Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:13][C:14]([O:16][CH3:17])=[O:15])[CH3:10])=[CH:5][CH:4]=1>CO.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C@H:12]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH3:10])=[CH:5][CH:4]=1
Reactant: COC(=O)C=C(N[C@@H](C)c1ccc(OC)cc1)c1cccnc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C[C@H](N[C@@H](C)c1ccc(OC)cc1)c1cccnc1
Reaction time: 30 h

Procedure:
The crude methyl N-[(S)-1-(4-methoxyphenyl)ethyl]-3-amino-3-(3-pyridyl)propenoate, (40.6 g, 130 mmol) was dissolved in methanol (200 mL) and mixed with 20% Pd(OH)2/C (4.1 g). The mixture was hydrogenated under atmospheric pressure for 30 h. The mixture was diluted with ethyl acetate (50 mL) and filtered through celite (20 g) to remove the catalyst. The celite was washed with hot (70° C.) ethyl acetate(200 mL). The combined filtrate was concentrated under reduced pressure to near dryness to an oily residue. Crude amine (27.5 g) was dissolved in hot ethyl acetate (40 mL). The resulting hot yellow solution was filtered and rinsed with 15 mL of hot ethyl acetate. The clear solution was concentrated to <50 mL and allowed to stand at room temperature overnight. The resulting white crystalline solid was collected by filtration and washed with cold ethyl acetate (EtOAc) (˜15-20 mL), then air dried. Yield of isolated solid: 15.5 g. HPLC analysis showed >99% desired diastereomer. A second crop was obtained from the filtrate after concentration to about 20 mL. Yield: 1.7 g identical by HPLC to first crop; total yield: 17.2 g (62.5%)
Reaction SMILES: [I:1][C@H:2]1[C@@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([CH2:18][OH:19])[O:12][C@@H:3]1[O:4][Si](CC)(CC)CC.C([Si](CC)(CC)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1I)C.O.FC(F)(F)C(O)=O>C1COCC1>[I:1][C@@H:2]([C@H:15]([C@@H:14]([C@@H:13]([CH2:18][OH:19])[OH:12])[OH:17])[OH:16])[CH:3]=[O:4]
Reactant: CC[Si](CC)(CC)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1I
Agent: CC[Si](CC)(CC)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1I
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C[C@@H](I)[C@@H](O)[C@H](O)[C@H](O)CO
Yield: 90 %

Procedure:
Mixture of 2-deoxy-2-iodo-1-O-triethylsilyl-α-D-mannopyranose (IX) and 1-O-triethylsilyl-2-iodo-2-deoxy-β-D-mannopyranose (VIII) (total of 3.55 g) was dissolved in THF (50 mL), water (20 mL) and trifluoroacetic acid (0.7 mL) and stirred at room temperature. Progress of the reaction was monitored by TLC and after substrate disappearance reaction mixture was washed with dichloromethane (5×10 mL). The remaining water solution was lyophilized and such obtained crude solid residue was purified by column chromatography (SilicaGel 60, Merck) using chloroform and chloroform:methanol 9:1, 7:3 as eluents, to give 2.3 g of 2-deoxy-2-iodo-D-mannose (X). Yield 90%.
Reaction SMILES: [NH:1]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].I[CH2:22][CH2:23][CH2:24][Si:25]([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]>C(#N)C>[CH2:30]([O:29][Si:25]([O:32][CH2:33][CH3:34])([O:26][CH2:27][CH3:28])[CH2:24][CH2:23][CH2:22][N:1]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[CH3:31]
Reactant: C1CNCCNCCCNCCNC1
Reactant: CCO[Si](CCCI)(OCC)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCO[Si](CCCN1CCCNCCNCCCNCC1)(OCC)OCC

