Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([CH:8]2[C:17]3[C:12](=[C:13](Cl)[CH:14]=[CH:15][CH:16]=3)[CH:11]([NH:19][C:20](=[O:22])[CH3:21])[N:10]([CH3:23])[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(O)(=O)/C=C\C(O)=O>CO>[C:2]1([CH:8]2[C:17]3[C:12](=[C:13]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:14]=[CH:15][CH:16]=3)[CH:11]([NH:19][C:20](=[O:22])[CH3:21])[N:10]([CH3:23])[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)NC1c2c(Cl)cccc2C(c2ccccc2)CN1C
Reactant: C1COCCN1
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Solvent: CCO
Product: CC(=O)NC1c2c(cccc2N2CCOCC2)C(c2ccccc2)CN1C
Yield: 70 %

Procedure:
A mixture of 7 g (0.02 mole) of 4-phenyl-8-chloro-acetylamino-2-methyl-1,2,3,4-tetrahydro-isoquinoline-hydrochloride, 70 ml of ethanol and 20 ml (20.0 g, 0.23 mole) of morpholine is refluxed for 5 hours. The reaction mixture is evaporated in vacuo, the residue is dissolved in a mixture of 200 ml of water and 200 ml of ether, 30 ml of a 30% aqueous sodium hydroxide solution is added, the layers are separated and the aqueous phase is extracted four times with 200 ml of ether each. The united ether solutions are dried over anhydrous sodium sulfate and evaporated. The oily residue (6.7 g) is dissolved in 100 ml of ethanol and a solution of 6.6 g (0.057 mole) of maleic acid and 30 ml of methanol is added. The precipitated product is filtered in the cold. The beige coloured dimaleate (10.7 g) is dissolved in 100 ml of water, the solution is made alkaline by adding 60 ml of a 35% aqueous sodium hydroxide solution and extracted once with 200 ml and four times with 100 ml of ether each. The ether phases are united, dried over anhydrous sodium sulfate, clarified with activated charcoal and dried. The ether is evaporated and the residue is crystallized from a mixture of ether and petrolether. Thus 5.1 g of (0.014 mole) of white crystalline 4-phenyl-2-methyl-8-morpholino-acetylamino-1,2,3,4-tetrahydro-isoquinoline are obtained. Mp.: 120° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH3:15])[C@H:10]([CH2:16][N:17]([CH:34]([CH3:36])[CH3:35])[C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:37]1([CH2:43][S:44](Cl)(=[O:46])=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH3:15])[S:44]([CH2:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:46])=[O:45])[C@H:10]([CH2:16][N:17]([CH:34]([CH3:36])[CH3:35])[C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CNC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C)S(=O)(=O)Cc2ccccc2)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3R*,4R*)-3-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-4-methylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (89 mg, 0.175 mmol) in CH2Cl2 (3 mL), alpha-toluenesulfonyl chloride (40 mg, 0.21 mmol) and triethylamine (30 μL, 0.21 mmol) are added under N2 atmosphere. The mixture is stirred overnight at RT, diluted with CH2Cl2 and poured into an aqueous saturated solution of NaHCO3. The organic layer is separated, and the aqueous one is extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude product is purified by preparative HPLC (C18-ODB-AQ, 5 μm, 20×50 mm, YMC, eluent: CH3CN /H2O+0.1% HCOOH flow: 20 mL/min). The HPLC fractions are collected, and the resulting solution is lyophilized to afford the title product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.3. tR (HPLC, Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.81 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH2:21])[CH:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[O:17][CH:18]([CH3:20])[CH3:19])[NH:10][CH:9]=1)[CH3:7])[CH3:2].O.[C:24]([OH:28])(=[O:27])[CH:25]=O.C([O-])([O-])=O.[K+].[K+]>C(OC(=O)C)C.O>[CH:18]([O:17][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[C:8]1[CH:6]([CH3:7])[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:22])[NH:21][CH:25]([C:24]([OH:28])=[O:27])[C:9]=1[NH:10]2)([CH3:20])[CH3:19]
Reactant: O=CC(=O)O
Reactant: CCOC(=O)C(N)C(C)c1c[nH]c2cccc(OC(C)C)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1NC(C(=O)O)c2[nH]c3cccc(OC(C)C)c3c2C1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 27.25 g 2-amino-3(4-isopropoxyindole-3-yl)butanoic acid ethylester in 70 ml ethylacetate was added 9.99 g glyoxylic acid hydrate dissolved in 70 ml water. The mixture was adjusted to pH 4 (10% K2CO3 -solution) and further stirred at room temperature for 6 hours. The yellow precipitate was collected by filtration, washed with ethylacetate and dried.
