Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:5][CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29]1([CH2:35][S:36](Cl)(=[O:38])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[C:19]([N:16]1[CH2:15][CH2:14][N:13]([C:10]2[CH:9]=[CH:8][C:7]([CH2:6][N:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[S:36]([CH2:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:38])=[O:37])=[CH:12][CH:11]=2)[CH2:18][CH2:17]1)(=[O:21])[CH3:20]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(=O)N1CCN(c2ccc(CNC3CCC3)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(CN(C3CCC3)S(=O)(=O)Cc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.9 %

Procedure:
To a solution of 1-(4-(4-((cyclobutylamino)methyl)phenyl)piperazin-1-yl)ethanone (185 mg, 0.64 mmol) in dichloromethane (1.5 mL) was added triethylamine (0.18 mL, 1.29 mmol), followed by phenylmethanesulfonyl chloride (185 mg, 0.96 mmol) and the reaction was stirred at ambient temperature for 16 hours. The reaction was then filtered through diatomaceous earth, concentrated and purified by preparative reverse phase HPLC to yield 62 mg of N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-cyclobutyl-C-phenyl-methanesulfonamide. 1H NMR (400 MHz, DMSO) δ 7.46-7.29 (m, 5H), 7.18 (d, J=8.6 Hz, 2H), 6.91 (d, J=8.7 Hz, 2H), 4.36 (s, 2H), 4.18 (s, 2H), 4.14-3.98 (m, 1H), 3.63-3.48 (m, 4H), 3.18-3.10 (m, 2H), 3.10-3.00 (m, 2H), 2.03 (s, 3H), 2.01-1.89 (m, 2H), 1.89-1.72 (m, 2H), 1.54-1.15 (m, 2H); LCMS (m/z) ES+ 442.2 [M+1]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[C:10]1([NH:9][C:6]([C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)=[O:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ncc[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 21 h
Yield: 95.2 %

Procedure:
To a solution of 1H-imidazole-2-carboxylic acid (0.975 g, 8.7 mmol) in DMF (30 mL) were added aniline (0.67 mL, 8.7 mmol), EDC.HCl (2.54 g, 13.05 mmol) and HOBt (1.76 g, 13.05 mmol). The reaction mixture was stirred at room temperature for 21 hours. Then, it was poured into water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulphate, filtered and concentrated. The crude residue was purified by flash chromatography (2% to 3% methanol in dichloromethane) to yield 1.55 g (96% yield) of the title compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH:27]=[C:26]1[C:34](O)=[O:35].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH:27]=[C:26]1[C:34]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:35]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(O)c1cc2ccccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)c1cc2ccccc2o1
Yield: 98.4 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (4.0 g), triethylamine (2.2 mL), benzofuran-2-carboxylic acid (3.1 g), WSC.HCl (3.6 g), and methylene chloride (100 mL), to give the captioned compound (5.6 g, 98%) as an oily product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH:35][C:36]1[CH:47]=[C:46]2[C:39]([NH:40][CH:41]=[C:42]2[CH2:43][CH2:44][NH2:45])=[CH:38][CH:37]=1.C(Cl)CCl.CO>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17]=1[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:12]([NH:45][CH2:44][CH2:43][C:42]1[C:46]2[C:39](=[CH:38][CH:37]=[C:36]([OH:35])[CH:47]=2)[NH:40][CH:41]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1c[nH]c2ccc(O)cc12
Reactant: O=C(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCCl
Product: O=C(NCCc1c[nH]c2ccc(O)cc12)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
2a was synthesized by the condensation of 3,4,5-tris(benzyloxy)benzoic acid (860 mg, 1.95 mmol) and 5-hydroxy tryptamine hydrochloride (496 mg, 2.34 mmol) according using standard EDC coupling method. The compound was isolated as white solid (874 mg, 75%) by elution with 2% methanol in chloroform. Rf: 0.470 (5% methanol in chloroform).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].C1N=CN([C:19](N2C=NC=C2)=[O:20])C=1>O1CCOCC1>[F:12][C:9]([F:10])([F:11])[O:8][C:6]1[CH:5]=[CH:4][C:3]2[O:13][C:19](=[O:20])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(OC(F)(F)F)ccc1O
Solvent: C1COCCO1
Product: O=c1[nH]c2cc(OC(F)(F)F)ccc2o1
Temperature: 70 °C
Reaction time: 7 h
Yield: 72.4 %

Procedure:
To a mixture of 2-amino-4-(trifluoromethoxy)phenol (1.01 g) and 1,4-dioxane (20 mL) was added CDI (1.10 g), followed by heating and stirring at 70° C. for 7 hours. The reaction mixture was cooled to room temperature, and then the solvent was concentrated to a half of the volume under reduced pressure. To the obtained residue was added water (30 mL), followed by adjusting to pH 4 by the addition of concentrated hydrochloric acid under ice-cooling, and stirring at the same temperature for 1 hour. The resulting solid was collected by filtration to obtain 5-(trifluoromethoxy)-1,3-benzoxazol-2(3H)-one (830 mg).
