Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][O:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][C:16]3=[O:27])=[CH:11][C:10]=2[F:28])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][C:45](Cl)=[O:46]>N1C=CC=CC=1>[CH3:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][C:45]([N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][O:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][C:16]3=[O:27])=[CH:11][C:10]=2[F:28])[CH2:8][CH2:7]1)=[O:46]
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCNCC2)c(F)c1
Reactant: COCCOCCOCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COCCOCCOCC(=O)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Reaction time: 18 h
Yield: 19.8 %

Procedure:
To a solution of 3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)-oxazolidin-2-one dihydrochloride (399 mg, 0.92 mmol) in pyridine (10 ml) was added triethylamine (0.31 ml, 2.2 mmol) and 2-(2-(2-methoxyethoxy)ethoxy)acetyl chloride (197 mg, 1 mmol). The mixture was stirred for 18 hours, evaporated to dryness, the residue dissolved in dichloromethane, and purified by chromatography on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 10% MeOH in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (95 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[C:12]([C:17]#[N:18])=[CH:13][CH:14]=[CH:15][CH:16]=1.O.O.[Sn](Cl)Cl>C(O)C.O1CCCC1>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:11]2[C:12]([C:17]#[N:18])=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:4]=1
Reactant: N#Cc1ccccc1-c1cc([N+](=O)[O-])ccc1F
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: N#Cc1ccccc1-c1cc(N)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.4 %

Procedure:
A cooled (0° C.) suspension of 2′-fluoro-5′-nitrobiphenyl-2-carbonitrile (24.2 g, 100 mmol) in ethanol (150 ml) and tetrahydrofuran (150 ml) was treated with tin(II) chloride dihydrate (67.7 g, 300 mmol) and the mixture was stirred to ambient temperature over 12 h. The solvent was removed in vacuo and the residue treated with ice-cold 2N sodium hydroxide (750 ml). The resulting slurry was stirred for 60 min then extracted with dichloromethane (2×400 ml). The organics were combined, washed with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give a red solid. Crystallisation from toluene gave 5′-amino-2′-fluorobiphenyl-2-carbonitrile as a cream-coloured solid (16 g, 75%): δH (400 MHz, CDCl3) 3.65 (2H, br), 6.67-6.73 (2H, m), 7.00 (1H, t, J 9), 7.44-7.49 (2H, m), 7.64 (1H, td, J 9 and 2), 7.75 (1H, dd, J 8 and 2); m/z (ES+) 213 (M++H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.Cl.[F:13][C:14]([F:48])([F:47])[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[N:18]=[C:17]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([C:37]3[CH:38]=[C:39]([S:43](Cl)(=[O:45])=[O:44])[CH:40]=[CH:41][CH:42]=3)[CH:32]=2)[N:16]=1>C1COCC1>[OH:2][CH2:1][CH2:3][NH:4][S:43]([C:39]1[CH:40]=[CH:41][CH:42]=[C:37]([C:33]2[CH:32]=[C:31]([C:17]3[N:16]=[C:15]([C:14]([F:13])([F:47])[F:48])[CH:20]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=4)[N:18]=3)[CH:36]=[CH:35][N:34]=2)[CH:38]=1)(=[O:44])=[O:45]
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Reactant: NCCO
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCO)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 0 °C
Yield: 76.2 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of ethanolamine (0.066 g, 1.08 mmol), triethylamine (0.11 ml, 0.76 mmol) and THF (2 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.21 g, 0.36 mmol) in THF (3 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/hexane) and crystallization (diethyl ether/hexane) yielded the title compound as a white solid (0.156 g, 76%). MS (ISP) 569.2 [(M+H)+]; mp 192.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[C:5]([CH3:22])[CH:4]=1)#N.[OH-:23].[Na+].[OH2:25]>CCO>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]([OH:25])=[O:23])=[CH:4][C:5]=2[CH3:22])[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1cc(C#N)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(=O)O)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Reaction time: 10 h
Yield: 92 %

