Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[C:6]([NH:9][CH2:10][CH3:11])[N:5]=[C:4]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[N:13]2)[N:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[NH2:1][C:2]1[C:7]([Br:8])=[C:6]([NH:9][CH2:10][CH3:11])[N:5]=[C:4]([N:12]2[CH:16]=[C:15]([C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[CH:14]=[N:13]2)[N:3]=1
Reactant: CCNc1nc(-n2cc(C(=O)O)cn2)nc(N)c1Br
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCNc1nc(-n2cc(C(=O)N3CCOCC3)cn2)nc(N)c1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.6 %

Procedure:
A mixture of 50 mg (0.15 mmol) of 1-[4-amino-5-bromo-6-(ethylamino)pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid (example 48), 15 μl (0.17 mmol) of morpholine, 32 μl (0.23 mmol) of triethylamine and 64 mg (0.17 mmol) of HATU in 1 ml of acetonitrile was stirred at room temperature for 10 min. The formed precipitate was filtered, washed with cold water and dried. 39 mg (64.4%) of a white solid were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C@@H:12]([O:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:11][C@H:9]2[NH:10][C@@H:6]1[CH2:7][CH2:8]2)=[O:4].Cl.[CH2:23](N(CC)CC)C.C1(=O)OC(=O)CC1.C(Cl)CCl>C(Cl)Cl.O>[CH3:23][N:10]1[C@H:6]2[C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[C@@H:12]([O:13][C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])[CH2:11][C@@H:9]1[CH2:8][CH2:7]2
Reactant: CCN(CC)CC
Reactant: COC(=O)[C@H]1[C@@H](OC(=O)c2ccccc2)C[C@@H]2CC[C@H]1N2
Agent: Cl
Agent: O=C1CCC(=O)O1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O
Product: COC(=O)[C@H]1[C@@H](OC(=O)c2ccccc2)C[C@@H]2CC[C@H]1N2C
Temperature: 25 °C

Procedure:
A solution of norcocaine hydrochloride (1 g, 3.07 mmol), triethylamine (0.86 ml, 6.14 mmol) in methylene chloride (20 ml) is treated with succinic anhydride (614 mg, 6.14 mmol) and the mixture heated at 45.degree. C. overnight, as described in U.S. Pat. No. 5,876,727. The solvents are removed under reduced pressure and the residue purified using silica gel flash chromatography (2:1 chloroform:methanol as the eluent). This gives succinylated norcocaine (1.0 g, 84%) as a thick syrup (3.beta.-(Benzoyloxy)-8-succinoyl-8-azabicyclo[3.2.1]octane-2.beta.-carboxylic acid methyl ester). To a solution of the acid (14 mg, 0.036 mmol) in distilled water (1 ml) at 0.degree. C., EDC (10.4 mg, 0.055 mmol) was added. After 5 minutes a solution of Qβ VLP in PBS (1 ml) is added dropwise and the mixture is allowed to warm to ambient temperature overnight. The conjugate is purified by dialysis against PBS and the degree of conjugation analyzed by mass spectral analysis. The resultant conjugate is used to immunize individuals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[CH3:25][O:26][CH2:27]Cl.O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:25][O:26][CH3:27])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(OCc3ccccc3)cc2[nH]1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2ccc(OCc3ccccc3)cc2n1COC
Reaction time: 0.25 h
Yield: 101.7 %

