Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[F:26])#[N:16]>>[N:3]1[C:4]2[N:5]([C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH:6]=[CH:7][C:2]=1[C:20]1[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[C:18]([F:26])[CH:19]=1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: Brc1ccn2c(n1)nc1ccccc12
Product: N#Cc1ccc(-c2ccn3c(n2)nc2ccccc23)cc1F
Yield: 35 %

Procedure:
The title compound was prepared using General Experimental Procedure A (Suzuki coupling reaction) from 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine and (4-cyano-3-fluorophenyl)boronic acid on a 0.1 mmol scale. The residue was washed with water (3×5 mL), EtOAc (3×2 mL), and DCM (3×2 mL) and dried under high vacuum to afford 4-(Benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)-2-fluorobenzonitrile (T747) as a orange solid (10 mg, 35%). 1H NMR (400 MHz, DMSO-d6): δ 9.74 (d, J=6.8 Hz, 1H), 8.46 (d, J=10.8 Hz, 1H), 8.41-8.38 (m, 2H), 8.19 (t, J=7.6 Hz, 1H), 7.98 (d, J=6.8 Hz, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.60 (t, J=7.2 Hz, 1H), 7.45 (t, J=7.2 Hz, 1H); MS (ESI) m/z [M+H]+289.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[CH2:8]([C:10]([CH2:19][CH3:20])([CH2:14][C:15](=O)[CH2:16]Br)[C:11]([NH2:13])=[O:12])[CH3:9].[CH:21]([NH2:23])=[S:22]>>[C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[CH2:8]([C:10]([CH2:19][CH3:20])([CH2:14][C:15]1[N:23]=[CH:21][S:22][CH:16]=1)[C:11]([NH2:13])=[O:12])[CH3:9]
Reactant: NC=S
Reactant: CCC(CC)(CC(=O)CBr)C(N)=O
Agent: O=C(O)CC(=O)O
Product: CCC(CC)(Cc1cscn1)C(N)=O

Procedure:
a reaction of diethyl (3-bromo-2-oxo-propyl)acetamide malonate with thioformamide to give diethyl (4-thiazolylmethyl)acetamide malonate and
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[CH2:2][CH2:3][CH3:4].Cl.Cl.[CH3:9][C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=1[NH:17][C:18]1[CH2:22][CH2:21][CH2:20][N:19]=1>>[ClH:6].[CH3:9][C:10]1[CH:15]=[C:14]([NH:16][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH:13]=[CH:12][C:11]=1[NH:17][C:18]1[CH2:22][CH2:21][CH2:20][N:19]=1
Reactant: CCCC(=O)Cl
Reactant: Cc1cc(N)ccc1NC1=NCCC1
Agent: Cl
Product: CCCC(=O)Nc1ccc(NC2=NCCC2)c(C)c1

Procedure:
The title compound was prepared by the method of Example 21 using 30.5 mmole of butanoyl chloride and 1.0 g (3.8 mmole) of the product compound of Example 9. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: [CH:1]([B-](F)(F)F)=[CH2:2].[K+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:33]([O:35][C:36]([C:38]1([CH3:51])[CH2:46][C:45]2[C:40](=[C:41]([CH3:49])[C:42](Br)=[C:43]([CH3:47])[CH:44]=2)[C:39]1=[O:50])=[O:37])[CH3:34]>C1COCC1.O.O.Cl[Pd]Cl>[CH2:33]([O:35][C:36]([C:38]1([CH3:51])[CH2:46][C:45]2[C:40](=[C:41]([CH3:49])[C:42]([CH:1]=[CH2:2])=[C:43]([CH3:47])[CH:44]=2)[C:39]1=[O:50])=[O:37])[CH3:34]
Reactant: C=C[B-](F)(F)F
Reactant: CCOC(=O)C1(C)Cc2cc(C)c(Br)c(C)c2C1=O
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1c(C)cc2c(c1C)C(=O)C(C)(C(=O)OCC)C2
Temperature: 85 °C
Reaction time: 48 h
Yield: 91.8 %

