Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClN1C(=O)CCC1=O.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[N:16][OH:17])[CH:10]=1.[CH2:18]([C:23]1[N:24]([CH2:51][CH2:52][CH3:53])[N:25]=[C:26]2[C:35]=1[C:34]1[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=1[N:28]=[C:27]2[N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:19][CH2:20][C:21]#[CH:22].C(N(CC)CC)C>C1COCC1.ClCCl>[CH2:51]([N:24]1[C:23]([CH2:18][CH2:19][CH2:20][C:21]2[O:17][N:16]=[C:15]([C:11]3[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=3)[CH:22]=2)=[C:35]2[C:26]([C:27]([N:36]([C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])[C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])=[N:28][C:29]3[CH2:30][CH2:31][CH2:32][CH2:33][C:34]=32)=[N:25]1)[CH2:52][CH3:53]
Reactant: ON=Cc1cccnc1
Reactant: C#CCCCc1c2c3c(nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2nn1CCC)CCCC3
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3c(c2c1CCCc1cc(-c2cccnc2)no1)CCCC3
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.9 %

Procedure:
Under a nitrogen atmosphere, N-chlorosuccinimide (2.1 g, 16 mmol) was added to a solution of 3-pyridine aldoxime (2.0 g, 16 mmol) in THF (10 mL). The solution was stirred at ambient temperature for 4 hours. A solution of di(tert-butyl) 1-pent-4-ynyl-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (4.00 g, 8.05 mmol), prepared as described in Example 615, and anhydrous triethylamine (2.5 mL, 18 mmol) in THF (10 mL) was added and the reaction solution was heated at 60° C. for 18 hours. The reaction solution was concentrated under reduced pressure to provide a black oil. The oil was dissolved in dichloromethane, washed sequentially with potassium carbonate, water, and brine, dried over sodium sulfate, and filtered. The filtrate was purified by column chromatography (silica gel, elution with a gradient of 20-80% ethyl acetate in hexanes) to provide 1.0877 g of di(tert-butyl) 2-propyl-1-[3-(3-pyridin-3-ylisoxazol-5-yl)propyl]-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16](=[O:18])[CH3:17].[Br:19]Br.[OH-].[Na+]>CC(OC)(C)C.C(O)(=O)C>[Br:19][CH2:17][C:16]([C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:7][C:2]=1[Cl:1])=[O:18]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: O=C(CBr)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[2-chloro-4-(4-chlorophenoxy)phenyl]ethanone (1000 g) was dissolved in MTBE (5000 mL) and a solution of bromine (563 g) in glacial acetic acid (400 mL) was added dropwise at room temperature. After completion of the addition the mixture was stirred for 1 h at room temperature and the pH was adjusted to 7-8 by addition of 10% NaOH solution. The organic layer was separated, extracted twice with MTBE and the combined organic phases were washed with sat. NaHCO3 solution (1×) and brine (2×). The solvent was evaporated and the crude product was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([OH:19])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[O:33]([NH2:35])[CH3:34].O>C(Cl)Cl>[CH3:34][O:33][NH:35][C:17](=[O:19])[CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8]
Reactant: CON
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: CONC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A warm solution of 2-[(2,6-dichlorophenyl)amino]-benzeneacetic acid (2.03 g; 7 mmol) in CH2Cl2 (100 mL) is treated with 1,1'-carbonyl-diimidazole (1.75 g; 11 mmol) and the mixture is stirred at room temperature for 5.0 minutes when a clear solution is obtained. The solution is then treated with methoxylamine hydrochloride (1.50 g; 18 mmol) and the reaction mixture stirred at room temperature for 108 hours. It is then decomposed with water, extracted with CH2Cl2, dried over Na2SO4 and then evaporated to dryness to give a solid. Fractional recrystallization of the crude product from a mixture of toluene-CH2Cl2 gives off-white crystalline solid (1.27 g; 55.8%); mp 177°-178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH2:36]([NH2:40])[CH2:37][CH2:38][CH3:39].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:36]([NH:40][C:28]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[CH:8][C:2]=1[Cl:1])=[O:34])[CH2:37][CH2:38][CH3:39]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50 mg) was dissolved in chloroform (5 ml) and triethylamine (1 ml), and a solution of triphosgene (45 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, butylamine (22 μl) was added to the reaction solution, and the mixture was stirred at room temperature for additional 30 min. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 30 mg (yield 46%) of the title compound.
