Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Br[CH:11]([Cl:14])[CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:14][CH2:11][CH2:12][CH2:13][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: CCC(Cl)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCCCCl)cc1

Procedure:
A mixture of 4-cyanophenol, 125.0 g (1.05 mole), bromochloropropane, 189.0 g (1.2 mole) and potassium carbonate, 145.0 g (1.05 mole) was heated overnight at reflux in 750 ml of acetone. The reaction mixture was filtered and stripped to dryness. The resulting residue was dissolved in chloroform and extracted with 5% sodium hydroxide. Removal of chloroform gave an oil which crystallized to a white solid. A 5-g sample was recrystallized from isopropyl ether. This furnished 1.22 g (24.4%) of white solid, m.p. 40°-44° C. which contained a dimer impurity.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([S:6][C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:24][N:25]1[C:29]([C:30](Cl)=[O:31])=[C:28]2[CH:33]=[C:34]([CH3:36])[CH:35]=[C:27]2[NH:26]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([S:6][C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH:12][C:30]([C:29]3[N:25]([CH3:24])[NH:26][C:27]4=[CH:35][C:34]([CH3:36])=[CH:33][C:28]=34)=[O:31])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Sc2ccc(CN)cc2)cc1
Reactant: Cc1cc2[nH]n(C)c(C(=O)Cl)c-2c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(Sc2ccc(CNC(=O)c3c4cc(C)cc-4[nH]n3C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.7 %

Procedure:
To a stirred mixture of 4-(4-methylthiophenoxy)benzylamine (124 mg, 0.505 mM), triethylamine (61 mg, 0.60 mM) and toluene (20 ml) was added dropwise a solution (10 ml) of 2,5-dimethylcyclopenta[1,2-c]-pyrazole-3-carbonyl chloride(100 mg, 0.503 mM) in toluene at 0°-10° C., and the mixture was stirred for 3 h at the room temperature. The mixture was poured into ice water, and the mixture was extracted with toluene. The extract was washed with saturated sodium hydrogen carbonate solution, water, saturated ammonium chloride solution and brine, dried with magnesium sulfate, and concentrated in vacuo. The residue was chromatographed over silica gel to give N-[4-(4-methylthiophenoxy)benzyl]-2,5-dimethylcyclopenta[1,2-c]pyrazole-3-carboxamide (138 mg, 67%) as colorless crystals, m.p. 138.0° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:4].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:22][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[N:7][NH:8]2)=[CH:13][CH:12]=1
Reactant: NC1CCCCC1
Reactant: O=C(CCl)Nc1n[nH]c2cc(Cl)ccc12
Solvent: CC#N
Product: O=C(CNC1CCCCC1)Nc1n[nH]c2cc(Cl)ccc12

Procedure:
The process is performed as in Example 75, starting with 500 mg of 2-chloro-N-(6-chloro-1H-indazol-3-yl)acetamide, 15 cm3 of acetonitrile and 0.7 cm3 of cyclohexylamine. The reaction medium is refluxed for 2 hours and then concentrated to dryness under reduced pressure (2 kPa; 50° C.); the crude product obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a methylene chloride/methanol/aqueous ammonia mixture (97/2.5/0.25 by volume). The fractions containing the expected product are combined and the residue is taken up in 20 cm3 of diisopropyl ether, filtered off and dried under reduced pressure (90 Pa; 45° C.) to give 492 mg of N-(6-chloro-1H-indazol-3-yl)-2-(cyclohexylamino)acetamide in the form of a white powder melting at 170° C.
Reaction SMILES: Cl[C:2]([C:16]1[N:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[N:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([NH:5][S:6]([CH3:9])(=[O:8])=[O:7])=[O:4].C(=O)(O)[O-:27].[K+]>O>[CH3:25][O:24][C:18]1[CH:19]=[C:20]([O:22][CH3:23])[N:21]=[C:16]([C:2]([OH:27])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]([NH:5][S:6]([CH3:9])(=[O:8])=[O:7])=[O:4])[N:17]=1
Reactant: O=C([O-])O
Reactant: COc1cc(OC)nc(C(Cl)(C(=O)NS(C)(=O)=O)c2ccccc2)n1
Agent: [K+]
Solvent: O
Product: COc1cc(OC)nc(C(O)(C(=O)NS(C)(=O)=O)c2ccccc2)n1
Reaction time: 72 h
Yield: 94.5 %