Procedure:
A solution of potassium vinyltrifluoroborate (0.186 g, 1.38 mmol), PdCl2, (0.033 g, 0.18 mmol), PPh3 (0.073 g, 0.27 mmol), Cs2CO3 (1.2 g, 3.69 mmol) and compound 5 (0.3 g, 0.92 mmol) in THF/H2O (9:1) (3 mL) was heated at 85° C. under an Argon atmosphere in a sealed tube. The reaction mixture was stirred at 85° C. for 48 h, then cooled to room temperature and diluted with H2O (6 mL) followed by extraction with ethyl acetate (30 mL), dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography (SiO2, 2 to 4% EtOAc in petroleum ether eluant) gave pure compound 6 (0.23 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[NH:5][C:6]=1[CH:7]=[O:8].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:18]([N:5]1[C:6]([CH:7]=[O:8])=[C:2]([Cl:1])[N:3]=[C:4]1[C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1[nH]c(-c2ccc([N+](=O)[O-])cc2)nc1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1c(Cl)nc(-c2ccc([N+](=O)[O-])cc2)n1Cc1ccccc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of 4-chloro-5-formyl-2-(4-nitrophenyl)imidazole (19.7 g, 78.3 mmol), benzyl bromide (14.5 g, 85.0 mmole) and potassium carbonate (11.7 g, 85.0 mmole) in DMF (150 ml) was heated to 110° C. for 1.5 hours. The mixture was evaporated and residue was poured into cold water and was allowed to stay overnight in the refrigerator. The tarry residue was pulverized and filtered. Yield of crude title compound: 33.4 g. The product was recrystallized from ethanol (96%, 350 ml). Yield: 14.0 g. NMR confirmed the structure of the title compound, Compound 7.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[SH:41][C@@H:42]1[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[O:48])[C@H:44]([C:60]([N:62]2[CH2:66][CH2:65][C@@H:64]([CH2:67][NH:68][C:69](=[NH:84])[CH2:70][C:71]([O:73][CH2:74][C:75]3[CH:80]=[CH:79][C:78]([N+:81]([O-:83])=[O:82])=[CH:77][CH:76]=3)=[O:72])[CH2:63]2)=[O:61])[CH2:43]1.C(OCC)(=O)C>C(#N)C.C(N(CC)C(C)C)(C)C>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:41][C@@H:42]3[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]4[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=4)=[O:48])[C@H:44]([C:60]([N:62]4[CH2:66][CH2:65][C@@H:64]([CH2:67][NH:68][C:69](=[NH:84])[CH2:70][C:71]([O:73][CH2:74][C:75]5[CH:76]=[CH:77][C:78]([N+:81]([O-:83])=[O:82])=[CH:79][CH:80]=5)=[O:72])[CH2:63]4)=[O:61])[CH2:43]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: N=C(CC(=O)OCc1ccc([N+](=O)[O-])cc1)NC[C@@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@@H](CNC(=N)CC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 60.8 %

Procedure:
To a solution of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (0.58 g) in anhydrous acetonitrile (10 ml), N,N-diisopropylethylamine (0.17 ml) and a solution of (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-(4-nitrobenzyloxycarbonylacetimidoylaminomethyl)pyrrolidin-1-ylcarbonyl]pyrrolidine (0.93 g) in anhydrous acetonitrile (10 ml) were added while stirring in an ice bath. The resulting mixture was stirred overnight at 0° C. To the reaction mixture, ethyl acetate was added. The resulting mixture was washed with water and saturated saline solution, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column (ethyl acetate/methanol=9/1), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-I -(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-(4-nitrobenzyloxycarbonylacetimidoylaminomethyl)pyrrolidin-1-ylcarbonyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (0.61 g) was obtained.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:12]1[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=1)[N:6]2[CH3:11].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:34][CH3:35])=[C:23]([S:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])[CH:24]=1>C(O)(C)C>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:34][CH3:35])=[C:23]([S:25]([N:28]2[CH2:29][CH2:30][N:31]([C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[C:5]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[N:6]4[CH3:11])[CH2:32][CH2:33]2)(=[O:26])=[O:27])[CH:24]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCNCC1
Reactant: Cn1cc(-c2nc3c(Cl)ncnc3n2C)cn1
Solvent: CC(C)O
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCN(c2ncnc3c2nc(-c2cnn(C)c2)n3C)CC1
Yield: 49 %

