Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([C:4]1([C:13]2NC=N[CH:14]=2)[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)[CH3:3].CC(=[O:23])CC=C>>[CH:13]([C:4]1([C:2](=[O:23])[CH3:3])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)=[CH2:14]
Reactant: CCC1(c2cnc[nH]2)Cc2ccccc2C1
Reactant: C=CCC(C)=O
Agent: Cl
Product: C=CC1(C(C)=O)Cc2ccccc2C1

Procedure:
EP 0247764 B (ORION-YHTYMÄ OY) Feb. 12, 1987 disclosed the following process for preparation of 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole hydrochloride. The process starts by reaction of alpha, alpha′-dibromo-o-xylene with 4-penten-2-one to obtain 1-(2,3-dihydro-2-vinyl-1H-inden-2-yl)ethanone. The obtained intermediate was brominated, e.g. with bromine, methylene chloride was used as solvent and 2-bromo-1-(2,3-dihydro-2-vinyl-1H-inden-2-yl)-ethanone was obtained, which is thereafter reacted with formamide in excess formamide to give a 4(5)-(2,3-dihydro-2-vinyl-1H-inden-2-ylimidazole hydrochloride. As the last step the vinyl group was catalytically hydrogenated to an ethyl group so as to form a product 4(5)-(2,3-dihydro-2-ethyl-1H-inden-2-yl) imidazole.
Reaction SMILES: [K].Cl[CH:3]([CH:9]=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:11][C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[CH:14][CH:13]=1.C(O)C>C(O)(=O)C>[C:4]([C:3]1[N:17]2[C:16]([CH3:18])=[CH:15][CH:14]=[CH:13][C:12]2=[N:11][CH:9]=1)([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Cc1cccc(N)n1
Reactant: CCOC(=O)C(Cl)C=O
Agent: [K]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2cccc(C)n12
Yield: 57.1 %

Procedure:
In 10 ml of ether was suspended 560 mg (5.0 mM) of potassium tert-butoxide and while the suspension was vigorously stirred, a solution of ethyl formate:370 mg (5.00 mM) and ethyl chloroformate: 613 mg (5.00 mM) in 10 ml of ether was added dropwise over 3 minutes at room temperature. This mixture was stirred at room temperature for 30 minutes and the precipitate that formed was recovered by filtration and rinsed with a small amount of ether. This precipitate was dried in vacuo to give 700 mg (yield 73.8%) of ethyl 2-chloro-2-formylacetate potassium salt as light-yellow solid. Then, 700 mg (3.69 mM) of ethyl 2-chloro-2-formylacetate potassium salt and 399 mg (3.69 mM) of 6-amino-2-methylpyridine were mixed with 20 ml of ethanol and after addition of 0.53 ml (9.23 mM) of acetic acid, the whole mixture was refluxed for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was diluted with 20 ml of ethyl acetate and 20 ml of purified water. Then, saturated aqueous NaHCO3 solution was added until the water layer became pH 8. This mixture was extracted with 40 ml of ethyl acetate and the organic layer was washed with 30 ml of saturated aqueous NaCl solution and dried over MgSO4. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to provide 430 mg (yield 57.1%) of the title compound as light-yellow liquid.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[CH2:9]([N:16]1[C:23](=[O:24])[C:20]2([CH2:22][CH2:21]2)[NH:19][C:18](=[O:25])[CH:17]1[CH2:26][OH:27])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:9]([N:16]1[C:23](=[O:24])[C:20]2([CH2:21][CH2:22]2)[NH:19][C:18](=[O:25])[CH:17]1[CH2:26][O:27][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1NC2(CC2)C(=O)N(Cc2ccccc2)C1CO
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC1C(=O)NC2(CC2)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
4-dimethylaminopyridine (660 mg, 5.00 mmol) and tert-butyldimethylchlorosilane (4.90 g, 32.0 mmol) were added to a dimethylformamide (100 ml) solution of the compound (7.15 g, 27.0 mmol) obtained in Step 4 above and triethylamine (4.5 ml, 32.0 mmol). The resulting mixture was stirred at room temperature for 16 hours, then ice water (200 ml) was added to the reaction mixture and the precipitated solid was collected by filtration. The solid obtained was purified by silica gel column chromatography [n-hexane:ethyl acetate=3:1 (v/v)] to give the title compound (8.63 g, 85%) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[C:15](Br)Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:23]([Sn:27](Cl)([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26].C(OCC)(=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCC(C=C(Br)Br)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[Sn](C#CC1CCN(C(=O)OC(C)(C)C)CC1)(CCCC)CCCC
Reaction time: 1 h
Yield: 86.6 %

