Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([OH:29])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>N1C=CC=CC=1>[CH3:30][S:31]([O:29][C@@H:10]([CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCCCCCOC[C@H](O)CO[Si](C)(C)C(C)(C)C
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOC[C@@H](CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-1-(tert-butyldimethylsilyloxy)-3-(hexadecyloxy)propan-2-ol (1 eq) in pyridine (0.5 M) at 0° C., was added MsCl (2 eq). The reaction was stirred at 0° C. for 1 h and quenched by H2O. The aqueous phase was extracted with DCM. The combined organic phases were washed with H2O, and the aqueous phase was back extracted with DCM. The combined organic phases were washed with saturated NaHCO3 and brine, dried over anhydrous Na2SO4 and concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-15% EtOAc/Hex to give (S)-1-(tert-butyldimethylsilyloxy)-3-(hexadecyloxy)propan-2-yl methanesulfonate as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10]C(=O)C(F)(F)F)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[N+:17]([O-])([OH:19])=[O:18]>OS(O)(=O)=O>[C:1]([C:4]1[CH:5]=[C:6]([NH2:10])[CH:7]=[CH:8][C:9]=1[N+:17]([O-:19])=[O:18])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1cccc(NC(=O)C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: CC(=O)c1cc(N)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The starting material, about 10 mmol of 3-acetyl-trifluoroacetylaminobenzene was gradually added to about 20 ml of concentrated H2SO4 at about −20° C., and then stirred for about 30 minutes. Then, nitric acid was added for about 10 minutes. The solution was stirred for about 2 hours. After the reaction was completed, the solution was poured into ice water. An organic layer was extracted twice from the ice water with about 50 mL ethyl acetate, and was washed with sodium hydrogen carbonate solution. And then the organic layer was dried with sodium sulfate anhydride, and distilled under reduced pressure to remove ethyl acetoacetate. Concentrated NH4OH was added, and the solution was stirred at about 50° C. for about 1 hour. Then, the solution was evaporated using a rotary. Extraction was performed with EtOAc and water. Then, 3-acetyl-4-nitro-aminobenzene was obtained in a form of about 54% brown solid using silica gel column chromatography (Hexane/EtOAc=3/1).
Reaction SMILES: C[N:2](/[CH:4]=[C:5](/[C:16](=O)[C:17]([F:20])([F:19])[F:18])\[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])C.Cl.[NH:23]([CH:25]1[CH2:30][CH2:29][C:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])([CH3:31])[CH2:27][CH2:26]1)N.CCN(C(C)C)C(C)C>CCO>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][C:28]1([CH3:31])[CH2:27][CH2:26][CH:25]([N:23]2[C:16]([C:17]([F:20])([F:19])[F:18])=[C:5]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])[CH:4]=[N:2]2)[CH2:30][CH2:29]1)[CH3:37]
Reactant: CCOC(=O)CC1(C)CCC(NN)CC1
Reactant: CN(C)/C=C(\C(=O)OCc1ccccc1)C(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC1(C)CCC(n2ncc(C(=O)OCc3ccccc3)c2C(F)(F)F)CC1
Reaction time: 8 h
Yield: 73.5 %

Procedure:
A solution of (Z)-benzyl 2-((dimethylamino)methylene)-4,4,4-trifluoro-3-oxobutanoate (2.018 g, 6.70 mmol) in EtOH (20 mL) was added dropwise to a solution of ethyl 2-(4-hydrazinyl-1-methylcyclohexyl)acetate hydrochloride (1.6 g, 6.38 mmol) and DIPEA (2.452 ml, 14.04 mmol) in EtOH (31.9 ml) at ambient temperature. The reaction was allowed to stir overnight. The solvent was removed and the residual oil was purified using a 40 g REDISEP™ Gold SiO2 column eluting with 0-25% EtOAc/hexane using the Gold resolution method. Fractions containing the desired product were combined and concentrated in vacuo to provide benzyl 1-(4-(2-ethoxy-2-oxoethyl)-4-methylcyclohexyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (2.12 g, 4.69 mmol, 73.4% yield) as a mixture of isomers (colorless syrup). LCMS=453.4 (M+H)+.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([CH:2]([O:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:8][CH:9]=1
Reactant: COC(=O)C(Br)c1ccc(Br)cc1
Reactant: Oc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1ccccc1)c1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 15 h
Yield: 63.8 %