Reaction SMILES: [C:1]([CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17])[CH2:6][C:7](O)=[O:8])(=[O:3])[NH2:2].B#B.O1CCCC1>C(Cl)Cl>[OH:8][CH2:7][CH2:6][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:17])([F:18])[F:19])[CH2:4][C:1]([NH2:2])=[O:3]
Reactant: NC(=O)CC(CC(=O)O)c1ccccc1C(F)(F)F
Agent: B#B
Solvent: ClCCl
Solvent: C1CCOC1
Product: NC(=O)CC(CCO)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
4-Carbamoyl-3-(2-trifluoromethylphenyl)butanoic acid (646 mg) was dissolved in methylene chloride (32 mL), and a diborane-tetrahydrofuran solution (7.12 mL) was added at 0° C. After stirring at room temperature for two hours, the reaction solution was cooled to 0° C. The reaction was terminated with 1 N hydrochloric acid, followed by dilution with ethyl acetate. The organic layer was washed with 1 N sodium hydroxide and brine and dried over magnesium sulfate. Concentration under reduced pressure gave a crude product (388 mg) which was used for the next reaction without purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13](O)[C:12]2[C:7](=[CH:8][C:9]([Cl:16])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].O=P(Cl)(Cl)[Cl:19]>>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([Cl:19])[C:12]2[C:7](=[CH:8][C:9]([Cl:16])=[CH:10][CH:11]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(O)c2ccc(Cl)cc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(Cl)c2ccc(Cl)cc2n1
Temperature: 140 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
7-Chloro-4-hydroxy-2-quinolinecarboxylic acid methyl ester (76 g) was added to POCl3 (100 mL) at rt, and heated at 140 degrees C. for 1 h, then cooled to rt. After the removal of excess POCl3 in vacuo, cold 1 N NaOH solution was added to pH 8, and precipitated solid was triturated, washed with water and dried under vacuum to afford 78 g (95.2%) of 4,7-dichloro-2-quinolinecarboxylic acid methyl ester as an off-white powder. LC-MS, 255 (M++1). 1H NMR (DMSO-d6): δ 3.95 (s, 3H), 7.91 (d, 1H), 8.22 (s, 1H), 8.26 (d, 1H), 8.33 (s, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][CH:8]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=O)[CH2:15][CH2:14]2)[CH2:9][CH3:10].O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1>[NH2:7][CH:8]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][CH2:15][CH2:14]2)[CH2:9][CH3:10]
Reactant: CCC(N)c1ccc2c(c1)CCC(=O)N2
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1COCCO1
Solvent: O
Product: CCC(N)c1ccc2c(c1)CCCN2
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.5 %

Procedure:
Example P-10:0.6 g of lithium aluminium hydride in 30 ml of absolute dioxane are placed under nitrogen in a sulfonation flask. The internal temperature is then increased to approximately 70° C. and a solution of 1.2 g of 6-(1-aminopropyl)-3,4-dihydro-quinolin-2-one in 30 mlof absolute dioxane is added dropwise over a period of 10 minutes. The batch is then stirred for 6 hours at an internal temperature of approximately 80°-85° C. and allowed to cool, and, while cooling with ice, water is added dropwise until all the excess lithium aluminium hydride has reacted. Approximately 40 ml of dioxane and sodium sulfate (approximately 10 g) are then added. After having stood for a short while, the batch is suction-filtered and the dioxane is removed under a water-jet pump vacuum. The dark-brown oil which remains can then be further purified by flash chromatography on silica gel (eluant: ethanol/ether 1:1) to yield 1.0 g of 6-(1-aminopropyl)-1,2,3,4-tetrahydro-quinoline in the form of a brown oil (1H-NMR).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:22][CH2:21][CH2:20][N:19]([CH:23]2[CH2:26][CH2:25][CH2:24]2)[CH2:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH:30]([CH3:32])[CH3:31]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH:30]([CH3:32])[CH3:31])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:22][CH2:21][CH2:20][N:19]([CH:23]2[CH2:24][CH2:25][CH2:26]2)[CH2:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Br
