Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C(N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC(N(C)C)=O>[C:25]([N:4]1[C:3](=[O:17])[C:2]([F:1])=[CH:15][N:6]([C@@H:7]2[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]2)[C:5]1=[O:16])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Reactant: O=C(Cl)c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)n1c(=O)c(F)cn([C@H]2C[C@H](O)[C@@H](CO)O2)c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
15 Grams of 2'-deoxy-5-fluoro uridine (FudR) was dissolved in 45 ml of dimethylacetamide. Thereto was added 9 ml of triethylamine. To the mixture being cooled with ice-water was added 8.6 g of benzoyl chloride and the whole mixture was stirred overnight. The reaction mixture was subjected to filtration. The resulting filtrate was subjected to evaporation to obtain the residue, and water was added to the residue. The aqueous solution was extracted with ethyl acetate, and the organic layer was dried with anhydrous sodium sulfate. The dried ethyl acetate solution was concentrated and the residue was recrystallized from ethanol to obtain the desired compound. The yield was 10.5 g. M.p. 126° to 127° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=[N+]([O-])c1cnccc1NCc1ccc(F)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A mixture of 90 parts of 4-chloro-3-nitropyridine, 71 parts of 4-fluorobenzenemethanamine, 63 parts of sodium carbonate and 900 parts of N,N-dimethylacetamide was stirred for 1 hour at 50° C. Water was added and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 106 parts (75%) of N-[(4-fluorophenyl)methyl]-3-nitro-4-pyridinamine; mp. 136.8° C. (intermediate 1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=O)[CH2:14][O:13][CH-]2)=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18].[OH-].[Na+]>C(O)C>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:15][CH2:14][OH:13])=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C1CO[CH-]N1c1ccc(NCCO)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])c1cc(NCCO)ccc1NCCO
Yield: 90 %

Procedure:
0.2 mole (53.4 g) of N-[4-(β-hydroxyethyl)amino-3-nitrophenyl]oxazolidone, prepared according to Example 5, is treated with 135 ml of 3N sodium hydroxide to which 55 ml of 96° strength ethanol has been added. 0.18 mole (44.2 g) of the expected product is obtained. It melts at 107° C.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH:5]([C:7](=[O:24])[S:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:19])=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=1)[NH2:6].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:23][C:20]([C:11]1[CH:10]=[C:9]([S:8][C:7]2[O:24][C:1](=[S:2])[NH:6][N:5]=2)[CH:14]=[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])[C:12]=1[OH:19])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1cc(SC(=O)NN)cc(C(C)(C)C)c1O
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(Sc2n[nH]c(=S)o2)cc(C(C)(C)C)c1O
Reaction time: 0.17 h

Procedure:
Thiophosgene (0.39 mL, 5.1 mmol) is added dropwise to a -78° C. solution of S-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] hydrazinecarbothioate (1.5 g, 5.1 mmol) in tetrahydrofuran (150 mL). The reaction mixture is stirred for 10 minutes then poured into a separatory funnel containing ethyl acetate and aqueous sodium bicarbonate. The organic phase is washed three times with water and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a solid which is crystallized from dichloromethane/hexane affording 1.1 g (62%) of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1,3,4-oxadiazole-2(3H)-thione, mp 129.0°-131.0° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([C:14]3([CH2:18][C:19]#[N:20])[CH2:17][NH:16][CH2:15]3)[CH:13]=2)[N:6]2[CH:21]=[CH:22][N:23]=[C:5]2[CH:4]=1.CCN(C(C)C)C(C)C.FC(F)(F)S(O[CH2:39][C:40]([F:43])([F:42])[F:41])(=O)=O>CN(C=O)C>[Cl:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([C:14]3([CH2:18][C:19]#[N:20])[CH2:17][N:16]([CH2:39][C:40]([F:43])([F:42])[F:41])[CH2:15]3)[CH:13]=2)[N:6]2[CH:21]=[CH:22][N:23]=[C:5]2[CH:4]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: N#CCC1(n2cc(-c3nc(Cl)cc4nccn34)cn2)CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CCC1(n2cc(-c3nc(Cl)cc4nccn34)cn2)CN(CC(F)(F)F)C1
Yield: 61.4 %