Procedure:
To a solution of methyl 2-bromo-2-(4-bromophenyl)acetate (9 g, 29.3 mmol) in N,N-dimethylformamide was added phenol (5.5 g, 60 mmol), cesium carbonate (9.5 g, 30 mmol), tetrabutylammonium iodide (1.08 g, 2.93 mmol). The mixture was stirred at 40° C. for 15 hours. Thin layer chromatography showed the start material was consumed completely. Then the mixture was concentrated under vacuum and purified by column chromatography (silica gel, petroleum ether/ethyl acetate=25:1) to give methyl 2-(4-bromophenyl)-2-phenoxyacetate (6 g, 61%).
Reaction SMILES: Br[CH2:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[S:4]1.C(C(C(C(O)=O)O)O)(O)=O.[CH2:28]([O:30][C:31]([C@@H:33]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]1)=[O:32])[CH3:29].C(Cl)(Cl)Cl>C1C=CC=CC=1>[CH2:28]([O:30][C:31]([C@@H:33]1[CH2:38][CH2:37][CH2:36][N:35]([CH2:2][CH:3]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[S:4]2)[CH2:34]1)=[O:32])[CH3:29]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: BrCC1Sc2ccccc2Oc2ccccc21
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H]1CCCN(CC2Sc3ccccc3Oc3ccccc32)C1
Yield: 53 %

Procedure:
A mixture of 11-bromomethyl-11H-dibenz[b,f][1,4]oxathiepine (6.15 g, 20 mmol, prepared similarly as described in Coll. Czech. Chem. Commun. 50, 1484, 1985), (R)-3-piperidinecarboxylic acid ethyl ester tartrate (4.7 g, 30 mmol) and chloroform (10 ml) was warmed to achieve dissolution. The solution was then allowed to stand for 1 week at room temperature, and was subsequently heated at reflux temperature for 7 h. After cooling, the mixture was diluted with benzene and washed with 5% ammonia. The organic phase was dried (potassium carbonate) and evaporated. The residue was purified by column chromatography on silica gel (55 g) using first benzene and then diethyl ether as eluents to give 4.1 g (53%) of (R)-1-(11H-dibenz[b,f][1,4]oxathiepin-11-ylmethyl)-3-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.[O:14]([NH2:16])[CH3:15]>>[CH3:15][O:14][N:16]=[CH:9][C:8]1[CH:11]=[CH:12][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: CON
Reactant: CC(=O)Nc1ccc(C=O)cc1
Agent: Cl
Product: CON=Cc1ccc(NC(C)=O)cc1
Yield: 98 %

Procedure:
Reaction of 4-acetamidobenzaldehyde with methoxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether as a white solid (98% yield). 1HNMR indicated a 95:5 mixture of E- to Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 2.19 (3H, s, CH3), 3.96 (3H, s, OCH3), 7.22 (1H, broad s, NH), 7.53 (4H, m, aromatics), 8.01 (1H, s, CH).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][C:6]1[CH:19]=[C:9]2[NH:10][C:11](=[O:18])[C:12]3[C:17]([N:8]2[N:7]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3.[C:23]([Zn]C#N)#[N:24]>CN(C=O)C.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>[O:18]=[C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]2[N:7]=[C:6]([CH2:5][C:4]3[CH:3]=[C:2]([CH:22]=[CH:21][CH:20]=3)[C:23]#[N:24])[CH:19]=[C:9]2[NH:10]1
Reactant: N#C[Zn]C#N
Reactant: O=c1[nH]c2cc(Cc3cccc(Br)c3)nn2c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: N#Cc1cccc(Cc2cc3[nH]c(=O)c4ccccc4n3n2)c1

