Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH2:3]N)[OH:2].C1(C)C(C)=CC=CC=1.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26](=[N:29][O:30][CH3:31])[C:27]#[N:28])=[CH:16][CH:15]=1>O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C.O>[CH3:31][O:30][N:29]=[C:26]([C:27]1[O:2][CH2:1][CH2:3][N:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[O:19][CH2:18][C:17]1[CH:16]=[CH:15][C:14]([Cl:13])=[CH:33][CH:32]=1
Reactant: CON=C(C#N)c1ccccc1OCc1ccc(Cl)cc1
Reactant: NCCO
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: O
Solvent: Cc1ccccc1C
Product: CON=C(C1=NCCO1)c1ccccc1OCc1ccc(Cl)cc1
Yield: 9.8 %

Procedure:
Zinc acetate dihydrate (400 mg, 1.8 mmol), ethanolamine (975 mg, 15.9 mmol) and xylene (8 ml) were added to 2-(4-chlorobenzyloxy)-α-methoxyiminophenylacetonitrile (4.00 g, 13.3 mmol), and the mixture was stirred under reflux for 63 hours. After completion of the reaction, water (100 ml) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give isomer A (1.31 g, 28.6%, as crystals) and isomer B (0.45 g, 9.8%, as crystals) of 2-(4-chlorobenzyloxy)phenyl 2-oxazolin-2-yl ketone O-methyloxime.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](O)([CH3:13])[CH3:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N-:15]=[N+:16]=[N-:17].[Na+]>>[N:15]([C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)([CH3:13])[CH3:12])=[N+:16]=[N-:17]
Reactant: CC(C)(O)c1ccc2ncccc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CC(C)(N=[N+]=[N-])c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
2-(Quinolin-6-yl)propan-2-ol (0.50 g, 2.67 mmol) and sodium azide (1.73 g, 26.70 mmol) were added successively to ice-cold trifluoroacetic acid (20 ml) and warmed to room temperature. After 12 h, the reaction mixture was cooled to 0° C., quenched with water and basified with sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as brown liquid (0.340 g, 60%). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.90 (dd J=4.1, 1.6 Hz, 1H), 8.41 (d, J=7.6 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H), 8.04 (d, J=9.0 Hz, 1H), 7.88 (dd, J=8.1, 2.2 Hz, 1H), 7.56 (q, J=4.2 Hz, 1H), 1.71 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:25]1C=C(C#CC2CC3(CCNC3)ON=2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:25]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(C#CC2=NOC3(CCNC3)C2)c1
Reactant: CCOC(=O)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Product: CCOC(=O)N1CCC2(CC1)CC(C#Cc1cccc(Cl)c1)=NO2

Procedure:
The title compound was synthesized following the method herein described for the compound of Example 112 but replacing Compound 22c for Compound 27d. After the usual work-up procedure the crude was purified by means of automated flash chromatography (Isolera®TM-Biotage; gradient Petroleum Ether-EtOAc from 9:1 to 8:2) giving the title compound as a white solid. Yield: 55.4%.
Reaction SMILES: C[O:2][C:3]([P:5](=[O:10])([O:8][CH3:9])[O:6][CH3:7])=O.[CH3:11][N:12]([CH3:17])[C:13]([NH:15][CH3:16])=[NH:14]>O1CCCC1>[CH3:11][N:12]([CH3:17])[C:13](=[N:14][C:3]([P:5](=[O:10])([O:8][CH3:9])[O:6][CH3:7])=[O:2])[NH:15][CH3:16]
Reactant: CNC(=N)N(C)C
Reactant: COC(=O)P(=O)(OC)OC
Solvent: C1CCOC1
Product: CNC(=NC(=O)P(=O)(OC)OC)N(C)C

Procedure:
A solution of 54 parts of dimethyl methoxycarbonylphosphonate and 33 parts of 1,1,3-trimethylguanidine in 1000 parts of anhydrous tetrahydrofuran was refluxed for one hour. The solvent was removed under reduced pressure to yield 71 parts of dimethyl 1-dimethylamino-1-methylaminomethyleneaminocarbonylphosphonate, nD25 = 1.4989.
Reaction SMILES: O=O.[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:5])[CH3:4].Cl[C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([CH:21]=1)[NH2:20].[H-].[Na+]>CN(C=O)C>[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:15]2[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([CH:21]=2)[NH2:20])=[CH:9][CH:8]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Oc2ccc([N+](=O)[O-])c(N)c2)cc1