Procedure:
To a suspension of tert-butyl 4-(4-cyano-2-methylphenyl)piperazine-1-carboxylate 293 (3.685 g, 12.23 mmol) in EtOH (Ratio: 1.000, 50 mL) and water (Ratio: 1.000, 10 mL) was added sodium hydroxide solution (8.48 mL, 162 mmol) at 23° C. The NaOH solution was rinsed forward with water (ratio: 1.000, 2.5 mL) The reaction was stirred at 90° C. for 10 hr. The reaction mixture was cooled to 23° C., neutralized with 3N HCl (52 mL), filtered, rinsed with H2O (3×10 mL), and the resulting solid was dried in vacuo to provide the title compound as an off-white solid (3.588 g, 11.20 mmol, 92% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (s, 9H) 2.29 (s, 3H) 2.81-2.90 (m, 4H) 3.42-3.53 (m, 4H) 7.05 (d, J=8.08 Hz, 1H) 7.70-7.77 (m, 2H) 12.61 (br. s., 1H). ESI-MS: m/z 321.2 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:7]1[C:15]2[CH2:14][S:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[C:23]([O:27][C:28](N=[N+]=[N-])=[O:29])([CH3:26])([CH3:25])[CH3:24]>O.O1CCOCC1>[C:23]([O:27][C:28]([C:3]([NH2:2])([C:7]1[C:15]2[CH2:14][S:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: NC(C(=O)O)c1cccc2c1CSC2
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C(N)(C(=O)O)c1cccc2c1CSC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
α-Amino(1,3-dihydrobenzo[c]thien-4-yl)acetic acid hydrochloride (0.01 m) is dissolved in a mixture of equal parts of water and dioxane. Triethylamine (0.01 m) and tert-butoxycarbonylazide (0.01 m) are added to the mixture which is stirred for 18 hours at room temperature. The dioxane is evaporated from the mixture, ethyl acetate is added and the pH of the aqueous phase is adjusted to about 2.5 with the addition of 1 N hydrochloric acid. The phases are separated and the aqueous phase is extracted a second time with additional ethyl acetate. The ethyl acetate is separated from the aqueous phase. These extracts are combined and dried over magnesium sulfate. Evaporation of the ethyl acetate gives α-(tert-butoxycarbonyl)amino(1,3-dihydrobenzo[c]thien-4-yl)acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:13])=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:28].[K+]>CC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:24]=[CH:23][C:22]([C:25]([OH:28])=[O:26])=[CH:21][C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=Cc1ccc(OCc2ccc(F)cc2)c(C(=O)Nc2cccnc2)c1
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccc(OCc2ccc(F)cc2)c(C(=O)Nc2cccnc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-formyl-N-3-pyridinylbenzamide (may be prepared as described in Example 82; 100 mg, 0.29 mmol) in acetone (10 ml) was added potassium permanganate (67.7 mg, 0.43 mmol) as a solution in 10 ml of water. The mixture was stirred at room temperature overnight. The mixture was quenched by adding 10 ml of 5% sodium sulfite solution. The solution was filtered through celite and mixed with 1 ml of acetic acid. The mixture was evaporated to a third volume, water (20 ml) was added and the mixture was filtered to yield the title compound as a white solid. This contains about 10% starting material and was used directly without further purification. 63 mg.
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]3[CH2:29][C:28](=[O:30])[O:27][CH:26]3[O:31]CC3C=CC=CC=3)=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:39])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CO>[C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]([CH:26]=[O:31])[CH2:29][C:28]([OH:30])=[O:27])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:39])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(NC(=O)C2CCCN3C(=O)CCC(NC(=O)c4ccccc4)C(=O)N23)C(OCc2ccccc2)O1
Agent: [Pd]
Solvent: CO
Product: O=CC(CC(=O)O)NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12
Reaction time: 6.3 h
Yield: 87.8 %

Procedure:
A mixture of 213e (2.29 g, 4.28 mmol), 10% palladium on carbon (1.8 g) and MeOH (160 ml) was stirred under H2 at atmospheric pressure for 6.3 h. After filtering and concentrating the hydrogenation was repeated with fresh catalyst (1.8 g) for 5 h. After filtering and concentrating the residue was triturated with diethyl ether, filtered and washed well with ether to give 214e as a white solid (1.67 g, 88%): mp 143-147° C.; [αa]D23 −125° (c 0.2, CH3OH). IR (KBr) 3391, 1657, 1651, 1538, 1421, 1280, 1258; 1H NMR (CD3OD) δ7.90 (2H, m), 7.63-7.46 (3H, m), 5.25 (1H, m), 5.08-4.85 (1H, m), 4.68-4.53 (2H, m), 4.33-4.24 (1H, m), 3.62-3.44, 3.22-3.11, 2.75-2.21, 2.15-1.92, 1.73-1.66 (11H, 5m). Anal. Calcd for C21H24N4O7H2O: C, 54.54; H, 5.67; N, 12.11. Found C, 54.48; H, 5.63; N, 11.92.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16].[CH2:19]=[C:20]1[O:24][C:22](=[O:23])[CH2:21]1>CO>[C:22]([NH:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])(=[O:23])[CH2:21][C:20]([CH3:19])=[O:24]
Reactant: C=C(C)C(=O)NCCCN
Reactant: C=C1CC(=O)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C=C(C)C(=O)NCCCNC(=O)CC(C)=O
Temperature: 0 °C
Reaction time: 20 h
Yield: 50 %

