Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].C[SiH](C)C.[Cl:6][C:7]1[C:8]([F:15])=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10]Br.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[CH:19][N:18]=1.O>O1CCCC1.BrC(Br)C.[Zn]>[Cl:16][C:17]1[CH:22]=[C:21]([CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[C:7]([Cl:6])[C:8]=2[F:15])[N:20]=[CH:19][N:18]=1
Reactant: Fc1c(Cl)cccc1CBr
Reactant: Clc1cc(Cl)ncn1
Agent: CC(Br)Br
Agent: C[SiH](C)C
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: Fc1c(Cl)cccc1Cc1cc(Cl)ncn1
Reaction time: 0.33 h
Yield: 35.2 %

Procedure:
In 10 ml of tetrahydrofuran was suspended 1.3 g of zinc (powder), to which dibromoethane (2 drops) was added. The mixture was heated under reflux for 5 minutes, to which trimethylsilane chloride was added. The mixture was further heated under reflux for 5 minutes, to which a solution of 2.2 g of 3-chloro-2-fluorobenzyl bromide dissolved in 20 ml of tetrahydrofuran was slowly added with heating under reflux, followed by stirring for 20 minutes. (The solution thus obtained is referred to as solution K). In 10 ml of tetrahydrofuran were suspended 1.5 g of 4,6-dichloropyrimidine and 0.1 g of dichlorobistriphenylphosphine palladium, to which the above solution K was added, followed by heating under reflux for 3 hours and further stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.89 g of 4-chloro-6-(3-chloro-2-fluorobenzyl)pyrimidine.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[N:5]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2)=[C:6]=[S:7]>C(Cl)Cl>[NH2:3][CH2:2][CH2:1][NH:4][C:6](=[S:7])[NH:5][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2
Reactant: S=C=Nc1cccc2[nH]ccc12
Reactant: NCCN
Solvent: ClCCl
Product: NCCNC(=S)Nc1cccc2[nH]ccc12
Reaction time: 1 h
Yield: 91.2 %

Procedure:
Ethylenediamine (0.289 mL, 4.33 mmol) is added to a solution of 4-isothiocyanatoindole (0.150 g, 0.866 mmol) in methylene chloride (10 mL). The clear solution becomes cloudy within a few seconds with the formation of a white precipitate. The reaction mixture is stirred for one hour followed by the removal of most of the methylene chloride by rotary evaporation. The mixture is filtered and the white precipitate is dried to afford 0.185 g of 4-[N'-(2-aminoethyl)thioureido]indole (91% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl.[C:21]1([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH2:30][NH2:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1>C(OCC)(=O)C.O.C(Cl)CCl.CN(C=O)C>[C:27]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:34]=[CH:33][CH:32]=[C:29]([CH2:30][NH:31][C:17](=[O:19])/[CH:16]=[CH:15]/[C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:28]=1
Reactant: NCc1cccc(-c2ccccc2)c1
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(/C=C/C(=O)NCc2cccc(-c3ccccc3)c2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a DMF (30 mL) solution of (E)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid (2.20 g), 3-phenylbenzylamine hydrochloride (2.30 g), IPEA (4.57 mL), EDC (1.96 g) and HOBT (1.38 g) were added one by one, and the reaction solution was agitated at room temperature overnight. After confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent:ethyl acetate→ethyl acetate ethanol=10:1), and 3.30 g of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([CH3:24])=[C:14]([C:19](=[O:23])[CH2:20][CH2:21][CH3:22])[CH:15]=2)[NH:10][CH:9]=1)=[O:7])C>C(O)C>[C:19]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[CH3:24])[NH:10][CH:9]=[C:8]([C:6]([OH:7])=[O:5])[C:17]2=[O:18])(=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(=O)c1cc2c(=O)c(C(=O)OCC)c[nH]c2cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCC(=O)c1cc2c(=O)c(C(=O)O)c[nH]c2cc1C

Procedure:
A mixture of 300 ml of ethanol and 100 ml of 2N sodium hydroxide solution is added to 50 g of 6-butyryl-7-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester and the mixture is heated to 70° and maintained at that temperature for 1 hour. The ethanol is removed, the remaining mixture is diluted with water and extracted by shaking with ether, and the aqueous phase is separated off and acidified with concentrated hydrochloric acid. The precipitated crude product is filtered off and recrystallised from ethanol. 6-Butyryl-7-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid having a melting point of 249°-252.5° is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:15]=[C:14]([CH3:16])[O:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:17]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[C:15]([Cl:17])=[C:14]([CH3:16])[O:13][N:12]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](c2cc(C)on2)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](c2noc(C)c2Cl)CC1

