Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]2[C@@H:29]([OH:30])[C:28](=[O:31])[N:27]([CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH3:36])[C:26]3[CH:38]=[CH:39][CH:40]=[CH:41][C:25]=3[S:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.[C:49]([O-:54])(=[O:53])[C:50]([O-:52])=[O:51]>C(Cl)Cl>[C:49]([OH:54])(=[O:53])[C:50]([OH:52])=[O:51].[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C@H:23]2[C@@H:29]([O:30][C:4](=[O:5])[C:3]3[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=3[Cl:1])[C:28](=[O:31])[N:27]([CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH3:36])[C:26]3[CH:38]=[CH:39][CH:40]=[CH:41][C:25]=3[S:24]2)=[CH:21][CH:22]=1
Reactant: O=C([O-])C(=O)[O-]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Reactant: CCN(C)CCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(C)CCN1C(=O)[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2Cl)[C@H](c2ccc(OC)cc2)Sc2ccccc21
Product: O=C(O)C(=O)O
Reaction time: 1 h
Yield: 83.5 %

Procedure:
A solution of 0.88 g of 2-chloro-4-nitrobenzoyl chloride in 3 ml of methylene chloride is dropwise added at room temperature to a mixture of 1.41 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methyl-N-ethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride, 15 ml of methylene chloride and 1 ml of triethylamine. The mixture is stirred for one hour. After the reaction, the mixture is evaporated to remove solvent. The residue is extracted with ethyl acetate, and the extract is washed with water, dried and then evaporated to remove solvent. The oil thus obtained is converted to its oxalate and then recrystallized from ethanol. 1.83 g of (+)-cis-2-(4-methoxyphenyl)-3-(2-chloro-4-nitrobenzoyloxy)-5-[2-(N-methyl-N-ethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one oxalate are thereby obtained as colorless needles. Yield: 83.5%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.[CH2:12]([O:19][C:20](=[O:24])[C@@H:21](O)[CH3:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C@@H:21]([C:20]([O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:24])[CH3:22])[CH:5]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: C[C@H](O)C(=O)OCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(O[C@H](C)C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.5 %

Procedure:
To a solution of (10.0 g, 55.5 mmol) of 3-hydroxy-benzoic acid methyl ester in tetrahydrofuran (125 mL), cooled to 0° C., is added (8.44 g, 55.5 mmol) of (S)-2-hydroxy-propionic acid benzyl ester, and (14.5 g, 55.5 mmol) of triphenyl phosphine. To this mixture is added a solution of (11.3 mL, 72.2 mmol) of diethylazodicarboxylate in tetrahydrofuran (25 mL) via a syringe pump over a 1 hour period. The reaction mixture is warmed to room temperature and stirred for 18 h then concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide 13 g of 3-((R)-1-benzyloxycarbonyl-ethoxy)-benzoic acid methyl ester as an oil.
Reaction SMILES: [C:1]1([C:11]2[CH:12]=[C:13](Br)[CH:14]=[C:15]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Mg].Br[CH2:30][CH2:31]Br.I[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43](I)=[CH:42][CH:41]=2)=[CH:36][CH:35]=1>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([C:11]2[CH:12]=[C:13]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:45]=[C:44]([C:4]5[C:5]6[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=6)[CH:1]=[CH:2][CH:3]=5)[C:43]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)=[C:42]([C:20]5[C:30]6[C:31](=[CH:19][CH:18]=[CH:17][CH:26]=6)[CH:23]=[CH:22][CH:21]=5)[CH:41]=4)=[CH:36][CH:35]=3)[CH:14]=[C:15]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Brc1cc(-c2cccc3ccccc23)cc(-c2cccc3ccccc23)c1
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Reactant: BrCCBr
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: c1ccc(-c2c(-c3cccc4ccccc34)cc(-c3ccc(-c4cc(-c5cccc6ccccc56)cc(-c5cccc6ccccc56)c4)cc3)cc2-c2cccc3ccccc23)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A solution of 3,5-di-α-naphthyl bromobenzene (10.0 g, 0.0244 mol) in anhydrous THF (70 mL) was added dropwise to magnesium turnings (0.59 g, 0.0244 mol) in 10 mL THF. The solution was heated at 60° C. during the addition and the reaction was initiated using 1,2-dibromoethane. After the addition was complete, the brown solution was heated at reflux for 2 hrs. and then cooled to room temperature. In a separate flask, 4,4′-diiodobiphenyl (3.3 g 0.008 mol) and 0.3 g of dichlorobis(triphenyl phosphine)palladium(II) were placed under nitrogen and 30 mL of anhydrous THF was added. The Grignard reagent prepared about THF solution was then added using needle-transfer and an orange solution resulted. Heat was applied and the solution turned to almost black. The mixture was then heated at reflux for 45 min. and cooled to room temperature during which time a solid precipitated out of solution. A 2.0 M solution of HCl was added to the mixture and after stirring for 30 minutes, the water layer was removed. The solid precipitate was collected by filtration and washed with water and diethyl ether to yield a white solid (5.3 g, 81%)
Reaction SMILES: [NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]3[N+:16]([O-:17])=[N:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=3)[CH2:7][S:8][C@H:3]12.C(=O)([O-])[OH:26].[Na+:29].O.[CH2:31]=[C:32]1[O:36][C:34](=[O:35])[CH2:33]1>CC(C)=O>[OH2:17].[OH2:26].[OH2:35].[C:34]([NH:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([O-:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]3[N+:16]([O-:17])=[N:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=3)[CH2:7][S:8][C@H:3]12)(=[O:35])[CH2:33][C:32]([CH3:31])=[O:36].[Na+:29]
Reactant: C=C1CC(=O)O1
Reactant: O=C([O-])O
Reactant: COc1ccc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)[n+]([O-])n1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(SCC2=C(C(=O)[O-])N3C(=O)C(NC(=O)CC(C)=O)[C@H]3SC2)[n+]([O-])n1

