Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1([CH2:12][CH3:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11].C1([Se]Cl)C=CC=CC=1.O.OO>C(OCC)(=O)C.O1CCCC1>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1([CH2:12][CH3:13])[CH2:10][CH2:9][CH:8]=[CH:7][C:6]1=[O:11]
Reactant: CCC1(CC(=O)OC)CCCCC1=O
Agent: Cl[Se]c1ccccc1
Agent: OO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCC1(CC(=O)OC)CCC=CC1=O
Reaction time: 4 h
Yield: 55.3 %

Procedure:
The ketone, 2-carbomethoxymethyl-2-ethylcyclohexanone (IX) (141 mmol, 28 g) was stirred in 1.25 l of ethyl acetate (dried over 3 Å molecular sieves) and treated with 169 mmol (32.5 g) of PhSeCl. The reaction was stirred under nitrogen for 4 hours then treated with 250 ml of water. The mixture was shaken vigorously in a separatory funnel and the organic phase was returned to the reaction flask. Tetrahydrofuran (550 ml) was then added followed by 35 ml of 30% H2O2 (aq.) added dropwise. The reaction mixture was stirred for one hour then washed with 500 ml of water and 500 ml of saturated Na2CO3 (aq.). The product was then dried over MgSO4 and concentrated in vacuo. Flash chromatography (4 inches diameter column, 20% ethyl acetate in petroleum ether eluent, 51/2 inches of silica gel) afforded 15.3 g (78.0 mmol, 55%) of the product as a pale yellow oil. Rf =0.9 in 15% ethyl acetate/petroleum ether on TLC.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[C:11]([F:12])=[CH:10][C:9]([O:13]CC3C=CC(OC)=CC=3)=[CH:8][C:7]=2[F:23])=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([C:4]([C:6]2[C:7]([F:23])=[CH:8][C:9]([OH:13])=[CH:10][C:11]=2[F:12])=[O:5])[CH2:2][CH2:3]1
Reactant: COc1ccc(COc2cc(F)c(C(=O)C3CC3)c(F)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1c(F)cc(O)cc1F)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of cyclopropyl {2,6-difluoro-4-[(4-methoxybenzyl)oxy]phenyl}methanone (700 mg, 2.20 mmol) in DCM (10 ml) was added to TFA (3.0 mL) and the resulting solution stirred for 2 hour at RT. The material was concentrated under reduced pressure and the residue purified via flash column chromatography (80 g silica gel, ISCO, eluting with 30-100% ethyl acetate in hexane) to afford the title compound as an oil. 1H NMR (CDCl3): δ 8.20 (s, 2H), δ 2.43-2.38 (m, 1H), δ 1.35-1.28 (m, 2H), δ 1.10-1.03 (m, 2H). LC/MS 221 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[N:15][C:14]([O:17][CH2:18][C:19](=[O:21])[NH:29][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: NCc1ccccc1
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)NCc1ccccc1
Yield: 90 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using benzylamine (20 μL, 0.21 mmol) as the coupling partner. Concentration (no chromatography) yielded 58 mg (90%) of the titled compound. ESI-MS m/z 381 (MH+), 379 (M−H−).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH2:22][CH3:23])[C:17](=[C:24]([S:27][CH2:28][CH:29]([OH:37])[CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[C:25]#[N:26])[NH:16][CH2:15][CH2:14]2)[CH3:9]>C1C=CC=CC=1>[CH2:8]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH2:22][CH3:23])[C:17](=[C:24]([S:27][CH2:28][CH:29]([O:37][C:1](=[O:3])[CH3:2])[CH2:30][N:31]1[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1)[C:25]#[N:26])[NH:16][CH2:15][CH2:14]2)[CH3:9]
Reactant: CCOc1cc2c(cc1OCC)C(=C(C#N)SCC(O)CN1CCOCC1)NCC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: CCOc1cc2c(cc1OCC)C(=C(C#N)SCC(CN1CCOCC1)OC(C)=O)NCC2

Procedure:
After adding 50 ml of benzene and 20 ml of acetic acid anhydride to 3.0 g of 2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(4-morpholinyl)propyl]mercaptoacetonitrile, the reaction mixture is refluxed for 1 hour, then evaporated to dryness under reduced pressure. After addition of ether, the residue crystallizes out to give the named product in a yield of 2.47 g, m.p.: 133° C. (from isopropanol).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][C:7]1([C:12]([O:14]C)=[O:13])[CH2:11][CH2:10][CH2:9][O:8]1.B(Br)(Br)Br.CO.O>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][C:7]1([C:12]([OH:14])=[O:13])[CH2:11][CH2:10][CH2:9][O:8]1
Reactant: COC(=O)C1(Cc2cccc(OC)c2)CCCO1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=C(O)C1(Cc2cccc(O)c2)CCCO1
Temperature: 0 °C
Yield: 99.1 %

