Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]2[C:7](=[C:8]([CH2:23][CH2:24][CH3:25])[C:9]3[O:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][C:13](=[O:22])[C:10]=3[CH:11]=2)[N:6]=[C:5]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:4]=1.O.[C:32](O)(=[O:34])[CH3:33]>C(OC(=O)C)(=O)C>[CH3:1][N:2]([C:3]1[C:12]2[C:7](=[C:8]([CH2:23][CH2:24][CH3:25])[C:9]3[O:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][C:13](=[O:22])[C:10]=3[CH:11]=2)[N:6]=[C:5]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:4]=1)[C:32](=[O:34])[CH3:33]
Reactant: CCCc1c2nc(C(=O)OCC)cc(NC)c2cc2c(=O)cc(C(=O)OCC)oc12
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCCc1c2nc(C(=O)OCC)cc(N(C)C(C)=O)c2cc2c(=O)cc(C(=O)OCC)oc12

Procedure:
A solution of diethyl 6-(N-methylamino)-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylate (1.25 g) in acetic acid (25 ml) and acetic anhydride (25 ml) was refluxed for 12 hours, then the solution was poured into water, extracted with ethyl acetate and the extract washed with sodium bicarbonate solution, dried and evaporated to give an oil. The oil crystallised from ethanol to give the required amide, 0.56 g (41%) mp 164°-5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12]([NH:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])(=[O:14])=[O:13])[CH:8]=2)[O:3]1.BrC[C:27]1[CH:28]=[C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=[CH:31][CH:32]=1.[CH3:39]CN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>C(#N)C>[C:33]1([C:29]2[CH:28]=[CH:27][CH:32]=[CH:31][CH:30]=2)[CH:34]=[CH:35][C:36]([CH2:39][N:15]([CH2:16][C:17]([OH:19])=[O:18])[S:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[O:3][C:2]([CH3:1])([CH3:24])[CH2:11][CH2:10]3)(=[O:13])=[O:14])=[CH:37][CH:38]=1
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Reactant: BrCc1cccc(-c2ccccc2)c1
Solvent: CC#N
Product: CC1(C)CCc2cc(S(=O)(=O)N(CC(=O)O)Cc3ccc(-c4ccccc4)cc3)ccc2O1
Temperature: 90 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
To a solution of tert-butyl 2-(2,2-dimethylchroman-6-sulfonamido)acetate (40 mg, 0.113 mmol) in acetonitrile (2 mL) was added 3-(bromomethyl)biphenyl (38.9 mg, 0.158 mmol) and resin-supported BEMP (74.5 mg, 0.164 mmol). The mixture was heated in an oil bath at 90° C. overnight. The reaction mixture was filtered, and the filtrate was concentrated to dryness. The crude mixture was taken in DCM (2 mL) and trifluoroacetic acid was added (1 mL). The mixture was stirred at RT for 1 hr and was concentrated to give a off white residue, which was purified by preparative HPLC using MeCN—H2O-0.1% TFA as the solvent to obtain the product as a white powder (25 mg, 45% in two steps). 1H NMR (400 MHz, CDCl3) δ 7.66-7.61 (m, 2H), 7.60 (d, J=1.4 Hz, 1H), 7.59-7.56 (m, 2H), 7.55 (d, J=1.7 Hz, 1H), 7.49-7.43 (m, 2H), 7.40-7.35 (m, 1H), 7.32 (d, J=8.2 Hz, 2H), 6.89 (dd, J=8.5, 7.2 Hz, 1H), 4.52 (s, 2H), 3.99 (s, 2H), 2.83 (t, J=6.7 Hz, 2H), 1.86 (t, J=6.7 Hz, 2H), 1.38 (s, 6H). LRMS [ESI, MH+] m/z calcd for C26H28NO5S 466.17. found 466.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 2 was prepared from bis(4-chlorophenyl) acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 7.34–7.13 (m, 12H), 4.75 (s, 1H), 3.41 (q, 2H, J=4.5 Hz), 2:94 (d, 2H, J=10.2 Hz), 2.51–2.40 (m, 4H), 1.97 (m, 2H), 1.82 (m, 2H), 1.68 (quintet, 2H, J=6.8 Hz), 1.59 (m, 3H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 566.2 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)C.O.[OH-].[K+]>C(O)CO.CO>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[N:6]([CH2:5][C:4]([OH:3])=[O:23])[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:12]3[N:13]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: OCCO
Solvent: O
Product: O=C(O)Cn1c(-c2ccc(F)cc2)nc2cccnc21
Temperature: 25 °C
Yield: 3.3 %

