH2:61][CH2:62]2)=[O:10])=[CH:11][CH:12]=1
Reactant: O=C(O)c1ccc(OC(F)F)cc1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCN(C(=O)c5ccc(OC(F)F)cc5)CC4)ncnc32)c(F)c1
Reaction time: 24 h
Yield: 12.1 %

Procedure:
4-Difluoromethoxy-benzoic acid (527 mg, 2.8 mmol) and HATU (1.06 g, 2.8 mmol) were stirred together in DMF at room temperature for 30 min. 1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (800 mg, 1.87 mmol) and triethylamine (785 μL, 5.61 mmol) were added next. The resulting mixture was allowed to stir for 24 hours. Progress of the reaction was monitored by TLC and LCMS. Removal of organic solvents in vacuo and purification by HPLC afforded Compound A193 as a beige solid (127 mg, 32%). Exact mass calculated for C25H22F2N5O5S 561.53, found 562.2 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:48]=[CH:47][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH:37]([C:40]([O:42]C(C)(C)C)=[O:41])[CH2:36]4)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH:37]([C:40]([OH:42])=[O:41])[CH2:36]4)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:47][CH:48]=1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCN5CCC(C(=O)OC(C)(C)C)C5)c[nH]4)c3)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCN5CCC(C(=O)O)C5)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of tert-butyl 1-(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)pyrrolidine-3-carboxylate (22 mg, 0.033 mmol) in 2 ml of methylene chloride was added 1 ml of TFA. The mixture was stirred at room temperature for 16 hours, and evaporated to dryness under reduced pressure. The residue was re-dissolved in 2 ml of methanol and poured into 10 ml of water with vigorous stirring. Saturated NaHCO3 solution was added dropwise until pH=7. The precipitates were filtered, washed with water and dried in vacuo to give 1-(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)pyrrolidine-3-carboxylic acid as light reddish solid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([N:13]2[CH2:17][CH2:16][CH:15]([S:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>ClCCl>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([N:13]2[CH2:17][CH2:16][CH:15]([S:18]([CH2:19][C:20]([OH:22])=[O:21])=[O:33])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)CSC1CCN(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Solvent: ClCCl
Product: O=C(O)CS(=O)C1CCN(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Yield: 90.3 %

Procedure:
A solution of ({1-[3,5-bis(trifluoromethyl)phenyl]pyrrolidin-3-yl}sulfanyl)acetic acid (500 mg) obtained in Example 1 and m-chloroperbenzoic acid (321 mg) in dichloromethane (25 mL) was stirred at room temperature for 2 hr. The solvent was evaporated, and the residue was purified by preparative HPLC (instrument: Gilson Inc., High throughput purification system; column: YMC Combiprep ODS-A, S-5 μm, 50×20 mm; solvent: SOLUTION A; 0.1% trifluoroacetic acid-containing water, SOLUTION B; 0.1% trifluoroacetic acid-containing acetonitrile; gradient cycle: 0.00 min (SOLUTION A/SOLUTION B=90/10), 1.00 min (SOLUTION A/SOLUTION B=90/10), 4.20 min (SOLUTION A/SOLUTION B=10/90), 5.40 min (SOLUTION A/SOLUTION B=10/90), 5.50 min (SOLUTION A/SOLUTION B=90/10), and 5.60 min (SOLUTION A/SOLUTION B=90/10); flow rate: 25 mL/min; detection method: UV 220 nm) to give the title compound (471 mg, yield 90%).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:21][CH:20]=1)=[C:17]=[O:18].[Br-].[Li+]>CCCCCCC>[O:18]=[C:17]1[N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:3][C@H:2]([CH2:4][N:5]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:15])[O:1]1
Reactant: O=C=Nc1ccc(N2CCOCC2=O)cc1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Agent: [Br-]
Agent: [Li+]
Solvent: CCCCCCC
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Yield: 89.5 %

Procedure:
(S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (3.87 g, 19.06 mmol, 1.1 eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77 g, 17.29 mmol) were dissolved in n-heptane (70 mL) respectively, and heated to reflux. Lithium bromide (0.15 g, 1.74 mmol) was added, the mixture was reacted for 4 h, white solid was obtained by filtration (6.53 g, yield: 89.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:28]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:5].[CH2:36]([N:40]=[C:41]=[O:42])[CH2:37][CH2:38][CH3:39]>C(Cl)(Cl)Cl>[CH2:32]([N:31]([CH2:34][CH3:35])[C:28]1[CH:29]=[CH:30][C:2]([NH:1][C:41]([NH:40][CH2:36][CH2:37][CH2:38][CH3:39])=[O:42])=[C:3]([CH:27]=1)[C:4]([NH:6][CH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][CH2:13]1)=[O:5])[CH3:33]
Reactant: CCN(CC)c1ccc(N)c(C(=O)NCC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1
Reactant: CCCCN=C=O
Solvent: ClC(Cl)Cl
Product: CCCCNC(=O)Nc1ccc(N(CC)CC)cc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
Step 3): To a solution of 2-amino-5-diethylamino-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide (593 mg, 1.259 mmol) in CHCl3 (20 ml) was added n-butylisocyanate (374 mg, 3.779 mmol). The solution was refluxed overnight and evaporated. The residue was purified by column chromatography on silica gel to give 5-diethylamino-2-(N'-n-butylureido)-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide, 366 mg (51%): mp 158°-160° C.;
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=O.[N+]([O-])(O)=O.[F:21][C:22]([F:37])([O:26][C:27]1[CH:28]=[C:29]([NH:33][C:34]([NH2:36])=[NH:35])[CH:30]=[CH:31][CH:32]=1)[CH:23]([F:25])[F:24]>>[F:21][C:22]([F:37])([O:26][C:27]1[CH:28]=[C:29]([NH:33][C:34]2[N:36]=[C:5]([C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:9][CH:8]=3)[CH:4]=[CH:3][N:35]=2)[CH:30]=[CH:31][CH:32]=1)[CH:23]([F:24])[F:25]
Reactant: CN(C)C=CC(=O)c1c[nH]c2ccccc12
Reactant: N=C(N)Nc1cccc(OC(F)(F)C(F)F)c1
Solvent: O=[N+]([O-])O
Product: FC(F)C(F)(F)Oc1cccc(Nc2nccc(-c3c[nH]c4ccccc34)n2)c1