Procedure:
Compounds of Formula (I), wherein R3 is —C(O)OCH3, A is phenyl, and X and Z are oxygen, D and T are CH, M is C, Q is N(R7)p, either p or q is 1, and the other is 0, can be prepared according to the synthetic sequence shown in Scheme 1 and further detailed in the Examples section following. 4-Acetamidophenol (1) in DMF is reacted with 5-chloro-2-nitroaniline (2) in the presence of 60% NaH to provide 5-(4-acetamidophenoxy)-2-nitroaniline (3). The nitroaniline (3) is then refluxed with Na2S2O4 to provide 4-(4-acetamidophenoxy)phenylene-1,2-diamine (4). (It is understood that reduction of nitro group of (3) can be effected in many ways, for example by use of H2, Pd/C; Raney Nickel with hydrazine; SnCl4 in HCl; etc.) Diamine (4) is refluxed with 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea in ethanol and the acetylated carbamate (5) is obtained. HCl is added to deacetylate the carbamate (5) to give methyl (5-(4-aminophenoxy)-1H-benzimidazol-2-yl)carbamate (7). Alternatively, carbamate (7) may be prepared by refluxing 3,4,4′-triaminodiphenylether (6) with 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea and then treating with conc. HCl to give carbamate (7). Carbamate (7) is then reacted with the appropriate phenyl isocyanate (8) to give the resultant benzimidazole (9) of the present invention. It is understood that R1 and R2 are as described above. When X of Formula (I) is sulfur and Z of Formula (I) is oxygen, the final compounds are obtained by following the same procedure using a phenylthiol derivative of 1. When X of Formula (I) is sulfur, the compound thus obtained can be oxidized with MCPBA (metachloroperbenzoic acid) to give compounds containing sulfone (SO2) or sulfine (SO) as X. Also, when 3-(3-substitutedphenyl)aminocarbonylamino)phenoxy derivatives of Formula 1 are prepared, 3-acetamidophenol is utilized instead of 4-acetamidophenol.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.[CH2:12]([N:14](CC)[CH2:15][CH3:16])[CH3:13].C(Cl)(=O)C(C)(C)C.C(NCC)C>O1CCCC1>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([N:14]([CH2:15][CH3:16])[CH2:12][CH3:13])=[O:3])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCN(CC)CC
Agent: CC(C)(C)C(=O)Cl
Solvent: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(C=O)cc1
Temperature: -4 °C
Reaction time: 2 h
Yield: 41.9 %

Procedure:
To a 12 L flask equipped with mechanical stirrer and cold bath was charged 300 g (2 mol) of 4-carboxybenzaldehyde, 4.5 L of tetrahydrofuran and 245 g (2.4 mol) of triethylamine. This solution was cooled to −4° C. with methanol/ice bath. To the reaction was charged 236 g (1.9 mol) of pivaloyl chloride at a rate that maintained the temperature below 5° C. After stirring for 2 h the resulting slurry was filtered and the filter cake was washed with 1 L of THF. The filtrates were returned to the reactor and cooled below −5° C. Diethylamine (438 g, 6 mol) was slowly added maintaining the temperature below 0° C. The reaction was stirred for several hours and allowed to warm. The solvent was then removed under vacuum and the resulting residue was dissolved in 2 L of ethyl acetate. The resulting solution was washed with 1 L of water and the aqueous layer was back-extracted with 2×500 mL ethyl acetate. The combined organic layer was washed with 3×500 mL of 1 N HCl and 3×500 mL of NaHCO3 (aq, sat). This solution was dried with Na2SO4 and the solvent was removed under vacuum to give a golden brown oil (172 g, 85%) containing ˜13% impurity by NMR. The aldehyde was used with out further purification.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:39])[C@@H:24]([NH:25][C:26](=[O:38])[C:27]([C:31]4[N:32]=[C:33]([NH2:37])[S:34][C:35]=4[Cl:36])=[N:28][O:29][CH3:30])[C@H:21]3[S:20][CH2:19][C:18]=2Cl)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C>ClCCl.[Zn]>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:39])[C@@H:24]([NH:25][C:26](=[O:38])[C:27]([C:31]4[N:32]=[C:33]([NH2:37])[S:34][C:35]=4[Cl:36])=[N:28][O:29][CH3:30])[C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Cl)CS[C@H]12)c1nc(N)sc1Cl
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12)c1nc(N)sc1Cl
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a solution of 7β-[2-(2-amino-5-chloro-4-thiazolyl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid diphenylmethyl ester (180 mg) in dichloromethane (5 ml) are added zinc powder (120 mg) and acetic acid (1 ml), and the mixture is stirred at -10° C. for 10 minutes. The reaction mixture is filtered, poured into iced water and extracted with ethyl acetate. The extract solution is washed with aqueous sodium hydrogen carbonate solution and water, dried and concentrated. Conventional work-up of obtained residue affords 7β-[2-(2-amino-5-chloro-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester. Similarly prepared are compounds of Table 1.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:19][CH2:20]Br.O>CN(C)C=O>[CH2:1]([NH:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:19][CH2:20][O:16][C:11]=2[CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)CCc1ccc(O)c(O)c1
Reactant: BrCCBr
Solvent: CN(C)C=O
Solvent: O
Product: CCCCNC(=O)CCc1ccc2c(c1)OCCO2
Reaction time: 4 h
Yield: 37.2 %