Procedure:
In 1.5 mL of DMF were combined 2-(3-(4-(7-chloroimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (0.059 g, 0.14 mmol), DIEA (0.15 mL, 0.84 mmol), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.049 g, 0.21 mmol) and allowed to proceed at ambient temperature with stirring. After 2 hours the DMF was removed under reduced pressure with heating and the crude was purified by means of silica gel chromatography eluting with 1:1 EtOAc/hexanes containing 0.25% NH4OH to afford 2-(3-(4-(7-chloroimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoro ethyl)azetidin-3-yl)acetonitrile (0.034 g, 0.086 mmol, 62% yield). MS (apci) m/z=396.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]([O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)[CH2:10][CH3:11]>>[Cl:1][C:2]1[N:7]=[C:6]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:9][CH2:10][CH3:11])=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CCCOc1ccc(B(O)O)cc1
Product: CCCOc1ccc(-c2ccnc(Cl)n2)cc1

Procedure:
2,4 dichloropyrimidine was coupled with 4-propoxyphenylboronic acid following procedure A. LC-MS showed the product had the expected M+H+ of 249.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13](I)[C:3]=1[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(O[CH2:22][CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=O)C.C(OCC)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:3]=1[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(=O)OCC=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1c(F)cccc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1c(F)cccc1CC=Cc1ccccc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Under an argon atmosphere, 300 mg of t-butyl N-(2-fluoro-6-iodobenzyl)carbamate, 0.29 mL of cinnamyl acetate, 1.28 mL of bistributyltin, and 70 mg of PdCl2(dppf)2 were dissolved in 2.5 mL of DMF, followed by stirring at 120° C. for 2 hours. After completion of the reaction, to the reaction liquid was added diethyl ether, followed by filtration through Celite, and to the filtrate was added water, followed by extraction with diethyl ether. Then, the organic layer was washed with an aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified using PLC (n-hexane:ethyl acetate=3:1) to obtain 121 mg (yield 52%) of a title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]C(Cl)(Cl)Cl)=[CH:4][N:3]=1>C(N)=O.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15][C:4]=2[N:3]=1
Reactant: Clc1ncc(-c2ccccc2SC(Cl)(Cl)Cl)c(Cl)n1
Solvent: NC=O
Solvent: O
Product: Clc1ncc2c(n1)sc1ccccc12
Temperature: 60 °C
Yield: 67.8 %

Procedure:
A solution of 2,4-dichloro-5-(2-((trichloromethyl)thio)phenyl)pyrimidine (12.5 g, 33.4 mmol) in formamide (498 ml) was degassed with nitrogen and heated at 60° C. overnight. The reaction solution was cooled to room temperature, diluted with water, filtered and washed with water and a small amount of cold ethanol. White precipitate was recrystallized from EtOH to afford 5.0 g (68% yield) of 2-chlorobenzo[4,5]thieno[2,3-d]pyrimidine as white needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:4]=1[C:5]([OH:7])=[O:6].[Br:13]Br>ClC1C=CC=CC=1>[Br:13][C:9]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([C:8]=1[CH3:12])[C:5]([OH:7])=[O:6]
Reactant: COc1cccc(C)c1C(=O)O
Reactant: BrBr
Solvent: Clc1ccccc1
Product: COc1ccc(Br)c(C)c1C(=O)O
Temperature: 35 °C
Reaction time: 2 h

Procedure:
700 g (4.212 mol) of 2-methoxy-6-methylbenzoic acid (IV′) were suspended in 2343.5 g of chlorobenzene, and 707.2 g (4.423 mol) of elemental bromine were subsequently added dropwise within 3 h at a constant internal temperature of 15° C. Afterwards, the mixture was stirred at 35° C. for 2 h. Subsequently, 628.7 g of chlorobenzene were distilled off at an internal temperature of 77-82° C. and 200 mbar, and the excess bromine and HBr were likewise removed from the reaction vessel. After analysis of the bromine content, the brominous chlorobenzene distillate could be reused in the next batch without any discharge. The amount of bromine to be used there could be correspondingly reduced.
Reaction SMILES: [Na].[CH3:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:12])=[CH:9][C:10]=1[OH:11])=[O:4].[CH2:13]([O:15][C:16](=[O:22])[C:17](OCC)=O)[CH3:14].Cl>C(O)C.C(OCC)C.O>[CH2:13]([O:15][C:16]([C:17]1[O:11][C:10]2[CH:9]=[C:8]([OH:12])[CH:7]=[CH:6][C:5]=2[C:3](=[O:4])[CH:2]=1)=[O:22])[CH3:14]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cc(=O)c2ccc(O)cc2o1

