Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]5[N:23](S(C6C=CC(C)=CC=6)(=O)=O)[C:24]([C:26]6[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH:27]=6)=[CH:25][C:18]=45)[CH:15]=[CH:16][C:11]=3[N:10]=[N:9]2)[CH2:3][CH2:2]1.[OH-].[Na+]>O1CCOCC1>[O:1]1[CH2:2][CH2:3][CH:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]5[NH:23][C:24]([C:26]6[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH:27]=6)=[CH:25][C:18]=45)[CH:15]=[CH:16][C:11]=3[N:10]=[N:9]2)[CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(-c4ccc5nnn(CC6CCOCC6)c5c4)ccnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(-c4ccc5nnn(CC6CCOCC6)c5c4)ccnc3[nH]2)CC1

Procedure:
A mixture of Example 36E (0.530 g, 0.792 mmol) and 5M aqueous sodium hydroxide (0.555 mL, 2.77 mmol) in dioxane (8 mL) was heated at 90° C. for 8 hours. The solvent was evaporated and the residue was treated with ethyl acetate and washed with aqueous NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated until most of solvent was evaporated. The resulting precipitate was filtered, washed with ethyl acetate/ether, and vacuum oven-dried to give the title compound. The filtrate was concentrated and purified on a 4 g column using the ISCO Companion flash system eluting with ethyl acetate to give additional title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[NH:12][C:11](=[S:22])[NH:10]2)=[CH:5][CH:4]=1.[Na].[CH2:24](I)[CH3:25].O>CO.CN(C)C=O>[CH2:24]([S:22][C:11]1[NH:12][C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1)[CH3:25]
Reactant: COc1ccc([C@H]2NC(=S)N[C@H]2c2ccc(OC)cc2)cc1
Reactant: CCI
Agent: [Na]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CCSC1=N[C@@H](c2ccc(OC)cc2)[C@@H](c2ccc(OC)cc2)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
12 g of cis-4,5-bis-(p-methoxyphenyl)-imidazolidine-2-thione are added to a solution of 0.88 g of sodium in 13 ml of methanol. The mixture is then diluted with 200 ml of dimethylformamide and left to stand overnight, 4 ml of ethyl iodide are added and the mixture is stirred for 5 hours at room temperature and poured into 300 ml of water. The crystals which have precipitated out are filtered off with suction and dissolved in methylene chloride. The solution is dried over sodium sulfate and evaporated and the residue is dissolved in acetone. The acetone solution is rendered weakly acid with methanolic hydrochloric acid (4.5μ) and the cis-2-ethylthio-4,5-bis-(p-methoxyphenyl)-imidazoline hydrochloride which has precipitated is filtered off. In order to liberate the base, this hydrochloride is treated with 2 N sodium hydroxide solution and the crude base is then rcrystallised from isopropanol/petroleum ether. cis-2-Ethylthio-4,5-bis-(p-methoxyphenyl)-imidazoline with a melting point of 92°-93° is obtained.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH:19]([O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26])([CH3:21])[CH3:20]>>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[C:23]([O:22][CH:19]([CH3:21])[CH3:20])[CH:24]=3)=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CC(C)Oc1cccc(N)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: CC(C)Oc1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1
Yield: 64 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 572 mg of 3-isopropoxyaniline in place of the 2,4-difluoroaniline. 228 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-[3-(propan-2-yloxy)phenyl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([CH2:25][CH2:26]CS([O-])(=O)=O)[CH2:10][CH2:9][N:8]([C:11](=[O:24])[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:7]1.Cl.[C:33]1([C:39]2([C:45]([NH2:47])=[O:46])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([CH2:25][CH2:26][N:42]2[CH2:41][CH2:40][C:39]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)([C:45]([NH2:47])=[O:46])[CH2:44][CH2:43]2)[CH2:10][CH2:9][N:8]([C:11](=[O:24])[C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)[CH2:7]1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3cccs3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3cccs3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(thiophen-2-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (8 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (12 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH2:27][C:28]2[S:29][CH:30]=[CH:31][N:32]=2)[S:11]([CH2:14][CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)(=[O:13])=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].NN>C1COCC1>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH2:27][C:28]2[S:29][CH:30]=[CH:31][N:32]=2)[S:11]([CH2:14][CH2:15][NH2:16])(=[O:12])=[O:13])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(N(Cc2nccs2)S(=O)(=O)CCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: C1CCOC1
Product: CC(C)N1CCC(N(Cc2nccs2)S(=O)(=O)CCN)CC1

Procedure:
2-Amino-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-thiazol-2-ylmethyl-amide was prepared by an analogous procedure as described for example 1 ii) starting from 178 mg (0.37 mmol) 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-thiazol-2-ylmethyl-amide and 0.75 ml (2 equiv.) of a 1M hydrazine-solution in THF. The product was obtained as brown oil. Yield: 140 mg MS (ES+): m/e=347.