Procedure:
A mixture of 0.392 g. of 7-amino-3-(3-methoxy-1-oxidopyridazin-6-yl)thiomethyl-3-cephem-4-carboxylic acid, 0.42 of sodium hydrogen carbonate, 5 ml. of water and 5 ml. of acetone is cooled to 5° C and under stirring, 0.2 g. of diketene is added, followed by further stirring at room temperature for 30 minutes. The acetone is distilled off and the residue is adjusted to pH 7 with 50 % phosphoric acid, washed with ethyl acetate and developed on a column of polystyrene resin (Amberlite XAD-2) with 5 % aqueous alcohol. The desired fractions are pooled and freeze-dried. The above procedure gives sodium 7-acetoacetamido-3-(3-methoxy-1-oxidopyridazin-6-yl)thiomethyl-3-cephem-4-carboxylate trihydrate as a powder with a faint brownish tinge. Yield 0.152 g. (32 %).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][C:14]#[N:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[Li+].[CH3:17][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:13]([CH3:17])[C:14]#[N:15])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: N#CCc1nc(-c2ccc(F)cc2)cs1
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: CC(C#N)c1nc(-c2ccc(F)cc2)cs1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 37.6 %

Procedure:
To a stirred solution of 2-(4-(4-fluorophenyl)thiazol-2-yl)acetonitrile (500 mg, 2.29 mmol) in THF (10 mL) at −78° C. was added LiHMDS (1M in THF; 2.06 mL, 2.06 mmol) and the reaction mixture was stirred at −78° C. for 10 min. Iodomethane (0.12 mL, 2.06 mmol) in THF (2 mL) was then added dropwise and the reaction mixture was stirred at −78° C. for 30 min. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl solution, water, brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to give the crude product; which was purified on a Teledyne ISCO automated column chromatography system (0-30% EtOAc/Hexanes) to give 2-(4-(4-fluorophenyl)thiazol-2-yl)propanenitrile (180 mg, yield 34%). MS (ESI) m/z: Calculated for C12H9FN2S: 232.05. found: 233.1 (M+H)
Reaction SMILES: O=[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].Cl.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26]N)=[CH:22][CH:21]=1>>[CH3:19][C:20]1[CH:21]=[C:22]2[C:23](=[CH:24][CH:25]=1)[NH:26][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:3]2[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: Cc1ccc(NN)cc1
Reactant: CCOC(=O)CCCCC(=O)c1ccccc1
Agent: Cl
Product: CCOC(=O)CCCc1c(-c2ccccc2)[nH]c2ccc(C)cc12
Yield: 58 %

