Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29](O)=[O:30])[CH:20]([CH3:22])[CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:34](CC)CC)C.C(Cl)(=O)OCC.N>O1CCCC1>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]([NH2:34])=[O:30])[CH:20]([CH3:22])[CH3:21])=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: CC(C)N(CCCCOCC(=O)O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)N(CCCCOCC(N)=O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
1.50 g of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid was dissolved in 20 ml of anhydrous tetrahydrofuran and 0.500 ml of triethylamine was added and then 0.376 ml of ethyl chlorocarbonate was added while stirring under ice cooling. After stirring under ice cooling for 45 minutes, a solution of saturated ammonia in 20 ml of tetrahydrofuran was added, followed by stirring for one hour. After removing an ice bath and stirring at room temperature for 18 hours, almost all of the solvent was evaporated. The residue was combined with water and then extracted with ethyl acetate. The extract was washed in turn with an aqueous saturated sodium hydrogen carbonate solution, 1N sodium hydroxide solution and water and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was washed with diethyl ether and then dried under reduced pressure to obtain 1.19 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]2)[CH2:7][CH2:6]1.[CH:26]1([C:30](O)=[O:31])[CH2:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C@H:13]2[CH2:14][CH2:15][C@H:16]([NH:19][C:30]([CH:26]3[CH2:29][CH2:28][CH2:27]3)=[O:31])[CH2:17][CH2:18]2)[CH2:7][CH2:6]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(Oc3c(F)cc(F)cc3F)CC2)CC1
Reactant: O=C(O)C1CCC1
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(Oc3c(F)cc(F)cc3F)CC2)CC1)C1CCC1

Procedure:
According to the synthesis of example 19 the title compound was prepared from Trans(4-{2-[4-(2,4,6-trifluoro-phenoxy)-piperidin-1-yl]-ethyl}-cyclohexyl)-amine and Cyclobutanecarboxylic acid. Preparative HPLC on reversed phase eluting with acetonitrile/water yielded the title compound. MS (m/e): 439.0 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C@:5]([C:9]([N:11]2[CH2:16][C@@H:15]3[CH2:17][C@H:12]2[CH2:13][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:10])([CH2:7][CH3:8])[CH:4]=[CH:3]1.[H][H]>[Pd].CO>[NH2:1][C@@H:2]1[CH2:3][CH2:4][C@@:5]([C:9]([N:11]2[CH2:16][C@@H:15]3[CH2:17][C@H:12]2[CH2:13][N:14]3[C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[O:10])([CH2:7][CH3:8])[CH2:6]1
Reactant: [H][H]
Reactant: CC[C@]1(C(=O)N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)C=C[C@@H](N)C1
Agent: [Pd]
Solvent: CO
Product: CC[C@]1(C(=O)N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)CC[C@@H](N)C1

