Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[H-].[Na+].[Cl:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1>CN(C=O)C>[ClH:18].[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1)[N:22]=[CH:21][N:20]=[C:19]2[CH:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([S:3]([NH:2][CH3:1])(=[O:5])=[O:4])[CH:7]=2)[NH:11][C:10]1=[O:15]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccc2c(c1)C(c1ncnc3cc(OCCCN4CCOCC4)c(OC)cc13)C(=O)N2
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
A solution of 5-methylaminosulphonyloxindole (262 mg, 1.16 mmol) in DMF (3.5 ml) was added dropwise to a suspension of sodium hydride (46 mg, 1.1 6 mmol, prewashed with hexane) in DMF (1.5 ml). The mixture was stirred for 30 minutes at ambient temperature and 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (130 mg, 0.38 mmol), (prepared as described for the starting material in Example 5), was added as a solid. The mixture was stirred for 45 minutes at 60° C. and was then partitioned between ether and water. The aqueous layer was separated and was adjusted to pH7-8 with 1M hydrochloric acid. The precipitate was collected by filtration, washed with water and ether, and dried under vacuum. The solid was suspended in methylene chloride/methanol (1/1) and 2.2M ethereal hydrogen chloride (1.5 ml) was added. The mixture was stirred for 10 minutes at ambient temperature and the volatiles were removed by evaporation. The solid residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum at 60° C. to give 6-methoxy-4-(5-methylaminosulphonyloxindol-3-yl)-7-(3-morpholinopropoxy)quinazoline hydrochloride (116 mg, 53%).
Reaction SMILES: [C:1]([O-])(=O)[C:2]1C=CC=C[CH:3]=1.[C:10]1([S:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=2[NH:30][CH2:31][C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[H-].[Na+].[CH3:44]I>CN(C=O)C>[CH3:44][N:30]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:40][CH:41]=1)[C:21]1[CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=[CH:25][C:20]=1[N:19]([S:16]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:17])=[O:18])[CH:2]([CH3:3])[CH3:1]
Reactant: CI
Reactant: COC(=O)c1ccc(CNc2cc(C(F)(F)F)ccc2NS(=O)(=O)c2ccccc2)cc1
Reactant: O=C([O-])c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(C)c2cc(C(F)(F)F)ccc2N(C(C)C)S(=O)(=O)c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Methyl 4-[2-(N-isopropyl-phenylsulfonylamino)-5-trifluoromethyl-phenyl]aminomethyl]benzoate (200 mg) prepared by the same procedure as Example 17 by using methyl 4-(2-phenylsulfonylamino-5-trifluoromethyl-phenylaminomethyl)benzoate (prepared in Example 27) was dissolved in DMF (5 ml). Sodium hydride (64 mg) and methyl iodide (200 μl) were added thereto. The mixture was stirred for 24 hours at 60° C. The reaction mixture was extracted with H2O-AcOEt, washed, dried over, filtered and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (hexane:AcOEt=5:1) to give the title compound (105 mg) having the following physical data.
Reaction SMILES: [CH3:1][C:2]#[N:3].C([Li])CCC.C[O:10][C:11]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:17]=[CH:16]2)=O.Cl>C1(C)C=CC=CC=1.CCCCCC>[O:10]=[C:11]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([Si:22]([CH:26]([CH3:28])[CH3:27])([CH:29]([CH3:31])[CH3:30])[CH:23]([CH3:24])[CH3:25])[CH:17]=[CH:16]2)[CH2:1][C:2]#[N:3]
Reactant: CC#N
Reactant: COC(=O)c1ccc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C(=O)CC#N)ccc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 95.9 %

Procedure:
To a solution of 393 μL of anhydrous CH3CN (7.5 mmol) in 6 mL of dry toluene cooled down to −78° C., 5.35 mL of butyllithium in hexane solution (1.6 N) were added dropwise. The mixture was left stirring at −78° C. for 20 minutes and then a solution of 500 mg of 1-triisopropylsilanyl-1H-indole-5-carboxylic acid methyl ester (1.5 mmol) in 2 mL of dry toluene were added and the reaction allowed to reach room temperature. Upon reaction completion after about 20 minutes the mixture was cooled down to 0° C. and HCl 2N was added to pH 2. The organic phase was separated, dried over Na2SO4 and concentrated under reduced pressure, affording 490 mg of title product which was used in the next step without further purification (yield=96%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[CH3:28])[CH:23]=O)[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[CH3:28])[CH2:23][N:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[C:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)[CH2:15][CH2:14]1)[CH3:18]
Reactant: CCOc1cc(C=O)ccc1C
Reactant: Cc1cncc(C(=O)NC2CCNCC2)c1
Product: CCOc1cc(CN2CCC(NC(=O)c3cncc(C)c3)CC2)ccc1C
Yield: 35 %

