Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC#N>[C:19]1([S:25]([N:6]2[CH:7]=[C:2]([F:1])[C:3]([NH:9][C:10]([NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:11])=[N:4][C:5]2=[O:8])(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Nc1ccccc1)Nc1nc(O)ncc1F
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CC#N
Product: O=C(Nc1ccccc1)Nc1nc(=O)n(S(=O)(=O)c2ccccc2)cc1F
Temperature: 70 °C
Reaction time: 1 h
Yield: 32.2 %

Procedure:
To a suspension of 1-(5-fluoro-2-hydroxypyrimidin-4-yl)-3-phenylurea (0.200 g, 0.8 mmol) in anhydrous CH3CN (4 mL) was added BSA (0.487 g, 2.4 mmol), and the mixture was warmed to 70° C. and stirred for 1 h. The resulting solution was cooled to room temperature, treated with benzenesulfonyl chloride (0.156 g, 0.9 mmol), and the mixture was stirred for 12 h. The solvent was evaporated, and the residue was partitioned between EtOAc and brine. The organic phase was dried over MgSO4, filtered, and concentrated to give the crude product as a white solid. Recrystallization from EtOAc and heptane afforded 1-(1-benzenesulfonyl-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)-3-phenylurea as a white solid (0.100 g, 32%): mp 210-214° C.; 1H NMR (400 MHz, DMSO-d6) δ 11.26 (dd, J=3.7, 1.1 Hz, 1H), 10.87 (m, 1H), 8.65 (m, 1H), 8.10 (d, J=7.5 Hz, 2H), 7.85 (t, J=7.5 Hz, 1H), 7.71 (m, 2H), 7.45 (m, 2H), 7.34 (m, 2H), 7.10 (m, 1H); ESIMS m/z 389 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([N+:26]([O-])=O)[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C>[NH2:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([C:29]#[N:30])=[C:16]2[NH:15][C:4]1[CH:5]=[CH:6][C:7]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:2]([Cl:1])[CH:3]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(Sc2ccccc2)c(Cl)c1
Solvent: CCO
Product: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Sc2ccccc2)c(Cl)c1
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A mixture of 6.753 g (15.6 mmol) 4-[(3-chloro-4-thiophenoxyphenyl)amino]-6-nitro-quinoline-3-carbonitrile, 250 ml ethanol, and 17.66 g (78.0 mmol) SnCl2 dihydrate was heated to reflux under N2. Removed heat at 2 hours, added large volume of ice water, and made basic with sodium bicarbonate. Stirred for 2 hours and with mixture still basic, extracted with chloroform. Stirred organic layer with Darco, dried with sodium sulfate, filtered, stripped solvent and dried in vacuo, giving 5.996 g of yellow-brown solid: mass spectrum (electrospray m/e): M+H=403.1, 405.1.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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>[CH3:8][C:6]1[C:5]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=[C:2]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH3:23])[N:7]=1
Reactant: Cc1nc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1ccccc1B(O)O
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccccc1-c1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c(C)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
A 50 mL round-bottom flask was purged with and maintained under an inert atmosphere of nitrogen then charged with tert-butyl 4-[(6-bromo-2-methylpyridin-3-yl)methyl]piperazine-1-carboxylate (800 mg, 2.16 mmol, 1.00 equiv), (2-methylphenyl)boronic acid (590 mg, 4.34 mmol, 2.00 equiv), tetrakis(triphenylphosphine)palladium (250 mg, 0.220 mmol, 0.10 equiv), potassium carbonate (898 mg, 6.50 mmol, 3.00 equiv), dioxane (12 mL), and water (2 mL). The resulting solution was stirred overnight at 80° C. and then diluted with water (10 mL) and extracted with dichloromethane (3×10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (22/78) to provide 800 mg (97% yield) of tert-butyl 4-[[2-methyl-6-(2-methylphenyl)pyridin-3-yl]methyl]piperazine-1-carboxylate as a yellow oil. LCMS (ESI, m/z): 382 [M+H]+.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([NH2:17])[C:11]=2[N:10]=[C:9]1[NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.C(N(CC)CC)C.[CH2:42]([S:45](Cl)(=[O:47])=[O:46])[CH2:43][CH3:44].O1CCOCC1.Cl>O1CCCC1>[Cl:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[Cl:33])[CH2:26][N:23]1[CH2:22][CH2:21][CH:20]([CH2:19][NH:18][C:9]2[NH:8][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([NH:17][S:45]([CH2:42][CH2:43][CH3:44])(=[O:47])=[O:46])[C:11]=3[N:10]=2)[CH2:25][CH2:24]1
