Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.CCOC(C)=O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:1][C:2]1[N:3]=[CH:4][C:5]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(I)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)nc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-bromo-5-iodopyridine (3.00 g, 10.6 mmol), tert-butyl piperazine-1-carboxylate (1.71 g, 9.2 mmol), Pd2(dba)3 (337 mg, 0.368 mmol), and XantPhos (640 mg, 1.1 mmol) were taken up in PhCH3 (90 mL). The resulting mixture was stirred 24 h at r.t. and was diluted with EtOAc (100 mL) and water (150 mL). The phases were separated, and the organic phase was dried over Na2SO4, filtered, and concentrated to afford a crude residue that was purified by silica gel chromatography to provide tert-butyl 4-(6-bromopyridin-3-yl)piperazine-1-carboxylate (4.01). LCMS-ESI+ (m/z): [M+H]+ calcd for C14H21BrN3O2: 342.08; found: 342.15.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[O:7][CH2:6][C:5]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)([CH2:8][O:9]CC2C=CC(OC)=CC=2)[CH2:4][O:3]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.O>[CH3:1][C:2]1([CH3:27])[O:3][CH2:4][C:5]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)([CH2:8][OH:9])[CH2:6][O:7]1
Reactant: COc1ccc(COCC2(c3ccc(F)c(F)c3)COC(C)(C)OC2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: CC1(C)OCC(CO)(c2ccc(F)c(F)c2)CO1
Reaction time: 4 h

Procedure:
To a stirred solution of 2,2-dimethyl-5-(3,4-difluorophenyl)-5-(4-methoxybenzyloxymethyl)-1,3-dioxane (360 mg, 1 mmol) in 10 ml of an 18:1 v/v mixture of dichloromethane-water was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (350 mg, 1.5 mmol) in small portions. The reaction mixture was stirred for 4 hours, then filtered and evaporated; purification on a silica column eluting with dichloromethane/methanol (19:1 v/v) afforded 2,2-dimethyl-5-(3,4-difluorophenyl) 5-hydroxymethyl-1,3-dioxane as a yellow oil. Nmr δ 7.2-7.0 (3H,m), 4.05 (2H,d), 4.00 (2H,d), 4.00 (2H,s), 1.75 (1H,broad), 1.4 (6H,d).
Reaction SMILES: Br[CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][C@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])=[O:4].C(N(CC)CC)C.[CH3:27][C:28]1([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[OH:34][C:28]1([CH3:27])[CH2:33][CH2:32][N:31]([C@H:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([O:5][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:7])=[O:4])[CH2:30][CH2:29]1
Reactant: C[C@H](OC(=O)C(Br)c1ccccc1)c1ccccc1
Reactant: CC1(O)CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@H](OC(=O)[C@@H](c1ccccc1)N1CCC(C)(O)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.7 %

Procedure:
To a solution of (S)-1-phenylethyl 2-bromo-2-phenylacetate (0.464 g, 1.45 mmol) in THF (8 mL) was added triethylamine (0.61 mL, 4.35 mmol), followed by tetrabutylammonium iodide (0.215 g, 0.58 mmol). The reaction mixture was stirred at room temperature for 5 minutes and then a solution of 4-methyl-4-hydroxypiperidine (0.251 g, 2.18 mmol) in THF (2 mL) was added. The mixture was stirred for 1 hour at room temperature and then it was heated at 55-60° C. (oil bath temperature) for 4 hours. The cooled reaction mixture was then diluted with ethyl acetate (30 mL), washed (H2O×2, brine), dried (MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography (0-60% ethyl acetate-hexane) to provide first the (S,R)-isomer of the title compound (0.306 g, 60%) as a white solid and then the corresponding (S,S)-isomer (0.120 g, 23%), also as a white solid. (S,R)-isomer: 1H NMR (CD3OD) δ 7.51-7.45 (m, 2H), 7.41-7.25 (m, 8H), 5.85 (q, J=6.6 Hz, 1H), 4.05 (s, 1H), 2.56-2.45 (m, 2H), 2.41-2.29 (m, 2H), 1.71-1.49 (m, 4H), 1.38 (d, J=6.6 Hz, 3H), 1.18 (s, 3H). LC-MS: Anal. Calcd. for C22H27NO3: 353; found: 354 (M+H)+. (S,S)-isomer: 1H NMR (CD3OD) δ 7.41-7.30 (m, 5H), 7.20-7.14 (m, 3H), 7.06-7.00 (m, 2H), 5.85 (q, J=6.6 Hz, 1H), 4.06 (s, 1H), 2.70-2.60 (m, 1H), 2.51 (dt, J=6.6, 3.3 Hz, 1H), 2.44-2.31 (m, 2H), 1.75-1.65 (m, 1H), 1.65-1.54 (m, 3H), 1.50 (d, J=6.8 Hz, 3H), 1.20 (s, 3H). LC-MS: Anal. Calcd. for C22H27NO3: 353; found: 354 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Br:14].C(OCC)C>CN(C)C=O>[Br-:8].[Br:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N+:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: BrCCCCCBr
Reactant: CN1CCCCC1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[N+]1(CCCCCBr)CCCCC1
Product: [Br-]
Reaction time: 8 h