Procedure:
The title compound (13 mg, 35%) was prepared analogously to example 30 from 5-methyl-N-(piperidin-4-yl)-nicotinamide and 3-ethoxy-4-methyl-benzaldehyde. MS: 368.5 (MH+).
Reaction SMILES: [O:1]=[C:2]1[CH:5]([NH:6][C:7](=[O:16])[CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]([S:17]NC2C=CC=CC=2)[N:3]1[CH:25]([C:30]([CH3:32])=[CH2:31])[C:26]([O:28][CH3:29])=[O:27].CO.B(F)(F)F.C[CH2:40][O:41]CC>C(Cl)Cl>[CH3:40][O:41][CH2:31][C:30]1([CH3:32])[CH:25]([C:26]([O:28][CH3:29])=[O:27])[N:3]2[C:2](=[O:1])[CH:5]([NH:6][C:7](=[O:16])[CH2:8][O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C@H:4]2[S:17]1
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)COc2ccccc2)C1SNc1ccccc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CO
Product: COCC1(C)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OC
Reaction time: 3 h

Procedure:
Methyl 2-oxo-3-(2-phenoxyacetamido)-4-anilinothio-α-isopropenyl-1-azetidineacetate (454 g) was dissolved in methylene chloride (20 ml). To this solution were added methanol (5 ml) and then boron trifluoride etherate (0.124 g) under cooling at 0° C. The mixture was stirred for 3 hours at the same temperature and further stirred for 2 hours to 5° to 10° C. After the reaction, the reaction mixture was washed with 5% sodium bicarbonate aqueous solution and then with water, dried and the solvent was distilled off. The oily residue (25 g) was subjected to column chromatography on silica gel and eluted with chloroform. The eluate was separated into each 50 ml fraction and the seventh and eighth fractions were combined. The solvent was distilled off to give oily methyl 2-methoxymethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate.
Reaction SMILES: Br.C(O)(=O)C.C(OC([NH:16][C:17]1([C:20]2[C:21]([F:41])=[CH:22][C:23]3[C:34](=[O:35])[C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][N:25]4[CH:26]([CH2:30][F:31])[CH2:27][O:28][C:29]=2[C:24]=34)[CH2:19][CH2:18]1)=O)C1C=CC=CC=1.C(OCC)C>O>[NH2:16][C:17]1([C:20]2[C:21]([F:41])=[CH:22][C:23]3[C:34](=[O:35])[C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][N:25]4[CH:26]([CH2:30][F:31])[CH2:27][O:28][C:29]=2[C:24]=34)[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1cn2c3c(c(C4(NC(=O)OCc5ccccc5)CC4)c(F)cc3c1=O)OCC2CF
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cn2c3c(c(C4(N)CC4)c(F)cc3c1=O)OCC2CF
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
1 ml of a 30% hydrogen bromide-acetic acid solution was added to 52 mg of ethyl 10-(1-benzyloxycarbonylaminocyclopropyl)-9-fluoro-3-fluoromethyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6carboxylate. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. To the residue obtained were added 10 ml of diethyl ether and 20 ml of water in this order. The aqueous layer was separated and 20 ml of ethyl acetate was added thereto. The resulting mixture was adjusted to pH 8.5 with a saturated aqueous sodium hydrogencarbonate solution. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 35 mg (yield: 90.8%) of ethyl 10-(1-aminocyclopropyl)-9-fluoro-3-fluoromethyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:10]1[CH2:14][CH2:13][C:12](=O)[CH2:11]1>C(O)C>[O:10]1[CH2:14][CH2:13]/[C:12](=[N:9]\[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])/[CH2:11]1
Reactant: O=C1CCOC1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCO
Product: CC(C)(C)OC(=O)N/N=C1\CCOC1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
A solution of hydrazinecarboxylic acid tert-butyl ester (8.85 g, 67 mmol) in ethanol (30 mL) was added to a solution of dihydro-furan-3-one (5.78 g, 67 mmol) in ethanol (100 mL). This mixture was heated at reflux for 19 hours, then cooled to room temperature and concentrated under reduced pressure. The resulting crude mixture was partitioned between water (100 mL) and dichloromethane (100 mL). The aqueous layer was basified and extracted with dichloromethane (50 mL). The combined organic extracts were dried over magnesium sulphate, filtered, and evaporated under reduced pressure to give an oil (10.56 g, 79%). APCI MS m/z 201 [MH]+
Reaction SMILES: [Na].CS(C)=O.[OH:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1.Br[CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CO>[CH2:27]([O:26][C:24]([CH:23]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[N:8]=1)[CH3:29])=[O:25])[CH3:28]
Reactant: Oc1ncn(-c2cccc(C(F)(F)F)c2)n1
Reactant: CCOC(=O)C(C)Br
Agent: [Na]
Solvent: CS(C)=O
Solvent: CO
Product: CCOC(=O)C(C)Oc1ncn(-c2cccc(C(F)(F)F)c2)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.1 %

