Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([CH3:21])[N:15]([CH3:16])[C:14]([CH2:18][CH3:19])([CH3:17])[CH2:13][C:5]2([NH:9][C:8](=[O:10])[N:7]([CH3:11])[C:6]2=[O:12])[CH:4]1[CH3:20])[CH3:2].[H-].[Na+].CI.[C:26](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([C:3]1([CH3:21])[N:15]([CH3:16])[C:14]([CH2:18][CH3:19])([CH3:17])[CH2:13][C:5]2([N:9]([CH3:26])[C:8](=[O:10])[N:7]([CH3:11])[C:6]2=[O:12])[CH:4]1[CH3:20])[CH3:2]
Reactant: CCC1(C)CC2(NC(=O)N(C)C2=O)C(C)C(C)(CC)N1C
Reactant: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCC1(C)CC2(C(=O)N(C)C(=O)N2C)C(C)C(C)(CC)N1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.95 g of Compound 64, obtained as described in Example 5, in 10 ml of dimethylformamide was added 0.67 g of 52.9% sodium hydride; the mixture was stirred overnight at room temperature. 2.26 g of methyl iodide were then added and the mixture was heated at 100° C for 15 hours, with stirring. After cooling the mixture, 100 ml of ice-water and 20 ml of a 20% aqueous potassium carbonate solution were added in turn; the mixture was then extracted with ethyl acetate. The extract was washed with water and dried over potassium carbonate. After removing the solvent from the extract, the residue was purified by column chromatography on silica gel (eluent: chloroform containing 2.5% of methanol), giving 2.9 g of Compound 136 as a white powder melting at 77° - 88° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14]Cl)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39].[CH2:40]([NH:42][CH2:43][CH2:44][OH:45])[CH3:41].O>CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][N:42]([CH2:43][CH2:44][OH:45])[CH2:40][CH3:41])=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39]
Reactant: CCNCCO
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OCCCCl)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCN(CCO)CCCOc1cc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1Cl)CNC2=O
Temperature: 90 °C
Reaction time: 72 h
Yield: 80.8 %

Procedure:
4-Chloro-5-(3-chloropropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (90.4 mg, 0.158 mmol) was dissolved in N,N-dimethylacetoamide (1.0 mL), and the solution was added with 2-(ethylamino)ethanol (0.321 mL, 2.37 mmol), followed by stirring at 90° C. for 72 hours. The reaction mixture was added with water. The obtained solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-chloro-5-[3-[N-ethyl(2-hydroxyethyl)amino]propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (79.8 mg, yield 81%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][CH:23]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:24](Cl)=[O:25]>>[Cl:22][CH:23]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:24]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)=[O:25]
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)C(Cl)c3ccccc3)CC1)O2

Procedure:
Compound 50 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, chloro(phenyl)acetyl chloride and conditions outlined in procedure N. M.p.=125-126° C.; 300 MHz 1H NMR (DMSO-d6) δ 7.62-7.88 (m, 3H), 7.35-7.55 (m, 6H), 6.44 (d, 1H), 4.15 (m, 2H), 3.30 (m, 2H), 3.0-3.13 (2s, 2H), 2.0 (m, 2H), 1.65 (m, 2H); LCMS: 454 [M+H].
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([CH3:23])[C:10]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.C1(N(C)C2CCCCC2)CCCCC1.N#N.[CH:40]([O:42]CCCC)=[CH2:41].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1>[C:40]([C:2]1[N:6]2[CH2:7][CH2:8][N:9]([CH3:23])[C:10]3([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]3)[C:5]2=[CH:4][CH:3]=1)(=[O:42])[CH3:41]
Reactant: C=COCCCC
Reactant: CN1CCn2c(Br)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Agent: N#N
Solvent: C1COCCO1
Product: CC(=O)c1ccc2n1CCN(C)C21CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 37.1 %

