Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(N(CC)CC)C.[C:33]([NH:40][CH2:41][C:42](O)=[O:43])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:42](=[O:43])[CH2:41][NH:40][C:33](=[O:34])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2=NN(C3CCN(C(=O)CNC(=O)OC(C)(C)C)CC3)C(=O)C2(C)C)cc1OC
Reaction time: 0.25 h

Procedure:
A mixture of 5 g of 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1), 1.9 ml of triethylamine and 2.5 g of N-BOC-glycine in 25 ml of DCM is stirred until complete dissolution (about 15 min). 3.9 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is added and the resulting mixture is stirred at RT for 3 h. After washing with 1 M sodium carbonate, the organic layer is dried over magnesium sulphate and evaporated. The residue is purified by column chromatography [silica, ethyl acetate]. The title compound is crystallized from diethyl ether.
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21]Cl)=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33]>CO>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:34]([CH2:35][CH3:36])[CH2:32][CH3:33])=[CH:17][CH:18]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: CCNCC
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2oc(Cl)cc2c1
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCN(CC)CC)cc1)c1ccc2oc(Cl)cc2c1
Yield: 81 %

Procedure:
According to the same procedure as example 1, step E described, 4-(2-(2-chlorobenzofuran-5-yl)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol (70 mg, 1.0 eq, made by example 11, step D) was reacted with diethylamine (3 mL) in MeOH (8 mL) under reflux to give the desired product (61 mg, 81%, Z/E=1/1.25) as a brown solid. 1HNMR (400 MHz, CDCl3) δ 7.23 (s, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.12 & 7.09 (d, J=8.8 Hz, 2H), 7.00 & 6.99 (d, J=8.4 Hz, 1H), 6.83 & 6.80 (d, J=8.8 Hz, 2H), 6.71 & 6.69 (d, J=8.4 Hz, 2H), 6.45 (s, 1H), 6.43 (d, J=8.8 Hz, 2H), 4.08 & 3.90 (t, J=5.8 Hz, 2H), 2.92 & 2.80 (t, J=5.8 Hz, 2H), 2.69 & 2.62 (q, J=7.0 Hz, 4H), 2.50 (q, J=7.6 Hz, 2H), 1.10 & 1.04 (q, J=7.2 Hz, 6H), 0.91 (t, J=7.6 Hz, 3H); m/z=490[M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.[CH2:16]([CH:23]1[CH2:27][CH2:26][CH2:25][NH:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:13]([C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Reactant: c1ccc(CC2CCCN2)cc1
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCCC1Cc1ccccc1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 2-benzylpyrrolidine (9.7 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (9.4 mg). Calcd for C21H19ClN2O2: 366.1135, found 366.1136.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH3:10])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC=CC=1>[CH2:9]([C:2]1([CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])[O:13][CH2:12][CH2:11][O:1]1)[CH3:10]
Reactant: OCCO
Reactant: CCC(=O)CCC(=O)OC
Solvent: Cc1ccccc1
Product: CCC1(CCC(=O)OC)OCCO1
Yield: 94.1 %

Procedure:
To a stirring solution of 4.05 g (28 mmol) of methyl 4-oxohexanoate (16), prepared as described above in Example 16, in 200 mL of toluene and 0.53 g (2.8 mmol) of tosyl acid was added 5.59 g (90 mmol) of ethylene glycol. After refluxing for 2 hours using a Dean-Stark trap, the solvent was removed under vacuum. The resulting orange oil was dissolved in 200 mL of EtoAc. The EtoAc was then washed with 2×200 mL of H2O. The organic layer was then dried over Na2S04 anhydrous, filtered, and concentrated in vacuo to yield 4.96 g (94%) of methyl 2-ethyl-1,3-dioxolane-2-propanoate (17), which was employed immediately in Example 18 below.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]([O:27][CH2:28][C:29]3([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:20]=[N:21][C:22]=2[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[CH2:37](OCC)C>C(Cl)Cl>[ClH:1].[ClH:1].[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[C:19]([O:27][CH2:28][C:29]3([OH:35])[CH2:34][CH2:33][N:32]([CH3:37])[CH2:31][CH2:30]3)[N:20]=[N:21][C:22]=2[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCCc1nnc(OCC2(O)CCNCC2)cc1-c1ccc(OCc2ccccc2)cc1
Reactant: CCOCC
Agent: Cl
Solvent: ClCCl
Product: CCCCc1nnc(OCC2(O)CCN(C)CC2)cc1-c1ccc(OCc2ccccc2)cc1

