Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:28][CH2:27][CH:26]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([Cl:54])[C:40]=1[OH:55]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]4[CH2:28][CH2:27][CH:26]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH2:25]4)=[N:22][CH:23]=2)=[CH:3][C:2]([C:43]2[CH:44]=[C:39]([Cl:38])[C:40]([OH:55])=[C:41]([Cl:54])[CH:42]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 80.2 %

Procedure:
Following general procedure M, tert-butyl (1-(5-((6-bromo-3-(cyclopropanecarbonyl)quinolin-4-yl)amino)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (98 mg, 0.173 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (80 mg, 0.275 mmol) to afford the desired product (90 mg, 80%) as a brown solid. ESI MS m/z 647 [C34H35Cl2N5O4+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]2[C:14]([CH2:19][OH:20])=[N:15][C:16]([Cl:18])=[CH:17][C:12]=2[N:11]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:49](Cl)([CH3:51])=[O:50]>C(Cl)Cl>[C:49]([O:20][CH2:19][C:14]1[C:13]2[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:10][N:11]([C:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:12]=2[CH:17]=[C:16]([Cl:18])[N:15]=1)(=[O:50])[CH3:51]
Reactant: OCc1nc(Cl)cc2c1c(OCc1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OCc1nc(Cl)cc2c1c(OCc1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of (3-(benzyloxy)-6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methanol (2.443 g, 4.59 mmol) and DIPEA (3.0 ml, 17.18 mmol) in DCM (25 ml) was charged with AcCl (0.70 ml, 9.84 mmol). Stirred at RT for 45 min. Diluted with DCM, washed organics with 2N HCl, dried over MgSO4, filtered, concentrated in vacuo and obtained (3-(benzyloxy)-6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl. MS: [M+H]+ m/z 574.
Reaction SMILES: [CH3:1][Si:2]1([CH:8]=[CH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1CCN2C(=NCCC2)CC1.Cl.[N+:32]([CH3:35])([O-:34])=[O:33]>>[N+:32]([CH2:35][CH:8]([Si:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])([O-:34])=[O:33]
Reactant: C[N+](=O)[O-]
Reactant: C[Si]1(C=CC(=O)OCc2ccccc2)CCCCC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: C[Si]1(C(CC(=O)OCc2ccccc2)C[N+](=O)[O-])CCCCC1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A solution of benzyl 3-(1-methyl-1-silacyclohexan-1-yl)acrylate (1.940 g, 7.08 mmol) in nitromethane (5 ml) was cooled on ice, and added with DBU (0.26 ml, 1.74 mmol), and the mixture was stirred for 30 minutes, and further stirred at room temperature for 17 hours. The reaction mixture was added with aqueous hydrochloric acid (1 N), the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate, and then treated in a conventional manner. The residue was purified by silica gel column chromatography [hexane/ethyl acetate (14:1)] to obtain benzyl 4-nitro-3-(1-methyl-1-silacyclohexan-1-yl)butanoate (1.711 g, 72%) mentioned in the title as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:3]=1N.N([O-])=O.[Na+].[ClH:18]>O>[Cl:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:3]=1[Cl:18]
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1cc(Cl)c(Cl)c(Cl)c1
Temperature: -6 °C
Reaction time: 0.5 h

