Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH:10]=[C:9]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:8]=2[CH:32]=1)#[N:3].[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH:42]=O)=[CH:37][CH:36]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1.C(O)C>[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]=[CH:42][CH2:12][C:9]2[C:8]3[CH:32]=[C:4]([C:2]#[N:3])[CH:5]=[CH:6][C:7]=3[O:11][CH:10]=2)=[CH:37][CH:36]=1
Reactant: N#Cc1ccc2occ(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2c1
Reactant: COc1ccc(CC=O)cc1
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C=CCc2coc3ccc(C#N)cc23)cc1
Reaction time: 24 h

Procedure:
2.14 g of (5-cyano-3-benzofuranyl)methyltriphenylphosphonium chloride and 0.7 g of 4-methoxyphenylacetaldehyde were dissolved in a solvent mixture of 100 ml of tetrahydrofuran and 100 ml of ethanol. The thus prepared solution was mixed with 0.71 g of 1,8-diazabicyclo[5.4.0]-7-undecene and stirred for 24 hours. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using toluene as an elution solvent, thereby obtaining 0.86 g of yellow and oily 3-[3-(4-methoxyphenyl)-allyl]-5-benzofurancarbonitrile as a mixture of E and Z forms. The thus obtained E/Z mixture was dissolved in 100 ml of ethanol, and the solution was subjected to catalytic hydrogenation under normal pressure in the presence of 370 mg of 5% palladium carbon catalyst. Thereafter, the catalyst was removed by filtration, and the solvent was distilled off to obtain 0.6 g of 3-[3-(4-methoxyphenyl)propyl]-5-benzofurancarbonitrile. The thus obtained methoxy compound was dissolved in 20 ml of dichloromethane. With stirring at -40° C., to the resulting solution was added dropwise 10 ml of a dichloromethane solution containing 0.4 ml of boron tribromide. The resulting mixture was warmed up to room temperature and stirred for 2 hours. The resulting reaction solution was poured into cold dilute hydrochloric acid and extracted with chloroform. After drying the resulting organic layer and distilling off the solvent, the thus obtained residue was purified by subjecting it to silica gel column chromatography using toluene as an elution solvent. In this way, 280 mg of 3-[3-(4-hydroxyphenyl)propyl]-5-benzofurancarbonitrile.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].Br[C:13]1[CH:14]=[CH:15][C:16]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[C:17]([CH:20]=1)[C:18]#[N:19]>C1(C)C(C)=CC=CC=1.CS(C)=O.[Pd]>[C:18]([C:17]1[CH:20]=[C:13]([C:4]2[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=2)[CH:14]=[CH:15][C:16]=1[O:21][CH2:22][CH:23]([CH3:25])[CH3:24])#[N:19]
Reactant: CC(C)COc1ccc(Br)cc1C#N
Reactant: CCOC(=O)c1scnc1C
Agent: [Pd]
Solvent: Cc1ccccc1C
Solvent: CS(C)=O
Product: CCOC(=O)c1sc(-c2ccc(OCC(C)C)c(C#N)c2)nc1C
Temperature: 140 °C
Reaction time: 24 h

Procedure:
To a test tube-type reaction vessel (60 mL) were added ethyl 4-methylthiazole-5-carboxylate (2.14 g, 12.5 mmol), 5-bromo-2-isobutoxybenzonitrile (2.54 g, 10.0 mmol) obtained in the Reference Example 1 and xylene (7.6 mL). After adding compounds listed in the Table 9 as a palladium compound (0.025 mmol), a ligand (0.10 mmol), a base (21.0 mmol), a carboxylic acid (0.10 mmol), and an additive (1.0 mmol), the reaction vessel was filled with nitrogen gas and sealed air-tight. The reaction mixture was heated to 140° C. and stirred for 24 hours. After the completion of the reaction, a part of the reaction solution was diluted with xylene and DMSO and the resulting solution was analyzed by HPLC measurement. The total HPLC area % of the compound A to D and TM (TM means target compound) was adjusted to 100%, the calculated yield of the subject material was calculated from each HPLC area %. Calculation of the yield from the HPLC area % of the subject material was carried out by applying corresponding numbers in the following calculation formula. Yield (%) of TM=total amount of TM (mol)/[{total amount of A (mol)+total amount of C (mol)×2+total amount of TM (mol)}]×100 Total amount of each compound (mol)=HPLC area value (mAU) of each compound/HPLC area value (mAU/mol) per mol of each compound
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N:14]1([CH2:20][CH2:21][OH:22])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][C:25]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.OCCCN1CCN(S(C2C=CC(C(O)=O)=CC=2)(=O)=O)CC1>>[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:9](=[O:11])[C:8]2[CH:7]=[CH:6][C:5]([S:2]([N:17]3[CH2:18][CH2:19][N:14]([CH2:20][CH2:21][OH:22])[CH2:15][CH2:16]3)(=[O:3])=[O:4])=[CH:13][CH:12]=2)=[CH:26][C:25]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: OCCN1CCNCC1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(O)c1ccc(S(=O)(=O)N2CCN(CCCO)CC2)cc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)N2CCN(CCO)CC2)cc1