Procedure:
To a solution of 6-benzyloxy-1H-indole-2-carboxylic acid ethyl ester (3.00 g, 10 mmol) in DMF (30 ml) was added 60% sodium hydride in oil (0.49 g, 12 mmol) under ice cooling and the mixture was stirred for 15 minutes. Then to the mixture was added chloromethyl methyl ether (1.0 ml, 13 mmol) under ice cooling and stirred for 0.5 hour. Water (60 ml) was added to the reaction mixture and extracted with AcOEt, the organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous sodium sulfate and evaporated to give the title compound (3.45 g) as a pale brown oil.
Reaction SMILES: C(Cl)(Cl)Cl.[NH4+:5].[OH-].O.[C:8]([C:16]([C:31]([OH:33])=[O:32])([OH:30])[C:17]([C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([OH:21])[C:18]([OH:20])=[O:19])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C>[C:22]([C:17]([C:18]([OH:20])=[O:19])([OH:21])[C:16]([C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:30])[C:31]([OH:33])=[O:32])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:23]1([CH2:22][C:17]([NH2:5])([C:16]2[CH:8]=[CH:9][CH:14]=[CH:13][CH:31]=2)[CH3:18])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: [NH4+]
Agent: O=C(O)C(O)(C(=O)c1ccccc1)C(O)(C(=O)O)C(=O)c1ccccc1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: CC(N)(Cc1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
The filtrate residue which was saved in Illustration 3, was treated with 1 L CHCl3 and 0.9 L 5% NH4OH, shaken vigorously, the layers separated and the organic phase washed with 4×800 ml 5% NH4OH and 2×500 ml H2O, then dried over MgSO4 and evaporated to an oil 32.3 g, which is enriched in (+)-1,2-diphenyl-2-propylamine. This oil (32.3 g, 0.153 mol) was dissolved in 200 ml hot 95% ethanol and added to a stirred solution of (+)-dibenzoyl tartaric acid monohydrate (57.55 g, 0.153 mol) in 600 ml of refluxing 95% ethanol. A white solid crystallized immediately, which was stirred at reflux for 5 minutes, then allowed to cool to ambient temperature. The solid was collected by filtration and vacuum dried at 80° C. for 8 hours to give 71.6 g of (+)-1,2-diphenyl-2-propylamine (+)-dibenzoyltartrate, mp 197°-198° C., [α]D =+95.8° (C=0.5, CH3OH). 5.0 g of this salt use dissolved in 250 ml CHCl3 and 200 ml 5% NH4OH, shaken vigorously, the layers separated and the organic phase washed with 3×200 ml 5% NH4OH and 2×200 ml H2O and dried over MgSO4. The solvent was evaporated to give 1.75 g of (+)-1,2-diphenyl-2-propylamine as an oil. The maleate salt was prepared by dissolving this oil in 25 ml ethyl acetate and adding the solution to a hot solution of maleic acid (1.02 g, 8.78 mmole) in 50 ml 3/1 ethyl acetate/isopropanol. Upon cooling a white solid crystallized, which was collected by filtration and vacuum dried to give 2.06 g of (+)-1,2-diphenyl-2-propylamine maleate, mp 177°-178° C., [α]D =+27.3° (C=1, CH3OH).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8](=[O:18])(=[O:17])[C:7]=2[CH:19]=1)#N.C(O)=[O:21]>O>[CH:5]1[C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8](=[O:18])(=[O:17])[C:7]=2[CH:19]=[C:3]([CH:1]=[O:21])[CH:4]=1
Reactant: O=CO
Reactant: N#Cc1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Solvent: O
Product: O=Cc1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Reaction time: 3 h

Procedure:
Mix 267 mg (1 mmole) 3-cyano-dibenzo[b,f]thiepin-5,5-dioxide with Raney allowy (500 mg) and a mixture of 4 ml formic acid and 1 ml water at the reflux temperature. After 3 hours, add 200 mg additional Raney alloy and heat for one hour to obtain complete reduction. Filter the reaction mixture while hot to remove the alloy, and wash with ethyl acetate to remove any occluded solvent. Wash the organic layer containing the product with water and with saturated sodium chloride solution. Separate the organic layer containing the product to produce a residue of a pale yellow oil, which crystallizes in a small volume of ethyl acetate, m.p. 167°-171° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][C:16]3[N:15]=[CH:14][C:13]4[CH2:19][N:20]([CH3:37])[C:21](=[O:36])[N:22]([CH:23]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)[C:12]=4[C:11]=3[N:10]=2)=[CH:5][CH:4]=1.[ClH:38]>ClCCl>[ClH:38].[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][C:16]3[N:15]=[CH:14][C:13]4[CH2:19][N:20]([CH3:37])[C:21](=[O:36])[N:22]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[C:12]=4[C:11]=3[N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc3ncc4c(c3n2)N(C2CCN(C(=O)OC(C)(C)C)CC2)C(=O)N(C)C4)cn1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(-c2ccc3ncc4c(c3n2)N(C2CCNCC2)C(=O)N(C)C4)cn1

Procedure:
tert-butyl 4-(9-(6-methoxypyridin-3-yl)-3-methyl-2-oxo-3,4-dihydropyrimido[5,4-c][1,5]naphthyridin-1(2H)-yl)piperidine-1-carboxylate (75 mg, 0.149 mmol) was dissolved in dichloromethane (10 mL), hydrogen chloride gas was blown to the system for 0.5 h, and a solid was precipitated. The reaction mixture was filtered, the filter cake was washed sequentially with dichloromethane and diethyl ether, and the resulting solid was dried to give 50 mg of the titled compound.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:13][NH2:14].C(O)C>CCOCC>[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:13][NH:14][C:4](=[O:6])[CH2:3][C:1]#[N:2]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CC#N
Solvent: CCOCC
Solvent: CCO
Product: N#CCC(=O)NCc1ccc(Cl)c(Cl)c1
Reaction time: 42 h