Procedure:
In accordance with the general procedure described in Example 32, reaction of 213 mg(1 mmol) of 3-dimethylamino-1-(3-indolyl)-2-propen- 1-one [described in EP-A-0 233 461] and 310 mg (1 mmol) of 3-(1,1,2,2-tetrafluoroethoxy)phenylguanidine nitrate gives N-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-4-(3-indolyl)-2-pyrimidine-amine; m.p. 140°-142°, FAB-MS: 403 (M+ +1).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]([NH:9][C:10]2[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=[C:12](S(C)(=O)=O)[N:11]=2)[CH2:3]1.[C@@H:23]([NH2:27])([CH2:25][CH3:26])[CH3:24].C(O)=O.C(=O)(O)[O-]>CN(C=O)C>[C@@H:23]([NH:27][C:12]1[N:11]=[C:10]([NH:9][C@@H:4]2[CH2:5][CH2:6][C@@H:7]([CH3:8])[C@H:2]([OH:1])[CH2:3]2)[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=1)([CH2:25][CH3:26])[CH3:24]
Reactant: C[C@@H]1CC[C@@H](Nc2nc(S(C)(=O)=O)ncc2C(N)=O)C[C@H]1O
Reactant: CC[C@H](C)N
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O=CO
Product: CC[C@H](C)Nc1ncc(C(N)=O)c(N[C@@H]2CC[C@@H](C)[C@H](O)C2)n1
Temperature: 90 °C
Yield: 66 %

Procedure:
To a stirring suspension of 4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (0.2 g, 0.609 mmol) in DMF (3 mL) was added (S)-(+)-sec-butylamine (0.305 mL, 3.05 mmol) and the reaction was heated to 90° C. overnight. The crude reaction mixture was concentrated under reduced pressure and then purified using reverse-phased semi-preparative HPLC (5-75% methanol+0.1% formic acid in water+0.1% formic acid, over 26 min). Fractions containing product were concentrated under reduced pressure and the resulting residue was redissolved in methanol (5 mL), passed over a Varian StratoSpheres HCO3 resin SPE tube for formic acid removal (0.9 mmol bicarbonate equiv.), and then concentrated under reduced pressure to afford 2-((S)-sec-butylamino)-4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)pyrimidine-5-carboxamide (0.129 g, 0.402 mmol, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80-1.24 (m, 15H) 1.35-1.45 (m, 1H) 1.54 (br. s., 1H) 1.66 (d, J=12.89 Hz, 1H) 1.92 (br. s., 1H) 2.14 (br. s., 1H) 2.97 (br. s., 1H) 3.71-3.99 (m, 1H) 4.55 (d, J=5.86 Hz, 1H) 6.96 (br. s., 1H) 8.34 (s, 1H) 8.90 (br. s., 1H); MS (ESI) m/z 322.5 [M+1]+.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:5])[CH3:4].[Cl:6][CH2:7][CH:8]([OH:11])[CH2:9]O.O>CC1C=CC(S(O)(=O)=O)=CC=1.C1CCCCC1>[Cl:1][CH2:2][C:3]1([CH3:4])[O:11][CH:8]([CH2:7][Cl:6])[CH2:9][O:5]1
Reactant: OCC(O)CCl
Reactant: CC(=O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Product: CC1(CCl)OCC(CCl)O1
Yield: 87.5 %

Procedure:
In a similar manner to the preceding Examples, 92.5 g (1 mol) of chloroacetone and 110.5 g (1 mol) of 3-chloro-1,2-propanediol are boiled together in a water separator with 0.5 g of p-TSA and 150 ml of cyclohexane. Once the equivalent quantity of water has separated, the cyclohexane is removed and the residue fractionated. 162 g (87%) of 2,4-bis(chloromethyl)-2-methyl-1,3-dioxolane are obtained. Bp.: 98° C. to 102° C. (1500 Pa); IR: acetal bands at 1120 cm−1, 1098 cm−1, 1053 cm−1, MS: m/e=169 (M−15), 135, 106, 93, 75, 57, 49, 43.