Procedure:
A stirred solution of 6-chloro-9-methyl-8-(1-methyl-1H-pyrazol-4-yl)-9H-purine (30 mg, 0.12 mmol), 1-(5-chloro-2-methoxyphenylsulfonyl)piperazine (43.6 mg, 0.15 mmol, Oakwood Products, Inc.), and triethylaminem (84.0 uL, 0.60 mmol) in isopropyl alcohol (2.0 mL) were heated to 80° C. for 16 hours. The resulting precipitate was collected by vacuum filtration, washed with ethanol (2 mL), water (2 mL) and diethyl ether (2 mL) and dried under reduced pressure, to give 29.6 mg (49% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.23 (s, 1H), 8.05 (s, 1H), 7.70 (dt, 2H), 7.27 (d, 1H), 3.95 (s, 3H), 3.88 (s, 3H), 3.83 (s, 3H), 3.31-3.25 (m, 4H). MS (EI) for C21H23ClN8O3S: 503.7 (MH+).
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[CH2:47]1[C:49]2([CH2:54][CH2:53][CH:52]([CH2:55][OH:56])[CH2:51][CH2:50]2)[CH2:48]1>>[Cl:17][C:18]1[C:19]([O:56][CH2:55][CH:52]2[CH2:53][CH2:54][C:49]3([CH2:47][CH2:48]3)[CH2:50][CH2:51]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: OCC1CCC2(CC1)CC2
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCC2CCC3(CC2)CC3)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with spiro[2.5]octan-6-ylmethanol, the title compound was obtained as a colorless solid (0.17 g, 40%): 1H NMR (300 MHz, CDCl3) δ 8.65-8.59 (m, 1H), 8.06 (d, J=8.1 Hz, 1H), 6.67 (d, J=13.8 Hz, 1H), 3.88 (d, J=6.3 Hz, 2H), 3.01 (s, 6H), 1.95-1.72 (m, 5H), 1.34-1.21 (m, 2H), 0.96-0.90 (m, 2H), 0.33-0.26 (m, 2H), 0.22-0.16 (m, 2H); MS (ES−) m/z: 417.2, 419.2 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([B:7]([OH:9])[OH:8])[S:5][CH:6]=1.[NH:10]([CH2:14][CH2:15]O)[CH2:11][CH2:12]O>>[CH3:1][C:2]1[CH:3]=[C:4]([B:7]2[O:9][CH2:15][CH2:14][NH:10][CH2:11][CH2:12][O:8]2)[S:5][CH:6]=1
Reactant: OCCNCCO
Reactant: Cc1csc(B(O)O)c1
Product: Cc1csc(B2OCCNCCO2)c1
Yield: 88 %