Procedure:
A solution of 113.3 g. (1.002 moles) of ethyl cyanoacetate and 176.4 g. (1.002 moles) of 3,4-dichlorobenzylamine in 400 ml. of absolute ethanol is heated at reflux with stirring for 42 hours which upon cooling the entire solution solidifies. The latter is broken-up, slurried in ether, isolated by filtration and dried in vacuo to give 179.8 g. of product as a white solid, m.p. 144°-5° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:16][CH2:15][CH2:14][CH2:13][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: NS(=O)(=O)c1ccc(OCCCCl)cc1
Yield: 89.5 %

Procedure:
A mixture of 25 g (0.144 mole) of p-hydroxybenzenesulfonamide, 45.5 g (0.289 mole) of 1-bromo-3-chloropropane and 59.7 g (0.432 mole) of anhydrous potassium carbonate in 500 ml of acetone was heated at reflux for 24 hr. The mixture was cooled, filtered and the filtrate concentrated under vacuum pump pressure at 90° C. to give 32.2 g of tan gum as residue. The gum was purified by column chromatography on 600 g of silica gel. Fractions containing the title compound eluted with 8% acetone in benzene were combined and concentrated under reduced pressure to yield 12.2 g (34%) of white solid, m.p. 106°-107.5° C. on recrystallization from 2-propanol.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1([CH3:27])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24](=O)[CH3:25])[CH:22]=2)[S:17][CH2:16][CH2:15]1.P(Cl)(OCC)(OCC)=O.C([N-]C(C)C)(C)C.[Li+]>O1CCCC1.CCCCCC>[CH3:13][C:14]1([CH3:27])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]#[CH:25])[CH:22]=2)[S:17][CH2:16][CH2:15]1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCS2
Agent: CC(C)[N-]C(C)C
Agent: CCOP(=O)(Cl)OCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: C#Cc1ccc2c(c1)C(C)(C)CCS2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1.441 g (14.2405 mmol) of diisopropylamine in 30 ml dry tetrahydrofuran under argon at -78° C. was added dropwise 9 ml of 1.6M (14.4 mmol) n-butyllithium in hexane. After stirring this solution at -78° C. for 1 hour, it was treated dropwise with a solution of 2.95 g (13.389 mmol) of 4,4-dimethyl-6-acetylthiochroman in 5 ml of dry tetrahydrofuran. After another hour of stirring at -78° C., the solution was treated with 2.507 g (14.53 mmol) of diethyl chlorophosphate and brought to room temperature, where it was stirred for 3.75 hours. This solution was then transferred using a double ended needle to a solution of lithium diisopropylamide (prepared as above using 2,882 g (28,481 mmol) of diisopropylamine and 18 ml of 1.6M (28.8 mmol) n-butyllithium in hexane) in 60 ml dry tetrahydrofuran at -78° C. The cooling bath was removed and the solution stirred at room temperature for 15 hours, then quenched with water and acidified to pH 1 with 3N hydrogen chloride. The mixture was stirred at room temperature for 12 hours, then treated with 65 ml water and 33 ml conc. hydrogen chloride and heated at reflux for 0.5 hours. After being cooled to room temperature, the organic layer was separated and the aqueous layer extracted with 5×50 ml benzene. The recovered organic fractions were combined and washed with 5% sodium carbonate solution, water, saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexanes) followed by kugelrohr distillation (150° C., 0.7 mm) to give the captioned compound as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=3)[OH:27])[C:10]3[N:14]=[C:13]([O:15]CC)[N:12](C(OC(C)(C)C)=O)[C:11]=3[CH:25]=2)=[C:5]([CH3:35])[O:4][N:3]=1.Cl>C(O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=3)[OH:27])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:25]=2)=[C:5]([CH3:35])[O:4][N:3]=1
Reactant: CCOc1nc2c(C(O)c3ccc(F)cn3)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: Cc1noc(C)c1-c1cc(C(O)c2ccc(F)cn2)c2[nH]c(=O)[nH]c2c1
Temperature: 60 °C