Procedure:
2,6-Dichloro-4-trifluoromethylaniline (3.3 kg, prepared as in Example 15) in concentrated hydrochloric acid (25 liters) was stirred for 1 hour and then cooled to -6° C. A solution of sodium nitrite (1.41 kg) in water (3 liters) was added over a period of 4 hours keeping the temperature between -5° and -12°. The mixture was then stirred between -5° and 0° until all solid had dissolved (3.5 hours). The mixture was then added in 2 liter portions over a period of 35 minutes to a solution of cuprous chloride (1.5 kg) in concentrated hydrochloric acid with stirring. The dark solution was left to stand for 30 minutes, filtered, and extracted with dichloromethane (1×15 liters, then 2×10 liters). The extracts were washed with water (2×25 liters) dried (MgSO4) and evaporated under reduced pressure to give 3,4,5-trichlorobenzotrifluoride (2.2 kg) with a boiling range of 98°-100°/40 Torr.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([OH:34])[CH:32]=3)[N:27]=[CH:26][N:25]=2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[NH:18]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:57][CH2:58][CH2:59][CH2:60]O.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[Br:57][CH2:58][CH2:59][CH2:60][O:34][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[O:35][CH3:36])[N:27]=[CH:26][N:25]=[C:24]2[O:23][C:22]1[C:14]([F:13])=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:37])=[CH:16]2
Reactant: OCCCBr
Reactant: COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1OCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
Diethyl azodicarboxylate (0.847 g, 4.86 mmol) was added to a solution of 4-(4-fluoro-2-methylindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (1.5 g, 4.42 mmol), (prepared as described for the starting material in Example 1), triphenylphosphine (1.74 g, 6.63 mmol) and 3-bromo-1-propanol (0.923 g, 6.63 mol) in methylene chloride. After stirring for 1 hour at ambient temperature, triphenylphosphine (1.16 g) and DEAD (0.770 g) was added. After stirring for 30 minutes, the volatiles were removed under vacuum and the residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride and ethyl acetate to give 6-(3-bromopropoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxyquinazoline (1.5 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[OH:19])=O)=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:9]=[CH:10][C:12]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:18])[CH:17]=3)[O:19]2)=[CH:4][CH:3]=1
Reactant: O=C(C=Cc1ccc(Cl)cc1)c1cc(Cl)ccc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Clc1ccc(C2C=Cc3cc(Cl)ccc3O2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
4,5'-Dichloro-2'-hydroxychalcone (7.32 g) was dissolved in ethanol (100 ml) and sodium borohydride (1.89 g) added in small portions. The reaction mixture was stirred for 1 hr at room temperature, evaporated to dryness, and diluted with water. The precipitated solid was filtered off, washed with water, and heated with acetic acid (100 ml) on the steam bath for 2 hr. The acetic acid was evaporated the residue dissolved in dichloromethane, and the solution washed sequentially with water, saturated sodium bicarbonate solution, and water, dried and evaporated. The residue was chromatographed on alumina, eluting with toluene, to give 4',6-dichloroflav-3-ene (3.84 g) as a colourless oil, identified by n.m.r. spectroscopy.
Reaction SMILES: [CH3:1][N:2]([C@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[C:3]1[C:4](=[O:17])[NH:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=2.N1C=CC=CC=1.[O:32](S(C(F)(F)F)(=O)=O)[S:33]([C:36]([F:39])([F:38])[F:37])(=O)=[O:34]>ClCCl>[CH3:1][N:2]([C@H:18]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:19])[C:3]1[C:4]([O:17][S:33]([C:36]([F:39])([F:38])[F:37])(=[O:34])=[O:32])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N(C)[C@@H](C)c3ccccc3)nc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N(C)[C@@H](C)c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-methyl 3-(methyl(1-phenylethyl)amino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (320 mg, 0.95 mmol) in dichloromethane (30 mL) was added pyridine (313 mg, 3.96 mmol), and Tf2O (559 mg, 1.98 mmol). The resulting solution was stirred overnight at room temperature and then concentrated under vacuum to get a residue, which was purified via silica gel chromatography (1% to 5% ethyl acetate in petroleum ether) to give (S)-methyl 3-(methyl(1-phenylethyl)amino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as a yellow solid (432 mg, crude).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:33])[C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH2:31][CH3:32])[C:16]2[C:17]([CH3:30])=[C:18]([CH:23]=[C:24]([C:26]#[C:27][CH2:28]O)[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:54]>C(Cl)Cl>[Br:54][CH2:28][C:27]#[C:26][C:24]1[CH:25]=[C:16]([N:15]([C@H:12]2[CH2:13][CH2:14][C@H:9]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:33])[CH2:10][CH2:11]2)[CH2:31][CH3:32])[C:17]([CH3:30])=[C:18]([CH:23]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCN(c1cc(C#CCO)cc(C(=O)OC)c1C)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCN(c1cc(C#CCBr)cc(C(=O)OC)c1C)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of methyl 3-(((trans)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)(ethyl)amino)-5-(3-hydroxyprop-1-yn-1-yl)-2-methylbenzoate (1.2 g, 2.62 mmol) in DCM (15 mL), PPh3 (1.37 g, 5.22 mmol) and CBr4 (1.7 g, 5.10 mmol) were added at 0° C. and reaction was stirred for 4 h at room temperature. On completion, reaction was quenched with ice water and extracted with dichloromethane. The combined organic layers were washed with water, dried, concentrated under reduced pressure. The crude material was purified by column chromatography to afford the title compound (0.5 g, 38.5% yield).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH3:32][S:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=[O:39])=[CH:36][C:35]=1[C:42]([F:45])([F:44])[F:43]>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[CH:38]([C:37]2[CH:40]=[CH:41][C:34]([S:33][CH3:32])=[C:35]([C:42]([F:45])([F:44])[F:43])[CH:36]=2)[OH:39])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reactant: CSc1ccc(C=O)cc1C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cnc2c(c1)cc(C(O)c1ccc(SC)c(C(F)(F)F)c1)n2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
To a −78° C. suspension of 1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridine (3.17 g, 11 mmol) in dry tetrahydrofuran (50 mL) was added n-butyllithium in n-hexane (1.6 M, 6.9 mL, 11 mmol) dropwise. The mixture was stirred at −78° C. for 30 min before adding 4-methylsulfanyl-3-trifluoromethyl-benzaldehyde (2.65 g, 12 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched by adding brine (20 mL). The mixture was extracted with ethyl acetate (300 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (20% ethyl acetate/hexanes) afforded (1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-methanol as colorless oil (5.08 g, 91%): LC/MS m/e calcd for C23H20F3N2O4S2 [M+H]+ 509.07, observed 509.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]5[C:31]([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=5)=[CH:20][CH:19]=4)[CH2:13][CH2:12]3)[N:9]=[CH:10][C:3]=12.N[NH:39][C:40]([NH2:42])=[S:41].C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O>[NH2:42][C:40]1[S:41][C:28]([C:27]2[CH:30]=[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:24]([C:21]3[CH:20]=[CH:19][C:18]([CH2:17][N:14]4[CH2:15][CH2:16][CH:11]([N:8]5[C:4]6=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]6[CH:10]=[N:9]5)[CH2:12][CH2:13]4)=[CH:23][CH:22]=3)=[N:25][CH:26]=2)=[N:29][N:39]=1
Reactant: NNC(N)=S
Reactant: N#Cc1cnc(-c2ccc(CN3CCC(n4ncc5c(N)ncnc54)CC3)cc2)c(-c2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(-c2cnc(-c3ccc(CN4CCC(n5ncc6c(N)ncnc65)CC4)cc3)c(-c3ccccc3)c2)s1