Procedure:
A solution of tert-butyl 6-bromo-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (2 g, 5.2 mmol) and N-cyclohexyl-N-methyl-cyclohexanamine (1.67 mL, 7.81 mmol) in 1,4-dioxane (8.0 mL) was purged with N2 for 5 minutes. 1-Vinyloxybutane (7.04 mL, 52.04 mmol), Pd(dba)3 (1.078 g, 1.04 mmol) and tri tert-butylphosphane (642.0 μL, 2.60 mmol) were added and the reaction was heated at 80° C. for 5 hours in a pressure vessel. The reaction was filtered through a plug of celite using ethyl acetate. The solvent was evaporated under reduced pressure. The crude product was purified by silica gel chromatography utilizing a gradient of 1-100% ethyl acetate in hexane to yield tert-butyl 6-acetyl-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (672.1 mg, 1.93 mmol, 37%) as a yellow solid. 1H NMR (400 MHz, DMSO) δ 7.04 (d, J=4.1 Hz, 1H), 6.12 (d, J=4.2 Hz, 1H), 4.17 (t, J=6.0 Hz, 2H), 3.83-3.68 (m, 2H), 3.21 (t, J=6.0 Hz, 2H), 3.17-2.91 (m, 2H), 2.31 (s, 3H), 2.24 (s, 3H), 2.07-1.97 (m, 2H), 1.72-1.59 (m, 2H), 1.41 (s, 9H). ESI-MS m/z calc. 347.2, found 348.5 (M+1)+; Retention time: 0.95 minutes (3 minute run).
Reaction SMILES: [C:1]([C:3]1[CH:50]=[CH:49][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]([NH:34]S(C(C)(C)C)=O)([C:12]3[C:20]([CH2:21][CH3:22])=[CH:19][C:18]([CH3:23])=[C:17]4[C:13]=3[CH:14]=[CH:15][N:16]4[S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH3:11])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(NS(C(C)(C)C)=O)(C3C(CC)=CC(C)=C4C=3C=CN4S(C3C=CC(C)=CC=3)(=O)=O)C)N(COCC[Si](C)(C)C)C=2C=1)#N.C([O-])(O)=O.[Na+]>Cl.CO>[NH2:34][C:10]([C:8]1[NH:7][C:6]2[CH:49]=[CH:50][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[N:9]=1)([C:12]1[C:20]([CH2:21][CH3:22])=[CH:19][C:18]([CH3:23])=[C:17]2[C:13]=1[CH:14]=[CH:15][N:16]2[S:24]([C:27]1[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=1)(=[O:26])=[O:25])[CH3:11]
Reactant: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(C)(NS(=O)C(C)(C)C)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(C)(NS(=O)C(C)(C)C)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(C)(N)c1nc2cc(C#N)ccc2[nH]1

Procedure:
A solution of (±)-N-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide and (±)-N-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide (330 mg, 0.451 mmol) in 1M HCl in MeOH (5 mL) was stirred at 60° C. for 6 h. The reaction mixture was neutralized with 5% aq. NaHCO3. The layers were separated and the aqueous layer was extracted with CH2Cl2. The organic phase was successively washed by H2O and brine, dried over Na2SO4, and filtered. After concentration, the residue was purified by silica gel flash column chromatography (CH2Cl2/EtOH=1/0 to 9/1) to give the title compound. MS (ESI−) m/z 496.4 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.Cl.[CH3:14][NH:15][O:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:15]([O:16][CH3:17])[CH3:14])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1ccc(Br)cc1
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)CCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a mixture of 24.95 g 3-(4-bromophenyl)propionic acid, 12.75 g N,O-dimethylhydroxylamine hydrochloride, 27.14 g EDC, and 17.66 g HOBt were added 300 mL DMF and 47.4 mL DIEA. The reaction mixture was stirred at room temperature for 17 hours and then poured into 700 mL ice water, extracted with 5×200 mL EtOAc. The combined EtOAc solution was washed with 200 mL 5% NaHCO3, 4×200 mL water, and 200 mL saturated brine, dried over Na2SO4, and concentrated under reduced pressure to give crude product as a yellow oil. It was purified on silica gel using 35-55% EtOAc in hexanes to give the title compound as yellowish oil. 1H NMR (CDCl3, 500 MHz) δ 7.40˜7.43 (m, 2H), 7.11˜7.14 (m, 2H), 3.63 (s, 3), 3.19 (s, 3H), 2.93 (t, J=7.8 Hz, 2H), 2.73 (t, J=7.7 Hz, 2H). LC-MS: 1.77 min. (M+H=272.1/274).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1.[CH2:34]([O:41][CH2:42][CH2:43]I)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([O:41][CH2:42][CH2:43][O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: ICCOCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-(4-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 22(j)] with 2-(benzyloxy)-ethyl iodide [Helv.Chim.Acta Vol.71, (1988),2039] there was obtained tert-butyl (3RS,4RS)-4-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless foam; MS: 599 (M+NH4)+.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[C:5]2=[N:4][C:3]=1C.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O(C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[OH:38][C:35]1[CH:36]=[CH:37][C:32]([C:2]2[N:6]3[CH:7]=[CH:8][N:9]=[C:10]([NH:11][CH2:12][C:13]4[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:17][CH:18]=4)[C:5]3=[N:4][CH:3]=2)=[CH:33][CH:34]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: Cc1nc2c(NCc3ccc(S(N)(=O)=O)cc3)nccn2c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(CNc2nccn3c(-c4ccc(O)cc4)cnc23)cc1
Temperature: 130 °C

