Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH3:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH:39][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:31])([F:32])[F:1])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:29])=[CH:36][CH:35]=1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: Cc1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(CNC(=O)c2cnc3cc(NC(=O)c4ccccc4-c4ccc(C(F)(F)F)cc4)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (40 mg, 0.092 mmol) was combined with 4-methylbenzylamine (17 mg, 0.14 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21 mg, 0.11 mmol), 1-hydroxybenzotriazole (14 mg, 0.10 mmol), and triethylamine (0.051 ml, 0.37 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with 4% methanol in dichloromethane. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 20 mg of the title compound as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[C:19]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)N)#[CH:20].[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[C:19]([C:21]1[CH:27]=[C:26]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:25]=[CH:23][CH:22]=1)#[CH:20]
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: C#Cc1cccc(N)c1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C#Cc1cccc(Nc2ncnc3ccc4nc(C#N)sc4c23)c1
Yield: 84 %

Procedure:
Prepared from VII and 3-ethynylaniline. Flash chromatography eluent (DCM-EtOAc, 7:3). Yield: 84%; yellow solid; mp 182° C.; IR (KBr) νmax/cm−1 3295, 3062, 2846, 2225, 1642, 1612, 1581, 1566, 1458, 1404, 1376, 1348, 1306, 1263, 1229, 1165, 1148, 1126, 971, 910, 888, 835; 1H NMR (300 MHz, DMSO-d6) δ 8.53 (d, 1H, J=8.7 Hz), 8.20 (s, 1H), 7.78 (d, 1H, J=8.7 Hz), 7.40-7.35 (m, 2H), 7.29 (m, 1H), 7.20 (m, 1H), 4.17 (s, 1H); HRMS calcd for C18H10N5S (M+H+): 328.0657, found 328.0659.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:30])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:30])=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Oc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1Oc1ccc(Cl)cc1)C1CCNCC1
Yield: 74.1 %

Procedure:
A solution of 4-[2-(4-chlorophenoxy)phenylcarbamoyl]piperidine-1-carboxylic acid tert-butyl ester (AMR01031, 410 mg, 0.95 mmol) in 4M HCl in dioxane (2 mL) was stirred at room temperature for 2 h. The resulting solution was concentrated under vacuum and the residue was dissolved in DCM, washed with 1M NaOH (1×20 mL), water and brine. The organic layer was dried (MgSO4), filtered and evaporated to give piperidine-4-carboxylic acid [2-(4-chlorophenoxy)phenyl]amide (233 mg, 74%) as a white solid (mp 138-140° C. from hexane/EtOAc), which was used in the next step without further purification. Rf: 0.11 (DCM/methanol 4:1 plus 3 drops of triethylamine) 1H NMR (270 MHz, CDCl3) δ 1.62 (2H, m, CH2), 1.83 (3H, m, CH2+NH), 2.35 (1H, tt, J=11.6, 3.7 Hz, CH), 2.62 (2H, br t, CH2), 3.20 (2H, br d, J=12.3 Hz, CH2), 6.80 (1H, td, ArH), 6.92 (2H, AA′BB′, ArH), 6.98 (1H, td, ArH), 7.11 (1H, td, ArH), 7.29 (1H, AA′BB′, ArH), 7.71 (1H, br s, NHCO) and 8.41 (1H, br d, J=7.9 Hz, ArH).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]([C:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:25])[CH:17]=[N:18][C:19]=2[NH:20]CC=C)=[O:12])=[CH:6][CH:5]=1)[CH3:2].C(O)(=O)C.C1([SiH3])C=CC=CC=1>ClCCl.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>[NH2:20][C:19]1[N:18]=[CH:17][C:16]([C:24]([N:26]([CH2:27][CH3:28])[CH2:29][CH3:30])=[O:25])=[CH:15][C:14]=1[NH:13][C:11](=[O:12])[CH2:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1
Reactant: C=CCNc1ncc(C(=O)N(CC)CC)cc1NC(=O)Cc1ccc(OCC)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOc1ccc(CC(=O)Nc2cc(C(=O)N(CC)CC)cnc2N)cc1
Reaction time: 6 h
Yield: 75.2 %

