Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[N:9][NH:10][C:4]=2[CH:3]=1.[C:15]1([C@H:21]([NH:23][C:24]([NH2:26])=[O:25])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(C)([O-])C.[K+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1COCC1>[CH3:14][S:11]([C:8]1[C:5]2[CH:6]=[N:7][C:2]([NH:26][C:24]([NH:23][C@@H:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:22])=[O:25])=[CH:3][C:4]=2[NH:10][N:9]=1)(=[O:13])=[O:12]
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Reactant: CS(=O)(=O)c1n[nH]c2cc(Cl)ncc12
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc(S(C)(=O)=O)c2cn1)c1ccccc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
6-Chloro-3-(methylsulfonyl)-1H-pyrazolo[4,3-c]pyridine (45 mg, 0.194 mmol), (R)-1-(1-phenylethyl)urea (38.3 mg, 0.233 mmol), and BrettPhos pre-catalyst (21.72 mg, 0.027 mmol) were taken up in THF (650 μL) in a 1.5 mL microwave vial. Potassium t-butoxide (1 M in THF, 583 μL, 0.583 mmol) was added and the vial was evacuated and back-filled with N2 (×3). The reaction mixture was stirred at 60° C. for 18 h. The crude reaction mixture was filtered through a Si-Thiol cartridge (6 mL, 500 mg) to remove excess Pd. The filtrate was concentrated in vacuo, dissolved in DMSO/MeOH (with a few drops of TFA), and purified by mass triggered, reverse phase prep-HPLC. The fractions containing pure product were concentrated in vacuo to afford (R)-1-(3-(methylsulfonyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. For C16H17N5O3S [M+1]+ 360. found 360. 1H NMR (500 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.92 (s, 1H), 7.87 (s, 1H), 7.50 (br s, 5H), 4.92-4.80 (m, 1H), 3.38 (s, 3H) 1.40 (d, J=7.0 Hz, 3H).
Reaction SMILES: C([Li])CCC.C(N[CH:10]([CH3:12])[CH3:11])(C)C.[Br:13][C:14]1C=C[C:17]2[O:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[O:21][C:16]=2[CH:15]=1.CI.Cl>O.O1CCCC1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[O:18][C:19]([F:24])([F:25])[C:20]([F:22])([F:23])[O:21][C:12]=2[C:10]=1[CH3:11]
Reactant: FC1(F)Oc2ccc(Br)cc2OC1(F)F
Reactant: CC(C)NC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Br)ccc2c1OC(F)(F)C(F)(F)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
Under nitrogen atmosphere, 11.7 ml of n-butyllithium (1.57 M-n-hexane solution) was dropwise added at −20° C. to a mixture of 1.85 g of diisopropylamine and 50 ml of tetrahydrofuran, and then the mixture was stirred at the same temperature for 30 minutes. 5.0 g of 6-bromo-2,2,3,3,-tetrafluoro-1,4-benzodioxane was dropwise added thereto at a temperature of at most −50° C., followed by stirring at the same temperature for 30 minutes. Then, 5.5 ml of methyl iodide was dropwise added thereto at a temperature of at most −70° C., and then the temperature was raised to room temperature, followed by a reaction for 15 hours. After completion of the reaction, the reaction mixture was put into water and then weakly acidified by an addition of hydrochloric acid. Then, the mixture was extracted with ethyl ether, and the extract was washed with water and dried over magnesium sulfate, followed by concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane) to obtain 3.40 g of oily 6-bromo-2,2,3,3,-tetrafluoro-5-methyl-1,4-benzodioxane. The NMR spectrum data of this product were as follows.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].O>C(Cl)(Cl)Cl>[Br:2][CH2:3][CH2:4][NH:5][C:14](=[O:15])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCBr
Reactant: O=C(Cl)OCc1ccccc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(NCCBr)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromoethylamine hydrobromide (120.0 g) in chloroform (1400 ml) was added triethylamine (204 ml), and thereto was added dropwise benzyl chloroformate (100 ml) under ice-cooling slowly. The mixture was stirred at 0° C. for one hour, and warmed to room temperature, and further stirred overnight. To the reaction mixture was added water, and the mixture was extracted twice with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and dried under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1) to give the title compound (110 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19](=[O:20])[N:11]3[CH2:12][CH2:13][CH2:14][CH:15]([C:16]([OH:18])=[O:17])[N:10]3[C:9]=2[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([S:27][CH3:28])[N:22]=2)=[CH:4][CH:3]=1.[N+](=[CH2:31])=[N-]>C(OCC)C.C(OCC)(=O)C.C(OCC)C>[CH3:31][O:17][C:16]([C@@H:15]1[CH2:14][CH2:13][CH2:12][N:11]2[C:19](=[O:20])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[C:9]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([S:27][CH3:28])[N:22]=3)[N:10]12)=[O:18]
Reactant: CSc1nccc(-c2c(-c3ccc(F)cc3)c(=O)n3n2C(C(=O)O)CCC3)n1
Reactant: C=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)[C@@H]1CCCn2c(=O)c(-c3ccc(F)cc3)c(-c3ccnc(SC)n3)n21
Reaction time: 0.08 h
Yield: 98 %