Procedure:
To a 5 mL microwave tube is added 4-[(3-Bromo-2-methyl-imidazo[1,2-a]pyrazin-8-ylamino)-methyl]-benzenesulfonamide (0.15 g, 0.379 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (0.084 g, 0.417 mmol), Na2CO3 (0.1 g, 0.95 mmol), Pd(OAc)2 (approx. 7 mg, 0.028 mmol), and (oxidi-2,1-phenylene)bis(diphenylphosphine) (20 mg, 0.038 mmol). The mixture is suspended in DMF (3 mL) and water (1 mL) and the vessel is sealed under a nitrogen atmosphere. The reaction vessel is heated to 130° C. in the CEM microwave for 20 min then allowed to cool and filtered through Celite and washed with EtOAc. The filtrate is evaporated and the residue is taken up in DMSO and purified by prep HPLC. The product, 4-{[3-(4-Hydroxy-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-methyl}-benzenesulfonamide, is obtained as a white solid (15 mg, 10%) LC-MS m/z 410 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[N:6]=1)=[N+]=[N-]>CO.[Pd].NCCN>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[N:6]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CN=[N+]=[N-])n1
Agent: [Pd]
Solvent: CO
Solvent: NCCN
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CN)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.2 %

Procedure:
A suspension of 2-azidomethyl-6-[(tert-butyldimethylsilyloxy)methyl]pyridine (2) (0.83 g, 2.98 mmol) and 5% Pd/C(en) (83.0 mg, 10 wt %) in MeOH (20 mL) was vigorously stirred for 5 hours at a room temperature under a hydrogen atmosphere. TLC was used to confirm there was no starting material in the reaction mixture. Then, the catalyst was removed by suction filtration with a kiriyama funnel. The filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3:MeOH=30:1 to 10:1) to give 2-aminomethyl-6-[(tert-butyldimethylsilyloxy)methyl]pyridine (3) (603 mg, 80%) as a yellow oil.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][CH:22]=3)=[O:20])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[BH4-].[Na+].[BH4-]>C(O)C.CN(C)C=O.O>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH:19]([OH:20])[C:21]3[CH:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][CH:22]=3)[CH2:16][CH2:17]2)=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CN2CCN(c3ccc(NS(C)(=O)=O)cc3)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(C(O)CN2CCN(c3ccc(NS(C)(=O)=O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(4-Methanesulphonamidophenyl)-4-(4-methanesulphonamidophenacyl)piperazine [see Example 5(D)] (0.77 g) was dissolved in ethanol (3 ml) and dimethylformamide (5 ml). Sodium borohydride (0.125 g) was then added portionwise over 5 minutes, and the mixture was stirred for 21/2 hours at ambient temperature. A further 25 mg. sodium borohydride was then added and the reaction mixture was heated at 60° for 2 hours. A further 20 mg. of borohydride was added, and the reaction mixture was heated at 70° for 41/2 hours. The mixture was then diluted with water, precipitating the impure product containing some unreduced starting material (0.51 g after drying). This impure product was refluxed for 41/2 hours in ethanol (35 ml), adding sodium borohydride (110 mg) portionwise during the first 2 hours. The mixture was then evaporated, the residue washed with water, and crystallized from methanol, yield of the pure title compound 0.118 g., m.p. 230°-2° (dec.).
Reaction SMILES: I[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1.N>>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:3]=[C:2]([C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[O:6][N:5]=1
Reactant: OB(O)c1cccnc1
Reactant: Ic1cc(-c2ccccn2)no1
Agent: N
Product: c1ccc(-c2cc(-c3cccnc3)on2)nc1