Procedure:
A solution of 1-methylpiperidine (˜26.04 g) in dimethylformamide (˜250 mL) was added slowly to a solution of 1,5-dibromopentane (˜226.3 g) in dimethylformamide (˜50 mL) with rapid stirring. Stirring of the solution was continued overnight. The reaction mixture was then poured into diethyl ether (˜1500 mL) producing a yellow oil. The diethyl ether was decanted and the oil poured into a solution of fresh diethyl ether (˜1500 mL) with acetone (˜250 mL) and then stirred overnight. The resulting waxy solid was filtered. After drying the product (˜51.8 g, ˜60%) was confirmed to be 1-(5-bromopentyl)-1-methylpiperidin-1-ium bromide by 1H NMR.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C@@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16]([CH3:25])([CH3:24])[O:15][C:14]2=[O:26])[CH2:9][CH:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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>[CH3:24][C:16]1([CH3:25])[O:15][C:14](=[O:26])[N:13]([C@H:10]2[CH2:11][CH2:12][C:7]([C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)=[CH:8][CH2:9]2)[C@H:17]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1(C)OC(=O)N([C@@H]2CC=C(OS(=O)(=O)C(F)(F)F)CC2)[C@H]1c1ccccc1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
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: C1COCCO1
Product: CC1(C)OC(=O)N([C@@H]2CC=C(c3cccnc3)CC2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 75.1 %

Procedure:
A microwave tube was charged with (S)-4-((S)-5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)cyclohex-1-en-1-yl trifluoromethanesulfonate (0.205 g, 0.489 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.120 g, 0.587 mmol), tetrakis(triphenylphosphine)palladium(0) (0.085 g, 0.073 mmol) and sodium carbonate (0.155 g, 1.466 mmol). Dioxane (1.70 mL) and water (0.25 mL) were added and the vial was charged with argon. The reaction mixture was heated to 100° C. with microwave for 1 h. The reaction mixture was purified via column chromatography on silica gel (RediSep 12 g column, gradient elution with 0% to 50% (90:10 CH2Cl2—MeOH—CH2Cl2) to afford (S)-5,5-dimethyl-4-phenyl-3-((S)-4-(pyridin-3-yl)cyclohex-3-en-1-yl)oxazolidin-2-one (0.128 g, 0.367 mmol, 75% yield) as a yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[O:29]1[C:33]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][CH2:31][CH2:30]1>>[CH3:28][N:4]1[C:3]([CH2:2][N:36]2[CH2:37][CH2:38][C:33]3([O:29][CH2:30][CH2:31][CH2:32]3)[CH2:34][CH2:35]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: C1COC2(C1)CCNCC2
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC4(CCCO4)CC3)n(C)c2n1

Procedure:
Alternatively, following General Procedure E for Displacement of alkyl bromide with amines, 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and 1-oxa-8-azaspiro[4.5]decane were reacted to give 370.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([Cl:15])[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1OB(O)O>>[Cl:15][C:4]1[CH:3]=[C:2]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[Cl:16])[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: OB(O)Oc1ccccc1Cl
Reactant: CCOC(=O)COc1ccc(Br)cc1Cl
Product: CCOC(=O)COc1ccc(-c2ccccc2Cl)cc1Cl

Procedure:
Prepared analogously to Example 130a from ethyl (4-bromo-2-chloro-phenoxy)-acetate (Z26) and 2-chlorophenylboric acid.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([Cl:15])=[CH:7][C:8]([Cl:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[C:1]([NH:4][C:5]1[C:13]([N+:16]([O-:18])=[O:17])=[C:9]([C:8]([Cl:14])=[CH:7][C:6]=1[Cl:15])[C:10]([OH:12])=[O:11])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cc(C(=O)O)c(Cl)cc1Cl
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1c(Cl)cc(Cl)c(C(=O)O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 85.7 %