Procedure:
72 g (0.359 mol) of cyclam and 15 g of Na2CO3 (dried at 100° C. under 1 mm Hg for 24 h) are placed in 2.5 l of acetonitrile in a 6 l reactor under a stream of nitrogen. The mixture is brought to reflux, a solution of 24.2 g (0.073 mol) of iodopropyltriethoxysilane in 500 ml of acetonitrile is then added dropwise and then the reaction mixture is maintained at reflux for 48 h. After evaporating the solvent on a rotary evaporator (still under a nitrogen atmosphere), pentane is added to the residue and the excess cyclam is filtered off. This operation is repeated three times, the filtrates are combined, the pentane is evaporated and compound 1 is obtained in the form of a colorless oil (15 g, 50.8%).
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[NH2:21][C@@H:22]([CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[C:23]([N:25]([CH3:27])[CH3:26])=[O:24].ClC1C=C2C(=CC=1)N(S(C1C=CC(OC)=CC=1OC(F)(F)F)(=O)=O)C(=O)C2(N[C@@H](CC(N)=O)C(N(C)C)=O)C1C=CC=CC=1OC>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:21][C@@H:22]([CH2:28][C:29]1[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=1)[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CN(C)C(=O)[C@@H](N)Cc1ccncc1
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Agent: COc1ccc(S(=O)(=O)N2C(=O)C(N[C@@H](CC(N)=O)C(=O)N(C)C)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Product: COc1ccccc1C1(N[C@@H](Cc2ccncc2)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 0.78 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and 0.54 g of the compound obtained in Step 83-2 as starting materials, 268 mg of a diastereoisomer mixture of the title compound (pale yellow amorphous) was obtained by a similar method to Step 4-2.
Reaction SMILES: [CH3:1][C@H:2]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH3:1][C@H:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][C:30]2[CH:31]=[CH:32][C:27]([O:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:28][CH:29]=2)=[O:15])=[CH:17][CH:18]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC[C@H](C)Oc1ccc(C(=O)O)cc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCC[C@H](C)Oc1ccc(C(=O)Oc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.3 %

Procedure:
{circle around (1)}: A mixture comprising 1.25 g of (S)-4-(1′-methylheptyloxy)benzoic acid, 1.0 g of 4-benzyloxyphenol, 1.03 g of DCC and 10 g of dichloromethane was stirred at room temperature for 30 minutes. Then, a catalytic amount of 4-N,N-dimethylaminopyridine was added to the mixture, and the mixture was further stirred at room temperature for 12 hours. After finishing the reaction, insoluble substances were filtered off, followed by distilling off dichloromethane from the filtrate under reduced pressure. The resultant residue was purified by means of silica gel column chromatography, whereby 2.21 g of (S)-4-[4′-(1″-methylheptyloxy)phenylcarbonyloxy)-1-benzyloxybenzene was obtained.
Reaction SMILES: [CH3:1][C:2]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:16]([OH:18])=O)([CH3:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[SH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1.N1C=CC=CC=1>ClCCl>[CH3:12][C:2]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:16]([S:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)=[O:18])([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC(C)(C)c1cc(C(=O)O)ccc1OC
Reactant: O=C(O)c1ccc(S)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCC(C)(C)c1cc(C(=O)Sc2ccc(C(=O)O)cc2)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Crude 3-(1,1-dimethyldecyl)-4-methoxybenzoic acid, prepared starting with 1.6 g (5 mmoles) of 3-(1,1-dimethyldecyl)-4-methoxybenzoic acid, described in Example 11 of European Patent No. 0.232.199 is dissolved in 20 ml of dichloromethane. The solution is slowly added to a mixture of 771 mg (5 mmoles) of 4-mercaptobenzoic acid and 8 ml of pyridine. The reaction mixture is stirred at ambient temperature for 8 hours, evaporated to dryness, taken up in water, acidified to pH 5 with 1N HCl and extracted o with ethyl ether (500 ml). The organic phase is decanted, washed with water, dried over magnesium sulfate and evaporated to dryness. The resulting residue is purified by chromatography on a silica column, by using as the eluant ethyl ether. 1.92 g (84% yield) of 4-[3-(1,1-dimethyldecyl)-4-methoxybenzoylthio] benzoic acid whose melting point is 186°-187° C. are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]2)=[C:19]([CH3:31])[CH:18]=1)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:59][CH2:60][CH2:61][CH2:62][CH2:63][O:64][C:65]1[CH:74]=[CH:73][CH:72]=[C:71]([OH:75])[C:66]=1[C:67]([O:69][CH3:70])=[O:68].C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]2)=[C:19]([CH3:31])[CH:18]=1)[C:13]([NH:59][CH2:60][CH2:61][CH2:62][CH2:63][O:64][C:65]1[CH:74]=[CH:73][CH:72]=[C:71]([OH:75])[C:66]=1[C:67]([O:69][CH3:70])=[O:68])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)ccc1C1CC(=O)NS1(=O)=O
Reactant: COC(=O)c1c(O)cccc1OCCCCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(C)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.5 %

