Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[S:18](Cl)(=[O:20])=[O:19].[OH:22][CH2:23][CH2:24][CH2:25][CH:26]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:27][C@@H:28]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[NH:29][C:30]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[S:18]([O:22][CH2:23][CH2:24][CH2:25][CH:26]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:27][C@@H:28]([C:49]([O:51][C:52]([CH3:54])([CH3:55])[CH3:53])=[O:50])[NH:29][C:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)(=[O:19])=[O:20]
Reactant: CC(C)(C)OC(=O)C(CCCO)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C(CCCOS(=O)(=O)c1ccc2ccccc2c1)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
At 0° C. triethylamine (0.68 mL, 4.90 mmol) and naphthalene-2-sulfonyl chloride (0.370 g, 1.63 mmol) were added to a solution of di-tert-butyl 4-(3-hydroxypropyl)-N-trityl-L-glutamate (0.457 g, 0.816 mmol) in dichloromethane (10 mL). The resulting mixture was stirred at 0° C. for 2 h and for 16 h at room temperature. The solution was concentrated and the crude product was purified by flash chromatography (silica, ethyl acetate/hexane) to afford di-tert-butyl 4-{3-[(2-naphthylsulfonyl)oxy]propyl}-N-trityl-L-glutamate (0.479 mg, 78%) as a mixture of (4S,4S)/(2S,4R) diastereoisomers. The isomers were separated by chiral HPLC (Chiralpak IC 5 μm 250×30 mm, ethanol/methanol 1:1, 30 mL/min):
Reaction SMILES: [K].[CH:2]([NH:4][CH:5]=[O:6])=[CH2:3].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C1COCC1>[CH2:8]([N:4]([CH:2]=[CH2:3])[CH:5]=[O:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: C=CNC=O
Reactant: CCCCCCCCCCBr
Agent: [K]
Solvent: C1CCOC1
Product: C=CN(C=O)CCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a dry 250 mL three-necked round-bottomed flask equipped with magnetic stirring bar and dropping funnel was placed 8 g (0.07 mol) of fresh N-vinylformamide potassium salt and 200 mL of anhydrous THF. 1-Bromodecane, 16.1 g (0.07 mol) was added to the reaction mixture dropwise at 10° C. over 30 minutes. When addition was complete, the reaction was allowed to stir overnight at ambient temperature. The reaction mixture was concentrated under reduced pressure to remove most of the solvent and diluted with 100 mL of water. The organic layer was extracted with diethyl ether. The combined organic layers were washed twice with water and dried over anhydrous magnesium sulfate. The product was recovered after concentration in vacuum and purification by chromatography on silica (diethyl ether/petroleum ether (v/v=2:8). Yield: 13.2 g (89%). IR (NaCl, v: cm−1):1702 (—NHC(═O)H); 1631 (C═C); 1H-NMR (CDCl3, δ: ppm): 8.43, 8.27 (2s, 1H, —C(═O)H); 7.37–7.28, 6.73–6.65 (m, 1H, H2C═CH—); 4.78–4.67 (m, 1H, HaHbC═CH—); 4.58–4.55 (d, 1H, HaHbC═CH—); 3.72–3.56 (t, 2H, —NCH2CH2—); 1.76–1.62 (m, 2H, —NCH2CH2(CH2)7CH3); 1.44–1.28 (m, 14H, —NCH2CH2(CH2)7CH3); 1.04–1.00 (t, 3H, —NCH2CH2(CH2)7CH3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].CC1C=CC(S(O[CH2:23][C@@H:24]2[CH2:26][O:25]2)(=O)=O)=CC=1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:9][CH2:23][C@@H:24]1[CH2:26][O:25]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: Oc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(OC[C@@H]2CO2)cc1F
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a stirred and cooled (ice-bath) mixture of 13.0 g of 3,4-difluorophenol and 200 ml of N,N-dimethylformamide, there were added 4.8 g of a dispersion of sodium hydride in mineral oil (50%) and, after stirring for 1 hour, a solution of 22.8 g of (S)-(oxiranylmethyl) 4-methylbenzenesulfonate (ester) in some N,N-dimethylformamide. Stirring at room temperature was continued overnight. The reaction mixture was poured into icewater and the product was extracted with methylbenzene. The extract was washed with NaCl(dil.) and water and was then dried, filtered and evaporated. The residue was distilled (13.3 Pa, 55° C.), yielding 9.5 g (51.0%)of (S)-[(3,4-difluorophenoxy)methyl]-oxirane (interm. 1).