Procedure:
5-Acetamido-2,4-dichlorobenzoic acid (9.6 g, 0.039 mol) was added in small portions over 30 min to a stirred ice-cooled solution of fuming nitric acid (1.8 mL, 0.043 mol) and conc sulfuric acid (120 mL). After the addition was complete, more fuming nitric acid (17 mL) and conc sulfuric acid (80 mL) were added at 30 min and 60 min intervals. The reaction mixture was then left to stir for an additional 2.5 h at 0° C., allowed to warm to 12-16° C. and left to stir at this temperature until all starting material was consumed (about 3 h). The solution was poured onto ice and extracted with ethyl acetate (3×). The organic extracts were combined, washed with brine, dried, and concentrated to give 3-acetamido-4,6-dichloro-2-nitrobenzoic acid as an orange solid (9.8 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23])(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1.[N:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][C:36]3([CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[CH2:35][CH2:34]2)=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][CH2:21][S:22]([N:41]2[CH2:40][CH2:39][C:36]3([CH2:37][CH2:38][N:33]([C:30]4[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=4)[CH2:34][CH2:35]3)[CH2:43][CH2:42]2)(=[O:24])=[O:23])(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1
Reactant: c1cc(N2CCC3(CCNCC3)CC2)ccn1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCS(=O)(=O)Cl)c(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCS(=O)(=O)N2CCC3(CCN(c4ccncc4)CC3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(1-(4-Methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)propane-1-sulfonyl chloride (1.3 mmol, 1 eq) in MC (5 ml) was added to a solution of 3-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane (1.56 mmol, 1.2 eq) and DIPEA (5.2 eq) at 0° C. and the mixture was stirred for 30 min. The reaction mixture was subsequently warmed to room temperature and stirred for 12 h. The reaction mixture was diluted with methylene chloride and washed with water and sat. sodium chloride solution. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product obtained in this way was purified by column chromatography (silica gel). Yield: 0.4 g (50%). MS, Rt=3.8 min, m/z=614.9 [MH]+.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9](CC1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][N:46]([CH3:57])[CH2:47][CH2:48][O:49][C:50]1[CH:56]=[CH:55][C:53]([NH2:54])=[CH:52][CH:51]=1.N[C:59]1C=CC=C[CH:60]=1>>[CH:8]12[N:7]([C:13]3[N:18]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:54][C:53]5[CH:55]=[CH:56][C:50]([O:49][CH2:48][CH2:47][N:46]([CH3:57])[CH3:45])=[CH:51][CH:52]=5)=[O:27])=[CH:23][CH:24]=4)[N:16]=[C:15]4[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=34)[CH:6]([CH2:59][CH2:60]1)[CH2:5][O:12][CH2:9]2
Reactant: Nc1ccccc1
Reactant: CN(C)CCOc1ccc(N)cc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Product: CCn1ncc2c(N3C4CCC3COC4)nc(-c3ccc(NC(=O)Nc4ccc(OCCN(C)C)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-(2-(dimethylamino)ethoxy)aniline as the aniline component. (34%, MS=557.5 (M+H))
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1Cl)([O-:3])=[O:2].[CH3:18][NH2:19].C(O)C>O>[CH3:18][NH:19][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: CN
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Solvent: O
Product: CNc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
Two and six-tenths grams (.01 mole) of 2,6-dinitro-4-t-butylchlorobenzene was reacted with 3.1 grams of 40% aqueous solution of methylamine in 50 ml. ethanol. The temperature was slowly increased as follows: 30° C for 1 hour; 40° C for 1 hour; 50° C for 1 hour, then 80° C for 5 hours. When the reaction was complete about 100 ml. H2O was added, precipitating the product. This was filtered, washed with portions of H2O and upon recrystallization from ethanol yielded 2.5 grams of N-methyl-2,6-dinitro-4-t-butylaniline as orange needles melting at 129°-130° C.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]3[CH:18]=[CH:19][CH:20]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:30][C:31]1[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34]>ClCCl>[CH:18]1[N:11]2[C:12]3[C:17]([N:8]([C:6]([C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:33](=[O:34])[C:32]5[CH:36]=[CH:37][CH:38]=[C:39]([Cl:40])[C:31]=5[Cl:30])=[CH:22][CH:21]=4)=[O:7])[CH2:9][C:10]2=[CH:20][CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: Nc1ccc(C(=O)N2Cc3cccn3-c3ccccc32)cc1
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3-c3ccccc32)cc1)c1cccc(Cl)c1Cl
Reaction time: 8 h
Yield: 13.3 %

