Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:21][CH2:20][CH:19]([C:22](OC)=[O:23])[CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[BH4-].[Na+].O>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([S:13]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][CH2:17]2)(=[O:14])=[O:15])=[CH:11][CH:12]=1
Reactant: COC(=O)C1CCN(S(=O)(=O)c2ccc(-c3ccccn3)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=S(=O)(c1ccc(-c2ccccn2)cc1)N1CCC(CO)CC1

Procedure:
To a stirred solution of methyl 1-{[4-(pyridin-2-yl)phenyl]sulfonyl}piperidine-4-carboxylate (0.40 g, 1.11 mmol) in anhydrous methanol (8 mL) is added sodium borohydride (0.59 g, 15.5 mmol). After 18 h water (20 mL) is added. The resulting solid is filtered, washed with water and suspended in MeCN. The suspension is concentrated under reduced pressure to give 0.26 g (72%) of 1-{[4-(pyridin-2-yl)phenyl]sulfonyl}piperidin-4-yl)methanol. m/z=333 [M++H].
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]3[N:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH2:20]4)[N:17]=[CH:18][C:10]=13)[CH2:2]2.[NH2:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:13]2[N:12]=[C:11]3[N:16]([CH:19]4[CH2:20][CH2:21][N:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:23][CH2:24]4)[N:17]=[CH:18][C:10]3=[C:9]([N:3]3[CH2:2][CH:1]4[O:8][CH:5]([CH2:6][CH2:7]4)[CH2:4]3)[N:14]=2)=[CH:32][CH:31]=1
Reactant: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(Cl)nc32)CC1
Reactant: CC1(C)OB(c2ccc(N)cc2)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: CCO
Solvent: Cc1ccccc1
Product: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(N)cc4)nc32)CC1
Temperature: 120 °C

