Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]/[C:2](/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH:3]\[C:4]#[N:5].[SH2:12]>CCO.C1COCC1>[C:6]1([C:2]2[CH:3]=[C:4]([NH2:5])[S:12][N:1]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: S
Reactant: N#C/C=C(\N)c1ccccc1
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cc(-c2ccccc2)ns1
Reaction time: 20 h

Procedure:
To a solution of (Z)-3-amino-3-phenylacrylonitrile (95 mg, 0.660 mmol) in EtOH (1.0 mL) and THF (1.0 mL) in a sealed tube, H2S gas was bubbled through for 5 min. It was then stirred at 90 C for 20 h. The mixture was concentrated in vacuo. The residue was dissolved in MeOH (2.0 mL), aq. H2O2 (30%, 0.5 mL) was added. After being stirred at room temperature for 2 min, the reaction was completed. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 3-phenylisothiazol-5-amine (22 mg).
Reaction SMILES: [NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:11]([O:13][CH3:14])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[H-].[Na+].Br[CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>CN(C=O)C>[NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:11]([O:13][CH3:14])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Reactant: O=C(CBr)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(OCC(=O)OCc2ccccc2)cc1)NC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
Under ice-cooling condition, to 25 ml of DMF solution containing 5.70 g of Z-Tyr-OCH3 was added 692 mg of sodium hydride (containing 60%) and the mixture was stirred for 30 minutes, then 3.96 g of benzyl bromoacetate was added thereto and the whole mixture was stirred at 50° C. for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue thus obtained was extracted with 100 ml of ethyl acetate. The ethyl acetate layer was washed with water and a saturated sodium chloride aqueous solution twice, respectively, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was added to a silica gel column and eluted with petroleum ether-chloroform (1:4) to obtain 6.00 g (yield: 72.6%) of the above-mentioned objective product.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:16](O)=[O:17])=[CH:11][C:10]=3[N+:19]([O-:21])=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:23][O:24][C:25](=[O:40])[CH2:26][C@@H:27]([NH2:39])[CH2:28][S:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1>>[CH3:23][O:24][C:25](=[O:40])[CH2:26][C@@H:27]([NH:39][C:16]([C:12]1[CH:13]=[C:14]2[C:9](=[C:10]([N+:19]([O-:21])=[O:20])[CH:11]=1)[NH:8][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH:15]2)=[O:17])[CH2:28][S:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=1
Reactant: COC(=O)C[C@@H](N)CSCc1ccc(OC)cc1
Reactant: O=C(O)c1cc([N+](=O)[O-])c2[nH]c(-c3ccccc3)cc2c1
Agent: Cl
Product: COC(=O)C[C@H](CSCc1ccc(OC)cc1)NC(=O)c1cc([N+](=O)[O-])c2[nH]c(-c3ccccc3)cc2c1

Procedure:
2-Phenyl-7-nitro-1H-indole-5-carboxylic acid prepared in Preparation 28 and (R)-3-amino-4-(4-methoxy-benzylsulfanyl)-butyric acid methyl ester hydrochloride prepared in Preparation 47 were reacted according to the same procedure as Example 92 to give the title compound.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][C:2]=12.Br[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][F:23])=[CH:16][CH:15]=1>>[F:23][CH2:22][CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]2[CH:8]=[CH:9][C:2]3[C:3]([CH:6]=2)=[N:4][O:5][N:1]=3)=[CH:15][CH:16]=1
Reactant: OB(O)c1ccc2nonc2c1
Reactant: FCCOc1ccc(Br)cc1
Product: FCCOc1ccc(-c2ccc3nonc3c2)cc1

Procedure:
Starting from 5-benzo[1,2,5]oxadiazoleboronic acid and 1-bromo-4-(2-fluoro-ethoxy)-benzene. Yellow-beige powder. MS(ES+): 259 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Se](=O)=[O:14]>>[CH3:1][C:2]1[C:11]([CH:12]=[O:14])=[N:10][C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=[Se]=O
Reactant: Cc1nc2ccccc2nc1C
Product: Cc1nc2ccccc2nc1C=O
Yield: 66 %