Procedure:
To a warm, stirred solution of 18.4 g (0.8 mole) of sodium metal in 250 ml of absolute ethanol was added dropwise a solution of 30.4 g (0.2 mole) of 2,4-dihydroxyacetophenone and 58.5 g (0.4 mole) of diethyloxalate in 50 ml of absolute ethanol and 50 ml of absolute ethyl ether over a 30 min period. The mixture was heated at reflux for 4 hr and then poured into a solution of 200 ml of concentrated hydrochloric acid and 1.8 liter of water. The mixture was extracted with two 500 ml portions of ethyl ether and the combined extracts were concentrated under reduced pressure to give a solid residue.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Cl:14][C:15]1[C:20]([CH3:21])=[C:19](Cl)[N:18]=[CH:17][N:16]=1>C1COCC1.CC(C)([O-])C.[K+]>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][C:19]2[C:20]([CH3:21])=[C:15]([Cl:14])[N:16]=[CH:17][N:18]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1c(Cl)ncnc1Cl
Reactant: CC(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a solution of 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (6.26 g, 33.4 mmol) and 4,6-dichloro-5-methyl-pyrimidine (5.45 g, 33.4 mmol) in 100 mL THF, 1M potassium tert-butoxide in THF (40 mL, 40 mmol) were added slowly by syringe pump. After 1 hour, everything had been added and mixture was concentrated. Residue was extracted with methylene chloride and water. Organic phases were dried over magnesium sulfate, filtered, and concentrated to give 4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester as a pale yellow solid (10.3 g, 98%). 1H NMR (CDCl3, 400 MHz) δ 1.22-1.24 (d, 6H), 1.74-1.81 (m, 2H), 1.95-2.04 (m, 2H), 2.24 (s, 3H), 3.40-3.45 (m, 2H), 3.74-3.81 (m, 2H), 4.90-4.98 (m, 1H), 5.31-5.37 (m, 1H), 8.40 (s, 1H).
Reaction SMILES: [S:1]([C:5]1[O:16][C:8]2=[N:9][CH:10]=[C:11](C(O)=O)[CH:12]=[C:7]2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].C(Cl)(Cl)Cl.[OH-].[Na+]>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[S:1]([C:5]1[O:16][C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: NS(=O)(=O)c1cc2cc(C(=O)O)cnc2o1
Agent: [Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccc2ncccc2c1
Solvent: ClC(Cl)Cl
Product: NS(=O)(=O)c1cc2cccnc2o1
Temperature: 225 °C
Yield: 42 %

Procedure:
A suspension of 2-sulfamoylfuro[2,3-b]pyridine-5-carboxylic acid (726 mg, 3.0 mmol) in quinoline (5 mL) containing copper dust (0.5 g) was heated under a nitrogen atmosphere at 225° C. for 3.5 hours. After cooling the reaction mixture to room temperature, chloroform and dilute sodium hydroxide solution were added. This biphasic mixture was filtered through a filter aid pad to remove black suspended material and then the basic aqueous layer was separated and acidified with conc. hydrochloric acid. The product was extracted into ethyl acetate which was dried over anhydrous sodium sulfate and filtered through a pad of charcoal. The residue obtained after removal of the solvent in vacuo was triturated with diethyl ether to give crude product (291 mg). This material was recrystallized from ethyl acetate to give pure product (250 mg, 42% yield), mp: 222°-223° C.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[Br:19][C:20]1[C:21]([NH2:26])=[N:22][O:23][C:24]=1[CH3:25]>O1CCCC1>[Br:19][C:20]1[C:21]([NH:26][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])=[N:22][O:23][C:24]=1[CH3:25]
Reactant: Cc1onc(N)c1Br
Reactant: O=C1Nc2ccccc2/C1=C/O
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: Cc1onc(NC=C2C(=O)Nc3ccccc32)c1Br

Procedure:
The named compound is prepared by substituting 4-bromo-5-methyl-isoxazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2211 gms. 4-bromo-5-methyl-isoxazol-3-ylamine by refluxing in tetrahydrofuran (2.7 mL).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:9]Br.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Br:9][CH2:2][C:1]([CH:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:3]
Reactant: CC(=O)C1CCCC1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(CBr)C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109.8 %