Procedure:
A suspension of methyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (2.3 mmol), 4-aminophenylboronic acid pinacol ester (0.76 g, 3.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.27 g, 10 mol %) in toluene/ethanol (1:1, 12 mL) and 2 M aqueous sodium carbonate solution (2.5 mL) was heated in a 10-20 mL Smith process vial in the microwave reactor for one hour at 120° C. The cooled mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude residue was purified via reverse-phase high performance liquid chromatography using a Phenomenex Gemini column, running a gradient elution of 20% acetonitrile/80% of 0.07% aqueous ammonium hydroxide to 95% acetonitrile over 10 minutes. After the concentration of fractions under reduced pressure, methyl 4-(6-(4-aminophenyl)-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate was obtained. MS (ES+): 464.6 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](/[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)\O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[CH3:37][N:38]([CH3:42])[C:39]([NH2:41])=[S:40]>CC(N(C)C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:40][C:39]([N:38]([CH3:42])[CH3:37])=[N:41][C:9]=2[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: CN(C)C(N)=S
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Product: CN(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To N-{3-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide (2.0 g, 4.72 mmol) in 25 mL DMA was added NBS (0.88 g, 4.95 mmol). The mixture stirred at rt for 30 min. N,N-Dimethylthiourea (0.6 g, 5.66 mmol) was added and the mixture heated to 40° C. overnight. The mixture was poured into 300 mL ice water and the crude product was collected by filtration. The crude product was then purified by flash chromatography to give the title compound of Step A (0.6 g, 1.18 mmol, 25% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.09 (s, 1H), 8.14 (d, J=5.5 Hz, 1H), 7.68 (s, 2H), 7.37 (d, J=7.9 Hz, 1H), 7.22 (ddd, J=17.3, 8.5, 8.2 Hz, 5H), 6.47 (d, J=5.5 Hz, 1H), 3.12 (s, 6H).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([NH:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[NH:27]C(=O)OC(C)(C)C)[N:15]=[CH:14]2.Cl>O1CCOCC1.ClCCl>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([NH:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[NH2:27])[N:15]=[CH:14]2
Reactant: COc1ccc(F)c(-c2ccc3nc(N[C@@H]4CCC[C@@H]4NC(=O)OC(C)(C)C)ncc3c2)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc3nc(N[C@@H]4CCC[C@@H]4N)ncc3c2)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of tert-butyl ((1S,2R)-2-((6-(2,6-difluoro-3-methoxyphenyl)quinazolin-2-yl)amino)cyclopentyl)carbamate (21 mg, 0.045 mmol) and 4M HCl in Dioxane (0.5 mL) in dichloromethane (1 mL) was stirred at room temperature for 16 h. LC-MS indicated complete consumption of SM. The reaction mixture was concentrated and used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][O:6][C@@H:5](/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C@@H:4]1[OH:19].[C:20]([O:24][C:25]([NH:27][CH2:28][C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].C1(N=C=NC2CCCCC2)CCCCC1.O>CN(C)C1C=CN=CC=1.ClCCl>[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]([O:19][C@@H:4]1[C@@H:3]([O:2][CH3:1])[C@@H:8]([CH3:9])[CH2:7][O:6][C@H:5]1/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCCCCCC/C=C\[C@@H]1OC[C@H](C)[C@H](OC)[C@H]1O
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCCCCC/C=C\[C@@H]1OC[C@H](C)[C@H](OC)[C@H]1OC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
A mixture of (2S,3R,4S,5S)-4-methoxy-5-methyl-2-[(Z)-1-nonenyl]tetrahydro-2H-pyran-3-ol (9.0 mg), N-(tert-butoxycarbonyl)glycine (17.5 mg), 4-dimethylamino pyridine (12.0 mg), and dicyclohexylcarbodiimide (21.0 mg) in dry dichloro-methane (0.5 ml) was stirred for 3 hours at room temperature. To the reaction mixture water was added, and the mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification of the residue by preparative thin layer chromatography gave (2S,3R,4S,5S)-4-methoxy-5-methyl-2-[(Z)-1-nonenyl]tetrahydro-2H-pyran-3-yl N-(tert-butoxycarbonyl)glycinate (12.8 mg, y. 91%); EI-MS: m/z 427 (M+)
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].CC#N.[F:13][C:14]([F:32])([F:31])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][NH:22][C:23]([CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24].[OH-].[Na+]>O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:28]2[CH2:29][CH2:30][CH:25]([C:23]([NH:22][CH2:21][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]([F:13])([F:31])[F:32])=[O:24])[CH2:26][CH2:27]2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O=C(NCc1ccccc1C(F)(F)F)C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: O=C(NCc1ccccc1C(F)(F)F)C1CCN(c2nc(Cl)nc(Cl)n2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of cyanuric chloride (1.00 g, 5.42 mmol, 1.00 equiv) in 1:1 CH3CN:H2O (9.0 mL) at 0° C. was added N-{[2-(trifluoromethyl)phenyl]methyl}-4-piperidinecarboxamide (1.55 g, 5.42 mmol, 1.00 equiv). This mixture was treated with 1 N NaOH to maintain a pH of 9-10, and the resulting suspension was stirred for 10 min at 0° C. This material was used in the next step without workup or purification. MS (ES+): m/e 433.8 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[N:19]=[CH:18][N:17]=[C:16]([NH:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:15]=1)[CH2:9][CH2:8]2)(=[O:4])=[O:3].C(N(CC)CC)C.Cl[C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]>C(Cl)Cl>[CH:38]([O:37][C:35]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:16]2[CH:15]=[C:14]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=4)[CH2:8][CH2:9]3)[N:19]=[CH:18][N:17]=2)[CH2:22][CH2:23]1)=[O:36])([CH3:40])[CH3:39]
Reactant: CC(C)OC(=O)Cl
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(NC2CCNCC2)ncn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(Nc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6c (104 mg, 0.21 mmol) and triethylamine (0.1 mL, 3.3 eq) in 1 mL of DCM, was added isopropyl chloroformate (0.24 mL, 1.1 eq). The mixture was stirred at room temperature for 2 h. The crude mixture was poured onto silica and eluted with ethyl acetate/hexane then chromatographed over a silica gel column (elution with 25-100% ethyl acetate and 0.1% TEA in hexanes) and finally purified on preparative HPLC to give 6-1, LC-MS 460.4 (MH+), tR=4.50 (Method 4). EC50: 611 nM.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([C@@H:17]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:14][C:15]=2Cl)=[CH:7][CH:6]=1.COC(NC1C=CC(B(O)O)=CC=1)=O.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[CH3:1][O:2][C:3](=[O:33])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([C@@H:17]([NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:14][CH:15]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)Nc1ccc(-c2nc([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)[nH]c2Cl)cc1
Agent: COC(=O)Nc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Nc1ccc(-c2c[nH]c([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)n2)cc1
Temperature: 80 °C

