Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:20])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)[C:5]([OH:7])=O.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[Br:20][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Br:1])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)[C:5]([NH:33][S:30]([C:27]1[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:29][CH:28]=1)(=[O:32])=[O:31])=[O:7]
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)c1cc(Br)c(OCc2cccc(Br)c2)c(Br)c1
Product: O=C(NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1cc(Br)c(OCc2cccc(Br)c2)c(Br)c1
Yield: 68.7 %

Procedure:
3,5-Dibromo-4-(3-bromobenzyloxy)benzoic acid (0.13 mmol) was coupled with 4-nitrobenzenesulphonamide (0.64 mmol) using the procedure described in Example 31. Purification on column (silica gel, chloroform/methanol 9:1) gave 58 mg (69%) of N-[3,5-dibromo-4-(3-bromobenzyloxy)benzoyl]-4-nitrobenzene-sulphonamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1.Cl.C(=O)([O-])O.[Na+].[N:25]#[C:26][NH2:27]>C(O)C.C(OCC)(=O)C>[NH2:27][C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1)=[NH:25]
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)cs1
Reactant: N#CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)Nc1nc(CCc2ccc(NC(=N)N)cc2)cs1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To a suspension of N-(4-(2-(4-aminophenyl)ethyl)-1,3-thiazol-2-yl)acetamide (26 g) in ethanol (500 ml) was added 4N hydrogen chloride in ethyl acetate (25 ml) and cyanamide (6.3 g). The mixture was refluxed for 26 hours. The reaction mixture was cooled to ambient temperature and poured into a mixture of ethyl acetate (500 ml) and saturated sodium hydrogen carbonate solution (500 ml). The resulted precipitate was collected by filtration and washed with water (300 ml) and ethanol (300 ml) to give N-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide (18 g) as white crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[OH:12])[CH3:2].[CH3:13]O>OS(O)(=O)=O>[CH3:13][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([CH2:1][CH3:2])=[C:4]([OH:12])[CH:5]=1
Reactant: CCc1ccc(C(=O)O)cc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCc1ccc(C(=O)OC)cc1O

Procedure:
To a solution of 4-ethyl-3-hydroxy-benzoic acid (3.76 g, 22.6 mmol) in MeOH (70 mL), cc H2SO4 (0.7 mL) is added. The solution is refluxed overnight, then concentrated to about 30 mL and poured into water. The aqueous layer is extracted with ether (50 mL×4) and the combined organic extracts are neutralized with a saturated aqueous solution of NaHCO3 (50 mL×2), washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to give the title compound as a white powder. TLC, Rf (CH2Cl2/MeOH 95:5)=0.7, MS (LC-MS): 179.2 [M−H]−, tR (HPLC, Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/2.8 min, flow: 1 ml/min): 4.86 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:21][C:6]2[NH:7][C:8](=[O:20])[N:9]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10](=[O:11])[C:5]=2[C:4]=1[CH3:22].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]2[N:41]=[C:40](C(Cl)(Cl)Cl)[O:39][N:38]=2)=[CH:27][CH:26]=1.C(=O)([O-])[O-:47].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[S:21][C:6]2[N:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:47])[O:39][N:38]=4)=[CH:27][CH:26]=3)[C:8](=[O:20])[N:9]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:10](=[O:11])[C:5]=2[C:4]=1[CH3:22]
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: O=C([O-])[O-]
Reactant: COc1sc2[nH]c(=O)n(CCc3ccccc3)c(=O)c2c1C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1sc2c(c1C)c(=O)n(CCc1ccccc1)c(=O)n2Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
A mixture of 6-methoxy-5-methyl-3-(2-phenylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.50 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.78 g), potassium carbonate (0.46 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (4 mL) and methanol (4 mL). 1N Aqueous sodium hydroxide solution (4 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 4 with water and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.86 g, 99%).
Reaction SMILES: S(Cl)Cl.[CH3:4][C:5](=O)[C:6]([CH3:9])([CH3:8])[CH3:7].Cl.CNC.[NH2:15][NH:16][C:17]([NH:19][NH2:20])=[S:18].[OH2:21]>>[C:6]([C:5]1[C:4](=[O:21])[N:16]([NH2:15])[C:17]([SH:18])=[N:19][N:20]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: O
Reactant: CC(=O)C(C)(C)C
Reactant: NNC(=S)NN
Agent: CNC
Agent: Cl
Agent: ClSCl
Product: CC(C)(C)c1nnc(S)n(N)c1=O