Reaction SMILES: [C:1]([CH:4]([CH:10]([CH3:12])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2].[Br:13]Br.C(Cl)(Cl)Cl.C(OCC)(=O)C>O>[Br:13][CH2:2][C:1](=[O:3])[CH:4]([CH:10]([CH3:11])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C(C)=O)C(C)C
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C(=O)CBr)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 2-acetyl-3-methylbutanoate (5.10 g, 29.6 mmol) in water (10 mL) at 0° C. was added bromine (1.53 mL, 29.6 mmol) dropwise over 2 h. Chloroform (30 mL) was added and the resulting solution was stirred at rt for 16 h. Ethyl acetate (300 mL) was added to the reaction solution and the organic phase was dried over sodium sulfate and concentrated to give the title compound. 1HNMR (500 MHz, CDCl3), δ4.300-4.282 (m, 2H), 2.601-2.575 (m, 1H), 2.406 (s, 2H), 1.331-1.303 (t, J=7.1 Hz, 3H), 1.085-1.072 (d, J=6.5 Hz, 3H), 1.048-1.035 (d, J=6.7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].S(Cl)(Cl)=O.C(Cl)Cl.[NH:22]1[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]1>CN(C=O)C>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:8]=2)=[O:13])[CH2:23]1
Reactant: O[C@@H]1CCNC1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Yield: 178.2 %

Procedure:
A solution of lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate (15.0 g, 70.8 mmol), thionyl chloride (53.1 mL, 106.2 mmol), CH2Cl2 (600 ml), and DMF (6 ml) was heated to reflux. After 3 h the resulting yellow solution was concentrated under reduced pressure, and the residue was suspended in CH2Cl2 (500 mL). (3R)-pyrrolidin-3-ol (2.3 g, 26.2 mmol) was then added dropwise. After 12 h the reaction was quenched with 1N NaOH (500 mL), the layers were separated, and the aqueous layer was extracted with 2×500 mL CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, then concentrated under reduced pressure. The resulting solid was triturated with Et2O then collected by filtration to give a white solid (13.2 g, 70%). MS: 283.2/285.2 (MH+); HPLC Rf: 3.49 min.; HPLC purity: 99%.
Reaction SMILES: [N:1]#[N:2].[CH3:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([S:14]([NH:17][C@H:18]([C:26]([OH:28])=O)[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[NH:25])[NH2:24])(=[O:16])=[O:15])=[CH:11]2)=[CH:6][CH:5]=1.C(OCC)C.S(Cl)([Cl:36])=O>>[N:1]#[N:2].[ClH:36].[CH3:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([S:14]([NH:17][C@H:18]([C:26]([Cl:36])=[O:28])[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[NH:25])[NH2:24])(=[O:16])=[O:15])=[CH:11]2)=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cc2c1
Agent: N#N
Solvent: CCOCC
Product: Cc1ccc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)cc2c1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 2.5 g of N2 -(7-methyl-2-naphthalenesulfonyl)-L-arginine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold dry diethyl ether resulted in a precipitate which was collected by filtration and washed several times with dry diethyl ether to give N2 -(7-methyl-2-naphthalenesulfonyl)-L-arginyl chloride hydrochloride.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[CH2:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH2:35][CH3:36]>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:40]5[CH2:41][CH2:42][N:37]([CH2:34][CH2:35][CH3:36])[CH2:38][CH2:39]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCCN1CCNCC1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Agent: OC1CCNC1
Product: CCCN1CCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)CC1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with 1-propylpiperazine. A yellow solid 135 was obtained (0.033 g, 64%). 1H-NMR (CDCl3, 400 MHz) δ 1.03 (t, J=7.3 Hz, 3H), 1.84-1.92 (m, 2H), 2.30-2.52 (br, 8H), 2.98-3.03 (m, 2H), 4.28-4.34 (m, 4H), 6.87 (s, 1H), 6.94 (d, J=1H), 7.01 (d, J=5.8 Hz, 1H), 7.04 (dd, J=2.2 Hz, 8.4 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.82 (s, 1H), 8.26 (d, J=5.9 Hz, 1H), MS (APCI) m/z 516 (M+H)+.