Procedure:
{4-[2-((S)-1-tert-butoxycarbonylamino-2-phenyl-ethyl)-5-chloro-1H-imidazol-4-yl]-phenyl}-carbamic acid methyl ester: To 92E (4.5 g, 12.2 mmol) were added 4-(methoxycarbonylamino)-phenyl boronic acid (2.97 g, 15.0 mmol), and potassium carbonate (5 g, 36 mmol). To this mixture was added 4:1 DME/water (100 mL) that had been degassed with N2. Tetrakis[(triphenyl)phosphine]palladium (0.7 g, 0.61 mmol) was added and the reaction was heated at 80° C. for 24 h. The reaction was cooled and solvents removed in vacuo. The residue was partitioned with ethyl acetate/water and the layers separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration afforded {4-[2-((S)-1-tert-butoxycarbonylamino-2-phenyl-ethyl)-1H-imidazol-4-yl]-phenyl}-carbamic acid methyl ester as a yellow foam (8.1 g). LCMS m/z 437.02 (M+H)+. To this intermediate (5.3 g, 12.2 mmol) in acetonitrile (60 mL) was added N-chlorosuccinimide (1.8 g, 13.4 mmol), and the reaction was heated to 55° C. for 24 h. The solvent was removed in vacuo, the residue was partitioned with ethyl acetate/saturated aqueous sodium carbonate, and the layers separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine and dried (MgSO4). Purification by silica gel chromatography (hexane/ethyl acetate) afforded 92F (1.92 g, 33.6% over 2 steps) as a yellow foam. LCMS m/z 471.3 (M+H)+. 1HNMR (400 MHz, CDCl3) δ: 1.39 (s, 9 H), 3.30 (d, J=7.07 Hz, 2 H) 3.79 (s, 3 H), 4.85 (d, J=7.58 Hz, 1 H), 5.20 (d, J=7.58 Hz, 1 H), 6.68 (s, 1 H), 7.14-7.32 (m, 4 H), 7.38-7.56 (m, 5 H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[C:46]([F:47])=[CH:45][CH:44]=[C:43]([F:48])[C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[C:43]([F:48])=[CH:44][CH:45]=[C:46]([F:47])[C:41]=2[F:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: OB(O)c1c(F)ccc(F)c1F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)ccc(F)c3F)sc2N)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,3,6-trifluorophenyl)boronic acid gave 260. 1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 7.85 (s, 1H), 7.65-7.52 (m, 3H), 7.39-7.27 (m, 1H), 5.03-4.83 (m, 2H), 4.16-3.90 (m, 2H), 3.73 (s, 3H), 3.39 (dd, J=7.1, 4.6 Hz, 1H), 2.18 (ddd, J=15.1, 6.7, 3.5 Hz, 1H), 1.87 (dt, J=14.1, 10.3 Hz, 1H), 1.69 (dtd, J=18.1, 13.8, 11.5, 7.4 Hz, 2H). LCMS (ES+) m/z 485 (M+1).
Reaction SMILES: C([N:8]1[CH2:15][CH2:14][C:11]2([CH2:13][CH2:12]2)[C@H:10]([OH:16])[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH2:12]1[C:11]2([CH2:14][CH2:15][NH:8][CH2:9][C@H:10]2[OH:16])[CH2:13]1
Reactant: O[C@@H]1CN(Cc2ccccc2)CCC12CC2
Agent: [Pd]
Solvent: CO
Product: O[C@@H]1CNCCC12CC2