Procedure:
To a degassed solution of 5-[[(4-ethoxyphenyl)acetyl]amino]-N,N-diethyl-6-(2-propenylamino)-3-pyridinecarboxamide (1.04 g, 2.53 mmol) in dichloromethane (20 mL) at room temperature was added palladium tetrakis (117 mg, 0.10 mmol), followed by acetic acid (580 μL, 10.14 mmol) and phenyl silane (625 μL, 5.07 mmol). The mixture was stirred for 6 hours. The reaction was then quenched with NaHCO3 saturated aqueous solution (50 mL) and extracted with EtOAc (20 mL). The aqueous phase was back-extracted with additional dichloromethane (2×20 mL). The organic phases were combined, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified using silica gel flash chromatography ([3% MeOH+1% NH4OHaq] in CH2Cl2) to provide 705 mg of the title compound 6-amino-5-[[(4-ethoxyphenyl)acetyl]amino]-N,N-diethyl-3-pyridinecarboxamide (75.2% yield from 5-[[(4-ethoxyphenyl)acetyl]amino]-N,N-diethyl-6-(2-propenylamino)-3-pyridinecarboxamide). 1H-NMR (400 MHz, CDCl3): δ 1.18 (br s, 6H), 1.43 (t, J=7.0 Hz, 3H), 3.42 (br s, 4H), 3.69 (s, 2H), 4.04 (q, J=7.0 Hz, 2H), 4.73 (s, 2H), 6.91 (d, J=8.6 Hz, 2H), 7.26 (d, J=8.6 Hz, 2H), 7.38 (m, 1H), 7.78 (s, 1H), 7.95 (m, 1H). MS (ESI) (M+H)+: 372.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.BrCC1C=CC=C(F)C=1>>[CH2:12]([O:10][C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: Fc1cccc(CBr)c1
Product: Nc1cccc(OCc2ccccc2)c1