Reactant: CCCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c(NCC2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)nc2c(N)cccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCCS(=O)(=O)Nc1cccc2[nH]c(NCC3CCN(Cc4ccc(Cl)c(Cl)c4)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 4-amino-2-{[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-amino}-benzimidazole-1-carboxylic acid tert-butyl ester (10 mg, 0.02 mmol) in tetrahydrofuran (1 ml), triethylamine (0.04 mmol) and propane-1-sulfonyl chloride (0.08 mmol) were added and the mixture was stirred at room temperature overnight. After adding a 4N hydrogen chloride-1,4-dioxane solution (1 ml) to the reaction mixture, it was stirred at 50° C. for 1 hour. The solvent was removed under reduced pressure, dichloromethane and 5N aqueous sodium hydroxide were added to the obtained residue, and after stirring, the organic layer was passed through SCX (Bond Elute SCX500MG). The SCX was washed with methanol and elution was performed with a 2N ammonia-methanol solution. The solvent was distilled off under reduced pressure to obtain propane-1-sulfonic acid (2-{[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazol-4-yl)-amide. The compound was identified by LC-MS.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)=[CH:28][C:27]=1[CH3:41])=[O:25].C(OCC)(=O)C>O1CCCC1.O>[CH3:41][C:27]1[CH:28]=[C:29]([C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)[CH:30]=[CH:31][C:26]=1[C:24](=[O:25])[CH2:23][C:11]([CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Cc1cc(-c2ccc([N+](=O)[O-])cc2)ccc1C(=O)CBr
Reactant: CCOC(=O)C(CCc1ccccc1)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(CCc1ccccc1)(CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 85.3 %

Procedure:
To a cold suspension (0–5° C.) of 95% sodium hydride (3.53 g, 13.0 mmol) in dry tetrahydrofuran (30 mL) was slowly added diethyl 2-phenylethylmalonate (3.53 g, 13 mmol). The ice bath was removed and the reaction mixture was stirred at rt for 45 minutes. A solution of 2-bromo-1-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)ethanone (4.06 g, 12.0 mmol) in dry tetrahydrofuran (50 mL) was slowly added, and the resulting mixture was stirred at rt for about 70 h. Ethyl acetate (80 mL) and water (20 mL) were added, and the layers were separated. The organic layer was washed with water (2×30 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give a dark, brown oil. This material was purified by flash chromatography (10:90 ethyl acetate/hexane) to give diethyl 2-[2-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]-2-(2-phenylethyl)malonate as a light yellow oil (5.30 g, 82% yield). LC-MS ret. time 4.01 min, m/z 517.9 (MH+); 1H NMR (CDCl3) δ 1.23–1.35 (m, 6H), 2.41–2.50 (m, 2H), 2.56 (s, 3H), 2.59–2.66 (m, 3.71 (s, 2H), 4.21–4.32 (m, 4H), 7.13–7.19 (m, 3H), 7.22–7.30 (m, 2H), 7.49–7.55 (m, 2H), 7.73–7.82 (m, 3H), 8.31 (d, 2H).
Reaction SMILES: Cl.C[O:3]C(=O)[C@H](C)N.CCN(CC)CC.N(C)(C)C.BC(O)=O.[CH:24]1([N:30]=[C:31]=[N:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C(Cl)Cl>[CH:33]1([NH:32][C:31]([NH:30][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:3])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: COC(=O)[C@H](C)N
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: BC(=O)O
Agent: CN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of L-alanine methyl ester hydrochloride (5.97 g, 42.8 mmol) in CH2Cl2 (100 ml) was added Et3N (4.33 g, 42.8 mmol), and the mixture was stirred for 20 minutes at room temperature. A solution of Me3N.BH2COOH (5.00 g, 42.8 mmol) in CH2Cl2 (50 ml) was then added to the reaction mixture, followed by N,N'-dicyclohexylcarbodiimide (DCC) (9.27 g, 49.1 mmol) in CH2Cl2 (50 ml). After 72 hours, the N,N'-dicyclohexylurea (DCU) precipitate which formed was filtered off, and the solvent was removed under reduced pressure. The solid residue was then washed with diethyl ether (3×300 ml), and the combined washes were filtered prior to removal of the ether under reduced pressure. This procedure was repeated with water (3×300 ml) as solvent, following which, evaporation of the water from the combined washes was aided by passage of a dry air stream over the solution. Further purification of the resulting yellow oil was performed by flash chromatography using ethyl acetate/acetone (95:5) as the mobile phase. After the peptide-containing fractions were combined and the solvent removed in vacuo, the peptide oil was distilled under vacuum at 50° C. Final purification of the distilled oil was performed by flash chromatography on a column packed with petroleum ether and eluted with ethyl acetate/n-butyl alcohol (95:5). The peptide-containing fractions were combined, and the solvent was removed by the passage of a dry air stream over the solution to give the desired crystalline dipeptide. (Due to the hygroscopic nature of (1), a clear oil may result, which may be crystallized by storage under high-vacuum for several weeks.) Yield: 0.452 g (5.23%).