Procedure:
2-Chloro-2-(4,6-dimethoxypyrimidin-2-yl)-N-methanesulfonyl-2-phenylacetamide (0.5 g) was stirred at room temperature with potassium bicarbonate (0.2 g) in water (10 ml) for 2 hours, by which time all was in solution. After standing for 3 days, the solution was washed with ether (twice) and acidified with hydrochloric acid. Ether extraction (3 times), washing with water (twice), drying over magnesium sulfate and evaporation under vacuum gave 0.45 g of the desired product as a yellow glass. This glass slowly crystallised to a solid, mp 94°-6° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[N:7]=[C:6]([O:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: COc1ccc(O)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Product: COc1ccc(Oc2nc(Cl)ncc2F)cc1

Procedure:
Using an analogous method to that described in Method 28, but starting from 2,4-dichloro-5-fluoropyrimidine and 4-methoxyphenol, the product was obtained. NMR: 3.84 (s, 3H), 6.79-7.00 (m, 2H), 7.06-7.18 (m, 2H), 8.31-8.36 (m, 1H); MS (M+): 254, 256.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH2:26][CH:27]=[CH2:28])=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C1C=CC=CC=1.CC#N.CC#N.Cl[Pd]Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([CH:26]=[CH:27][CH3:28])=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: C=CCc1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: Cl[Pd]Cl
Solvent: CC#N
Solvent: c1ccccc1
Product: CC=Cc1c([N+](=O)[O-])ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Yield: 74 %

Procedure:
To a solution of 10.0 g (24.0 mmole) of (R)-[8-allyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate in 700 mL of benzene was added 1.03 g of bis(acetonitrile)dichloropalladium (II) and the mixture was refluxed under nitrogen for 48 hours. The catalyst was then removed by filtration and the filtrate concentrated in vacuum to a brown oil. Column chromatography on silica gel with methylene chloride as eluant gave 7.2 g of the title compound as a mixture of E and Z isomers. A sample of {(2R)-7-nitro-8[(E)-1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate was obtained as a yellow solid (m.p. 105-106° C.) by evaporation of a pure E isomer-containing fraction.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].CN(C)[CH:12]=[CH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([Cl:27])=[C:20]([N:22]([CH3:26])[C:23](=[O:25])[CH3:24])[CH:21]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[Cl:27][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:6]3[N:5]=[C:4]([CH3:7])[C:3]([C:8]#[N:9])=[C:2]3[N:1]=[CH:12][CH:13]=2)=[CH:21][C:20]=1[N:22]([CH3:26])[C:23](=[O:25])[CH3:24]
Reactant: Cc1n[nH]c(N)c1C#N
Reactant: CC(=O)N(C)c1cc(C(=O)C=CN(C)C)ccc1Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N(C)c1cc(-c2ccnc3c(C#N)c(C)nn23)ccc1Cl
Yield: 72.6 %

Procedure:
A mixture of 0.055 g (0.43 mmol) of 5-amino-3-methyl-1H-pyrazole-4-carbonitrile and 0.120 g (0.43 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-chloro-phenyl]-N-methyl-acetamide in 12 mL of glacial acetic acid was refluxed for 1.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 106 mg of N-{2-chloro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 73%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1.CS[C:13](=[NH:18])[NH:14][N+:15]([O-:17])=[O:16]>>[N+:15]([NH:14][C:13]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1)=[NH:18])([O-:17])=[O:16]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: NCCSCc1ccon1
Product: N=C(NCCSCc1ccon1)N[N+](=O)[O-]