Procedure:
A solution of 6-(4-{[4-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl]methyl}phenyl)-5-phenylnicotinonitrile (4A-4; 0.035 g, 0.072 mmol) and thiosemicarbazide (0.010 g, 0.108 mmol) in TFA (2 mL) was heated to 60° C. for 16 hr. The reaction was then cooled, poured onto ice, and basified with saturated aqueous sodium bicarbonate. The resulting precipitate was filtered, taken up in DMF and purified by reverse phase HPLC (5% CH3CN: 95% H2O+0.1% TFA to 95% CH3—CN: 5% H2O+0.1% TFA). 1H-NMR (500 MHz, d6 DMSO) δ 9.72 (bs, 1H), 9.07 (d, J=2.19, 1H), 8.93 (bs, 1H), 8.42 (bs, 1H), 8.36 (s, 1H), 8.29 (s, 1H), 8.10 (d, J=1.96, 1H), 7.65 (bs, 2H), 7.22-7.49 (m, 9H), 4.93-5.03 (m, 1H), 4.34 (s, 2H), 3.49 (d, J=12.21, 2H), 3.19-3.35 (m, 2H), 2.32-2.56 (m, 2H), 2.15 (d, J=11.96, 2H). HRMS m/z (M+H) Calcd: 561.2292, found: 561.2256.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](O)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4](C(=O)C2C=CC=CC=2)[CH2:3]1.[O:23]([CH2:30]CN1CCC(O)(C2C=CC=CC=2)C(C(=O)C2C=CC=CC=2)C1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[O:23]([CH2:30][CH2:1][N:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CN1CCC(O)(c2ccccc2)C(C(=O)c2ccccc2)C1
Reactant: O=C(c1ccccc1)C1CN(CCOc2ccccc2)CCC1(O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: c1ccc(OCCN2CCC(c3ccccc3)(c3ccccc3)CC2)cc1