Reaction SMILES: [C:1]1([CH2:11][CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].Br[CH2:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>CN(C)C=O>[CH3:30][C:29]([CH3:32])([CH3:31])[C:28](=[O:33])[CH2:27][C:12]([CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C(Cc1cccc2ccccc12)C(=O)OCC
Reactant: CC(C)(C)C(=O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(=O)C(C)(C)C)(Cc1cccc2ccccc12)C(=O)OCC
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
5.00 g (16.9 mmole) of diethyl (1-naphthylmethyl)malonate were dissolved in 50 ml of anhydrous dimethylformamide, and 1.00 g (18.5 mmole) of sodium methoxide was added to the solution, whilst ice-cooling, after which the mixture was stirred for 30 minutes. At the end of this time, a solution of 3.31 g (18.5 mmole) of 1-bromopinacolone (i.e. 1-bromo-3,3-dimethyl-2-butanone) dissolved in 10 ml of anhydrous dimethylformamide was added dropwise to the mixture, which was then stirred overnight at room temperature. The solvent was then removed by distillation under reduced pressure, and the resulting residue was mixed with a saturated aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent: a 6: 1 by volume mixture of hexane and ethyl acetate), to afford 5.51 g (82%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([F:15])=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[OH-].[K+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Br>CN(C)C=O>[F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([F:15])=[CH:9][CH:10]=3)[N:5]([CH2:18][CH:20]3[CH2:21][O:22]3)[C:4]=2[CH:3]=1
Reactant: BrCC1CO1
Reactant: Fc1ccc2c(c1)[nH]c1cc(F)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1ccc2c3ccc(F)cc3n(CC3CO3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a stirred solution of 2,7-difluoro-9H-carbazole (0.400 g, 2.0 mmol) in N,N-dimethylformamide (5 mL) at 0° C. was added 85% potassium hydroxide (0.156 g, 2.4 mmol) and the mixture was stirred for 1 hr. Epibromohydrin (0.326 mL, 3.9 mmol) was added and the mixture was slowly warmed to room temperature and stirred for 16 hrs. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (10-50% methylene chloride/hexanes) to afford the desired product as a white solid (0.47 g, 92%). 1H NMR (300 MHz, CDCl3) δ 7.93 (dd, 2H, J=8.4, 5.4 Hz), 7.14 (dd, 2H, J=9.9, 2.4 Hz), 6.99 (td, 2H, J=9.0, 2.4 Hz), 4.60 (dd, 1H, J=15.9, 2.7 Hz), 4.25 (dd, 1H, J=15.9, 5.1 Hz), 3.35 (m, 1H), 2.86 (t, 1H, J=4.5 Hz), 2.57 (dd, 1H, J=4.8, 2.7 Hz).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)[C@H:20]([CH2:30]OS(C)(=O)=O)[CH2:19][CH2:18][O:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[CH2:39]1[C:43]2([CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]([OH:49])[CH2:41][O:40]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[F:1][C:2]([F:36])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)[C@H:20]([CH2:30][N:46]3[CH2:45][CH2:44][C:43]4([CH2:39][O:40][CH2:41][CH:42]4[OH:49])[CH2:48][CH2:47]3)[CH2:19][CH2:18][O:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: C[C@@H](O[C@H]1OCC[C@@H](COS(C)(=O)=O)[C@@H]1c1ccc(F)c(F)c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OC1COCC12CCNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C[C@@H](O[C@H]1OCC[C@@H](CN2CCC3(CC2)COCC3O)[C@@H]1c1ccc(F)c(F)c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A mixture of methanesulfonic acid [(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)-phenyl)ethoxy]-3-(3,4-difluorophenyl)-tetrahydropyran-4-yl]methyl ester (Description 16; 0.275 g, 0.49 mmol), 2-oxa-8-aza-spiro[4.5]decan-4-ol hydrochloride (Description 8; 0.1 g, 0.37 mmol), potassium carbonate (237 g, 1.7 mmol) and acetonitrile (3 ml) was stirred at 55° C. overnight and then at 65° C. for 18 hours. The mixture was treated with water and extracted into dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by preparative TLC (dichloromethane:methanol) to give the title compound.