Procedure:
A solution of N-[3-[(4-fluorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester (70.0 g, 0.2205 mole) in ethylene glycol was refluxed for 2 hours, cooled and 14% of the solution was removed. To the remaining solution (0.19 mole) was added 88 ml of water and solid potassium hydroxide pellets (21.4 g, 0.38 mole). The solution was heated at reflux for an additional 11/4 hours, filtered into ice water (2 liter) and acidified with 3N hydrochloric acid. The resulting solid was collected by filtration, washed with water and dried under high vacuum at 60° C. overnight to give 45.5 g of crude title compound (88% yield). A 3.5-g portion of the solid was dissolved in hot methanol and filtered while hot, and water was added to the cloud point. Upon cooling to room temperature, solid precipitated which was collected and recrystallized again from methanol/water to give 2.00 g of title compound after drying under high vacuum at 50° C., mp >250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:18]3=4)[CH2:10][CH:9]2[CH3:33])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:38][C:39]([O:41][CH3:42])=[O:40]>CN(C)C=O>[CH3:42][O:41][C:39](=[O:40])[CH2:38][O:32][C:30]1[CH:29]=[CH:28][C:19]2[O:20][CH:21]=[C:22]3[NH:27][CH:26]=[CH:25][CH:24]=[C:23]3[C:17](=[CH:16][CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)([OH:34])[CH:9]([CH3:33])[CH2:10]3)[C:18]=2[CH:31]=1
Reactant: CC1CN(CCC=C2c3cc(O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)C1)C1=CC=CNC1=CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.5 %

Procedure:
A solution of 5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3-methyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-ol (0.14 g, 0.28 mmol) in dimethylformamide (3 mL) was treated with sodium hydride (60% in mineral oil, 0.016 g, 0.4 mmol) and methyl bromoacetate (0.038 mL, 0.4 mmol). The mixture was allowed to stir at rt for 2 hr, then quenched with aqueous brine, and extracted with ethyl acetate (3×10 mL). The combined organics were washed several time with water, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate→87:10:3 ethyl acetate/methanol/triethylamine) to yield 0.07 g (50%) of the title compound, ESI-MS m/z: 549 [M+1].
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22].O>C(O)C>[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[CH:2][C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22]
Reactant: CC(=O)c1ccccc1
Reactant: Cc1ccc(C=O)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C=CC(=O)c2ccccc2)cc1[N+](=O)[O-]
Yield: 85.6 %

Procedure:
To a solution of acetophenone (7.4 g) and 4N-sodium hydroxide solution (16 ml) in ethanol {60 ml) was added 4-methyl-3-nitrobenzaldehyde (7.4 g) at ambient temperature under stirring and the resultant mixture was stirred at same condition for 1.5 hours. To the reaction mixture was added water and resulting precipitate was collected by filtration. The precipitate was dissolved in a mixture of ethyl acetate and tetrahydrofuran. The solution was washed with brine and dried over magnesium sulfate. The solvent was concentrated in vacuo and the crystalline residue was collected by filtration to give 3-(4-methyl-3-nitrophenyl)-1-phenyl-2-propen-1-one (10.25 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.O[NH:15]/[C:16](=[N:36]\[H])/[CH2:17][N:18]1[CH2:22][CH2:21][C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]1=[O:35].Cl.C(N=C=NCCCN(C)C)C>ClC(Cl)C.C(OCC)(=O)C>[C:29]1([C:20]2([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][CH2:22][N:18]([CH2:17][C:16]3[N:15]=[C:7]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:11][CH:10]=4)[O:9][N:36]=3)[C:19]2=[O:35])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: [H]/N=C(/CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C1N(Cc2noc(-c3ccc(C(F)(F)F)cc3)n2)CCC1(c1ccccc1)c1ccccc1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
4-(Trifluoromethyl)benzoic acid (0.416 g, 2.187 mmol), (Z)—N-hydroxy-2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetimidamide (0.451 g, 1.458 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.559 g, 2.92 mmol) in dichloroethane were stirred together at room temperature for 3 hours. The reaction was then heated to 85° C. and stirred at this temperature for 16 hours. The reaction was cooled, poured in ethyl acetate/1 N HCl (1:1, 200 mL) and the layers separated. The organic layer was washed with brine (100 mL), dried over magnesium sulfate and concentrated. The residue was loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences) and eluted with a gradient of 5% ethyl acetate/hexanes to 35% ethyl acetate/hexanes (flow=40 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.20 (d, J=8.3, 2H), 7.80 (d, J=8.4, 2H), 7.48-7.15 (m, 10H), 4.81 (s, 2H), 3.50 (t, J=6.5, 2H), 2.84 (t, J=6.5, 2H); MS (ESI+) m/z 464.1 (M+H)+.
Reaction SMILES: [CH:1]1([N:7]([CH2:12][CH2:13][N:14]([CH2:25][CH2:26][C:27]2[C:35]3[S:34][C:33](=[O:36])[NH:32][C:31]=3[C:30]([OH:37])=[CH:29][CH:28]=2)[C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8](=[O:11])[CH:9]=[CH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[F:39][C:40]1[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:41]=1[CH2:42][CH2:43][NH2:44].C(N(CC)CC)C>C(O)C>[CH:1]1([N:7]([C:8](=[O:11])[CH2:9][CH2:10][NH:44][CH2:43][CH2:42][C:41]2[CH:45]=[CH:46][CH:47]=[C:48]([F:49])[C:40]=2[F:39])[CH2:12][CH2:13][N:14]([CH2:25][CH2:26][C:27]2[C:35]3[S:34][C:33](=[O:36])[NH:32][C:31]=3[C:30]([OH:37])=[CH:29][CH:28]=2)[C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=CC(=O)N(CCN(CCc1ccc(O)c2[nH]c(=O)sc12)C(=O)OCc1ccccc1)C1CCCCC1
Reactant: NCCc1cccc(F)c1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(OCc1ccccc1)N(CCc1ccc(O)c2[nH]c(=O)sc12)CCN(C(=O)CCNCCc1cccc(F)c1F)C1CCCCC1
Temperature: 60 °C