Procedure:
A solution of trans-4-(5-methyl-isoxazol-3-yl)-cyclohexanecarboxylic acid methyl ester (250 mg, 1.12 mmol) and N-chlorosuccinimide (164 mg, 1.23 mmol) in N,N-dimethylformamide (2.2 ml) was stirred for 24 h at room temperature. The reaction mixture was partitioned between tert-butyl methyl ether (50 ml) and water (50 ml). The layers were separated. The aqueous layer was extracted with one 50 ml-portion of tert-butyl methyl ether. The combined organic layers were washed with one 50 ml-portion of 0.1 M aqueous sodium hydroxide solution, one 50 ml-portion of water and one 30 ml-portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (275 mg, 95%) as light yellow oil, which was used in the next step without further purification. MS m/e: 257 (M+)
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].O>CN(C)C=O>[Si:27]([O:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Yield: 93.1 %

Procedure:
To a solution of 1.0 g of 3β-hydroxyandrost-5-en-17-one (Coffey S. in Rodd's Chemistry of Carbon Compounds, 1970, IID, 257) in 10 ml of dimethylformamide, 1.7 g of imidazole and 1.95 g of t-butyldimethylsilyl chloride were added at 0° C. After 12 hrs the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give 1.3 g of crude 3β-tert-butyldimethylsilyloxy-androst-5-en-17-one
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH3:26][N:27]1[CH:34]=[N:33][C:29]([CH2:30][CH2:31][NH2:32])=[CH:28]1.C(N(CC)C(C)C)(C)C.[I-].[K+]>C(O)CCC>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][NH:32][CH2:31][CH2:30][C:29]2[N:33]=[CH:34][N:27]([CH3:26])[CH:28]=2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2)=[O:5]
Reactant: Cn1cnc(CCN)c1
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCCl)ccc1Cl
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cn1cnc(CCNCCNc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)c1
Yield: 16.2 %

Procedure:
Prepared as in Example 32 using 2-chloro-5-[(2-chloroethyl)amino]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 29c, 0.200 g), 1-methylhistamine (0.400 g), N,N-diisopropylethylamine (1 ml), potassium iodide (0.080 g) and n-butanol (4 ml) to give the title compound as a gum (0.040 g).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[Cl:13][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([F:14])[CH:20]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2ncccc2c1Cl
Reactant: OB(O)c1cccc(F)c1
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+]
Product: Cc1c(-c2cccc(F)c2)nc2ncccc2c1Cl

Procedure:
Prepared according to procedure F using 2,4-dichloro-3-methyl-1,8-naphthyridine (200 mg, 0.939 mmol), 3-fluorophenylboronic acid (131 mg, 0.939 mmol), sodium carbonate (199 mg, 1.877 mmol) and Pd(PPh3)4. Product used without further purification in the next step. Mass Spectrum (ESI) m/e=273.0 (M+1)
Reaction SMILES: [CH3:1][O:2][SiH:3]([O:6][CH3:7])[O:4][CH3:5].C(O)(=O)C.[CH3:12][O:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25]>>[CH3:12][O:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][Si:3]([O:6][CH3:7])([O:4][CH3:5])[O:2][CH3:1]
Reactant: CO[SiH](OC)OC
Reactant: C=CCCCCCCCCOCOC
Solvent: CC(=O)O
Product: COCOCCCCCCCCCC[Si](OC)(OC)OC