Procedure:
A mixture of Example 61B (0.075 g, 0.212 mmol), dicyanozinc (0.03 g, 0.254 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.024 g, 0.021 mmol) in DMF (2 mL) was heated in a microwave (Personal Chemistry SmithSynthesizer) at 150° C. for 10 minutes. The mixture was evaporated and purified by chromatography on silica gel with 10% MeOH/CH2Cl2 to provide the desired product. 1H NMR (500 MHz, DMSO-d6) δ ppm 4.08 (s, 2 H) 5.76 (s, 1 H) 7.46 (t, J=7.63 Hz, 1 H) 7.53 (t, J=7.63 Hz, 1 H) 7.69 (dd, J=12.36, 7.78 Hz, 2 H) 7.79-7.88 (m, 2 H) 8.02 (d, J=7.93 Hz, 1 H) 8.12 (d, J=7.93 Hz, 1 H) 12.12 (s, 1 H).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[NH2:13][C:14]1[C:23]2[N:24]=[C:25]([CH2:35]Cl)[N:26]([CH2:27][C:28]3([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1>CN(C=O)C>[NH2:13][C:14]1[C:23]2[N:24]=[C:25]([CH2:35][N:5]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])[N:26]([CH2:27][C:28]3([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Nc1nc2ccccc2c2c1nc(CCl)n2CC1(O)CCCCC1
Agent: [K]
Solvent: CN(C)C=O
Product: Nc1nc2ccccc2c2c1nc(CN1C(=O)c3ccccc3C1=O)n2CC1(O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium phthalimide (2.59 g, 14.0 mmol) was added to a solution of 1-{[4-amino-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol (5.07 g, 13.3 mmol) in DMF (50 mL), and the reaction mixture was stirred at room temperature overnight. An analysis by HPLC indicated the presence of starting material, and additional potassium phthalimide (1 g) was added. The reaction was stirred for an additional five hours, and then concentrated under reduced pressure. The residue was triturated with methanol, and the resulting white solid was isolated by filtration. The filtrate was concentrated under reduced pressure, and the residue was triturated with methanol to afford additional white solid, which was isolated by filtration. The two solids were combined to provide 2-({4-amino-1-[(1-hydroxycyclohexyl)methyl]-1H-imidazo[4,5-c]quinolin-2-yl}methyl)-1H-isoindole-1,3(2H)-dione.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH:8]1[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.C(OCC)(=O)C>[C:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH:8]1[CH2:9][N:10]([C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:30])[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1OC1CNC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1OC1CN(C(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.5 %

Procedure:
To a stirred solution of 3-(2-tert-butylphenoxy)azetidine (0.30 g, 1.46 mmol) and triethylamine (0.16 g, 1.61 mmol) in THF (10.0 mL) was added benzoyl chloride (0.23 g, 1.61 mmol). After stirring for 16 h at room temperature, the reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica gel; 85:15 to 50:50 heptane/ethyl acetate) provided (3-(2-tert-butylphenoxy)azetidin-1-yl)(phenyl)methanone (0.21 g, 46%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]([CH2:7][C@@:8]2([CH3:34])[N:12]3[C:13]([S:16]([NH:19][C@@H:20]([CH3:24])[C:21]([OH:23])=O)(=[O:18])=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)[C:9]2=[O:33])=[CH:5][CH:4]=1)#[N:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.Cl.[NH2:71][CH2:72][C:73]([NH2:75])=[O:74].C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[C:73]([CH2:72][NH:71][C:21](=[O:23])[C@@H:20]([NH:19][S:16]([C:13]1[N:12]2[C@@:8]([CH2:7][C:6]3[CH:35]=[CH:36][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)([CH3:34])[C:9](=[O:33])[N:10]([C:25]3[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=3)[C:11]2=[N:15][CH:14]=1)(=[O:17])=[O:18])[CH3:24])(=[O:74])[NH2:75]
Reactant: C[C@H](NS(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)O
Reactant: NCC(N)=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@H](NS(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)NCC(N)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
The above carboxylic acid (0.05 g, 0.091 mmol) was dissolved in anhydrous DMF (2 mL) and benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) (0.071 g, 0.137 mmol) was added to the reaction solution. The reaction mixture was stirred at room temperature for 10 min and glycinamide hydrochloride (0.015 g, 0.137 mmol) was added to the mixture followed by N,N-diisopropylethylamine (0.039 mL, 0.227 mmol). The reaction mixture was stirred at room temperature for another 15 min. The mixture was then diluted with EtOAc (10 mL) and washed with water (×2), 1N HCl, saturated NaHCO3 and then water (×1). The organic phase was dried over Na2SO4 and concentrated. The crude product was purified by silica gel preparative thin layer chromatography using CH2Cl2-MeOH (95:5) as an eluent to afford 0.043 g of the title compound as a white foam (M+1, 604.2).
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][NH:8][CH:7]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:6]1.C(N(CC)CC)C.[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1[Cl:34])[CH:30]([C:35](Cl)=[O:36])[CH2:29][C:28]2=[O:38].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[ClH:24].[ClH:1].[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1[Cl:34])[CH:30]([C:35]([N:8]1[CH2:9][CH2:10][N:5]([CH3:4])[CH2:6][CH:7]1[CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:36])[CH2:29][C:28]2=[O:38]
Reactant: CN1CCNC(CN2CCCC2)C1
Reactant: O=C1CC(C(=O)Cl)c2cc(Cl)c(Cl)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)C2CC(=O)c3cc(Cl)c(Cl)cc32)C(CN2CCCC2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a suspension of 2.0 g of 4-methyl-2-(pyrrolidin-1-ylmethyl)piperazine trihydrochloride in 150 ml of methylene chloride was added 4.3 ml of triethylamine with vigorous stirring in an atmosphere of nitrogen. After stirring for 20 minutes, the mixture was cooled to -10° C. in an ice and salt bath and 50 ml of methylene chloride solution containing 1.9 g of 5,6-dichloro-3-oxoindan-1-carbonyl chloride was added dropwise to it. The reaction mixture was stirred at -10° C. for an hour and a half and subsequently at room temperature for two hours and a half and poured into a saturated aqueous solution of sodium bicarbonate. The resulting aqueous mixture was extracted with diethyl ether and the extract was washed with a saturated aqueous solution of sodium chloride followed by drying over anhydrous magnesium sulfate and distilling off the solvent. The residue was purified by column chromatography through silica gel and 1.60 g of the desired compound was obtained from the fractions eluted with a 10:3 mixture of ethyl acetate and triethylamine. To a solution of the product dissolved in methylene chloride was added a two molar quantity of a 4 N 1,4-dioxane solution of hydrogen chloride and the mixture was concentrated. The residue was recrystallized from a mixture of ethanol and acetone to afford the title compound melting at 250°-255° C. (dec.).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[C:19](=[O:25])[CH:18]([CH2:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH2:17]2.C(Br)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[CH2:17][CH:18]([CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH2:11][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:29][CH2:28]3)[C:19](=[O:25])[C:20]2=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1cc2c(cc1OC)C(=O)C(CC1CCNCC1)C2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Yield: 95.3 %