Procedure:
A suspension of 4-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-piperidin-4-ol dihydrochloride (0.1 mmol) aqueous formaldehyde (37%, 0.3 mmol) and molecular sieves in anhydrous DCM may be stirred for 20 minutes. To this suspension at room temperature may be added sodium triacetoxyborohydride (0.3 mmol). The reaction mixture may be monitored by LCMS until the reaction is complete. The reaction may be quenched with saturated NaHCO3 and the layers may be separated. The organic layer may be dried and the solvent may be removed under reduced pressure. The crude product may be purified by flash chromatography using with 1-5% (2N ammonia in MeOH) in DCM to give 4-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-1-methyl-piperidin-4-ol. The neutral amine may be treated with 2N HCl in diethyl ether and DCM. The volatiles may be removed under reduced pressure and the salt triturated with diethyl ether and filtered to provide the title compound. LCMS: m/z 463 [M+1]. 1H NMR (400 MHz, CDCl3) δ 7.32-7.49 (5H, m), 7.19-7.25 (2H, m), 7.02-7.09 (2H, m), 6.78 (1H, bs), 5.12 (2H, s), 4.58-4.83 (1H, m), 4.32 (2H, s), 2.54-2.69 (3H, m), 2.40-2.51 (2H, m), 2.27-2.36 (3H, m), 1.71-1.83 (2H, m), 1.59-1.70 (2H, m), 1.18-1.51 (5H, m), 0.81 (3H, t).
Reaction SMILES: [C:1]([CH:5]1[NH:19][C:18](=[O:20])[CH:17]([CH2:21][N:22]([O:25]CC2C=CC=CC=2)[CH:23]=[O:24])[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]1=[O:33])([CH3:4])([CH3:3])[CH3:2].CO.[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([CH:5]1[NH:19][C:18](=[O:20])[CH:17]([CH2:21][N:22]([OH:25])[CH:23]=[O:24])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]1=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)C1NC(=O)C(CN(C=O)OCc2ccccc2)CCCC=CCCCCNC1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)C1NC(=O)C(CN(O)C=O)CCCCCCCCCNC1=O

Procedure:
The cyclic compound 14 (50.0 mg) was dissolved in ethyl acetate and methanol (1:1, 10 mL) and 20 mg of 10% Pd/C as added. The mixture was exposed to 1 atm of hydrogen until all the starting material was consumed. The charcoal was removed by filtration and the filtrate was concentrated to give the desired compound quantitatively. 1H NMR (250 MHz, CDCl3) δ 9.39 (brs, 1H), 8.37 (brs, 0.27H), 7.86 (brs, 0.73H), 7.40 (d, J=8.7 Hz, 0.27H), 6.94 (brs, 1H), 6.57 (brs, 0.73H), 4.33 (m, 1H), 3.81 (m, 2H), 3.43 (m, 1H), 2.87 (m, 2H), 1.64 (brs, 2H), 1.45-1.23 (m, 16H), 0.96 (s, 9H); 13C NMR (63 MHz, CDCl3) δ 175.0, 173.3, 171.2, 170.9, 157.2, 61.1, 60.4, 52.7, 44.5, 38.5, 34.6, 29.8, 28.0, 27.8, 27.5, 26.8, 26.5, 25.2, 21.1, 14.2. HRESI-MS: C19H35N3O4Na+ ([M+Na]+), callc'd 392.2520, found 392.2504. HPLC analysis showed a purity of ˜96% (FIG. 1).
Reaction SMILES: [CH2:1]([N:3]1[C:12]([CH3:13])=[CH:11][C:10](=[O:14])[C:5]([C:6]([O:8]C)=[O:7])=[C:4]1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[CH3:2].Cl>[OH-].[Na+]>[CH2:1]([N:3]1[C:12]([CH3:13])=[CH:11][C:10](=[O:14])[C:5]([C:6]([OH:8])=[O:7])=[C:4]1[C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[CH3:2]
Reactant: CCn1c(C)cc(=O)c(C(=O)OC)c1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCn1c(C)cc(=O)c(C(=O)O)c1-c1ccc(Cl)cc1
Yield: 95.5 %