Procedure:
A mixture of 23.199 g (62.85 mmole) 1-(t-butoxycarbonyl)-4-(2,2-dibromoethen-1-yl)piperidine (prepared as in Step B3 above) and 600 mL anhydrous THF was cooled with dry ice acetone bath under nitrogen. To this mixture was added 88 mL of a 1.6 M butyl lithium solution in hexanes dropwise with stirring and cooling over 50 minutes. After one hour, the flask was transferred into an ice bath. After another hour, a solution of 28.64 g (87.99 mmole) tributyltin chloride in 100 mL THF was added with stirring and cooling over 35 minutes. After three h, the mixture was concentrated under vacuum to remove some THF, and the residue was partitioned between 600 mL ice water and 800 mL ether. The organic layer was washed with 200 mL of water (1×), 2% sodium bicarbonate (1×), water (2×), and saturated brine (1×), dried over sodium sulfate and concentrated under vacuum to give 30.104 g crude product as a green-yellowish liquid. FC on 275 g silica gel using cold 2.5˜15% ethyl acetate in hexanes as quickly as possible to give 27.115 g title compound as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15](Cl)=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[F:18][C:19]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:20]=1[NH2:21]>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([NH:21][C:20]4[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:19]=4[F:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(Cl)c1cc2c(s1)-c1cc(Br)ccc1OC2
Product: O=C(Nc1ccc(F)cc1F)c1cc2c(s1)-c1cc(Br)ccc1OC2

Procedure:
8-Bromo-4H-thieno[3,2-c]chromene-2-carbonyl chloride 4bp is reacted with 2,4-difluoroaniline to give 5bp, as in General Procedure B-bp.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].Br[CH2:17][C:18]#[C:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]>>[C:1]([NH:4][C:5]([CH2:17][C:18]#[C:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)CCCC#CCBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Product: CCOC(=O)C(CC#CCCCC(=O)OC)(NC(C)=O)C(=O)OCC

Procedure:
Under the reaction conditions described in Example 1A diethyl acetamidomalonate and methyl 7-bromohept-5-ynoate reacted to give diethyl acetamido-(6-methoxycarbonylhex-2-ynyl)malonate as a yellow oil.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]#[CH:9])[C:4](=[O:10])[CH2:3]1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[CH3:15][C:14]([Si:11]([CH3:13])([CH3:12])[O:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]#[CH:9])[C:4](=[O:10])[CH2:3]1)([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CCN1C[C@@H](O)CC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCN1C[C@@H](O[Si](C)(C)C(C)(C)C)CC1=O
Reaction time: 8 h
Yield: 93.8 %

