Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:24][CH2:23][CH:4]([CH:5]([C:7]3[N:12]=[C:11]4[N:13]([CH3:22])[C:14](=[O:21])[N:15]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:10]4=[CH:9][CH:8]=3)[CH2:6]1)[CH2:3][NH:2]2.[O:25]1[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[N:26]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCOCC1>[CH3:18][C:17]([CH3:19])([CH3:20])[CH2:16][N:15]1[C:10]2[C:11](=[N:12][C:7]([CH:5]3[CH2:6][CH:1]4[CH2:24][CH2:23][CH:4]3[CH2:3][N:2]4[C:30]([C:27]3[CH:28]=[CH:29][O:25][N:26]=3)=[O:31])=[CH:8][CH:9]=2)[N:13]([CH3:22])[C:14]1=[O:21]
Reactant: O=C(O)c1ccon1
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3CC4CCC3CN4)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3CC4CCC3CN4C(=O)c3ccon3)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-(2-Azabicyclo[2.2.2]oct-5-yl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (5-1, 30.2 mg, 0.09 mmol, 1.0 equiv), isoxazole-3-carboxylic acid (2-6, 15.6 mg, 0.14 mmol, 1.5 equiv), DIPEA (48 μL, 0.28 mmol, 3.0 equiv) and HATU (52.4 mg, 0.14 mmol, 1.5 equiv) were added to anhydrous 1,4-dioxane (0.92 mL). After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 5-2 as a white solid. MS m/z (M+H): calculated=424.2343; observed=424.2345.
Reaction SMILES: [OH:1][PH:2]([CH2:4][CH:5]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[O:3].[C:22](O)([CH3:25])([CH3:24])[CH3:23].O>ClCCl.CN(C)C1C=CN=CC=1>[C:22]([O:3][PH:2]([CH2:4][CH:5]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[O:1])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)CCC(C[PH](=O)O)C(=O)OC(C)(C)C
Reactant: CC(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)CCC(C[PH](=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a solution of di-tert-butyl 2-[(hydroxy-phosphinyl)methyl]pentane-1,5-dioate (315 g, 0.977 mol) in dichloromethane (1000 ml) cooled in an ice bath and under nitrogen were added tert-butanol (123.1 g, 1.66 mol), 4-dimethylaminopyridine (1 g, 8.2 mmol), andl-ethyl-3-(3-dimethylaminopropyl) carbodiimide (281 g, 1.47 mol). The reaction was allowed to stir overnight. Water was added to the reaction mixture and the dichloromethane layer was retained and dried, and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography and the desired product was eluted with 1:1 to 2:3 hexane/ethyl acetate. The fractions containing product were concentrated under reduced pressure leaving a clear oil (260 g, 70%). 1H NMR (CDCl3) : δ 1.4 (m, 27H), 1.8 (m, 1H), 1.9 (m, 2H), 2.1 (m, 1H), 2.3 (m, 2H), 2.7-2.8 (m, 1H), 6.7 & 8.0 (d, 1H, the P-H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22].Cl>C(O)C>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:13]=1)([O-:19])=[O:18]
Reactant: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1F
Reactant: Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1Oc1ccccc1
Temperature: 0 °C
Yield: 79.3 %

Procedure:
To 250 ml of an aqueous solution containing 73.5 g of phenol and 31.2 g of sodium hydroxide was added 50.0 g of N-(2-fluoro-5-nitrophenyl)methanesulfonamide, followed by reflux for 5 hours. To the ice-cooled reaction solution were successively added 50 ml of 36% hydrochloric acid and 200 ml of ethanol with stirring. The precipitate was collected by filtration, successively washed with ethanol and water, and air-dried to give 52.2 g of N-(5-nitro-2-phenoxyphenyl)methanesulfonamide as yellow prisms.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[N:3]=1.[NH2:23][C:24]1[CH:28]=[C:27]([CH3:29])[N:26](C(OC(C)(C)C)=O)[N:25]=1.C(O)(=O)C>CC(N(C)C)=O>[F:21][C:13]([F:22])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)[C:4]1[N:3]=[C:2]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cc(N)nn1C(=O)OC(C)(C)C
Reactant: Fc1ccc(C(F)(F)c2nc(Cl)c3cccc(F)c3n2)nc1
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(F)cccc23)n[nH]1
Temperature: 100 °C
Yield: 4 %

Procedure:
To 4-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-fluoroquinazoline (295 mg, 0.90 mmol) in DMA (2.2 mL) were added tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate and acetic acid (0.12 mL), and the mixture was heated at 100° C. for 6.5 h. The mixture was allowed to cool to rt and was purified by preparative reverse-phase HPLC using an ammonium acetate modifier. A later eluting fraction was treated with saturated aq NaHCO3 and concentrated under reduced pressure. The aqueous residue was extracted with DCM (3×30 mL) and the combined extracts were washed with saturated aq NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was treated with DCM, whereupon a precipitate formed, which was collected by filtration to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-fluoro-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine as a colorless solid (13 mg, 4%). 1H NMR (300 MHz, DMSO-d6) δ 12.23 (br s, 1H), 10.86 (br s, 1H), 8.67 (s, 1H), 8.52 (d, J=9 Hz, 1H), 8.00-8.02 (m, 2H), 7.77 (m, 1H), 7.63 (m, 1H), 5.97 (s, 1H), 2.17 (s, 3H). LCMS (ESI) m/z 389 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[C:4](=[N:6][OH:7])Cl.[CH2:13]([O:15][C:16](=[O:20])[C:17]#[C:18][CH3:19])[CH3:14].CCN(CC)CC>CCOCC>[CH2:13]([O:15][C:16]([C:17]1[C:4]([C:3]2[C:8]([F:12])=[CH:9][CH:10]=[CH:11][C:2]=2[I:1])=[N:6][O:7][C:18]=1[CH3:19])=[O:20])[CH3:14]
Reactant: CC#CC(=O)OCC
Reactant: ON=C(Cl)c1c(F)cccc1I
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(-c2c(F)cccc2I)noc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of 2-iodo-6-fluorobenzoyl chloride oxime (26.6 mmol) and ethyl-2-butynoate (3.72 ml, 31.92 ml, 1.2 eq.) in Et2O (106 ml) under N2, stirring at 0-5° C. added dropwise a solution of Et3N (4.81 ml, 34.6 mmol, 1.3 eq) in Et2O (13 ml) over 1 h. The reaction was allowed to warm to room temperature and stirred overnight. Et2O was added and then washed with H2O, brine, dried (MgSO4), filtered, and concentrated. The crude residue was chromatographed on silica gel using ethyl acetate in hexanes (1-20%) to give the title compound (8.21 g, 82%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C@H:9]([C:12]1[C:21]([C:22]([NH:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[O:23])=[C:20]([OH:30])[C:19]2[C:14](=[C:15]([C:31]([F:34])([F:33])[F:32])[CH:16]=[CH:17][CH:18]=2)[N:13]=1)[CH2:10][CH3:11].N1C=CC=CC=1.Cl>O>[C:1]([NH:8][C@H:9]([C:12]1[C:21]([C:22]([NH:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[O:23])=[C:20]([OH:30])[C:19]2[C:14](=[C:15]([C:31]([F:33])([F:32])[F:34])[CH:16]=[CH:17][CH:18]=2)[N:13]=1)[CH2:10][CH3:11])(=[O:3])[CH3:2]
Reactant: CC[C@H](N)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC[C@H](NC(C)=O)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Temperature: 25 °C

Procedure:
10 ml of acetic anhydride and 6 g of 2-[(1S) 1-aminopropyl]-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline carboxamide of Example 8 were added dropwise with stirring to 60 ml of pyridine and stirring was maintained for 90 minutes at ambient temperature. The solution was poured into 150 ml of iced water and concentrated hydrochloric acid was added until a pH of 1. The precipitate was filtered, washed with water and then dissolved in tetrahydrofuran. The organic phase was dried, and concentrated to dryness under reduced pressure. The residue was taken up in ether, filtered and dried under reduced pressure at 80° to obtain 5.3 g of 2-[(1S) 1-(acetylamino)-propyl]-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline carboxamide melting at 275° C. and having a specific rotation of [α]D =+43.5°±4° (c=0.3% in DMF).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].CCN(C(C)C)C(C)C.