Procedure:
Under a nitrogen atmosphere at 80° C., a mixture of 64 g of trimethoxysilane and 0.57 g of acetic acid was dropped in a mixture of 100 g of 10-(methoxymethoxy)-1-decene and a catalytic amount of a solution of tetrahydrofuran chloroplatinate. The resultant mixture was stirred for 3 hours at 80° C., and then the reaction mixture was distilled under reduced pressure, to obtain 131 g of an intended substance.
Reaction SMILES: CN.[O:3]=[C:4]1[N:10]2[CH2:11][CH2:12][C@H:9]2[C:8]2=[C:13]([C:16]3[O:20][C:19]([CH2:21][N:22]4C(=O)C5C(=CC=CC=5)C4=O)=[N:18][N:17]=3)[N:14]=[CH:15][N:7]2[C:6]2[CH:33]=[CH:34][S:35][C:5]1=2>C(O)C>[NH2:22][CH2:21][C:19]1[O:20][C:16]([C:13]2[N:14]=[CH:15][N:7]3[C:6]4[CH:33]=[CH:34][S:35][C:5]=4[C:4](=[O:3])[N:10]4[CH2:11][CH2:12][C@H:9]4[C:8]=23)=[N:17][N:18]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nnc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)o1
Agent: CN
Solvent: CCO
Product: NCc1nnc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)o1
Reaction time: 1 h
Yield: 66.6 %

Procedure:
30 ml of methylamine (33% in ethanol) were added dropwise at 70° to a suspension of 2.5 g (5.4 mmol) of (S)-2-[5-(8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-1-yl)-1,3,4-oxadiazol-2-ylmethyl]-2,3-dihydro-1H-isoindole-1,3-dione in 30 ml of ethanol and the mixture was stirred at 70° for one hour. The precipitate obtained was filtered off while hot and the yellowish powder obtained was washed colourless with ethanol. There were obtained 1.18 g (66%) of (S)-1-(5-aminomethyl-1,3,4-oxadiazol-2-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]-diazepin-8-one as a colourless powder of m.p. 233°-235°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[CH:15]([CH3:20])[C:16](=O)[CH2:17][CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([NH:24][NH2:25])[CH3:23]>C(#N)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:24]([CH2:22][CH3:23])[N:25]=[C:16]([CH2:17][CH3:18])[C:15]=2[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(=O)C(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCNN
Solvent: CC#N
Solvent: O
Product: CCc1nn(CC)c(C2CCN(C(=O)OC(C)(C)C)CC2)c1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1-(tert-butoxycarbonyl)-4-(1,3-dioxo-2-(R/S)-methylpent-1-yl)piperidine (435 mg, 1.5 mmol) (from Step D) in 2:1 v/v acetonitrile/water (12 mL) was treated with ethylhydrazine (34% sol'n in water, 0.28 mL, 1.6 mmol) and the resulting mixture was stirred at rt for 20 h. The reaction mixture was partitioned between 75 mL of ether and 25 mL of sat'd sodium chloride and the layers were separated. The organic layer was dried over magnesium sulfate and concentrated. MPLC (Biotage) on a 40S silica cartridge using 4:1 v/v, then 1:1 v/v hexanes/ethyl acetate as the eluent afforded the title compound:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[N:5][C:6]([C:10]([O:12]CC)=O)=[C:7](Cl)[N:8]=1.Cl.[CH2:16]([O:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH2:25])=[NH:24])[CH:17]([CH3:19])[CH3:18]>C(N(CC)CC)C>[CH3:1][S:2][C:3]1[N:4]=[N:5][C:6]2[C:10](=[O:12])[NH:25][C:23]([C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[O:20][CH2:16][CH:17]([CH3:19])[CH3:18])=[N:24][C:7]=2[N:8]=1
Reactant: CCOC(=O)c1nnc(SC)nc1Cl
Reactant: CC(C)COc1ccccc1C(=N)N
Agent: Cl
Solvent: CCN(CC)CC
Product: CSc1nnc2c(=O)[nH]c(-c3ccccc3OCC(C)C)nc2n1

Procedure:
In a similar manner to Example 85 reaction of 3-methylthio-5-chloro-6-carboethoxy-1,2,4-triazine (prepared from 3-methylthio-5-oxo-6-carboethoxy-4,5-dihydro-1,2,4-triazine, 1.5 g) with 2-isobutoxybenzamidine hydrochloride (2.37 g) and triethylamine (1.75 g) afforded the crude title compound (1.71 g). This was recrystallized from acetonitrile, then dissolved in chloroform, the organic solution was washed with 2 Normal hydrochloric acid (×2), chloroform removed under reduced pressure and the residue recrystallized twice from ethanol to afford the title compound, 0.32 g, m.p. 237-238° C.
Reaction SMILES: O[C:2]1([CH2:11]Cl)[CH2:6][S:5][C:4]([CH2:7][N:8]([CH3:10])[CH3:9])=[N:3]1.C[OH:14].[OH-].[K+]>O>[CH3:9][N:8]([CH2:7][C:4]1[S:5][CH:6]=[C:2]([CH2:11][OH:14])[N:3]=1)[CH3:10]
Reactant: CO
Reactant: CN(C)CC1=NC(O)(CCl)CS1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CN(C)Cc1nc(CO)cs1
Temperature: 25 °C