Procedure:
A mixture of 25 g of (S)-4-hydroxy-1-(2-propynyl)-2-pyrrolidinone, 39.8 g of t-butyldimethylsilyl chloride and 38.5 ml of triethylamine in 200 ml of dichloromethane was stirred under argon overnight. The mixture was washed with 300 ml of water, dried and evaporated. The residual oil was purified by chromatography, (silica gel) giving 42.7 g of (S)-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-(2-propynyl)-2-pyrrolidinone.
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([CH3:15])([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C([Si](C)(C)[O:25][C@@H:26]1[CH2:30][CH2:29][N:28]([S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[NH:40][C:41]2[C:46]([Cl:47])=[CH:45][N:44]=[C:43](Cl)[N:42]=2)(=[O:33])=[O:32])[CH2:27]1)(C)(C)C>>[Cl:47][C:46]1[C:41]([NH:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[S:31]([N:28]2[CH2:29][CH2:30][C@@H:26]([OH:25])[CH2:27]2)(=[O:32])=[O:33])=[N:42][C:43]([NH:1][C:2]2[C:17]([O:18][CH3:19])=[CH:16][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([OH:14])([CH3:15])[CH3:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:44][CH:45]=1
Reactant: COc1cc2c(cc1N)CCN(CC(C)(C)O)CC2
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(S(=O)(=O)c2ccccc2Nc2nc(Cl)ncc2Cl)C1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CC[C@@H](O)C3)n1)CCN(CC(C)(C)O)CC2
Yield: 47 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from 1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-2-methyl-propan-2-ol and {2-[(R)-3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1-sulfonyl]-phenyl}-(2,5-dichloro-pyrimidin-4-yl)-amine. Product was isolated as white solid (58 mg, 47%). mp: 205-206° C., MS (ESI+): 617 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.33 (s, 1H), 8.48 (d, J=8 Hz, 1H), 8.17 (s, 1H), 7.97 (m, 2H), 7.53 (m, 2H), 7.25 (m, 1H), 6.65 (s, 1H), 3.60 (br s, 1H), 3.89 (s, 3H), 3.42 (q, 6 Hz, 3H), 3.30 (m, 2H), 2.87-2.72 (m, 8H), 2.48 (s, 2H), 1.95 (m, 1H), 1.88 (m, 1H), 1.57 (s, 6H), 1.22 (s, 6H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]1[C:14]([S:22][CH3:23])=[N:15][C:16]([CH3:21])=[CH:17][C:18]=1[S:19][CH3:20])=[O:11].[CH3:24][O:25][C:26]([C:28]1[C:36]2[O:35][C:34]([SH:37])=[N:33][C:32]=2[CH:31]=[CH:30][CH:29]=1)=[O:27].C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[CH3:24][O:25][C:26]([C:28]1[C:36]2[O:35][C:34]([S:37][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]3[C:14]([S:22][CH3:23])=[N:15][C:16]([CH3:21])=[CH:17][C:18]=3[S:19][CH3:20])=[O:11])=[N:33][C:32]=2[CH:31]=[CH:30][CH:29]=1)=[O:27]
Reactant: COC(=O)c1cccc2nc(S)oc12
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CCCCCCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc2nc(SCCCCCCCCC(=O)Nc3c(SC)cc(C)nc3SC)oc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
To a DMF (4 ml) solution of 9-bromo-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]nonanamide (90 mg, 0.22 mmol) and 7-methoxycarbonyl-2-mercaptobenzoxazole (45 mg, 0.22 mmol) were added 18-crown-6 (6 mg, 0.02 mmol) and potassium carbonate (36 mg, 0.26 mmol), and the mixture was stirred at 80° C. for 4 hours. The rdaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was recrystallized from a mixture of ethyl acetate and hexane to obtain 84 mg (yield 72%) of the desired compound as a colorless powdery crystal.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C([O-])(O)=O.[Na+]>O.ClCCCl>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([C:6]2[CH:7]=[C:8]3[O:9][CH2:1][O:2][C:3]3=[CH:4][C:5]=2[CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: COC(=O)C(C)c1ccc2c(c1)OCO2
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: COC(=O)C(C)c1cc2c(cc1C(=O)c1ccc([N+](=O)[O-])cc1)OCO2
Yield: 12.3 %

Procedure:
To a mixture of methyl 2-(3,4-methylenedioxyphenyl)propionate (1.0 g, 4.8 mmol), 4-nitrobenzoic acid (1.6 g, 9.6 mmol) and 1,2-dichloroethane (35 mL) was added P2O5 (4 g) and the mixture obtained was heated to reflux for 12 h. Water was added to the reaction mixture and it was neutralized to pH=7-8 by NaHCO3 solution. It was extracted with EtOAc and washed with brine. The product (211 mg, 12.3%) was obtained by a chromatographic purification (EtOAc:Hex=1:4). 1H NMR (CDCl3) 8.31 (d, J=8.7, 2H), 7.94 (d, J=8.7, 2H), 7.00 (s, 1H), 6.73 (s, 1H), 6.06 (s, 2H) 4.15 (q, J=7.1, 1H), 3.59 (s, 3H), 1.51 (d, J=7.1, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[NH:15][CH2:14][CH2:13][N:12]=2)[CH:2]=1.[CH:22](I)([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:22]([N:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:11]([C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[N:12][CH2:13][CH2:14]1)([CH3:24])[CH3:23]
Reactant: c1ccc2c(c1)NCCN=C2c1cnc2ccccc2c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N1CCN=C(c2cnc3ccccc3c2)c2ccccc21
Temperature: 100 °C
Reaction time: 48 h
Yield: 8.6 %