[C:18](Cl)(=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C1COCC1>[OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[C:18]([OH:36])(=[O:1])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCCCCCCC(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1.33 g. of N-hydroxy succinimide (11.56 mmole) and DIEA (1.5 ml, 8.62 mmole) were dissolved in 50 ml of anhydrous THF and gently stirred at 0° C. under nitrogen atmosphere. To this were added dropwise and during 1 h a solution of stearoyl chloride (2.35 g, 7.7 mmole) in 50 ml of anhydrous THF. After, the mixture was stirred at 0° C. for 2 h and overnight at room temperature. Solvent was removed under reduced pressure and the remaining white solid was redissolved in 200 ml of DCM. The organic phase were washed with DDW (2×100 ml), dried over anhydrous MgSO4, filtered and evaporated to dryness. The reaming solid was dissolved in 100 ml of ethyl acetate and 200 ml of hexane and kept at −20° C. overnight. The resulting white crystals were collected by filtration and dried in vacuum over NaOH-pellets. The crystallized product was free from unreacted acid chloride as determined by 1H-NMR. The remaining filtrate was also evaporated to yield the product contaminated with 10% of the starting acid as determined by 1H-NMR.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].N1C=CC=CC=1.O[C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([C:32](=[O:34])[CH3:33])[N:27]=[CH:26]2>ClCCl>[C:32]([N:28]1[C:29]2[C:25](=[CH:24][C:23]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:31][CH:30]=2)[CH:26]=[N:27]1)(=[O:34])[CH3:33]
Reactant: CC(=O)n1ncc2cc(O)ccc21
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)n1ncc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
112 μl (1.2 eq; 0.667 mmol) of trifluoromethanesulfonic anhydride and 337 μl (17.5 eq; 49.557 mmol) of pyridine, under an argon atmosphere, are added dropwise to a solution of 98 mg (1 eq; 0.556 mmol) of 1-(5-hydroxyindazol-1-yl)ethanone in 10 ml of dichloromethane on amylene, pre-cooled to 0° C. The medium is stirred and kept at 0° C. overnight under an argon atmosphere. 112 μl of trifluoromethanesulfonic anhydride and 337 μl of pyridine are added to the medium, which is stirred for 2 hours at 0° C. 112 μl of trifluoromethanesulfonic anhydride and 337 μl of pyridine are then added, and the medium is then stirred for 3 hours at 0° C. The reaction mixture is washed with 10 ml of water. The aqueous phase is treated with 2 times 10 ml of dichloromethane. The organic phase is dried over magnesium sulfate and then filtered and the solvent is evaporated off under reduced pressure in a rotary evaporator to obtain 168.9 mg of trifluoromethanesulfonic acid 1-acetyl-1H-indazol-5-yl ester are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.O.[OH-].[Na+].[N+:15]([O-])([OH:17])=[O:16]>C(Cl)(Cl)Cl.S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:15]([O-:17])=[O:16])=[C:5]([CH2:9][CH2:10][NH2:11])[CH:4]=1
Reactant: COc1cccc(CCN)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc([N+](=O)[O-])c(CCN)c1
Reaction time: 3 h
Yield: 21 %

Procedure:
To a solution of 2-(3-methoxyphenyl)ethylamine (1.51 g) in chloroform (30 ml), fuming nitric acid (specific gravity=1.52; 0.84 ml) and sulfuric acid (1.07 ml) were successively added dropwise under ice cooling and stirred under ice cooling for 3 h. Water and 2 N aqueous sodium hydroxide solution were added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=9:1) to give 400 mg of the titled compound (yield, 21%)
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7](C(O)=O)[N:8]=[CH:9][N:4]2[CH:3]=1>ClC1C=CC(Cl)=CC=1Cl.CCCCCC>[Br:1][C:2]1[S:6][C:5]2=[CH:7][N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: O=C(O)c1ncn2cc(Br)sc12
Solvent: CCCCCC
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: Brc1cn2cncc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
A solution of 2-bromoimidazo[5,1-b]thiazole-7-carboxylic acid (27 mg, 0.11 mmol) in 1,2,4-trichlorobenzene (1 ml) was stirred at 210° C. for one hr and then at 220° C. for 30 min. The reaction solution was allowed to cool to room temperature and was diluted with hexane, followed by extraction with 2 M hydrochloric acid (3 ml×3). The aqueous layer was neutralized with a 2 M aqueous solution of sodium hydroxide and was extracted with ethyl acetate (5 ml×3). The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was thoroughly dried to give 2-bromoimidazo[5,1-b]thiazole (18 mg, 80%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:30])(=O)=O.[Na]>C(O)(C)C>[Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[N:17]([CH3:30])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)c(Cl)cc1Cl
