Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH2:10][C:11](Cl)=[O:12].[NH2:14][CH:15]([CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([O:25][CH3:26])[CH2:21][CH2:20]1)[C:16]#[N:17].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[C:16]([CH:15]([NH:14][C:11](=[O:12])[CH2:10][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=1[CH3:9])[CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([O:25][CH3:26])[CH2:21][CH2:20]1)#[N:17]
Reactant: CON1CCC(CC(N)C#N)CC1
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CON1CCC(CC(C#N)NC(=O)Cc2c(C)cc(C)cc2C)CC1
Reaction time: 0.5 h

Procedure:
At room temperature, (2,4,6-trimethyl-phenyl)-acetyl chloride (10.6 g, 54 mmol) was added dropwise to a mixture of 2-amino-3-(1-methoxy-piperidin-4-yl)-propionitrile (6.6 g, 36 mmol) and K2CO3 (9.9 g, 72 mmol) in 100 ml of THF. After the addition, the mixture was stirred for 0.5 h. The reaction mixture was diluted with 50 ml of water and extracted with EtOAc five times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel Yield: 10.6 g of N-[1-cyano-2-(1-methoxy-piperidin-4-yl)-ethyl]-2-(2,4,6-trimethyl-phenyl)-acetamide as a solid.
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[CH:7][C:8]([NH2:20])=[C:9]([CH:19]=1)[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:11])[C:2]([CH3:4])=[O:3].[BH4-].[Na+].CO>C(O)C.O>[NH:1]([C:5]1[CH:6]=[CH:7][C:8]([NH2:20])=[C:9]([CH:19]=1)[CH:10]([OH:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1ccc(N)c(C(=O)c2ccccc2Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: CC(=O)Nc1ccc(N)c(C(O)c2ccccc2Cl)c1

Procedure:
A solution of 108.92 g of 5-acetamino-2-amino-2'-chlorobenzophenone in 1.4 l of ethanol is treated dropwise at room temperature with a solution of 15.9 g of sodium borohydride in 100 ml of water. The solution obtained is then heated to boiling under reflux until decolourization occurs and subsequently, after the addition of 300 ml of methanol, heated for a further 15 minutes. The organic solvents are distilled off in vacuo and the residue is suspended in 0.5 l of water. The crystals obtained are recrystallized from ethanol/water. There is obtained 5-acetamino-2-amino-2'-chlorobenzhydrol of melting point 137°-138°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:15])=[C:4]([CH3:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]=1[CH3:13].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.ClCCl.C(OC(C)C)(C)C>N1C=CC=CC=1>[CH3:11][C:8]1([CH3:10])[CH2:7][C:6]2[C:12]([CH3:13])=[C:2]([NH:1][S:22]([C:19]3[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=3)(=[O:24])=[O:23])[C:3]([CH3:15])=[C:4]([CH3:14])[C:5]=2[O:9]1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(C)O2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC(C)OC(C)C
Product: Cc1ccc(S(=O)(=O)Nc2c(C)c(C)c3c(c2C)CC(C)(C)O3)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
5-Amino-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran (2.00 g, 9.74 mmol) and p-toluenesulfonyl chloride (2.04 g, 10.7 mmol) were dissolved in pyridine (30 ml) and stirred at 50° C. for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform. The mixture was washed with 1N hydrochloric acid and saturated saline and dried and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (hexane-ethyl acetate, 97:3). The crude crystals were recrystallized from dichloromethane-isopropyl ether to obtain the desired compound (2.41 g, yield: 68.8% yield), m.p. 219°-220° C. (dichloromethane-isopropyl ether).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=2)[CH:8]=[N:7]1.[Cl-].[NH4+]>[Fe].C(O)C.O>[CH3:18][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:15])[CH:13]=2)[CH:8]=[N:7]1
Reactant: CN(C)CCCn1ncc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN(C)CCCn1ncc2ccc(N)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of dimethyl-{3-(6-nitro-indazol-1-yl)-propyl}-amine (0.400 g, 1.61 mmol), iron powder (0.897 g, 16.1 mmol), and ammonium chloride (0.0430 mg, 0.811 mmol) in a 4:1 solution of ethanol/H2O was heated to reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was taken up and stirred in triethylamine/ethyl acetate (1/4, 30 mL) for 15 minutes, filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4) and concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.95 (m, J=14.75, 7.63 Hz, 2 H), 2.28 (m, 6 H), 2.38 (t, J=6.95 Hz, 2 H), 4.18 (t, J=6.95 Hz, 2 H), 5.30 (s, 2 H), 6.50 (m, 2 H), 7.35 (m, 1 H), 7.71 (s, 1 H); MS (DCI/NH3) m/z 219 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])/[C:3](=[CH:7]\[CH3:8])/[C:4]([OH:6])=O.CCOC(OC(OCC)=O)=O.[F:30][C:31]([F:48])([F:47])[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[C:43]([CH2:45][NH2:46])[CH:42]=[CH:41][N:40]=2)=[CH:35][CH:34]=1>C1COCC1>[CH3:1][N:2]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])/[C:3](=[CH:7]\[CH3:8])/[C:4]([NH:46][CH2:45][C:43]1[CH:42]=[CH:41][N:40]=[C:39]([C:36]2[CH:35]=[CH:34][C:33]([O:32][C:31]([F:48])([F:30])[F:47])=[CH:38][CH:37]=2)[CH:44]=1)=[O:6]
Reactant: C/C=C(/C(=O)O)N(C)S(=O)(=O)c1ccc(F)cc1
Reactant: NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C/C=C(/C(=O)NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1)N(C)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.3 %

