Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[N:8]1.C(N(CC)CC)C.[O:54]1[CH:58]=[CH:57][CH:56]=[C:55]1Cl.[C:60](=O)(O)[O-:61].[Na+]>O1CCCC1>[NH:17]1[C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:60]([C:55]3[O:54][CH:58]=[CH:57][CH:56]=3)=[O:61])=[CH:42][CH:41]=2)=[N:20][CH:19]=[N:18]1
Reactant: O=C([O-])O
Reactant: Clc1ccco1
Reactant: Nc1ccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)cc1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)cc1)c1ccco1
Temperature: 25 °C
Reaction time: 16 h
Yield: 5 %

Procedure:
To a solution of 4-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]1H-indazol-3-yl}phenylamine (0.300 g, 0.498 mmol) was added tetrahydrofuran (4.50 mL), triethylamine (0.345 mL, 2.48 mmol), and 2-furyl chloride (0.058 mL, 0.735 mmol). The mixture was stirred for 16 h at ambient temperature and poured into saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated. Purification by preparative HPLC (30–80% acetonitrile/water) followed by washing with saturated sodium bicarbonate and extraction with ethyl acetate gave the title compound (0.0086 g, 5% yield). 1H NMR (DMSO-d6) δ 8.75 (d, 1H), 8.10 (m, 6H), 7.74 (m, 1H), 7.39 (d, 1H), 6.75 (m, 1H). ES-MS (m/z) 371 [M+1]+
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:24]5[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH:29]=5)[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.C(O)(=O)C>[Pd].C(O)C>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([CH:24]5[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]5)[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(C3=CCN(C)CC3)cc2c1=O
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(C3CCN(C)CC3)cc2c1=O
Yield: 49.1 %

Procedure:
N-Cyclopropyl-4-methyl-3-[6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-oxoquinazolin-3(4H)-yl]benzamide (0.284 g) and 10% Palladium on carbon (0.028 g) were stirred in ethanol (6 ml) and acetic acid (0.5 ml) under an atmosphere of hydrogen for 24 hours. The catalyst was removed by filtration through diatomaceous earth (Celite®) and the filtrate was concentrated under reduced pressure. Purification by column chromatography on a silica column eluting with 10% methanol/ethyl acetate+1% aqueous ammonia solution to give the title compound (0.140 g) as a white foam solid; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 1.78 (m, 4H), 2.00 (m, 2H), 2.13 (s, 3H), 2.20 (s, 3H), 2.67 (m, 1H), 2.88 (m, 3H), 7.52 (d, 1H), 7.71 (d, 1H), 7.82 (m, 2H), 7.90 (d, 1H), 8.02 (s, 1H), 8.24 (s, 1H), 8.42 (d, 1H); Mass Spectrum: M+H+ 417.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:5](=[O:24])[N:6]([CH2:22][CH3:23])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)=[CH:11][CH:10]=[C:9]([CH3:21])[N:8]=2.Cl.[C:26](N1C=CC=N1)(=[NH:28])[NH2:27].C(N(C(C)C)CC)(C)C>O1CCOCC1>[OH2:24].[ClH:20].[Cl:20][C:16]1[CH:15]=[C:14]([C:13]2[C:12]3[C:7](=[N:8][C:9]([CH3:21])=[CH:10][CH:11]=3)[N:6]([CH2:22][CH3:23])[C:5](=[O:24])[C:4]=2[CH2:3][CH2:2][NH:1][C:26]([NH2:28])=[NH:27])[CH:19]=[CH:18][CH:17]=1
Reactant: CCn1c(=O)c(CCN)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(=O)c(CCNC(=N)N)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Product: O
Reaction time: 122 h
Yield: 172.4 %

Procedure:
To a 15 ml 1,4-dioxane solution containing 314 mg of 3-(2-aminoethyl)-4-(3-chlorophenyl)-1-ethyl-7-methyl-1,8-naphthyridin-2(1H)-one were added 404 mg of 1-amidinopyrazole monohydrochloride and 0.48 ml of diisopropylethylamine, followed by stirring for 122 hours. The reaction solution was evaporated, the resulting solid was removed by filtration, and the solid was further washed with chloroform. The combine filtrate and washings were concentrated and the residue was purified by a silica gel column chromatography (chloroform-methanol-aqueous ammonia). The resulting oily substance was dissolved in 5 ml of ethanol, and 0.5 ml of 4M hydrogen chloride-ethyl acetate and acetonitrile were added thereto successively. The solvent was evaporated to obtain 347 mg of 4-(3-chlorophenyl)-1-ethyl-3-(2-guanidinoethyl)-7-methyl-1,8-naphthyridin-2(1H)-one monohydrochloride monohydrate as a colorless solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].CCCCCC>CC(=O)CC>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1ccc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1
Reaction time: 18 h
Yield: 56.4 %