Reactant: COS(=O)(=O)OC
Agent: [Na]
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)c(Cl)cc1Cl

Procedure:
using isopropyl 2,4-dichloro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate and dimethyl sulphate with sodium isopropylate in isopropanol there is obtained isopropyl 2,4-dichloro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, 1H-NMR (CDCl3, 400 MHz, 7.78 ppm (s, 1H), 7.65 ppm (s, 1H), 5.23 ppm (m, 1H), 3.42 ppm (s, 3H), 2.96 ppm (m, 2H), 2.82 ppm (m, 2H), 2.17 ppm (m, 2H), 1.35 ppm (d, 6H),
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:6]2[CH:17]=[CH:18][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:20][C:5]=2[N:4]=1)[CH3:2].Br[C:31]1[CH:32]=[N:33][CH:34]=[N:35][CH:36]=1.C([O-])(O)=O.[Na+]>COCCOC.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>[CH2:1]([C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][OH:16])=[CH:12][CH:13]=2)[C:6]2[CH:17]=[CH:18][C:19]([C:31]3[CH:32]=[N:33][CH:34]=[N:35][CH:36]=3)=[CH:20][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1-c1ccc(CCO)cc1
Reactant: Brc1cncnc1
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: COCCOC
Solvent: O
Product: CCc1nc2cc(-c3cncnc3)ccc2n1-c1ccc(CCO)cc1
Temperature: 70 °C
Reaction time: 17 h
Yield: 50.3 %

Procedure:
To a solution of 2-{4-[2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-1-yl]phenyl}ethanol (step 1, 100 mg, 0.26 mmol) and 5-bromopyrimidine (45 mg, 0.28 mmol) in 1,2-dimethoxyethane (3.5 ml) was added sat. NaHCO3 aq. (1.2 ml) and Pd(PPh3)4 (60 mg, 0.05 mmol). This mixture was stirred at 70° C. for 17 h. The reaction mixture was diluted with water and extracted with CH2Cl2 (3×10 ml). The organic layer was dried (MgSO4) and concentrated to give light brown oil. This mixture was purified by SiO2 preparative TLC (CH2Cl2/methanol=10/1) to afford 45 mg (50%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[O:14][C:15]=2[CH3:16])=[N:7][CH:8]=1.[OH:22][C:23]1[C:27]([CH:28]=[O:29])=[CH:26][N:25]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]=1.CN(C)C=O.[H-].[Na+]>O>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:13]1[O:14][C:15]([CH3:16])=[C:11]([CH2:10][O:9][C:6]2[N:7]=[CH:8][C:3]([CH2:2][O:22][C:23]3[C:27]([CH:28]=[O:29])=[CH:26][N:25]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:24]=3)=[CH:4][CH:5]=2)[N:12]=1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cn1
Temperature: 90 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a mixture of 5-chloromethyl-2-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}pyridine (0.58 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.30 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.07 g) at room temperature, and the mixture was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:3, v/v) to give 3-[(6-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}pyridin-3-yl)methoxy]-1-phenyl-1H-pyrazole-4-carbaldehyde as colorless crystals (0.56 g, yield 77%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 122-123° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[C:29]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:28][CH:27]=[C:26]([F:34])[C:25]=3[F:35])[C:5]2=[CH:4][CH:3]=1.[CH3:37][O:38][CH:39]([Si:41]([CH3:44])([CH3:43])[CH3:42])[CH3:40].[H-].[Li+].[Cl:47][CH2:48][CH2:49][CH2:50]I>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:50][CH2:49][CH2:48][Cl:47])[CH:11]3[C:24]3[C:29]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:28][CH:27]=[C:26]([F:34])[C:25]=3[F:35])[C:5]2=[CH:4][CH:3]=1.[CH3:37][O:38][CH:39]([Si:41]([CH3:44])([CH3:43])[CH3:42])[CH3:40]
Reactant: CC(C)Oc1ccc(F)c(F)c1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: ClCCCI