Procedure:
0.18 g of 2,3-dihydro-5,6-dimethoxy-2-((piperidin-4-yl)methyl)inden-1-one p-toluenesulfonic acid salt were dissolved in 10 mL of dry N,N′-dimethylformamide. 0.073 g of benzyl bromide and 0.3 g of potassium carbonate were added thereto. The resulted mixture was stirred until the reaction completed. Then 60 mL of water were added and the solution was extracted with 4×30 mL of ethyl acetate. The extracts were combined, washed with 15 mL of Na2CO3 solution and with 15 mL NaCl solution, and dried over anhydrous MgSO4. Drying agent was then filtered off. The solvent was removed in vacuo yielding 0.141 g of product, 96% yield. 1H NMR (CDCl3), 7.15-7.35 (m, 5H), 7.09 (s, 1H), 6.78 (s, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.48 (s, 2H), 3.17 (dd, 1H, J=8.0 Hz, J=17.6 Hz), 2.82-2.92 (m, 2H), 2.58-2.74 (m, 2H), 1.80-2.03 (m, 3H), 1.57-1.76 (m, 2H), 1.40-1.56 (m, 1H), 1.18-1.40 (m, 3H).
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:22])[N:11]([CH2:20][CH3:21])[C:12](=[O:19])[N:13]([CH2:17][CH3:18])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([S:42][CH2:43][CH2:44][NH2:45])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>CCO>[CH2:17]([N:13]1[C:14]2=[CH:15][N:45]([CH2:44][CH2:43][S:42][C:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:9]2[C:10](=[O:22])[N:11]([CH2:20][CH3:21])[C:12]1=[O:19])[CH3:18]
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(CC)c1=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCn1c(=O)c2c(-c3ccccc3)n(CCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(CC)c1=O
Temperature: 25 °C