Procedure:
1 g of 4-(chlorosulfonyl)benzoic acid was reacted with 615 μL of 2-(piperazin-1-yl)ethanol via Procedure H. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 125 mg of 4-(4-(3-hydroxypropyl)piperazin-1-ylsulfonyl)benzoic acid by Procedure G and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-(2-hydroxyethyl)piperazin-1-ylsulfonyl)benzamide. MS (Q1) 501.3 (M)+.
Reaction SMILES: [NH:1]([C:8]1([C:14]([NH2:16])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].II>C1(C)C=CC=CC=1.C(Cl)Cl>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27][CH2:28][C:19]=1[CH2:18][N:11]1[CH2:10][CH2:9][C:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:14]([NH2:16])=[O:15])[CH2:13][CH2:12]1
Reactant: NC(=O)C1(Nc2ccccc2)CCNCC1
Reactant: ClCC1=Cc2ccccc2CC1
Agent: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: NC(=O)C1(Nc2ccccc2)CCN(CC2=Cc3ccccc3CC2)CC1

Procedure:
A mixture of 4-anilino isonipecotamide (5.5 g), 3,4-dihydro-2-chloromethylnaphthalene (4.0 g), and powdered sodium carbonate (3.5 g) in toluene (200 ml) containing several crystals of iodine is refluxed for 14 hours with vigorous stirring under nitrogen. The reaction mixture is then cooled, diluted with methylene chloride (100 ml), and filtered. The filtrate is concentrated and the crude product triturated with ethyl acetate (100 ml) to give the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C@@H:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:9]1[OH:10])=[O:6].[N:19]([O-])=[O:20].[Na+].O.C(O)C>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:19]=[O:20])[C:5]([NH:7][C@@H:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:9]1[OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: O=C(NCCCl)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: O=CO
Product: O=NN(CCCl)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Reaction time: 1 h

Procedure:
1-(2-chloroethyl)-3-(β-D-mannopyranosyl)urea (500 mg) was dissolved in 10 ml of 99% formic acid, and the resulting solution was admixed with 250 mg of sodium nitrite in an ice-bath under stirring, while the sodium nitrite was added in small portions to said solution. The mixture was agitated for 1 hour and then admixed with 10 ml of cold water, followed by agitation for further 30 minutes to complete the nitrosation. The reaction solution was treated with 20 ml of Amberlite IR-120 (H+ form) and was then agitated for 20 minutes for the removal of sodium cation. After the cation-exchange resin was filtered off from the reaction mixture, the filtrate was concentrated to dryness by evaporating the solvent under a reduced pressure. A crystalline solid was yielded. This solid was digested with ethanol to give the titled compound. Yield 308 mg (55.9%). mp. 98°-100° C. (decomposition with foaming). [α]D25 -10° (c 0.5, H2O).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2([OH:18])[CH:15]3[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]3)[CH2:11]2)=[CH:4][CH:3]=1.[CH2:19]([Br:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[Br-:26].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2([OH:18])[CH:15]3[CH2:16][CH2:17][N+:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH2:13][CH2:14]3)[CH2:11]2)=[CH:6][CH:7]=1
Reactant: OC1(CCc2ccc(Cl)cc2)CN2CCC1CC2
Reactant: CCCCCCCBr
Product: CCCCCCC[N+]12CCC(CC1)C(O)(CCc1ccc(Cl)cc1)C2
Product: [Br-]

Procedure:
In a manner similar to Example II, Method B, react 3-[2-(4-chlorophenyl)ethyl)-1-azabicyclo[2.2.2]octan-3-ol with heptyl bromide to afford the title compound.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][SH:15])=[CH:10][CH:9]=1.I[C:17]1[CH:22]=[N:21][NH:20][C:19](=[O:23])[CH:18]=1>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][S:15][C:17]2[CH:22]=[N:21][NH:20][C:19](=[O:23])[CH:18]=2)=[CH:10][CH:9]=1
Reactant: O=c1cc(I)cn[nH]1
Reactant: SCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=c1cc(SCc2ccc(Cl)cc2)cn[nH]1
Temperature: 100 °C
Reaction time: 18 h
Yield: 51.9 %