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCCN(C2CCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)O[C@@H]1C[C@@H](C(=O)N2CCCN(C3CCC3)CC2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.1 %

Procedure:
To a solution of (2S,4R)-2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (287 mg, 0.78 mmol) in DMF (7.8 mL) was added NaH (90%; 31 mg). After 30 min, 2-bromopropane (109 μL, 1.17 mmol) was added and the mixture was allowed to warm to rt and was stirred for 18 h. The mixture was diluted with satd. aq. NaHCO3 and extracted with CH2Cl2. The combined organic layers were dried and concentrated. The crude product was purified by FCC to provide the desired product (26 mg, 8%). MS (ESI): mass calcd. for C22H39N3O4, 409.29; m/z found, 410.4 [M+H]+. 1H NMR (CDCl3): 4.74-4.58 (m, 1H), 4.33-4.16 (m, 1H), 3.74-3.33 (m, 7H), 2.90-2.78 (m, 1H), 2.59-2.30 (m, 4H), 2.19-2.11 (m, 1H), 2.10-1.96 (m, 4H), 1.87-1.72 (m, 3H), 1.69-1.53 (m, 2H), 1.40 (d, J=17.6 Hz, 9H), 1.12 (dd, J=6.0, 2.2 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:11]([C:16]([O:18]CC)=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=1.[OH-].[Na+].O.C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:11]([C:16]([OH:18])=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1ccccc1-c1ccc(OC)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2ccccc2C(=O)O)c(Cl)c1
Temperature: 110 °C
Reaction time: 4.5 h
Yield: 82.1 %

Procedure:
Ethyl 2′-chloro-4′-methoxybiphenyl-2-carboxylate (67.7 g) was dissolved in ethanol (100 ml), 4N aqueous sodium hydroxide (100 ml) was added, and the mixture was stirred at an oil bath temperature of 110° C. for 4.5 hr. The reaction mixture was cooled to room temperature, water (200 ml) and toluene (100 ml) were added, and the mixture was stirred overnight. To the reaction mixture was added activated carbon (3.6 g), and the mixture was further stirred for 1 hr. The insoluble material was filtered off through celite, and the insoluble material was washed with toluene (30 ml) and water (300 ml). The obtained filtrates were combined to allow for layer separation. The obtained aqueous layer was washed with toluene (100 ml), the aqueous layer was acidified with concentrated hydrochloric acid (40 ml), and stirred at room temperature for 1 hr. The precipitated solid was collected by filtration. The obtained solid was air-dried for 3 hr, and dried under reduced pressure at 60° C. overnight to give the title compound (50.2 g).
Reaction SMILES: [CH:1](/[C@H:6]1[CH2:11][CH2:10][C@H:9]([CH:12]([C:16](O)=[O:17])[C:13](O)=[O:14])[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O>C(OCC)C>[CH:1](/[C@H:6]1[CH2:7][CH2:8][C@H:9]([CH:12]([CH2:13][OH:14])[CH2:16][OH:17])[CH2:10][CH2:11]1)=[CH:2]\[CH2:3][CH2:4][CH3:5]
Reactant: CCC/C=C/[C@H]1CC[C@H](C(C(=O)O)C(=O)O)CC1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCC/C=C/[C@H]1CC[C@H](C(CO)CO)CC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 28.6 g of [trans-4-(1E-pentenyl)cyclohexyl]malonic acid in 150 ml of absolute diethyl ether is added dropwise in an inert gas atmosphere within 1 hr. to a suspension of 8.6 g of lithium aluminium hydride in 250 ml of absolute diethyl ether in such a manner that the mixture does not boil too strongly. The mixture is heated to boiling for a further 4 hours and then there are cautiously added dropwise thereto 15 ml of ice-cold water and thereafter 250 ml of 25 percent (v/v) sulphuric acid until the aqueous phase thickens to a grey sludge. The ether phase is decanted and the residue is extracted with four 200 ml portions of diethyl ether. The combined ether phase is washed once with 25 ml of 25 percent sulphuric acid, with two 25 ml portions of saturated sodium hydrogen carbonate solution and with two 25 ml portions of saturated sodium chloride solution, then dried over sodium sulphate and concentrated. Fractional distillation of the residue in a high vacuum gives pure 2-[trans-4-(1E-pentenyl)cyclohexyl]-1,3-propanediol.