Procedure:
Acid 11A (515 mg, 2.5 mmol) was dissolved in 10 ml of THF and at rt DEPC (1.1 equiv, 0.38 ml) and [2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (1.1 equiv., 737 mg) were added to the solution. The mixture was stirred at rt overnight then evaporated. The residue was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (1:1 EtOAc:petroleum ether) afforded 200 mg of a pale yellow solid. Yield=15% 1HNMR (DMSO, 200 MHz) δ 1.74 (3H, d J=7.4 Hz), 3.06 (3H, s), 4.40 (2H, d, J=6 Hz), 6.83 (1H, q, J=7 Hz), 7.44 (5H, m), 7.83 (3H, m), 8.18 (2H, d, J=8.2 Hz), 8.59 (1H, d, J=5.2 Hz), 8.70 (1H, bt) [M+1] 524.3 (C24H21F4N3O4S requires 523.50).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][NH:15][C@H:14]([C:17]([NH:19][C:20]2([C:23]#[N:24])[CH2:22][CH2:21]2)=[O:18])[CH2:13]1)(=[O:11])=[O:10].Cl.[CH3:26][C:27]1([CH3:39])[CH2:32][CH2:31][CH2:30][N:29]([C:33]2([C:36](O)=[O:37])[CH2:35][CH2:34]2)[CH2:28]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:36]([C:33]2([N:29]3[CH2:30][CH2:31][CH2:32][C:27]([CH3:39])([CH3:26])[CH2:28]3)[CH2:35][CH2:34]2)=[O:37])[C@H:14]([C:17]([NH:19][C:20]2([C:23]#[N:24])[CH2:22][CH2:21]2)=[O:18])[CH2:13]1)(=[O:11])=[O:10]
Reactant: CC1(C)CCCN(C2(C(=O)O)CC2)C1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)CN2)CC1
Agent: Cl
Product: CC1(C)CCCN(C2(C(=O)N3C[C@H](S(=O)(=O)c4ccccc4Cl)C[C@H]3C(=O)NC3(C#N)CC3)CC2)C1
Yield: 15 %

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7A with 1-(3,3-dimethylpiperidin-1-yl)cyclopropanecarboxylic acid hydrochloride 16M carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(3,3-dimethylpiperidin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide as a light yellow solid (15%). MS ISP (m/e): 533.3 (100) [(M+H)]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:7][C:6]=1[C:22]1[CH:23]=[N:24][CH:25]=[N:26][CH:27]=1)=[O:4].[OH-].[Li+].Cl.O>C1COCC1.CO>[CH3:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[C:6]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[CH:9]=1
Reactant: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)cc1-c1cncnc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)cc(-c2cncnc2)c1C(=O)O
Temperature: 50 °C
Reaction time: 40 h
Yield: 95.4 %