Reaction SMILES: Cl[C:2]1(Cl)[C@@H:6]2[N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:8][CH2:9][C@@H:5]2[CH2:4][C:3]1=[O:20].[Cl-].[NH4+]>[Zn]>[O:20]=[C:3]1[CH2:2][C@@H:6]2[N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:8][CH2:9][C@@H:5]2[CH2:4]1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H]2CC(=O)C(Cl)(Cl)[C@@H]21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Product: O=C1C[C@H]2CCN(C(=O)OCc3ccccc3)[C@H]2C1

Procedure:
Azabicycles of general formula (43), (44), (45), (46) and (47), wherein R is aryl or heterocycle, R′ is alkyl and R1 is as defined in formula (I), may be prepared as described in Scheme 12. Benzyl (cis)-6,6-dichloro-5-oxohexahydrocyclopenta[b]pyrrole-1(2H)-carboxylate, prepared as described in Tetrahedron Lett. (1997) 38(11), 1869–1872, may be treated with zinc dust and ammonium chloride to provide benzyl (cis)-5-oxohexahydrocyclopenta[b]pyrrole-1(2H)-carboxylate. Benzyl (cis)-5-oxohexahydrocyclopenta[b]pyrrole-1(2H)-carboxylate may be processed as described in Schemes 2–8 to provide azabicycles of general formula (43), (44), (45), (46) and (47).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:4]=1[C:5]([O:7]C)=O.[C:16]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].CCN(C(C)C)C(C)C>CC(O)(C)C>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([N:24]2[CH2:2][C:3]3[C:4](=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:11][CH:12]=3)[C:5]2=[O:7])=[CH:25][CH:26]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CC(C)(C)c1ccc(N2Cc3cccc([N+](=O)[O-])c3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-bromomethyl-6-nitro-benzoate (0.73 mmol, 1 eq.) and t-BuOH (3 mL) in a sealed reaction vial was added 4-t-butylaniline (0.73 mmol, 1 eq) and DIEA (0.38 mL, 3 eq). The reaction was stirred at RT for 30 min then heated at 170° C. for 10 min in a microwave. A yellow solid was filtered and washed with t-BuOH and H2O then dried under high-vacuum to afford 2-(4-tert-butyl-phenyl)-7-nitro-2,3-dihydro-isoindol-1-one. MS m/e 311 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:8]([NH:10][C@H:11]1[C@H:18]2[C@H:14]([CH2:15][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[CH2:17]2)[CH2:13][CH2:12]1)=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].C(N(CC)C(C)C)(C)C.[C:39](Cl)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]>ClCCl>[CH3:41][C:40]([CH3:43])([CH3:42])[C:39]([N:2]([CH3:1])[C@H:3]([C:8]([NH:10][C@H:11]1[C@H:18]2[C@H:14]([CH2:15][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=3)[CH2:17]2)[CH2:13][CH2:12]1)=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6])=[O:44]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CN[C@@H](CC(C)C)C(=O)N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)N(C)C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N2-methyl-N1-{(3aS,4R,6aR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide (38.9 mg, 0.095 mmol) from Example 166 in dichloromethane (0.5 mL) was added N,N-diisopropylethylamine (24.77 μL, 0.142 mmol) followed by pivaloyl chloride (12.79 μL, 0.104 mmol), and the resultant reaction mixture was stirred at room temperature overnight. The reaction was reduced in volume and loaded onto a silica gel cartridge (Analogix®, Burlington, Wis., RS-4). The title compound was eluted with a gradient of 0% to 100% ethyl acetate/hexanes over 15 