Reaction SMILES: Br[CH:2](C)[C:3](OC)(OC)[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[CH:5]=1.[C:21]([O-:24])(=[O:23])C.[K+].CN(C)C=O>O>[CH3:15][O:14][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH:5]=[C:4]([CH:3]([CH3:2])[C:21]([OH:24])=[O:23])[CH:13]=[CH:12]2
Reactant: CC(=O)[O-]
Reactant: COc1ccc2cc(C(OC)(OC)C(C)Br)ccc2c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Reaction time: 48 h
Yield: 97 %

Procedure:
A mixture of 2-bromo-1,1-dimethoxy-1-(6-methoxy-2-naphthyl)-propane (3.39 g; 10 mmol), potassium acetate (1.2 g; 12 mmol), N,N-dimethylformamide (14 ml) and of water (8 ml) is heated at 100° C. under stirring for 48 h. The reaction mixture is worked up as described in example 1a to provide 2-(6-methoxy-2-naphthyl)-propionic acid (2.23 g; 9.7 mmol; yield 97%), m.p. 155°-157° C.
Reaction SMILES: CCN(CC)CC.[CH2:8]([CH:11]([CH2:15][CH2:16][CH3:17])[C:12]([OH:14])=O)[CH2:9][CH3:10].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:42][C:43]1[CH:44]=[C:45]([CH:47]=[CH:48][CH:49]=1)[NH2:46]>CN(C=O)C.O>[Br:42][C:43]1[CH:44]=[C:45]([NH:46][C:12](=[O:14])[CH:11]([CH2:8][CH2:9][CH3:10])[CH2:15][CH2:16][CH3:17])[CH:47]=[CH:48][CH:49]=1
Reactant: CCCC(CCC)C(=O)O
Reactant: Nc1cccc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CCC)C(=O)Nc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Et3N (3.24 mL, 23.25 mmol) was added to a solution of 2-propylpentanoic acid in (2 g, 11.62 mmol) in DMF. The reaction mixture was cooled to 0° C. HATU (6.63 g, 17.4 mmol) was added to the reaction mixture which was stirred for 15 min and then 3-bromoaniline (2.5 g, 17.43 mmol) was added. The reaction mixture was stirred for 2 h at 0° C. The reaction mixture was diluted with H2O, extracted with EtOAc, and organic layer was concentrated under reduced pressure. The residue was washed with pentane to give N-(3-bromophenyl)-2-propylpentanamide as a white solid. Yield (1.6 g, 47%); 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 7.12 (bs, 1H), 2.21-2.14 (m, 1H), 1.73-1.63 (m, 2H), 1.51-1.45 (m, 2H), 1.43-1.25 (m, 4H), 0.92 (t, J=7.2 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:5]2.C(=O)([O-])O.[Na+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].O>CN(C)P(=O)(N(C)C)N(C)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][CH:6]2[CH2:5][C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:3]=3)[CH2:7]2)(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: Nc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Reactant: COC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: COC(=O)CNc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Reaction time: 4 h
Yield: 76.8 %

Procedure:
Into a solution of 0.5 g of 5-amino-2-(4-chlorophenyl)sulfonylaminoindan in 5 ml of hexamethylphosphoric triamide are added 0.2 g of sodium hydrogen carbonate and 0.25 g of methyl bromoacetate at 5 to 10° C., and the mixture is stirred at the same temperature for 4 hours. Water is added to the reaction mixture, followed by extraction with ethyl acetate. The extract is washed, dried and the solvent is evaporated. The residue is purified by separation through silica gel column chromatography (eluant: chloroform : ethyl acetate=7 : 3), and further recrystallized from ethyl acetate-n-hexane mixture to give 0.47 g of methyl N-[2-(4-chlorophenyl)sulfonylaminoindan-5-yl]glycinate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][O:17][CH3:18])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]CCCC.ClCC[I:35]>C1COCC1.O.[Au]>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][O:17][CH3:18])[C:10]=1[I:35])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCI
Reactant: COCOc1cccc(NC(=O)OC(C)(C)C)c1
Agent: [Au]
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COCOc1cccc(NC(=O)OC(C)(C)C)c1I
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 13 (124 mg, 0.49 mmol) in 2.0 mL anhydrous THF was cooled to −20° C. and treated with TMEDA (0.26 mL, 1.71 mmol) followed by n-BuLi (0.69 mL of a 2.5 M solution in hexanes, 1.71 mmol) in a slow dropwise manner. The resulting gold solution stirred for 4 h at −20° C. The reaction mixture was treated with 1-chloro-2-iodoethane (0.126 mL, 1.71 mmol) and stirred for 15 min at 25° C. The reaction was diluted with H2O (30 mL), extracted with Et2O (3×20 mL), and the combined organic extracts were washed with saturated aqueous NaCl, dried Na2SO4) and concentrated under reduced pressure. Flash chromatography (SiO2, 2.5×10 cm, 0-10% EtOAc/hexane gradient) yielded recovered 13 (51.8 mg, 41%) and 14 (85.5 mg, 46%) as a white solid: mp 82-84° C.; 1H NMR (CDCl3, 400 MHz) δ7.72 (d, J=8.2 Hz, 1H), 7.21 (t, J=6.0 Hz, 1H), 7.01 (br s, 1H), 6.72 (dd, J=1.2, 8.2 Hz, 1H), 5.21 (s, 2H), 3.47 (s, 3H), 1.49 (s, 9H);13C NMR (CDCl3, 100 MHz) δ156.0, 152.5, 140.1, 129.5, 113.4, 108.9, 94.8, 82.4, 80.9, 54.4, 28.3; IR (film) νmax 3388, 2977, 1736, 1592, 1515, 1465, 1406, 1252, 1226, 1153, 1005 cm−1; FABHRMS (NBA/CsI) m/z 511.9351 (C13H18INO4+Cs+ requires 511.9335).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[N:15]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:23])[C:13]2[C:8](=[CH:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[N:7]=1)[CH2:3][C:4]#[CH:5].C(N(C(C)C)CC)(C)C.[O:34]=[C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](=[O:44])[N:36]1[CH2:45][CH2:46][CH:47]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.ClC(Cl)C>[Cl:24][C:10]1[CH:9]=[C:8]2[C:13]([C:14](=[O:23])[N:15]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]([C@H:2]([NH:1][CH2:47][CH2:46][CH2:45][N:36]3[C:37](=[O:44])[C:38]4[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:35]3=[O:34])[CH2:3][C:4]#[CH:5])=[N:7]2)=[CH:12][CH:11]=1
Reactant: C#CC[C@@H](N)c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1
Reactant: O=CCCN1C(=O)c2ccccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CC[C@@H](NCCCN1C(=O)c2ccccc2C1=O)c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a mixture of (R)-(1-amino-but-3-ynyl)-7-chloro-3-phenylamino-3H-quinazolin-4-one (4.60 g, 12.2 mmol) and diisopropylethylamine (DIPEA) (5.5 ml) in dichloromethane (60 ml) was added a solution of 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionaldehyde (2.45 g, 12.1 mmol) in dichloroethane (10 ml), followed by a solution of sodium triacetoxy borohydride (NaBH(OAc)3) (0.25M in dichloroethane, 100 ml). The reaction mixture was stirred at room temperature and the reaction progress was monitored by HPLC/MS. Upon completion, a saturated sodium carbonate solution (100 ml) was added. The resulted organic layer was collected and washed with brine solution. The solvent was removed and residue was purified by flash column to afford 2-{3-[(R)-1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-but-3-ynylamino]-propyl}-isoindole-1,3-dione (6.1 g, 95%) as off-white solid. M.p. 78-80° C. LCMS: m/e 526 [M+H]. 1H NMR (DMSO-d6): δ 9.09 (s, br, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.83-7.76 (m, 5H), 7.58 (dd, J=8.8 and 2.0 Hz, 1H), 7.17 (t, J=7.6 Hz, 2H), 6.83 (brm, 1H), 6.65 (m, 2H), 4.1 and 4.0 (s, s, br, 1H, rotomers), 3.6 (t, J=6.8 Hz, 2H), 2.75 (s, br, 1H), 2.67-2.52 (brm, 2H), 2.35 (brm, 2H), 1.67 (brm, 2H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:23]1[N:28]=[CH:27][C:26]2[CH:29]=[N:30][N:31]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[N:33]=3)[C:25]=2[CH:24]=1)CCC.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>CN(C)C(=O)C.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]>[F:38][C:34]1[N:33]=[C:32]([N:31]2[C:25]3[CH:24]=[C:23]([C:2]4[N:7]=[C:6]([NH:8][CH2:9][C:10]5[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=5)[CH:5]=[N:4][CH:3]=4)[N:28]=[CH:27][C:26]=3[CH:29]=[N:30]2)[CH:37]=[CH:36][CH:35]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2c(cn1)cnn2-c1cccc(F)n1
