Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([F:25])[C:22]([O:26][CH3:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([F:25])[C:22]([O:26][CH3:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:37]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c23)cc1F
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A169) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[C:25]1([CH:31]2[CH2:36][NH:35][CH2:34][CH2:33][NH:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:35]4[CH2:34][CH2:33][NH:32][CH:31]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:36]4)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: c1ccc(C2CNCCN2)cc1
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCNC(c5ccccc5)C4)c(F)cc3cc2c1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
A suspension of 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.8 g) and (RS)-2-phenylpiperazine (3.2 g) in dimethyl sulphoxide (30 cc) is heated to a temperature in the region of 100° C. with stirring for 1 hour and a half. The solution obtained, at approximately 100° C., is poured with stirring into a mixture of water (150 cc) and ice (50 g). The suspension obtained is extracted at approximately 20° C. with trichloromethane (3×40 cc). The combined organic extracts are washed with water (2×50 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C. The solid obtained is recrystallized in a mixture of dimethylformamide (40 cc) and ethanol (40 cc). (RS)-3-Ethoxycarbonyl-7,9-difluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine (2 g) is obtained in the form of a yellow solid, m.p. 216° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH:26]2[CH:24]([O:25]2)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].FC(F)(F)S([O-])(=O)=O.[Ca+2].FC(F)(F)S([O-])(=O)=O>C(#N)C>[C:15]([O:19][C:20]([N:22]1[CH2:23][C@@H:24]([OH:25])[C@H:26]([N:11]2[CH2:12][CH2:13][CH2:14][N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[CH2:27]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Clc1ccc(N2CCCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Ca+2]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N2CCCN(c3ccc(Cl)cc3)CC2)C1
Temperature: 80 °C
Reaction time: 17 h
Yield: 43.1 %

Procedure:
To a solution of 1-(4-Chloro-phenyl)-[1,4]diazepane (1.00 g, 4.80 mmol) in acetonitrile (10 mL) was added 6-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.925 g, 5.00 mmol) and Calcium(II) trifluoromethanesulfonate (0.676 g, 2.00 mmol). The solution was stirred at 80° C. for 17 hours under nitrogen atmosphere. The reaction was concentrated in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organics were washed with brine, dried over MgSO4, and evaporated. The residue was purified by silica gel chromatography (ethyl acetate→87:10:3 ethyl acetate:methanol:triethylamine) to yield 0.819 g (41%) of the title compound. EST-MS m/z: 396 (M+1), FAS method rt: 1.25 min.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2([OH:33])[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][CH:16]2[CH2:29][N:30]([CH3:32])[CH3:31])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.Cl.C[Si](C)(C)[Cl:37].O>>[ClH:37].[CH3:31][N:30]([CH2:29][CH:16]1[CH2:17][CH:18]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:20][C:15]1([C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=1)[OH:33])[CH3:32]
Reactant: CN(C)CC1CC(CCc2ccccc2)CCC1(O)c1cccc(OCc2ccccc2)c1
Reactant: C[Si](C)(C)Cl
Agent: Cl
Solvent: O
Product: CN(C)CC1CC(CCc2ccccc2)CCC1(O)c1cccc(O)c1
Yield: 63 %

Procedure:
Compound (50) was hydrogenated corresponding to the conditions described in Example 23, step 2. The base obtained was converted into the hydrochloride with trimethylchlorosilane/water. Compound (49) was obtained in a yield of 63% theoretical.
Reaction SMILES: CC(CC(C)(C)C)C[C:4](O)=[O:5].[C:12]([OH:22])(=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18](C)C>>[CH:13]1([CH2:12][OH:22])[CH2:14][CH2:15][CH:16]([CH2:4][OH:5])[CH2:17][CH2:18]1
Reactant: CC(CC(=O)O)CC(C)(C)C
Reactant: CC(C)CCCCCC(=O)O
Product: OCC1CCC(CO)CC1