Procedure:
1.5 g of N-butyl-3-(3,4- dihydroxyphenyl)propionamide was dissolved in 10 ml of N,N-dimethylformamide and 2.3 g of potassium carbonate anhydride was added to the solution. Then 2.3 g of 1,2-dibromoethane and 100 mg of cupric oxide were added to the solution and the resulting solution was stirred at 130°-140° C. for 4 hours. After cooling, the solution was poured over iced water and extracted with ethyl acetate; the organic layer was isolated, washed with water, dried with sodium sulfate anhydride and the solvent was removed by evaporation under reduced pressure. The residue was purified by chromatography on a silica gel column with a mixed solvent (chloroform:methanol=100:l) and thus 0.62 g of oily N-butyl-3-(1,4-benzodioxane-6-yl)propionamide was obtained.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][C:6]=2[CH:5]=[C:4]([NH2:15])[CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[S:25](Cl)(=[O:27])=[O:26].N1C=CC=CC=1>ClCCl>[Br:1][C:2]1[C:10]2[O:9][C:8]([Si:11]([CH3:12])([CH3:14])[CH3:13])=[CH:7][C:6]=2[CH:5]=[C:4]([NH:15][S:25]([C:19]2[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=2[O:17][CH3:16])(=[O:27])=[O:26])[CH:3]=1
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Reactant: C[Si](C)(C)c1cc2cc(N)cc(Br)c2o1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C)cc1S(=O)(=O)Nc1cc(Br)c2oc([Si](C)(C)C)cc2c1
Yield: 99.4 %

Procedure:
Coupling of the amine (4.5 g, 15.9 mmol) from Step 1 with 2-methoxy-5-methylphenylsulfonyl chloride (3.5 g, 15.9 mmol) in dichloromethane (200 mL) using pyridine as a base (3.2 mL, 40 mmol) required 2.5 hours at ambient temperature. Washing the resulting mixture with water, drying and concentration yielded 7.4 g (100%) of N-(7-bromo-2-trimethylsilanyl-benzofuran-5-yl)-2-methoxy-5-methyl-benzenesulfonamide as a dark orange solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16]3[C:28]4[NH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][C:25]=5[O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:20]=4[C:19]4[C:37](=[O:41])[NH:38][C:39](=[O:40])[C:18]=4[C:17]=3[C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:44]([O:51][CH2:52]Cl)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C=O)C.O>[CH2:44]([O:51][CH2:52][N:38]1[C:39](=[O:40])[C:18]2[C:17]3[C:13]4[C:14](=[C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:10]=[CH:11][CH:12]=4)[NH:15][C:16]=3[C:28]3[NH:27][C:26]4[C:25]([O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:24][CH:23]=[CH:22][C:21]=4[C:20]=3[C:19]=2[C:37]1=[O:41])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C1NC(=O)c2c1c1c3cccc(OCc4ccccc4)c3[nH]c1c1[nH]c3c(OCc4ccccc4)cccc3c21
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2c(c3c4cccc(OCc5ccccc5)c4[nH]c3c3[nH]c4c(OCc5ccccc5)cccc4c23)C(=O)N1COCc1ccccc1
Yield: 61.7 %