Procedure:
To a solution of (2S)-2-[(benzyloxy)carbonyl]amino-3-[4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)-3-methylphenyl]propanoic acid (85 mg, 0.19 mmol) in N,N-dimethylformamide (2.0 mL) were added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (88.4 mg, 0.200 mmol) at 0° C. under an atmosphere of nitrogen. After stirring for 15 min, methyl 2-(4-aminobutoxy)-6-hydroxybenzoate (54.7 mg, 0.228 mmol) and N,N-diisopropylethylamine (99.5 μL, 0.571 mmol) was added. The reaction mixture was warmed to room temperature for 1 h. The reaction was diluted with ethyl acetate and quenched with saturated sodium bicarbonate solution. The aqueous phase was extracted with EtOAc once. The combined organic solutions were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by preparative LCMS to yield the desired product (73 mg, 57%). 1H NMR (400 MHz, CD3OD): δ 8.00 (m, 1H), 7.38–7.15 (m, 9H), 6.48 (m, 2H), 5.45 (m, 1H), 5.03 (m, 2H), 4.30 (m, 1H), 3.94 (m, 2H), 3.85 (s, 3H), 3.3 (m, 4H), 3.02 (m, 1H), 2.87 (m, 1H), 2.42 (s, 3H), 1.6 (m, 4H); MF=C33H37N3O10S; LCMS found for C33H38N3O10S (M+H)+: m/z=668.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][N:20]=[C:19]2[NH:28][C:29]1[S:30][C:31]2[CH:37]=[C:36]([NH2:38])[CH:35]=[CH:34][C:32]=2[N:33]=1>O>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][N:20]=[C:19]2[NH:28][C:29]1[S:30][C:31]2[CH:37]=[C:36]([NH:38][C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=3)=[O:11])[CH:35]=[CH:34][C:32]=2[N:33]=1
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: O
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)Nc5cccc(C(F)(F)F)c5)cc4s3)c2cc1OC

Procedure:
1-[2-(6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl]-3-(3-trifluoromethylphenyl)urea was prepared from 3-trifluoromethylphenyl isocyanate (16 μL, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 3. The mixture was poured into water (20 mL) and the resulting precipitate was purified by pTLC (dichloromethane:methanol=9:1) to obtain a yellow solid (44 mg, 81 μmol, 72%). LC/ESI-MS: m/z=541 [M+H]+; m/z=539 [M−H]−; Rt=3.59 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[ClH:11]>O>[Cl:11][C:7]1[C:2]([OH:1])=[N:3][CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=1
Reactant: Cl
Reactant: O=[N+]([O-])c1ccc(O)nc1
Solvent: O
Product: O=[N+]([O-])c1cnc(O)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a warm (50° C.) solution of 2-hydroxy-5-nitro-pyridine (17 g, 121 mmol) in concentrated HCl (80 mL) was added dropwise NaClO3 (4.5 g, 42.5 mmol) in water (70 mL), keeping the internal temperature below 60° C. The reaction mixture was stirred for 15 min and then cooled to 0° C. The resulting precipitate was collected by vacuum filtration and dried to provide 19.7 g of the title compound. tR: 5.45 min (HPLC 3); ESI-MS: 173 [M−H]− (LC-MS 2); Rf=0.55 (hexane/EtOAc, 1:1).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:11]=O.[H][H]>>[CH3:11][NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([OH:10])=[O:9]
Reactant: C=O
Reactant: [H][H]
Reactant: Nc1ccccc1C(=O)O
Product: CNc1ccccc1C(=O)O

Procedure:
At least two processes for the preparation of the subject compound are known in the prior art. In one such process anthranilic acid is used as the starting compound and reacted with formaldehyde and hydrogen as described in J. Soc. Org. Synthetic Chem. (Japan) 11,434 (1953), Chem. Abst. 49, 955a (1955), to produce N-methylanthranilic acid. This resulting intermediate is thereafter reacted with thionyl chloride and methanol to produce the desired methyl N-methylanthranilate. This step is described in Aust. J. Chem. 27, 537 (1974). The disadvantages of this process lie in the use of a relatively expensive starting material and the relatively poor yields of final product. Typical reported reaction yields based on the starting compound amount to about 36% overall for the two steps.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[CH:17]1[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:16]=1[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Nc1ncccc1Br
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: COCCOC
Solvent: O
Product: Nc1ncccc1-c1ccc2ccccc2c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 68.8 %