Procedure:
46.1 gms of crude methyl 1-ethyl-6-methyl-2-(4'-chlorophenyl)-4-oxonicotinate is suspended in 600 mls of 5% aqueous NaOH solution and warmed to 80°-85°. After 11/2 hours at this temperature the reaction mixture is cooled and acidified with dilute HCl. The resulting solid precipitate is collected by filtration, yielding 42 gms of 1-ethyl-6-methyl-2-(4'-chlorophenyl)-4-oxonicotinic acid, mp (methylene chloride/ether)=235°-7°.
Reaction SMILES: [CH:1]1([C:6]2([CH3:22])[CH2:14][C:13]3[C:8](=[C:9]([Cl:20])[C:10]([Cl:19])=[C:11]([S:15]C(=O)C)[CH:12]=3)[C:7]2=[O:21])[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[OH-].[Na+]>O1CCCC1>[CH:1]1([C:6]2([CH3:22])[CH2:14][C:13]3[C:8](=[C:9]([Cl:20])[C:10]([Cl:19])=[C:11]([SH:15])[CH:12]=3)[C:7]2=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(=O)Sc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C2CCCC2)Cc2cc(S)c(Cl)c(Cl)c2C1=O
Reaction time: 0.33 h

Procedure:
To a solution of 300 mg of 5-acetylthio compound prepared in (2) in the mixture of 1.3 ml of methanol and 0.6 ml of tetrahydrofuran was dropped 1.35 ml of 5% aqueous solution of sodium hydroxide and the mixture was stirred for 20 minutes at ambient and then concentrated under reduced pressure. 2 ml of water was added to the residue and the mixture was acidified to pH 1 with 1N hydrochloric acid under cooled with ice. The mixture was extracted with diethyl ether and the extract was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 210 mg of the title compound as crude product having following physical data.
Reaction SMILES: [CH3:1][N+:2]([CH2:5][CH:6]([OH:11])[CH2:7][C:8]([OH:10])=[O:9])([CH3:4])[CH3:3].[Cl-].[OH-].[Na+]>C(O)C>[OH:11][CH:6]([CH2:7][C:8](=[O:9])[O-:10])[CH2:5][N+:2]([CH3:4])([CH3:1])[CH3:3]
Reactant: C[N+](C)(C)CC(O)CC(=O)O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[N+](C)(C)CC(O)CC(=O)[O-]