Procedure:
To a solution of 2-(4-fluorophenyl)-3-(2-methylsulfanylpyrimidin-4-yl)-1-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, 30, in diethyl ether/ethyl acetate (2.5:1, 7o mL) is added freshly generated diazomethane in diethyl ether (5 mL). The reaction is stirred for 5 minutes then quenched by the addition of HOAc (0.5 mL). The resulting solution is washed with NaHCO3, brine, dried, and concentrated in vacuo to afford 1 g (98% yield) of the desired product as a light yellow solid.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:22])=[C:17]([CH:21]=1)[C:18](O)=O>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:22])=[C:17]([CH2:18][C:9]2[S:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:11][CH:10]=2)[CH:21]=1
Reactant: c1ccc(-c2cccs2)cc1
Reactant: Cc1ccc(Br)cc1C(=O)O
Product: Cc1ccc(Br)cc1Cc1ccc(-c2ccccc2)s1

Procedure:
2-Phenylthiophene and 5-bromo-2-methylbenzoic acid obtained in Reference Example 4-(1) were treated in a manner similar to Reference Example 5 to give the target compound. APCI-Mass m/Z 343/345 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][NH:12]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:30](Cl)(=[O:33])[O:31][CH3:32]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][N:12]2[C:30]([O:31][CH3:32])=[O:33])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2cccc(C(C)(C)C)c2)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2cccc(C(C)(C)C)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.2 %

Procedure:
Methyl 2-(3-tert-butylphenyl)piperidine-4-carboxylate (2.56 g, 9.30 mmol) was dissolved in DCM (100 mL) and DIPEA (2.429 mL, 13.94 mmol) added followed by methyl carbonochloridate (0.9 mL, 11.43 mmol) at 0° C. The solution was stirred at room temperature for 1 h. The reaction mixture was washed with 1 M aq HCl (pH 4) followed by brine, satd NaHCO3. The organic phase was passed through a phase separator and evaporated to yield dimethyl 2-(3-tert-butylphenyl)piperidine-1,4-dicarboxylate (3.17 g, quant.) as a brown oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1>C(N)(C)C.O>[CH:6]([NH:7][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1)([CH3:8])[CH3:5]
Reactant: Fc1ccc(C#Cc2ccnc(Cl)n2)cc1
Solvent: CC(C)N
Solvent: O
Product: CC(C)Nc1nccc(C#Cc2ccc(F)cc2)n1
Temperature: 25 °C