Procedure:
The title compound was prepared from 2,3-dimethylquinoxaline (6c) and selenium dioxide using methods as described in the literature for similar compounds (Kepez et al., 1989) in 66% yield.
Reaction SMILES: CCN=C=NCCCN(C)C.[Cl:12][C:13]([Cl:31])([Cl:30])[C:14]1[O:18][N:17]=[C:16]([CH:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:28][CH:27]([NH2:29])[CH2:26]3)[CH2:21][CH2:20]2)[N:15]=1.[F:32][C:33]([F:48])([F:47])[C:34]1[CH:35]=[C:36]([CH:44]=[CH:45][CH:46]=1)[C:37]([NH:39][CH2:40][C:41](O)=[O:42])=[O:38]>>[Cl:31][C:13]([Cl:30])([Cl:12])[C:14]1[O:18][N:17]=[C:16]([CH:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:28][CH:27]([NH:29][C:41]([CH2:40][NH:39][C:37](=[O:38])[C:36]4[CH:44]=[CH:45][CH:46]=[C:34]([C:33]([F:48])([F:32])[F:47])[CH:35]=4)=[O:42])[CH2:26]3)[CH2:21][CH2:20]2)[N:15]=1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: NC1CN(C2CCC(c3noc(C(Cl)(Cl)Cl)n3)CC2)C1
Agent: CCN=C=NCCCN(C)C
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3noc(C(Cl)(Cl)Cl)n3)CC2)C1

Procedure:
The title compound was prepared by the EDCI coupling of 1-[4-(5-trichloromethyl-[1,2,4]oxadiazol-3-yl)-cyclohexyl]-azetidin-3-ylamine (as prepared in the previous step) and (3-trifluoromethyl-benzoylamino)-acetic acid (Bionet Building Blocks). Purification by HPLC gave cis and trans isomers.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][C:36]=1[CH3:37])[CH2:29][C:30]1([NH2:33])[CH2:32][CH2:31]1.FC(F)(F)C([O-])=O>>[CH3:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][C:36]=1[CH3:37])[CH2:29][C:30]1([NH:33][CH2:21][CH:20]([C:12]2[C:13]3[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=3[C:9]([OH:8])=[CH:10][CH:11]=2)[OH:24])[CH2:31][CH2:32]1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Reactant: Cc1ccc(CC2(N)CC2)cc1C
Agent: O=C([O-])C(F)(F)F
Product: Cc1ccc(CC2(NCC(O)c3ccc(O)c4c3OCC(=O)N4)CC2)cc1C

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 175 mg (1 mmol) 1-(3,4-dimethyl-benzyl)-cyclopropylamine. Yield: 233 mg (47%, trifluoroacetate); mass spectroscopy: [M+H]+=383.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](=O)[CH3:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:15][N:16]([CH3:18])[NH2:17].C(O)(=O)C>C(O)C>[CH3:15][N:16]([CH3:18])[N:17]=[C:12]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:11][CH2:10][CH2:9]1)[CH3:13]
Reactant: CN(C)N
Reactant: CC(=O)C1(c2ccc(Cl)cc2)CCC1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=NN(C)C)C1(c2ccc(Cl)cc2)CCC1

Procedure:
A mixture of 1-[1-(4-chlorophenyl)cyclobutyl]ethanone (40 g), N,N-dimethylhydrazine (50 ml), glacial acetic acid (2 ml) and ethanol (35 ml) was heated under reflux for 78 hours. Removal of the solvent gave a residue which was distilled (104°-106°/0.1 mm Hg) to give 1- [1-(4-chlorophenyl)cyclobutyl]ethanone N,N-dimethylhydrazone.
Reaction SMILES: O=[C:2]([CH3:12])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]CC)=[O:8].BrC(C)CCCCC(OCC)=O.[CH3:25][CH2:26][CH2:27][C:28]1[C:33]([OH:34])=[C:32]([C:35]([CH3:37])=[O:36])[CH:31]=[CH:30][C:29]=1[OH:38]>>[C:35]([C:32]1[CH:31]=[CH:30][C:29]([O:38][CH:2]([CH3:12])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[C:28]([CH2:27][CH2:26][CH3:25])[C:33]=1[OH:34])(=[O:36])[CH3:37]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CCCCC(C)=O
Agent: CCOC(=O)CCCCC(C)Br
Product: CCCc1c(OC(C)CCCCC(=O)O)ccc(C(C)=O)c1O