Reactant: COc1ccc(CNc2cncc(Br)n2)cc1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: COc1ccc(CNc2cncc(-c3cc4c(cn3)cnn4-c3cccc(F)n3)n2)cc1
Temperature: 150 °C
Yield: 74.5 %

Procedure:
A mixture of 6-bromo-N-[(4-methoxyphenyl)methyl]pyrazin-2-amine (0.9932 mmol; 768.8 mg), tributyl-[1-(6-fluoro-2-pyridyl)pyrazolo[4,3-c]pyridin-6-yl]stannane (2.173 mmol; 1093 mg), tricyclohexylphosphine (0.1192 mmol; 33.42 mg) and Tris(dibenzylideneacetone)dipalladium (0) (0.04966 mmol; 45.47 mg) in N,N-Dimethylacetamide (15 mL) was purged with Argon for 1 min. The reaction mixture was sealed and heated at 150° C. under microwave for 45 min. The mixture was partitioned between EtOAc and water. The organic layer was concentrated and the residue was purified on silica eluted with 0 to 100% EtOAc in Heptane to afford 6-[1-(6-fluoro-2-pyridyl)pyrazolo[4,3-c]pyridin-6-yl]-N-[(4-methoxyphenyl)methyl]pyrazin-2-amine (316.3 mg, 48%).
Reaction SMILES: [ClH:1].O1CCOCC1.[CH3:8][O:9][C:10]1[CH:30]=[CH:29][C:13]([C:14]([O:16][CH2:17][C:18]([NH:21]C(OC(C)(C)C)=O)([CH3:20])[CH3:19])=[O:15])=[CH:12][CH:11]=1>C(Cl)Cl>[ClH:1].[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH2:17][C:18]([NH2:21])([CH3:20])[CH3:19])=[O:15])=[CH:29][CH:30]=1
Reactant: COc1ccc(C(=O)OCC(C)(C)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(C(=O)OCC(C)(C)N)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A solution of hydrochloric acid in dioxane (5.0 mL, 20.0 mmol) was added to a solution of 2-[(tert-butoxycarbonyl)amino]-2-methylpropyl 4-methoxybenzoate (0.32 g, 1.0 mmol) in DCM (10 mL) and the mixture was stirred for 1.5 h at room temperature. The reaction mixture was concentrated to give the title compound (0.26 g, 100%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.32 (br s, 3 H), 8.11 (m, J=8.9 Hz, 2 H), 7.06 (m, J=8.9 Hz, 2 H), 4.24 (s, 2 H), 3.85 (s, 3 H), 1.35 (s, 6 H). m/z (APCI+) for C12H17NO3 224.0 (M+H)+.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)[C@H:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4]1.C(O)C.[H][H]>[Pd].CCOCC>[ClH:1].[NH2:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[O:9][C@H:6]1[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][C@H:5]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN1CC[C@H](Oc2cccc([N+](=O)[O-])c2)[C@H](c2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CN1CC[C@H](Oc2cccc(N)c2)[C@H](c2ccccc2)C1

Procedure:
A solution of 4.6 g of cis-1-methyl-4-(3-nitrophenoxy)-3-phenylpiperidine hydrochloride of Example 18, in 110 ml of 190 proof ethanol is hydrogenated at 45 psi of hydrogen and room temperature over 0.46 g of 10% palladium on carbon catalyst. Hydrogen uptake stops after 2.5 hours. The catalyst is filtered off, and the filtrate is concentrated in vacuo to afford a foam which solidifies upon trituration with ether to afford a crude solid, mp s 232°, 249.5° C. dec, This material is recrystallized from absolute ethanol by boiling the filtered solution down, cooling, filtering and washing with absolute ethanol and then ether to yield cis-4-(3-aminophenoxy)-1-methyl-3-phenylpiperidine hydrochloride, mp 259°-260.5° C.