Reaction SMILES: [C:1]([OH:6])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH3:7][CH:8](O)[CH3:9].S(=O)(=O)(O)O>>[CH:8]([O:5][C:1](=[O:6])/[CH:2]=[CH:3]/[CH3:4])([CH3:9])[CH3:7]
Reactant: CC(C)O
Reactant: C/C=C/C(=O)O
Agent: O=S(=O)(O)O
Product: C/C=C/C(=O)OC(C)C
Temperature: 25 °C
Yield: 76 %

Procedure:
Crotonic acid (193.7 g, 2.25 mol) was dissolved in 2-propanol (860 mL, 11.25 mol) in a 2 L flask and then well stirred, after which sulfuric acid (24 mL, 0.45 mol) was slowly added in droplets to the mixture and refluxed and stirred for 48 hours or longer. The stirred mixture was cooled to room temperature, after which the obtained mixture was washed with distilled water (1000 mL), and the organic layer was separated, neutralized and subjected to atmospheric distillation (80° C.), thus obtaining 220 g (1.71 mol, yield 76.3%) of crotonic acid isopropyl ester.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[CH:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].[C:27](Cl)(=O)[C:28](Cl)=O.C(O)C.N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[CH:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([O:14][CH2:27][CH3:28])=[O:13])(=[O:7])=[O:6]
Reactant: COc1ccc(COC(C(=O)O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(OCc1ccc(OC)cc1)C(C)(C)COS(=O)(=O)CCCCl
Yield: 506.8 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R/S)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoic acid (14) (0.5 g, 1.2 mmol) dissolved in 5 mL of anhydrous dichloromethane (DCM) was reacted with 0.14 mL (0.2 g, 0.14 mmol) of oxalyl chloride. After the reaction was complete, a solution of 5 mL of ethanol (EtOH) and 0.16 mL of pyridine (0.15 g, 1.9 mmol) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 0.31 g (58% yield) of the title compound (23a) as a colorless oil. Rf=0.59 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=1.05 (s, 3H), 1.06 (s, 3H), 1.33 (t, J=6.8 Hz, 3H), 2.25-2.33 (m, 2H), 3.22-3.26 (m, 2H), 3.65-3.68 (m, 2H), 3.81 (s, 1H), 3.82 (s, 3H), 3.97 (d, J=9.2 Hz, 1H), 4.19-4.31 (m, 4H), 4.56 (d, J=11.2 Hz, 1H), 6.88 (d, J=8.4 Hz, 2H), 7.26 (d, J=9.2 Hz, 2H) ppm. MS (ESI) m/z 458.97 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]3[CH2:18][CH2:19][N:20]([C:22](=O)[CH2:23][CH2:24][CH:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[OH:26])[CH2:21][C:5]=3[C:4]=2[CH:3]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].O>C1(C)C=CC=CC=1>[CH:28]1[C:27]([CH:25]([OH:26])[CH2:24][CH2:23][CH2:22][N:20]2[CH2:21][C:5]3[C:4]4[CH:3]=[C:2]([F:1])[CH:10]=[CH:9][C:8]=4[N:7]([C:11]4[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=4)[C:6]=3[CH2:18][CH2:19]2)=[CH:32][CH:31]=[C:30]([F:33])[CH:29]=1
Reactant: O=C(CCC(O)c1ccc(F)cc1)N1CCc2c(c3cc(F)ccc3n2-c2ccc(F)cc2)C1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: OC(CCCN1CCc2c(c3cc(F)ccc3n2-c2ccc(F)cc2)C1)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of 1.16 g 8-fluoro-5-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyryl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.0025 mole) in toluene (35 ml) was stirred under nitrogen while 0.0132 mole of sodium bis(2-methoxyethoxy)aluminum hydride (70% in benzene) was added. The resulting mixture was heated on a steam bath one hour, cooled to room temperature and poured into water, and extracted with ethyl acetate. The organic layer was concentrated in vacuo. The resulting residue was chromatographed on silica gel with ethyl acetate as eluant and monitoring by tlc (two solvent systems: 9:1 CHCl3 :methanol and acetonitrile) with authentic flutroline as control. Product fractions were combined, evaporated to drynes, the residue triturated with diisopropyl ether to yield title product, 175 mg; m.p. 141.5-144; mixed up with authentic flutroline, no depression.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][C:18]2[CH2:17][CH2:16][C:15](=[O:21])[NH:14][C:13]=2[N:12]=1)(=O)=O.[Na+].[I-].CCN(CC)CC.[Cl:31][C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[N:39]1[CH2:45][CH2:44][CH2:43][N:42](CCCCOC2C=C3C(CCC(=O)N3)=CC=2)[CH2:41][CH2:40]1>CC#N>[Cl:31][C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[N:39]1[CH2:45][CH2:44][CH2:43][N:42]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[N:12]=[C:13]3[C:18]([CH2:17][CH2:16][C:15](=[O:21])[NH:14]3)=[CH:19][CH:20]=2)[CH2:41][CH2:40]1