Procedure:
A solution of 2-chloro-4-(4-fluoro-phenylethynyl)-pyrimidine (1 equiv.) in iso-propylamine (0.2 M) is heated at 35° C. for 24 h. The mixture is cooled to rt, diluted with water, and extracted with EtOAc. The organic layer is concentrated and the residue purified by column chromatography to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:15]1[CH2:20][CH2:19][S:18][CH2:17][CH2:16]1>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:15]2[CH2:20][CH2:19][S:18][CH2:17][CH2:16]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Br
Reactant: C1CSCCN1
Solvent: ClCCl
Product: O=C(O)c1cc(S(=O)(=O)N2CCSCC2)ccc1Br

Procedure:
This product is prepared by the reaction of 2-bromo-5-chlorosulfonyl benzoic acid with excess thiomorpholine in methylene chloride. The product, m.p. 195°-197.5° C., is purified by solution in aqueous sodium hydroxide, crystallization by acidifying the basic solution, and recrystallization from acetone-hexane.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:58]/[O:59][CH:60]([C:75]([O:77]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:76])[C:61]2[CH:66]=[CH:65][C:64]([O:67][C:68](=[O:70])[CH3:69])=[C:63]([O:71][C:72](=[O:74])[CH3:73])[CH:62]=2)/[C:27]([NH:29][C@@H:30]2[C:56](=[O:57])[N:32]3[C:33]([C:44]([O:46]CC4C=CC(OC)=CC=4)=[O:45])=[C:34]([CH:37]=[CH:38][C:39]4[CH:43]=[CH:42][S:41][N:40]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C([O-])=O>C(Cl)Cl.C1(OC)C=CC=CC=1>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:58]/[O:59][CH:60]([C:75]([OH:77])=[O:76])[C:61]2[CH:66]=[CH:65][C:64]([O:67][C:68](=[O:70])[CH3:69])=[C:63]([O:71][C:72](=[O:74])[CH3:73])[CH:62]=2)/[C:27]([NH:29][C@@H:30]2[C:56](=[O:57])[N:32]3[C:33]([C:44]([OH:46])=[O:45])=[C:34]([CH:37]=[CH:38][C:39]4[CH:43]=[CH:42][S:41][N:40]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1
Reactant: COc1ccc(COC(=O)C2=C(C=Cc3ccsn3)CS[C@@H]3[C@H](NC(=O)/C(=N\OC(C(=O)OC(c4ccccc4)c4ccccc4)c4ccc(OC(C)=O)c(OC(C)=O)c4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(C=Cc4ccsn4)CS[C@H]23)c2csc(N)n2)C(=O)O)cc1OC(C)=O
Yield: 82 %