Procedure:
A mixture of tert-butyl (1S,4S)-5-{[(1R,4S)-4-amino-1-ethylcyclopent-2-en-1-yl]carbonyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (2.12 g, 6.32 mmol) and 5% palladium on carbon in methanol (35 ml) was stirred at room temperature under 48 psi of hydrogen for 21 hours. The reaction was filtered through celite and the filter cake washed with methanol. The filtrate and washings were concentrated under reduced pressure to give tert-butyl (1S,4S)-5-{[(1S,3R)-3-amino-1-ethylcyclopentyl]carbonyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as a brown oil/foam (2.46 g, theoretical yield 2.13 g) which was used without further purification in the next step.
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)[Cl:5].[CH:9]1[C:21]2[CH:20]([CH2:22][O:23][C:24]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[O:36][N:35]=[C:34]([C@@H:37]5[CH2:42][CH2:41][C@@H:40]([NH:43][O:44][CH2:45][C:46]6[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=6)[CH2:39][N:38]5[C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[N:33]=4)[CH2:28][CH2:27]3)=[O:25])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH:18]1[C:19]2[CH:20]([CH2:22][O:23][C:24]([N:26]3[CH2:27][CH2:28][CH:29]([C:32]4[O:36][N:35]=[C:34]([C@@H:37]5[CH2:42][CH2:41][C@@H:40]([N:43]([O:44][CH2:45][C:46]6[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=6)[C:4]([Cl:5])=[O:3])[CH2:39][N:38]5[C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[N:33]=4)[CH2:30][CH2:31]3)=[O:25])[C:21]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H](NOCc2ccccc2)CC[C@H]1c1noc(C2CCN(C(=O)OCC3c4ccccc4-c4ccccc43)CC2)n1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)C(=O)Cl)CC[C@H]1c1noc(C2CCN(C(=O)OCC3c4ccccc4-c4ccccc43)CC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
Diphosgene (144 mg, 0.727 mmol) was added to a solution of (2S,5R)-tert-butyl 2-(5-(1-(((9H-fluoren-9-yl)methoxy) carbonyl)piperidin-4-yl)-1,2,4-oxadiazol-3-yl)-5-(benzyloxyamino)piperidine-1-carboxylate (380 mg, 0.559 mmol) and TEA (113 mg, 1.118 mmol) in DCM (5.0 mL). The mixture was stirred at 0° C. for 1 h, then, DCM (20 mL) was added and the mixture was washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated to give (2S,5R)-tert-butyl 2-(5-(1-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidin-4-yl)-1,2,4-oxadiazol-3-yl)-5-(benzyloxy(chlorocarbonyl)amino)piperidine-1-carboxylate (400 mg), which was directly used in the next step. ESI-MS (EI+, m/z): 742 [M+H]+.
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:12]3[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[N:9]12[CH2:14][CH2:13][CH:12]([CH2:11][CH2:10]1)[C@@H:7]([O:6][C:5]1[CH:15]=[CH:16][C:2]([C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:17])[CH:23]=3)=[CH:3][CH:4]=1)[CH2:8]2
Reactant: Ic1ccc(OC2CN3CCC2CC3)cc1
Reactant: Nc1cccc(B(O)O)c1
Product: Nc1cccc(-c2ccc(O[C@H]3CN4CCC3CC4)cc2)c1

Procedure:
The product of Example 1A (165 mg, 0.5 mmol) was treated with 3-amino-phenylboronic acid (Lancaster, 137 mg, 1 mmol) according to the procedure of Example 1B. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:2, Rf. 0.25) as an oil (38 mg, yield, 26%). 1H NMR (MeOH-d4, 300 MHz) δ 1.40-1.53 (m, 1H), 1.62-1.85 (m, 2H), 1.96-2.20 (m, 2H), 2.80-2.94 (m, 5H), 3.28-3.40 (m, 1H), 4.52-4.60 (m, 1H), 6.66 (ddd, J=7.8, 2.3, 1.0 Hz, 1H), 6.89 (ddd, J=7.3, 1.6, 1.0 Hz, 1H), 6.92-6.96 (m, 3H), 7.13 (t, J=7.8, Hz, 1H), 7.48 (dt, J=8.8, 2.1 Hz, 2H) ppm. MS (DCl/NH3) m/z 295 (M+H)+.
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(#N)C.[CH2:31]([O:33][C:34]([CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2([C:63]([O:65][CH2:66][CH3:67])=[O:64])[CH2:54][C:53]3[C:48](=[C:49]([O:61]C)[C:50]([O:59][CH3:60])=[C:51]([O:57][CH3:58])[C:52]=3[O:55]C)[CH2:47]2)=[CH:42][CH:41]=1)=[O:35])[CH3:32]>O>[CH2:31]([O:33][C:34]([CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2([C:63]([O:65][CH2:66][CH3:67])=[O:64])[CH2:54][C:53]3[C:52](=[O:55])[C:51]([O:57][CH3:58])=[C:50]([O:59][CH3:60])[C:49](=[O:61])[C:48]=3[CH2:47]2)=[CH:42][CH:41]=1)=[O:35])[CH3:32]
Reactant: CCOC(=O)CCCOc1ccc(C2(C(=O)OCC)Cc3c(c(OC)c(OC)c(OC)c3OC)C2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CCCOc1ccc(C2(C(=O)OCC)CC3=C(C2)C(=O)C(OC)=C(OC)C3=O)cc1
Reaction time: 0.25 h
Yield: 70.8 %