Procedure:
To a solution of 0.43 g (1.20 mmol) of 5-methyl-3-pyrimidin-5-yl-3′-trifluoromethyl-biphenyl-4-carboxylic acid methyl ester in 12 ml of THF/MeOH (1:1) was added 2.89 ml (2.90 mmol) of lithium hydroxide solution (1 molar in water) drop by drop and the reaction mixture was then heated up to 50° C. After 40 hours, the reaction mixture was poured into crashed ice and acidified with HCl/H2O (1N) to pH 3.0 and then extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 3:2) to give 0.410 g (99%) of the title compound as colorless solid. MS: 357.0 (M−H−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([C:13]([O:15]C)=[O:14])[CH2:9][CH2:8]2.P([O-])([O-])([O-])=O.Cl.CC(=O)OCC(COC(=O)C)OC(=O)C.[OH-].[Na+].C(=O)(O)[O-].[Na+].COC1C=CC=C2C=1C[C@@H](C(OC)=O)CC2>C(O)(C)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@H:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]2
Reactant: COC(=O)C1CCc2cccc(OC)c2C1
Agent: COC(=O)[C@H]1CCc2cccc(OC)c2C1
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)OCC(COC(C)=O)OC(C)=O
Solvent: CC(C)(C)O
Product: COc1cccc2c1C[C@H](C(=O)O)CC2
Reaction time: 7 h

Procedure:
1.1 g (0.0051 mol) of methyl 8-methoxy-1,2,3,4-tetrahydro-2-naphthoate are dissolved in 39 ml of tert-butanol, and 112 ml of phosphate buffer at pH 7 are added to the solution prepared in this way. The pH of the solution, which rises to 7.3-7.5, is lowered to 7.1 by the addition of 1N HCl. 1.25 g of Sigma PPL enzyme (known as porcine pancreatic lipase type II, crude, Sigma L-3126--46 U/mg using triacetin) are added to the mixture. The pH tends to drop as the reaction progresses, but is kept constant by the addition of a 0.25N solution of NaOH, the pH being controlled by an automatic titration apparatus. After 7 hours, the mixture is poured into a 5% solution of sodium bicarbonate in order to stop the reaction by inactivation of the enzyme. Extraction is carried out with ethyl ether and the two phases are separated. The organic phase contains the unreacted ester principally of (S) configuration, which can be recovered. The aqueous phase is acidified with 10% sulfuric acid and extracted with chloroform; the organic phase is filtered on Celite and dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give 0.42 g of the title acid. ee 98% (HPLC performed under conditions (d)).
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(COS(C)(=O)=O)C(=O)N(CC(C)C)N=1.[Cl:26][C:27]1[CH:53]=[CH:52][C:30]([CH2:31][N:32]2[C:37](=[O:38])[C:36]([C:39]([O:41]C)=[O:40])=[CH:35][C:34]([C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[C:45]([F:51])[CH:44]=3)=[N:33]2)=[CH:29][CH:28]=1>>[C:39]([C:36]1[C:37](=[O:38])[N:32]([CH2:31][C:30]2[CH:29]=[CH:28][C:27]([Cl:26])=[CH:53][CH:52]=2)[N:33]=[C:34]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[C:45]([F:51])[CH:44]=2)[CH:35]=1)([OH:41])=[O:40]
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(Cc2ccc(Cl)cc2)c1=O
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(COS(C)(=O)=O)c1=O
Product: COc1ccc(-c2cc(C(=O)O)c(=O)n(Cc3ccc(Cl)cc3)n2)cc1F
Yield: 96 %