Procedure:
To a 100 ml, three-necked, flask equipped with an agitator and a condensor were added 3.0 g (0.014 mol) of 4-hydroxy-4-chloromethyl-2-(dimethylaminomethyl)thiazoline (prepared as in Example 1), 45 ml of methanol and 4 ml of water. Potassium hydroxide [1.8 ml of a 45% (weight percent) aqueous solution] was added dropwise to the reaction solution at a rate such that the reaction temperature was maintained at room temperature. Once potassium hydroxide addition was completed, the reaction mixture was stirred at room temperature for an additional hour. A 1 ml sample of the reaction mixture was then removed from the flask, placed into a 50 ml volumetric flask and then diluted to volume with a 4:1 (v:v) acetonitrile/water solution. One milliliter of the diluted sample solution was then placed in a 25 ml volumetric flask and further diluted to volume with a 4:1 (v:v) acetonitrile/water solution. Ten microliters of this solution were then assayed using the HPLC assay technique described in Example 3. Such HPLC assay indicated that 85.5% of the thiazoline substrate had converted to the desired titled product.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Si:9]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:11])=[CH:5][CH:4]=1.[Na+].[I-].ClCl.C([I:27])C1C=CC=CC=1.[SiH4]>CC(C)=O>[I:27][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Si:9]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:11])=[CH:5][CH:4]=1
Reactant: CO[Si](OC)(OC)c1ccc(CCl)cc1
Reactant: ICc1ccccc1
Agent: ClCl
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CO[Si](OC)(OC)c1ccc(CI)cc1

Procedure:
A solution of 1.7 grams of 4-chloromethylphenyltrimethoxysilane, UTF-24M, in 60 mL of dry acetone was stirred with 1.7 g of NaI and heated at reflux under an argon atmosphere for 5 h. The reaction was performed under yellow Safelight conditions. Acetone was removed under vacuum, and the product was extracted with toluene. The resulting colorless to light yellow liquid was stored as a 0.067M stock solution in toluene. The iodinated silane will be referred to as UTF-24I. A 1H NMR spectrum of UTF-24I in C6D6 exhibited resonances at δ=7.61 (doublet) and 7.02 (doublet) for the aromatic ring protons, δ=3.86 for the benzylic protons, and δ=3.43 for the methoxy protons. These values are in comparison to the 1HNMR spectrum for the chloro (UTF-24M) starting material, which gave resonances at δ=7.68 (doublet), 7.08 (doublet), 4.03 and 3.45. The upfield shift of the benzylic protons is consistent with replacement of chlorine by the less electronegative iodine atom. See the monograph by: E. D. Becker, "High Resolution NMR", Academic Press, New York, pg. 73 (1969). This example demonstrates that a benzyl iodide containing silane can be prepared in solution.
Reaction SMILES: [Br:1][C:2]1[CH:46]=[CH:45][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]3[CH:20]=[C:19]([C:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=5)[C:22]=4[CH:38]([CH3:40])[CH3:39])[O:18][C:17]3=[O:41])=[C:8]2[CH:42]([CH3:44])[CH3:43])=[CH:4][CH:3]=1.C(N1C2C(=CC=CC=2)C(C2(C3C4C(=CC=CC=4)N(CC)C=3C)C=COC2=O)=C1C)C>>[Br:1][C:2]1[CH:46]=[CH:45][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]3[C:17](=[O:41])[O:18][CH:19]([C:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]([CH2:30][C:31]5[CH:32]=[CH:33][C:34]([Br:37])=[CH:35][CH:36]=5)[C:22]=4[CH:38]([CH3:40])[CH3:39])[CH:20]=3)=[C:8]2[CH:42]([CH3:44])[CH3:43])=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C2=CC(c3c(C(C)C)n(Cc4ccc(Br)cc4)c4ccccc34)C(=O)O2)c2ccccc2n1Cc1ccc(Br)cc1
Agent: CCn1c(C)c(C2(c3c(C)n(CC)c4ccccc34)C=COC2=O)c2ccccc21
Product: CC(C)c1c(C2=CC(c3c(C(C)C)n(Cc4ccc(Br)cc4)c4ccccc34)OC2=O)c2ccccc2n1Cc1ccc(Br)cc1