Procedure:
A solution of DL-carnitine hydrochloride (1.0 g, 5.05 mmol) and sodium hydroxide (0.303 g, 7.58 mmol) in ethanol (15 ml) was stirred at room temperature for 2 h. The formed white precipitate (NaCl) was removed by filtration, and the solvent was evaporated under reduced pressure to give a white solid, carnitine inner salt. A suspension of the carnitine inner salt and 1-iodooctadecane (2.31 g, 6.06 mmol) in DMF-dioxane (3:5, 40 ml) was heated with an oil-bath at 120° C. under argon for 4 h. The solvent was removed under reduced pressure, and the residue was purified by a silica gel column using CH3OH--CH3Cl (v/v, 0-10%) as eluent to give the stearyl carnitine ester as a white solid. A solution of a fresh prepared stearic anhydride (1.94 g, 3.52 mmol), stearyl carnitine ester (0.953 g, 1.76 mmol) and 4-dimethylaminopyridine (0.429 g, 3.52 mmol) in CH3Cl (dry, 15 ml) was stirred at room temperature under argon for four days. The solvent was removed under reduced pressure, and the residue was washed twice by cold diethyl ether. The solid was chromatographied on a silica gel column using MeOH--CHCl3 (v/v, 1:5) as eluent to give the stearyl stearoyl carnitine ester iodide. The iodide was exchanged by chloride with an anion exchange column to give the stearyl stearoyl carnitine ester chloride as a white solid. 1H NMR (300 MHz, CDCl3) δ5.67 (q, 1 H), 4.32 (d, 1 H), 4.07 (m, 3 H), 3.51 (s, 9 H), 2.82 (t, 2 H), 2.33 (t, 2 H), 1.59 (broad m, 4 H), 1.25 (broad s, 58 H), 0.88 (t, 6 H). LSIMS (NBA): m/e 680.6 for M+ (C43H86NO4). Anal. Calcd for C43H86 ClNO4.H2O: C, 70.30; H, 12.07; N, 1.91. Found: C, 70.08; H, 12.24; N, 1.75.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:32]([CH2:34][O:35]C(=O)C)=[O:33]>>[OH:35][CH2:34][C:32]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][CH:28]4[CH2:29][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:33]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c1
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c[nH]c23)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A171) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:11][O:12][CH3:13].[Li]CCCC.[I:19]I>C1COCC1>[I:19][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:11][O:12][CH3:13]
Reactant: II
Reactant: COCOc1cc(OC)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1cc(OC)ccc1I
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 83.6 %