Procedure:
Reacting 3-[(2-aminoethyl)thiomethyl]isoxazole with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N'-[2-(3-isoxazolylmethylthio)ethyl]guanidine.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH:23]1[CH2:29][CH:28]2[N:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:25]([CH2:26][CH2:27]2)[CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH:23]1[CH2:24][CH:25]2[N:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:28]([CH2:27][CH2:26]2)[CH2:29]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(ON)C2
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCC1CC(ONC(=O)[C@@H]1CC[C@@H]3CN1C(=O)N3OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.15 g, 0.54 mmol) in dry DCM (20 mL) were added tert-butyl 3-(aminooxy)-8-azabicyclo[3.2.1]octane-8-carboxylate 45 (0.15 g, 0.62 mmol, J. Med. Chem. 2008, 51, 4601-4608), 1-hydroxybenzotriazole (0.11 g, 0.81 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.16 g, 0.81 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give tert-butyl 3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]-8-azabicyclo[3.2.1]octane-8-carboxylate 46 (0.26 g, 96%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([C:8]2[CH:29]=[CH:28][C:11]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([C:18](OCC)=[O:19])=[C:14]3[C:23](OCC)=[O:24])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[NH2:32][NH2:33]>C(O)C>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([C:8]2[CH:29]=[CH:28][C:11]([CH2:12][N:13]3[C:14]4[C:23](=[O:24])[NH:32][NH:33][C:18](=[O:19])[C:15]=4[CH:16]=[CH:17]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccn(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1C(=O)OCC
Reactant: NN
Solvent: CCO
Product: O=C(c1ccc(Cl)cc1)c1ccc(Cn2ccc3c(=O)[nH][nH]c(=O)c32)cc1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
In ethanol (70 ml) was dissolved 1-[4-(4-chlorobenzoyl)benzyl]-2,3-diethoxycarbonylpyrrole (3.31 g) followed by addition of anhydrous hydrazine (10.54 g) and the mixture was refluxed for 3 hours. The solvent was then distilled off under reduced pressure and the resulting crystals were suspended in water (150 ml) and, after addition of concentrated hydrochloric acid (30 ml), stirred at 85° C. for 30 minutes. The crystals were rinsed with water, methanol and ether serially and dried under reduced pressure to provide 1.46 g (yield 81%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C:12]([O:15][C:16]([NH:18][C@@H:19]1[CH2:24][NH:23][CH2:22][CH2:21][CH2:20]1)=[O:17])([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C>>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:23]1[CH2:22][CH2:21][CH2:20][C@H:19]([NH:18][C:16](=[O:17])[O:15][C:12]([CH3:13])([CH3:11])[CH3:14])[CH2:24]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2[N+](=O)[O-])C1
Yield: 99 %

Procedure:
The method of Example 1 was followed using 1 eq each of 4-chloro-3-nitropyridine, (S)-3-N-Boc-amino piperidine and diisopropylethylamine yielding (S)-tert-butyl 1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate, (99%). LCMS (m/z): 323.1 (MH+); LC Rt=2.13 min.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].S(Cl)([Cl:25])(=O)=O>C(OCC)C>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([Cl:25])=[C:8](/[CH:14]=[CH:15]/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)c1c(O)cc(OC)cc1/C=C/c1ccccc1
Solvent: CCOCC
Product: COC(=O)c1c(O)cc(OC)c(Cl)c1/C=C/c1ccccc1
Temperature: 0 °C
Yield: 85.2 %

Procedure:
Dissolve compound 7 (12 g, 0.042 mol) in anhydrous diethyl ether (150 ml), dropwise add in sulfuric chloride (11.2 g, 0.084 mol) at room temperature, when addition finishes, reflux the mixture for 3h, after completion of the reaction, cool the reaction mixture to 0° C., filter out the white solid precipitation to obtain the target product as a white solid (11.4 g, 85%). 1H NMR (400 MHz, CDCl3): 3.82 (s, 3H), 3.94 (s, 3H), 6.48 (d, J=16.0 Hz, 1H), 6.52 (s, 1H), 7.20 (d, J=16.0 Hz, 1H), 7.30 (t, J=8.0 Hz, 1H), 7.38 (t, J=8.0 Hz, 2H), 7.50 (d, J=8.0 Hz, 2H),
Reaction SMILES: [OH:1][CH:2]1[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[C:16](#[N:20])[CH2:17][C:18]#[N:19].C(NCC)C>C(O)C>[NH2:20][C:16]1[O:1][C:2]2[CH2:3][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][C:7]=2[C:17]=1[C:18]#[N:19]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(O)C1
Reactant: N#CCC#N
Solvent: CCNCC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2c(oc(N)c2C#N)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.9 %