Procedure:
A solution of methyl indole-5-carboxylate, (21.7 g), p-toluenesulfonyl chloride (47.3 g), and K2CO3 (68.4 g) in 2-butanone (310 ml) was refluxed under a nitrogen atmosphere for 18 hr. Additional p-toluenesulfonyl chloride (12.0 g) and K2CO3 (17 g) was added to the reaction mixture and reflux was continued for 18 hr. The reaction mixture was filtered hot and the filtrate was evaporated to give an ivory solid that was tritrated with hexane to give methyl 1-(4-methylphenylsulfonyl)indole-5-carboxylate (23.0 g, 56%) as an ivory solid: NMR (80 MHz, CDCl3): 2.34 (s, 3H, ArCH3), 3.91 (s, 3H, OCH3), 6.7 (d, 1H, H2 -indole).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([CH2:13][OH:14])[O:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].ClC1C=CC(O[CH2:22][C:23]#[N:24])=CC=1.CC(C)([O-])C.[K+].Cl>CN(C=O)C.O>[OH:14][CH2:13][CH:10]1[CH2:11][O:12][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[C:15]([CH2:22][C:23]#[N:24])[C:8]=2[O:9]1
Reactant: N#CCOc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc2c(c1)OC(CO)CO2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1c([N+](=O)[O-])ccc2c1OC(CO)CO2
Temperature: -2.5 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
A solution of racemic (7-nitro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanol (1.00 g, 4.73 mmol) and 4-chlorophenoxyacetonitrile (827 mg, 4.94 mmol) in DMF (12 mL) was added dropwise to a solution of potassium tert-butoxide (2.12 g, 18.9 mmol) in DMF (20 mL) at −5-0° C. After the addition was complete (7 minutes), the reaction mixture was stirred for 1 hour at −5-0° C. The reaction mixture was acidified with 1 N HCl before drowning into water (200 mL). The mixture was extracted with EtOAc (3×100 mL) and the combined organic layers were washed with 1N NaOH (3×50 mL) to remove most of the 4-chlorophenol. After removal of solvent, the residue was purified by flash chromatography on silica gel, gradient elution using 2:3, 1:1, 3:2, 100:0 ethyl acetate/hexane, to give 139 mg, 14% recovered starting material and 804 mg, 68% yield of the title compound as a solid. 1H NMR (CDCl3) δ 7.77 (1H, d, J=9.12 Hz); 7.01 (1H, d, J=9.12 Hz); 4.50-4.40 (2H, m); 4.30-3.91 (5H, m); 2.25-2.21 (1H, m). 13C NMR (CDCl3) δ 148.07, 141.71, 141.55, 119.44, 117.07, 116.96, 115.71, 74.36, 65.31, 61.18, 14.89.
Reaction SMILES: [C:1]([O:23][CH2:24][CH:25]=[CH2:26])(=[O:22])[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]CC1C=CC(OC)=CC=1)=[O:11])=[O:5].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:24]([O:23][C:1](=[O:22])[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5])[CH:25]=[CH2:26]
Reactant: C=CCOC(=O)CCC(=O)OCCCC(=O)OCc1ccc(OC)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)CCC(=O)OCCCC(=O)O

Procedure:
According to a similar procedure to that described in Example 13-(2), allyl 4-[(4-methoxybenzyl)oxy]-4-oxobutyl succinate (546 mg, 1.50 mmol) obtained from Example 14-(4) was treated with anisole (0.50 ml) and trifluoroacetic acid (5 ml), to afford 4-[4-(allyloxy)-4-oxobutyryloxy]butyric acid, and then treated with oxalyl chloride (290 mg) to give crude allyl 4-chloro-4-oxobutyl succinate.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH3:17])[CH:8]=1.[N+:18]([O-])([O-:20])=[O:19].[K+]>>[F:6][C:7]1[C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH3:17])[CH:8]=1
Reactant: COc1cc(F)ccc1C(C)=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1cc(F)c([N+](=O)[O-])cc1C(C)=O
Temperature: 0 °C
Yield: 92.8 %