Procedure:
To tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-((5-fluoropyridin-2-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-1-carboxylate (41.2 mg, 0.09 mmol) in ethanol (5 mL) was added hydrochloric acid (0.66 mL, 2.64 mmol, 4 M in 1,4-dioxane). The mixture was heated to 60° C. for 6 hours and then concentrated in vacuo. Purification by reverse-phase HPLC (25-50% acetonitrile/water with 0.01% trifluoroacetic acid, Gemini C18 5μ) afforded 6-(3,5-dimethylisoxazol-4-yl)-4-((5-fluoropyridin-2-yl)(hydroxy)methyl)-1H-benzo[d]imidazol-2(3H)-one as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[Na+].[Na+].[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>COCCOC.C(OCC)(=O)C.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>[CH:11]([O:10][C:5]1[CH:4]=[CH:3][C:2]([C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:13])[CH3:12]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)Oc1ccc(Br)cc1C=O
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: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)Oc1ccc(-c2ccc(F)cc2)cc1C=O
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-2-isopropoxy-benzaldehyde (504 mg, 2.07 mmol) in 1,2-dimethoxyethane (5 mL) were added tetrakis(triphenylphosphine)palladium(0) (87 mg, 0.075 mmol), 2M aqueous sodium carbonate (2.5 mL), and 4-fluorobenzeneboronic acid (396 mg, 2.83 mmol). The reaction mixture was stirred for 2 hours at reflux temperature, cooled, diluted with ethyl acetate, washed with water, saturated brine solution, dried (Na2SO4), and evaporated. The title compound was purified by flash chromatography eluting with 4% diethyl ether in hexane; yield 347 mg.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8](OCC)=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6](=[O:18])(=[O:17])[N:5]=1)[CH3:2].C[Si](C)(C)[NH:21][Si](C)(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:8]([NH2:21])=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6](=[O:18])(=[O:17])[N:5]=1)[CH3:2]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CCOC(=O)C1=C(OCC)C(OCC)=NS1(=O)=O
Solvent: ClCCl
Product: CCOC(=O)C1=C(N)C(OCC)=NS1(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere, a solution of 1.41 g (5.3 mmol) of the Example 3 compound in 15 ml of methylene chloride was stirred in an ice bath while a solution of 1.2 g (7.9 mmol) hexamethyldisilazane in 10 ml methylene chloride was added dropwise. The solution was allowed to warm to room temperature at which temperature stirring was continued for 18 hours. The solution was then evaporated in vacuo to an oil which was redissolved in 20 ml of a mixture of methylene chloride (15) -ethanol (5). After stirring at room temperature for one hour, the solution was again concentrated in vacuo, leaving a solid, 1.1 g (85%), mp 163°-165°. Recrystallization from ethyl acetate provided analytically pure title compound, mp 172.5°-173°.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[Al](C)C.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C@@:21]([OH:47])([CH2:41][N:42]1[CH:46]=[N:45][CH:44]=[N:43]1)[C@H:22]([S:24][C@@H:25]1[CH2:30][O:29][C@@H:28]([C:31]2[CH:40]=[CH:39][C:34]([C:35](OC)=[O:36])=[CH:33][CH:32]=2)[O:27][CH2:26]1)[CH3:23]>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:35](=[O:36])[C:34]2[CH:39]=[CH:40][C:31]([C@H:28]3[O:27][CH2:26][C@H:25]([S:24][C@H:22]([CH3:23])[C@:21]([C:15]4[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=4[F:13])([OH:47])[CH2:41][N:42]4[CH:46]=[N:45][CH:44]=[N:43]4)[CH2:30][O:29]3)=[CH:32][CH:33]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc([C@H]2OC[C@H](S[C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CO2)cc1
Reactant: Nc1ccc(Br)cc1
Agent: C[Al](C)C
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(Br)cc3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(4), a reaction was carried out using commercially available 4-bromoaniline (205 mg, 1.2 mmol), trimethylaluminium (1.1 ml, 1.07M n-hexane solution, 1.2 mmol) and methyl 4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzoate (150 mg, 0.30 mmol), obtained in Example 12(1), and the reaction mixture was treated using a similar procedure to that described in Example 3(4) to afford the title compound (182 mg, yield 95%) as a white solid which was recrystallized from ethyl acetate to give white powdery crystals.
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([CH3:13])[CH:6]=1)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)=O>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:13][C:7]1[CH:6]=[C:5]([OH:4])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: C=CCOc1ccc(C=O)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O=CO
Product: Cc1cc(O)ccc1C=O
Reaction time: 0 h
Yield: 35 %