Procedure:
The title compound (88%, oil) was prepared from 4-methylthiophen-2-boronic acid and diethanolamin.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]([CH2:24][CH2:25][CH:26]=O)[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:7]=2[CH2:6]1)(=[O:4])=[O:3].[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[C:30]=1[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[C:30]=1[N:38]1[CH2:43][CH2:42][N:41]([CH2:26][CH2:25][CH2:24][N:11]2[C:8]3[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][C:7]=3[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)=[N:12]2)[CH2:40][CH2:39]1
Reactant: O=[N+]([O-])c1cccc(Cl)c1N1CCNCC1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCC=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(c3c(Cl)cccc3[N+](=O)[O-])CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
To a stirred solution of 3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propionaldehyde (0.5 g, 1.25 mmol) and 1-(2-chloro-6-nitrophenyl)-piperazine (0.301 g, 1.25 mmol) in CH2Cl2 (6 mL) was added sodium sulfate (0.354 g, 2.50 mmol) and sodium triacetoxyborohydride (0.396 g, 1.87 mmol). The mixture was allowed to stir at room temperature overnight. The mixture was diluted with CH2Cl2 and washed with water. The CH2Cl2 layer was dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica, 10% acetone/CH2Cl2) to afford of 1-{3-[4-(2-chloro-6-nitro-phenyl)-piperazin-1-yl]-propyl}-5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (0.380 g, 49%). MS (electrospray): exact mass calculated for C27H30CIF3N6O4S, 626.2; m/z found, 627.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.73 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.2 Hz, 2H), 7.54 (dd, J=8.2, 1.2 Hz, 1H), 7.49 (dd, J=8.2,1.2 Hz, 1H), 7.10 (t, J=8.2 Hz, 1H), 4.58 (s, 2H), 4.13 (t, J=6.5 Hz, 2H), 3.71 (t, J=5.9 Hz, 2H), 3.01-3.11 (m, 4H), 2.95 (t, J=5.9 Hz, 2H), 2.92 (s, 3H), 2.42-2.53 (m, 4H), 2.40 (t, J=6.5 Hz, 2H), 2.12 (q, J=6.5 Hz, 2H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:28]2[CH2:33][CH2:32][CH:31]([CH2:34]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:30][CH2:29]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.O>[C:10]([C:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:34][CH:31]1[CH2:30][CH2:29][N:28]([S:25]([C:22]2[CH:21]=[CH:20][C:19]([CH3:18])=[CH:24][CH:23]=2)(=[O:26])=[O:27])[CH2:33][CH2:32]1)#[N:11]
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCC(CC(C#N)(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Yield: 86.2 %

Procedure:
Sodium hydride (3.2 g, 80 mmol; 60% dispersion in oil) was added to a stirred solution of diphenylacetonitrile (13.5 g, 70 mmol) in toluene (200 ml) and the mixture was heated under reflux for 2 hours, treated with a solution of 1-(4-methylphenylsulphonyl)-4-(4-methylphenylsulphonyloxymethyl)piperidine (25.0 g, 60 mmol--see Preparation 15) in toluene (50 ml), heated under reflux for a further 2 hours, allowed to cool to room temperature and diluted with water. The layers were separated and the organic layer was washed with water and saturated brine, dried over magnesium sulphate and evaporated. The residue was crystallised from ethanol to give the title compound (23.0 g, 86%) as colourless crystals, m.p. 130° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:11]=[C:10]([C:21]([O:23]C)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+].Cl>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:11]=[C:10]([C:21]([OH:23])=[O:22])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(Oc2ncccn2)cc(-c2ccc(C)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(Oc3ncccn3)cc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 4′-methyl-5-(pyrimidin-2-yloxy)biphenyl-3-carboxylate (60 mg, 0.19 mmol) in tetrahydrofuran (3 mL) was added 2.5 M aqueous lithium hydroxide solution (0.77 mL, 1.9 mmol). The mixture was stirred at room temperature overnight, and then acidified to pH=5 by addition of 2N aqueous HCl and extracted with EtOAc (50 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated to afford the title product. 1H NMR (CD3OD, 400 MHz): 8.63 (d, 2H, J=4.8 Hz), 8.16 (t, 1H, J=1.6 Hz), 7.74 (t, 1H, J=2.0 Hz), 7.65 (t, 1H, J=2.0 Hz), 7.56 (d, 2H, J=8.0 Hz), 7.29 (d, 2H, J=8.0 Hz), 7.24 (t, 1H, J=4.8 Hz), 2.39 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:29])[C@@H:5]([N:10]1[CH2:14][C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:17]=2[F:27])=[CH:12][C:11]1=[O:28])[CH2:6][CH:7]([CH3:9])[CH3:8])C.O.[OH-].[Li+:32]>O1CCCC1>[Li+:32].[F:27][C:17]1[C:18]([N:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:13]1[CH2:14][N:10]([C@@H:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([O-:29])=[O:3])[C:11](=[O:28])[CH:12]=1
Reactant: CCOC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(N3CCCC3)c2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)[O-])N1CC(Oc2cccc(N3CCCC3)c2F)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 126.3 %