Procedure:
The titled compound was prepared as the bishydrochloride salt according to Method CC using 5-iodo-3-(pyridin-2-yl)isoxazole [prepared as described by Ku, Y.-Y.; Grieme, T.; Sharma, P.; Pu, Y.-M.; Raje, P.; Morton, H.; King, S. Org. Lett. 2001, 3, 4185-4187] (136 mg, 0.5 mmol) and pyridin-3-ylboronic acid (Aldrich, 92 mg, 0.750 mmol). 1H NMR (300 MHz, DMSO-d6) d ppm 7.52-7.64 (m, 1H), 7.75-7.83 (m, 1H), 7.86 (s, 1H), 8.03 (td, J=7.7, 1.6 Hz, 1H), 8.11 (dt, J=7.9, 1.2 Hz, 1 H), 8.58 (dt, J=8.0, 1.9 Hz, 1H), 8.75-8.79 (m, 1H), 8.81 (dd, J=5.2, 1.6 Hz, 1H), 9.32 (d, J=2.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 224 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].C1CCNCC1.[N+:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24]>O1CCCC1>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[O:6])=[O:31])=[CH:33][CH:34]=1)([O-:25])=[O:24]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc([N+](=O)[O-])cc3)c2)CC1
Yield: 110.5 %

Procedure:
To a mixture of 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and (piperidinomethyl)-polystyrene (176 mg, 0.458 mmol) in tetrahydrofuran (1 mL) was added 4-nitrobenzoyl chloride (85 mg, 0.458 mmol) in tetrahydrofuran (1 mL). The reaction mixture was mixed for 18 h at ambient temperature. The reaction mixture was filtered and the filter cake was rinsed with methanol. The filtrate solution was diluted with 10% acetic acid in methanol and poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed with methanol to remove impurities, then treated with a 7M ammonia in methanol to elute the product from the column. The solvent was evaporated to give 93 mg (>100%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:18])[N:3]1[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1.I[CH2:32][CH3:33]>>[O:1]=[C:2]1[N:6]([CH2:32][CH3:33])[C:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:18])[N:3]1[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:28])[F:29])[CH:20]=1
Reactant: CCI
Reactant: C=CCOCC1(c2ccccc2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Product: C=CCOCC1(c2ccccc2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CC

Procedure:
The procedure of Example 1, Step 1 applied to 0.23 g of 4-[2,5-dioxo-4-phenyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-trifluoromethylbenzonitrile with 0.18 mL of iodoethane provides the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@@:8]([NH:14]S(C(C)(C)C)=O)([CH2:12][OH:13])[CH:9]([F:11])[F:10])[CH:7]=1.[ClH:22].CC(O)C>C(Cl)Cl>[NH2:14][C@@:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:21])([CH:9]([F:10])[F:11])[CH2:12][OH:13].[ClH:22]
Reactant: CC(C)(C)S(=O)N[C@@](CO)(c1cc(Br)ccc1F)C(F)F
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: N[C@@](CO)(c1cc(Br)ccc1F)C(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid [(R)-1-(5-bromo-2-fluoro-phenyl)-2,2-difluoro-1-hydroxymethyl-ethyl]-amide (10 g, 25.76 mmol) in DCM (100 ml) was added under argon a 30% HCl in IPA solution (10 ml, 91.6 mmol) below 25° C. After stirring for 30 min at 25° C., cooled down to −10° C., filtered and dried to provide the title compound HCl salt as white crystals: ESIMS: 284, 286 [(M+H)+], 1H NMR (400 MHz, DMSO-d6): δ 9.42 (b, 3H), 7.84 (m, 1H), 7.74 (m, 1H), 7.35 (dd, 1H), 6.68 (t, 1H), 4.03 (m, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[C:10]([OH:12])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:46]([O:48][C:49]([C:51]1([NH2:60])[CH2:59][C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52]1)=[O:50])[CH3:47]>CO.C(Cl)Cl.C(Cl)Cl>[CH2:46]([O:48][C:49]([C:51]1([NH:60][C:10]([CH:2]2[CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[O:1]2)=[O:12])[CH2:59][C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52]1)=[O:50])[CH3:47]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)C1Cc2ccccc2O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)C2Cc3ccccc3O2)Cc2ccccc2C1
Yield: 171.4 %