Procedure:
Following the procedure of Example 15, ethyl 6-oxo-heptanoate was transformed into ethyl 6-bromoheptanoate. The reaction of 4.74 g. of ethyl 6bromoheptanoate and 3.88 g. of 2,4-dihydroxy-3-propylacetophenone followed by hydrolysis in the usual manner gave 300 mg. of the title product as an oil.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:11][C@H:12]([CH:28]([CH3:30])[CH3:29])[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=[O:14].O1CCOCC1>CO>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH:18]2[CH2:17][CH2:16][N:15]([C:13](=[O:14])[C@H:12]([NH:11][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[CH:28]([CH3:30])[CH3:29])[CH2:20][CH2:19]2)=[CH:22][CH:23]=1
Reactant: CC(C)[C@@H](N)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)[C@@H](NC(=O)Nc1ccccc1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction tube was charged with phenyl isocyanate (12 mg), (R)-2-amino-1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methylbutan-1-one hydrochloride (17 mg) and 1,4-dioxane (0.75 mL). The reaction mixture was shaken overnight at rt. After this time, the resulting solution was diluted with MeOH and purified by preparative LC-MS to provide Example 201. MS found: (M+H)+=429.
Reaction SMILES: C[Mg]Cl.O1CCC[CH2:5]1.[F:9][C:10]1[CH:11]=[CH:12][C:13]([O:28][CH3:29])=[C:14]([C:16]([CH3:27])([CH3:26])[CH2:17][C:18]([OH:25])([C:21]([F:24])([F:23])[F:22])[CH:19]=[O:20])[CH:15]=1.[Cl-].[NH4+]>C(OCC)C>[F:9][C:10]1[CH:11]=[CH:12][C:13]([O:28][CH3:29])=[C:14]([C:16]([CH3:27])([CH3:26])[CH2:17][C:18]([C:21]([F:24])([F:23])[F:22])([OH:25])[CH:19]([OH:20])[CH3:5])[CH:15]=1
Reactant: C1CCOC1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1ccc(F)cc1C(C)(C)CC(O)(C(C)O)C(F)(F)F
Reaction time: 2 h

Procedure:
8 ml of 3 M methylmagnesium chloride-tetrahydrofuran solution is added in drops to the solution of 3.6 mg (11.7 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal in 150 ml of diethyl ether at +2° C. Stirring is continued for 1 hour at +2° C. and for 2 hours at room temperature. Then, it is hydrolyzed with saturated ammonium chloride solution while being cooled with ice, the organic phase is separated, dried on sodium sulfate and concentrated by evaporation. Column chromatography on silica gel with hexane-ethyl acetate yields 2.23 g of the product.
Reaction SMILES: [O:1]1[CH2:4][C:2]1([C:5]([F:8])([F:7])[F:6])[CH3:3].[C:9]([CH2:12][N:13]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][N:19]([CH2:25][C:26]([OH:28])=[O:27])[CH2:18][CH2:17][N:16]([CH2:29][C:30]([OH:32])=[O:31])[CH2:15][CH2:14]1)([OH:11])=[O:10].[OH-].[K+]>O1CCOCC1.O>[OH:1][C:2]([C:5]([F:8])([F:7])[F:6])([CH3:3])[CH2:4][N:22]1[CH2:23][CH2:24][N:13]([CH2:12][C:9]([OH:11])=[O:10])[CH2:14][CH2:15][N:16]([CH2:29][C:30]([OH:32])=[O:31])[CH2:17][CH2:18][N:19]([CH2:25][C:26]([OH:28])=[O:27])[CH2:20][CH2:21]1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: CC1(C(F)(F)F)CO1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(O)(CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1)C(F)(F)F
Temperature: 70 °C
Reaction time: 24 h

Procedure:
10.29 g (86.58 mmol) of 2,3-epoxy-2-trifluoromethylpropane and 10 g (28.86 mmol) of 1,4,7-tris-carboxymethyl-1,4,7,10-tetraazacyclododecane are dissolved in a mixture of 50 ml of dioxane/80 ml of water, and the pH is brought to 10 with 6N potassium hydroxide solution. It is stirred for 24 hours at 70° C. (with exclusion of pressure). It is evaporated to dryness, the residue is taken up with 300 ml of water/50 ml of methanol and extracted twice with 100 ml of tert-butyl methyl ether. The aqueous solution is adjusted to pH 1 with 5N hydrochloric acid and evaporated to dryness. The residue is boiled out (extracted) with 200 ml of methanol/80 ml of methylene chloride. It is cooled in an ice bath and precipitated potassium chloride is filtered out. The filtrate is concentrated by evaporation in a vacuum, the residue is dissolved in 45 ml of water/20 ml of ethanol and then put on a column of poly-(4-vinylpyridine). The product is eluted with a solution of ethanol/water 1:3. After concentration by evaporation in a vacuum, the residue is chromatographed on a reversed-phase column (RP 18/mobile solvent=gradient of water/tetrahydrofuran). After concentration by evaporation of the main fraction, 11.04 g (71% of theory) of a strongly hygroscopic, vitreous solid is obtained.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]1[C:35]([F:36])=[C:34]([F:37])[CH:33]=[CH:32][C:31]=1[O:38][CH3:39]>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:29][C:30]3[C:31]([O:38][CH3:39])=[CH:32][CH:33]=[C:34]([F:37])[C:35]=3[F:36])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(F)c(F)c1CBr
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc(C)cc1
Product: COc1ccc(F)c(F)c1Cn1ccc2c(-c3ccc(C)cc3)c(C(OC(C)(C)C)C(=O)O)c(C)nc21