Procedure:
To a solution containing (S)-2-[4-(2-fluoro-3-pyrrolidin-1-yl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid ethyl ester (0.120 g, 0.29 mmol) in tetrahydrofuran (4 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 1.2 mL, 0.6 mmol). The mixture was stirred at 25° C. for 2 h, and the solvents evaporated. The residue was rinsed with diethyl ether which afforded (S)-2-[4-(2-fluoro-3-pyrrolidin-1-yl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid lithium salt (0.140 g, 100%) as a yellow solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6](/[CH:16]=[CH:17]/[C:18](=[NH:22])OCC)[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1.C(N(CC)CC)C.Cl.Cl[CH2:32][CH2:33][CH2:34][CH:35]([C:40]1[CH:45]=[CH:44][C:43]([N:46]([CH3:48])[CH3:47])=[CH:42][CH:41]=1)[C:36]([NH:38][NH2:39])=O>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6](/[CH:16]=[CH:17]/[C:18]2[N:22]=[C:36]3[CH:35]([C:40]4[CH:45]=[CH:44][C:43]([N:46]([CH3:48])[CH3:47])=[CH:42][CH:41]=4)[CH2:34][CH2:33][CH2:32][N:38]3[N:39]=2)[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1
Reactant: CN(C)c1ccc(C(CCCCl)C(=O)NN)cc1
Reactant: CCOC(=N)/C=C/c1ccc(-n2cnc(C)c2)c(OC)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cc(/C=C/c2nc3n(n2)CCCC3c2ccc(N(C)C)cc2)ccc1-n1cnc(C)c1
Temperature: 80 °C
Reaction time: 22 h

Procedure:
A solution of 4 N hydrochloric acid in ethyl acetate (2.64 mL) was added to tert-butyl N′-[5-chloro-2-(4-dimethylaminophenyl)pentanoyl]hydrazinecarboxylate (106.9 mg), and the reaction solution was stirred at room temperature for four hours. The reaction solution was concentrated under reduced pressure to obtain 5-chloro-2-(4-dimethylaminophenyl)pentanoic acid hydrazide hydrochloride. A solution of ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate hydrochloride (77.6 mg) and triethylamine (0.16 mL) in ethanol (1.25 mL) was added to a solution of the resulting 5-chloro-2-(4-dimethylaminophenyl)pentanoic acid hydrazide hydrochloride and triethylamine (0.291 mL) in ethanol (1.25 mL), and the reaction solution was stirred at 80° C. in a nitrogen atmosphere for 22 hours. The reaction solution was cooled to room temperature, and then the solvent was evaporated from the reaction solution under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the resulting residue, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=1:1→ethyl acetate→ethyl acetate:methanol=9:1) and further purified by silica gel column chromatography (elution solvent: ethyl acetate→ethyl acetate:methanol=9:1) to obtain 26.6 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C:13]1[CH:27]=[CH:26][C:16]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:15][C:14]=1[CH3:28].[C:29]([C:31]1[CH:41]=[CH:40][C:34]([C:35]([N:37]=[C:38]=[O:39])=[O:36])=[CH:33][CH:32]=1)#[N:30].C(N(C(C)C)CC)(C)C>C(#N)C>[C:29]([C:31]1[CH:32]=[CH:33][C:34]([C:35]([NH:37][C:38](=[O:39])[NH:12][C:13]2[CH:27]=[CH:26][C:16]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])=[CH:15][C:14]=2[CH3:28])=[O:36])=[CH:40][CH:41]=1)#[N:30]
Reactant: Cc1cc(OCC(=O)OC(C)(C)C)ccc1N
Reactant: N#Cc1ccc(C(=O)N=C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cc(OCC(=O)OC(C)(C)C)ccc1NC(=O)NC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.1 %