Procedure:
A 1.7 g portion of sodium was dissolved in 30 ml of methanol, and the solution was added to 150 ml of dimethylsulfoxide. To it was added 17 g of 3-hydroxy-1-(3-trifluoromethylphenyl)-1,2,4-1H-triazole, and the solution was heated on the steam bath for 90 minutes. To it was then added 13.4 g of ethyl 2-bromopropionate, and heating was continued for 90 minutes more. The mixture was then cooled and poured over ice-water. The solid was collected, dried and recrystallized from ethanol to obtain 20.5 g of the desired product, m.p. 100°-102°.
Reaction SMILES: C[Si]([C:5]1[NH:13][C:12]2[C:11](=[O:14])[NH:10][C:9]([N:15]([Si](C)(C)C)[Si](C)(C)C)=[N:8][C:7]=2[N:6]=1)(C)C.[C:24]([O:32][CH2:33][CH2:34][O:35][CH2:36]Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:24]([O:32][CH2:33][CH2:34][O:35][CH2:36][N:6]1[CH:5]=[N:13][C:12]2[C:11](=[O:14])[NH:10][C:9]([NH2:15])=[N:8][C:7]1=2)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(OCCOCCl)c1ccccc1
Reactant: C[Si](C)(C)c1nc2nc(N([Si](C)(C)C)[Si](C)(C)C)[nH]c(=O)c2[nH]1
Product: Nc1nc2c(ncn2COCCOC(=O)c2ccccc2)c(=O)[nH]1
Yield: 32 %

Procedure:
A mixture of guanine (2.0 g), ammonium sulfate (1.5 g), and hexamethyldisilazane (126 g) was heated at reflux under nitrogen overnight. Excess hexamethyldisilazane was removed by distillation at reduced pressure. Dry benzene (10 ml) was added to the residual oil and any remaining ammonium sulfate removed by filtration. To this solution was added triethylamine (4 ml) and a solution of 2-benzoyloxyethoxymethyl chloride (2.8 g) in dry benzene (15 ml) and the mixture heated at reflux under nitrogen overnight. The solvent was evaporated in a rotary evaporator at reduced pressure and the residue dissolved in 95% ethanol. The solution was warmed on a steam bath for 1/2 hour to effect hydrolysis of the silyl groups. The ethanol was then evaporated and the residual solid thoroughly washed with water, filtered and dried. Recrystallization from methanol and then from water (residual guanine was insoluble in the hot solvents and was removed by filtration) afforded 9-(2-benzoyloxyethoxymethyl)guanine (0.58 g., 14% of theoretical), m.p. 222°-226° C. A later condensation of the tris-(trimethylsilyl) guanine with a 60% excess of 2-benzoyloxyethoxymethyl chloride gave a 32% yield of 9-(2-benzoyloxyethoxymethyl)guanine.
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[N:6]=[CH:5][C:4]([C:3]([N:26]4[CH2:31][CH2:30][S:29][CH2:28][CH2:27]4)=[O:25])=[CH:9][CH:8]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[N:19][CH:20]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cn3)noc2C)nc1
Reactant: C1CSCCN1
Product: Cc1onc(-c2ccc(Cl)cn2)c1COc1ccc(C(=O)N2CCSCC2)cn1
Yield: 59 %