Procedure:
Benzyl 2-(N-cyclohexylacrylamido)ethyl(2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)carbamate prepared as in Example 12 step i) (0.33 g), 2,3-difluorophenethylamine hydrochloride (0.244 g) and triethylamine (0.176 mL) were dissolved in ethanol (3 mL) and heated at 60° C. for 48 h. The mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to afford the sub-title product (0.420 g) as a light brown gum.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:23][CH2:24][S:25][C:26]4[N:30]=[CH:29][N:28](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:27]=4)[CH:17]=3)=[O:13])=[N:6][C:5]=2[S:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:23][CH2:24][S:25][C:26]4[N:30]=[CH:29][NH:28][N:27]=4)[CH:17]=3)=[O:13])=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: Cc1csc2nc(C(=O)NCc3ccnc(OCCSc4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3)[nH]c(=O)c12
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1csc2nc(C(=O)NCc3ccnc(OCCSc4nc[nH]n4)c3)[nH]c(=O)c12
Yield: 21 %

Procedure:
A solution of 5-methyl-4-oxo-N-({2-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]thio}ethyl)oxy]pyridin-4-yl}methyl)-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxamide (395.0 mg, 0.576 mmol), triethylsilane (0.097 mL, 0.605 mmol) and trifluoroacetic acid (3.0 mL) in dichloromethane (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate-IPE to give the title compound as a white powder (53.6 mg, 21%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][C:21]=2[N+:22]([O-])=O)[N:18]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:17](=[O:30])[C:16]3([CH3:32])[CH3:31])=O)[CH:5]=[CH:6][CH:7]=1.[CH2:33](Cl)Cl.[CH3:36][OH:37]>>[CH3:31][C:16]1([CH3:32])[C:15]2[CH:14]=[C:13]3[NH:12][C:10]([CH2:9][CH2:8][C:4]4[CH:3]=[C:2]([NH:1][C:36](=[O:37])[CH3:33])[CH:7]=[CH:6][CH:5]=4)=[N:22][C:21]3=[CH:20][C:19]=2[N:18]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:17]1=[O:30]
Reactant: ClCCl
Reactant: CO
Reactant: CCCCCN1C(=O)C(C)(C)c2cc(NC(=O)CCc3cccc(N)c3)c([N+](=O)[O-])cc21
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(CCc4cccc(NC(C)=O)c4)nc3cc21

Procedure:
N-{3-[2-(7,7-Dimethyl-6-oxo-5-pentyl-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-ethyl]-phenyl}-acetamide is prepared from 3-(3-amino-phenyl)-N-(3,3-dimethyl-6-nitro-2-oxo-1-pentyl-2,3-dihydro-1H-indol-5-yl)-propionamide as described in Example 3b. Under the microwave conditions the acetylated product is formed. The desired N-{3-[2-(7,7-dimethyl-6-oxo-5-pentyl-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-ethyl]-phenyl}-acetamide (229 mg) is obtained by flash chromatography on silica gel eluting with CH2Cl2/MeOH (99:1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][CH:9]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=O)[CH2:15][CH2:14]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:22]([NH2:26])[CH:23]([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:24][CH:23]([CH3:25])[CH2:22][NH:26][C:19]([CH:16]1[CH2:15][CH2:14][N:13]([CH:9]2[CH2:10][CH2:11][CH2:12][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]2)[CH2:18][CH2:17]1)=[O:21]
Reactant: CC(C)CN
Reactant: CCOC(=O)N1CCCC(N2CCC(C(=O)O)CC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCCC(N2CCC(C(=O)NCC(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.4 %