Procedure:
Triethylamine (24 g, 0.24 mole) was added dropwise at 0° C. to a solution of N-(3-aminopropyl)methacrylamide hydrochloride (40 g, 0.24 mole) and diketene (20 g, 0.24 mole) in methanol (800 ml). After addition, the temperature was maintained at 0° C. for 2 hours under stirring. Stirring was continued at 20° C. for 20 hours. The solvent was then removed. The residue was dissolved in chloroform (1 liter), washed with 5% hydrochloric acid (200 ml), washed with saturated NaHCO3 (200 ml), dried over anhydrous magnesium sulfate, and filtered. Excess solvent was removed. The residue was recrystallized from benzene (500 ml) and ethyl ether (500 ml) to give N-(3-acetoacetamidopropyl)methacrylamide (m.p.=93°-94° C.) at a yield of 50%.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][C:20]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:30]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)[CH3:31].[BH3-]C#N.[Na+].[OH-].[Na+]>CC(O)=O.CO.ClCCl>[CH2:30]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36][N:27]2[CH2:28][CH2:29][CH:24]([CH2:23][NH:22][C:20](=[O:21])[CH2:19][NH:18][C:16]([O:15][CH2:14][CH:12]3[C:13]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)=[O:17])[CH2:25][CH2:26]2)=[CH:34][CH:33]=1)[CH3:31]
Reactant: CCc1ccc(C=O)cc1
Reactant: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)NCC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CCc1ccc(CN2CCC(CNC(=O)CNC(=O)OCC3c4ccccc4-c4ccccc43)CC2)cc1
Temperature: 60 °C
Reaction time: 13 h
Yield: 62.1 %

Procedure:
To A solution of 4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]piperidine (1.00 g, 2.33 mmol) in 2.5% AcOH/CH3OH (80 mL) were added 4-ethylbenzaldehyde (1.09 g, 8.16 mmol) and NaBH3CN (6.59 g, 10.5 mmol). The reaction mixture was stirred at 60° C. for 13 h. After the mixture was cooled to room temperature, 1 N aqueous NaOH solution (50 mL) and dichloromethane (50 mL) were added. The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (SiO2, CH3OH/AcOEt 2:8) afforded 1-(4-ethylbenzyl)-4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]piperidine (740 mg, 62%).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[Cl-].[Li+].CS([Cl:34])(=O)=O.Cl>ClCCl.C(N(CC)CC)C>[Cl:34][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(Nc1ccc(CO)cc1)C1=Cc2cc(-c3ccccc3)ccc2CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(CCl)cc1)C1=Cc2cc(-c3ccccc3)ccc2CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of N-[4-(hydroxymethyl)phenyl]-7-phenyl-3,4-dihydronaphthalene-2-carboxamide (566 mg), lithium chloride (135 mg), triethylamine (446 μl) and dichloromethane (50 ml) was added methanesulfonyl chloride (172 μl), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added dilute hydrochloric acid. The organic layer was separated, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give N-[4-(chloromethyl)phenyl]-7-phenyl-3,4-dihydronaphthalene-2-carboxamide (494 mg) as colorless crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[OH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20](O)[C:16]=1[C:17]([O-:19])=[O:18].[C:25]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[C:9]([O:8][C:7]([NH:6][CH2:5][CH2:4][CH2:3][CH2:2][O:1][C:20]1[CH:21]=[CH:22][CH:23]=[C:15]([OH:14])[C:16]=1[C:17]([O:19][CH3:25])=[O:18])=[O:13])([CH3:10])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCCCCO
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C([O-])c1c(O)cccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)OC(C)(C)C