Procedure:
As described for example 301, [6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (108 mg, 0.3 mmol) was converted, using thiomorpholine instead of 4-aminotetrahydropyran to the title compound (76 mg, 59%) which was obtained as a white solid. MS: m/e=431.3 [M+H]+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][CH2:3]1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>CO.[Pd]>[C:21]([O:20][C:18]([N:12]1[CH2:17][CH2:16][N:15]([CH:2]2[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][CH2:3]2)[CH2:14][CH2:13]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(O)CC1CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C2CCC(CC(=O)O)CC2)CC1
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To 2-(4-oxocyclohexyl)acetic acid (0.576 g, 3.7 mmol) and tert-butyl piperazine-1-carboxylate (0.700 g, 3.7 mmol) in MeOH, was added Pd on carbon (80 mg), and the resultant reaction mixture was stirred under hydrogen atmosphere overnight. The catalyst was removed via filtration and the solvent was removed under reduced pressure to afford the acid as white solid (1.2 g. 99%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(CC)CC>C1COCC1.CN(C=O)C>[C:20]([NH:1][CH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(Oc2ccc(CCNC(=O)c3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine amine starting material of Example 34 (100 mg, 0.39 mmol), benzoyl chloride (50 μL, 0.43 mmol) and Et3N (120 μL, 0.86 mmol) in THF (4 mL) and DMF (0.5 mL). Stir the mixture at room temperature for 3 hours. Eliminate the solvent and purify by flash chromatography on silica gel (eluent: EtOAc/hexane 75/25) to give the title compound. (90 mg, 65%). Electrospray MS M+1 ion=362, 1H-NMR (methanol-d4, 400 MHz): 8.62 (d, 1H, J=2.8 Hz), 8.24 (dd, 1H, J=2.8 and 9.0 Hz), 7.79-7.76 (m, 2H), 7.55-7.42 (m, 5H), 7.09-7.06 (m, 2H), 6.96 (d, 1H, J=9.0 Hz), 3.62 (t, 2H, J=7.3 Hz), 2.95 (t, 2H, J=7.3 Hz).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:23]1([PH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([P:29]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: C=CCCCCCCCCCCCCCCCCCCCC
Reactant: c1ccc(Pc2ccccc2)cc1
Product: CCCCCCCCCCCCCCCCCCCCCCP(c1ccccc1)c1ccccc1
Yield: 96 %

Procedure:
In a manner similar to Example 1, docosene (obtained from Aldrich) and diphenylphosphine were reacted under nitrogen at 250° C. for 27 hours. Removal of unreacted olefin and diphenylphosphine by vacuum distillation gave docosyldiphenylphosphine. The yield was 96% based on recovered olefin. The conversion was 57% based on recovered olefin.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:18]O>>[Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: Cc1cc(Cl)c(C(=O)O)cc1I
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(I)c(C)cc1Cl
Temperature: 60 °C
Yield: 88 %

Procedure:
To a solution of 2-chloro-5-iodo-4-methylbenzoic acid (Preparation 49, 2.50 g, 8.43 mmol) in methanol (50 mL) was added concentrated sulfuric acid (1.2 mL) and the reaction was heated at 60° C. for 18 hours. The reaction was cooled, concentrated in vacuo, diluted with water and basified with potassium carbonate until pH=9. The aqueous solution was extracted with EtOAc (3×100 mL), the organic layers combined, washed with water (100 mL), brine (100 mL), dried over magnesium sulphate and concentrated in vacuo to afford the title compound (2.3 g, 88%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1>CN(C)C=O>[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][O:9][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([Br:12])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: OCc1ccc(Br)cc1
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(COCc2ccc(Br)cc2)cc1
Temperature: 0 °C
Yield: 89.9 %