Procedure:
tert-Butyl 3-hydroxy-4-oxopiperidine-1-carboxylate from Example 45A (3.88 g, 64% purity, 11.5 mmol) was dissolved in ethanol (10 mL), and propanedinitrile (758 mg, 11.5 mmol) was added. Within 10 min, diethylamine (0.84 g, 11.5 mmol) was added dropwise, whilst the temperature was kept below 30° C. Subsequently, the reaction mixture was stirred for 20 h at rt. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1). The product was triturated with petroleum ether/tert-butyl methyl ether (3:1) to yield 1.45 g (47%) of the title compound as yellow crystals.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CN(C=O)C.F[C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([S:25][C:26]2[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=2)[CH:24]=1)[C:20]#[N:21]>CCOCC.[OH-].[Na+]>[I:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:17]2[CH:18]=[C:19]([CH:22]=[C:23]([S:25][C:26]3[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=3)[CH:24]=2)[C:20]#[N:21])=[CH:6][CH:5]=1
Reactant: Cn1ccnc1Sc1cc(F)cc(C#N)c1
Reactant: Oc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cn1ccnc1Sc1cc(C#N)cc(Oc2ccc(I)cc2)c1
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
A mixture of NaH (60%, 312 mg, 7.8 mmol) in oil was rinsed with dry pentane by syringe (3×3 mL) and excess solvent removed under a steam of N2. Solid 4-iodophenol (1.72 g, 7.8 mmol) was added followed by 16 mL of DMF under ice-bath cooling which resulted in a vigorous evolution of gas. After 15 min, solid 3-fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzonitrile (910 mg, 3.9 mmol) was added and the resulting mixture microwave heated at 160° C. for 10 min. After cooling to rt, the mixture was diluted with ether and 3 M aqueous NaOH and shaken. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. The resulting 1.8 g of residue was adsorbed to 4.5 g SiO2 from CH2Cl2 and subjected to MPLC on a 40 g column of SiO2 eluting with % EtOAc in hexanes (time): 33% (10 min), 35-50% (20 min ramp) which provided 1.60 g (95%) of the title compound: 1H NMR (500 MHz, DMSO-d6): δ 3.63 (s, 3H), 6.82 (dd, 1H, J=2, 1 Hz), 6.90 (d, 2H, J=8 Hz), 7.13 (d, 1H, J=1 Hz), 7.26 (t, 1H, J=2 Hz), 7.37 (dd, 114, J=2, 1 Hz), 7.50 (d, 1H, J=1 Hz), 7.75 (d, 2H, J=8 Hz); LCMS (m/z): 434.3 [C17H12IN3OS+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][C:23]=5[NH2:25])[NH:18][N:17]=4)[NH:13][C:12]=3[CH:26]=2)[CH2:4][CH2:3]1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][C:23]=5[NH:25][C:27](=[O:34])[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[NH:18][N:17]=4)[NH:13][C:12]=3[CH:26]=2)[CH2:4][CH2:3]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCN(c2ccc3nc(-c4n[nH]c5cccc(N)c45)[nH]c3c2)CC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc3nc(-c4n[nH]c5cccc(NC(=O)c6ccccc6)c45)[nH]c3c2)CC1
Reaction time: 8 h

Procedure:
3-[6-(4-Methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-4-ylamine as dissolved in CH2C2 and benzoyl chloride (1.1 equivalent) is added followed by diisopropylethylamine (1.1 equivalent). The resulting mixture is stirred overnight. The solution is then concentrated and the resulting residue is purified by preparatory HPLC to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[OH:9].CC(O[CH2:14][C:15]1[CH2:24][S:23][C@@H:18]2[C@H:19]([NH2:22])[C:20](=[O:21])[N:17]2[C:16]=1[C:25]([OH:27])=[O:26])=O>C(#N)C.B(F)(F)F>[NH2:22][CH:19]1[C:20](=[O:21])[N:17]2[C:16]([C:25]([OH:27])=[O:26])=[C:15]([CH2:14][C:7]3[CH:6]=[C:4]([OH:5])[C:3]([OH:9])=[C:2]([F:1])[CH:8]=3)[CH2:24][S:23][C@H:18]12
Reactant: Oc1cccc(F)c1O
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Solvent: CC#N
Product: NC1C(=O)N2C(C(=O)O)=C(Cc3cc(O)c(O)c(F)c3)CS[C@H]12
Reaction time: 40 h