Procedure:
154.5 g (1.5 moles) of sulfur dichloride were initially introduced into a stirred flask and 100 g (1.0 mole) of pinacolone were added dropwise in the course of 2 hours at 20°-40° C., whilst stirring and cooling slightly, HCl being released via the reflux condenser. After the reaction mixture had been stirred for a further hour at 40° C., it was added dropwise in the course of 30-60 minutes at 60°-80° C., whilst cooling, to 220 ml of a 40.5% strength solution of 2 moles of dimethylamine in water. A solution of 140 g (3.5 moles) of NaCH in 300 ml of water was then added and the mixture was heated under reflux for 4-6 hours, dimethylamine being released as a gas via the reflux condenser and being absorbed in water. After cooling to 60°-70° C., the pH of the mixture was adjusted to 3.0 with hydrochloric acid, whilst continuing to cool (hydrogen sulfide being released as a gas and being absorbed in sodium hydroxide solution) and elementary sulfur, which had precipitated at the same time, was filtered off. 106 g (1.0 mole) of thiocarbohydrazide were added to the clear filtrate and the mixture was reacted at pH 1 and 50°-80° C. to give 6-tert.-butyl-3-mercapto-4-amino-1,2,4-triazin-5-(4H)-one. This was very sparingly soluble in the reaction mixture and could be isolated easily by filtering off.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:25][C:26](Br)=[O:27].[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:25][C:26]([NH:36][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]
Reactant: O=C(Br)CBr
Reactant: NCc1ccccc1
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OC)c(OC)c1
Product: COc1ccc2c(c1)CCN(CC(=O)NCc1ccccc1)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 1-(3,4-dimethoxy-benzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with benzylamine
Reaction SMILES: [CH:1]([O:4][C:5]([CH:7]1[CH2:11][S:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[O:20][CH3:21])=[N:8]1)=[O:6])([CH3:3])[CH3:2].[OH-].[K+].[CH3:24]I>ClCCl>[CH:1]([O:4][C:5]([C@@:7]1([CH3:24])[CH2:11][S:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[O:20][CH3:21])=[N:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: COc1ccc(C2=NC(C(=O)OC(C)C)CS2)c(OC)c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(C2=N[C@@](C)(C(=O)OC(C)C)CS2)c(OC)c1

Procedure:
Isopropyl-2-(2,4-dimethoxyphenyl)-4,5-dihydro-thiazole-4-carboxylate is reacted with 50% potassium hydroxide and excess methyl iodide in dichloromethane in the presence of O(9)-allyl-N-9-anthracenylmethylcinchonidium bromide to form isopropyl-2-(2,4-dimethoxyphenyl)-4-methyl-4,5-dihydro-thiazole-4-(S)-carboxylate in enantiomeric excess.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=2)=[N:6][CH:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[C:4]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].Cl.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH:33]1[C:38]([OH:40])=[O:39]>>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=2)[NH:8][C:3]([CH2:2][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH:33]2[C:38]([OH:40])=[O:39])=[C:4]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nc(C(F)(F)F)cs2)=NC1c1ccc(Cl)cc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nc(C(F)(F)F)cs2)=NC1c1ccc(Cl)cc1Cl
Yield: 84.3 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(4-(trifluoromethyl)thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.1 g, 0.18 mmol) was reacted with morpholine-3-carboxylic acid hydrochloride (0.03 g, 0.18 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.09 g, 80%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:22]Br)[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH3:22])[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CC[C@@H](CBr)NC(=O)OCc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 97.3 %