minutes: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.81 (d, J=7.4, 1H), 7.74 (s, 1H), 7.60-7.55 (m, 2H), 7.43 (dd, J=6.6, 14.3, 1H), 5.45 (dd, J=7.0, 8.7, 1H), 4.35-4.29 (m, 1H), 3.57 (d, J=13.5, 1H), 3.44 (d, J=13.5, 1H), 3.13 (s, 3H), 2.73 (dd, J=2.6, 8.9, 1H), 2.53-2.45 (m, 1H), 2.41 (ddd, J=2.7, 8.3, 12.0, 1H), 2.37-2.32 (m, 1H), 2.29 (dd, J=3.0, 9.0, 1H), 2.26-2.21 (m, 1H), 2.05 (dq, J=6.0, 12.0, 1H), 1.86-1.80 (m, 3H), 1.55 (ddd, J=6.9, 12.8, 19.6, 2H), 1.41-1.31 (m, 1H), 1.30 (s, 9H), 0.88 (d, J=6.7, 3H), 0.82 (d, J=6.6, 3H); MS (ESI+) m/z 496 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][OH:17])[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[Na+].[Na+].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:29](Cl)=[O:30]>C(OCC)(=O)C.O>[CH3:38][O:37][C:33]1[CH:32]=[C:28]([CH:27]=[C:26]([O:25][CH3:24])[C:34]=1[O:35][CH3:36])[C:29]([N:11]1[CH2:12][CH2:13][CH2:14][C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)([CH2:15][CH2:16][OH:17])[CH2:10]1)=[O:30]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CCCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Combine 3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)piperidine (1.08 g, 3.94 mmol) and sodium carbonate (0.21 g, 2.00 mmol) in 1/1 ethyl acetate/water (50 mL). Cool the reaction mixture to 0° C. with an ice bath. Add 3,4,5-trimethoxybenzoyl chloride (0.83 g, 3.58 mmol). Warm to ambient temperature. After 18 hours, separate the layers and extract the aqueous layer three times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel to give the title compound: Rf=0.5 (silica gel, 1/1 ethyl acetate/hexane). Elemental Analysis calculated for C23H27Cl2NO5: C 58.97; H 5.81; N 2.99; Found C 58.85; H 5.90; N 2.96.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[C:6]1([S:12][C:13](Br)([F:15])[F:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C=O)C>[CH3:1][Si:2]([C:13]([S:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([F:15])[F:14])([CH3:4])[CH3:3]
Reactant: FC(F)(Br)Sc1ccccc1
Reactant: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: C[Si](C)(C)C(F)(F)Sc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
Into a mixture of 0.22 g (9.2 mmol) Mg turnings, 1.99 g (18.3 mmol) of TMSCl and 20 ml DMF at room temperature, was added 1.1 g (4.6 mmol) bromodifluoromethyl phenyl sulfide (24). The reaction was stirred at room temperature for another 1 h. Excess TMSCl was removed under vacuum (˜10 mmHg). The residue was washed with ice water and then extracted with dichloromethane (20 mL×3). The organic phase was further washed with brine and water successively, and dried over MgSO4. After solvent removal, the crude product was further purified by silica gel chromatography (pentane as eluent) to give 905 mg (85% yield) product 21 as colorless liquid, b.p. 86˜87° C./4 Torr. 1H NMR (500 MHz, CDCl3): δ0.25 (s, 9H); 7.37 (m, 3H); 7.59 (d, 2H). 13C NMR (125 MHz, CDCl3): δ−4.2; 126.3 (t, 3JC-F=4.1 Hz); 128.8; 129.3; 134.0 (t, 1JC-F=300.1 Hz); 136.2. 19F NMR (470 MHz, CDCl3): δ−88.1 (s). 29Si NMR (99 MHz, CDCl3): 7.7 (t, 2JSi-F=31.28 Hz). IR (neat): 3064; 2965; 2904; 1884; 1585; 1475; 1441; 1414; 1307; 1255; 1076; 1025; 962; 884; 850; 825; 744; 703; 690; 631; 607; 496 cm−1. GC-MS (m/z): 232 (M+), 109 (PhS+), 73 (Me3Si+). HRMS (DEI): m/z calculated for C10H14F2SSi (M+) 232.0553, found 232.0545.