Procedure:
3-Nitro-phenol was reacted with bromomethyl-benzene according to the procedure from Example 199A substituting bromomethyl-benzene for 1-bromomethyl-3-fluoro-benzene then reduced according to the procedure from Example 199B to provide the title compound.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.[CH2:30]([C:32]1[C:33]([OH:55])=[CH:34][C:35]([OH:54])=[C:36]([C:38]2[C:39]([C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=3)=[C:40]([C:43]([OH:45])=O)[NH:41][N:42]=2)[CH:37]=1)[CH3:31].[C:56]([NH:63][CH2:64][CH2:65][CH2:66][NH2:67])([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57]>C(Cl)Cl>[CH2:30]([C:32]1[C:33]([OH:55])=[CH:34][C:35]([OH:54])=[C:36]([C:38]2[C:39]([C:46]3[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=3)=[C:40]([C:43]([NH:67][CH2:66][CH2:65][CH2:64][NH:63][C:56](=[O:57])[O:58][C:59]([CH3:61])([CH3:60])[CH3:62])=[O:45])[NH:41][N:42]=2)[CH:37]=1)[CH3:31]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CCc1cc(-c2n[nH]c(C(=O)O)c2-c2ccc(OC)cc2)c(O)cc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCc1cc(-c2n[nH]c(C(=O)NCCCNC(=O)OC(C)(C)C)c2-c2ccc(OC)cc2)c(O)cc1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
HOBT (572 mg, 4.2 mmol), NMM (1.55 ml, 14.1 mmol) and EDAC.HCl (820 mg, 4.3 mmol) were added at 0° C. consecutively to a solution of 5-(5-ethyl-2,4-dihydroxy-phenyl)-4-(4-methoxyphenyl)-2H-pyrazole-3-carboxylic acid (500 mg, 1.4 mmol) in 40 ml of dry DCM. The resulting mixture was stirred at 0° C. for 15 minutes. Then a solution of N—BOC-1,3-diaminopropane (740 mg, 4.3 mmol) in 5 ml of dry DCM was added. The resulting mixture was stirred at 0° C. for one our and at room temperature for 2.5 hours. The reaction mixture was washed with 50 ml of 10% w/v aqueous citric acid solution, 50 ml 20% aqueous KHCO3 solution and 50 ml of distilled water. The organic extracts were dried over MgSO4 and evaporated under reduced pressure. The crude material was purified by automated column chromatography on a 40 g RediSep™ normal phase silica cartridge using an ISCO Companion™ eluting with a mixture of 5% methanol in DCM was used. The fractions containing the desired product were combined and evaporated under reduced pressure go give the title compound as a white solid (450 mg, 63%); 1H NMR Spectrum: δH (400 MHz, DMSO-d6) 0.90 (3H t, J=7.5 Hz), 1.38 (9H, s), 1.56 (2H t, J=6.9 Hz), 2.28 (2H q, J=7.4 Hz), 2.95 (2H d, J=6.1 Hz), 3.15-3.20 (2H, m), 3.72 (3H, s), 6.41 (1H, s), 6.57 (2H, s), 6.72 (1H, s br), 6.78 (2H d, J=7.3 Hz), 7.12-7.14 (2H, m), 7.92-8.02 (1H, m br), 9.28-9.35 (2H, m), 12.89 (1H, s, br);
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Cl[S:13]([C:16]1[CH:17]=[CH:18][C:19]2[O:28][C:27]3[CH2:26][CH2:25][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:23][C:22]=3[C:20]=2[CH:21]=1)(=[O:15])=[O:14]>C1COCC1>[N:3]1([S:13]([C:16]2[CH:17]=[CH:18][C:19]3[O:28][C:27]4[CH2:26][CH2:25][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:23][C:22]=4[C:20]=3[CH:21]=2)(=[O:15])=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)Cl)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)n4ccc5ccccc54)cc3c2C1
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 19 mg, 0.484 mmol) was added to a solution of indole (42 mg, 0.363 mmol) in THF (1.5 mL) under N2 at room temperature, and the reaction stirred for 30 min. The product of step B (90 mg, 0.242 mmol) was then added and the reaction held for 2 h. It was quenched with H2O (10 mL), diluted with ether (10 mL) and the organic phase removed. The aqueous phase was extracted with ether (2×10 mL) and the combined organic phases dried over Na2SO2 and concentrated. Purification by combiflash (silica gel, hexane/ethyl acetate, 100:0 to 40:60) provided tert-butyl 8-(1H-indol-1-yl-sulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (28 mg, 25%) as a clear oil. 1H NMR (CDCl3, 300 MHz) δ 8.02 (d, J=9.0 Hz, 2H), 7.76 (dd, J=9.1, 2.2 Hz, 1H), 7.60 (d, J=4.0 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.33 (t, J=1.4 Hz, 1H), 7.28 (t, J=1.4 Hz, 1H), 6.66 (d, J=3.6 Hz, 1H), 4.53 (br s, 2H), 3.80 (t, J=6.2 Hz, 2H), 2.82 (t, J=6.2 Hz, 2H), 1.52 (s, 9H).
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8](OC)[CH:7]=1.Cl[C:16]1[N:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.C(CC(C)(C)C)(C)C>[CH:2]([C:6]1[CH:7]=[CH:8][C:9]([O:12][C:16]2[N:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=2)=[CH:10][CH:11]=1)=[O:3]
Reactant: COc1cc(C2OCCO2)ccc1O
Reactant: N#Cc1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)CC(C)(C)C
Solvent: CC(=O)N(C)C
Product: N#Cc1cnc(Oc2ccc(C=O)cc2)cn1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 81.8 %

Procedure:
Dissolve 4-[1,3]dioxolan-2-yl-2-phenol (Example 388, Part C2) (1.70 g, 10.2 mmol), 5-chloropyrazine-2-carbonitrile (Example 404, Part A) (1.50 g, 10.7 mmol) and K2CO3 (3.71 g, 26.9 mmol) in DMA (27.0 mL) and isooctane (13.4 mL). Beat at 110° C. for about 2.25 hours. Cool to room temperature and quench with water (100 mL). Extract with dichloromethane (3× 100 mL). Wash the extract with saturated aqueous NaHCO3 (1× 50 mL) and brine (1× 75 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography, eluting with 0-30% ethyl acetate in hexanes. Concentrate the eluant, then take the solid up in 88% formic acid (46 mL) and stir at room temperature for 4 hours. Dilute the reaction mixture with water (50 mL). Extract with dichloromethane (2× 100 mL). Wash the extract with saturated aqueous NaHCO3 (1× 50 mL), dry over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 30% ethyl acetate in hexanes to give the title compound (1.88 g, 77.7%): TOF MS ES+ 225.1 (M)+, HRMS calcd for C12H7N3O2 225.0538 (M)+, found 225.0527, time 0.38 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=11.5 min, 100% purity.
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:15][OH:16])[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[NH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:15][OH:16])[CH2:9]1
Reactant: OCC1CCCCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: OCC1CCCCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
(1-Benzyl-azepan-3-yl)-methanol (144) (0.0922 g, 0.4192 mmol) dissolved in MeOH (1 mL) was added to a stirring suspension of 10% Pd/C (14.4 mg) in 5 mL MeOH. The reaction was purged with H2, and the reaction was stirred at room temperature overnight. The reaction was judged complete by 1H-NMR analysis of an aliquot from the reaction. The reaction was filtered through a pad of Celite wet with MeOH and was rinsed with MeOH, and concentrated in vacuo to obtain pure azepan-3-yl-methanol (145) in 60% yield (0.0323 g). Compound 145 was used in the next Example without further purification. 1H NMR (CDCl3, partial) 3.14-2.70 (4H, m), 1.92-1.73 (4H, m), 1.68-1.42 (3H, m) ppm. 13C NMR (CDCl3, 75 MHz) 67.32, 52.01, 50.33, 41.31, 31.05, 29.76, 25.44 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][CH:8]([CH3:12])[CH2:9][CH2:10]O)=[C:4]([F:15])[CH:3]=1.CC[N+]([S:23]([N:26]=[C:27]([O:29][CH3:30])[O-:28])(=[O:25])=[O:24])(CC)CC>C1COCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[S:23](=[O:25])(=[O:24])[N:26]([C:27]([O:29][CH3:30])=[O:28])[CH2:10][CH2:9][CH:8]2[CH3:12])=[C:4]([F:15])[CH:3]=1
Reactant: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Reactant: CC(CCO)NCc1ccc(Br)cc1F
Solvent: C1CCOC1
Product: COC(=O)N1CCC(C)N(Cc2ccc(Br)cc2F)S1(=O)=O
Temperature: 65 °C