Procedure:
To a solution of tert-butyl(4S)-4-{[(benzyloxy)carbonyl]amino}-5-bromopentanoate (4.5 g, 11.7 mmol) and tributyltin hydride (6.3 ml, 23.4 mmol) in toluene (45 ml) was added 2,2′-azobisisobutyronitrile (0.19 g, 1.2 mmol) and the mixture was stirred at 80° C. for 20 minutes. To the reaction mixture was added water, and the solution was extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and the organic solvent was removed under reduced pressure. The residue was purified with silica gel chromatography to give tert-butyl (4R)-4-{[(benzyloxy)carbonyl]amino}pentanoate (3.5 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8](=[O:23])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18]COCC)=[CH:14][CH:13]=2)=[O:11])[S:4][N:3]=1>C(O)(C)C.O1CCCC1>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8](=[O:23])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:11])[S:4][N:3]=1
Reactant: CCOCOc1ccc(C(=O)CC(=O)c2snc(Cl)c2Cl)cc1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: O=C(CC(=O)c1snc(Cl)c1Cl)c1ccc(O)cc1
Reaction time: 12 h
Yield: 88.8 %

Procedure:
To a solution of 1-(3,4-dichloro-5-isothiazolyl)-3-(4-ethoxymethoxyphenyl)-1,3-propanedione (1.20 g) in a mixture of isopropanol (20 ml) and tetrahydrofuran (20 ml) concentrated hydrochloric acid (3.40 g) was added at room temperature and the mixture was stirred for 12 hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent hexane:ethyl acetate=50:50) to obtain 1-(3,4-dichloro-5-isothiazolyl)-3-(4-hydroxyphenyl)-1,3-propanedione (0.90 g). mp 224-227° C.
Reaction SMILES: CC[C:3](C1C=CC=CC=1)=[S:4].Br[CH2:12][C:13]([C:15]1[CH:25]=[CH:24][C:18]2[O:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=2[CH:16]=1)=[O:14].C[S-].[Na+]>CO>[CH3:22][C:20]1([CH3:23])[O:19][C:18]2[CH:24]=[CH:25][C:15]([C:13](=[O:14])[CH2:12][S:4][CH3:3])=[CH:16][C:17]=2[O:21]1
Reactant: CC1(C)Oc2ccc(C(=O)CBr)cc2O1
Reactant: CCC(=S)c1ccccc1
Agent: C[S-]
Agent: [Na+]
Solvent: CO
Product: CSCC(=O)c1ccc2c(c1)OC(C)(C)O2
Reaction time: 15 h

Procedure:
The procedure is as in Example 4 for the preparation of α-methylthioacetophenone, starting with a stirred solution of 5-(2-bromoacetyl)-2,2-dimethyl-1,3-benzodioxole (14.9 g) in methanol (150 cc). Sodium methanethiolate (3.8 g) is added in the course of 5 minutes at a temperature in the region of 20° C., and the mixture is left with stirring for 15 hours at the same temperature. 2,2-Dimethyl-5-[2-(methylthio)acetyl]-1,3-benzodioxole (11 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: FC(F)(F)C1C=C(C(Cl)=O)C=CC=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][N:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.[F:36][C:37]([F:50])([F:49])[C:38]1[CH:39]=[C:40]([C:44]([N:46]=[C:47]=[S:48])=[O:45])[CH:41]=[CH:42][CH:43]=1>C1(C)C=CC=CC=1.C(O)C>[F:49][C:37]([F:36])([F:50])[C:38]1[CH:39]=[C:40]([C:44]([N:46]=[C:47]=[S:48])=[O:45])[CH:41]=[CH:42][CH:43]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][N:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:47]([NH:46][C:44](=[O:45])[C:40]2[CH:41]=[CH:42][CH:43]=[C:38]([C:37]([F:36])([F:50])[F:49])[CH:39]=2)=[S:48])=[CH:31][CH:30]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: O=C(N=C=S)c1cccc(C(F)(F)F)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4cccc(C(F)(F)F)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
3-(Trifluoromethyl)-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-(trifluoromethyl)-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-(trifluoromethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (75 mg, yield 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:17]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH:3]=[C:4]([OH:9])[CH:5]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Nc1cc(O)cc(Br)c1
Product: O=S(=O)(Nc1cc(O)cc(Br)c1)c1ccc(F)cc1
Yield: 104.6 %