Procedure:
The title compound was prepared from methyl 2-(tert-butoxy)-2-(6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2-(bromomethyl)-3,4-difluoro-1-methoxybenzene in a manner similar to that described in Example 25 as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=7.64 (d, J=7.0 Hz, 1 H), 7.43-7.38 (m, 1 H), 7.34 (d, J=7.4 Hz, 2 H), 7.12 (d, J=3.5 Hz, 1 H), 7.00 (dd, J=9.2, 10.1 Hz, 1 H), 6.73 (dd, J=6.4, 11.9 Hz, 1 H), 6.24 (d, J=3.5 Hz, 1 H), 5.54 (s, 1 H), 5.48 (d, J=6.0 Hz, 2 H), 3.86 (s, 3 H), 2.78 (s, 3 H), 2.47 (s, 3 H), 0.95 (s, 9 H); LCMS (m/z) ES+=509 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][CH2:21][C:22]#[CH:23])[CH2:16][CH2:15]2)=[C:10]([CH2:24][NH:25][CH3:26])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:15][CH2:16][C@H:17]([N:20]([C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([Cl:27])=[CH:29][CH:30]=3)[CH2:21][C:22]#[CH:23])[CH2:18][CH2:19]2)=[C:10]([CH2:24][NH:25][CH3:26])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: C#CCN[C@H]1CC[C@H](c2ccc(C(=O)OC(C)(C)C)cc2CNC)CC1
Product: C#CCN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccc(C(=O)OC(C)(C)C)cc2CNC)CC1

Procedure:
from trans-4-(4-tert.butoxycarbonyl-methylaminomethylphenyl)-N-propargylcyclohexylamine and 4-chlorobenzoylchloride. Colourless oil. Rf value: 0.46 (silica gel, petroleum ether/ethyl acetate=2:1, v:v).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([NH:50][C:51]2[N:56]=[CH:55][C:54]([NH2:57])=[CH:53][N:52]=2)=[CH:46][CH:45]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)=[CH:7][C:3]=1[C:4]([NH:57][C:54]1[CH:53]=[N:52][C:51]([NH:50][C:47]2[CH:46]=[CH:45][C:44]([O:43][CH3:42])=[CH:49][CH:48]=2)=[N:56][CH:55]=1)=[O:6]
Reactant: COc1ccc(Nc2ncc(N)cn2)cc1
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccc(C(F)(F)F)c1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(Nc2ncc(NC(=O)c3cc(NC(=O)c4cccc(C(F)(F)F)c4)ccc3Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-5-(3-trifluoromethyl-benzoylamino)-benzoic acid (0.524 g, 1.53 mmol, 1.1 equiv) was combined with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (0.305 g, 1.74 mmol, 1.25 equiv) and diluted with DCM (10 mL). This was immediately treated with 4-methyl morpholine (0.458 mL, 4.16 mmol, 3 equiv) and allowed to stir at ambient temperature for 1 hour. Intermediate 68 (0.3 g, 1.38 mmol, 1 equiv) was then added in one portion. Stirring was continued overnight. After 18 h, reaction solvents were removed and resulting crude solids were purified via silica gel chromatography. Eluting with 1:1 EtOAc in Hexanes afforded desired product. Beige solids (0.19 g, 26%).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[C:7]([O:13][CH3:14])(=[O:12])[CH2:8][C:9]([CH3:11])=[O:10]>C1(C)C=CC=CC=1>[C:9]([CH:8]([C:7]([O:13][CH3:14])=[O:12])[CH:3]1[CH2:4][CH2:5][C:1](=[O:6])[CH2:2]1)(=[O:10])[CH3:11]
Reactant: O=C1C=CCC1
Reactant: COC(=O)CC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)C(C(C)=O)C1CCC(=O)C1
Temperature: 40 °C
Reaction time: 24 h
Yield: 98.9 %