Procedure:
In a similar manner to Example 1, starting material step (a), the product of step (b) (2.9 g), 4-cyanobenzoyl isocyanate (1.23 g), diisopropylethylamine (1.23 ml) and acetonitrile (125 ml total) were reacted to give, after stirring at ambient temperature overnight, a solid, which was crystallised from acetonitrile/ether to give t-butyl 4-[3-(4-cyanobenzoyl)ureido]-3-methylphenoxyacetate (611 mg) as an off-white solid: NMR Spectrum (DMSO-d6) 1.44 (9H, s), 2.27 (3H, s), 4.61 (2H, s), 6.73 (1H, dd), 6.81 (1H, d), 7.72 (1H, d), 8.00 (2H, d), 8.13 (2H, d), 10.41 (1H, s), 11.23 (1H, s); Mass Spectrum m/Z 432 (M+Na)+.
Reaction SMILES: Br[CH2:2][C@@H:3]([OH:25])[C@@H:4]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CO>[Cl:13][C:8]1[CH:7]=[C:6]([CH2:5][C@H:4]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:3]2[CH2:2][O:25]2)[CH:11]=[C:10]([Cl:12])[CH:9]=1
Reactant: O=C(N[C@@H](Cc1cc(Cl)cc(Cl)c1)[C@H](O)CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(N[C@@H](Cc1cc(Cl)cc(Cl)c1)[C@H]1CO1)OCc1ccccc1
Reaction time: 8 h
Yield: 96.2 %

Procedure:
Step BF (7): To a suspension of benzyl (2S,3S)-4-bromo-1-(3,5-dichlorophenyl)-3-hydroxybutan-2-ylcarbamate (100 mg, 224 umol) in MeOH (2.4 mL) was added K2CO3 (12 mg). The reaction was stirred vigorously overnight. Solvents were removed in vacuo, and the residue partitioned between EtOAc and water three times. The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the solid benzyl (S)-2-(3,5-dichlorophenyl)-1-((S)-oxiran-2-yl)ethylcarbamate (78.9 mg, 97% yield). 1H NMR (DMSO-d6) δ 7.08-7.55 (m, 9H) 4.99 (d, J=12.8 Hz, 1H) 4.89 (d, J=12.8 Hz, 1H) 3.60-3.78 (m, 1H) 2.89-3.06 (m, 2H) 2.60-2.79 (m, 3H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:25])[CH2:15][P:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])[OH:17])[CH3:3].[CH2:26](O)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH3:12][CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:2]([CH3:1])[CH3:3])[C:5]=1[NH:13][C:14](=[O:25])[CH2:15][P:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:17])[O:18][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH3:26])[CH3:11]
Reactant: CCCCCCCCCCCCO
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CP(=O)(O)c1ccccc1
Product: CCCCCCCCCCCCOP(=O)(CC(=O)Nc1c(C(C)C)cccc1C(C)C)c1ccccc1

Procedure:
In a process analogous to Example 7, using (±)-[2-[[2,6-bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phenyl phosphinic acid in place of (±)-[2-[[2,6-bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phosphonic acid, ethyl ester and 1-dodecanol in place of 1-nonanol, the title compound is obtained as a sticky white solid; mp 66°-68° C.
Reaction SMILES: [CH:1]1([CH2:5][CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=2)=[O:9])[CH2:4][CH2:3][CH2:2]1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(#N)C>[CH:1]1([CH2:5][CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:14][CH:15]=2)=[O:9])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCCC1CCC1)c1ccc(Cl)nn1
Reactant: C1CNCCN1
Solvent: CC#N
Product: O=C(NCCC1CCC1)c1ccc(N2CCNCC2)nn1
Yield: 78.8 %

Procedure:
To a solution of 6-chloropyridazine-3-carboxylic acid (2-cyclobutylethyl)-amide (1.2 g, 5.00 mmol) in acetonitrile (40 mL) was added piperazine (1.29 g, 15.00 mmol). The reaction mixture was heated to reflux overnight. The mixture was evaporated and the solid residue was taken in ethyl acetate (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined ethyl acetates were dried over Na2SO4 and concentrated in vacuo to give the title compound as yellow solid (1.14 g, 78.4% yield).