Procedure:
To a solution of 3-bromopyridin-2-amine (1.0 g) in 1,2-dimethoxyethane (50 mL) were added naphthalen-2-ylboronic acid (1.292 g), sodium carbonate (1.225 g), tetrakis(triphenylphosphine)palladium(0) (0.334 g) and water (10 mL) at room temperature. The reaction mixture was stirred under a nitrogen atmosphere at 80° C. for 5 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was washed with acetonitrile to give the title compound (0.876 g).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH3:9])=[N:5][C:4]=1[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:14]([F:24])[CH:13]=1)[CH3:11])=[O:2].CC(C)=[O:27].OS(O)(=O)=O.O=[Cr](=O)=O.[Cr](O)(O)(=O)=O.CC(O)C>CC(C)=O.S(=O)(=O)(O)O.O>[F:24][C:14]1[CH:13]=[C:12]([CH:10]([C:4]2[N:5]=[C:6]([NH:8][CH3:9])[S:7][C:3]=2[C:1]([OH:27])=[O:2])[CH3:11])[CH:17]=[CH:16][C:15]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)=O
Reactant: CNc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)c(C=O)s1
Agent: O=[Cr](=O)(O)O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: CNc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)c(C(=O)O)s1
Reaction time: 1 h
Yield: 20 %

Procedure:
5-Formyl-4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-methylaminothiazole (1.00 g, 2.9 mmoles) was dissolved in acetone (20 ml). Jones reagent (chromic acid (VI) dissolved in a mixture of concentrated sulfuric acid and water) (2 ml) was added dropwise thereinto while cooling the system with ice, after which it was stirred for one hour. Then, an additional 2 ml of Jones reagent was added dropwise and the resulting mixture was stirred for one hour. A small quantity of 2-propyl alcohol was added to the reaction mixture, it was extracted with ether, and the ether layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain the desired 4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-methylamino-5-thiazolecarboxylic acid (205 mg, 0.58 mmole, yield 20%) as a white crystalline product.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][C:8]2[C:9](=[O:15])[NH:10][C:11](=[S:14])[NH:12][CH:13]=2)[CH:4]=[N:3][CH:2]=1.CCN(C(C)C)C(C)C.Cl[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([C:43]([F:46])([F:45])[F:44])[CH:37]=2)=[C:31]([CH:34]=1)[C:32]#[N:33]>C(Cl)Cl>[F:42][C:39]1[CH:40]=[CH:41][C:36]([O:35][C:30]2[CH:29]=[CH:28][C:27]([CH2:26][S:14][C:11]3[NH:12][CH:13]=[C:8]([CH2:7][C:5]4[CH:6]=[N:1][CH:2]=[N:3][CH:4]=4)[C:9](=[O:15])[N:10]=3)=[CH:34][C:31]=2[C:32]#[N:33])=[CH:37][C:38]=1[C:43]([F:44])([F:45])[F:46]
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1cncnc1
Reactant: N#Cc1cc(CCl)ccc1Oc1ccc(F)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(CSc2nc(=O)c(Cc3cncnc3)c[nH]2)ccc1Oc1ccc(F)c(C(F)(F)F)c1
Temperature: 60 °C
Yield: 38.4 %

Procedure:
To a suspension of 5-(5-pyrimidinylmethyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (38 mg, 0.173 mmol) and DIPEA (0.079 mL, 0.455 mmol) in DCM (1 mL), was added 5-(chloromethyl)-2-{[4-fluoro-3-(trifluoromethyl)phenyl]oxy}benzonitrile (50 mg, 0.152 mmol). The solution was heated at 60° C. overnight. Purification via MDAP then afforded the title compound (30 mg, 38.5% yield). LCMS: rt=3.14 min, [M+H+]=514
Reaction SMILES: C[C:2]1[N:3]=[C:4]2[S:21][CH:20]=[CH:19][N:5]2[C:6](=[O:18])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[CH3:22][O:23][C:24]1[C:25]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O.[O-][CH2:41]C.[Na+]>C(O)C>[CH3:22][O:23][C:24]1[C:25]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[C:26](/[CH:27]=[CH:41]/[C:20]2[S:21][C:4]3=[N:3][CH:2]=[C:7]([C:8]4[CH:9]=[CH:10][C:11]([C:14]([F:16])([F:15])[F:17])=[CH:12][CH:13]=4)[C:6](=[O:18])[N:5]3[CH:19]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: CC[O-]
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C(F)(F)F)cc1
Reactant: COc1cccc(C=O)c1OCc1ccccn1
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2cn3c(=O)c(-c4ccc(C(F)(F)F)cc4)cnc3s2)c1OCc1ccccn1
Yield: 47.9 %