Reaction SMILES: Br.C[O:3][C:4]1[CH:24]=[CH:23][C:7]([CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[OH-].[Na+].C(=O)([O-])O.[Na+]>O>[OH:3][C:4]1[CH:24]=[CH:23][C:7]([CH2:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)[CH2:13][CH2:14]2)=[CH:6][CH:5]=1
Reactant: COc1ccc(CC2CCN(c3ccc(OC)cc3)CC2)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Oc1ccc(CC2CCN(c3ccc(O)cc3)CC2)cc1
Temperature: 100 °C
Yield: 108.7 %

Procedure:
48% hydrobromic acid (300 ml) was added to 4-(4-methoxybenzyl)-1-(4-methoxyphenyl)piperidine (10.58 g) and heated at 100° C. for 21 hours. After being cooled to room temperature, the reaction mixture was diluted with water and neutralized by adding a sodium hydroxide aqueous solution and a sodium hydrogen carbonate aqueous solution. The insoluble matter formed was collected by filtration and dried to afford the title compound as a grayish brown powder (10.46 g).
Reaction SMILES: [C:1]([CH2:3][CH:4]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:5]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)[C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8])#[N:2].[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>C(O)(C)C>[C:1]([CH2:3][CH:4]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:5]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)[CH:6]([OH:11])[C:7]([CH3:10])([CH3:9])[CH3:8])#[N:2]
Reactant: CC(C)(C)C(=O)C(C(CC#N)c1ccccc1)n1ccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CC(C)O
Product: CC(C)(C)C(O)C(C(CC#N)c1ccccc1)n1ccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30 %

Procedure:
96.5 (0.33 mole) of 6-cyano-2,2-dimethyl-4-imidazol-1-yl-5-phenyl-3-hexanone (obtained as described in Example 1) were dissolved in 400 ml of isopropanol, and 15.12 g (0.4 mole) of sodium borohydride were added in portions at 0° to 20° C. The mixture was subsequently stirred at room temperature for 24 hours, 800 ml of 2 N hydrochloric acid were added dropwise at 0° to 10° C. and the mixture was subsequently stirred again at room temperature for 24 hours. The reaction mixture was then neutralized with 1.5 liters of saturated sodium bicarbonate solution and extracted three times with 400 ml of methylene chloride each time. The combined organic phases were washed with water, dried over sodium sulphate and concentrated. The residue was boiled up in 300 ml of diisopropyl ether, and the crystals formed on cooling were filtered off. 28.7 g (30% of theory) of 6-cyano-2,2-dimethyl-4-imidazol-1-yl-5-phenyl-3-hexanol were obtained as a diastereomer mixture of melting point 212° to 228° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][C:16]1[NH:17][C:18]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:35]I>CN(C)C=O>[CH2:1]([O:8][C:9]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][C:16]1[N:20]([CH3:35])[C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:18]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CNCCCc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CCCNCC(=O)OCc2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
A solution of 6.4 g (0.015 mol) of 2-[3-(N-benzyloxycarbonylmethylamino)propyl]-4,5-diphenylimidazole in 120 ml of dimethylformamide is treated at 15°-20° under argon with 0.018 mol of sodium hydride (0.8 g of a 55% dispersion in mineral oil) and thereupon stirred at room temperature for a further 30 minutes. A solution of 1.85 ml (0.03 mol) of methyl iodide in 10 ml of dimethylformamide is added thereto at 15°-20° within 15 minutes and the mixture is stirred at room temperature for a further 3 hours. After concentration under reduced pressure the residue is partitioned between ice-water and ethyl acetate. The organic phase, dried over sodium sulphate, is evaporated and the residual oil is chromatographed on 100 g of silica gel with ethyl acetate as the elution agent. The 2-[3-(N-benzyloxycarbonylmethylamino)propyl]-1-methyl-4,5-diphenylimidazole (6.4 g of oil) obtained is dissolved in 300 ml of methanol and hydrogenated at room temperature and normal pressure in the presence of 1 g of 5% palladium-on-active charcoal. The product, isolated in the usual manner, is chromatographed on 70 g of silica gel with methanol/concentrated ammonium hydroxide (100:1) as the elution agent. There are obtained 2.95 g (64%) of 1-methyl-2-[3-(methylamino)propyl]-4.5-diphenylimidazole as a thick oil.