Procedure:
Following the procedure of Example 1 (7), 2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one was reacted to yield the title compound as a pale yellow crystalline powder (yield: 96.0%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=3)=[N:7][NH:8]2)=[CH:4]C=1C#N.S(=O)(=O)(O)O.[C:30]([OH:33])(=[O:32])[CH3:31]>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=3)=[N:7][NH:8]2)=[CH:4][C:31]=1[C:30]([OH:33])=[O:32]
Reactant: N#Cc1cc2c(/C=C/c3ccc4ccccc4c3)n[nH]c2cc1F
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc2c(/C=C/c3ccc4ccccc4c3)n[nH]c2cc1F
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a suspension of 588 mg of 6-fluoro-3-[(E)-2-(naphthalen-2-yl)-vinyl]-1H-indazole-5-carbonitrile in 3 mL of acetic acid and 1 mL of water was added 3 mL of concentrated sulfuric acid, and stirred at 110° C. for 1 hours. After allowing to cool, the reaction solution was added with ice, and extracted with a mixed solvent of 30 mL ethyl acetate/15 mL tetrahydrofuran. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resultant crude product was dissolved in 6 mL of 1,4-dioxane, added with 6 mL of 4N lithium hydroxide, and stirred at 120° C. for 15 hours. The reaction solution was made acidic with 5N hydrochloric acid, and then extracted with a mixed solvent of 30 mL ethyl acetate/20 mL tetrahydrofuran. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, to afford 477 mg of the title compound as ocher crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[CH:12][CH:11]=[N:10]1)[NH2:5].C[Al](C)C.[NH:18](/[C:22](/[CH3:28])=[CH:23]\[C:24](OC)=[O:25])[C:19]([CH3:21])=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:24](=[O:25])[CH:23]=[C:22]([CH3:28])[N:18]=[C:19]2[CH3:21])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[CH:12][CH:11]=[N:10]1
Reactant: Nc1ccc(-n2cccn2)c(F)c1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(-n3cccn3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.2 %

Procedure:
To a solution of 3-fluoro-4-(1H-pyrazol-1-yl)aniline (0.65 g, 3.68 mmol) in CH2Cl2 (30 mL) was added trimethylaluminum (18.4 mL, 36.8 mmol, 2 M in heptane) slowly. The reaction mixture was stirred at rt for 0.5 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (634 mg, 4.04 mmol) in CH2Cl2 (10 mL). The reaction was stirred at rt for 3 days, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (100 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:2) to give the title compound as a white solid (400 mg, 38%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[C:18]([N+:30]([O-:32])=[O:31])=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:28])([CH3:27])[C:21]=3[CH:29]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH:33]O>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[C:18]([N+:30]([O-:32])=[O:31])=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:28])([CH3:27])[C:21]=3[CH:29]=2)=[O:33])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: OO
Reactant: CC(=O)Nc1ccc(SCCCCOc2cc3c(cc2[N+](=O)[O-])NC(=O)OC3(C)C)cc1
Product: CC(=O)Nc1ccc(S(=O)CCCCOc2cc3c(cc2[N+](=O)[O-])NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-acetamido-phenylmercapto)-butoxy]-7-nitro-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[N:4]=[CH:3]1.C(N(CC)CC)C.[C:20]1([C:26](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[C:20]1([C:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:2]2[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[N:4]=[CH:3]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CCc1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 3-(imidazol-4-yl)propionate hydrochloride, as described above in Step B, (20.2 g, 106 mmol) in dry CHCl3 (500 mL) were added triethylamine (44 mL, 318 mmol), then a solution of triphenylmethyl chloride (29.5 g, 106 mmol) in CHCl3 (100 mL). The mixture was stirred at ambient temperature for 18 hours, then washed with H2O (250 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to yield the product as a pale solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)[CH:7]=[CH:6]2.[C:22]([CH2:26][C:27](Cl)=[O:28])([CH3:25])([CH3:24])[CH3:23].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[C:17]=1[C:27](=[O:28])[CH2:26][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(-c3cc4ccccc4o3)ccc2c1
Reactant: CC(C)(C)CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc2cc(-c3oc4ccccc4c3C(=O)CC(C)(C)C)ccc2c1