Reaction SMILES: [C:1]1([CH:7]=[C:8]([CH3:11])[CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](OC)([O:16][CH3:17])([O:14]C)[CH3:13].C(O)(=O)CC>>[CH3:11][C:8](=[CH2:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:13][C:12]([O:16][CH3:17])=[O:14]
Reactant: CC(=Cc1ccccc1)CO
Reactant: COC(C)(OC)OC
Solvent: CCC(=O)O
Product: C=C(C)C(CC(=O)OC)c1ccccc1
Yield: 122.4 %

Procedure:
3-Phenyl-2-methyl-2-propen-1-ol (50 g, 0.32 mol) and trimethyl orthoacetate (263 g, 2.2 mol) were heated together in the presence of propionic acid (0.3 ml) in a bath at 145° C. for 6 hours, while distilling the methanol formed during the reaction. After removing the residual methanol and the excess orthoacetate under vacuum, the product was purified by distillation through a 20-cm Widmer column. 80 g of the desired product were obtained (yield=78%). B.P.=55° C./0.001 mbar
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10](F)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ncnc(F)c1F
Reactant: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC#CCOc1ncnc(N2CCCCC2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
0.2 g of 4-(2-butynyloxy)-5,6-difluoropyrimidine and 0.12 g of piperidine were added to 0.3 ml of toluene, then the mixture was stirred at room temperature for 3 hours. Then the reaction mixture was subjected to silica gel column chromatography to obtain 0.25 g of 4-(2-butynyloxy)-5-fluoro-6-piperidinopyrimidine (referred as the present compound (2) hereinafter).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1CCC(N=C=NC2CCCCC2)CC1.[CH3:31][C:32]([CH3:38])([CH2:36]O)[C:33]([OH:35])=[O:34].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:31][C:32]([CH3:38])([CH2:36][O:14][C:13](=[O:15])[C@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[C:33]([OH:35])=[O:34]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(CO)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(C)(C)C(=O)O
Reaction time: 2 h

Procedure:
N-Boc-L-valine (10.8 g, 50 mmole), 4-dimethylaminopyridine (610 mg, 5 mmole) and DCC (6.18 g, 30 mmole) were dissolved in methylene chloride (100 ml). After stirring for 2 hour the mixture was filtered. To the filtrate were added 2,2-dimethyl-3-hydroxy-propionic acid (3.54 g, 30 mmole) and pyridine (10 ml). After 18 hr, the reaction mixture was filtered, and the filtrate was poured into sodium hydrogen carbonate aqueous solution, the organic phase was then washed with citric acid aqueous solution and water succesively. After evaporation the product was isolated with silica gel column chromatography to yield 4.4 g. This compound can be activated and esterified directly to a drug or further modified as described below.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:24][CH3:25])=[C:9]([C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[O:26]([C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:25][O:24][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([O:39][C:36]3[CH:35]=[CH:34][C:33]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:38][CH:37]=3)=[CH:3][CH:4]=[N:5]2)=[CH:10][C:9]=1[C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:13]
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: COc1cc2nccc(Cl)c2cc1C(=O)NCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(Oc4ccccc4)cc3)c2cc1C(=O)NCCCN1CCOCC1
Temperature: 100 °C
Yield: 59.8 %

Procedure:
A mixture of 4-chloro-7-methoxy-N-(3-morpholinopropyl)quinoline-6-carboxamide (0.154 g), 4-phenoxyphenol (0.11 g), potassium carbonate (0.207 g) and DMF (4 ml) was stirred and heated to 100° C. for 16 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The aqueous phase was further extracted with ethyl acetate and the combined organic extracts were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.13 g); NMR Spectrum: (CDCl3) 1.86 (m, 2H), 2.47 (m, 6H), 3.6 (m, 2H), 3.7 (m, 4H), 4.11 (s, 3H), 6.48 (d, 1H), 7.04-7.18 (m, 7H), 7.37 (m, 2H), 7.51 (s, 1H), 8.02 (t, 1H), 8.65 (d, 1H), 9.19 (s, 1H); Mass Spectrum M+H+ 514.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:32]=[C:31]([F:33])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH:21]=[CH:20][N:19]=3)=[N:10]2)=[C:6]([F:34])[CH:5]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[O:41]1[CH2:45][CH2:44]OS1=O>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:32]=[C:31]([F:33])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[N:23]=[C:22]([N:24]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH2:44][CH2:45][OH:41])[CH:21]=[CH:20][N:19]=3)=[N:10]2)=[C:6]([F:34])[CH:5]=1)[CH3:2]