Procedure:
143.8 mg of 1,11-dibenzyloxy-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione was dissolved in 50 ml of DMF, 128.8 mg of 60% oily sodium hydride (NaH) was added, 36.5 μl of benzyloxymethyl chloride was gradually added under ice cooling over a period of 10 minutes, and the mixture was subjected to reaction at 0° C. for further 1 hour. The reaction solution was diluted with water and extracted with ethyl acetate, the ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Kiezel gel 60; eluted with chloroform) to give the desired 6-benzyloxymethyl-1,11-dibenzyloxy-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (yield: 61.7%).
Reaction SMILES: C[N:2]1[N:6](CCCCC2C=CC(OCC3C=CC4C(=CC=CC=4)N=3)=CC=2)C=N[NH:3]1.[CH3:29][CH:30]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH2:51][C:52]3[CH:61]=[CH:60][C:59]4[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=4)[N:53]=3)=[CH:46][CH:45]=2)=[CH:38][CH:37]=1)[CH2:31][CH2:32][C:33]#[N:34].[Na].[Cl-].[NH4+]>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:29][CH:30]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH2:51][C:52]3[CH:61]=[CH:60][C:59]4[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=4)[N:53]=3)=[CH:46][CH:45]=2)=[CH:40][CH:41]=1)[CH2:31][CH2:32][C:33]1[NH:6][N:2]=[N:3][N:34]=1
Reactant: CC(CCC#N)Cc1ccc(OCc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Reactant: CN1NN=CN1CCCCc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(CCc1nnn[nH]1)Cc1ccc(OCc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Temperature: 135 °C

Procedure:
5-(3-methyl-4-(4-(4-(2-quinolinylmethyloxy)phenyl)butyl)tetrazole. A mixture of 4-methyl-5-(4-(4-(2-quinolinylmethyloxy)benzyloxy)phenyl) valeronitrile (1.5 g.), sodium aside (3 g), ammonium chloride (1.9 g) in dimethylformamide (20 ml) is stirred and heated at 135° C. for 18 hours. After cooling, the reaction mixture is poured into ice water and the insoluble material is taken up by chloroform. The residue from the evaporation of chloroform is purified by silica gel dry column (5% methanol in chloroform as eluant) to yield 5-(3-methyl-4-(4-(4-(2-quinolinylmethyloxy)benzyloxy)-phenyl)butyl)tetrazole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[C:26]([CH2:30]O)[N:27]([CH3:29])[N:28]=2)=[CH:20][C:19]=1[C:32]([F:35])([F:34])[F:33].CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:30][C:26]3[N:27]([CH3:29])[N:28]=[C:24]([C:21]4[CH:22]=[CH:23][C:18]([F:17])=[C:19]([C:32]([F:34])([F:33])[F:35])[CH:20]=4)[CH:25]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cn1nc(-c2ccc(F)c(C(F)(F)F)c2)cc1CO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3cc(-c4ccc(F)c(C(F)(F)F)c4)nn3C)cc21

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 2 e]) was reacted with [5-(4-fluoro-3-trifluoromethyl-phenyl)-2-methyl-2H-pyrazol-3-yl]-methanol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give {6-[5-(4-fluoro-3-trifluoromethyl-phenyl)-2-methyl-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester as white solid.
Reaction SMILES: C([NH:9][C:10]1[NH:14][N:13]=[C:12]([S:15]([NH:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])(=[O:17])=[O:16])[N:11]=1)(=O)C1C=CC=CC=1.[OH-].[Na+]>>[NH2:9][C:10]1[NH:14][N:13]=[C:12]([S:15]([NH:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])(=[O:17])=[O:16])[N:11]=1
Reactant: O=C(Nc1nc(S(=O)(=O)Nc2c(F)cccc2F)n[nH]1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(S(=O)(=O)Nc2c(F)cccc2F)n[nH]1
Yield: 72.7 %