Procedure:
After 400 mg of p-methoxybenzyl 7β-[(Z)-2-(2-tritylamino-4-thiazolyl)-2-[[(R S)-(diphenylmethoxycarbonyl)(3,4-diacetoxyphenyl)methoxy]imino]acetamido]-3-[2-(isothiazol-3-yl)vinyl]-3-cephem-4-carboxylate were dissolved in 4 ml of methylene chloride and 2 ml of anisole, 8 ml of trifluoroacetate was added therein under ice-cooling, and the reaction solution was reacted for 90 min. as it was. The residue obtained by evaporating off methylene chloride and trifluoroacetate was powdered by using ethyl ether. The powder obtained by filtering off was further added to 24 ml of trifluoroacetate under ice-cooling, and then 6 ml of water was added therein, and the reactants were reacted for 30 min. as they were, and further reacted for 2 hrs. at the room temperature. The residue obtained by evaporating off trifluoroacetate and water under the reduced pressure was powdered by adding ethyl ether and filtered off to give 190 mg of 7β-[(Z)-2-(2-amino-4-thiazolyl)-2-[ [(R S)-(carboxy)(3,4-diacetoxyphenyl)methoxy]imino]acetamido]-3-[2-(isothiazol-3-yl)vinyl]-3-cephem-4-carboxylic acid.trifluoroacetate.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@@H:14]([NH:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH2:15][CH2:16][CH3:17])[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:30]=[O:31])(=O)C.[F:32][C:33]1[C:38](O)=[C:37]([F:40])[C:36]([F:41])=[C:35]([F:42])[C:34]=1[F:43].CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@@H:14]([N:18]([CH:30]=[O:31])[O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH2:15][CH2:16][CH3:17])[C:11]([O:13][C:38]2[C:37]([F:40])=[C:36]([F:41])[C:35]([F:42])=[C:34]([F:43])[C:33]=2[F:32])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC[C@H](NOC1CCCCO1)[C@@H](CCCc1ccccc1)C(=O)O
Reactant: CC(=O)OC=O
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Product: CCC[C@@H]([C@@H](CCCc1ccccc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)N(C=O)OC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of (2R,3S)-2-(3-phenyl-1-propyl)-3-(2-tetrahydropyranyloxyamino)hexanoic acid (0.93 g, 2.66 mmol) in pyridine (2 mL) at 0° C. is added formic acetic anhydride (0.4 mL). The resulting solution is stirred at 0° C. for 1 h, concentrated in vacuo, and diluted with 11 mL of EtOAc. To the solution of crude acid is added pentafluorophenol (0.51 g, 2.79 mmol), NMM (0.28 g, 2.79 mmol) and dicyclohexylcarbodiimide (0.58 g, 2.79 mmol). The resulting solution is stirred at 23° C. for 20 h and is filtered. The filtrate is washed with 1 N hydrochloric acid, 1 M aqueous sodium carbonate solution, and saturated aqueous sodium chloride solution. The organic layer is dried over magnesium sulfate, concentrated, and purified by silica gel chromatography (elution with 9:1 hexanes-EtOAc) to provide pentafluorophenyl (2R,3S)-2-(3-phenyl-1-propyl)-3-(formyl-2-tetrahydropyranyloxyamino)hexanoate as an oil (0.84 g, 58% yield).
Reaction SMILES: [Li]C(C)(C)C.[C:6]1([NH:12][C:13]2[N:14]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=[CH:16][N:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:45]=[C:46]([O:50][CH3:51])[C:47]=1[O:48][CH3:49])[C:42](Cl)=[O:43]>C1COCC1>[C:6]1([NH:12][C:13]2[N:14]([C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:15]=[C:16]([C:42]([C:41]3[CH:45]=[C:46]([O:50][CH3:51])[C:47]([O:48][CH3:49])=[C:39]([O:38][CH3:37])[CH:40]=3)=[O:43])[N:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(Nc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c(Nc3ccccc3)n2)cc(OC)c1OC
Reaction time: 8 h
Yield: 43.6 %