Procedure:
To a round bottom flask was charged with tert-butyl 4-hydroxybutylcarbamate (400 mg, 2.1 mmol), 463 mg of 2,6-dihydroxybenzoate (463 mg, 2.7 mmol), and triphenylphosphine (777 mg, 3.0 mmol). The flask was vacuumed and back flushed with nitrogen (3×), capped with a rubber septum, and kept under positive nitrogen atmosphere. THF (anhydrous) was then added, followed by dropwise addition of DEAD (433 μL, 2.7 mmol). Most of the starting material was consumed within the first 30 min. Solvent was then removed in vacuo, and the residue was purified on a silica gel chromatography eluting with 15-30% EtOAc in hexane to give the ether product (410 mg, 57%) as a cloroless oil.
Reaction SMILES: [F-].[Cs+].CN1CCCC1=O.Cl.[F:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:32]=[CH:31][C:21]([C:22]([NH:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[O:23])=[CH:20][N:19]=2)[CH:15]=[CH:16][CH:17]=1.Cl[C:34]1[N:39]=[CH:38][C:37]([C:40]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[O:41])=[CH:36][CH:35]=1>O>[F:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:32]=[CH:31][C:21]([C:22]([NH:24][CH:25]3[CH2:26][CH2:27][N:28]([C:34]4[CH:35]=[CH:36][C:37]([C:40]([N:42]5[CH2:43][CH2:44][O:45][CH2:46][CH2:47]5)=[O:41])=[CH:38][N:39]=4)[CH2:29][CH2:30]3)=[O:23])=[CH:20][N:19]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(c1ccc(Cl)nc1)N1CCOCC1
Reactant: O=C(NC1CCNCC1)c1ccc(-c2cccc(F)c2)nc1
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(NC1CCN(c2ccc(C(=O)N3CCOCC3)cn2)CC1)c1ccc(-c2cccc(F)c2)nc1
Temperature: 96 °C
Yield: 15.3 %

Procedure:
To a vial containing CsF (684 mg, 4.50 mmol) and 1-methyl-2-pyrrolidinone (NMP, 2 mL) was added 6-(3-fluorophenyl)-N-(piperidin-4-yl)nicotinamide hydrochloride (247 mg) and (6-chloropyridin-3-yl)(morpholino)methanone (170 mg, 0.750 mmol). The reaction mixture was heated to 96° C. for 24 hrs. After allowing the reaction to cool to room temperature the reaction was diluted with H2O (3 mL) and the mixture extracted with ethyl acetate (3×10 mL). The organics were combined, dried (MgSO4) and the solvent removed to give an oil, which after chromatography (silica, 5% MeOH: DCM) gave 6-(3-fluorophenyl)-N-{1-[5-(morpholin-4-ylcarbonyl)pyridin-2-yl]piperidin-4-yl}nicotinamide (55 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.09 (1H, s), 8.53 (1H, d, J=7.7 Hz), 8.30 (1H, dd, J=8.4, 1.6 Hz), 8.23 (2 H, d, J=11.9 Hz), 8.15 (1H, d, J=8.4 Hz), 8.02 (1H, d, J=7.9 Hz), 7.98 (1H, br. s.), 7.53-7.61 (1H, m), 7.26-7.37 (1H, m), 5.02 (1H, br. s.), 4.45 (1H, br. s.), 4.24 (1H, br. s.), 3.86 (1H, br. s.) 3.73 (1H, br. s.), 3.30 (3H, br. s.), 1.87-2.05 (5H, m), 1.61 (2H, br. s.), 0.75 (3H, t, J=7.3 Hz)
Reaction SMILES: [CH2:1]1[CH:11]2[N:5]([C:6]3[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=3[S:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=32)[CH2:4][CH2:3][NH:2]1.[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[CH2:22]>C(O)C>[CH2:25]([O:24][C:20](=[O:23])[CH2:21][CH2:22][N:2]1[CH2:3][CH2:4][N:5]2[C:6]3[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=3[S:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]2[CH2:1]1)[CH3:26]
Reactant: c1ccc2c(c1)Sc1ccccc1N1CCNCC21
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)CCN1CCN2c3ccccc3Sc3ccccc3C2C1
Reaction time: 24 h