Procedure:
A mixture of K2CO3 (65.4 mg, 0.47 mmol), (4-chlorophenyl)methanethiol (250 mg, 1.58 mmol), and 5-iodopyridazin-3(2H)-one (35 mg, 0.16 mmol) was stirred at 100° C. for 18 hours. After removal of the precipitate by filtration and concentration of the filtrate, the crude product was purified by prep-HPLC (C18 column/H2O:MeOH:TFA 90:10:0.1 to 10:90:0.1 gradient) to yield 5-(4-chlorobenzylthio)pyridazin-3(2H)-one 9A (21 mg, 51.6% yield). 1H NMR (400 MHz, Chloroform-D) δ ppm 11.08 (1H, br. s.), 7.57 (1H, d, J=2.01 Hz), 7.33 (4H, s), 6.57 (1H, d, J=2.01 Hz), 4.12 (2H, s).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[C:12](O)(=[O:22])[C:13]1[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:15]([OH:17])=[O:16]>C(Cl)Cl>[C:15]([C:14]1[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=1[C:12]([NH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=[O:22])([OH:17])=[O:16]
Reactant: NCCCSc1ccncc1
Reactant: O=C(O)c1ccccc1C(=O)O
Solvent: ClCCl
Product: O=C(O)c1ccccc1C(=O)NCCCSc1ccncc1
Yield: 92.3 %

Procedure:
A solution of 340 mg (2.02 mmol) of 4-(3-aminopropylthio)pyridine and 738 mg (4.98 mmol) of anhydrous phthalic acid in 5 ml of methylene chloride was stirred at room temperature for 30 minutes. The resulting crystals were filtered and dried to obtain 590 mg of the desired compound (92.3%, colorless powder), mp: 151.0°-153.3° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([NH:14][C:15]([NH2:17])=[S:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C[I:19].[CH3:20]COCC>CC(C)=O>[IH:19].[CH:10]1[C:11]2[CH:12]([NH:14][C:15]([S:16][CH3:20])=[NH:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CCOCC
Reactant: CI
Reactant: NC(=S)NC1c2ccccc2-c2ccccc21
Solvent: CC(C)=O
Product: CSC(=N)NC1c2ccccc2-c2ccccc21
Product: I
Reaction time: 4 h

Procedure:
To 7.85 g. (0.033 mole) of N-(9-fluorenyl)thiourea in 200 ml acetone is added 4.68 g (0.033 mole) of methyl iodide. The mixture is allowed to stand at room temperature for about 4 hours. Ether (400 ml) is added and the mixture allowed to stand overnight, affording the crystalline product, methyl N-(9-fluorenyl)carbamimidothioate hydroiodide, which is filtered off; m.p. (208) 212°-14° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6]CC1CCCCC1)=[O:5])#[N:2].[CH2:14]([N:18]=[C:19]=[O:20])[CH2:15][CH2:16][CH3:17].[C:21]1([CH3:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:14]([N:18]([CH2:27][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:19]([NH:6][C:4](=[O:5])[CH2:3][C:1]#[N:2])=[O:20])[CH2:15][CH2:16][CH3:17]
Reactant: N#CCC(=O)NCC1CCCCC1
Reactant: CCCCN=C=O
Reactant: Cc1ccccc1
Product: CCCCN(CC1CCCCC1)C(=O)NC(=O)CC#N
Yield: 30 %

Procedure:
2-Cyano-N-(cyclohexylmethyl)acetamide (from step (a) example 13, 7.66 g, 42.5 mmol) was also condensed with butyl isocyanate (Adrich, 7.60 ml, 63.7 mmol) in anhydrous toluene (70 mL) in a Parr bomb at 120° C. for 24 h to provide 1-butyl-3-(2-cyanoacetyl)-1-(cyclohexylmethyl)urea (3.51 g, 30%), 1H-NMR (DMSO-d6) consistent with structure. Unreacted 2-cyano-N-(cyclohexylmethyl)acetamide was also recovered (5.97 g, 70%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:15]1[O:16][CH:17]=[CH:18][N:19]=1)CCC>C1(C)C=CC=CC=1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:15]2[O:16][CH:17]=[CH:18][N:19]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Solvent: Cc1ccccc1
Product: COc1cccc(-c2ncco2)c1
Reaction time: 8 h