Procedure:
In nitrogen atmosphere, cone. sulfuric acid 36 mL was added to 1-(4-fluoro-2-methoxyphenyl)ethanone 5.50 g, followed by heating to homogeneity. Cooling the same with salt-ice, potassium nitrate 3.47 g was added little by little, followed by an hour's stirring. The reaction liquid was poured in ice water, and the precipitated crystals were recovered by filtration and washed with water. Drying the crystals, 6.47 g of the title compound was obtained.
Reaction SMILES: C1(S(O)(=O)=O)C=CC=CC=1.C(OC([NH:18][CH2:19][C@:20]1([CH2:28][C:29]([OH:31])=[O:30])[CH2:26][C@@H:25]2[C@H:21]1[CH:22]=[C:23]([CH3:27])[CH2:24]2)=O)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[NH2:18][CH2:19][C@:20]1([CH2:28][C:29]([OH:31])=[O:30])[CH2:26][C@@H:25]2[C@H:21]1[CH:22]=[C:23]([CH3:27])[CH2:24]2
Reactant: CC1=C[C@@H]2[C@H](C1)C[C@]2(CNC(=O)OC(C)(C)C)CC(=O)O
Agent: O=S(=O)(O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=C[C@@H]2[C@H](C1)C[C@]2(CN)CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
[(1R,5S,6S)-6-tert-butoxycarbonylaminomethyl-3-methylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid benzenesulfonic acid (5.6 g, 15.8 mmol) was suspended in methylene chloride (50 mL). To the suspension, triethylamine (4.4 ml, 31.7 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The resulting solid was collected by filtration and washed with isopropanol to obtain the compound of interest as a white solid (2.4 g, 77%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CO[CH:10]=[C:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13].CC(N(C)C)=O.Cl>C(OCC)C>[C:21]1([C:11]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:13])=[O:14])=[CH:10][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC=C(c1ccccc1)S(=O)(=O)c1ccccc1
Reactant: Nc1ccccn1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: O=S(=O)(C(=CNc1ccccn1)c1ccccc1)c1ccccc1
Yield: 12.2 %

Procedure:
A solution of 2-aminopyridine (1.05 g) and 2-methoxy-1-phenyl-1-phenylsulphonylethene (2.0 g) in a mixture of anhydrous dimethylacetamide (50 ml) and a solution of hydrogen chloride in diethyl ether (6N; 0.5 ml) was heated at reflux for 25 hours, and then it was cooled and poured onto ice (150 g). The yellow precipitate was filtered off, subjected twice to medium pressure chromatography on silica gel, eluting with chloroform, triturated with light petroleum ether (b.p. 60°-80° C.) and recrystallised from a mixture of diethyl ether and light petroleum ether (b.p. 60°-80° C.), to give 1-phenyl-1-phenylsulphonyl-2-(pyrid-2-ylamino)ethene (0.3 g), m.p. 159°-160° C.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][N:25]4[CH:29]=[CH:28][N:27]=[C:26]4[C:30]([O:32]CC)=[O:31])=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>O>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][N:25]4[CH:29]=[CH:28][N:27]=[C:26]4[C:30]([OH:32])=[O:31])=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1nccn1CCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nccn1CCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
A mixture of ethyl 1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-2-imidazolecarboxylate (300 mg), 1N aqueous sodium hydroxide (1.32 ml) and tetrahydrofuran (3 ml) was stirred for 2 hours at room temperature. To the reaction mixture were added 1N hydrochloric acid (1.32 ml) and then water. The resulting crystalline precipitate was collected by filtration and washed with ether. Recrystallization from tetrahydrofuran gave 1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]-phenyl]propyl]-2-imidazolecarboxylic acid (176 mg, 63%) as colorless prisms, mp 116° C. (decomp.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([CH2:10][CH3:11])[CH:3]=1.P(Br)(Br)[Br:13]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:13])=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: BrP(Br)Br
Reactant: CCc1cc(Br)ccc1CO
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)ccc1CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a solution of (4-bromo-2-ethyl-phenyl)-methanol (7.9 g, 36.7 mmol) in anhydrous CHCl3 (122 mL) was added PBr3(4.2 mL, 44.1 mmol). The resulting mixture was stirred at room temperature for 2 hours before it was quenched by the addition of water. The organic layer was washed with NaHCO3, brine and dried over MgSO4. The solvent was removed in vacuo and the residue was filtered through a pad of silica gel with 20% EtOAc in hexanes. The solvent was removed in vacuo to afford the desired product (8.4 g, 83%). 1H NMR (300 MHz, CDCl3): δ 1.29 (t, J=7.5 Hz, 3 H), 2.71–2.78 (m, 2 H), 4.48 (s, 2H), 7.17–7.20 (m, 1H), 7.29–7.32 (m, 1 H), 7.36–7.38 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:26][CH2:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][CH2:38][NH2:39]>COCCOC.CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:39][CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28][CH2:27][NH2:26])=[O:8])=[CH:9][CH:10]=1
Reactant: NCCCNCCCCNCCCN
Reactant: O=C(O)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: COCCOC
Solvent: CN(C)C=O
Product: NCCCNCCCCNCCCNC(=O)c1ccc(O)cc1
Reaction time: 48 h