Procedure:
To a solution of 2.50 g of methyl 2-(3-methoxybenzyl)-tetrahydro-2-furancarboxylate in 50 ml of dichloromethane was added 22 ml of a 1 M solution of boron tribromide in dichloromethane at −70° C. under an atmosphere of nitrogen gas. After warming to 0° C., the mixture was cooled again to −70° C., and 20 ml of methanol was added. 200 ml of dichloromethane and 100 ml of water were further added. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated, to give 2.20 g of the title compound.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:27]([O:28]C(=O)C)[C@H:26]([O:32]C(=O)C)[C@@H:25]([CH2:36][O:37]C(=O)C)[O:24][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=1)(=O)C.C[O-].[Na+]>CO.O1CCCC1>[O:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]([CH3:22])[CH3:23])=[CH:19][CH:20]=1)[C@@H:6]1[O:24][C@H:25]([CH2:36][OH:37])[C@@H:26]([OH:32])[C@H:27]([OH:28])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2ccccc2Cc2ccc(N(C)C)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)c1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 98.8 %

Procedure:
To a solution of 2-[4-(N,N-dimethylamino)benzyl]phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.10 g) in methanol (2 mL) and tetrahydrofuran (1 mL) was added sodium methoxide (28% methanol solution; 0.007 mL), and the mixture was stirred at room temperature for 70 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on aminopropyl silica gel (eluent: dichloromethane/methanol=8/1) to give 2-[4-(N,N-dimethylamino)benzyl]phenyl β-D-glucopyranoside (0.069 g).
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=1.Cl[C:23]1[C:24]([C:33]([OH:35])=[O:34])=[N:25][C:26]2[N:27]([N:30]=[CH:31][CH:32]=2)[C:28]=1[F:29]>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:23]2[C:24]([C:33]([OH:35])=[O:34])=[N:25][C:26]3[N:27]([N:30]=[CH:31][CH:32]=3)[C:28]=2[F:29])=[C:16]([F:21])[CH:15]=1
Reactant: O=C(O)c1nc2ccnn2c(F)c1Cl
Reactant: Nc1ccc(Br)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1nc2ccnn2c(F)c1Nc1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of i-Pr2NH (3.50 equivalents) in THF at 0° C. is added n-BuLi (3.50 equivalents, 2.5 M solution in hexanes). After stirring 15 minutes, the mixture is cooled to −78° C. 4-Bromo-2-fluorophenylamine (2.50 equivalents) is added. After vigorous stirring for 10 minutes, a mixture of the 6-chloro-7-fluoropyrazolo[1,5-a]pyrimidine-5-carboxylic acid (1.00 equivalent) in THF is added. The dry-ice bath is removed after 30 minutes, and the reaction mixture is stirred for 17 hours at room temperature. The reaction mixture is treated with a 10% aqueous HCl solution, extracted with EtOAc, dried (MgSO4), and concentrated. Trituration with methylene chloride give desired product.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([NH2:14])[CH:11]=[C:10]([NH:15][C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[N:9]=2)=[CH:4][CH:3]=1.[NH2:26][CH:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:14][C:12]1[CH:11]=[C:10]([NH:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[N:9]=[C:8]([C:5]2[CH:6]=[N:7][C:2]([NH:26][CH:27]3[CH2:31][CH2:30][NH:29][C:28]3=[O:32])=[CH:3][CH:4]=2)[CH:13]=1
Reactant: Nc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(F)nc2)c1
Reactant: NC1CCNC1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Nc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(NC3CCNC3=O)nc2)c1
Temperature: 130 °C
Reaction time: 72 h