Procedure:
To a solution of 27.4 g (685 mmol) of sodium hydride contained at 60% in mineral oil in dry dimethylformamide (425 ml) was added 42.4 g (227 mmol) of 4-bromobenzyl alcohol in an atmosphere of argon, and the mixture was allowed to react at 40-50° C. for 30 min. Then, 62.4 g (250 mmol) of 4-bromobenzyl bromide was added, and the mixture was reacted at room temperature for 15 hours. The reaction mixture was added to ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with dichloromethane-hexane (1:1) yielded 72.7 g (204 mmol) of 4-bromobenzyl ether.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=O.[NH2:19][C@H:20]([C:24]([N:26]([CH3:55])[C@H:27]([C:31]([N:33]1[CH2:54][CH2:53][CH2:52][C@H:34]1[C:35]([N:37]1[CH2:51][CH2:50][CH2:49][C@H:38]1[C:39]([NH:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH:21]([CH3:23])[CH3:22].Cl.C(N(CC)CC)C>CN(C=O)C>[N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([NH:19][C@H:20]([C:24]([N:26]([CH3:55])[C@H:27]([C:31]([N:33]1[CH2:54][CH2:53][CH2:52][C@H:34]1[C:35]([N:37]1[CH2:51][CH2:50][CH2:49][C@H:38]1[C:39]([NH:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])=[O:36])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:5]
Reactant: CC(C)[C@H](N)C(=O)N(C)[C@H](C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)NCc1ccccc1)C(C)C
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1)C(=O)N(C)[C@H](C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)NCc1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3.74 g Z-D-Pro-OH (15 mmol, BACHEM) and 8.25 g H-Val-MeVal-Pro-Pro-NHBn×HCl (15 mmol) were dissolved in 80 ml dry DMF. After cooling to 0° C., 2.4 g DEPCN (2.25 ml, 15 mmnol) and 4.2 ml triethylamine (30 mmol) were added. The reaction mixture was stirred at 0° C. for several hours and room temperature overnight, then the DMF was evaporated under reduced pressure. The residue was diluted with ethyl acetate and thoroughly washed with dilute aqueous HCl (pH 2), water, dilute aqueous NaOH (pH 9-10), and water. The organic phase was dried over sodium sulfate and evaporated to dryness to yield 9.2 g of the desired protected pentapeptide.
Reaction SMILES: [I-].[K+].[CH2:3]([N:5]([CH2:30][CH3:31])[C:6]([C:8]1[N:12]=[C:11]([CH2:13]Cl)[N:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22](=O)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]=1)=[O:7])[CH3:4].[NH3:32]>O.O1CCOCC1>[CH2:30]([N:5]([CH2:3][CH3:4])[C:6]([C:8]1[N:12]=[C:11]2[CH2:13][N:32]=[C:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:16]3[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=3[N:10]2[N:9]=1)=[O:7])[CH3:31]
Reactant: CCN(CC)C(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Reactant: N
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)C(=O)c1nc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
An amount of 1.99 g (0.012 mole) of potassium iodide is dissolved in 6 ml of water. The obtained solution is diluted with 20 ml of dioxane; an addition is then made at 25°, with stirring, of a solution of 4.3 g (0.01 mole) of N,N-diethyl-1-(2-benzoyl-4-chlorophenyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxamide in 40 ml of dioxane, and the reaction solution heated for 1 hour at 50°. There is then added 35 ml of conc. aqueous ammonia solution, the mixture heated for a further 2 hours at 50°, and subsequently concentrated in vacuo. Water is added to the residue and extraction performed twice with methylene chloride. The organic phase is washed with water and saturated sodium chloride solution; it is then dried over sodium sulphate and concentrated in vacuo to dryness. The residue is recrystallised from benzene/cyclohexane to obtain pure N,N-diethyl-6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxamide, M.P. 175°-177° .
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.C(O[K])(C)(C)C>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:10]=1
Reactant: Brc1ccccn1
Reactant: Nc1cccnc1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: c1ccc(Nc2cccnc2)nc1
Yield: 89.3 %

Procedure:
2-Bromopyridine (0.3 mL, 3.16 mmol), 3-aminopyridine (327 mg, 3.48 mmol), tBuOK (532 mg, 4.74 mmol), (±)-BINAP (79 mg, 0.126 mmol) and Pd2(dba)3 (72 mg, 0.079 mmol) were stirred in toluene (5 mL) at 90° C. under Ar(g) for 19 h. The reaction mixture was then diluted with CH2Cl2 (5 mL) and silica was added followed by the removal of the solvent under reduced pressure. The resulting dry loaded material was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:3 to 100:6) to furnish I as a brown oil (483 mg, 90%).