Procedure:
A water (1.0 ml) solution of CAN (795 mg, 1.45 mmols) was dropwise added to an acetonitrile (6.0 ml) solution of ethyl 2-[4-(4-ethoxycarbonyl-1-oxabutyl)phenyl]-4,5,6,7-tetramethoxy-2-indancarboxylate (300 mg, 0.581 mmols) with cooling with ice and stirring was continued for 15 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried. The solvent was evaporated in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=10:1 to 5:1) to obtain the entitled compound (200 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[C@@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[C@@:12]3([CH2:38]O)[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[F-:58].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[C@@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[C@@:12]3([CH2:38][F:58])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OC[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O[C@]1(CF)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a solution of the compound from Example 138, Step A (63 mg, 0.1 mmol) in anhydrous dichloromethane (5 mL) under argon, were added 4-dimethylaminopyridine (DMAP) (2 mg, 0.015 mmol) and triethylamine (62 μL, 0.45 mmol). The solution was cooled in an ice bath and p-toluenesulfonyl chloride (30 mg, 0.15 mmol) was added. The reaction was stirred at room temperature overnight, washed with NaHCO3 (2×10 mL), water (10 mL), brine (10 mL), dried over Na2SO4 and concentrated to a pink solid in vacuo. The solid was dissolved in anhydrous THF (5 mL) and cooled in an icebath. Tetrabutylammonium fluoride (1M solution in THF, 1 mL, 1 mmol) was added and the mixture stirred at room temperature for 4 h. The solvent was removed in vacuo, the residue taken up in dichloromethane, and washed with NaHCO3 (2×10 mL), water (10 mL) and brine (10 mL). The dichloromethane layer was dried over anhydrous Na2SO4, concentrated in vacuo, and purified by flash chromatography (SiO2, 2:1 hexanes/EtOAc) to afford the title compound (20 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([OH:10])[C:5]([OH:11])=[CH:4][CH:3]=1.Br[CH2:13]Br.[F-].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:13][O:10][C:6]=2[C:7]=1[CH:8]=[O:9]
Reactant: BrCBr
Reactant: O=Cc1c(Br)ccc(O)c1O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1c(Br)ccc2c1OCO2
Temperature: 100 °C
Yield: 31.2 %

Procedure:
6-Bromo-2,3-dihydroxybenzaldehyde (1.82 g, 8.39 mmol) was dissolved in DMF (20 mL) and dibromomethane (1.57 g, 9.00 mmol) and potassium fluoride (2.44 g, 42.00 mmol) were added. The reaction mixture was heated to 100° C. for 2 h at which time TLC analysis indicated the reaction complete. The reaction mixture was cooled to ambient temperature and partitioned between water and methylene chloride. The organic layers were washed 4× with water, dried with magnesium sulfate, and concentrated by rotary evaporation to afford 0.60 g of product (2.62 mmol, 31% yield) as an oil. 1H NMR (CDCl3) δ 10.24 (s, 1H), 7.09 (d, J=8.3 Hz, 1H), 6.79 (d, J=8.3 Hz, 1H), 6.10 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13].C(OC(=O)C)(=O)C>C(O)(=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH2:13][CH2:12][C:11]([OH:15])=[O:14])[NH:8]2)=[CH:4][CH:3]=1
Reactant: C=CC(=O)O
Reactant: Fc1ccc2cc[nH]c2c1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)CCc1cc2ccc(F)cc2[nH]1
Temperature: 20 °C
Yield: 52.2 %