Procedure:
3,5,5 trimethylhexanoic acid i.e. iso-nonanoic acid (5.87 moles).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.[P:19]([O:26]CC)([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>CN(C=O)C.O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[CH:4][CH:5]=2)=[O:10])=[CH:12][CH:13]=1
Reactant: COc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Reactant: CCOP(OCC)OCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccc(C(=O)c2ccc(OC)cc2)cc1)OCC
Temperature: 150 °C
Reaction time: 10 h
Yield: 72 %

Procedure:
(4-(bromomethyl)phenyl)(4-methoxyphenyl)methanone, 32-c, (3 g, 10 mmol) and triethyl phosphite (2 g, 11.9 mmol) was dissolved in DMF (20 ml), and then stirred for 10 h at 150° C. The resulting mixture was cooled to ambient temperature, diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). The organic layer was combined, washed with brine (2×100 ml), dried over Na2SO4 anhydrous, purified by chromatography on silica gel (petroleum ether/ethyl acetate=1:1.5). The pure product, 32-d, was obtained as a colorless oil (2.6 g, 72% yield). 1H NMR (300 MHz, CDCl3) δ 1.20-1.27 (m, 6H), 2.80-2.88 (d, J=22.8, 2H) 3.81 (s, 3H), 3.93-4.07 (m, 4H), 6.86-6.90 (m, 2H), 7.31-7.35 (m, 2H), 7.62-7.93 (m, 4H). LC-MS 363 [MH]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][S:12][CH2:13][C:14](=[O:16])[CH3:15])=[CH:9][C:4]=2[O:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:25])C=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][S:12]([CH2:13][C:14](=[O:16])[CH3:15])=[O:25])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)CSCCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)CS(=O)CCc1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 82 %

Procedure:
4 g of [{2-(1,3-benzodioxol-5-yl)ethyl}thio]propan-2-one was dissolved in 70 ml of chloroform. 3.2 g of 90% m-chloroperbenzoic acid was added to the solution under cooling with ice/water. The mixture was stirred for 40 min. 150 ml of chloroform and an aqueous sodium carbonate solution were added to the reaction mixture. After separation of the layers thus formed, the chloroform layer was washed with water three times and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was recrystallized from isopropyl ether to obtain 3.5 g of the intended compound in the form of colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:10][CH:9]=1
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 13.9 g 4-(5-bromo-2-chloro-benzyl)-phenol in 140 ml dichloromethane is cooled in the ice bath. Then 7.54 g tert-butyldimethylsilylchlorid in 20 ml dichloromethane are added followed by 9.8 ml triethylamine and 0.5 g dimethylaminopyridine. The solution is stirred for 16 h at ambient temperature and then diluted with 100 ml dichloromethane. The organic phase is washed twice with aqueous 1 M hydrochloric acid and once with aqueous sodium hydrogen carbonate solution and then dried over sodium sulphate. After the solvent has been eliminated the residue is filtered through silica gel (cyclohexane/ethyl acetate 100:1).
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[O:13][CH2:12][C:11](=O)[N:10]([CH2:16][CH2:17][O:18][CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].B.C1COCC1.O>C1COCC1>[C:1]([O:4][C:5]1[C:14]2[O:13][CH2:12][CH2:11][N:10]([CH2:16][CH2:17][O:18][CH:19]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc2c1OCC(=O)N2CCOC(c1ccccc1)c1ccccc1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Oc1cccc2c1OCCN2CCOC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
8-acetoxy-4-(2-(diphenylmethoxy)ethyl)-3-oxo-3,4-dihydro-2H-1,4-benzooxazine (630 mg) was dissolved in THF (10 ml), and a 1.0M borane THF solution (4.5 ml) was added to the resultant solution at 0° C., followed by stirring at room temperature for 4 hours. After water was added to the reaction solution to terminate reaction, the reaction solution was extracted with ethyl acetate. The resultant organic layer was washed with water, saturated sodium bicarbonate water, water and saturated brine, dried over sodium sulfate, and then concentrated. The residue was purified by medium-pressure column chromatography (solvent:ethyl acetate/cyclohexane=1/5) to obtain the colorless oily object compound (550 mg, yield 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13](O)([CH3:15])[CH3:14])[CH:9]=2)[CH:4]=1.O>CN(C)P(N(C)C)(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([CH3:15])=[CH2:14])[CH:9]=2)[CH:4]=1
Reactant: COc1ccc2cc(C(C)(C)O)ccc2c1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=C(C)c1ccc2cc(OC)ccc2c1