Procedure:
2,3-Dihydro-5-(3-quinolinyl)-1H-1,4-benzodiazepine (0.12 g, 0.44 mmol) was dissolved in 5 mL of dimethyl formamide, and added with isopropyl iodide (0.11 g, 0.65 mmol) and potassium carbonate (0.10 g, 0.72 mmol), followed by stirring at 100° C. for 48 hours. Isopropyl iodide (0.22 g, 1.29 mmol) and potassium carbonate (0.20 g, 1.45 mmol) were added to the resulting reaction solution, followed by stirring at 100° C. for 14 hours. The resulting reaction solution was cooled to room temperature, and cold water was poured into the reaction solution, followed by extracting with ethyl acetate. The organic layer was washed with brine, followed by drying magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:ethyl acetate=7:3) to obtain the target compound (0.012 g, yield: 8.7%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1>C(O)CCC>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][NH:16][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:20][CH:21]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: NCCc1ccc(N)cc1
Solvent: CCCCO
Product: COc1cc2ncnc(NCCc3ccc(N)cc3)c2cc1OC
Temperature: 25 °C
Yield: 79.5 %

Procedure:
A solution of 4-chloro-6,7-dimethoxy-quinazoline (2 g, 8.92 mmol) and 4-(2-amino-ethyl)-phenyl amine (1.3 g, 9.82 mmol) in 1-butanol (20 mL) was heated at 80° C. overnight. After the solution was cooled to room temperature, the solvent was removed and the residue was purified by silica gel column chromatography (eluted by 5% methanol in CH2Cl2) to get the title compound (2.3 g, 68%). 1H-NMR (300 MHz CDCl3) δ 8.57 (s, 1H), 7.19 (s, 1H), 7.48 (d, 2H, J=8.1 Hz), 6.66 (d, 3H, J=7.8 Hz), 5.36 (t, 1H, NH), 4.00 (s, 3H), 3.93 (s, 1H), 3.85 (q, 2H, J=6.6 Hz), 3.62 (s, 1H), 2.92 (t, 2H, J=6.6 Hz).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[CH3:19][NH:20][C:21](=[O:29])[CH2:22][N:23]1[C:27]([SH:28])=[N:26][N:25]=[N:24]1>>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:28][C:27]3[N:23]([CH2:22][C:21](=[O:29])[NH:20][CH3:19])[N:24]=[N:25][N:26]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CNC(=O)Cn1nnnc1S
Product: CNC(=O)Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Yield: 44 %

Procedure:
7-ACA and N-methyl-5-mercapto-1H-tetrazol-1-ylacetamide were reacted as in example 23a to give the title compound, 44.0% yield; δ(CF3CO2H), 3.05 (3H,d, J5 Hz, --CONHCH3), 3.92 (2H,s, C2 methylene), 4.63 (2H,bs, --CH2S--), 5.47 (4H,s, --CH2CO-- and β-lactam protons), 7.5-7.8 (1H,m, --CONH--).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:25])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH2:22][CH2:23][OH:24])([CH3:21])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1>>[CH2:1]([O:8][C:9]1[C:10]([CH3:25])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH3:21])([CH2:22][CH2:23][O:24][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CCO)O2
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CCOc1ccc([N+](=O)[O-])cc1)O2

Procedure:
2-(6-Benzyloxy-2,5,7,8-tetramethylchroman-2-yl)ethanol (prepared as described in Preparation 39) was reacted with p-chloronitrobenzene and the reaction mixture was treated and purified as described in Preparation 2, to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:16][CH:18]3[O:20][CH2:19]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Product: Clc1cccc(N2CCN(CC3CO3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1.50 g of 4-(3-chlorophenyl)piperazine and 0.31 g of sodium hydride was added 2.4 ml of epichlorohydrin and the reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction mixture was extracted with 100 ml of ethyl acetate, and the extract was washed 5 times with 100 ml of water, then dried with anhydrous magnesium sulfate. The solvent was removed by evaporation to obtain the residue which was purified by means of a silica gel column chromatography (eluent:ethyl acetate:n-hexane=1:1) to obtain 1.66 g of 4-(3-chlorophenyl)-1-(2,3-epoxypropyl)piperazine as in the form of an oily substance.
Reaction SMILES: N[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[N:8]2[C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=[C:4]([Cl:26])[N:3]=1.N(OCCC(C)C)=O.[I:35]CI>O1CCCC1>[Cl:26][C:4]1[N:3]=[C:2]([I:35])[N:10]=[C:9]2[C:5]=1[N:6]=[C:7]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[N:8]2[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15]
Reactant: N#Cc1cccc(-n2c(-c3cccc(F)c3)nc3c(Cl)nc(N)nc32)c1
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: N#Cc1cccc(-n2c(-c3cccc(F)c3)nc3c(Cl)nc(I)nc32)c1
Temperature: 25 °C
Yield: 50 %