Procedure:
1-(1-(ethoxycarbonyl)azepan-4-yl)piperidine-4-carboxylic acid (0.26 g assumed 0.89 mmol) was dissolved in DMF (4 mL) and isobutylamine (0.81 g, 1.1 mL, 11.0 mmol), HATU (0.51 g, 1.34 mmol) and DIPEA (0.46 g, 0.62 mL, 3.56 mmol) were added. The reaction mixture was stirred at rt overnight and the solvents were removed in vacuo. The residue was partitioned between DCM and sat. NaHCO3 sol., the organic layer was washed with sat. NaCl sol. and dried (MgSO4). The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 25 mL per min, gradient 0% to 3% MeOH in DCM]) to give ethyl 4-(4-((2-methylpropyl)carbamoyl)piperidin-1-yl)azepane-1-carboxylate (17 mg, 2%) as a pale yellow gum.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH2:7]([O:9][C:10]([C:12]1[S:16][C:15](Br)=[N:14][CH:13]=1)=[O:11])[CH3:8].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>COCCOC.CCOC(C)=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>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:15]1[S:16][C:12]([C:10]([O:9][CH2:7][CH3:8])=[O:11])=[CH:13][N:14]=1
Reactant: OB(O)c1ccccc1F
Reactant: CCOC(=O)c1cnc(Br)s1
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: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(-c2ccccc2F)s1
Temperature: 80 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.58 g, 0.5 mmol), and a degassed solution of 2.0M Na2CO3 (10 mL) are added to a degassed solution of 2-bromo-1,3-thiazole-5-carboxylic ethyl ester (1.18 g, 5.0 mmol) and 2-fluorophenylboronic acid (0.77 g, 5.5 mmol) in DME (10 mL). The resulting suspension is stirred under argon at 80° C. for 4 hours. The reaction mixture is cooled, diluted with EtOAc, and then washed with two portions of 1.0 M NaOH, then one portion of brine. The combined organic phases are concentrated in vacuo, and the resulting oil purified with flash chromatography. Yield 37%. HRMS (FAB) calculated for C12H10FNO2S+H 252.0495, found 252.0496.
Reaction SMILES: Cl[CH2:2][O:3][C:4]([O:6][CH:7]([CH2:24][O:25][C:26](=[O:39])[C@H:27]([CH:36]([CH3:38])[CH3:37])[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][O:9][C:10](=[O:23])[C@H:11]([CH:20]([CH3:22])[CH3:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:5].[Na+].[I-:41]>C(#N)C>[I:41][CH2:2][O:3][C:4]([O:6][CH:7]([CH2:24][O:25][C:26](=[O:39])[C@H:27]([CH:36]([CH3:38])[CH3:37])[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][O:9][C:10](=[O:23])[C@H:11]([CH:20]([CH3:22])[CH3:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:5]
Reactant: [I-]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)OC(=O)OCCl
Agent: [Na+]
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)OC(=O)OCI
Yield: 92 %

Procedure:
A solution of 2-O-chloromethoxycarbonyl-1,3-di-O-(N-tert-butoxycarbonyl-L-valyl)propane-1,2,3-triol (7.86 g, 13.5 mmol) and NaI (8.09 g 54.0 mmol) in 135 mL dry acetonitrile was refluxed at 80° C. for 4 h under N2. The reaction mixture was concentrated under vacuum, and then partitioned between 150 mL diethyl ether and 50 mL H2O. The aqueous layer was reextracted with 2×25 mL ether. The combined organic phases were washed successively with 25 mL aqueous Na2S2O3 and 50 mL brine, dried over Na2SO4, and concentrated. Flash column chromatography (silica gel, 2/1 hexane-ethyl acetate gave 8.38 g (92%) title product (alternative name: 2-iodomethoxycarbonyloxy-1,3-bis-(N-tert-butoxycarbonyl-L-valyloxy)propane or 1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propyl iodomethyl carbonate) as a white solid.
Reaction SMILES: [NH2:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]1=O.C(O[C:18](=[NH:27])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)C>>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3]1=[N:27][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)=[N:1][N:2]1[CH2:11][CH2:10]2
Reactant: COc1ccc2c(c1)CCN(N)C2=O
Reactant: CCOC(=N)c1cccc(OC)c1
Product: COc1cccc(-c2nc3n(n2)CCc2cc(OC)ccc2-3)c1