Agent: COC(C)[Si](C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(F)c(F)c1C1N(CCCCl)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in example 24c, racemic (2′S,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (1.8 g, 2.72 mmol) prepared in example 73a was reacted with LiH (1.0 g, 125 mmol) and 1-chloro-3-iodo-propane (5.0 g, 24.5 mmol) in N,N-dimethyl-formamide (40 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-1′-(3-chloro-propyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white form (Yield: 0.67 g, 33.5%).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[NH:30][C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:38]=[N+:39]=[N-:40].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:40][N:39]=[N:38][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[CH:24]=[C:25]([C:29]3[NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[N:30]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3nc4ccccc4[nH]3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4[nH]3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-propyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-cyanobiphenyl and sodium azide in dimethyl-formamide.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)[N:17]=2)[N:10]([C:25](=[O:35])[CH:26]([NH:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]([CH3:29])[CH3:28])[CH2:9]1)=O)(C)(C)C.Cl.C(N(C(C)C)CC)(C)C.C(Cl)(=O)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCl>[CH3:34][O:33][C:31](=[O:32])[NH:30][CH:26]([C:25]([N:10]1[CH:11]([C:13]2[N:14]=[CH:15][CH:16]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)[N:17]=2)[CH2:12][N:8]([C:6](=[O:5])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:9]1)=[O:35])[CH:27]([CH3:29])[CH3:28]
Reactant: COC(=O)NC(C(=O)N1CN(C(=O)OC(C)(C)C)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CN(C(=O)c2ccccc2)CC1C1=NC(c2ccc(Br)cc2)C=N1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(4-Bromo-phenyl)-3′-(2-methoxycarbonylamino-3-methyl-butyryl)-2′,3′,4′,5′-tetrahydro-1H-[2,4]biimidazolyl-1′-carboxylic acid tert-butyl ester (55.6 mg, 0.101 mmol) was dissolved in dichloromethane (0.5 mL) and HCl (4M dioxane, 0.5 mL) was added. The resultant suspension was stirred at room temperature for 20 minutes, after which all volatiles were removed in vacuo. The crude material was dissolved in THF (1 mL) and diisopropyl ethylamine (26.0 mg, 0.202 mmol) was added, followed by benzoyl chloride (15.6 mg, 0.11 mmol). The reaction was stirred at room temperature. After 10 minutes, all starting material was consumed. All volatiles were removed in vacuo and the crude brown solid {1-[1′-Benzoyl-4-(4-bromo-phenyl)-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester was used in the coupling reaction without further analysis or purification: LCMS-ESI+: calc'd for C26H28BrN5O4: 554.4 (M+). Found: 554.3/556.4 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5](/[C:9](/[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[N:10]\NC(OC(C)(C)C)=O)=[C:4]([F:25])[CH:3]=1.Cl.NO.C([O-])(=[O:31])C.[Na+]>C(O)C.O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[N:10][OH:31])=[C:4]([F:25])[CH:3]=1
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)OC(=O)N/N=C(/c1ccncc1)c1cc(F)c(Br)cc1F
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C(c1ccncc1)c1cc(F)c(Br)cc1F
Yield: 114.1 %

Procedure:
A solution of Z/E 1-(4-bromo-2,5-difluorophenyl)-1-(4-pyridinyl)methanimine (Intermediate 1, 150 mg) in ethanol (2 ml) was treated with a solution of hydroxylamine hydrochloride (44 mg) and sodium acetate (50 mg) in water (0.4 ml) then stirred at reflux for 2 h. The ethanol was removed under vacuum and the residue was partitioned between water and ethyl acetate. The aqueous layer was re-extracted with ethyl acetate and the combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated under vacuum. The residue was purified on an SPE cartridge (silica, 2 g) eluting with cyclohexane/ethyl acetate (4:1 to 1:1) to give the title compound as a white foam (130 mg).