Procedure:
A solution of 1.22 g 2-methoxy-6-(1-hydroxy-1-methylethyl)naphthalene in 25 ml hexamethylphosphoramide (HMPA) was heated to 240° C. for 15 minutes. The solution was cooled, poured into water, and the brown solid which had formed was filtered off and washed with isopropanol. Recrystallization of the brown solid from isopropanol gave 2-methoxy-6-isopropenylnaphthalene, mp 101° to 103 5° C.
Reaction SMILES: CC([Si](C)(C)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][O:13][C:14]([NH:16][C@H:17]([C:21]([NH:23][C@H:24]([C:33]([O:35][CH3:36])=[O:34])[CH2:25][O:26][CH2:27][CH:28]([O:31][CH3:32])[O:29][CH3:30])=[O:22])[CH2:18][CH2:19][OH:20])=[O:15])(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:32][O:31][CH:28]([O:29][CH3:30])[CH2:27][O:26][CH2:25][C@@H:24]([C:33]([O:35][CH3:36])=[O:34])[NH:23][C:21](=[O:22])[C@H:17]([CH2:18][CH2:19][OH:20])[NH:16][C:14]([O:13][CH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:6]=1)=[O:15]
Reactant: COC(=O)[C@H](COCC(OC)OC)NC(=O)[C@H](CCO)NC(=O)OCc1ccccc1[Si](C)(C)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](COCC(OC)OC)NC(=O)[C@H](CCO)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.8 %

Procedure:
A solution of N-[0-[(1,1-dimethylethyl)dimethylsilyl]-N-[(phenylmethoxy)carbonyl]-L-homoseryl]-O-(2,2-dimethoxyethyl)-L-serine, methyl ester [5.56 g, 10 mmol, prepared as described in Example 10(h)] in methanol (65 ml) was cooled to 0° C. (ice salt bath), treated with p-toluenesulfonic acid monohydrate (386 mg, 2.0 mmol) and stirred at 0° C. for 1.5 hours. The reaction was quenched with sodium bicarbonate solution (198 mg. in 20 ml water), stirred for 5 minutes then evaporated to remove the methanol. The aqueous phase was extracted with ethyl acetate (2×200 ml) and the combined organic extract was washed with water (110 ml), 5% sodium bicarbonate (80 ml) and brine (80 ml), dried (anhydrous sodium sulfate), filtered, evaporated to dryness and dried in vacuo. The crude product was chromatographed on silica gel column (Merck), eluting the column with ethyl acetate:hexane (2:1) and ethyl acetate:methanol (98:2) to give 3.975 g of title product as a syrup. TLC (ethyl acetate:hexane, 4:1) Rf =0.17.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11].[Cl-].[Li+]>C(N(CC)CC)C.CN(C)C=O.[Cu](I)I>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]#[C:10][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ncc(Cl)cc1I
Agent: I[Cu]I
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc(Cl)cnc1N
Temperature: 40 °C

Procedure:
A suspension of 2.54 g of 5-chloro-3-iodopyridin-2-ylamine, 2.12 ml of ethynyltrimethylsilane, 0.38 g of copper iodide and 0.47 g of lithium chloride in 7 ml of triethylamine and 75 ml of dimethylformamide is degassed under argon for approximately 15 minutes. 0.408 g of [1,1′-bis(diphenylphosphino)ferrocene] palladium(II) chloride is added to the above suspension. The mixture is heated at around 40° C. for approximately 19 hours and then concentrated to dryness under reduced pressure (13 kPa). The residue is taken up with 50 ml of water, and extracted with three times 100 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: cyclohexane/ethyl acetate (70/30 by volume)]. 1.63 g of 5-chloro-3-trimethylsilanylethynylpyridin-2-ylamine are obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:8][NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7][CH2:6]1)=[O:4].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.O.C(=O)(O)[O-].[K+]>CCOCC>[CH3:1][O:2][C:3]([C:5]1([CH2:8][N:9]([C:18]2[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=2)[CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(CNC2CCCC2)CC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: COC(=O)C1(CN(c2nc(Cl)ncc2[N+](=O)[O-])C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.2 %