Procedure:
Under an atmosphere of argon, 12.6 mg (0.02 mmol, S/C=50) of Ru[(S,S)-Tsdpen] (hexamethylbenzene), 84 μL (1.0 mmol) of 2-cyclopentenone, 108 μL (1.0 mmol) of methyl acetoacetate, and 1 mL of dry toluene were placed in a 20 mL Schlenk tube and stirred at 40° C. for 24 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 196 mg (99% yield) of the title compound. The optical rotation [α]D25 was +83.5 (c 1.35, CHCl3). The percentage diastereomeric excess and the percentage enantiomeric excess were measured by 1H NMR and HPLC (CHIRALCEL OD manufactured by Daicel Chemical Industries, Ltd., hexane:2-propanol=80:20, flow rate 1.0 mL/min, detection at 210 nm), and the results were that the product was a 1:1 diastereomeric mixture and each diastereomer was present in 91% ee.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)[N:5]=[C:4]([O:17][CH3:18])[CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.COC1C=C(C2C=CC=CC=2)N=C(N2C=CC(C(F)(F)F)=N2)N=1>>[CH3:18][O:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=2)[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)[N:5]=1
Reactant: COc1cc(Cl)nc(-n2ccc(C(F)(F)F)n2)n1
Reactant: Cc1ccc(B(O)O)cc1
Agent: COc1cc(-c2ccccc2)nc(-n2ccc(C(F)(F)F)n2)n1
Product: COc1cc(-c2ccc(C)cc2)nc(-n2ccc(C(F)(F)F)n2)n1
Yield: 75 %

Procedure:
4-Methoxy-6-(4-methyl-phenyl)-2-(3-trifluoromethyl-pyrazol-1-yl)-pyrimidine 307c was synthesized from compound 305 (1 g, 3.59 mmol) and (4-methyl-phenyl)-boronic acid 306c (732 mg, 5.39 mmol), according to the procedure as described for compound 307b, as a white solid in 75% yield. MS (ESI, EI+) m/z=335 (MH+).
Reaction SMILES: O[C@@H:2]1[C@H:6]([CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C@@H:5](/[CH:16]=[CH:17]/[C@@H:18]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH2:19]CC2C=CC=CC=2)[C@H:4]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH2:3]1.C(N(CC)C(C)C)(C)C.[C:50](Cl)(=O)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>ClCCl.CN(C)C1C=CN=CC=1>[C:51]1([CH2:50][CH2:19][C@H:18]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)/[CH:17]=[CH:16]/[C@@H:5]2[C@@H:6]3[C@@H:2]([O:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7]3)[CH2:3][C@H:4]2[O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: O=C(O)CCCC=CC[C@@H]1[C@@H](/C=C/[C@H](CCc2ccccc2)OC2CCCCO2)[C@H](OC2CCCCO2)C[C@@H]1O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C1CCC/C=C\C[C@@H]2[C@@H](/C=C/[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCCC=CC[C@@H]2[C@@H](/C=C/[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 7-((1R,2R,3R,5S)-5-hydroxy-2-((S,E)-5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)pent-1-enyl)-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoic acid (32 g from example 48) in 320 mL dichloromethane was treated with N,N-diisopropyl-ethylamine (12.3 g, 94.8 mmol) and benzoyl chloride (7.9 g, 56.3 mmol. This mixture was then stirred for 10 minutes at room temperature under an atmosphere of nitrogen, followed by addition of 4-(dimethylamino)-pyridine (11.9 g, 97.7 mmol) at 0° C. while stirring for 10 minutes. The resulting mixture was quenched with a saturated sodium bicarbonate solution (300 mL) and extracted with dichloromethane (100 mL). The organic layer is dried over magnesium sulfate and concentrated under reduced pressure to give 29.0 g of crude product. The crude product was purified by column chromatography providing 9.4 g of the title compound (58.6% yield, 3 steps).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][N:21]([C:24]2[S:25][C:26]([C:30](O)=[O:31])=[C:27]([CH3:29])[N:28]=2)[C:20](=[O:33])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][N:21]([C:24]2[S:25][C:26]([C:30]([NH:9][CH2:8][C:5]3[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=3)=[O:31])=[C:27]([CH3:29])[N:28]=2)[C:20](=[O:33])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Reactant: Cc1cnc(CN)cn1
Product: Cc1cnc(CNC(=O)c2sc(-n3ccc(OCc4ccccc4)cc3=O)nc2C)cn1
Yield: 42 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use (5-methylpyrazin-2-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 42% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.83 (t, J=5.7 Hz, 1H), 8.61 (d, J=8.1 Hz, 1H), 8.44 (s, 2H), 7.48-7.31 (m, 5H), 6.39 (dd, J=8.1, 2.7 Hz, 1H), 6.23 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.48 (d, J=5.7 Hz, 2H), 2.54 (m, 3H), 2.43 (s, 3H); MS (ES+) m/z 448.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:41])=[C:4]([C@@H:12]([NH:19][C:20](=[O:40])[CH2:21][NH:22][C:23](=[O:39])[C:24]2[CH:29]=[C:28]([NH:30][C:31]3[NH:32][CH2:33][CH:34]([OH:37])[CH2:35][N:36]=3)[CH:27]=[C:26]([OH:38])[CH:25]=2)[CH2:13][C:14]([O:16]CC)=[O:15])[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.C(#N)C.O.O.[OH-].[Li+]>O.C(#N)C>[Br:1][C:2]1[C:3]([OH:41])=[C:4]([C@@H:12]([NH:19][C:20](=[O:40])[CH2:21][NH:22][C:23](=[O:39])[C:24]2[CH:29]=[C:28]([NH:30][C:31]3[NH:36][CH2:35][CH:34]([OH:37])[CH2:33][N:32]=3)[CH:27]=[C:26]([OH:38])[CH:25]=2)[CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])[CH:7]=1
Reactant: CCOC(=O)C[C@H](NC(=O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1)c1cc(C(C)(C)C)cc(Br)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)c1cc(Br)c(O)c([C@H](CC(=O)O)NC(=O)CNC(=O)c2cc(O)cc(NC3=NCC(O)CN3)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.6 %