Reaction SMILES: Cl.[F:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1.[CH3:13][C:14]([C:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1)=[O:15].O>C(O)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][N:9]3[CH:10]([CH2:13][C:14](=[O:15])[CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]43)[C:11]=2[CH:12]=1
Reactant: CC(=O)C1=CCCCC1
Reactant: Fc1ccc2c(c1)C=NCC2
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C1CC2c3cc(F)ccc3CCN2C2CCCCC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 19.5 g (0.1 mole) of 3,4-dihydro-7-fluoroisoquinoline hydrochloride and 18.6 g (0.15 mole) of 1-cyclohexen-1-yl methyl ketone in 22 ml of ethanol is refluxed with stirring overnight then cooled to room temperature. The solution is poured into water, whereupon a suspension of undissolved material forms, and is extracted with ether. The aqueous layer and its suspended solid are stirred and treated with ammonium hydroxide solution to pH 8.5 to 9.0. The suspended solid is broken up, collected by decantation washed with water, dissolved in methylene chloride, dried over sodium sulfate and evaporated. The remaining residue is dissolved in benzene and chromatographed on alumina and eluted with benzene. The resulting solid is triturated with hexane and dried to give 2,3,4,4a,6,7,11b, 12,13,13a-decahydro-10-fluoro-1H-dibenzo[a,f]quinolizin-13-one, M.P. 130°-136°C.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:4]=1[CH2:5][SH:6].CS(O[C@H:17]1[CH2:22][CH2:21][C@H:20]2[C@H:23]3[C@H:33]([C:34](=[O:36])[CH2:35][C@:18]12[CH3:19])[C@:31]1([CH3:32])[C:26](=[CH:27][C:28](=[O:37])[CH:29]=[CH:30]1)[CH2:25][CH2:24]3)(=O)=O>C(O)C>[Cl:2][C:3]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:4]=1[CH2:5][S:6][C@@H:17]1[CH2:22][CH2:21][C@H:20]2[C@H:23]3[C@H:33]([C:34](=[O:36])[CH2:35][C@:18]12[CH3:19])[C@:31]1([CH3:32])[C:26](=[CH:27][C:28](=[O:37])[CH:29]=[CH:30]1)[CH2:25][CH2:24]3
Reactant: SCc1ccc(Cl)cc1Cl
Reactant: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@@H]2OS(C)(=O)=O
Agent: [Na]
Solvent: CCO
Product: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@H]2SCc1ccc(Cl)cc1Cl

Procedure:
To 1.04 gm. of sodium metal dissolved in 80 ml. of ethanol is added 5.55 ml. of 2,4-dichlorobenzylmercaptan followed by 1.5 gm. of 17β-methanesulfonyloxy-1,4-androstadiene-3,11-dione. Heat at reflux for 76 hours under an atmosphere of nitrogen. In a manner similar to that described in Example 1E, isolate the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](N)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[N:6]2[CH3:12].[I:20]CI.N(OCCC(C)C)=O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]([I:20])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[N:6]2[CH3:12]
Reactant: ICI
Reactant: Cn1c(-c2cccc(F)c2)nc2c(Cl)nc(N)nc21
Agent: CC(C)CCON=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(-c2cccc(F)c2)nc2c(Cl)nc(I)nc21
Yield: 75 %

Procedure:
6-Chloro-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl-amine (960 g) was dissolved in 9.6 liters of tetrahydrofuran and then 774.3 g of cuprous iodide and 1.49 liters of diiodomethane were added thereto. Isoamyl nitrite (1.49 liters) was added dropwise during 1 hour into the mixture with heating under reflux. The reaction solution was heated under reflux for 15 minutes, cooled, diluted with 4 liters of ethyl acetate and then filtered through Celite followed by washing with ethyl acetate three times (3×2 liters). The filtrate and the washings were combined and washed with 8 liters of water and 8 liters of brine. The organic layer was dried over 2 kg of anhydrous sodium sulfate and concentrated to about 3 liters. The concentrated solution was diluted with 10 liters of hexane and the resulting crystals were filtered and washed with 1 liter of hexane. The crystals were then dried at 50° C. for 4 hours to give 1076 g of 6-chloro-8-(3-fluorophenyl)-2-iodo-9-methyl-9H-purine. The yield was 75%.