Procedure:
To a solution of 4.88 g (0.0247 mole) of 1-cyclopentylaminomethyl-cyclopropanecarboxylic acid methyl ester and 4.48 g (0.0231 mole) of 2,4-dichloro-5-nitro-pyrimidine in 100 mL of ether was added 50 mL of water and 4.62 g (0.0462 mole) of potassium bicarbonate. The mixture was stirred at ambient temperature for 5 hours. The resulting two-layer mixture was separated and the aqueous layer was extracted with ether. The combined ether extracts were washed successively with aqueous sodium carbonate and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 7.80 g of 1-{[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-methyl}-cyclopropanecarboxylic acid methyl ester (IV-53) as a yellow solid.
Reaction SMILES: [Na].[O:2]=[C:3]1[NH:7][C:6](=[O:8])[CH:5](P(OCC)(=O)OCC)[NH:4]1.[CH3:17][C:18]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]([N+:27]([O-:29])=[O:28])[C:19]=1[CH:20]=O>C(O)C.O>[CH3:17][C:18]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]([N+:27]([O-:29])=[O:28])[C:19]=1[CH:20]=[C:5]1[NH:4][C:3](=[O:2])[NH:7][C:6]1=[O:8]
Reactant: Cc1ccc([N+](=O)[O-])c(C=O)c1C
Reactant: CCOP(=O)(OCC)C1NC(=O)NC1=O
Agent: [Na]
Solvent: CCO
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(C=C2NC(=O)NC2=O)c1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium (0.41 g, 0.018 g atom) was dissolved in ethanol (40 mL) and diethyl 2,4-dioxoimidazolidine-5-phosphonate (4.21 g, 18 mmol) added. After 5 minutes, 2,3-dimethyl-6-nitrobenzaldehyde (2.66 g, 15 mmol) was added in one portion and the mixture stirred at room temperature for 90 minutes. The mixture was diluted with water, filtered and the solid washed with water and air dried gave 5-[(2,3-dimethyl-6-nitrophenyl)methylene]-2,4-imidazolidinedione as a single geometrical isomer (3.35 g, 86%). Analytical sample prepared by crystallization from methanol had m.p. 293°-295° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[C:20]2[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=2[CH:15]=[CH:14][CH:13]=1)[CH3:6])=[O:4].[CH3:28][NH:29][C:30]([C:32]1[CH:42]=[CH:41][C:35]([CH:36]=[CH:37][C:38](O)=[O:39])=[CH:34][CH:33]=1)=[O:31].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[Cl:27][C:8]1[C:7]([N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:38](=[O:39])[CH:37]=[CH:36][C:35]2[CH:41]=[CH:42][C:32]([C:30](=[O:31])[NH:29][CH3:28])=[CH:33][CH:34]=2)=[CH:25][CH:24]=[C:23]([Cl:26])[C:9]=1[CH2:10][O:11][C:12]1[C:20]2[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1C
Reactant: CNC(=O)c1ccc(C=CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(C)n4C)c2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
To a mixture of 4-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-1,2-dimethyl-1H-benzimidazole (100 mg), 4-(methylcarbamoyl)cinnamic acid (55.4 mg) and dimethylformamide (1 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61.2 mg) and 1-hydroxybenzotriazole (49.7 mg), and the mixture was stirred for 3 hours at ambient temperature. To the mixture was added water, and the mixture was extracted with dichloromethane. The separated organic layer was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (dichloromethane—methanol) to give 4-[2,6-dichloro-3-[N-methyl-N-[4-(methyl-carbamoyl)cinnamoylglycy]amino]benzyloxy]-1,2-dimethyl-1H-benzimidazole (121 mg).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([C:13]#[C:14][NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9]C=1>CN1CCCC1=O.O>[C:13]1([C:14]2[NH:15][C:16]3[C:17]([CH:1]=2)=[CH:18][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:20][CH:21]=3)[CH:9]=[CH:10][CH:11]=[CH:12][CH:7]=1
Reactant: FC(F)(F)Oc1ccc(NC#Cc2ccccc2)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: FC(F)(F)Oc1ccc2[nH]c(-c3ccccc3)cc2c1
Yield: 83.8 %