Procedure:
To a solution of 16.1 g (0.143 mol) of acetylcyclopentane in 175 ml of methanol cooled in an ice bath was added 7.7 ml (0.15 mol) of bromine during 5 min. The reaction mixture was then allowed to warm to 10°-15° and held there by occasional application of the ice bath for 45 min until the reaction mixture became colorless. Then 100 ml of water was added and it was allowed to stir at room temperature for 0.5 hr. It was partially neutralized by the cautious addition of 10 g (72 mmol) of solid potassium carbonate, diluted with 200 ml of water and extracted with 4×150 ml of ether. The combined organic extracts were washed with 2×100 ml of saturated sodium bicarbonate solution and with 3×100 ml of water, dried over magnesium sulfate and concentrated in vacuo at room temperature to leave 30 g (110%) of bromoacetylcyclopentane as an oil whose nmr spectrum indicated that it was mainly the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].CC(O)=O.[BH3-]C#N.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.O>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[OH:1])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccccc1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2O)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2-hydroxyaniline (5.0 g, 46 mmol), N-t-butyloxycarbonyl-4-piperidinone (9.05 g, 46 mmol) and HOAc (5.7 mL, 100 mmol) in dry toluene (250 mL) was refluxed with azeotropic removal of water for 24 h. The solution was cooled to ambient temperature and to it was added NaCNBH3 (5.8 g, 92 mmol). The resulting mixture was stirred at ambient temperature for 24 h. EtOAc (250 mL) was added and the solution was washed with saturated aqueous NaHCO3 (4×100 mL). The organic phase was dried (MgSO4), filtered, and the solvents were removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using a gradient elution of 15-25% EtOAc-hexanes. 1-t-Butyloxycarbonyl-4-(2-hydroxyphenylamino)piperidine was obtained as a solid (45% yield).
Reaction SMILES: [C:1]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:19])[C:15](I)=[C:16]([F:17])[C:11]=3[N:10]=[C:9]2[O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([O:29][CH3:30])=[O:28])[CH2:22]2)=[CH:3][CH:2]=1.[C:37]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C([O-])([O-])=O.[K+].[K+]>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.CN(C=O)C>[C:37]1([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:42]=[CH:41][C:40]([C:15]2[C:14]([F:19])=[CH:13][C:12]3[N:8]([CH2:7][C:4]4[CH:3]=[CH:2][C:1]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[CH:6][CH:5]=4)[C:9]([O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([O:29][CH3:30])=[O:28])[CH2:22]4)=[N:10][C:11]=3[C:16]=2[F:17])=[CH:39][CH:38]=1
Reactant: COC(=O)C1CCCC(Oc2nc3c(F)c(I)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)C1
Reactant: OB(O)c1ccc(-c2ccccc2)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: CN(C)C=O
Product: COC(=O)C1CCCC(Oc2nc3c(F)c(-c4ccc(-c5ccccc5)cc4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)C1
Temperature: 120 °C

Procedure:
A 50 mL flask was charged with methyl 3-{[1-(biphenyl-4-ylmethyl)-4,6-difluoro-5-iodo-1H-benzimidazol-2-yl]oxy}cyclohexanecarboxylate (0.4 g, 0.664 mmol), 4-biphenylboronic acid (0.130 g, 0.664 mmol), Pd(PPh3)4 (0.038 g, 0.033 mmol), DMF (9 mL), and 1 M aqueous K2CO3 (1.3 ml, 1.30 mmol). The reaction was degassed with N2 and then heated at 120° C. for 1 h. Then the volatiles were removed in vacuo and the resulting residue was partitioned between EtOAc and H2O. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. Chromatography of the resulting residue over silica (preparative TLC) eluting with 40% EtOAc/hexanes afforded the title compound. LC-MS: calculated for C40H34F2N2O3 628.25, observed m/e: 629.17 (M+H)+ (Rt 3.83/4 min).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:4]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:6]=1.C([O-])(O)=O.[Na+].C(Cl)(Cl)=O.[N-]=C=O.C(C1C=C(N[C:41]([NH:43][C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:47]([O:54][C:55]3[CH:60]=[CH:59][N:58]=[C:57]([NH:61][CH2:62][CH:63]4[CH2:65][CH2:64]4)[N:56]=3)=[CH:46][CH:45]=2)=[O:42])N(C)N=1)(C)(C)C>C(Cl)Cl.C1(C)C=CC=CC=1.C1COCC1>[C:7]([C:5]1[CH:6]=[C:2]([NH:1][C:41]([NH:43][C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:47]([O:54][C:55]3[CH:60]=[CH:59][N:58]=[C:57]([NH:61][CH2:62][CH:63]4[CH2:65][CH2:64]4)[N:56]=3)=[CH:46][CH:45]=2)=[O:42])[N:3]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:4]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(Oc2ccnc(NCC3CC3)n2)c2ccccc12
Agent: O=C(Cl)Cl
Agent: O=C([O-])O
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(NCC4CC4)n3)c3ccccc23)cc1
Temperature: 0 °C
Yield: 37.6 %