Procedure:
To a stirred solution of 2-bromo-5-methoxy-1-methoxymethoxybenzene (1.04 g, 4.23 mmol) in THF (13 mL) at −95° C. (hexanes/N2) was added n-BuLi (1.6 M in hexanes, 2.91 mL, 4.65 mmol) and the resulting solution was stirred for 5 min. To this solution was then added by syringe a solution of I2 (1.28 g, 5.07 mmol) in THF (8.5 mL) until a yellow color persisted. The solution was then permitted to warm to 23° C. and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, petroleum ether:Et2O 8:1) to provide 2-iodo-5-methoxy-1-methoxymethoxybenzene as a pale-orange oil (1.04 g, 84%). See also Tsukayama, M., 1997.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([Cl:19])=[C:9]([CH:18]=1)[C:10]([NH:12][C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)=[O:11].[CH3:20][C:21]1([C:24](O)=[O:25])[CH2:23][CH2:22]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:19][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][NH:3][C:24]([C:21]2([CH3:20])[CH2:23][CH2:22]2)=[O:25])=[CH:18][C:9]=1[C:10]([NH:12][C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)=[O:11]
Reactant: NCc1ccc(Cl)c(C(=O)Nc2ncc[nH]2)c1
Reactant: CC1(C(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C(=O)NCc2ccc(Cl)c(C(=O)Nc3ncc[nH]3)c2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
Dissolve 5-(aminomethyl)-2-chloro-N-(1H-imidazol-2-yl)benzamide dihydrochloride (100 mg, 0.35 mmol, 1.0 equiv) and 1-methylcyclopropanecarboxylic acid (45.3 mg, 0.45 mmol, 1.3 equiv) in DMF (0.697 mL), add triethylamine (82.5 μL, 0.59 mmol, 1.7 equiv) and BOP (231 mg, 0.52 mmol, 1.5 equiv). Stir the mixture at 60° C. overnight, and purify the crude mixture by flash chromatography on silica gel eluting with a 20% to 60% EtOAc/hexanes gradient. Recrystallize the material from EtOAc, filter, and wash with EtOAc to provide the title compound as a white solid (116 mg, 55%). 1H NMR (DMSO-d6, 400 MHz) δ 11.76 (br s, 2H), 8.13 (t, 1H, J=6.0 Hz), 7.43 (d, 1H, J=8.2 Hz), 7.39 (d, 1H, J=1.3 Hz), 7.29 (dd, 1H, J=8.2, 1.3 Hz), 6.74 (br s, 2H), 4.25 (d, 2H, J=6.0 Hz), 1.26 (s, 3H), 0.93 (app q, 2H, J=3.1 Hz), 0.50 (app q, 2H, J=3.2 Hz). MS (m/z) (35Cl/37Cl) 333/335 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:19](=O)[CH3:20])=[CH:10][C:11]3[O:17][CH2:16][CH2:15][CH2:14][O:13][C:12]=3[CH:18]=2)=[CH:4][CH:3]=1.C([O:24][C:25]([C:27]1[CH:50]=[CH:49][C:30]2[N:31]([CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[C:32]([C:34]3[CH:39]=[CH:38][C:37]([NH2:40])=[C:36]([CH:41]=O)[CH:35]=3)=[N:33][C:29]=2[CH:28]=1)=[O:26])C.[OH-].[K+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:19]3[CH:20]=[CH:41][C:36]4[C:37](=[CH:38][CH:39]=[C:34]([C:32]5[N:31]([CH:43]6[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]6)[C:30]6[CH:49]=[CH:50][C:27]([C:25]([OH:26])=[O:24])=[CH:28][C:29]=6[N:33]=5)[CH:35]=4)[N:40]=3)=[CH:10][C:11]3[O:17][CH2:16][CH2:15][CH2:14][O:13][C:12]=3[CH:18]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1cc2c(cc1-c1ccc(Cl)cc1)OCCCO2
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(N)c(C=O)c1)n2C1CCCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc5c(cc4-c4ccc(Cl)cc4)OCCCO5)ccc3c1)n2C1CCCCC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
1-[8-(4-Chloro-phenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-ethanone (76 mg, 0.25 mmol) and 2-(4-amino-3-formyl-phenyl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid ethyl ester (98 mg, 0.25 mmol) were dissolved in 500 μL ethanol and 500 μL 10% ethanolic KOH were added. The reaction was stirred at 75° C. overnight. The reaction was acidified with 4N hydrochloric acid, extracted three times with ethyl acetate, the organic extracts were dried with sodium sulfate and then evaporated. Purification via reverse-phase HPLC gave 132 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](=[O:12])[NH:9][C@H:8]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@H:7]3[C:6]=2[CH:5]=[C:4]([CH2:23][CH2:24][CH3:25])[CH:3]=1.Br[C:27]1C=CC(C(N(CC)CC)=O)=C(Cl)C=1>>[Cl:1][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:27])[C@H:8]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:15][C@@H:7]3[C:6]=2[CH:5]=[C:4]([CH2:23][CH2:24][CH3:25])[CH:3]=1
Reactant: CCN(CC)C(=O)c1ccc(Br)cc1Cl
Reactant: CCCc1cc(Cl)c2c(c1)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1NC2=O
Product: CCCc1cc(Cl)c2c(c1)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1N(C)C2=O

Procedure:
Following the procedure described in Example 15, Part A, (3aR,9bS)-tert-butyl 6-chloro-5-oxo-8-propyl-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate, the first eluting compound from Example 23, Part J, was converted into the title compound. LRMS (ESI): 379.17/381.15 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([CH2:17][C:18]([Cl:20])=[CH2:19])(C(OC)=O)[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[OH-].[K+]>CO.O>[CH3:1][O:2][C:3](=[O:21])[CH:4]([CH2:17][C:18]([Cl:20])=[CH2:19])[CH2:5][C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7]
Reactant: C=C(Cl)CC(CC(=O)OC(C)(C)C)(C(=O)OC)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=C(Cl)CC(CC(=O)OC(C)(C)C)C(=O)OC
Reaction time: 24 h