Procedure:
To a solution of potassium tert-butoxide (173 mg) in 1-methyl-2-pyrrolidone (3.7 mL) was added dropwise a solution of 2-phenylethynyl-4-trifluoromethoxyaniline (204 mg) in 1-methyl-2-pyrrolidone (3.7 mL) at room temperature under stirring, and the mixture was stirred for 6 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (171 mg).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][CH3:8])[C:3]=1[Br:9].[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:9][C:3]1[C:4]([CH2:7][CH3:8])=[N:5][O:6][C:2]=1[NH:1][S:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:18])=[O:17]
Reactant: CCc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CCc1noc(NS(=O)(=O)c2ccccc2)c1Br
Yield: 70 %

Procedure:
N-(4-Bromo-3-ethyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-ethylisoxazole and benzenesulfonyl chloride according to the procedures described in Example 25b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give off-white crystals, m.p. 90-93° C., yield 70%.
Reaction SMILES: CN(C)C=O.[SH:6][C:7]1[O:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[N:10][N:11]=1.[OH-].[K+].[F:24][C:25]([F:29])=[C:26]([F:28])[F:27]>C(Cl)(Cl)Cl>[F:24][C:25]([F:29])([S:6][C:7]1[O:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)=[N:10][N:11]=1)[CH:26]([F:28])[F:27]
Reactant: FC(F)(F)c1cccc(-c2nnc(S)o2)c1
Reactant: FC(F)=C(F)F
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: FC(F)C(F)(F)Sc1nnc(-c2cccc(C(F)(F)F)c2)o1
Temperature: 60 °C

Procedure:
60 ml of dimethylformamide and 7.38 g of 2-mercapto-5-(3'-trifluoromethylphenyl)-1,3,4-oxadiazole (m.p. 154°-155° C.) and 0.7 g of potassium hydroxide are stirred in an autoclave. 22 g of tetrafluoroethylene are pressed in, and the reaction mixture is heated for 19 hours at 60° C. (10-12·105Pa). After cooling and release of pressure, the solution is poured into ice-water, the product is taken up in chloroform, the chloroform solution is washed with 1n sodium hydroxide solution, and the solvent is removed in vacuo, affording as reside the title compound in the form of an oil with a refractive index nD22 of 1.4926.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][NH:10][C:9]2=[O:13])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][N:10]([C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:9]2=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]ncn1-c1cccc(Br)c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1n(-c2cccc(Br)c2)cnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-(3-bromophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (250 mg, 1.04 mmol) and NaH (50 mg of a 60% dispersion in mineral oil, 1.25 mmol) in DMF (3 mL) was stirred at room temperature for 30 min. To the solution was added 1,1′,1″-(chloromethanetriyl)tribenzene (305 mg, 1.09 mmol) and the mixture stirred at room temperature for 4 hr. The reaction mixture was diluted with EtOAc, washed with H2O and brine, dried over Na2SO4 then concentrated in vacu. The residue was purified by silica gel chromatography (EtOAc/Hexanes) to give 4-(3-bromophenyl)-2-(triphenylmethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one as a pale yellow foam. 1H NMR (400 MHz, DMSO-d6) δ 7.22-7.31 (m, 15H), 7.40-7.42 (m, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.90 (s, 1H), 8.60 (s, 1H).