Reaction SMILES: C([N:4]1[CH2:26][CH2:25][C:7]2[N:8]([CH2:16][CH:17]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[OH:18])[C:9]3[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1)C=C.CN1C(=O)CC(=O)N(C)C1=O>C(Cl)Cl.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:15][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:16][CH:17]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[OH:18])[C:7]3[CH2:25][CH2:26][NH:4][CH2:5][C:6]=3[C:14]=2[CH:13]=1
Reactant: C=CCN1CCc2c(c3cc(Cl)ccc3n2CC(O)c2cccnc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Product: OC(Cn1c2c(c3cc(Cl)ccc31)CNCC2)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a degassed solution of 2-(2-allyl-8-chloro-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-3-yl-ethanol (1.0 g, 2.7 mmol) in DCM were added 1,3-dimethyl barbituric acid (1.27 g, 8.1 mmol) and Pd(PPh3)4 (63 mg, 0.054 mmol) and the reaction mixture was stirred at RT for 3 h. The solvent was removed under reduced pressure. The residue was dissolved in saturated potassium carbonate solution and extracted with EtOAc (3×50 mL). The combined organic layer was washed with saturated potassium carbonate (6×20 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (neutral alumina, 20% methanol in DCM) followed by reverse phase HPLC to yield 2-(8-chloro-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-3-yl-ethanol. 1H NMR (CD3OD, freebase) δ (ppm): 8.4 (d, 1H), 8.37 (s, 1H), 7.8 (d, 1H), 7.4 (d, 1H), 7.39 (m, 1H), 7.2 (d, 1H), 7.02 (d, 1H), 5.1 (t, 1H), 4.33 (d, 2H), 4.3 (s, 2H), 3.38-3.5 (m, 2H), 3.1 (m, 1H), 2.9 (m, 1H). Separation by chiral HPLC provides enantiomers II-89a-b.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2.[N:23]1([CH2:29][C:30](O)=[O:31])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:30](=[O:31])[CH2:29][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2
Reactant: Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1
Reactant: O=C(O)CN1CCOCC1
Product: O=C(CN1CCOCC1)Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine and morpholin-4-yl-acetic acid; MS: m/e=421.2 (M+H+).
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[CH2:27]([O:29][C:30](=[O:55])[CH2:31][N:32]1[C:40]2[C:35](=[C:36]([Br:41])[CH:37]=[CH:38][CH:39]=2)[CH:34]([C:42]2[C:43]([OH:53])=[CH:44][C:45]3[O:49][C:48]([CH3:51])([CH3:50])[CH2:47][C:46]=3[CH:52]=2)[C:33]1=[O:54])[CH3:28]>>[CH2:27]([O:29][C:30](=[O:55])[CH2:31][N:32]1[C:40]2[C:35](=[C:36]([Br:41])[CH:37]=[CH:38][CH:39]=2)[C:34]([C:42]2[C:43]([OH:53])=[CH:44][C:45]3[O:49][C:48]([CH3:51])([CH3:50])[CH2:47][C:46]=3[CH:52]=2)([CH2:5][OH:16])[C:33]1=[O:54])[CH3:28]
Reactant: CCOC(=O)CN1C(=O)C(c2cc3c(cc2O)OC(C)(C)C3)c2c(Br)cccc21
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)OC(C)(C)C3)c2c(Br)cccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with ethyl[4-bromo-3-(6-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained (25%): MS (ES+) m/z 490.5 (M+1), 492.5 (M+1).