Procedure:
To a suspension of crude (3S)-ethyl 3-(3-bromo-5-(tert-butyl)-2-hydroxyphenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoate (1.389 g, 2.19 mmol) in a 1:1 mixture of acetonitrile/water (10.0 mL) was added lithium hydroxide monohydrate (0.735 g, 17.51 mmol) at room temperature and the reaction mixture was stirred at room temperature for 3 h to afford a pale yellow solution. Acetonitrile was evaporated on a rotary evaporator to give a pale yellow aqueous residue. The residue was extracted with dichloromethane (2×25 mL) to remove HOBt and DIPU. The aqueous layer was neutralized with TFA (3.0 mL in 5.0 mL CH3CN) and the mixture was evaporated in vacuo to give a pale viscous residue. The crude product was purified by reverse-phase HPLC on Biotage SP1 system using a gradient 10-40% CH3CN in water containing 0.05% TFA to afford a colorless glassy solid. The purified product was dissolved in water containing a few drops of acetonitrile and lyophilized to afford a colorless powder (778.0 mg). LC/MS analysis of the purified product shows the desired product's mass: m/z 606 (79BrM+H) and m/z 608 (81BrM+H), Calc'd for C26H32BrN5O7: 606.466. 1H NMR (400 MHz, DMSO-d6): δ 1.25 (s, 9H, (CH3)3C—), 2.70 (ABq, JAB=16.00 and 8.73 Hz and JAB=15.95 and 5.45 Hz, 2H, —CH2—COOH), 3.17 (d, J=12.0 Hz, 2H), 3.35 (d, J=11.0 Hz, 2H), 3.89 (d, J=6.0 Hz, 2H), 4.09 (M, 1H), 5.45 (brm, 1H, —NH—CH—CH2—COOH), 6.75 (brt/m, J=2.02 Hz, 1H), 7.13 (dt, 2H), 7.26 (d, J=2.30 Hz, 1H), 7.34 (d, J=2.32 Hz, 1H), 8.60 (d, J=8.26 Hz, 1H), 8.64 (t, J=5.85 Hz, 1H), 9.31 (s, 1H), 9.60 (s, 1H), 10.02 (brs, 1H), 12.27 (brs, 1H, —COOH). 1H NMR spectrum of the sample was consistent with the suggested structure of the product.