Procedure:
The title compound of Example 2B (1502 g, 4.18 mol) was dissolved in MeOH (2650 mL). While maintaining a temperature of 30° or below for the ensuing mixture, a cold solution of KOH (329 g, 5.85 mol) in H2O (1335 mL) was added dropwise over 20 min. The mixture was stirred vigorously for 24 h.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1.Cl>[Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:14]/[C:15]([OH:17])=[O:16]
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(C=O)c(Cl)c1O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccc(/C=C/C(=O)O)c(Cl)c1O
Temperature: 100 °C
Yield: 91.9 %

Procedure:
2-Chloro-3-hydroxy-4-methoxybenzaldehyde (1.86 g, 10 mmol) was dissolved in pyridine (7 ml), malonic acid (1.25 g, 10 mmol) and piperidine (0.1 ml) were added and the mixture was heated at 100° C. for 2 hrs, then it was poured in 100 ml HCl 1N and extracted with AcOEt. This was dried and evaporated, and the residue was triturated with diethyl ether and filtered, giving 2.10 g of (E)-3-(2-chloro-3-hydroxy-4-methoxy-phenyl)-acrylic acid as a white solid, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH:8]=[O:9].C(N(CC)CC)C.[C:17]1([C:23](Cl)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[CH3:7][N:6]1[C:2]([NH:1][C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:3]([CH:8]=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc(C=O)c1N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ncc(C=O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 70 h
Yield: 92 %

Procedure:
To a suspension of 5-amino-1-methylpyrazole-4-carbaldehyde (25 g, 200 mmol) and triethylamine (22.2 g, 220 mmol) in dichloromethane (500 ml) was added triphenylmethyl chloride (61.3 g, 220 mmol) at room temperature. The mixture was stirred at room temperature for 70 hours. The reaction mixture was washed with successively 10% aqueous citric acid solution, brine and 10% aqueous sodium hydrogencarbonate solution. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with ethyl acetate to give 1-methyl-5-triphenylmethylaminopyrazole-4-carbaldehyde (67.6 g) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]=[C:13]=[O:14].Cl.Cl.[CH2:22]([O:29][C:30](=[O:38])[CH2:31][C@@H:32]([NH2:37])[CH2:33][N:34]([CH3:36])[CH3:35])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[CH2:22]([O:29][C:30](=[O:38])[CH2:31][C@@H:32]([NH:37][C:13]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]1[CH:15]=[CH:16][CH:17]=[C:18]([F:19])[C:2]=1[F:1])=[O:14])[CH2:33][N:34]([CH3:35])[CH3:36])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C=NCCCCCCOCc1cccc(F)c1F
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)NCCCCCCOCc1cccc(F)c1F
Reaction time: 1 h
Yield: 13.3 %

Procedure:
A solution of [6-(2,3-difluoro-benzyloxy)-hexyl]-isocyanate (224 mg, 0.83 mmol) in dichloromethane (1 mL) was added at 0° C. to a suspension of (R)-3-amino-4-dimethylamino butyric acid benzyl ester dihydrochloride (255 mg, 0.83 mmol) in dichloromethane (4 mL), then a solution of triethylamine (167 mg, 1.65 mmol) in dichloromethane (1 mL) was added dropwise over 25 min. The reaction mixture was kept at <5° C. for 1 h, then allowed to reach room temperature over 1 h. Insoluble material was removed by filtration and the filtrate evaporated. The residue was purified by preparative HPLC to afford (R)-3-{3-[6-(2,3-difluoro-benzyloxy)-hexyl]-ureido}-4-dimethylamino-butyric acid benzyl ester (56 mg, 13%) as a colorless oil.