Procedure:
3-Amino-5-bromophenol (300 mg, 1.4 mmol, prepared according to WO 2011119704 A1 20110929) was treated with 4-fluorobenzene-1-sulfonyl chloride (326 mg, 1.68 mmol) according to the method described in Preparation 15b to give 507 mg (99% yield) of the title compound as an oil. Purity 70%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][C:11]#[N:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)OCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][C:11]#[N:12]
Reactant: Oc1ccccc1Br
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCOc1ccccc1Br
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed 2-bromophenol (5.1 g, 29.48 mmol, 1.00 equiv), 2-bromoacetonitrile (5.3 g, 44.19 mmol, 1.50 equiv), potassium carbonate (8 g, 57.97 mmol, 2.00 equiv), N,N-dimethylformamide (20 mL). The resulting solution was stirred overnight at 60° C. in an oil bath. The resulting solution was diluted with 5×50 mL of EA. The organic layer was washed with 50 mL of H2O. Organic layers were collected and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100). This resulted in 6 g (96%) of 2-(2-bromophenoxy)acetonitrile as a brown solid.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.C(N)=O.[C:18]([C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:30])[CH2:28]Br)=[CH:23][CH:22]=1)(=O)[CH3:19].[CH:31]([NH2:33])=[S:32].[OH-].[Na+]>O1CCOCC1>[S:32]1[CH:19]=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:30])[CH3:28])=[CH:23][CH:22]=2)[N:33]=[CH:31]1
Reactant: CC(=O)c1ccc(C(=O)CBr)cc1
Reactant: NC=S
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: NC=O
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-c2cscn2)cc1
Temperature: 25 °C
Yield: 36 %

Procedure:
To a stirred suspension of phosphorus pentasulfide (24.5 g, 110 mmol) in dioxane (250 ml) was added formamide (28.4 g. 630 mmol), and the mixture was heated at reflux temperature for 2 hours. The reaction mixture was cooled down to room temperature, and the solution was decanted away from solids. To a stirred solution of 1-(4-acetylphenyl)-2-bromo-1-ethanone (2.0 g, 8.3 mmol) in dioxane (80 ml) was added the thioformamide solution, and the mixture was heated at reflux temperature for 13 hours. The reaction mixture was cooled down to room temperature, and made basic by addition of 0.5M NaOH aqueous solution. The whole was extracted with diethylether. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:4) to give the title compound (610 mg, 36% yield).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH2:23][C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][C:33]=4[F:34])[N:30]=[CH:29][CH:28]=[CH:27]5)=[CH:21][N:22]=3)[N:19]=2)[CH2:10]1)C)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:34][C:33]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][CH:29]=[N:30]2)=[CH:25][C:24]=1[CH2:23][C:20]1[N:18]2[N:19]=[C:14]([N:11]3[CH2:12][CH2:13][CH:9]([NH:7][CH3:6])[CH2:10]3)[CH:15]=[CH:16][C:17]2=[N:22][CH:21]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc3ncc(Cc4cc5cccnc5cc4F)n3n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1CCN(c2ccc3ncc(Cc4cc5cccnc5cc4F)n3n2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(rac)-{1-[3-(7-Fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-pyrrolidin-3-yl}-methyl-carbamic acid tert-butyl ester (Stage 260.1, 179 mg, 0.376 mmol) was dissolved in DCM (7.5 mL) and TFA (3 mL). The RM was stirred at rt for 1 h. A basic work up (1 M Na2CO3) followed by a crystallization in Et2O afforded the title compound as white crystals (tR 2.28 min (conditions 13), MH+=377, 1H-NMR in DMSO-d6: 8.83 (m, 1H); 8.30 (d, 1H); 7.93 (d, 1H); 7.75 (m, 2H); 7.48 (dd, 1H); 7.35 (s, 1H); 6.74 (d, 1H); 4.37 (s, 2H); 3.52-3.35 (m, 3H); 3.23-3.17 (m, 2H); 2.27 (s, 3H); 2.07 (m, 1H); 1.86 (bs, 1H); 1.80 (m, 1H)).
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9](/[CH:40]=[CH:41]/[C:42]2C=C[C:45](OC)=[CH:44][CH:43]=2)=[N:8]1.O1[CH2:55][CH2:54][O:53][CH2:52]C1>Cl>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3/[CH:40]=[CH:41]/[C:42]2[CH:55]=[C:54]([O:53][CH3:52])[CH:45]=[CH:44][CH:43]=2)=[N:17]1
Reactant: C1COCCO1
Reactant: COc1ccc(/C=C/c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)cc1
Agent: Cl
Product: COc1cccc(/C=C/c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Yield: 17.4 %