Procedure:
When proceeding as described in Example 2 but replacing the corresponding 1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine by 1-(2-phenoxyethyl)-3-benzoyl-4-hydroxy-4-phenylpiperidine and reacting 20 g. thereof with benzene in the presence of anhydrous aluminum chloride, 13 g. of 1-(2-phenoxyethyl)-4,4-diphenylpiperidine are obtained. Its boiling point is 145° C./0.01 mm. Hg. The compound yields a fumaric acid salt melting at 199.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9](C(OCC)=O)[C:10](=[O:12])[NH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[OH-].[K+].IC[CH2:22][CH2:23][C:24]([CH3:29])([N+:26]([O-:28])=[O:27])[CH3:25]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[C:8]2[NH:9][C:10](=[O:12])[N:11]([CH2:22][CH2:23][C:24]([CH3:29])([N+:26]([O-:28])=[O:27])[CH3:25])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(CCCI)[N+](=O)[O-]
Reactant: CCOC(=O)n1c(=O)[nH]c2cccc(OC)c21
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c1[nH]c(=O)n2CCC(C)(C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.0 g (17 mmol) ethyl 7-methoxy-2-oxo-2,3-dihydro-benzimidazol-1-carboxylate in DMF are combined with 85% potassium hydroxide solution (3.3 g, 51 mmol) while being cooled with the ice bath. After 30 minutes a solution of 5.2 g (21 mmol) 1-iodo-4-methyl-4-nitro-pentane in DMF is added and the mixture is stirred overnight at ambient temperature. The reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic phases are washed with water, dried and freed from the solvent. The oil remaining is purified by chromatography on a silica gel column (cyclohexane/ethyl acetate gradient). Yield: 0.5 g (8%); mass spectroscopy: [M+H]+=366.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[S:10][C:9]([NH:12][C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28]([NH:31][CH2:32][CH2:33][CH3:34])[CH2:29][CH3:30]>C(#N)C.ClCCl>[CH2:28]([N:31]([CH2:2][C:3]1[C:11]2[S:10][C:9]([NH:12][C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH2:32][CH2:33][CH3:34])[CH2:29][CH3:30]
Reactant: Cc1cc(C)c(Nc2nc3cccc(CBr)c3s2)c(C)c1
Reactant: CCCNCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CCCN(CCC)Cc1cccc2nc(Nc3c(C)cc(C)cc3C)sc12
Reaction time: 0.67 h
Yield: 59 %

Procedure:
To 0.045 g (0.12 mmol) of 7-(bromomethyl)-N-mesityl-1,3-benzothiazol-2-amine in 0.5 mL of acetonitrile and 2 mL of dichloromethane was added 0.086 g (0.62 mmol) of potassium carbonate and 85 μl, (0.62 mmol) of dipropylamine. The reaction was stirred for 40 min, diluted with dichloromethane and filtered. The filtrate was concentrated and purified by flash chromatography eluting with a 25% ethyl acetate/hexanes mixture to give 0.027 g (57%) of the title compound as a light yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13][NH2:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13][NH:14][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(CN)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(CNCc1ccc(F)cc1)OC
Reaction time: 8 h
Yield: 93.9 %