Procedure:
The solution of 6-fluoroindol (300 mg, 2.22 mmol), acrylic acid (352 mg, 4.88 mmol) and acetic anhydride (453 mg, 4.44 mmol) in acetic acid (1.1 mL) was heated at 90° C. for 15 h. The reaction mixture was cooled to 20° C. then concentrated in vacuo. The residue was dissolved in 3N NaOH. The solution was filtered to remove insoluble material and the filtrate was acidified with conc. HCl and extracted with CHCl3. The organic solution was dried over MgSO4, filtered and concentrated in vacuo to give 3-(6-fluoroindolyl)propionic acid (240 mg, 52%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[Li]CCCC.[N+:13]([C:16]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:17]=1[CH:18]=[O:19])([O-:15])=[O:14]>O1CCCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:16]([N+:13]([O-:15])=[O:14])=[C:17]([CH:18]([OH:19])[C:3]#[C:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH:20]=1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C#CC(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C#CC(O)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
To a solution of ethyl propiolate (4.05 mL, 40 mmol) in tetrahydrofuran (125 mL) at -78° C. under nitrogen was added n-BuLi (2.5 mL, 40 mmol, 1.6M in hexane). The reaction mixture was stirred at about -70° C. for 0.5 hours and then 2-nitro-5-chlorobenzaldehyde (6.75 g, 36.4 mmol) was added dropwise. The reaction mixture was stirred at -78° C. for 0.25 hours, warmed to -60° C., quenched with acetic acid (5 mL) and then warmed to room temperature. The reaction mixture was partitioned between ether (250 mL) and water (250 mL). The layers were separated and the organic layer was washed with brine (250 mL) and dried over Na2SO4. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography eluting with hexane/ethyl acetate (4:1) to afford 6.12 g (59%) of the title compound as a yellow oil which solidified on standing.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:12]([O:14][C:15](=[O:25])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:25])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[F:11])[CH:19]=1)[CH3:13]
Reactant: CCOC(=O)COc1cccc(N)c1
Reactant: O=C(O)c1cc(Br)ccc1F
Product: CCOC(=O)COc1cccc(NC(=O)c2cc(Br)ccc2F)c1

Procedure:
5-Bromo-2-fluoro-benzoic acid (250 mg, 1.14 mmol) was coupled to aniline (64)(245 mg, 1.25 mmol) using Method D. The residue was purified by column chromatography eluting with a stepped gradient of 10-15% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH3:1][NH:2][CH:3]([CH3:16])[CH2:4][CH2:5][CH:6]([N+:13]([O-:15])=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:17]=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:1][N:2]1[CH2:17][C:6]([N+:13]([O-:15])=[O:14])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH:3]1[CH3:16]
Reactant: C=O
Reactant: CNC(C)CCC(c1ccccc1)[N+](=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1CCC(c2ccccc2)([N+](=O)[O-])CN1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
To a suspension of 138 mg (0.621 mmol) Methyl-(1-methyl-4-nitro-4-phenyl-butyl)-amine in 2.2 ml dioxane under argon at room temperature, was added 49.8 ul (0.683 mmol) formaldehyde (37% in water). The mixture was stirred at room temperature for 30 minutes and then at 65° C. for 4.5 hours. The mixture was cooled to room temperature and diluted with ethyl acetate. Sodium sulfate was added. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified on silica (Eluent: heptane/ethyl acetate 0 to 20%) to provide 76 mg (52%) of the title compound as a colorless oil. MS (m/e): 235.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[O:15]1.C(Cl)Cl>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:27][C:24]1[CH:23]=[CH:22][C:21]([B:16]2[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:28])([CH3:13])[O:15]2)=[CH:26][CH:25]=1)(=[O:11])=[O:10]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)OB(c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared by adding 2,3-dichloro-benzenesulfonyl chloride (11.2 g) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenylamine (10.0 g) to a reaction vessel containing a magnetic stirring bar, followed by 200 ml dry DCM and 4.1 ml pyridine. The reaction mixture was stirred at RT for 20 h before being cooled on an ice-bath and quenched with 1M aqueous sodium hydroxide solution. The organic phase was separated and the aqueous phase acidified with 2M aqueous hydrochloric acid and extracted three times with EtOAc. The combined organic phases were washed with brine and dried over sodium sulfate and evaporated to afford the crude product. Purification by flash chromatography on silica gel using a mixture of EtOAc and heptane as the eluent afforded 2,3-dichloro-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzenesulfonamide as a colorless solid after evaporation of the solvents under reduced pressure. Yield: 15.11 g (77%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[OH-].[Na+].Cl>O1CCCC1.O>[CH2:5]([O:4][C:2](=[O:3])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: NCCc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)NCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.9 %