Reaction SMILES: C(N(CC)CC)C.[Si:8]([O:15][C@@H:16]([CH3:37])[C@@H:17]([OH:36])[CH2:18][CH2:19][C:20]1[C:25]2[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[O:28][C:24]=2[CH:23]=[CH:22][CH:21]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:38][S:39]([O:36][C@H:17]([C@@H:16]([O:15][Si:8]([C:11]([CH3:14])([CH3:12])[CH3:13])([CH3:10])[CH3:9])[CH3:37])[CH2:18][CH2:19][C:20]1[C:25]2[N:26]=[C:27]([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)[O:28][C:24]=2[CH:23]=[CH:22][CH:21]=1)(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O)CCc1cccc2oc(-c3ccc(Cl)cc3)nc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](CCc1cccc2oc(-c3ccc(Cl)cc3)nc12)OS(C)(=O)=O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (0.248 ml) was added to an ice-cooled solution of (3S,4S)-4-(tert-butyldimethylsilyloxy)-1-[2-(4-chlorophenyl)-4-benzoxazolyl]-pentan-3-ol (P0006; 0.40 g) and methanesulfonyl chloride (0.139 ml) in dichloromethane (13 ml) and the mixture was stirred at 5° C. for 30 min. The mixture was washed with water, dried and evaporated. The residual oil (494 mg) was chromatographed over silica gel (15 g) eluting with a mixture of hexane and dichloromethane (2:1) to dichloromethane to give a colorless oil of (3S,4S)4-(tert-butyldimethylsilyloxy)-1-[2-(4-chlorophenyl)-4-benzoxazolyl]-3-pentyl methanesulfonate (P0007; 372 mg).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH2:10])[O:7][N:6]=1)([CH3:4])[CH3:3].C([O-])([O-])=O.[K+].[K+].[C:17](Cl)(=[O:25])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1COCC1>[F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:17](=[O:25])[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:7][N:6]=1)([CH3:4])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(F)c1cc(N)on1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(F)c1cc(NC(=O)Oc2ccccc2)on1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
To a mixture of 3-(2-fluoropropan-2-yl)isoxazol-5-amine (4.32 g, 0.03 mol) and K2CO3 (8.28 g, 0.06 mol) in THF (100 mL) at 0° C. was added dropwise a solution of phenyl carbonochloridate (6 mL, 0.045 mol) in THF (50 mL). The mixture was stirred at 0° C. for 1 h, then at 40° C. for 20 h. Analysis by LC-MS and TLC indicated that the starting material was almost completely consumed and a new product had formed. The mixture was poured into water (150 mL) and the resulting mixture was extracted with EtOAc (100 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-4% EtOAc in petroleum ether to afford phenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate as a white solid (6 g, 76%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:30][C:31]1([CH3:42])[O:36][CH2:35][CH2:34][NH+:33]([CH2:37][B-](F)(F)F)[CH2:32]1>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:37][N:33]5[CH2:34][CH2:35][O:36][C:31]([CH3:42])([CH3:30])[CH2:32]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Reactant: CC1(C)C[NH+](C[B-](F)(F)F)CCO1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCOC(C)(C)C3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and (2,2-dimethyl-morpholinium-4-yl)methyltrifluoroborate following a procedure analogous to that described for Intermediate 3. LC (method 3): tR=1.27 min; Mass spectrum (ESI+): m/z=520 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[OH:14])[CH:6]=[CH:7][C:8]([OH:10])=[O:9].N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9]
Reactant: COc1cc(C=CC(=O)O)ccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1cc(/C=C/C(=O)O)ccc1O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
3-methoxy-4-hydroxy-cinnamic acid (8 g, 41.2 mmol) and imidazole (8.4 g, 123.6 mmol) were charged in a 500 mL round-bottom flask and dissolved in 30 mL of dimethylformamide. Tert-butyldimethylsilyl chloride (13.04 g, 86.5 mmol) was added thereto at 0° C., followed by stirring for 30 minutes. The reaction liquid was concentrated by distillation under reduced pressure and dichloromethane (200 mL) was added thereto, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate, concentrated and dissolved in tetrahydrofuran (180 mL)/methanol (500 mL), and a 0.00035M potassium carbonate aqueous solution (175 mL) was added thereto, followed by stirring for 1 hour. After being concentrated by distillation under reduced pressure, the resulting solid was filtered, washed with water, and dried under vacuum to afford the title compound.