Procedure:
A suspension containing 1.16 ml of 1-bromo-3-methoxybenzene (9.2 mmol), 2.12 ml of 2-(tributylstannanyl)-1,3-oxazole (5.9 mmol) and 276 mg (0.2 mmol) of tetrakis[triphenylphosphine]palladium in 50 ml of toluene is stirred overnight at reflux under argon. The toluene is evaporated off using a rotary evaporator, and the residue is then suspended in ethyl acetate. After filtering the suspension, the filtrate is evaporated to dryness and the crude product is purified by chromatography over silica gel, eluting with CH2Cl2 and then with CH2Cl2/acetone 98/2 to yield the title product in the form of an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH:9]([NH2:12])([CH3:11])[CH3:10].CCN(CC)CC>C1COCC1>[Cl:8][C:4]1[N:3]=[C:2]([NH:12][CH:9]([CH3:11])[CH3:10])[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)Nc1cncc(Cl)n1
Temperature: 60 °C
Reaction time: 12 h
Yield: 52.1 %

Procedure:
To a mixture of 2,6-dichloropyrazine (5 g, 33.78 mmolm, Aldrich) and isopropyl amine (2.4 g, 50.67 mmol, Aldrich) in dry THF (5 mL) was added Et3N (2.5 mL) and the reaction was stirred at 60° C. for 12 h. The reaction was cooled to RT, treated with ice cold water (˜25 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was triturated with n-pentane to give 6-chloro-N-isopropylpyrazin-2-amine (3 g, 52.5%) as a white solid. MS (ESI, pos. ion) m/z: 172.0 (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 7.81 (s, 1H), 7.64 (s, 1H), 7.46 (d, J=7.2 Hz, 1H), 3.93-3.88 (m, 1H), 1.15 (d, J=5.6 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH2:24]([N:26]([CH2:30][CH3:31])[CH2:27][CH2:28]Cl)[CH3:25].C(=O)([O-])[O-].[K+].[K+].[C:38]([O-:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([O-:43])=[O:42]>CC(C)=O>[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:25][CH2:24][N:26]([CH2:30][CH3:31])[CH2:27][CH3:28])[C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2O)cc1
Reactant: CCN(CC)CCCl
Reactant: O=C([O-])/C=C/C(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)CCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2cc(Cl)ccc21
Product: O=C(O)/C=C/C(=O)O

Procedure:
A mixture of 1.01 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 0.57 g of 2-(diethylamino)ethyl chloride hydrochloride, 1.24 g of potassium carbonate and 30 ml of acetone is treated in the same manner as described in Example 15. The crude product is converted into its fumarate and then recrystallized from ethanol. 1.22 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(diethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one fumarate are obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[CH3:22][O:23][NH:24][CH3:25]>>[CH3:22][O:23][N:24]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1)[CH3:25]
Reactant: COC(=O)c1cccc2nc(-c3ccc(CBr)cc3)oc12
Reactant: CNOC
Product: COC(=O)c1cccc2nc(-c3ccc(CN(C)OC)cc3)oc12
Yield: 65 %

Procedure:
Following the experimental procedure as described in Example 144 C, and replacing methyl 2-(4-(bromomethyl)phenyl)benzo[d]oxazole-4-carboxylate with methyl 2-(4-(bromomethyl)phenyl)benzo[d]oxazole-7-carboxylate and substituting dimethylamine with methoxy(methyl)amine, methyl 2-(4-((methoxy(methyl)amino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (Yield: 65%. LC-MS (ESI) m/z: 327 (M+1)+) was made.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]([F:14])([F:13])[CH3:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=1.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.N.CO>C(O)C>[F:13][C:11]([C:9]1[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=[C:2]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([C:17]([F:16])([F:25])[F:26])=[CH:19][CH:20]=3)[N:7]2[N:8]=1)([F:14])[CH3:12]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(Cl)n2nc(C(C)(F)F)nc2n1
Agent: N
Solvent: CCO
Solvent: CO
Product: Cc1cc(Nc2ccc(C(F)(F)F)cc2)n2nc(C(C)(F)F)nc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of Intermediate 3 (10 g, 43 mmol) in ethanol (150 mL), 4-(trifluoromethyl)aniline (ALDRICH, 6.93 g, 43 mmol) was added and the mixture was stirred at room temperature for 1 h. 7M Ammonia in MeOH (6.14 mL, 43 mmol) was added to neutralize the hydrochloride salt and solvent was removed in vacuo. The crude mixture was purified by flash chromatography (Si, eluting with Hexane/EtOAc mixtures from 95:5 to 40:60%) to yield the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].Cl[C:23]1C(Cl)=C(C(=O)CCC)C=CC=1OCCCC(O)=O>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([C:16](=[O:21])[C:17](=[CH2:23])[CH2:18][CH2:19][CH3:20])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: CCCCC(=O)c1ccc(OCCCC(=O)O)c(Cl)c1Cl
Reactant: CCCC(=O)c1ccc(OCCCC(=O)O)c(Cl)c1Cl
Product: C=C(CCC)C(=O)c1ccc(OCCCC(=O)O)c(Cl)c1Cl