Procedure:
The expected ester is obtained in the form of a brown solid with a yield of 58% by following a procedure analogous to Preparation X and starting from ethyl ε-oxobenzenehexanoate and 4-methylphenylhydrazine hydrochloride.
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]([CH3:47])[C@H:44]([C:48]([N:50]2[CH2:54][CH2:53][C@H:52]([CH2:55][N:56]([CH3:70])[C:57]([O:59][CH2:60][C:61]3[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=3)=[O:58])[CH2:51]2)=[O:49])[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]([CH3:47])[C@H:44]([C:48]([N:50]4[CH2:54][CH2:53][C@H:52]([CH2:55][N:56]([CH3:70])[C:57]([O:59][CH2:60][C:61]5[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=5)=[O:58])[CH2:51]4)=[O:49])[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: CN(C[C@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C)C1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
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](CN(C)C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C)C3)[C@H](C)[C@H]12
Yield: 47.6 %

Procedure:
To a solution of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (0.72 g) in anhydrous acetonitrile (5 ml), N,N-diisopropylethylamine (0.21 ml) and a solution of (2S,4S)-4-mercapto-1-methyl-2-[(3S)-3-(N-methyl-N-4-nitrobenzyloxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]pyrrolidine (0.54 g) in anhydrous acetonitrile (5 ml) were added while stirring in an ice bath. The resulting mixture was allowed to react 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=6/4), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-1-methyl-2-[(3S)-3-(N-methyl-N-4-nitrobenzyloxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (0.46 g) was obtained.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C:13]([CH2:16][OH:17])([CH2:14][OH:15])[O:12][C@@H:11]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:10]1[OH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>O1CCCC1>[CH2:1]([O:8][C@H:9]1[C:13]([CH2:14][O:15][S:35]([CH3:34])(=[O:37])=[O:36])([CH2:16][O:17][S:35]([CH3:34])(=[O:37])=[O:36])[O:12][C@@H:11]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:10]1[O:27][S:35]([CH3:34])(=[O:37])=[O:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn([C@@H]2OC(CO)(CO)[C@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]c1=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cn([C@@H]2OC(COS(C)(=O)=O)(COS(C)(=O)=O)[C@H](OCc3ccccc3)[C@H]2OS(C)(=O)=O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.9 %