Procedure:
3-fluorocatechol 1.0 g was dissolved in 15% borontrifluoride acetonitrile solution. To the solution was added 7-aminocephalosporanic acid at 5° C. After the stirring for 40 hours at room temperature, the reaction mixture was concentrated to dryness and dissolved in water with the addition of sodium bicarbonate pH 7.0). The solution was washed with ethyl acetate and acidified with 6N-hydrochloric acid to pH The resulting crude crystals were collected by filtration and washed with water to give a mixture of the title compounds (1.74 g). The isolation and purification by high performance liquid chromatography (eluent; 3% acetonitrile in potassium phosphate buffer pH 6.0, column; ODS) gave the fractions of A and B as the order of elution. Each fraction was concentrated to dryness and the resulting solids were slurried in N,N-dimethylacetamide and filtered, respectively. Each DMAc solutions of title compounds A and B were submitted to the next step (Exp. 9 and Exp. 10) without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.C([Li])CCC.Cl>O1CCCC1.CCCCCC>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[O:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:17]([OH:22])[OH:18]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccccc1CCOC1CCCCO1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccccc1CCOC1CCCCO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
To a solution of 2-[2-(2-bromophenyl)ethoxy]tetrahydropyran (3.58 g, 12.5 mmol) and triisopropyl borate (3.70 ml, 16.1 mmol) in tetrahydrofuran (10.0 ml) was added a solution (10.0 ml) of 1.6M n-butyllithium in hexane at −78° C., and the mixture was stirred for 2 hr while gradually raising the temperature to 0° C. 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1-2:1) to give 2-[2-(tetrahydropyran-2-yloxy)ethyl]phenylboronic acid (1.77 g, yield 56.6%).
Reaction SMILES: [C:1]1([C:9]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([O:16][CH3:17])=[CH:14][CH:13]=2)=O)[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.[CH3:20][NH:21][CH3:22].C1(C)C=CC=CC=1>C(OCC)C.[Ti](Cl)(Cl)(Cl)Cl>[CH3:6][O:5][C:4]1[CH:7]=[CH:8][C:1]([C:9](=[CH:11][C:12]2[CH:19]=[CH:18][C:15]([O:16][CH3:17])=[CH:14][CH:13]=2)[N:21]([CH3:22])[CH3:20])=[CH:2][CH:3]=1
Reactant: CNC
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc(C=C(c2ccc(OC)cc2)N(C)C)cc1

Procedure:
A solution of 307.56 g. of desoxyanisoin in three liters of diethyl ether was cooled to about 0° C. by means of an external ice/alcohol bath. Under a nitrogen atmosphere, 441 ml. of dimethylamine were added to the solution with stirring. A solution of 79 ml. of titanium tetrachloride in 500 ml. of toluene was then added to the reaction mixture over a 90 minute period at such a rate to keep the temperature below 5° C. The reaction was then allowed to stir overnight at room temperature. The reaction was filtered and the precipitate was washed with two liters of diethyl ether. The ether filtrate and wash were combined and evaporated in vacuo. The residue was crystallized from ether/Skelly B to provide 272.2 g. of the desired title intermediate, m.p. about 67°-69° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27]I>>[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:10]([OH:12])=[O:11]
Reactant: O=C(O)Cc1ccc(F)cc1F
Reactant: ClCCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: O=C(O)C(CCCCCl)c1ccc(F)cc1F
Yield: 89 %

Procedure:
Step AM (1): 2-(2,4-Difluorophenyl)acetic acid (2.5 g, 14.52 mmol) was deprotonated with NaHMDS (1.0 M in THF, 29.0 mL, 29.0 mmol) and reacted with 1-chloro-4-iodobutane (1.78 mL, 14.5 mmol) using a procedure analogous to Step AC (1) to afford 6-chloro-2-(2,4-difluorophenyl)hexanoic acid (3.39 g, 89% yield). LC-MS (M−H)− 261.1. The crude product was used for subsequent chemistry without purification.