Procedure:
By conducting the reaction as described in Example 2, Step B, except that an equimolar amount of 4-(2,3-dichloro-4-valerylphenoxy)butyric acid was substituted for the 4-(2,3-dichloro-4-butyrylphenoxy)butyric acid, there was obtained 4-[2,3-dichloro-4-(2-methylenevaleryl)phenoxy]butyric acid, m.p. 85°-87° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[O:30][CH2:31][CH2:32][CH3:33])=[CH:11][CH:10]=1)#[N:2].C[Sn]([N:38]=[N+:39]=[N-:40])(C)C>C1(C)C=CC=CC=1>[CH2:31]([O:30][C:17]1[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:40][N:39]=[N:38][N:2]=3)=[CH:14][CH:13]=2)[C:20]2[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1)[CH2:32][CH3:33]
Reactant: CCCOc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCCOc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 1-[(2′-cyanobiphenyl-4-yl)methyl]-2-propoxybenzimidazole-7-carboxylate (0.69 g) and trimethyltin azide (0.7 g) in toluene (15 ml) was heated for 4 days under reflux. The reaction mixture was concentrated to dryness and to the mixture was added methanol (20 ml) and 1N-HCl (10 ml). After stirring at room temperature for 30 minutes, the mixture was adjusted to pH 3-4 with 1N NaOH. After removal of the solvent, the residue was extracted with chloroform-water. The organic layer was washed with water and dried, and the solvent was evaporated to dryness to give a syrup. The syrup was purified by column chromatography on silica gel to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals (0.31 g, 43%), m.p. 157-159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-])=O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>C(O)(=O)C.O.C(OCC)(=O)C.[Fe]>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([NH2:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(C(=O)O)c(Cl)cc1F
Temperature: 25 °C

Procedure:
A solution of 2-chloro-4-fluoro-5-nitrobenzoic acid (18.0 g, 0.0824 mol) in 75 ml of acetic acid was heated at reflux temperature. Iron powder (18.4 g, 0.328 mol) was added in several portions and the resulting suspension was cooled to room temperature and diluted with water and ethyl acetate. The mixture was filtered and the filtrate was saved. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the title compound as a tan solid. Yield: 9.00 g (58.1%); mp.: 153-155° C.; identified by NMR and mass spectral analysis.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[C:36]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37]>>[C:36]([C:40]1[CH:45]=[CH:44][C:43]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]5)=[CH:22][CH:21]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:4][CH:3]=2)=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Product: CC(C)(C)c1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)cc1

Procedure:
5-{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 4-tert-butylphenylboronic acid (36 mg, 0.2 mmol) to give 5-{4-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1O)([O-:3])=[O:2].[CH3:11][O:12][C:13](=[O:21])[C:14]([CH3:20])([CH3:19])[CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-:23].[K+].[K+]>C(#N)C>[CH3:19][C:14]([CH3:20])([CH2:15][CH2:16][CH2:17][O:23][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:13]([O:12][CH3:11])=[O:21]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(C)(C)CCCBr
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)(C)CCCOc1cccc([N+](=O)[O-])c1
Yield: 94 %

Procedure:
A mixture of 27.8 g (200 mmol) of 2-nitrophenol, 44.6 g (200 mmol) of methyl-5-bromo-2,2-dimethylpentanoate (Journal of Medicinal Chemistry, Vol. 26, pp 1020-1027 (1983)) and 30.5 g (220 mmol) of anhydrous potassium carbonate in 300 ml of acetonitrile is stirred at reflux for 18 hours. The inorganic salts are removed, washed with acetonitrile and the filtrate is concentrated on a rotary evaporator. The residue is taken up in diethyl ether and the solution washed with 2N potassium hydroxide (3×50 ml), brine, dried (magnesium sulfate), and evaporated to afford 55.9 g of crude product. Distillation gives 52.9 g of 2,2-dimethyl-5-(3-nitrophenoxy)pentanoic acid, methyl ester, bp 160°-165° C. (0.5 mm).