Procedure:
6′-Fluoro-N6-[4-(trifluoromethyl)pyridin-2-yl]-2,3′-bipyridine-4,6-diamine (50 mg, 0.143 mmol), 3-aminopyrrolidin-2-one (39.1 mg, 0.286 mmol), tribasic potassium phosphate (60.8 mg, 0.286 mmol), and N,N-diisopropylethylamine (0.050 ml, 0.286 mmol) were dissolved in dimethylsulfoxide (0.5 mL). The mixture was heated to 130° C. with stirring for three days. After allowing to cool to room temperature, the reaction mixture was partitioned between ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (15 mL). The layers were separated, and the organic layer was washed with water (3×5 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified using reverse phase HPLC (15 to 85% acetonitrile/water with 0.1% TFA gradient). The fractions containing the product were partitioned between 10% isopropanol/chloroform and 1:1 saturated aqueous sodium bicarbonate solution:brine. The layers were separated, and the aqueous layer was extracted with additional 10% isopropanol/chloroform. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 3-[(4-amino-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}-2,3′-bipyridin-6′-yl)amino]pyrrolidin-2-one. MS ESI calcd. for C20H19F3N7O [M+H]+ 430. found 430. 1H NMR (500 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.62 (s, 1H), 8.50 (d, J=2.2 Hz, 1H), 8.40 (d, J=5.1 Hz, 1H), 7.88 (dd, J=2.4, 8.8 Hz, 1H), 7.83 (s, 1H), 7.08 (d, J=5.3 Hz, 1H), 6.94 (d, J=7.3 Hz, 1H), 6.61 (d, J=8.8 Hz, 1H), 6.53 (d, J=1.6 Hz, 1H), 6.46 (s, 1H), 5.97 (s, 2H), 4.60-4.52 (m, 1H), 3.25-3.20 (m, 2H), 2.52-2.46 (m, 1H), 1.87-1.79 (m, 1H). rhSyk IC50=4 nM.
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23](C4CCCCO4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCCCO2)cc1
Agent: CC[SiH](CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2ncnc3[nH]ncc23)cc1
Reaction time: 1 h
Yield: 61.1 %

Procedure:
Triethylsilane (150 μL, 0.94 mmol) was added to a solution of 4-(4-methanesulfonyl-phenoxy)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (150 mg, 0.4 mmol) in dichloromethane (3 mL). A solution of trifluoroacetic acid (1 mL) in dichloromethane (3 mL) was added dropwise and then the reaction mixture was stirred for 1 h. Toluene (2 mL) was added and the volatiles were evaporated. The residue was purified by column chromatography, eluting with 0-5% methanol/ethyl acetate to give 4-(4-methanesulfonyl-phenoxy)-1H-pyrazolo[3,4-d]pyrimidine (71 mg, 61%) as a white solid.
Reaction SMILES: CO[C:3]1[C:4]([O:12]C)=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.NC([C:20](O)=[O:21])CCSC.O>CS(O)(=O)=O>[OH:12][C:4]1[CH:3]=[C:8]([O:21][CH3:20])[CH:7]=[CH:6][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: CSCCC(N)C(=O)O
Reactant: COc1cccc([N+](=O)[O-])c1OC
Agent: CS(=O)(=O)O
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of dimethoxynitrobenzene (30.0 g, 0.163 mol) in 99% methanesulfonic acid (300 ml) was added dl-methionine (31.8 g, 0.212 mol) and the mixture was stirred at rt for 24 h. The solution was poured onto ice and stirred with water (1.5 l). The precipitate was filtered and washed with water. The title compound was collected as a yellow solid (23.1 g, 84%).
Reaction SMILES: C(OC([NH:8][C:9]1[N:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:13][CH:14]=1)=O)(C)(C)C.O1CCOCC1.Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O1CCOCC1.O.[Cl-].[Na+].O>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:13][CH:14]=1
Reactant: COC(=O)Cc1cnc(NC(=O)OC(C)(C)C)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)Cc1cnc(N)cn1
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a solution of methyl {5-[(tert-butoxycarbonyl)amino]pyrazin-2-yl}acetate (0.4811 g) in dioxane (5 mL) was added a 4 M hydrogen chloride dioxane solution (5 mL), followed by stirring overnight. The reaction mixture was concentrated and the obtained crude product was collected by filtration and washed with ethyl acetate. The obtained crude product was dissolved in water, and saturated aqueous sodium bicarbonate and ethyl acetate were added thereto, followed by stirring for 1 hour. Saturated brine was added thereto, followed by extraction with ethyl acetate (10 mL×20 times), and the obtained organic layer was washed with saturated brine, dried using anhydrous magnesium sulfate. After concentration under reduced pressure, methyl (5-aminopyrazin-2-yl)acetate (0.2662 g) was obtained as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:13]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=O)[C:14]1=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:24]([NH:32][NH2:33])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([N:13]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)/[C:16](=[N:33]/[NH:32][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)/[C:14]1=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN1C(=O)C(=O)c2ccccc21
Reactant: NNC(=O)c1ccccc1
Product: CCCCCCCCCCCCN1C(=O)/C(=N\NC(=O)c2ccccc2)c2ccccc21
Yield: 100 %