Procedure:
3-Amino-5-tert-butyl-2-(p-tolyl)-2H-pyrazole (2.39 g, 9.00 mmol, 1 equiv.) was dissolved in 35 mL methylene chloride and 35 mL saturated aqueous NaHCO3 was added. The biphasic mixture was stirred until all solids had completely dissolved and was then cooled to 0° C. The organic layer was then treated with phosgene in one portion via syringe while not stirring (15.8 mL of a 20% solution toluene, 31.5 mmol, 3.5 equiv.). The resulting mixture was stirred vigorously at 0° C. for 1 h. The organic layer was separated, dried (Na2SO4) and filtered. The methylene chloride was removed in vacuo and the resulting isocyanate in toluene was treated with a solution of aminonaphthyl-chloropyrimidyl ether intermediate (see Example 4) (2.45 g, 9.0 mmol, 1.0 equiv.) in 40 mL anhydrous THF. The mixture was stirred at room temperature for 3.5 h, then the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel using 0–10% MeOH in methylene chloride eluent mixtures, followed by recrystallization from ether, providing 1.90 g (40%) of the urea intermediate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:19])[CH2:10][S:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:19])/[C:10](/[S:11][C:12]2[CH:13]=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=2)=[CH:25]\[C:24]2[CH:27]=[CH:28][C:21]([Br:20])=[CH:22][CH:23]=2)=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: COc1ccc(C(=O)CSc2ccc(Br)cc2)cc1
Product: COc1ccc(C(=O)/C(=C\c2ccc(Br)cc2)Sc2ccc(Br)cc2)cc1

Procedure:
The title compound is prepared by the methods described in Synthesis Example 1. A solution of 1-(4-methoxyphenyl)-2-(4-bromophenylthio)ethanone (10 mmol) and 4-bromobenzaldehyde (10 mmol) was subjected to the procedure described as Method B in part C of Synthesis Example 1 and the product obtained was purified by column chromatography.
Reaction SMILES: [NH2:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([F:14])=[C:7]([F:13])[CH:8]=2)[N:3]=1.[CH3:15][O-:16].[Na+]>O1CCCC1.CO>[NH2:1][C:2]1[C:11]([O:16][CH3:15])=[N:10][C:9]2[C:4](=[CH:5][C:6]([F:14])=[C:7]([F:13])[CH:8]=2)[N:3]=1
Reactant: C[O-]
Reactant: Nc1nc2cc(F)c(F)cc2nc1Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc2cc(F)c(F)cc2nc1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.4 %

Procedure:
To 2-amino-3-chloro-6,7-difluoroquinoxaline (610 mg, 2.83 mmol) dissolved in tetrahydrofuran (40 ml), 25 wt % sodium methoxide (6.12 g, 28.3 mmol) in methanol was added at room temperature and stirred further at room temperature for 1.5 hour. The resulting mixture was concentrated under the reduced pressure to remove the solvent. The product was extracted with ethyl acetate and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 570 mg of the titled compound (yield, 95%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.C(OC([NH:21][CH2:22][C:23]1[CH:24]=[C:25]([CH2:31][CH:32]([O:38][CH:39]([CH3:41])[CH3:40])[C:33]([O:35]CC)=[O:34])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30])=O)(C)(C)C>>[CH:39]([O:38][CH:32]([CH2:31][C:25]1[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([CH2:22][NH:21][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:13])[CH:24]=1)[C:33]([OH:35])=[O:34])([CH3:41])[CH3:40]
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CNC(=O)c1ccc2ccccc2c1

Procedure:
Using 2-naphthalene carboxylic acid and ethyl 3-[3-([(tert-butoxycarbonyl)amino]methyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 2-isopropoxy-3-(4-methoxy-3-[(2-naphthylcarbonyl)amino]methylphenyl]propanoic acid was obtained in the same method as in Example 38).