Procedure:
At −78° C., t-BuLi in THF (1.7 M, 0.34 mL, 0.58 mmol) was added to a solution of trityl protected compound (d) (116 mg, 0.289 mmol) in THF. Then 3,4,5-trimethoxybenzoyl chloride (66.5 mg, 0.289 mmol) was added and stirred overnight. The reaction mixture was quenched with saturated NH4Cl, and dried with MgSO4. Filtration and evaporation of the solvent followed by chromatography afforded compound (e) (75 mg, 43.7%). 1H NMR (500 MHz, CDCl3) δ 7.55-7.41 (m, 5H), 7.32 (s, 1H), 7.28-7.18 (m, 15H), 6.94 (s, 2H), 3.78 (s, 6H), 3.70 (s, 3H). MS: 594.2 (M−H)−; 596.3 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].CN(C)C=O.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C@:21]1([O:45][CH2:44]1)[C@H:22]([N:24]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]([F:42])([F:41])[CH:38]([F:40])[F:39])=[CH:31][CH:30]=2)[C:25]1=[O:43])[CH3:23]>O>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C@@:21]([OH:45])([CH2:44][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)[C@H:22]([N:24]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH2:36][C:37]([F:41])([F:42])[CH:38]([F:39])[F:40])=[CH:33][CH:34]=2)[C:25]1=[O:43])[CH3:23]
Reactant: c1nc[nH]n1
Reactant: C[C@@H](N1CCN(c2ccc(OCC(F)(F)C(F)F)cc2)C1=O)[C@@]1(c2ccc(F)cc2F)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](N1CCN(c2ccc(OCC(F)(F)C(F)F)cc2)C1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 0.41 g of 1H-1,2,4-triazole, 0.19 g of 60% sodium hydride in oil and 12 ml of dimethylformamide was stirred at room temperature for 20 minutes, and added with 0.85 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolidinone obtained in Step 3 and the resultant mixture was heated at 60° C. for 4 hours. After cooling, 20 ml of water was added to the reaction mixture and the mixture was extracted with 80 ml of ethyl acetate. The extract was washed with 20 ml of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient eluent: hexane:ethyl acetate=1:2→1:5) to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2,2,3,3-tetrafluoropropoxy) phenyl]-2-imidazolidinone (Compound B) as a colorless powder.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])=[O:12])=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:5]2=[N:6][CH:7]=1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)=[N:28]1.CC(C)([O-])C.[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:16][CH2:15][C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]([CH:36]4[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]4)=[N:28]3)[N:3]=2)[N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=1)=[O:12])([CH3:18])[CH3:17]
Reactant: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3ccccc23)CC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3nc(C4CCN(C(=O)OC(C)(C)C)CC4)c4ccccc43)nc12
Temperature: 125 °C
Yield: 88.2 %

Procedure:
To a stirred solution of 2-bromo-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 338 μmol), tert-butyl 4-(1H-indazol-3-yl)piperidine-1-carboxylate (102 mg, 338 μmol) in dioxane (2.5 mL) was added sodium tert-butoxide (71.5 mg, 744 μmol) and bis(tri-tert-butylphosphine)palladium(0) (17.3 mg, 33.8 μmol). The mixture was degassed then heated in sealed tube at 125° C. for 15 h. The mixture was cooled, filtered through celite, and the filter cake washed with ethyl acetate. The combined filtrates were concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave tert-butyl 4-(1-(7-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1H-indazol-3-yl)piperidine-1-carboxylate (198 mg, 88%).
Reaction SMILES: C([Li])CCC.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4:10].C[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(OCC)C.C(Cl)Cl>[CH-:12]1[CH:13]=[CH:14][CH:15]=[CH:16]1.[CH-:12]1[CH:13]=[CH:14][CH:15]=[CH:16]1.[Zr+2:10]
Reactant: [Zr+4]
Reactant: CCCCCC
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: ClCCl
Product: [Zr+2]
Product: c1cc[cH-]c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
10 ml (25 mmol) of a 2.5M solution of butyllithium in hexane were added to a solution of 3.1 g (8.3 mmol) of the ligand system a5 in 30 ml of diethyl ether at room temperature under Ar protection. An orange coloration initially occurred, and after 45 minutes the solution became cloudy. After the mixture had been stirred overnight, 10 ml of hexane were added to the now beigecolored suspension and the mixture was filtered over a G3 frit. The precipitate was washed with 20 ml of hexane and dried under an oil pump vacuum for a long period of time. The virtually colorless powder was added rapidly to a suspension of 1.8 g (7.72 mmol) of zirconium tetrachloride in 30 ml of methylene chloride at -78° C. The mixture was warmed to room temperature in the course of 1-2 hours and, after stirring at room temperature for 30 minutes, was evaporated completely. The residue was dried under an oil pump vacuum and was first washed with 60 ml of hexane. The product was then isolated by extraction several times with a total of 180 ml of toluene. The combined extracts were concentrated and left to crystallize at -35° C. The first fraction gave 0.76 g of zirconocene A in the pure racemic form (orange-colored crystals ). The subsequent fractions contained an increasing amount of the meso form. 1.78 g (43% ) of compound A were isolated in total. 1H-NMR (CDCl3) of the racemate: 6.85-7.55 (m,6,aromatic H), 6.80 (s,2,β-H), 2.72 (q,4,CH2), 2.20 (s,6,CH3), 1.30 (t,6,CH3), 1.27 (s,6,Si-CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH2:11].[CH:16](OCC)(OCC)OCC.[CH3:26][C:27]1([CH2:32][NH2:33])OCCO1>[Ti](Cl)(Cl)(Cl)Cl>[CH3:26][C:27]1[N:11]([C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:16]=[N:33][CH:32]=1
Reactant: Nc1ccccc1Cc1ccccc1Cl
Reactant: CC1(CN)OCCO1
Reactant: CCOC(OCC)OCC
Agent: Cl[Ti](Cl)(Cl)Cl
Product: Cc1cncn1-c1ccccc1Cc1ccccc1Cl