Procedure:
The title compound was prepared as a pale orange solid, using 1-dodecyl-isatin and benzhydrazide according to the synthetic method D. The resulting solid was washed with ethanol. Yield: 100%. 1H NMR (DMSO-d6): δ 0.82 (t, J=6.6 Hz, 3H), 1.20-1.28 (m, 18H), 1.62-1.66 (m, 2H), 3.77 (t, J=6.9 Hz, 2H), 7.16-7.24 (m, 2H), 7.48 (t, J=7.5 Hz, 1H), 7.60-7.73 (m, 4H), 7.92 (d, J=7.8 Hz, 2H), 13.91 (br s, 1H). 13C NMR (DMSO-d6): δ 14.38 (CH3), 22.53 (CH2), 26.67 (CH2), 27.38 (CH2), 29.07 (CH2), 29.14 (CH2), 29.32 (CH2), 39.36 (CH2), 29.43 (CH2), 29.45 (CH2), 31.73 (CH2), 39.75 (CH2), 110.68 (CH), 119.65 (C), 121.27 (CH), 123.70 (CH), 127.88 (CH), 129.65 (CH), 132.22 (CH), 132.41 (C), 133.40 (CH), 143.44 (C═N), 161.61 (C═O). HRMS (ES+) calcd for C27H36N3O2 (M+H+), m/e, 434.2812. found, 434.2802.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[CH2:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]2)[CH:6]=[CH:7][CH:8]=1>O1CCOCC1.CCOCC>[ClH:1].[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(=Cc2cccc(F)c2)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Fc1cccc(C=C2CCCNC2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of HCl in dioxane (4M, 30 mL) was added to a solution of tert-butyl 3-[1-(3-fluorophenyl)methylidene]piperidine-1-carboxylate (Intermediate 227, 2.38 g) in ether (30 mL) and the mixture was stirred at room temperature for 5 hours. The mixture was concentrated in vacuo and the residue was treated with ether. The solid was collected by filtration, washed with ether and dried under vacuum to give 3-[1-(3-fluorophenyl)methylidene]piperidine hydrochloride (1.64 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([Cl:17])=[CH:4][C:3]=1[CH2:18][O:19][CH2:20][CH2:21][C:22]#[CH:23].[Li+].CC([N-]C(C)C)C.[Si:32](Cl)([CH3:35])([CH3:34])[CH3:33]>O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=2)[C:5]([Cl:17])=[CH:4][C:3]=1[CH2:18][O:19][CH2:20][CH2:21][C:22]#[C:23][Si:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCCOCc1cc(Cl)c(Cc2ccc(CC)cc2)cc1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Product: CCc1ccc(Cc2cc(Br)c(COCCC#C[Si](C)(C)C)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.3 %

Procedure:
To a cooled solution (−78° C.) of 1-bromo-2-((but-3-ynyloxy)methyl)-4-chloro-5-(4-ethylbenzyl)benzene (BT) (96 mg, 0.245 mmol) was added LDA (2M in THF, 0.18 mL, 0.36 mmol). After stirring for 20 min, TMS-Cl (50 μL, 0.393 mmol) was added. After stirring for another 2.5 h, additional TMS-Cl (30 μL, 0.236 mmol) was added. The reaction solution was stirred at −78° C. for 70 min and then warmed to room temperature with stirring for 1.5 h. Water was added and the mixture was extracted with ethyl acetate and the extracts were washed with brine, and dried over Na2SO4. The solution was concentrated and the resulting residue was purified by preparative TLC to afford 72 mg of title product.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:6][NH:5][CH2:4]1.Cl.Cl[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[C:19](=[O:20])[C:18]([N:21]3[CH:25]=[CH:24][N:23]=[N:22]3)=[CH:17][NH:16]2)[CH:10]=1.C(N(C(C)C)C(C)C)C>O1CCCC1>[CH3:2][CH:3]1[CH2:6][N:5]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([N:15]3[C:19](=[O:20])[C:18]([N:21]4[CH:25]=[CH:24][N:23]=[N:22]4)=[CH:17][NH:16]3)[CH:10]=2)[CH2:4]1
Reactant: O=c1c(-n2ccnn2)c[nH]n1-c1cc(Cl)ncn1
Reactant: CC1CNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(c2cc(-n3[nH]cc(-n4ccnn4)c3=O)ncn2)C1