Procedure:
Following the procedure described in Step 2 of Example 1, the title compound was prepared from 2-(6-methoxy-2-naphthyl)-1-benzofuran (3.00 g, 10.9 mmol), t-butyl acetyl chloride (2.3 mL, 16 mmol), and tin (IV) chloride (1.7 mL, 14 mmol) in chloroform (60 mL). The reaction mixture was refluxed for 24 hours. Purification by HPLC using 7-8% ethyl acetate in hexane as the mobile phase yielded a yellow solid (1.09 g), mp ˜140° C. 1HNMR (200 MHz, DMSO-d6): δ8.35 (s, 1H), 7.9-8.1 (m, 3H), 7.7-7.85 (m, 2H), 7.35-7.5 (m, 3H), 7.3 (d, 1H, J=9.0 Hz), 3.95 (s, 3H), 2.75 (s, 2H), and 0.85 ppm (s, 9H).
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]2[N:21]3[C:22]4[N:13]([C:14](=[O:24])[CH:15]=[CH:16][C:17]=4[CH:18]=[CH:19][C:20]3=[O:23])[CH2:12]2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[O:32]1[C:36]2[CH:37]=[C:38]([CH:41]=O)[CH:39]=[CH:40][C:35]=2[CH2:34][CH2:33]1>C(Cl)(Cl)Cl.CO>[ClH:1].[O:32]1[C:36]2[CH:37]=[C:38]([CH2:41][NH:3][CH:4]3[CH2:5][CH2:6][N:7]([CH2:10][C@H:11]4[N:21]5[C:22]6[N:13]([C:14](=[O:24])[CH:15]=[CH:16][C:17]=6[CH:18]=[CH:19][C:20]5=[O:23])[CH2:12]4)[CH2:8][CH2:9]3)[CH:39]=[CH:40][C:35]=2[CH2:34][CH2:33]1
Reactant: O=Cc1ccc2c(c1)OCC2
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=c1ccc2ccc(=O)n3c2n1C[C@H]3CN1CCC(NCc2ccc3c(c2)OCC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26 %

Procedure:
A solution of (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione dihydrochloride (for a preparation see Example 5A(j)) (133 mg, 0.356 mmol) and triethylamine (0.124 ml, 0.891 mmol) in chloroform (4.5 ml) and methanol (0.5 ml) at rt was stirred at rt for 15 min then 2,3-dihydro-1-benzofuran-6-carbaldehyde (44 mg, 0.297 mmol) in chloroform (2 ml) was added dropwise at rt. The reaction mixture was stirred at rt overnight. The reaction was quenched with NaHCO3 (aq) (20 ml), extracted with 20% MeOH/DCM (3×30 ml). The combined organic layers were dried over MgSO4, filtered, evaporated and chromatographed (0-50% MeOH/DCM). The relevant fractions were combined and evaporated to deliver the free base of the title compound as a pale yellow clear oil (18 mg, 0.04 mmol, 26%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][N:29]([CH3:37])[C:30](=[O:36])[CH2:31][CH2:32][C:33](O)=[O:34]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[CH2:32][CH2:31][C:30]([N:29]([CH3:37])[CH3:28])=[O:36])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CN(C)C(=O)CCC(=O)O
Agent: Cl
Product: CN(C)C(=O)CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (48 mg, 52%), MS (ISP) m/z=458.6 [(M+H)+], mp 188° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and 4-(dimethylamino)-4-oxobutanoic acid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]2[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[NH:10][CH2:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[C:80]([CH2:82][C:83](O)=[O:84])#[N:81].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(#N)C>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[N:34]=[N:33][N:32]=3)=[CH:23][CH:24]=2)[C:7]2[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[N:10]([C:83](=[O:84])[CH2:82][C:80]#[N:81])[CH2:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)CC(C(=O)OC)NC2
Reactant: N#CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)CC(C(=O)OC)N(C(=O)CC#N)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
A mixture of methyl 2-n-butyl-1-{2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-6-carboxylate (0.81 g), dicyclohexyl-carbodiimide (0.26 g), 1-hydroxybenzotriazole (0.17 g), cyanoacetic acid (0.11 g) and acetonitrile (10 ml) is stirred at room temperature overnight. After the reaction is completed, ethyl acetate is added to the reaction mixture, and the mixture is waehed with aqueous sodium hydrogen carbonate solution, dried, and the solvent is distilled off under reduced pressure. The resulting residue is purified by silica gel column chromatography (solvent; ethyl acetate) to give methyl 2-n-butyl-5-cyanoacetyl-1-{2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-6-carboxylate (0.83 g) as foam.