Procedure:
To a solution of nucleoside 5 (1100 mg, 2.91 mmol) in anhydrous tetrahydrofuran (20 cm3) was added anhydrous pyridine (5 cm3) followed by methanesulfonyl chloride (1.2 ml, 15.5 mmol). The mixture was stirred under a nitrogen atmosphere for 18 h at room temperature. The reaction mixture was evaporated to dryness under reduced pressure and dissolved in ethyl acetate. The organic phase was washed with saturated aqueous solution of sodium hydrogen carbonate (3×10 cm3) and dried (Na2SO4). The organic phase was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (2% methanol, v/v) as elutxnt to afford nucleoside 11 (908 mg, 51%). δC (CDCl3) 163.3, 150.6, 135.6, 134.6, 128.7, 128.3, 112.2, 87.9, 85.0, 83.1, 80.9, 77.2, 76.9, 76.6, 73.3, 66.6, 66.2, 38.6, 37.6, 37.6, 12.2.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C@@H:3]([OH:5])[CH3:4].[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:12](F)=[N:13][CH:14]=1>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[C:12]([O:5][C@@H:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])=[N:13][CH:14]=1
Reactant: Fc1ncc(Cl)cc1-c1ccc(Cl)cc1
Reactant: C[C@H](O)C(F)(F)F
Solvent: CN(C)C=O
Product: C[C@H](Oc1ncc(Cl)cc1-c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a mixture of 1.133 g (S)-1,1,1-trifluor-2-propanol in 10 ml dry DMF 397 mg sodium hydride (60%) was added and the mixture was stirred at room temperature for 30 minutes. The resulting solution was added dropwise at RT to a solution of 2.185 g 5-chloro-3-(4-chloro-phenyl)-2-fluoro-pyridine in 20 ml dry DMF. The reaction mixture was then stirred at room temperature for 2 h. The resulting light yellow mixture was partitioned between water and ethyl acetate, the phases were separated. The organic phase was dried over MgSO4 and purified by chromatography on silica gel with a gradient of heptane to heptane:ethyl acetate=9:1 to yield 2.330 g (76.80%) of the title compound as colorless liquid, 336.1 (M+H)+.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:13]1[C:18]([C:19]2[CH:20]=[CH:21][C:22]([F:26])=[CH:23][C:24]=2[F:25])=[CH:17][C:16]([C:27]([OH:29])=[O:28])=[C:15]([OH:30])[CH:14]=1.[CH2:31](O)[CH2:32][CH3:33].O>CN(C=O)C>[F:25][C:24]1[CH:23]=[C:22]([F:26])[CH:21]=[CH:20][C:19]=1[C:18]1[CH:13]=[CH:14][C:15]([OH:30])=[C:16]([C:27]([O:29][CH2:31][CH2:32][CH3:33])=[O:28])[CH:17]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: CCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
CDI (972 mg, 5.99 mmol) was added to a solution of diflunisal (1.50 g, 5.99 mmol) in DMF (30 mL). The reaction mixture was stirred at 50° C. for 2 h and n-PrOH (1.13 mL, 14.97 mmol) was dropwise added. The reaction mixture was stirred at 50° C. for 3 h and allowed to reach r.t. It was poured into H2O (50 mL) and extracted with Et2O (2×50 mL). The organic layer was washed with NaHCO3 (20 mL, saturated aqueous solution), dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (2% EtOAc/hexanes) to furnish 1.33 g of propyl 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylate (yellow-coloured oil, yield: 76%).
Reaction SMILES: C(C1NC=CN=1)(=S)N.[CH2:9]1[NH:14][C:12](=[O:13])[NH:11][CH2:10]1.[CH2:15]([N:22]=[C:23]=[S:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][C:23]([N:11]1[CH2:10][CH2:9][NH:14][C:12]1=[O:13])=[S:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1NCCN1
Reactant: S=C=NCc1ccccc1
Agent: NC(=S)c1ncc[nH]1
Product: O=C1NCCN1C(=S)NCc1ccccc1
Reaction time: 6 h

Procedure:
The starting thiocarbamoylimidazole required for the above reaction is made as follows: 86g ethyleneurea and 149G benzylisothiocyanate are treated together with stirring for 6 hrs. at 150°. Upon cooling, a solid mass is obtained, which is triturated with ether and then with hot alcohol and filtered. Recrystallization from chloroform-methanol gives 1-(benzylthiocarbamoyl)-2-oxo-tetrahydroimidazole.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH2:10][CH:11]1[CH2:16][C:15]([CH3:18])([CH3:17])[N:14]([CH3:19])[C:13]([CH3:21])([CH3:20])[CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C(C)=CC=CC=1.C(Cl)(Cl)Cl>[Cl:3][C:2]1[N:1]=[C:8]([NH:10][CH:11]2[CH2:12][C:13]([CH3:21])([CH3:20])[N:14]([CH3:19])[C:15]([CH3:17])([CH3:18])[CH2:16]2)[N:7]=[C:5]([NH:10][CH:11]2[CH2:12][C:13]([CH3:20])([CH3:21])[N:14]([CH3:19])[C:15]([CH3:18])([CH3:17])[CH2:16]2)[N:4]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN1C(C)(C)CC(Nc2nc(Cl)nc(NC3CC(C)(C)N(C)C(C)(C)C3)n2)CC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.0 g of cyanuric chloride and 20.0 g of 4-amino-1,2,2,6,6-pentamethylpiperidine were dissolved in 100 ml of xylene, and the solution was stirred at room temperature for 1 hour. 50 ml of a saturated aqueous solution of potassium carbonate were then added to the resulting solution and the mixture was stirred for a further 2 hours at 60° C. At the end of this time, water and chloroform were added to the mixture, which was then allowed to stand at room temperature. The resulting crystals were filtered off and then recrystallized from benzene, to give the title compound in the form of crystals melting at 290° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18](Cl)[C:17]([CH2:21][C:22]([O:24]CC)=O)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH2:29])[CH3:28].C(O)(C)C>O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]3[CH2:21][C:22](=[O:24])[N:29]([CH2:27][CH3:28])[C:18]=3[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN
Reactant: CCOC(=O)Cc1cnc(N2CCN(Cc3ccccc3)CC2)nc1Cl
Solvent: CC(C)O
Solvent: O
Product: CCN1C(=O)Cc2cnc(N3CCN(Cc4ccccc4)CC3)nc21
Temperature: 120 °C
Yield: 46 %