Procedure:
43 mg (0.4 mmol) of 3-methylazetidine hydrochloride, 100 mg (0.3 mmol) of the compound from Example 12A and 174 ml (130 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are suspended in 2 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 1.5 h. The reaction mixture is concentrated under reduced pressure, taken up in water with addition of aqueous 1 N sodium hydroxide solution (pH=9-10) and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 25 mg (25% of theory)
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][C:12]2[C:17]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH:30]4[CH2:32][CH2:31]4)[CH2:22][CH2:21]3)=[O:19])=[CH:16][N:15]=[C:14]([CH3:33])[CH:13]=2)=[CH:6][C:5]=1[Cl:34].O.O.[OH-].[Li+].Cl>O1CCOCC1.C(OCC)(=O)C>[Cl:34][C:5]1[CH:6]=[C:7]([O:11][C:12]2[C:17]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH:30]4[CH2:31][CH2:32]4)[CH2:22][CH2:21]3)=[O:19])=[CH:16][N:15]=[C:14]([CH3:33])[CH:13]=2)[C:8]([Cl:10])=[CH:9][C:4]=1[C:3]([OH:35])=[O:2]
Reactant: COC(=O)c1cc(Cl)c(Oc2cc(C)ncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(Oc2cc(Cl)c(C(=O)O)cc2Cl)c(C(=O)N2CCN(C3CC3)c3ccccc32)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
To a solution of 130 mg (0.254 mmol) 2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoic acid methyl ester (Example 65) in 2 mL dioxane was added 2 mL water and 13 mg (0.317 mmol) lithium hydroxide monohydrate. The reaction mixture was stirred at room temperature for 4 hours and then poured on 20 mL 1N aqueous hydrochloric acid and 20 mL ethyl acetate The layers were separated and the aqueous layer was extracted with 20 mL ethyl acetate. The combined organic layers were washed with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum to give 125 mg (98.9%) of the title compound as a light yellow solid. MS (ESI): m/z=498.098 [M+H]+.
Reaction SMILES: Cl.O1[C:6]2([CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][CH2:7]2)[O:5]CC1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>O>[C:16]1([CH2:15][CH2:14][CH2:13][NH:12][CH:9]2[CH2:10][CH2:11][C:6](=[O:5])[CH2:7][CH2:8]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(CCCNC2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC(NCCCc2ccccc2)CC1
Reaction time: 48 h

Procedure:
A mixture of (1,4-dioxa-spiro[4.5]dec-8-yl)-(3-phenyl-propyl)-amine hydrochloride (1:1) (3.35 g, 10.7 mmol), H2O (25 ml) and trifluoroacetic acid (2.47 ml, 32.2 mmol) was left at r.t for 48 h. NaHCO3 (10%, 100 ml) was added and the solution was extracted with CH2Cl2. Drying of the organic layer (Na2SO4) and evaporation left 4-(3-phenyl-propylamino)-cyclohexanone as a slightly coloured oil (2.4 g, 97%, MS: m/e=232.2 (M+H+)).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C@H:15]([NH:33][S@](C(C)(C)C)=O)[CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:5][CH:4]=1>CO>[ClH:2].[NH2:33][C@@H:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=1)[CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1
Reactant: CCOC(=O)c1ccc(N2CCC([C@@H](N[S@@](=O)C(C)(C)C)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1ccc(N2CCC([C@@H](N)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 215 %

Procedure:
HCl (1.16 ml, 4.63 mmol, 4.0M in dioxane) was added to a solution of ethyl 4-(4-((R)-(4′-chlorobiphenyl-2-yl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidin-1-yl)benzoate (INTERMEDIATE 128, 0.128 g, 0.23 mmol) in MeOH (3.5 ml) and the reaction mixture was stirred at r.t. for 3 hours. The reaction mixture was concentrated under reduced pressure and dried under vacuum to provide (R)-ethyl 4-(4-(amino(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoate hydrochloride salt (INTERMEDIATE 133, STEP 1, 0.12 g), which was used in the preparation of INTERMEDIATE 133, STEP 2 without further purification.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(=O)([O-])[O-].[K+].[K+].F[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24]>C(#N)C.[Cl-].[Na+].O.C(Cl)Cl>[F:22][C:20]1[CH:19]=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[C:16]([CH:21]=1)[O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)cc1Oc1ccccc1O
Temperature: 28 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
Catechol (103.8 g, 0.94 mol) and potassium carbonate (129.9 g, 0.94 mol) are added to a solution of 2,4-difluoronitrobenzene (50.0 g, 0.314 mol) in acetonitrile. The reaction mixture is stirred at 28° C. for 24 hours, poured into brine and extracted with ether. The organic extract is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a brown gum. Flash chromatography of the gum using silica gel and a 10% hexanes in methylene chloride solution gives the title product as a yellow solid (43 g) which is identified by 1HNMR spectral analysis.