Procedure:
A mixture of 1,3,4,14b-tetrahydro-2H-dibenzo[b,f]pyrazino[1,2-d][1,4]thiazepine (1.5 g, 5.6 mmol), ethyl acrylate (0.61 g, 6.1 mmol) and ethanol (40 ml) was heated at reflux temperature for 5 minutes and then left to stand for 24 h at room temperature, affording crude 3-(1,3,4,14b-tetrahydro-2H-dibenzo[b,f]pyrazino[1,2-d][1,4]thiazepin-2-yl)propionic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([NH2:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH2:15][CH3:16])[CH:14]=1)[NH:11][N:10]=[CH:9]2.[C:19](C1NC=CN=1)(C1NC=CN=1)=[O:20].[NH:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[NH:39][C:38]2=[O:47])[CH2:33][CH2:32]1>O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[CH:4]([NH:17][C:19]([N:31]1[CH2:32][CH2:33][CH:34]([N:37]2[CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[NH:39][C:38]2=[O:47])[CH2:35][CH2:36]1)=[O:20])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH2:15][CH3:16])[CH:14]=1)[NH:11][N:10]=[CH:9]2
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: CCc1cc(CC(N)C(=O)OC)cc2cn[nH]c12
Solvent: C1CCOC1
Product: CCc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)OC)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of (±)-2-amino-3-(7-ethyl-1H-indazol-5-yl)-propionic acid methyl ester (100 mg, 0.41 mmol) in tetrahydrofuran (2 mL) at 0° C. was treated with carbonyl diimidazole (66 mg, 1 equiv). The reaction was stirred for 5 min, warmed to room temperature, stirred for 15 min, and then treated with 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (103 mg, 1.1 equiv). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by column chromatography to give 188 mg (92%) as a white solid. 1H-NMR (CDCl3, 500 MHz) δ 1.36 (t, J=7.6, 3H), 1.69 (m, 4H), 2.86 (m, 2H), 2.90 (q, J=7.6, 2H), 3.22 (dd, J=5.5, 4.9, 2H), 3.75 (s, 3H), 4.03 (dd, J=44.0, 13.7, 2H), 4.26 (s, 2H), 4.51 (m, 1H), 4.84 (m, 1H), 5.02 (m, 1H), 6.70 (d, J=7.9, 1H), 6.90-7.05 (m, 4H), 7.16 (dd, J=7.6, 7.6, 1H), 7.34 (s, 1H), 8.03 (s, 1H). Mass spec.: 505.29 (MH)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][C:19]([C:21]([OH:23])=O)=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[O:49]=[C:48]([N:50]1[CH2:51][CH2:52][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:54][CH2:55]1)[CH2:47][NH:46][C:21]([C:19]1[NH:20][C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:17][CH:18]=1)=[O:23]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(-c2ccccc2)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 72 %

Procedure:
DIPEA (102 mg, 0.14 mL, 0.79 mmol) was added to a stirred solution of 5-phenyl-1H-pyrrole-2-carboxylic acid (37 mg, 0.19 mmol) in DMF (4 mL). HOBT (30 mg, 0.22 mmol) and EDCI (57 mg, 0.29 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (prepared by the method as described above) (83.6 mg, 0.23 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated to afford 69 mg (72% yield) of 5-phenyl-1H-pyrrole-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 89.78%. 1H NMR (DMSO-d6): δ 11.7 (s, 1H), 8.2-8.1 (bs, 1H), 7.9-7.7 (s, 4H), 7.7-7.6 (s, 1H), 7.6-7.5 (s, 1H), 7.45-7.3 (t, 2H), 7.3-7.2 (t, 1H), 6.9-6.8 (s, 1H), 6.6-6.5 (s, 1H), 4.28-4.04 (d, 2H), 3.84-3.5 (bs, 4H), 3.5-3.4 (s, 2H), 3.2-3.0 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[N:5][C:6]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:7][C:8]=1[CH:9]([OH:11])[CH3:10].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:4]=[N:5][C:6]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:7][C:8]=1[C:9](=[O:11])[CH3:10]
Reactant: COc1nnc(-c2ccncc2)cc1C(C)O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1nnc(-c2ccncc2)cc1C(C)=O
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of 0.91 g 1-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-ethanol in 10 ml CH2Cl2 is added a suspension of 1.70 g Dess-Martin Periodinane in 10 ml CH2Cl2 at room temperature. After being stirred for 3 h, the suspension is extracted with 5% aq. Na2S2O3 solution. The organic layer is washed with water, dried over MgSO4 and concentrated in vacuo. The residue is purified by chromatography to give 0.83 g (92%) of the desired product as a yellow solid.