Reaction SMILES: [F:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:18](Br)[C:19]#[CH:20].O>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:5]2[N:6]([CH2:20][C:19]#[CH:18])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1COc2cc(F)c([N+](=O)[O-])cc2N1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#CCN1C(=O)COc2cc(F)c([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirred solution of the compound of Step C, Example 3, (4.0 gm, 18.86 mmol) in DMF (100 mL), under N2, at 5° C. (ice-bath) was added sodium hydride (60% in mineral oil, 753.0 mg, 18.86 mmol) portionwise. When gas evolution stopped, propargyl bromide (80%, 2.24 gm, 18.86 mmol) was added dropwise. The dark solution was stirred at room temperature for 17 hours. The reaction was carefully poured into water (150 mL) and EtOAc (600 mL) was added. The organic layer was separated and evaporated to dryness. The residue was chromatographed on silica gel using 25% of ethyl acetate in hexane as eluent. Fractions of compound of interest were combined and evaporated to dryness to yield the title compound of Step D, Example 3, as a yellow solid (2.7 gm), 57%; m.p. 105°-107° C.; IR (nujol, cm-1): 1695.3 (C=O) and 2120.6 (C≡C); 1H NMR δ: 4.76-4.81 (m,4H), 6.91-6.94 (d,1H), 7.97-7.98 (d,1H), 2.35 (s,1H).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[O:13][CH:14]=[C:15]([CH2:17][O:18][C:19]3[CH:33]=[CH:32][C:22]([CH2:23][S:24][CH2:25][CH2:26][N:27]4[CH:31]=[CH:30][N:29]=[N:28]4)=[CH:21][CH:20]=3)[N:16]=2)=[CH:6][CH:5]=1.ClC1C=C(C(OO)=[O:44])C=CC=1>ClCCl.C(OCC)(=O)C>[F:35][C:2]([F:1])([F:34])[O:3][C:4]1[CH:5]=[CH:6][C:7](/[CH:10]=[CH:11]/[C:12]2[O:13][CH:14]=[C:15]([CH2:17][O:18][C:19]3[CH:33]=[CH:32][C:22]([CH2:23][S:24]([CH2:25][CH2:26][N:27]4[CH:31]=[CH:30][N:29]=[N:28]4)=[O:44])=[CH:21][CH:20]=3)[N:16]=2)=[CH:8][CH:9]=1
Reactant: FC(F)(F)Oc1ccc(/C=C/c2nc(COc3ccc(CSCCn4ccnn4)cc3)co2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=S(CCn1ccnn1)Cc1ccc(OCc2coc(/C=C/c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: -30 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of 101 mg (0.20 mmol) 1-[2-(4-{2-[2-(E)-(4-trifluoromethoxy-phenyl)vinyl]-oxazol-4-ylmethoxy}-benzylsulfanyl)-ethyl]-1H-[1,2,3]triazole in 8 ml dichloromethane at −30° C. were added dropwise during 20 min 54 mg (0.24 mmol) 3-chloro-benzenecarboperoxoic acid dissolved in 2 ml ethyl acetate. After 1 hour stirring at −30° C. the mixture was allowed to warm up over night, diluted with dichloromethane, washed with sodium bicarbonate solution, then with water, dried and evaporated. Elution from silica with ethyl acetate/methanol 9:1 furnished 77 mg (74%) title compound as off-white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.N1C(C)=CC=CC=1C.C(Cl)Cl.FC(F)(F)S(O[Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])(=O)=O>O.CO>[CH:31]([Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[O:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)([CH3:33])[CH3:32]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: CCOC(=O)C1CCC(O)CC1
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CCOC(=O)C1CCC(O[Si](C(C)C)(C(C)C)C(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
Ethyl 4-hydroxycyclohexylcarboxylate (s36) (26.0 g), 2,6-lutidine (23.3 g) and methylene chloride (200 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to 0° C. Triisopropylsilyl trifluoromethanesulfonate (50 g) was added dropwise in the temperature range of 0° C. to 5° C. After 1 hour of stirring at 0° C., the reaction mixture was allowed to come to room temperature, and the stirring was continued for another 8 hours. Methanol was added to the reaction mixture to terminate the reaction. The reaction mixture was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water three times, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder to give ethyl 