Procedure:
In the manner given in Example 3, α-(o-chlorophenyl)-o-toluidine is reacted with triethyl orthoformate, the resulting oil is heated with 2-methyl-2-(aminomethyl)-1,3-dioxolane, and the resulting product treated with titanium tetrachloride to give 5-methyl-1-[α-(o-chlorophenyl)-o-tolyl]imidazole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[CH3:17]O>>[CH3:17][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=1[Br:11]
Reactant: Nc1ccc(Br)c(C(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(N)ccc1Br
Temperature: 25 °C

Procedure:
5-Amino-2-bromobenzoic acid (10.8 g, 50 mmol) was dissolved in methanol (100 mL). Conc. H2SO4 (2 mL) was added slowly and the reaction mixture heated to reflux for 4 h. The mixture was concentrated and the residue was allowed to cool to room temperature. It was poured over crushed ice. The organic product was extracted using diethyl ether (2×200 mL). The organic extract was washed with water, 10% aqueous NaHCO3, dried (anhydrous Na2SO4) and concentrated to get the title compound.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[OH:16][C@H:17]([C@H:19]1[CH2:23][NH:22][C:21](=[O:24])[CH2:20]1)[CH3:18].Cl[C:26]1[C:27]2[N:28]([N:42]=[CH:43][CH:44]=2)[CH:29]=[C:30]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=2)[N:31]=1>CN(C=O)C>[CH3:41][O:40][C:34]1[CH:33]=[C:32]([C:30]2[N:31]=[C:26]([O:16][C@@H:17]([C@H:19]3[CH2:23][NH:22][C:21](=[O:24])[CH2:20]3)[CH3:18])[C:27]3[N:28]([N:42]=[CH:43][CH:44]=3)[CH:29]=2)[CH:37]=[CH:36][C:35]=1[O:38][CH3:39]
Reactant: COc1ccc(-c2cn3nccc3c(Cl)n2)cc1OC
Reactant: C[C@H](O)[C@H]1CNC(=O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(-c2cn3nccc3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Temperature: 25 °C
Reaction time: 0.13 h

Procedure:
A solution of 1M sodium bis(trimethylsilyl) amide in THF (0.18 mL, 0.18 mmol) was added to a solution of (R)-4-((R)-1-hydroxyethyl)pyrrolidin-2-one 1.18 (22.9 mg, 0.18 mmol) in DMF (1 mL) at room temperature, forming a white precipitate. After 8 minutes, a solution of 4-chloro-6-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrazine 5.03 (34 mg, 0.12 mmol) in DMF (1.1 mL) was added under argon. Dark brown solution stirred at room temperature overnight. Mixture was quenched by addition of water, brine and ethyl acetate and layers were separated. Aqueous was extracted with ethyl acetate and combined organic layers were washed with 50% brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Resulting residue was purified by silica gel column chromatography (0-10% methanol in dichloromethane) to yield (R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrazin-4-yloxy)ethyl)pyrrolidin-2-one 5.04.