Procedure:
The compound of Step B, 13.54 g (76.9 mmole), 1.72 g (7.69 mmole) palladium acetate, and 12.09 g (46.2 mmole) triphenylphosphine were mixed in a 250 ml flask. Formic acid, 3.2 ml (84.6 mmole), was added and the reaction was swirled. Within 15 seconds, the reaction foamed, exothermed and formed a gum which was dissolved in ethyl acetate, washed once with sodium bicarbonate and once with brine. The organic layer was chromatographed on 350 ml silica, eluting with 20%, then 40% ethyl acetate/hexane. The fractions were combined and the product crystallized from methylene chloride/hexane to give 3.61 g (35%) of product which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:5]=1[NH2:22])([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:6]1[CH:7]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:9]=[C:4]([NH2:1])[C:5]=1[NH2:22]
Reactant: [H][H]
Reactant: Nc1c(-c2ccccn2)cc(-c2cccnc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(-c2cccnc2)cc(-c2ccccn2)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To a solution of 2-nitro-6-pyridin-2-yl-4-pyridin-3-yl-phenylamine (75 mg, 0.26 mmol) in ethyl acetate (20 mL) was added 10% palladium on carbon (50 mg). The resulting suspension was placed in a Parr hydrogenation apparatus under 40 psi hydrogen gas while shaking at ambient temperature for one hour. The catalyst was removed by filtration and the filtrate concentrated in vacuo to afford compound the title compound (50 mg, 0.19 mmol).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:8]([CH2:15][CH2:16][O:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:7].[OH-].[Na+].CN(C)[CH:30]=[O:31]>>[CH:30]([C:12]1[CH:13]=[CH:14][C:9]([N:8]([CH2:6][CH3:7])[CH2:15][CH2:16][O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:11]=1)=[O:31]
Reactant: CN(C)C=O
Reactant: CCN(CCOC(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(CCOC(=O)c1ccccc1)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82 %

Procedure:
Phosphorous oxychloride (0.33mL, 3.5 mmol) was added to dry dimethylformamide (3 mL) at 0° C. for 15 minutes. After cooling to room temperature, N-ethyl-(2-benzoyloxyethyl)aniline (1 g, 3.5 mmol) was added followed by stirring at room temperature for 5 minutes and then at 90° C. for 30 minutes. The dark green solution was then cooled to room temperature and made basic to pH 8 by addition of 1 molar sodium hydroxide solution. Product was extracted into diethyl ether (3×20 mL). The combined ether extracts were washed with water (30 mL), saturated sodium chloride (30 mL), dried over magnesium sulfate and solvent removed under reduced pressure. Product was isolated as a clear yellow oil (0.90 g, 82% yield).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1.[C:21](=[O:23])=[O:22]>C1COCC1.C(OCC)C.O>[F:20][C:16]1[N:15]=[C:14]([F:13])[CH:19]=[CH:18][C:17]=1[C:21]([OH:23])=[O:22]
Reactant: Fc1cccc(F)n1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(F)nc1F
Temperature: -78 °C

Procedure:
A solution of n-butyl lithium in THF (2.62 M, 29.1 mL) was added dropwise to a solution of diisopropylamine (11.7 mL) in tetrahydrofuran (310 mL) under ice-cooling in a nitrogen atmosphere. The reaction solution was stirred under ice-cooling for one hour and then cooled to −78° C. A solution of 2,6-difluoropyridine (8 g) in tetrahydrofuran (10 mL) was added dropwise to the reaction solution. The reaction solution was stirred at −0.78° C. for three hours. Then, an excess amount of crushed dry ice was added in a nitrogen stream, and the reaction solution was stirred at −78° C. for 20 minutes and at room temperature for three hours. Water and diethyl ether were added to the reaction solution, and the aqueous layer was separated. The aqueous layer was adjusted to pH 1 by concentrated hydrochloric acid. Ethyl acetate was added to the aqueous layer, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 10.4 g of the title compound.
Reaction SMILES: [N:1]([C:4]1[C:13]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:5]=1[F:32])=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][C:4]1[C:13]([S:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:5]=1[F:32]
Reactant: COC(=O)c1cc(SCc2ccc(OC)cc2)c(N=[N+]=[N-])c(F)c1Nc1ccccc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(SCc2ccc(OC)cc2)c(N)c(F)c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To a solution of methyl 4-azido-5-(4-methoxybenzylthio)-3-fluoro-2-((2-chlorophenyl)amino)-benzoate (21.63 g, 45.74 mmol) in MeOH (500 mL) was added and 10% palladium on carbon (3.40 g) under nitrogen atmosphere. Then the nitrogen atmosphere was completely changed to hydrogen atmosphere. The mixture was stirred for 2 h at ambient temperature. After the insoluble matter was filtered off, the solvent was evaporated in vacuo to give the desired product (19.93 g, 97.5% yield). 1H NMR (400 MHz, CDCl3): δ 8.99 (s, 1H), 7.82 (s, 1H), 7.21 (m, 1H), 7.17 (m, 3H), 6.87 (m, 3H), 6.69 (m, 1H), 4.63 (s, 2H), 3.85 (s, 5H), 3.81 (s, 3H).