Procedure:
The title compound was synthesized by condensation of Intermediate 5 (350 mg, 1.127 mmol) with 3-methoxy-2-(pyridin-2-ylmethoxy)benzaldehyde (411 mg, 1.692 mmol) in presence of sodium ethoxide (153 mg, 2.207 mmol) in ethanol (20 ml) according to the procedure described in Example 24 to give 289 mg of the desired product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 3.81 (s, 3H), 5.00 (s, 2H), 6.79 (d, J=16.2 Hz, 1H), 6.90-6.98 (m, 1H), 7.05 (d, J=4.5 Hz, 2H), 7.30-7.36 (m, 1H), 7.46-7.60 (m, 4H), 7.72-7.84 (m, 3H), 7.99-8.04 (m, 1H), 8.10 (d, J=15.6 Hz, 1H), 8.48-8.56 (m, 1H); ESI-MS (m/z) 512.18 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH3:11]>>[CH2:9]([N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH2:10][CH3:11]
Reactant: O=C1CCNCC1
Reactant: CCCCl
Product: CCCN1CCC(=O)CC1

Procedure:
1-Propyl-4-piperidone is prepared from 4-piperidone and 1-chloropropane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [Li][CH2:2]CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:8]=1.C[Si](C)(C)[O:25][C@@H:26]1[C@@H:31]([O:32][Si](C)(C)C)[C@H:30]([O:37][Si](C)(C)C)[C@@H:29]([CH2:42][O:43][Si](C)(C)C)[O:28][C:27]1=[O:48].Cl.C(=O)(O)[O-].[Na+]>C1COCC1.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.CO>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C@@:27]2([O:48][CH3:2])[C@H:26]([OH:25])[C@@H:31]([OH:32])[C@H:30]([OH:37])[C@@H:29]([CH2:42][OH:43])[O:28]2)=[CH:8][C:9]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Reactant: COc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: [Li]CCCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 101.3 %

Procedure:
A cold (−78° C.) solution of n-BuLi (124 mL, 2.5 M in hexane, 0.310 mol) was added dropwise under argon to a solution of 4-bromo-1-chloro-2-(4-methoxybenzyl)benzene (80 g, 0.258 mol) in dry THF/toluene (1:2 (v/v), 480 mL) cooled at −78° C. at such a rate as to keep the reaction temperature below −70° C. After the addition, the mixture was stirred for 40 min before transferred by a cannula to a stirred solution of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one (157 g, 0.335 mol) in toluene (480 mL) precooled to −78° C. at a rate as to keep the internal temperature below −70° C. The mixture was stirred for 3 h at −78° C. until starting material was consumed and was quenched slowly by hydrochloric acid (36-38%, 47.3 mL, 0.567 mol) in methanol (320 mL), keeping the internal temperature below −45° C. The reaction mixture was gradually warmed to room temperature and stirred overnight. The mixture was neutralized with saturated sodium bicarbonate aqueous solution to pH 7.5. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (2×1.0 L). The combined organic layers were washed with brine (2×1.0 L), dried over sodium sulfate, and concentrated. The residue was dried under vacuum at 40° C. to give the crude product as an off-white solid (111 g), which was used in the next step without further purification. Purity (HPLC) 66% (UV); MS ESI (m/z) 425[M+1]+.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[NH2:10][C:11]1[N:16]=[C:15]([OH:17])[C:14](Br)=[C:13]([CH3:19])[N:12]=1.O.Cl>C(O)CO>[NH2:10][C:11]1[N:16]=[C:15]([OH:17])[C:14]([S:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=2)=[C:13]([CH3:19])[N:12]=1
Reactant: OCc1ccc(S)cc1
Reactant: Cc1nc(N)nc(O)c1Br
Agent: Cl
Solvent: O
Solvent: OCCO
Product: Cc1nc(N)nc(O)c1Sc1ccc(CO)cc1
Temperature: 155 °C

Procedure:
A stirred mixture of (4-mercaptophenyl)methanol (6.72 g), 2-amino-5-bromo-6-methylpyrimidin-4-ol (10.76 g) and K2 CO3 (7.29 g) in ethylene glycol (120 ml) was heated at 155° C. for 9 h. After cooling the mixture was poured into water (500 ml) and neutralised with conc. HCl. The precipitate was filtered, washed with water then 50% EtOH/ether and dried to give the subtitle compound as a solid, 6.7 g. 1H NMR DMSO-d6: δ11.07 (brs, 1H); 7.18 (d, 2H); 6.99 (d, 2H); 6.87 (brs, 2H); 5.09 (s, 1H); 4.41 (s, 2H); 2.24 (s, 3H)