Reaction SMILES: [N:1]1([C:7]2[S:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27].CCN(C(C)C)C(C)C>CN1CCCC1=O>[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[S:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccccc1CCl
Reactant: Cc1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2nsc(N3CCN(Cc4ccccc4C)CC3)n2)cc1
Temperature: 165 °C

Procedure:
A mixture of 5-(piperazin-1-yl)-3-p-tolyl-1,2,4-thiadiazole (17.3 mg, 66.4 μmol), 1-(chloromethyl)-2-methylbenzene (14.0 mg, 99.7 μmol) and DIPEA (42.9 mg, 58.0 μl) in 0.8 mL N-Methyl-2-pyrrolidinone was heated in the microwave oven 165° C. for 12.5 min. The resulting reaction mixture solution was purified by preparative HPLC on reversed phase eluting with a gradient formed from MeCN, water and NEt3 to yield after evaporation of the product containing fractions 17.5 mg (72%) of the title compound as yellow viscous oil. MS (m/e): 365.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[S:14][C:13]([NH2:15])=[N:12][C:11]=2[C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:11]1[N:12]=[C:13]([NH:15][C:21]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[O:28])[S:14][C:10]=1[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)=[O:9]
Reactant: Cc1cc(C(=O)c2sc(N)nc2-c2ccco2)ccn1
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(=O)c2sc(NC(=O)c3ccncc3)nc2-c2ccco2)ccn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
Compound 331 (150 mg, 0.526 mmol) was dissolved in DMF (2 mL), and isonicotinic acid (259 mg, 2.10 mmol), EDC hydrochloride (403 mg, 2.10 mmol) and 1-hydroxybenzotriazole monohydrate (322 mg, 2.10 mmol) were added thereto, followed by stirring at 60° C. for 3 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was recrystallized from 2-propanol to afford the entitled Compound 332 (78.0 mg, 38%).
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si](CC(C)C)(C)C)[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[CH3:39][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:37][CH:38]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccc(O[Si](C)(C)CC(C)C)c2)=CCC3(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccc(O)c2)=CCC3(C)C)cc1
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(3-((2,2-dimethylethyl)-dimethylsiloxy)-phenyl)-2-naphthalenyl)ethynyl]benzoate (Compound H) 60.0 mg (0.114 mmol) in 1.0 ml of THF at room temperature was added 91.5 mg (0.35 ml, 0.35 mmol) of tetrabutylamonium flouride (1M solution in THF). After stirring overnight, the solution was diluted with EtOAc and washed with H2O and saturated aqueous NaCl, before being dried over MgSO4. Removal of the solvents under reduced pressure, followed by column chromatography (4: 1, Hexanes:EtOAc) afforded the title compound as a colorless solid. 1H NMR (CDCl3): δ7.98 (2H, d, J=7.8 Hz), 7.52 (2H, d, J=8.3 Hz), 7.39-7.21 (4H, m), 6.93 (1H, d, J=7.5 Hz), 6.84 (1H, d, 7.1 Hz), 6.83 (1H, s), 6.01 1H, t, J=4.7 Hz), 4.91 (1H, s), 4.39 (2H, q, J=7.1 Hz), 2.35 (2H, d, J=4.7 Hz), 1.39 (3H, t, J=7.1 Hz), 1.34 (6H, s).