Procedure:
100 mg (S)-6-benzyl-6-aza-spiro[2.5]octan-4-ol were dissolved in 1 ml methanol and hydrogenated over palladium on barium sulfate. After de-benzylation (IPC by GC), the catalyst was filtered and the filtrate was concentrated under reduced pressure to provide the title compound. The hydrochloride salt of the title compound can be obtained by treating the aminoalcohol with HCl in ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[C:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])[NH2:23].C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:28]2[CH:29]=[CH:30][C:25]([C:22](=[O:24])[NH2:23])=[CH:26][CH:27]=2)=[CH:8][CH:7]=1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)OC(C)(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: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C(N)=O)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
(S)-3-(4-Bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester and 4-carbamoylphenyl boronic acid (2 eq.) were coupled in 7:2 toluene-H2O with Na2CO3 (3 eq.) and Pd(PPh3)4 (0.1 eq.). After heating for 4 hours at 80° C., the reaction mixture was purified by flash chromatography to provide (S)-2-tert-butoxycarbonylamino-3-(4′-carbamoyl-biphenyl-4-yl)-propionic acid methyl ester. The product was deprotected according to General Procedure C to provide an amine-HCl salt, which was coupled with (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester according to General Procedure L. The product was deprotected according to General Procedure C to provide an amine-HCl salt, which was treated with excess NEt3 in DCM to produce a free amine. The free amine was coupled with 2,5-dimethyloxazole-4-carboxylic acid (2 eq.) in dry DCM with HBTU (2.2 eq.) and NEt3 (3 eq.). After reacting for 2 hours at room temperature, the reaction mixture was purified by flash chromatography to provide the product, which was hydrolyzed acording to general procedure B to give the title compound (11 mg). LCMS (m/z) 876.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[C:12]1([CH:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1CCCC1>CO>[Br:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][CH:7]=1)[O:11][C:21]1([CH2:20][CH2:19][CH:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:23][CH2:22]1)[CH2:1][C:2]2=[O:3]
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: C1CCNC1
Solvent: CO
Product: O=C1CC2(CCC(c3ccccc3)CC2)Oc2ccc(Br)cc21
Yield: 65.2 %

Procedure:
In a 50 mL round bottom flask was placed 5-bromo-2-hydroxyacetophenone (1 g, 4.65 mmol) and 4-phenylcyclo-hexanone (810 mg, 4.65 mmol). They were dissolved in MeOH (9.3 mL). To this solution was added pyrrolidine (764 μL, 9.30 mmol) dropwise. To the flask was attached a condenser and the reaction mixture was heated at reflux overnight (˜14 hours). The next morning the volatiles were remove under reduced pressure and the crude material was purified by flash chromatography (ISCO, 40 g SiO2 cartridge, Ethyl Acetate/Hexanes as the eluents). The corresponding fractions were combined and concentrated yielding 6-bromo-4′-phenylspiro[chroman-2,1′-cyclohexan]-4-one (1.12 g, 3.03 mmol, 65%).
Reaction SMILES: [C:1]1([C:7]2([CH2:13][NH:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[O:16])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[C:31]([N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:13][NH:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])[CH2:12][CH2:11]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1ccccc1C(=O)NCC1(c2ccccc2)CCNCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccccc1C(=O)NCC1(c2ccccc2)CCN(C(=O)c2ccccc2)CC1

Procedure:
A solution of 0.083 g (0.255 mmol) of 4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)piperidine (Example 2), 0.083 mL (1 mmol) of pyridine and 0.12 mL (1 mmol) of benzoyl chloride in 2 mL of methylene chloride was mixed for 18 hr. The reaction was diluted with methylene chloride and washed with saturated NaHCO3. The organic fraction was dried over MgSO4 and the filtrate was concentrated. The residue was purified by chromatography (silica, ethyl acetate) to give the title compound.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[CH3:14][CH2:15][CH2:16]I.O>CS(C)=O>[NH2:3][CH2:4][CH2:5][CH2:6][N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCI
Reactant: NCCCNc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCN(CCCN)c1ccccn1
Reaction time: 8 h
Yield: 40.5 %