Reaction SMILES: [Cl-].[CH3:2][NH2+:3][CH3:4].[CH2:5]=O.[C:7]([N:10]1[CH2:15][CH2:14][N:13]2[CH:16]=[CH:17][CH:18]=[C:12]2[CH2:11]1)(=[O:9])[CH3:8].N>O>[C:7]([N:10]1[CH2:15][CH2:14][N:13]2[C:16]([CH2:2][N:3]([CH3:5])[CH3:4])=[CH:17][CH:18]=[C:12]2[CH2:11]1)(=[O:9])[CH3:8]
Reactant: C=O
Reactant: CC(=O)N1CCn2cccc2C1
Reactant: C[NH2+]C
Agent: N
Agent: [Cl-]
Solvent: O
Product: CC(=O)N1CCn2c(CN(C)C)ccc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.5 %

Procedure:
A mixture of 1.35 g of dimethylammonium chloride, 1.24 g of a 40% solution of formaldehyde, and 2.45 g of 2-acetyl-1,2,3,4-tetrahydropyrrolo-[1,2-a]-pyrazine was stirred for 4 hours at room temperature. 10 ml of water, alkalized with a 25% solution of ammonia, was added to the reaction mass and the product was extracted with benzene. Benzene was removed by distillation and the residue was distilled under vacuum to give 1.7 g (51.5%) of the title compound. The boiling point was 177°-178° C. at 1 mm Hg. Nmr (CDCl3): δ2.23 (s) (9H, CH3); 3.38 (s) (2H, CH2N); 3.8-4.2 (m) (4H, 3,4-CH2); 4.7 (s) (2H, 1-CH2); 5.8-5.95 (m) (1H, 7-H); 5.95-6.1 (m) (1H, 8-H). Anal. calculated for C12H19N3O: C 65.13%; H 8.65%; N 18.99%; and found: C 65.36%; H 8.76%; N 19.21%.
Reaction SMILES: [CH3:1][C:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:8]=32)[S:4][CH:3]=1.[CH3:18][I:19]>CC(C)=O>[I-:19].[CH3:1][C:2]1[N:9]2[C:5](=[N+:6]([CH3:18])[C:7]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][C:8]=32)[S:4][CH:3]=1
Reactant: CI
Reactant: Cc1csc2nc3ccc(C(F)(F)F)cc3n12
Solvent: CC(C)=O
Product: Cc1csc2n1c1cc(C(F)(F)F)ccc1[n+]2C
Product: [I-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
375 mg (1.46 mmol) of 3-methyl-6-(trifluoromethyl)[1,3]thiazolo[3,2-a]benzimidazole 5a were solubilised in acetone (15 mL), then CH3I (10 eq, 0.9 mL) was added and the solution stirred at r.t. for 12 h. 3,9-dimethyl-6-(trifluoromethyl)[1,3]thiazolo[3,2-a][3,1]benzimidazol-9-ium iodide 6a was recovered by evaporation of the solvent (orange powder, 570 mg, 98%). Mp=>270° C.; 1H NMR (300 MHz, DMSO-d6) δ=2.94 (3H, d, J=1.2, CH3), 4.18 (3H, s, NH3), 7.51 (1H, q, J=1.2, H5), 8.13-8.17 (1H, m, Ar), 8.28-8.21 (1H, m, Ar), 8.52-8.56 (1H, m, Ar); 13C NMR (75 MHz, DMSO-d6) δ=13.44, 33.35, 111.68 (q, J=4), 112.76, 113.98, 123.59 (q, J=4), 123.95 (q, J=272), 124.08 (q, J=33), 126.48, 133.42, 138.76, 157.50; HRMS m/z C12H10F3N2S [M−I]+ calcd: 271.0511, found: 271.0513.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[N:16]1[N:17]=[CH:18][CH2:19][CH:20]=1.[C:21]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O.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>[CH3:21][N:16]1[CH:20]=[C:19]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:18]=[N:17]1
Reactant: C1=NN=CC1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cc1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(Oc3ccc(N)cc3)ccn2)cn1
Temperature: 90 °C
Yield: 82.1 %

Procedure:
4-(2-Chloro-pyridin-4-yloxy)-phenylamine (0.7 g, 3.2 mmol), 1-methyl-4-(4,4,5,5-tetramethyl)-[1,3,2]dioxaborolan-2-yl)-4H-pyrazole (1.0 g, 4.8 mmol), Cs2CO3 (4.0 g, 12.3 mmol) and Pd(PPh3)4 (0.45 g, 0.4 mmol) were combined in a mixture of DMF and water (3:1, 20 mL). The reaction mixture was degassed, blanketed with argon and heated to 90° C. overnight. The reaction mixture was diluted with water and extracted with EtOAc (3×50 mL). The combined organics were washed with saturated brine, dried (MgSO4), concentrated in vacuo and purified by silica gel chromatography to provide 4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzenamine (0.7 g, 74% yield). 1H NMR (300 MHz, DMSO-d6), δ 8.29 (d, J=5.7 Hz, 1 H), 8.19 (s, 1 H), 7.90 (s, 1 H), 7.10 (d, J=2.4 Hz, 1 H), 6.83 (d, J=8.7 Hz, 2 H), 6.62 (d, J=8.7 Hz 2 H), 6.52 (dd, J=2.4, 5.7 Hz, 1 H), 5.10 (s, 2 H), 3.84 (s, 3 H); MS (ESI) m/z: 267.3 (M+H+)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[OH:44])O1.C(=O)([O-])[O-].[K+].[K+].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.O>[OH:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4O)nccc3c2)cc1