Procedure:
Hydrolysis was performed by stirring 1-((1E)-2-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}vinyl-4-methoxybenzene in 4 mL of 4.0 N commercial solution of HCl in dioxane and 2 mL of 6.0 N aqueous HCl at room temperature for 6.5 hours. A mixture of 2 isomers was isolated after purification by preparative HPLC (3% of the minor isomer) (0.014 g, 17.4% yield) 1H NMR (DMSO-d6) δ 8.8 (s, 1H), 8.55 (s, 1H), 8.15 (d, 1H), 7.7 (t, 3H), 7.5 (d, 2H), 7.0 (d, 2H), 3.8 (s, 3H); ES-MS (m/z) 318 [M+1]+.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26]O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC>ClCCl.C(OCC)(=O)C>[Br:29][CH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)[Si](OCc1ccccc1CO)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCc1ccccc1CBr)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.1 %

Procedure:
In dichloromethane (50 ml) were dissolved [2-[(t-butyldiphenylsilyloxy)methyl]phenyl]methanol (3.00 g, 7.97 mmol) and carbon tetrabromide (3.40 g, 10.3 mmol). Under ice cooling, a dichloromethane solution (5 ml) of triphenylphosphine (2.70 g, 10.3 mmol) was added dropwise. After stirring at room temperature for 14 hours, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was subjected to silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=30:1 eluate was concentrated under reduced pressure, whereby the title compound (3.12 g, 7.10 mmol, 89%) was obtained as a colorless oil.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[F:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH2:27][C:28]([OH:30])=[O:29])=[C:13]([CH3:26])[C:14]2=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)=[CH:10][C:9]=1[O:31][CH3:32].CC(C)=[O:35]>O.CO>[F:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH2:27][C:28]([OH:30])=[O:29])=[C:13]([CH3:26])[C:14]2=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:25])=[O:35])=[CH:20][CH:19]=2)=[CH:10][C:9]=1[O:31][CH3:32]
Reactant: CC(C)=O
Reactant: COc1cc2c(cc1F)C(=Cc1ccc(SC)cc1)C(C)=C2CC(=O)O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1F)C(=Cc1ccc(S(C)=O)cc1)C(C)=C2CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of sodium periodate, 4.28 g (20 mol) in 40 ml of water is added dropwise to 6-fluoro-5-methoxy-2-methyl-1-(p-methylthiobenzylidene)-3-indenylacetic acid, 3.70 g (10 mmol) in 300 ml methanol and enough acetone to cause solution. This solution is stirred overnight at room temperature and filtered. The filtrate is evaporated at 30° to a small volume which causes the product to precipitate. The suspension is diluted with several volumes of water, and is cooled. Collected crystals are washed with water and methanol-water (1:1). The product is dried in vacuo over potassium hydroxide pellets and then in a vacuum oven at 70° C. The crude product is recrystallized from methylene chloride-petroleum ether to give 6-fluoro-5-methoxy-2-methyl-1-(p-methylsulfinyl-benzylidene)-3-indenylacetic acid (m.p. 190°-193°). 6-fluoro-5-methoxy-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylacetic acid is prepared according to the procedure of Example 1, part G by the addition of 1.0 mol of m-chloroperbenzoic acid per mol of 6-fluoro-5-methoxy-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenyl acetic acid in an acetone solution.