Procedure:
12.4 g of 4-Fluorobenzaldehyde were dissolved in 100 ml of toluene and reacted with 10.5 g 2-aminoacetaldehyde dimethylacetal and 1.90 g (10 mmol) p-toluenesulfonic acid monohydrate for two hours at a Dean Stark apparatus. The solution was allowed to cool down, extracted with saturated sodium bicarbonate, water and brine, dried over magnesium sulfate and evaporated to dryness. The crude product was dissolved in 100 ml of ethanol. 1.89 g of sodium borohydride were added portionwise. Stirring was continued overnight. For workup, acetic acid was added until no gas evolution could be observed. Then the solution was evaporated to dryness, taken up in dichloromethane and washed twice with water. The organic layer was extracted with brine, dried over magnesium sulfate and evaporated to dryness. The obtained crude product (20 g) was used without purification. Rt=0.86 min (Method #1). Detected mass: 182.1 (M−OMe−), 214.2 (M+H+).
Reaction SMILES: C(N(C(=O)C1C=CC(O)=CC=1)C1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.Cl[CH2:39][C:40]([N:42]([CH2:44][CH3:45])[CH3:43])=O>>[CH2:44]([N:42]([CH2:40][C:39]1[CH:19]=[CH:18][C:17]([O:22][CH2:39][CH2:40][N:42]([CH2:44][CH3:45])[CH3:43])=[CH:16][CH:15]=1)[C:43]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:45]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CCN(C)C(=O)CCl
Product: CCN(C)CCOc1ccc(CN(CC)c2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 115 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-ethyl-N-methylacetamide (7.9 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.4 mg) was obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:17]=[C:16](F)[CH:15]=[C:14]([Br:19])[CH:13]=1>C1COCC1>[Br:11][C:12]1[CH:17]=[C:16]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:15]=[C:14]([Br:19])[CH:13]=1
Reactant: OCc1ccccc1
Reactant: Fc1cc(Br)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1cc(Br)cc(OCc2ccccc2)c1
Reaction time: 1 h
Yield: 75.2 %

Procedure:
Sodium hydride (9.9 g, 0.414 mol, 95% dry) was added in portions to a stirred solution of benzyl alcohol (41.0 g, 0.394 mol) in THF (1.0 L) at room temperature under a nitrogen atmosphere and stirred for 1 h. To this solution was added dropwise 1,3-dibromo-5-fluorobenzene (100.0 g, 0.394 mol). After stirring overnight, the mixture was partitioned with H2O (600 mL) and EtOAc (4×600 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography on silica gel eluting with hexanes afforded the sub-title compound (101.3 g, 75%) as a yellow oil.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].Br[CH:12]([OH:14])[CH3:13]>C(O)C>[OH:14][CH2:12][CH2:13][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7]
Reactant: CC(O)Br
Reactant: O=Cc1cccc(O)c1
Agent: [Na]
Solvent: CCO
Product: O=Cc1cccc(OCCO)c1

Procedure:
1.42 g of sodium were dissolved in 200 ml of ethanol. 7.5 g of 3-hydroxybenzaldehyde and 10.5 g of bromoethanol were added and the resulting solution was refluxed for 5 hours. The solution was purified by column chromatography (silica, CH2Cl2).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[Si:49]([O:56][CH2:57][C@@H:58](O)[CH3:59])([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]>O>[Si:49]([O:56][CH2:57][C@H:58]([O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2)[CH3:59])([C:52]([CH3:53])([CH3:54])[CH3:55])([CH3:51])[CH3:50]
Reactant: C[C@H](O)CO[Si](C)(C)C(C)(C)C
Reactant: Cc1ccc2cccc(O)c2n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2cccc(O[C@H](C)CO[Si](C)(C)C(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.8 %

Procedure:
To a solution of 2-methylquinolin-8-ol (0.40 g, 2.5 mmol) in tetrahydrofuran (2.1 mL, 2.5 mmol) was added triphenylphosphine (1.6 g, 6.3 mmol), diethyl azodicarboxylate (0.63 mL, 4.0 mmol), and (S)-1-(tert-butyldimethylsilyloxy)propan-2-ol (0.62 g, 3.3 mmol). The resultant mixture was allowed to stir at ambient temperature for 24 hours. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (2×20 mL). The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by normal phase chromatography on silica gel (10-30% ethyl acetate/hexanes) to provide the title compound (0.33 g, 40%).