Procedure:
To a microwave vial charged with 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate JJJ) (100 mg, 0.224 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (49 mg, 0.224 mmol), potassium carbonate (155 mg, 1.121 mmol) and Pd(Ph3P)4 (26 mg, 0.022 mmol) was added Dioxane (1120 μl) and Water (374 μl) and irradiated at 100° C. for 30 min affording conversion to desired product as the primary species. The organic layer was decanted, the aqueous rinsed with EtOAc and the combined organics dried under reduced pressure. The crude material will be used as is for subsequent reactions. m/z (ESI) 504.0 (M+H)+
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]([CH3:4])[CH3:3].[CH3:7][O:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=1>C1COCC1>[OH:17][CH:16]([C:13]1[CH:12]=[CH:11][C:10]([C:9]([O:8][CH3:7])=[O:18])=[CH:15][CH:14]=1)[CH2:1][CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C[Mg]Br
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)CC(C)C)cc1
Temperature: -40 °C

Procedure:
In a 22 L reactor methyl-4-formylbenzoate (500 g) is dissolved in THF (5 L). The solution is cooled to −40° C., and isobutylmagnesium bromide (2.0 M in Et2O, 1.67 L) is added by addition funnel, maintaining the internal temperature less than −20° C. The reaction is followed by HPLC and when the amount of methyl-4-formylbenzoate is found to be less than 1%, the reaction is quenched with MeOH (148 mL) while maintaining the internal temp below 2° C. The reaction is charged with 5 M HCl (700 mL) while maintaining the internal temp below 10° C. Transfer the resultant biphasic mixture to a 12 L With bottom valve, rinsing with 300 mL of heptane. The resulting layers are separated and the organic layer is washed with 1 M HCl (500 mL). The aqueous layers are combined and extracted with tert-butyl methyl ether (500 mL). The combined organic extracts are concentrated in vacuo. The resulting residue is diluted with heptane (800 mL) and concentrated in vacuo to dry the material azeotropically. The resulting oil is purified by silica gel chromatography to give 246.3 g (37%) of the desired carbinol as a yellow oil that solidifies on standing in the refrigerator to a white waxy solid. 1H NMR (500 MHz, CDCl3): δ 8.0 (d, 2H), 7.4 (d, 2H), 4.8 (dd, 1H), 3.9 (s, 3H), 1.85 (s, 1H), 1.71 (m, 2H), 1.48 (m, 1H), 0.95 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[Br:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][O:12]1>>[BrH:9].[CH3:7][C:5]1[N:6]([CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)[C:2](=[NH:1])[S:3][C:4]=1[CH3:8]
Reactant: Cc1nc(N)sc1C
Reactant: BrCC1CCCO1
Product: Br
Product: Cc1sc(=N)n(CC2CCCO2)c1C

Procedure:
A mixture of 2-amino-4,5-dimethylthiazole and 2-(bromomethyl)tetrahydrofuran were processed using the method described in Example 12A to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.43-1.64 (m, 1H) 1.73-2.00 (m, 3H) 2.17 (s, 3H) 2.19 (s, 3H) 3.53-3.68 (m, 1H) 3.71-3.85 (m, 1H) 3.91-4.17 (m, 3H) 9.34 (s, 1H),), MS (DCI/NH3) m/z 212 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[O-:10][C:11]#[N:12].[Na+].[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25])([O:16][CH3:17])=[O:15]>C(#N)C.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:11]([NH:12][S:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:14]([O:16][CH3:17])=[O:15])(=[O:26])=[O:25])=[O:10])[N:3]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Reactant: N#C[O-]