Procedure:
To a 40 mL vial containing a stirring bar, 2,3-dihydro-1-benzofuran-2-carboxylic acid (0.4 g, 2.44 mmol) is charged with dry DCM (7 mL). Stirring is initiated. HBTU (922 mg, 2.43 mmol) and the DIPEA (0.95 mL, 8.0 mmol) are added. The 2-aminoindane-2-carboxylic acid ethyl ester (500 mg, 2.44 mmol) is added. The reaction is allowed to stir for 16 h. Analysis by tlc of the reaction mixture (silica, 10% MeOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are diluted with EtOAc (50 mL) and transferred to a separatory funnel. This is washed consecutively with dilute aqueous NaHCO3 (25 mL) and brine (25 mL), dried over MgSO4, filtered and evaporated in vacuo to provide 1.47 g of viscous yellow oil. This material is dissolved in 10 mL of DCM and purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 15% EtOAc in heptanes for 3 column volumes followed by a linear gradient to 50% over 8 column volumes and then 90% EtOAc for 2 column volumes with a ramp of 1 column volume. 25 mL fractions are collected. Fractions 3 through 6 are combined and evaporated in vacuo. Pumping to a constant weight gives amorphous white solid 0.68 g.
Reaction SMILES: [B]=O.[CH:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]1(=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][C:12]1=O>N1CCCCC1.C1C=CC=CC=1>[CH:13](=[C:12]1[C:3](=[O:10])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:11]1=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1Cc2ccccc2C1=O
Agent: [B]=O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: O=C1C(=Cc2ccccc2)C(=O)c2ccccc21
Reaction time: 0.5 h

Procedure:
(8) (Chem. Pharm. Bull. 1974, 22(2), 448-451). Boron oxide (720 mg, 10.26 mmol) and benzaldehyde (800 mg, 7.53 mmol) were added to a stirred solution of the indandione (1.00 g, 6.84 mmol) and piperidine (3 drops) in 10.2 ml of benzene. The solution was refluxed with stirring for 30 minutes. After filtration of the solution, the filtrate was concentrated under reduced pressure. The resulting crystalline solid was recrystallized from ethanol to afford 1.00 g (62.4%) of yellowish-green platelets: mp 149.5-150.0° C. (lit. mp 150° C., Okukawa, et al., Chem. Pharm. Bull., 1974, 22(2), 448-451). 1H NMR (250 MHz) δ 8.47-8.45 (m, 2 H), 8.06-7.99 (m, 2 H), 7.90 (s, 1 H), 7.84-7.79 (m, 2 H), 7.58-7.50 (m, 3 H); 13C NMR (62.7 MHz) 190.5, 189.2, 147.2, 142.7, 140.2, 135.6, 135.4, 134.3, 133.4, 133.2, 129.3, 129.0, 123.5, 123.5 ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:6][CH:5]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:8][CH:9]=1
Reactant: CCCCCCC(=O)NCCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCCCCCC(=O)NCCc1ccc(N)cc1
Reaction time: 4 h
Yield: 95.9 %

Procedure:
1H NMR (400 MHz, CDCl3) δ8.16 (d, 2H), 7.35 (d, 2H), 5.43 (s, 1H), 3.54 (m, 2H), 2.93 (t, 2H), 2.12 (t, 2H), 1.57 (m, 3H), 1.26 (m, 5H), 0.86 (t, 3H). 10% Palladium on carbon (380 mg, 10 wt %) was added to a solution of heptanoic acid [2-(4-nitro-phenyl)-ethyl]-amide (3.80 g, 13.6 mmol) and methanol (80 mL) in a Parr bottle and the resulting mixture hydrogenated at 55 psi for 4 h. The reaction mixture was filtered through a plug of Celite and the Celite plug washed thoroughly with ethyl acetate. The combined filtrates were concentrated under reduced pressure to provide 3.24 g (96%) of heptanoic acid [2-(4-amino-phenyl)-ethyl]-amide as an off-white solid.