Reactant: O=S1OCCO1
Reactant: CCOc1cc(F)c(Cn2nc(-c3nccc(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1cc(F)c(Cn2nc(-c3nccc(N(CCO)c4ccncc4)n3)c3ccccc32)c(F)c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
120 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-N-(pyridin-4-yl)-pyrimidin-4-amine (5-1-1, 0.262 mmol, 1. eq.) were suspended in 12 ml of dry DMF. 426 mg of cesium carbonate (1.31 mmol, 5 eq.) and 142 mg of 1,3,2-dioxathiolane 2-oxide (1.31 mmol, 5 eq.) were added under nitrogen atmosphere. The reaction mixture was stirred at 60° C. bath temperature for 18 hours. 142 mg of 1,3,2-dioxathiolane 2-oxide (1.31 mmol, 5 eq.) were added and the mixture was stirred at 60° C. bath temperature for further 22 hours. Then the mixture was partitioned between water and dichloromethane/isopropanol 4:1. The phases were separated and the aqueous layer was extracted twice with dichloromethane/isopropanol 4:1. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography and preparative TLC to yield 14.2 mg (0.03 mmol, 10.5%) of the analytically pure target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([Br:13])=[C:7]([CH2:9][C:10](O)=[O:11])[CH:8]=1.CN(C=O)C.S(Cl)([Cl:21])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([Br:13])=[C:7]([CH2:9][C:10]([Cl:21])=[O:11])[CH:8]=1
Reactant: COc1ccc(Br)c(CC(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(Br)c(CC(=O)Cl)c1
Temperature: 0 °C

Procedure:
5-Methoxy-2-bromophenylacetic acid (56 g, 0.23 mol) is dissolved in CH2Cl2 (350 mL) and a catalytic amount of DMF is added and the solution stirred and cooled to 0° C. Thionyl chloride (41 mL, 0.34 mol) is added dropwise. The reaction mixture is heated at reflux temperature overnight and then cooled to room temperature. Solvents are removed by rotary evaporator. Twice benzene (500 mL) is added to the residual oil and the benzene solution is evaporated by rotary evaporator to remove any additional volatile components. The residual oil is crystallized from hexanes to give 5-methoxy-2-bromophenylacetyl chloride.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(C(C)C)C(C)C.[CH:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH:16]1[NH:25][C:26]([N:28]1[CH2:33][CH2:32][C:31]3([C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH2:36][NH:35][CH2:34]3)[CH2:30][CH2:29]1)=[O:27])[CH2:22]2.Cl>C(Cl)Cl>[CH:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH:16]1[NH:25][C:26]([N:28]1[CH2:33][CH2:32][C:31]3([C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH2:36][N:35]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:34]3)[CH2:30][CH2:29]1)=[O:27])[CH2:22]2
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNCc1ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1Cc2ccccc2C2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)C1
Reaction time: 0.08 h
Yield: 33 %

Procedure:
A vial, equipped with a flea stir bar, was charged with methanesulfonyl chloride (4.5 μL, 58 μmol), DIEA (15 μL, 90 μmol) and CH2Cl2 (1 mL). A solution of N-(2-adamantyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamide (25 mg, 53 μmol) in CH2Cl2 (1 mL) was added and the mixture was stirred overnight. A 10-mL Chem-Elut cartridge was wetted with 5% aq HCl (6 mL) and allowed to stand for 5 min. The reaction mixture was applied to the cartridge and eluted with ether (20 mL). The eluate was evaporated to dryness and the residue was purified by preparative HPLC to afford N-(2-adamantyl)-2-(methylsulfonyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamide (8 mg, 33%). LC-MS Method 1 tR=1.89 min, =458; 1H NMR (CDCl3) δ=1.60-2.15 (18H), 2.92 (s, 3H), 3.13 (m, 2H), 3.51 (s, 2H), 3.90 (d, 2H), 3.99 (s, 1H), 4.45 (s, 2H), 4.88 (1H), 7.05-7.40 (4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([O:24][CH3:23])[CH:30]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: COc1cccc(B(O)O)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(-c2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)c1
Yield: 87 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxybiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 3-methoxyphenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 20% ethyl acetate in dichloromethane) furnished 0.062 g (87%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxybiphenyl-3-carboxamide as a white solid.