Procedure:
The compound is prepared according to the procedure of Example 1 from 2-amino-6-methoxy-3,4-dihydro-1(2H)-isoquinolinone (prepared according to the procedure described in Belgian Pat. No. 780,885; m.p. 101°-3° C) and m-methoxybenzimidic acid ethyl ester; m.p. 132°-3° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([S:18][C:19]3[CH:20]=[C:21]([C:25]4(C#N)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:22]=[CH:23][CH:24]=3)=[CH:7][CH:8]=2)[N:3]=1.Cl[CH2:34][CH:35]=O.[O:37]1CCOCC1>O.C([O-])(O)=O.[Na+]>[C:12]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([S:18][C:19]4[CH:20]=[C:21]([C:25]5([OH:37])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[CH:22]=[CH:23][CH:24]=4)=[CH:7][CH:8]=3)[N:3]3[CH:34]=[CH:35][N:1]=[C:2]3[CH:11]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#CC1(c2cccc(Sc3ccc4c(-c5ccccc5)cc(N)nc4c3)c2)CCOCC1
Reactant: C1COCCO1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: OC1(c2cccc(Sc3ccc4c(-c5ccccc5)cc5nccn5c4c3)c2)CCOCC1
Temperature: 70 °C

Procedure:
To 1t (78 mg, 0.18 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was added chloroacetaldehyde (50 wt %, 0.04 mL, 0.27 mmol) and saturated aqueous NaHCO3 (2 drops), and the reaction was heated to 70° C. until no starting material was seen by tlc analysis. The mixture was concentrated and purified by preparative HPLC to give the desired product, 1u.
Reaction SMILES: [CH:1]1([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:26])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:30][C:31]([O:33]CC)=O.[CH3:36][NH2:37].CO>O1CCCC1>[CH:1]1([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]([CH2:30][C:31]([NH:37][CH3:36])=[O:33])[C:18]3=[O:26])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=c1[nH]c2ccccc2n1C1CCN(C2CCCc3ccccc32)CC1
Reactant: CN
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)Cn1c(=O)n(C2CCN(C3CCCc4ccccc43)CC2)c2ccccc21
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
1-[1-(1,2,3,4-Tetrahydronaphthalen-1-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one (476 mg) was dissolved in tetrahydrofuran (5 ml), 60% sodium hydride (66 mg) was added, and the suspension was stirred at 50° C. for 30 min. After cooling to room temperature, ethyl bromoacetate (0.167 ml) was added, and the mixture was stirred for 1 hr. 40% Methylamine-methanol solution (5 ml) was added, the mixture was stirred at room temperature for 1 hr, and the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (567 mg) as a pale-yellow powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7](O)=O)[CH2:3][CH2:2]1.[F:10][C:11]1[CH:12]=[C:13]([NH2:18])[C:14]([NH2:17])=[CH:15][CH:16]=1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]2[NH:17][C:7]([CH:4]3[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]3)=[N:18][C:13]=2[CH:12]=1
Reactant: Nc1ccc(F)cc1N
Reactant: O=C(O)C1CCNCC1
Product: Fc1ccc2[nH]c(C3CCNCC3)nc2c1
Temperature: 180 °C

Procedure:
To a mixture of piperidine-4-carboxylic acid (18.33 g, 0.14 mol) and 4-fluoro-benzene-1,2-diamine (18.01 g, 0.14 mol) was added polyphosphoric acid (138.39 g) and the mixture heated at 180° C. (internal temperature) for 2 h 45 minutes. The reaction mixture was cooled, reheated to 80° C. and the reaction was quenched by cautious addition to water (300 mL). The mixture was made basic (pH 8) by the addition of concentrated aqueous NaOH. The aqueous phase was extracted sequentially with 3:7 isopropanol:CH2Cl2 (2×200 mL) and CH2Cl2 (150 mL) and the combined organic phase dried (Na2SO4) and concentrated. The aqueous phase was reextracted with n-butanol (2×200 mL), the organic layer dried (Na2SO4) and concentrated. The crude product was stirred in diethyl ether, filtered and dried to give crude 5-fluoro-2-piperidin-4-yl-1H-benzoimidazole. Further purification was achieved by preparing the hydrochloride salt.