4-triisopropylsilyloxycyclohexylcarboxylate (37) (43.4 g). The yield based on the compound (s36) was 87.5%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][CH2:13][CH2:14][N:15]([CH2:26][C:27]([OH:29])=O)[C:16]3[S:20][N:19]=[C:18]([N:21]4[CH:25]=[CH:24][N:23]=[CH:22]4)[N:17]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH:37]([CH3:39])[CH3:38]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][CH2:12][CH2:13][CH2:14][N:15]([C:16]3[S:20][N:19]=[C:18]([N:21]4[CH:25]=[CH:24][N:23]=[CH:22]4)[N:17]=3)[CH2:26][C:27]([N:37]([CH3:39])[CH3:38])=[O:29])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(CCCN(CC(=O)O)c1nc(-n2ccnc2)ns1)Cc1ccc2c(c1)OCO2
Reactant: CNC
Product: CN(C)C(=O)CN(CCCNCc1ccc2c(c1)OCO2)c1nc(-n2ccnc2)ns1

Procedure:
2-[{3-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-propyl}-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-amino]-N,N-dimethyl-acetamide was prepared following the procedures described in the preparation of Example 56 using [[3-(benzo[1,3]dioxol-5-ylmethyl-tert-butoxycarbonyl-amino)-propyl]-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-amino]-acetic acid and Me2NH. [M+H]+ 443.99; 1H NMR (400 MHz, d6-DMSO) δ 8.34 (s, 1H), 7.75 (s, 1H), 7.12 (s, 1H), 6.99 (s, 1H), 6.87 (m, 2H), 6.03 (s, 2H), 4.51 (br s, 1H), 3.78 (br s, 2H), 3.38 (br s, 2H), 3.05 (s, 3H), 2.89 (s, 3H), 2.75 (m, 2H), 2.53 (m, 2H), 1.89 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[CH:6][C:5]=1[NH:17]C(=O)C.[ClH:23]>CCO>[ClH:23].[ClH:23].[ClH:23].[F:22][C:2]([F:1])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[CH:6][C:5]=1[NH2:17]
Reactant: CC(=O)Nc1cc(N2CCN(C)CC2)ccc1OC(F)(F)F
Agent: Cl
Solvent: CCO
Product: CN1CCN(c2ccc(OC(F)(F)F)c(N)c2)CC1

Procedure:
A solution of N-[2-trifluoromethoxy-5-(4-methyl-piperazin-1-yl)-phenyl]-acetamide (4.75 g, 15 mmol) in EtOH (100 mL) was treated with HCl 37% (35 mL). After 1 h under reflux the mixture was concentrated and tritured with hexane to give in quantitative yield, 5.74 g of 2-trifluoromethoxy-5-(4-methyl-piperazin-1-yl)-phenylamine trihydrochloride salt.
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:8]2[CH:21]=[C:22]([Cl:24])[CH:23]=[C:7]2[C:6]=1[OH:25])=[O:4].[NH2:26][C@H:27]([C:29]([OH:31])=[O:30])[CH3:28].C[O-].[Na+]>>[Cl:24][C:22]1[CH:23]=[C:7]2[C:6]([OH:25])=[C:5]([C:3]([NH:26][C@@H:27]([CH3:28])[C:29]([OH:31])=[O:30])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:8]2[CH:21]=1
Reactant: C[C@H](N)C(=O)O
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(OC)cc2)c1=O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(Cn2c(=O)c(C(=O)N[C@@H](C)C(=O)O)c(O)c3cc(Cl)cn32)cc1

Procedure:
Prepared according to the reaction condition used in Example 19 step a) from 6-chloro-4-hydroxy-2-oxo-1-(4-methoxy-benzyl)-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester, L-alanine and NaOMe. ESI (m/z): 420 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[CH:5][P:4](C2C=CC=CC=2)[CH:3]=1.[C:14]1([C:20]#[C:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:7][C:6]1[C:2]2([CH3:1])[CH2:3][P:4]([C:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:20]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C(#Cc1ccccc1)c1ccccc1
Reactant: Cc1cp(-c2ccccc2)cc1C
Product: CC1=C(c2ccccc2)P2CC1(C)C(c1ccccc1)=C2c1ccccc1

Procedure:
The starting compound 3,4-dimethyl-2,5,6-triphenyl-1-phosphanorbornadiene required for the preparation of NORBOS can be obtained according to the prior art in good yield in a two-stage synthesis. In the first process step, phenyldichlorophosphine or phenyldibromophosphine, or a mixture thereof, is reacted with dimethylbutadiene to give the 1-halo-2,5-dihydrophospholium salt, which is dehydrohalogenated by 2-methylpyridine to give 3,4-dimethyl-1-phenylphosphole. The reaction of the phosphole with diphenylacetylene in the second process step produce 3,4-dimethyl-2,5,6-triphenyl-1-phosphanorbornadiene.