Procedure:
A mixture of 3-(4-bromo-2-fluorobenzylamino)butan-1-ol (800 mg, 2.9 mmol) and Burgess' Reagent (2.07 g, 8.7 mmol) in anhydrous THF (10 mL) was heated at 65° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography using petroleumn ether/EtOAc (6/1) as eluting solvents to afford methyl 6-[(4-bromo-2-fluorophenyl)methyl]-5-methyl-1,1-dioxo-1λ6,2,6-thiadi-azinane-2-carboxylate as light yellow oil. (900 mg, 79%). 1H NMR (500 MHz, CDCl3) δ 7.45 (t, 1H), 7.17 (d, 1H), 7.25-7.23 (m, 1H), 4.44 (dd, 2H), 4.20-4.25 (m, 1H), 3.92-3.99 (m, 1H), 3.88 (s, 3H), 3.45-3.51 (m, 1H), 1.87-2.00 (m, 2H), 1.23 (d, 3H); LCMS (ESI): m/z=397.0 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[N:13]([S:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)(=[O:16])=[O:15])[CH:12]=[C:11]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(OCC)(=O)C.[ClH:38]>C(OCC)(=O)C.CC(O)C>[ClH:38].[CH3:24][NH:23][CH2:22][C:11]1[CH:10]=[C:9]([C:8]2[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=2)[N:13]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:12]=1
Reactant: CN(Cc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2cccs2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2cccs2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of tert-butyl {[5-(2-cyanopyridin-3-yl)-1-(2-thienylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (195 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 140 mg, 84%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20]CC4C=CC=CC=4)=[CH:17][CH:18]=3)[C:13](=[O:28])[N:12]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=3)[C:11]2=[O:40])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([O-])=O.[NH4+]>CCO.[Pd]>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=3)[C:13](=[O:28])[N:12]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=3)[C:11]2=[O:40])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCN(C(C)=O)CC3)c2=O)cc1OC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc(Cn2c(=O)c3cc(O)ccc3n(C3CCN(C(C)=O)CC3)c2=O)cc1OC
Yield: 89.9 %

Procedure:
A mixture of 0.64 g of 1-(1-acetylpiperidin-4-yl)-6-(benzyloxy)-3-(3,4-dimethoxybenzyl)quinazoline-2,4(1H,3H)-dione obtained in stage 2.1, 0.44 g of ammonium formate and 0.125 g of Pd/C (10%) in 10 ml of EtOH purged beforehand with nitrogen is irradiated under a microwave field at 80° C. for 2 h 00. The mixture is filtered and the filtrate is evaporated under reduced pressure to give 0.48 g of the expected product.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:27]1[C:31](=[O:32])[CH2:30][CH:29]([S:33]([OH:36])(=[O:35])=[O:34])[C:28]1=[O:37].[Na:38].C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C=O>[Na:38].[CH2:1]([O:8][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][N:27]1[C:31](=[O:32])[CH2:30][CH:29]([S:33]([OH:36])(=[O:35])=[O:34])[C:28]1=[O:37])=[O:23])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCCCCCCCCCCCC(=O)OCc1ccccc1
Reactant: O=C1CC(S(=O)(=O)O)C(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C(CCCCCCCCCCCCC(=O)ON1C(=O)CC(S(=O)(=O)O)C1=O)OCc1ccccc1
Reaction time: 2 h
Yield: 41.5 %