Reactant: O=C1CCc2ccc(OCCCCN3CCCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Reactant: CS(=O)(=O)OCCCCOc1ccc2c(n1)NC(=O)CC2
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCc2ccc(OCCCCN3CCCN(c4cccc(Cl)c4Cl)CC3)nc2N1
Temperature: 70 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
Intermediate 12 (85 mg, 0.27 mmol) was dissolved in CH3CN then NaI (55 mg, 0.37 mmol), Et3N (91 mg, 0.9 mmol), and intermediate 2 (102 mg, 0.36 mmol) were added. The resulting mixture was stirred at 70° C. overnight. Precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=30:1) to give 7-(4-(4-(2,3-dichlorophenyl)-1,4-diazepan-1-yl)butoxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (compound 3) (78 mg, 63%). 1H NMR (300 MHz, CDCl3): δ 7.64 (s, 1H), 7.38 (d, J=8.1 Hz, 1H), 7.27-7.15 (m, 2H), 7.06 (d, J=8.1 Hz, 1H), 6.37 (d, J=8.1 Hz, 1H), 4.36 (t, J=6.0 Hz, 2H), 3.61-3.49 (m, 7H), 3.32-3.20 (m, 5H), 2.90-2.85 (m, 2H), 2.67-2.62 (m, 2H), 2.21-2.16 (m, 2H), 1.90-1.85 (m, 2H). HPLC: 99%, RT 2.682 min. MS (ESI) m/z 463.1 [M+H]+. mp: 110-111° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@H:9]1[C:14]1[NH:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28](B4OC(C)(C)C(C)(C)O4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:41]1[CH:66]=[CH:65][C:44]2[NH:45][C:46]([C@@H:48]3[CH2:52][C@H:51]([CH3:53])[CH2:50][N:49]3[C:54](=[O:64])[C@@H:55]([NH:59][C:60](=[O:63])[O:61][CH3:62])[CH:56]([CH3:58])[CH3:57])=[N:47][C:43]=2[CH:42]=1.C(Cl)Cl.C([O-])(O)=O.[Na+]>CC(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@H:9]1[C:14]1[NH:15][CH:16]=[C:17]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:41]4[CH:66]=[CH:65][C:44]5[NH:45][C:46]([C@@H:48]6[CH2:52][C@H:51]([CH3:53])[CH2:50][N:49]6[C:54](=[O:64])[C@@H:55]([NH:59][C:60]([O:61][CH3:62])=[O:63])[CH:56]([CH3:57])[CH3:58])=[N:47][C:43]=5[CH:42]=4)=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[N:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1C[C@@H](c2nc(-c3ccc(-c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2cc(I)ccc2[nH]1)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2cc(-c3ccc(-c4ccc(-c5c[nH]c([C@@H]6C[C@H](C)CN6C(=O)OC(C)(C)C)n5)cc4)cc3)ccc2[nH]1)C(C)C
Temperature: 80 °C
Yield: 37.9 %

Procedure:
To a suspension of (2S,4S)-4-methyl-2-{4-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (138 mg, 0.2606 mmol), methyl ((S)-1-((2S,4S)-2-(5-iodo-1H-benzo[d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (126.2 mg, 0.2606 mmol), Pd(DPPF)(Cl)2.CH2Cl2 (21.3 mg, 0.02606 mmol) in 2-propanol (1.4 mL) is added 1M aqueous NaHCO3 (1.3 mL, 1.3 mmol). The reaction mixture is heated at 80° C. for 19 hours, cooled to RT, and extracted with dichloromethane (2×10 mL). The organic layer is dried over Na2SO4, filtered, and concentrated to dryness. The residue is purified by flash column chromatography on silica gel (50 to 100% EtOAc in hexanes) to give (2S,4S)-2-[4-(4′-{2-[(2S,4S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-4-methyl-pyrrolidin-2-yl]-1H-benzoimidazol-5-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (75 mg, 38%). HPLC: Waters symmetry shield RP18 3.5 μm 4.6 mm×50 mm, solvent A: 0.01% TFA in acetonitrile, solvent B: 0.01% TFA in water, gradient: 15:85 A:B to 90:10 A:B over 10 minutes, RT=4.87 min.