Procedure:
Add dropwise via an addition funnel a solution of ethyl chloroformate (0.74 mL, 7.7 mmol) in tetrahydrofuran (7 mL) to a stirred solution of tyramine (1.0 g, 7.3 mmol), sodium hydroxide (0.7 g, 17.1 mmol), and water (7 mL). Stir at room temperature for 18 hours then pour the reaction into 1N aqueous hydrochloric acid so the pH=1-2. Extract with ethyl acetate (3×25 mL). Dry the combined ethyl acetate extracts over sodium chloride/magnesium sulfate, filter, and concentrate on a rotary evaporator to yield 1.3 g, 6.2 mmol of [2-(4-hydroxy-phenyl)-ethyl]-carbamic acid ethyl ester: 1H NMR (CDCl3, 300.00 MHz): 7.01 (d, 2H); 6.78 (d, 2H); 6.26 (s, 1H); 4.78 (s, 1H); 4.14-4.09 (m, 2H); 3.40-3.38 (m, 2H); 2.74-2.69 (m, 2H); 1.24-1.19 (m, 3H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH2:17][CH2:18][CH3:19])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:14][CH2:13][CH2:12][C:11]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]([CH2:16][CH2:17][CH2:18][CH3:19])[CH:10]=2)[CH2:29][CH2:28]1
Reactant: CCCCc1cc(CCC=O)n(-c2ccccc2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccccc2)n1

Procedure:
196.6 mg (86%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-butyl-1H-pyrazol-5-yl)propanal (140 mg, 0.546 mmol), 1-(2-fluorophenyl)piperazine (130 mL, 0.819 mmol), and NaBH(OAc)3 (excess amount).
Reaction SMILES: [C:1]([N:4]1[CH2:10][C@H:9]([NH2:11])[C:8](=[O:12])[N:7]([CH:13]([CH3:15])[CH3:14])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)(=[O:3])[CH3:2].[CH3:20][CH:21]([C:25]([NH:27][CH2:28][C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])=[O:26])[C:22](O)=[O:23]>>[C:1]([N:4]1[CH2:10][C@H:9]([NH:11][C:22](=[O:23])[CH:21]([CH3:20])[C:25]([NH:27][CH2:28][C:29]([F:34])([F:35])[C:30]([F:31])([F:32])[F:33])=[O:26])[C:8](=[O:12])[N:7]([CH:13]([CH3:15])[CH3:14])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1C[C@H](N)C(=O)N(C(C)C)c2ccccc21
Reactant: CC(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Product: CC(=O)N1C[C@H](NC(=O)C(C)C(=O)NCC(F)(F)C(F)(F)F)C(=O)N(C(C)C)c2ccccc21

Procedure:
In an analogous manner to that described in Example 20 d) and 27, the condensation of (S)-5-acetyl-3-amino-1-isopropyl-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one and (2RS)-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid [see Example 25 b)] yielded the title compound as a white solid; MS: m/e=493 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[F:15][C:16]1[CH:17]=[C:18]([OH:28])[CH:19]=[C:20]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([O:28][CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]3)[CH:19]=[C:20]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:21]=1
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Reactant: Oc1cc(F)cc(C2CCOCC2)c1
Product: Cn1c(=O)ccc2cc(COc3cc(F)cc(C4CCOCC4)c3)ccc21
Yield: 46 %

Procedure:
Using a similar procedure to that described in Example 14, 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one was reacted with 4-(5-fluoro-3-hydroxyphenyl)-3,4,5,6-tetrahydro-2H-pyran to give 4-[5-fluoro-3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]-3,4,5,6-tetrahydro-2H-pyran in 46% yield, m.p. 126°-127° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14](=[NH:18])OCC)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:26]([NH:28][NH2:29])=[O:27]>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]([NH:29][NH:28][CH:26]=[O:27])=[NH:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: NNC=O
Reactant: CCOC(=N)c1ccc(-c2ccc(Cl)cc2)o1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: N=C(NNC=O)c1ccc(-c2ccc(Cl)cc2)o1
Reaction time: 0.25 h

Procedure:
To a mixture of 120 g (0.42 mole) of ethyl 5-(4-chlorophenyl)-2-furimidate hydrochloride in 700 ml of absolute ethanol was added dropwise 62 ml (0.46 mole) of triethylamine at a temperature of 2°-4° while under a nitrogen atmosphere. To this stirring mixture was added portionwise 28 g (0.47 mole) of formic acid hydrazide while maintaining the temperature at 4°-7° by means of an ice bath. The mixture was kept at 5°-7° for 15 minutes, allowed to warm to 23° over a 21/2 hour period, cooled to 10°, filtered, and washed in stirring S.D.A #32 to yield 52 g (47%). An analytical sample was prepared by drying a sample in a vacuum pistol with refluxing chloroform, m.p. 155°-157° (Mel-Temp).