Procedure:
As described for Example 157, 0.47 g of 4,5-dihydro-5-(4-aminobenzoyl)pyrrolo[1,2-a]quinoxaline, 346 μl of triethylamine and 5 ml of dichloromethane are chilled (ice bath) and 0.415 g of 2,3-dichlorobenzoyl chloride in 2 ml of dichloromethane added. After stirring overnight, an additional 346 μl of triethylamine is added and an additional 0.415 g of 2,3-dichlorobenzoyl chloride added. The mixture is stirred for 2 hours, diluted with 50 ml of dichloromethane and the solution washed with 20 ml each of H2O, 2 N citric acid, 1 M NaHCO3 and brine. The organic layer is dried (Na2SO4) and filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue is chromatographed on thick layer silica gel plates with ethyl acetate-hexane (1:1) as solvent to give 0.100 g of white solid, m.p. 230-240° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:18]1(B(O)O)[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1>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>[C:18]1([C:2]2[CH:3]=[C:4]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: OB(O)C1=CCCCC1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(Br)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CN1CCN(c2ccc([N+](=O)[O-])c(C3=CCCCC3)c2)CC1
Temperature: 100 °C
Yield: 123 %

Procedure:
A mixture of 102 mg (0.340 mmol) 1-(3-bromo-4-nitro-phenyl)-4-methyl-piperazine (as prepared in Example 9, step (a)), 59.7 mg (0.474 mmol) cyclohexen-1-ylboronic acid, 43.8 mg (0.0379 mmol) of tetrakis(triphenylphosphine)palladium (0) under Ar was treated with 206 μL (0.412 mmol) of 2.0 M degassed aq Na2CO3, 0.6 mL degassed anh toluene and 0.2 mL degassed anh EtOH and the mixture was heated at 100° C. for 21 h. After cooling to RT, the mixture was poured into EtOAc (10 mL), washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo. Chromatography on a 5-g silica SPE column with 1-3% EtOH in dichloromethane afforded 126 mg of the title compound (74% purity by RP-HPLC (C18 column) as a mixture with triphenylphosphine) as a yellow oil that was used in the following reaction without further purification. Mass spectrum (ESI, m/z): Calcd. for C17H23N3O3, 302.2 (M+H), found 302.2.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:35]=[CH:36][CH:37]=2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([CH:25]=[C:26]([NH:28]C(=O)C(F)(F)F)[N:27]=4)[CH:24]=3)[CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[OH-].[Na+].O>C(O)C>[NH2:28][C:26]1[N:27]=[C:22]2[CH:21]=[CH:20][C:19]([O:18][C:14]3[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]4[CH:35]=[CH:36][CH:37]=[C:6]([C:3]5([C:1]#[N:2])[CH2:4][CH2:5]5)[CH:7]=4)[CH:17]=[CH:16][CH:15]=3)=[CH:24][N:23]2[CH:25]=1
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)C(F)(F)F)cn5c4)c3)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)cn5c4)c3)c2)CC1
Temperature: 45 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
To a solution of 3-(1-cyanocyclopropyl)-N-[3-({2-[(trifluoroacetyl)amino]imidazo[1,2-a]pyridin-6-yl}oxy)phenyl]benzamide (450 mg, 0.89 mmol) in ethanol (8.0 mL) was added 1N aqueous sodium hydroxide solution (8.9 mL), and the mixture was stirred at 45° C. for 8 hr. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/methanol=100/0→80/20), and fractions containing the desired product were concentrated under reduced pressure to give N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (200 mg, 55%) as a colorless solid.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C([N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:14][CH2:13]1)C1C=CC=CC=1>C(Cl)Cl>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[Cl:25])[O:18][CH:15]1[CH2:16][CH2:17][N:12]([C:1]([Cl:4])=[O:2])[CH2:13][CH2:14]1
Reactant: Clc1ccc(OC2CCN(Cc3ccccc3)CC2)cc1Cl
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)N1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 1 h