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-diethylpyrimidine-2,4(1H,3H)-dione (step 3) (850 mg, 2.327 mmol), 2-(tritylthio)ethanamine (commercially available, 1115 mg, 3.49 mmol) and triethylamine (0.973 mL, 6.98 mmol) were combined in EtOH (Volume: 20 mL) and the mixture heated at reflux for 20 mins. The reaction mixture was cooled to RT and evaporated under vacuum. The residue was partitioned between DCM and water and extracted with DCM. The organic phase was passed through a hydrophobic frit and evaporated onto silica. The silica was deposited onto a 10 g silica cartridge and purification by chromatography on silica eluting with 10-50% EtOAc in iso-hexane afforded the title compound as a white solid;
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)=[O:19])=[CH:16][C:10]=3[CH:9]=2)=[CH:6][C:5]([C:32]2[N:33]=[N:34][N:35]([CH2:37][CH2:38][CH2:39][O:40][Si](C(C)(C)C)(C)C)[N:36]=2)=[CH:4][N:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)=[O:19])=[CH:16][C:10]=3[CH:9]=2)=[CH:6][C:5]([C:32]2[N:33]=[N:34][N:35]([CH2:37][CH2:38][CH2:39][OH:40])[N:36]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCn1nnc(-c2cnc(N)c(-c3cc4cc(NC(=O)Nc5ccc(Cl)c(C(F)(F)F)c5)ccc4s3)c2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Nc1ncc(-c2nnn(CCCO)n2)cc1-c1cc2cc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)ccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the solution of 1-(2-(2-amino-5-(2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2H-tetrazol-5-yl)pyridin-3-yl)benzo[b]thiophen-5-yl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (100 mg, 0.142 mmol, 1 eq) in anhydrous tetrahydrofuran (3 mL) under nitrogen atmosphere at 0° C. was added dropwise a solution of tetrabutylammonium fluoride (1.0 M in THF, 0.43 mL, 3 eq). The reaction was stirred at room temperature for 2 hours and then partitioned between ethyl acetate and aqueous ammonium chloride. The organic layer was isolated, further washed with saturated aqueous sodium bicarbonate, brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted and concentrated and loaded onto silica. The mixture was subject to a gradient column chromatography (EtOAc-Hex 4:1 to MeOH-EtOAc 1:100). The product fractions were collected and concentrated. The solid residue was triturated in ethyl acetate yielding 1-(2-{2-amino-5-[2-(3-hydroxypropyl)-2H-tetrazol-5-yl]pyridin-3-yl}-1-benzothien-5-yl)-3-[4-chloro-3-(trifluoromethyl)phenyl]urea as a white solid in the amount of 50 mg.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[CH:15][C:14]([Cl:25])=[CH:13][CH:12]=2)=[O:7])(C)(C)C.Cl>O1CCOCC1>[Cl:25][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([N:26]1[CH2:27][CH2:28][CH2:29][CH2:30]1)[C:8]([C:6]([OH:7])=[O:5])=[C:17]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1
Reactant: CC(C)(C)OC(=O)c1c(N2CCCC2)nc2ccc(Cl)cc2c1-c1cccc(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1c(N2CCCC2)nc2ccc(Cl)cc2c1-c1cccc(Cl)c1

Procedure:
The title compound was prepared in analogy to example 91 step E from 6-chloro-4-(3-chloro-phenyl)-2-pyrrolidin-1-yl-quinoline-3-carboxylic acid tert-butyl ester (70 mg, 0.16 mmol) and 4N HCl in dioxane. Off white solid (44 mg, 72%). LC-MS (ESI): 387 (M+H)+.
Reaction SMILES: [CH2:1]1[O:4][C@H:2]1[CH3:3].[Si:5]([O:22][C@H:23]([CH3:35])[C@H:24]([NH2:34])[C:25]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[C:27]([F:33])[CH:26]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl([O-])(=O)(=O)=O.[Li+].C(Cl)Cl>C(OCC)C>[Si:5]([O:22][C@H:23]([CH3:35])[C@H:24]([NH:34][CH2:1][C@@H:2]([OH:4])[CH3:3])[C:25]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[C:27]([F:33])[CH:26]=1)([C:18]([CH3:19])([CH3:20])[CH3:21])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C[C@H]1CO1
Reactant: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](N)c1cc(F)c(F)c(F)c1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@H](O)CN[C@H](c1cc(F)c(F)c(F)c1)[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (S)-(−)-propylene oxide (0.1 ml) and (1R,2R)-2-tert-butyldiphenylsilanyloxy-1-(3,4,5-trifluorophenyl)propylamine (212 mg) in diethyl ether (1 ml) was added to a suspension of lithium perchlorate (750 mg) in diethyl ether (1 ml), and the reaction solution was stirred in a nitrogen atmosphere at room temperature overnight. Methylene chloride and ice water were added to the reaction solution. After stirring the reaction solution, the organic layer was separated. The aqueous layer was subjected to extraction with methylene chloride again. The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:heptane=9:1 to 4:1) to obtain 172 mg of the title compound.