Procedure:
A mixture of 16.9 g (0.045 mole) of 5-benzoylamino-N-(2,6-difluorophenyl)-1,2,4-triazole-3-sulfonamide and 75 ml of 6N sodium hydroxide was heated to reflux for a total of 4 hours. The resulting solution was treated witch decolorizing carbon, filtered, and acidified with hydrochloric acid. The solids that formed were collected by filtration and dried to obtain a total of 14.8 g of crude product. This material was taken up dilute aqueous sodium hydroxide, treated again with decolorizing carbon, filtered and acidified to pH 5.0. The resulting slurry was chilled and the solids collected by filtration and dried to obtain 9.0 g of the title compound as a white solid, m.p. 255°-257° (dec.). The carbon nmr spectrum was consistent with the assigned structure and the melting point with that in the art.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:19][N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][CH2:30][C:31]#[C:32][Si](C)(C)C.O>C1COCC1>[CH2:29]([C:21]1[N:20]([CH3:19])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=1)[CH2:30][C:31]#[CH:32]
Reactant: Cn1c(CCC#C[Si](C)(C)C)nc2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#CCCc1nc2ccccc2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
TBAF (0.24 mL, 0.83 mmol) was added to a solution of 1-methyl-2-(4-trimethylsilanyl-but-3-ynyl)-1H-benzoimidazole (178 mg, 0.69 mmol) in THF (2.5 mL) and the reaction mixture was stirred for 2 hours at room temperature. After the addition of water, the solvent was evaporated and the aqueous phase was extracted with DCM. The organic phase was washed with brine, dried over MgSO4, filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 90 mg (0.49 mmol, 70%) of 2-but-3-ynyl-1-methyl-1H-benzoimidazole as a brown solid.
Reaction SMILES: [CH3:1][CH:2]([O:9][C:10]1([OH:21])[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH2:22](Br)[C:23]#[CH:24]>>[CH2:24]([O:15][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][C:10]([O:9][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8])([OH:21])[CH:11]([O:19][CH3:20])[CH:12]=1)[C:23]#[CH:22]
Reactant: COC1C=C(C(=O)O)C=CC1(O)OC(C)CCCC(C)C
Reactant: C#CCBr
Product: C#CCOC(=O)C1=CC(OC)C(O)(OC(C)CCCC(C)C)C=C1

Procedure:
By utilizing the procedure of Example 8, by reacting p-[(1,5-dimethylhexyl)oxy]vanillic acid with propargyl bromide, there is obtained p-[(1,5-dimethylhexyl)oxy]vanillic acid propargyl ester; nD24 = 1.5151.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22](Br)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:34]4[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[C:36]([O:37][CH3:38])[CH:35]=4)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3cc(Br)ccc3C2=O)cc1
Reactant: COc1ccc(B(O)O)cc1OC
Product: COc1ccc(-c2ccc3c(c2)CN(Cc2ccc(C(=O)Nc4ccccc4N)cc2)C3=O)cc1OC
Reaction time: 0.33 h
Yield: 52 %

Procedure:
The procedure of Example 2 was repeated except that N-(2-aminophenyl)-4-((5-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 56 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 3,4-dimethoxyphenyl boronic acid instead of phenyl boronic acid were used, and the reaction was performed for 20 mins, to obtain the title compound (52%).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:24])=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[ClH:41].[N:42]1([CH2:48][CH2:49][C:50](O)=[O:51])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1.Cl>CCOCC.C(Cl)Cl>[ClH:41].[CH3:25][C:2]1([CH3:1])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:24][C:50](=[O:51])[CH2:49][CH2:48][N:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Reactant: O=C(O)CCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2CCC1

Procedure:
2.8 g. (8.2 mmoles) of 4,4-dimethyl-9-hydroxy-7-(3-methyl-2-octyl)-1,2,3,4-tetrahydrocyclopenta[c] [l] benzopyran, 1.77 g. (8.6 mmoles) of dicyclohexylcarbodiimide and 1.65 g. (8.5 mmoles) of β-piperidinopropionic acid hydrochloride (m.p. 216°-220°, J. Am. Chem. Soc. 73, 3168 (1951)) were combined with 125 ml. of methylene chloride and stirred at room temperature for about 20 hours. The reaction mixture was filtered and the methylene chloride removed using a rotary evaporator. The residue was treated with benzene and filtered to remove a small quantity of insoluble material. The benzene was evaporated and the dark viscous residue was chromatographed using 100 g. of 60-100 mesh Florisil activated magnesium silicate and methanol/chloroform graded solvent mixtures. Chromatography gave a small quantity of orange oil which was dissolved in ether and treated with a solution of ethereal HCl. The desired compound appeared as white crystals which were filtered and washed with additional ether. The colorless crystals (86 mg., m.p. 106°-107°) were pure by thin layer chromatography (10% MeOH/CHCl3) and the nmr and infrared spectra are in agreement with the proposed structure.