Procedure:
Sodium hydride (1.14 g) was dissolved in dimethylsulphoxide (DMSO) (20 ml) at 70°-75° C. The solution was cooled and 2-(3-aminopropylamino)pyridine (6.57 g) in DMSO (20 ml) was added at room temperature. N-Propyl iodide (8.13 g) in DMSO (10 ml) was added dropwise maintaining the temperature at 20°-25° C. After allowing the mixture to stand overnight, water (250 ml) was added and this mixture was extracted with ether. The ether extracts were washed with hydrochloric acid (2N) and the aqueous layers made alkaline to pH 10.5. The aqueous layer was extracted with ether and chloroform. The pH was adjusted to pH 14 and the aqueous layer was extracted again with ether. The final ether extract was dried (K2CO3O, and the ether was evaporated to give 2-[N-(3-aminopropyl)-N-propylamino]pyridine (3.4 g) as an oil which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:18][CH2:19]Br)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]>C(N(CC)CC)C.C(Cl)Cl.[OH-].[Na+]>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:18][CH2:19][N:5]2[CH2:6][CH2:7][CH:3]([CH2:2][OH:1])[CH2:4]2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: OCC1CCNC1
Reactant: COc1ccc(CCBr)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCN2CCC(CO)C2)cc1OC

Procedure:
3 g (0.03 mol) of 3-hydroxymethyl-pyrrolidine and 7.5 g of 2-(3,4-dimethoxy-phenyl)-ethylbromide are heated in 20 ml of triethylamine for 7 hours at 100° C. The excess triethylamine is then distilled off in vacuo and the residue obtained is dissolved in methylene chloride and 6 molar sodium hydroxide solution. The organic phase is separated off, dried over magnesium sulphate and concentrated by evaporation in vacuo. The residue obtained is then purified over 400 g of alumium oxide (neutral, activity II) with methylene chloride and with increasing amounts of ethanol (up to 1%). Yield: 5.4 g (67.8% of theory), Rf value: 0.41 (aluminium oxide, neutral, eluant: 5% ethanol in methylene chloride).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)[CH2:2]1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24][CH2:25][N:26]([CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=[CH:8][CH:7]=3)[CH2:27][CH2:28]2)=[CH:19][CH:18]=1
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Reactant: CCOC(=O)C1(c2ccc(Cl)cc2)CCNCC1
Solvent: CCO
Product: CCOC(=O)C1(c2ccc(Cl)cc2)CCN(CC(O)COc2cccc3ccccc23)CC1

Procedure:
To a solution of 5.0 parts of 1,2-epoxy-3-(1-naphthoxy)propane in 79 parts of ethanol is added 5.0 parts of 4-(p-chlorophenyl)-4-ethoxycarbonylpiperidine. The resulting mixture is then refluxed for 24 hours. The solvent is stripped from the reaction mixture under reduced pressure to afford 3-[4-(p-chlorophenyl)-4-ethoxycarbonylpiperidino]-1-(1-naphthoxy)-2-propanol. This material is dissolved in isopropanol and treated with a solution of hydrochloric acid in isopropanol. The resulting salt is separated by filtration and recrystallized from a mixture of isopropanol and ethyl ether to give 3-[4-(p-chlorophenyl)-4-ethoxycarbonylpiperidino]-1-(1-naphthoxy)-2-propanol hydrochloride. This compound exhibits a melting point of 196°-198° C. and is represented by the following structural formula ##STR8##
Reaction SMILES: CC([N:5]([C:9]([CH3:31])([CH3:30])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[C:25]3[C:26]([CH3:29])=[N:27][O:28][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:31][C:9]([C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[C:25]3[C:26]([CH3:29])=[N:27][O:28][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)=[O:11])([CH3:30])[NH2:5]
Reactant: Cc1noc2cccc(Oc3ccc(NC(=O)C(C)(C)N(C(=O)[O-])C(C)(C)C)cc3)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc2cccc(Oc3ccc(NC(=O)C(C)(C)N)cc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
1,1-dimethylethyl[1,1-dimethyl-2-({4-[(3-methyl-1,2-benzisoxazol-4-yl)oxy]phenyl}amino)-2-oxoethyl]carbamate (Intermediate 24, 34 mg) was dissolved in 4.0 ml of dichloromethane and then TFA (1.0 ml) was added. The reaction mixture was stirred at room temperature for 1 hour. After removal of the volatiles, the residue was charged on a SCX cartridge and eluted successively with dichloromethane, MeOH, NH3 (2.0 M solution in MeOH). Evaporation afforded 18 mg of the title compound.