Procedure:
According to the General Procedure using 4-hydroxybenzoic acid (80 mg, 0.58 mMol), dicyclohexylcarbodiimide (125 mg, 0.61 mMol), and spermine (430 mg, 2.13 mMol) in DME/DMF (4 ml, 3:1), activation during 3 h and coupling over 48 h. The product was eluted over silica gel with dichloromethane/methanol/0.880 ammonia solution (2:2:1). The desired amide was in fractions 8-12 and was homogeneous when monitored by tic on silica (CH2Cl2 /MeOH/NH4OH, 2:2:1), Rf =0.29, (23 mg, 12%), lyophilisation gave 7 mg of a colourless, viscous oil whose spectroscopic data include: pmr (90 MHz, 2H2O) 1.4-1.9 (m, 8H, 4×CH2 --CH2), 2.5-2.9 (m, 10H, 5×CH2 --N), 3.25 (t, J=7, 2H, CON2H--CH2 --CH2) 6.6-6.9 (m, 2H, 2×ArH 3,5), and 7.0-7.3 (m, 2H, 2×ArH2,6)ppm; M+1 323 (FAB matrix m-nitrobenzyl alcohol) C17H30N4O2 requires M+ 322).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([NH2:22])=[N:20][CH:21]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][O:24][C:25](=[O:31])[CH2:26][CH2:27][C:28](O)=[O:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.O>CN(C)C=O.C(N(CC)C(C)C)(C)C>[O:29]=[C:28]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[CH:21][N:20]=1)[CH2:27][CH2:26][C:25]([O:24][CH3:23])=[O:31]
Reactant: COC(=O)CCC(=O)O
Reactant: Nc1ccc(COCc2ccc(-c3ccccc3)cc2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)Nc1ccc(COCc2ccc(-c3ccccc3)cc2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of 5-[(4-phenylphenyl)methoxymethyl]pyridin-2-amine (0.189 g) in N,N-dimethylformamide (6.0 mL), N,N-diisopropylethylamine (0.453 mL), 4-methoxy-4-oxobutanoic acid (0.174 g), and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.376 g) were added at room temperature, and the mixture was stirred at 80° C. for 2 hours. The reaction solution was cooled to room temperature, and water was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column (Yamazen Corporation, elution solvent: dichloromethane/ethyl acetate) to obtain the title compound (0.171 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:38]1([CH2:44][C:45]([NH2:47])=[O:46])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:35])[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:41]3[CH2:42][CH2:43][N:38]([CH2:44][C:45]([NH2:47])=[O:46])[CH2:39][CH2:40]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:33])[CH3:34])=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Reactant: NC(=O)CN1CCNCC1
Agent: Cl
Product: COc1ccc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(CC(N)=O)CC2)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-acetamide dihydrochloride (Matrix Scientific) to give the title compound. LC-MS: 638.2 [(M+H)+]
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[N:20]1([C:25]2[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=2)[CH:24]=[CH:23][CH:22]=[N:21]1>>[N:20]1([C:25]2[CH:26]=[C:27]([C:15]3[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=3)[CH:28]=[CH:29][CH:30]=2)[CH:24]=[CH:23][CH:22]=[N:21]1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Reactant: OB(O)c1cccc(-n2cccn2)c1
Product: O=C(O)c1cccc(COc2ccc(-c3cccc(-n4cccn4)c3)cc2)c1