Procedure:
3-[2-Amino-6-chloro-8-(3-fluorophenyl)-9H-9-purinyl]-benzonitrile (2.6 g) was dissolved in 105 ml of tetrahydrofuran, then 2.9 ml of isoamyl nitrite, 5.8 ml of diiodomethane and 1.37 g of cuprous iodide were added thereto and the mixture was heated under reflux for 1 hour. After the resulting mixture was cooled to room temperature, it was filtered to remove unnecessary substances and washed with 100 ml of ethyl acetate. The filtrate was concentrated to dryness and purified by a silica gel column (50 g of silica gel). It was eluted with ethyl acetate and hexane (1:1). The fractions containing the aimed product were collected, concentrated and suspended in 100 ml of a mixed solvent of ethyl acetate and hexane (1:4), and the resulting precipitates were collected by filtration to give 1.7 g of 3-[6-chloro-8-(3-fluorophenyl)-2-iodo-9H-9-purinyl]benzonitrile. The yield was 50%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[O:7][CH2:8][CH2:9]Cl.[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26][NH2:27].O>CS(C)=O>[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26][NH:27][CH2:9][CH2:8][O:7][C:6]1[CH:11]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:12][CH3:13]
Reactant: NCCCc1c[nH]c2ccc(F)cc12
Reactant: COc1ccc(F)cc1OCCCl
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(F)cc1OCCNCCCc1c[nH]c2ccc(F)cc12
Temperature: 90 °C
Reaction time: 12 h
Yield: 72.1 %

Procedure:
A solution of 2-(5-fluoro-2-methoxy-phenoxy)ethylchloride (0.3 g, 1.5 mmol), 3-(5-fluoro-1H-indol-3-yl)propylamine (0.56 g, 2.9 mmol) in dimethylsulfoxide (20 ml) was allowed to stir for 12 h at 90° C. The reaction mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×150 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride) afforded 0.39 g (77%) of product as a white solid: mp 119-122° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](F)[CH:14]=2)=[CH:4][CH:3]=1.[C:31]1([C@@H:37]([NH2:39])[CH3:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24][CH2:25]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:39][C@H:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH3:38])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CCOC(=O)N1CCC(c2nc(-c3ccc(F)cc3)c(-c3ccnc(F)c3)s2)CC1
Product: CCOC(=O)N1CCC(c2nc(-c3ccc(F)cc3)c(-c3ccnc(N[C@@H](C)c4ccccc4)c3)s2)CC1
Yield: 67.3 %

Procedure:
4-(4-Fluorophenyl)-2-(1-ethoxycarbonylpiperidin-4-yl)-5-(2-fluoro-4-pyridinyl)thiazole (2.4 g. 5.5 mmol) and 1-(S)-phenylethylamine (5.5 ml are heated to 195° C. for 5 h. The reaction mixture is evaporated and purified by SiO2 chromatography (ethyl acetate/cyclohexane 20/80 to 30/70) to yield the title compound as a white foam (2.0 g 67.3%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[N:18][CH:17]=[CH:16][C:11]=1[C:12]([NH:14][NH2:15])=[O:13].C(Cl)Cl.IC.[CH2:25]([OH:27])[CH3:26]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[N:18][CH:17]=[CH:16][C:11]=1[C:12]1[O:13][C:17]([NH:18][CH2:19][CH2:10][N:9]2[CH2:3][CH2:2][O:27][CH2:25][CH2:26]2)=[N:15][N:14]=1
Reactant: NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Reactant: CCO
Solvent: ClCCl
Solvent: CI
Product: Fc1cc(I)ccc1Nc1cnccc1-c1nnc(NCCN2CCOCC2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acid hydrazide (500 mg; 1.34 mmol; 1 eq) in DCM (5 mL) 4-(3-Isothiocyanato-ethyll)-morpholine (255 mg; 1.61 mmol; 1.2 eq) was added. The reaction mixture was refluxed for 4 hrs under argon. A yellow solid precipitated out, which was filtered to afford an intermediate that was suspended in ethanol (5 mL). Iodomethane (190 mg; 1.34 mmol; 1.0 eq) was then added and the reaction mixture was stirred overnight at RT. It was then heated to 80° C. and stirred for another 2 hr. Filtration afforded the yellow solid product 153 mg. LC/MS (Method A) [0.41 min; 511(M+1)]