Procedure:
Substituting 3,5-bis[1-(4-bromobenzyl)-2-isopropyl-3-indolyl]-2(3H)-furanone for 3,5L -bis(1-ethyl-2-methyl-3-indolyl)-2(3H)-furanone in the procedure described in part B above in this example, there is obtained 3,5-bis[1-(4-bromobenzyl)-2-isopropyl-3-indolyl]-2(5H)-furanone (Formula IV: R=4-BrC6H4CH2 ; R1 =(CH3)2CH; Y=H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].Br[CH2:25][CH2:26][CH2:27][CH2:28]Br>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]2[O:10][CH2:28][CH2:27][CH2:26][CH2:25][N:11]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)(=[O:13])=[O:14])[C:5]=12)=[O:23]
Reactant: COC(=O)c1cccc(O)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: BrCCCCBr
Product: COC(=O)c1cccc2c1N(S(=O)(=O)c1ccc(OC)cc1)CCCCO2
Yield: 29.9 %

Procedure:
In the same manner as described in Example 159, 0.400 g (1.187 mmol) of the product of Example 31 and 0.198 mL (1.662 mmol) of 1,4-dibromobutane provided 0.139 g (30%) of the desired product as a white solid. Electrospray Mass Spec: 392 (M+H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][NH:12][C:13](=[O:33])[C:14]1[CH:19]=[C:18]([CH:20]=[O:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=1[F:32])(C(C)(C)C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.O>[F:23][C:16]1[C:15]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[C:14]([CH:19]=[C:18]([CH:20]=[O:21])[C:17]=1[F:22])[C:13]([NH:12][O:11][CH2:10][CH2:9][OH:8])=[O:33]
Reactant: CC(C)(C)[Si](C)(C)OCCONC(=O)c1cc(C=O)c(F)c(F)c1Nc1ccc(I)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 72 %

Procedure:
N-[2-(Tert-butyldimethylsilanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-5-formyl-benzamide (37.1 g as a crude product containing the desilylated product) prepared in Step E was dissolved in a mixed solvent of tetrahydrofuran (200 ml) and water (16 ml). To this solution, p-toluenesulfonic acid monohydrate (1.76 g, 9.25 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure. The resultant residue was triturated with ethyl acetate to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide (16.0 g, 72% yield in two steps) as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([N:21]2[C:30]3[C:25](=[CH:26][C:27]([F:32])=[C:28](F)[CH:29]=3)[C:24](=[O:33])[N:23]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:22]2=[O:42])[CH:18]=[CH:19][CH:20]=1>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([N:21]2[C:30]3[C:25](=[CH:26][C:27]([F:32])=[C:28]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:29]=3)[C:24](=[O:33])[N:23]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:22]2=[O:42])[CH:18]=[CH:19][CH:20]=1
Reactant: COc1cccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(F)cc32)c1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Product: COc1cccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(N4CCCC4)cc32)c1
Yield: 86.7 %

Procedure:
Using General Method 4, the reaction of pyrrolidine (0.077 mL, 0.9 mmol), triethylamine (0.12 mL, 0.9 mmol), and 1-(3-methoxyphenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example E-1, 0.12 g, 0.3 mmol) provided 0.12 g of the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[CH:17]([CH:19]=[CH2:20])=[O:18].C(N(CC)CC)C>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:20][CH2:19][CH:17]=[O:18])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C=CC=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(SCCC=O)cc(C(C)(C)C)c1O

Procedure:
2,6-bis(1,1-Dimethylethyl)-4-mercaptophenol (36.4 g, 0.15 mole) was dissolved in methanol (250 ml) in a 1 liter, round bottom, 3-necked flask equipped with a stirrer, gas inlet and gas outlet. The solution was flushed with argon and freshly distilled acrolein (25 g, 0.45 mole) and triethylamine (2.4 ml) were added dropwise over a one hour period and the solvent was evaporated on a rotary evaporator and the product purified by chromatography over silica, m.p. ca. 64-65° C.