Procedure:
3-(3′-Pyrazol-1-yl-biphenyl-4-yloxymethyl)-benzoic acid was prepared using the procedure described above for the synthesis of Example 4 from 3-(4-iodo -phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1) and 3-(1H-pyrazol-1-yl)phenylboronic acid (available from ASDI Inc., Newark, Del.). Mass spectrum MH+=371.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.N1C=CN=C1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(Cl)Cl.O>[Si:20]([O:10][CH2:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([CH3:8])[CH:5]=1)[NH2:1])([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21]
Reactant: Cc1cc(N)cc(CO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(N)cc(CO[Si](C)(C)C(C)(C)C)c1

Procedure:
To a solution of (3-amino-5-methylphenyl)methanol (prepared according to: Behrens, C.; Egholm, M.; Buchardt, O. Synthesis 1992, 12, 1235-1236, 750 mg, 5.47 mmol) in CH2Cl2 (25 mL) was added imidazole (447 mg, 6.56 mmol) then TBDMSCl (989 mg, 6.56 mmol) at room temperature. After 72 hours the mixture was diluted with H2O. The layers were separated and the aqueous extracted with CH2Cl2 (2×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (20% EtOAc/hexanes) gave 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-methylaniline as a clear oil. 1H-NMR (300 MHz, CDCl3) δ 6.58 (s, 1H), 6.50 (s, 1H), 6.40 (s, 1H), 4.60 (s, 2H), 3.60 (bs, 2H), 2.24 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].B([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)(O)O.C(N(CC)CC)C>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]([CH3:12])=[C:2]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH:3]=1)=[O:6]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc(C)c(Br)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-c2ccc(C(=O)O)cc2)c1
Temperature: 100 °C
Yield: 71.3 %

Procedure:
A stirred solution of methyl 3-bromo-4-methylbenzoate (2.6 g, 0.011 mole) in dry DMF (20 ml) under argon was treated with 4-boronobenzoic acid (1.85 g, 0.011 mole) and tetrakis (triphenylphosphine) palladium(0) (400 mg), followed by triethylamine (4.68 ml, 0.046 mole). The mixture was heated at 100° C. for 18 hours, then concentrated in vacuo. The residue was treated with ethyl acetate and extracted with 10% NaHCO3 solution. The basic extract was acidified with dil. HCl and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated in vacuo to afford the title compound as a light orange solid (2.12 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH:20]1([CH2:26][NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>ClCCl.CO>[CH:20]1([CH2:26][NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:16](=[O:18])[C:15]#[C:14][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[CH:13][CH:12]=3)=[CH:31][CH:30]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(O)C#Cc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: Nc1ccc(CNCC2CCCCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(C#Cc1ccc(-c2ccc(Cl)cc2)cc1)Nc1ccc(CNCC2CCCCC2)cc1

Procedure:
Prepared analogously to Example 3.8. from (4′-chlorobiphenyl-4-yl)propynoic acid and 4-[(cyclohexylmethylamino)methyl]phenylamine hydrochloride. Yield: 60 mg (13% of theory); melting point: 205° C.-210° C.; C29H29ClN2O (M=457.01); calc.: molecular ion peak (M+H)+: 457/459 (Cl); found: molecular ion peak (M+H)+: 457/459 (Cl); Rf value: 0.60 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[Cl:11][C:12]1[C:17]([S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1.[OH-].[Na+]>C(#N)C.O>[Cl:11][C:12]1[C:17]([S:18]([NH:21][C:22]([NH:1][C:2]2[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=2)=[O:23])(=[O:19])=[O:20])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: COc1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1cccnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccnc2Cl)n1

Procedure:
To a stirred suspension of 1.4 g of 2-amino-4-methoxy-6-methylpyrimidine in 20 ml of dry acetonitrile at room temperature was added 2.2 g of 2-chloropyridine-3-sulfonylisocyanate. The mixture was stirred for several hours and filtered. Evaporation of the filtrate yielded a solid residue which was stirred in approximately 30 ml of water while adjusting the pH of this mixture to 11 by the addition of 10% NaOH. This solution was filtered, the filtrate pH adjusted to pH 7 by adding 10% hydrochloric acid and the resulting neutral solution was again filtered. The desired product was then precipitated from this filtrate by adjusting the pH to 2, collected in a sintered funnel and dried in a vacuum oven at room temperature. It melted at 165°-168°.