Procedure:
To a stirred solution of 16 g (0.16 mole) of phosgene in 200 ml of methylene chloride at 15° C. under nitrogen gas was added dropwise a solution of 47.2 g (0.14 mole) of 1-benzyl-4-(3,4-dichlorophenoxy)piperidine in 100 ml of methylene chloride. The addition was complete within 1 hr and stirring was continued for an additional hour. The mixture was concentrated on a rotary evaporator to give a light oil. The oil was dissolved in isopropyl either and the mixture filtered to remove a small amount of insoluble material. The filtrate was washed with 50 ml of water, dried over magnesium sulfate, filtered and concentrated in vacuo to an oil. The oil was triturated four times with 100 ml of hexane decanting off the hexane each time after cooling. The oil residue, 37 g (86%), was treated with 10 ml of triethylamine to quaternize (precipitate) any excess benzyl chloride.
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].[CH:5]1[C:17]2[CH:16]([CH2:18][CH2:19][OH:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1>C1(C)C=CC=CC=1>[Cl:3][C:1]([O:20][CH2:19][CH2:18][CH:16]1[C:17]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[C:10]2[C:15]1=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:2]
Reactant: OCCC1c2ccccc2-c2ccccc21
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)OCCC1c2ccccc2-c2ccccc21
Reaction time: 0.5 h

Procedure:
A phosgene solution (12.4 ml of a 1.93M solution in toluene) was added dropwise with stirring to a solution of 2-(9-fluorenyl)ethanol (1.26 g, 6 mmol). After 0.5 hours the solution was put under vacuum to remove the phosgene, and concentrated to give 2-(9-fluorenyl)ethyl chloroformate (1.64 g, 6 mmol). This was dissolved in 10 ml dioxane, and to it added dropwise a solution of anthranilic acid (0.85 g, 6.2 mmol) and potassium carbonate (0.86 g, 6.2 mmol) in 15 ml water. After 3 hours, the dioxane was evaporated, and the solution diluted with an equal amount of water. Acidification with 10% HCl yielded a white precipitate which was washed with water and dried. (1.98 g, 88%), mp 177° C. IR(KBr) 3175, 1709, 1684, 1594, 1537, 1450, 1380, 1301, 1259, 1205, 1146, 1049, 753, 740 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.46 (q, 2H, J=6.8), 4.14 (t, 3H, J=6.8), 7.10 (t, 1H, J=6.5), 8.46 (m, 13H), 10.13 (s, 1H). Anal. calcd for C23H19NO4 : C, 73.98; H, 5.13; N, 3.75. Found: C, 73.87; H, 5.19; N, 3.73.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([O:31][C:32]([NH:34][C@@H:35]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:36]([OH:38])=O)=[O:33])[CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30].CCN(C(C)C)C(C)C.[CH3:52][O:53][C@:54]1([C:63]2[CH:68]=[CH:67][C:66]([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=3[CH:75]=[CH2:76])=[CH:65][CH:64]=2)[CH2:58][NH:57][C@H:56]([C:59]([O:61][CH3:62])=[O:60])[CH2:55]1>C(Cl)Cl>[CH2:25]([O:31][C:32]([NH:34][C@@H:35]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:36]([N:57]1[CH2:58][C@:54]([O:53][CH3:52])([C:63]2[CH:64]=[CH:65][C:66]([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=3[CH:75]=[CH2:76])=[CH:67][CH:68]=2)[CH2:55][C@H:56]1[C:59]([O:61][CH3:62])=[O:60])=[O:38])=[O:33])[CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30]
Reactant: C=Cc1ccccc1-c1ccc([C@@]2(OC)CN[C@H](C(=O)OC)C2)cc1
Reactant: C=CCCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCOC(=O)N[C@H](C(=O)N1C[C@](OC)(c2ccc(-c3ccccc3C=C)cc2)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
HATU (139 mg, 0.365 mmol) was added to a solution of (S)-2-((hex-5-enyloxy)carbonylamino)-3,3-dimethylbutanoic acid (128 mg, 0.498 mmol), DIEA (0.174 mL, 0.996 mmol) and (2S,4R)-methyl 4-methoxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (112 mg, 0.332 mmol) in DCM (5 mL). The reaction was stirred at r.t. overnight. The reaction was evaporated and purified on the Biotage (10-40% EtOAc in hexanes) to give (2S,4R)-methyl 1-((S)-2-((hex-5-enyloxy)carbonylamino)-3,3-dimethylbutanoyl)-4-methoxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (151 mg, 79% yield) as a clear oil. LCMS: rt=2.05 min. [M+Na]30 =599; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.