Procedure:
A mixture of 1.41 g (3.76 mmol, Referential Example 71) of ethyl 2-(4-benzylpiperazino)-4-chloropyrimidine-5-acetate, 5 ml of ethylamine and 20 ml of isopropanol was placed in a pressure vessel, in which they were heated at 120° C. for 2 hours. The solvent was then driven off under reduced pressure. The residue was added with water, followed by extraction with chloroform. After drying the organic layer with MgSO4, it was concentrated. The residue was purified by silica gel column chromatography to obtain 0.58 of the above-identified compound (yield: 46%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1.CC(C)([O-])C.[K+]>CS(C)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)([O-:10])=[O:9]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A mixture of 1-fluoro-2-nitrobenzene (0.46 g, 3.3 mmol) and methyl 4-amino-benzoate (0.5 g, 3.3 mmol) was cooled in an ice-bath, treated dropwise with a solution of potassium tert-butoxide (0.5 g, 4.9 mmol) in DMSO, stirred at room temperature overnight, quenched with water at 0° C. and extracted with ethyl acetate. The extracts were combined, washed sequentially with water and brine, dried over Na2SO4 and concentrated under vacuum to afford the title compound in 56% yield, identified by NMR and mass spectral analyses. 1H NMR (400 MHz, DMSO-d6): 9.5 (s, 1H), 8.22 (d, J=8 Hz, 1H), 8.06 (d, J=8.4 Hz, 2H), 7.46 (d, J=4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 6.91 (m, 1H), 3.92 (s, 3H). LCMS (ESI+) 272 (MH+).
Reaction SMILES: C[N:2]1CCN(C2C=CC(NC3C4N(N=CN=4)C(C4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.Br[C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[CH:45][CH:44]=2)=[N:35][CH:34]=1.CC1(C)C(C)(C)OB([C:63]2[CH:64]=[C:65]3[C:69](=[CH:70][CH:71]=2)[C:68](=[O:72])[NH:67][CH2:66]3)O1>C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1.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>[NH3:2].[O:52]1[CH2:53][CH2:54][N:49]([C:46]2[CH:47]=[CH:48][C:43]([NH:42][C:36]3[C:37]4[N:38]([N:39]=[CH:40][N:41]=4)[C:33]([C:63]4[CH:64]=[C:65]5[C:69](=[CH:70][CH:71]=4)[C:68](=[O:72])[NH:67][CH2:66]5)=[CH:34][N:35]=3)=[CH:44][CH:45]=2)[CH2:50][CH2:51]1
Reactant: CC1(C)OB(c2ccc3c(c2)CNC3=O)OC1(C)C
Reactant: Brc1cnc(Nc2ccc(N3CCOCC3)cc2)c2ncnn12
Reactant: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
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: C1COCCO1
Product: N
Product: O=C1NCc2cc(-c3cnc(Nc4ccc(N5CCOCC5)cc4)c4ncnn34)ccc21
Yield: 79 %

Procedure:
This compound may be prepared using methods as described for Compound 6, step 4 using (5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-(4-morpholin-4-yl-phenyl)-amine (1.0 g, 2.67 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-1-one (see description for Compound 79) (1.03 g, 4.01 mmol) and Pd(PPh3)4 (0.77 g, 0.67 mmol) in 1.5M Na2CO3 (14.3 mL) and dioxane (40 mL). Purification by silica gel column chromatography eluting with DCM followed by 96:4 DCM:NH3 (7M in MeOH) affords the title compound (0.895 g, 79%). 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 3.12 (4H, m), 3.79 (4H, m), 4.51 (2H, s), 7.01 (2H, d), 7.84 (1H, d), 7.92 (2H, d), 8.01 (1H, s), 8.09 (1H, d), 8.23 (1H, s), 8.72 (1H, s), 8.73 (1H, s), 10.02 (1H, s). LCMS: Rt 2.51 min (97.8%), m/z (APCI) 428 (M+H)+.