Procedure:
In 0.4 ml of anhydrous dimethyl formamide was dissolved 1,14-tetradecanedioic acid monobenzyl ester (100 mg, 0.29 mmole). To the obtained solution were added sodium N-hydroxysulfosuccinimide (63 mg, 0.29 mmole) and a solution of DCC (65 mg, 0.29 mmole) in 0.4 ml of anhydrous dimethylformamide and the resulting mixture was stirred for 14 hours at a room temperature. The reaction mixture was filtered and the filtrate was stirred for 2 hours at a temperature under ice cooling. The solid that formed was collected by filtration and dried under reduced pressure to give N-(13-benzyloxycarbonyltridecanoyloxy)sulfosuccinimide sodium salt (66 mg, 42%) having the following properties.
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([O:38]C)=[O:37])=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:31]=[CH:32][C:33]([C:36]([OH:38])=[O:37])=[CH:34][CH:35]=3)=[CH:28][CH:29]=2)=[O:23])=[CH:16][CH:17]=1)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc(C(=O)OC)cc3)cc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc(C(=O)O)cc3)cc2)cc1)C(=O)O
Yield: 72.8 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-butyl-3-[4-[2-(4′-methoxycarbonylbiphenyl-4-carbonylamino)ethoxy]phenyl]propionate (243 mg), which is the product of Reference example 12, was reacted with aqueous sodium hydroxide solution (1N, 1.83 ml) and the reaction mixture was treated to give the title compound (163 mg) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:23][CH2:24][O:25][CH2:26][CH2:27]Cl.C(=O)([O-])[O-].[K+].[K+].O>C(O)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(N)cc2)CC1
Reactant: ClCCOCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(N3CCOCC3)cc2)CC1
Yield: 69.9 %

Procedure:
1-tert-Butoxycarbonyl-4-(4-aminobenzyl)piperidine (1 g, 3.45 mmol) was dissolved in 1-butanol (20 mL). To the solution were added bis(2-chloroethyl) ether (490 mg, 3.45 mmol) and potassium carbonate (1 g, 7.23 mmol), and the mixture was heated for 30 hours under reflux. The reaction mixture was poured into water (50 mL), and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to give 1-tert-butoxycarbonyl-4-(4-morpholinobenzyl)piperidine (869 mg) as a colorless oily substance. This compound (859 mg, 2.39 mmol) was dissolved in ethyl acetate (10 mL). To the solution was added 4N-hydrogen chloride in ethyl acetate (5 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure to give the titled compound (562 mg) as colorless powders.
Reaction SMILES: Br[C:2]1[N:19]([CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]2)[C:5]2[C:6]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=3)=[N:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=1.[F:28][C:29]1[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=1[NH2:31].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[Cl:18][C:16]1[CH:17]=[C:12]([C:6]2[C:5]3[N:19]([CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]4)[C:2]([NH:31][C:30]4[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=4[F:28])=[N:3][C:4]=3[CH:9]=[C:8]([C:10]#[N:11])[N:7]=2)[CH:13]=[N:14][CH:15]=1
Reactant: Nc1ccccc1F
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@H]1CC[C@H](Cn2c(Nc3ccccc3F)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 75 °C

Procedure:
To a sealed tube were added 2-bromo-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Preparative Example 3.1) (0.010 g, 0.045 mmol), 2-fluoroaniline (0.0050 g, 0.045 mmol), Cs2CO3 (0.022 g, 0.067 mmol), chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II) (0.0050 g, 0.0056 mmol), and dioxane (0.5 mL). The reaction vessel was purged with argon, sealed and warmed to 75° C. for 8 hours with stirring. The reaction was cooled and diluted with dioxane (1.0 mL) and was passed through a syringe filter. The collected eluent was concentrated in vacuo to afford 4-(5-chloropyridin-3-yl)-2-((2-fluorophenyl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile as a crude residue. MS ESI calc'd. for C26H24ClFN6 [M+H]+ 475. found 475.