Reactant: Cc1cc(C)nc(N)n1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(C)n1
Temperature: 25 °C

Procedure:
A slurry of 7.0 grams (0.057 moles) of 4,6-dimethyl-2-pyrimidinamine, 6.0 grams (0.092 moles) sodium cyanate, and 13.5 grams (0.057 moles) 2-carbomethoxybenzenesulfonyl chloride in 60 ml acetonitrile was stirred 1 hour at reflux (81°). The reaction was diluted with 60 ml water, allowed to cool to room temperature and filtered. The solid was washed with 20 ml water and dried. There was obtained 16.0 grams (77.0% of theory) of the title compound. The product was 98% pure as assayed by high pressure liquid chromatography. The m.p. and IR spectrum of the title compound were identical to those of an authentic sample prepared as described in U.S. Pat. No. 4,394,506.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:30][CH:31]1[C:57](=[O:58])[N:33]2[C:34]([C:54]([OH:56])=[O:55])=[C:35]([CH2:38][S:39][C:40]3[S:41][C:42]([CH2:45][NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[N:43][N:44]=3)[CH2:36][S:37][C@H:32]12.C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([NH:30][CH:31]2[C:57](=[O:58])[N:33]3[C:34]([C:54]([OH:56])=[O:55])=[C:35]([CH2:38][S:39][C:40]4[S:41][C:42]([CH2:45][NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[N:43][N:44]=4)[CH2:36][S:37][C@H:32]23)=[O:12])[N:8]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: CC(C)(C)OC(=O)NCc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CNC(=O)OC(C)(C)C)s3)CS[C@H]12)c1csc(NC=O)n1
Yield: 89.6 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetic acid (syn isomer, 2 g.), N,N-dimethylformamide (0.45 g.), phosphoryl chloride (1.03 g.), 7-amino-3-(5-tert-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (2.6 g.), trimethylsilylacetamide (5.9 g.) and bis(trimethylsilyl)acetamide (3.4 g.) and ethyl acetate (50 ml.) were treated in a similar manner to that of Example 6-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-(5-tert-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 4.0 g.).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[C:6]([CH3:21])[CH:5]=[C:4]([N+:22]([O-])=O)[N:3]=1.[NH4+].[Cl-]>CO.C1COCC1.CCOC(C)=O.[Zn]>[CH3:21][C:6]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[C:2]([CH3:1])[N:3]=[C:4]([NH2:22])[CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])nc(C)c1Oc1ccnc(-c2cnn(C)c2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(N)nc(C)c1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
A 0° C. mixture of 2,4-dimethyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-nitropyridine (285 mg, 0.876 mmol) and NH4Cl (1.87 g, 35 mmol) in MeOH (5 mL) and THF (5 mL) was treated portion-wise with zinc dust (573 mg, 8.76 mmol), allowed to warm to RT and stirred overnight. The mixture was diluted with EtOAc, warmed slightly, the solids removed via filtration through diatomaceous earth and washed with EtOAc. The filtrate was concentrated to dryness and purified via silica gel chromatography (MeOH/EtOAc) to afford 4,6-dimethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (156 mg, 60%) as a white amorphous solid. 1H NMR (400 MHz, DMSO-d6): δ 8.30 (d, J=5.7 Hz, 1H), 8.23 (s, 1H), 7.93 (s, 1H), 7.10 (d, J=2.4 Hz, 1H), 6.44 (dd, J=5.7, 2.4 Hz, 1H), 6.22 (s, 1H), 5.81 (s, 2H), 3.84 (s, 3H), 2.02 (s, 3H), 1.92 (s, 3H); MS (ESI) m/z: 296.1 (M+H+).