Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C>C1(C)C=CC=CC=1>[CH:10](=[N:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:8]=[C:7]([Cl:9])[CH:6]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1cc(Cl)cc(N=Cc2ccccc2)c1

Procedure:
To a reaction flask, equipped with a Dean-Stark trap, is added 3,5-dichloroaniline (16.2 g., 0.10 mole), benzaldehyde (10.6 g., 0.10 mole), p-toluenesulfonic acid monohydrate (0.2 g.), and toluene (100 ml.). The reaction mixture is then warmed to reflux and the water (1.65 ml.) collected by azeotroping. The cooled reaction mixture is treated with charcoal and the filtrate reduced in vacuo to give an amber oil that crystallizes on standing to give N-benzylidene-3,5-dichloroaniline which is recrystallized from pentane. m.p. 52°-53° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([OH:27])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:29]1[C:33]2C=CC=CC=2N=N1.Cl.CN.CN1CCOCC1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH3:33][NH:29][C:25](=[O:27])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CNC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of N-tertiarybutoxycarbonyl-O-benzyl-L-tyrosine (7.4 g, 20 mM), 1-hydroxybenzotriazole (3 g, 20 mM), methylamine HCl (1.3 g, 20 mM) and N-methylmorpholine (2 g, 20 mM) in CH2Cl2 (20 ml) stired and cooled to 0° was added DCC (4.2 g, 20 mM). After being allowed to stir and warm to room temperature overnight the reaction mixture was filtered and washed with saturated aqueous sodium bicarbonate solution, 3N citric acid and brine. The dried organic extract was then concentrated in vacuo to give N-tertiarybutoxycarbonyl-O-benzyl-L-tyrosine N-methylamide as a solid. Recrystallisation from dichloromethane/hexane gave (4.5 g); m.p. 165°-172°; (Found: C, 68.85; H, 7.43; N, 7.39. C22H28N2O4 requires C, 68.73; H, 7.34; N, 7.29%); δ (CDCl3) 1.40 (9H, s, OC(CH3)3); 2.73 (3H, d, J=5 Hz, CONHCH3); 2.96 (2H, m, CH2Tyr); 4.25 (1H, m, α-CH); 5.03 (2H, s, CH2C6H5); 5.80 (1H, br, CONH); 6.86 (2H, d, J=8 Hz, Tyr); 7.12 (2H, d, J=8 Hz, Tyr); 7.3-7.5 (5H, m, C6H5).
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:13]([CH2:34][O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:12][C@@H:11]1[O:44][C@H:45]1[C@@H:58]([O:59][C:60](=[O:67])[C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C@H:57]([O:68][C:69](=[O:76])[C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[C@@H:56]([CH2:77][O:78][C:79](=[O:86])[C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)[O:55][C@@H:46]1[O:47]CC1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.CCOC(C)=O.[Pd]>[C:1]([O:9][C@H:10]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:25][C:26](=[O:33])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:13]([CH2:34][O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:12][C@@H:11]1[O:44][C@H:45]1[C@@H:58]([O:59][C:60](=[O:67])[C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C@H:57]([O:68][C:69](=[O:76])[C:70]2[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=2)[C@@H:56]([CH2:77][O:78][C:79](=[O:86])[C:80]2[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=2)[O:55][CH:46]1[OH:47])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC[C@H]1O[C@H](O[C@@H]2[C@@H](OCc3ccccc3)O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(OC[C@H]1O[C@H](O[C@@H]2C(O)O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reaction time: 72 h
Yield: 98.5 %

Procedure:
The disaccharide 28 (670 mg, 0.577 mmol) was dissolved in MeOH (3 mL) and EtOAc (30 mL). Palladium on charcoal (5%, 80 mg) was added. The mixture was stirred under 50 psi of hydrogen at r.t. o/n. TLC indicated ˜60% conversion. More palladium on charcoal (5%, 80 mg) was added. Stirring was continued at 50 psi for 3 days. TLC indicated complete conversion. The mixture was filtered through a plug of Celite and rinsed with EtOAc (5×1 mL). The combined filtrate and washings were evaporated to dryness to give the title compound 29 as a colourless foam (609 mg, 99%). The product was used directly for the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27]CC2C=CC=CC=2)=[C:23]([O:35]CC2C=CC=CC=2)[CH:22]=1)[C:10]([O:12][C@H:13]([CH3:19])[CH2:14][O:15][C:16](=[O:18])[CH3:17])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[OH:35][C:23]1[CH:22]=[C:21]([CH2:20][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:10]([O:12][C@H:13]([CH3:19])[CH2:14][O:15][C:16](=[O:18])[CH3:17])=[O:11])[CH:26]=[CH:25][C:24]=1[OH:27]
Reactant: [H][H]
Reactant: CC(=O)OC[C@@H](C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(=O)OC[C@@H](C)OC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
To a solution of (1R)-2-acetyloxy-1-methylethyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate (18) (12.7 g, 22.1 mmol) in 100 mL of methanol, 10% Pd—C (200 mg) pre-mixed with 10 mL of methanol was added under a nitrogen atmosphere. The nitrogen was exchanged with hydrogen using the evacuation refill cycle method. The mixture was stirred under hydrogen at room temperature for 4 hours. After filtration and washing with methanol, the filtrate was concentrated to afford 8.8 g (100% yield) of the title compound (19). 1H NMR (400 MHz, CDCl3): δ 1.21 (d, J=6.4 Hz, 3H), 1.43 (s, 9H), 2.07 (s, 3H), 2.95 (m, 2H), 4.05 (dd, J=12.0, 6.4 Hz, 1H), 4.12 (dd, J=12.0, 3.2 Hz, 1H), 4.48 (dd, J=14, 6.4 Hz, 1H), 5.04 (d, 1H, NH), 5.15 (m, 1H), 6.53 (d, J=8.0 Hz, 1H), 6.66 (s, 1H), 6.74 (d, J=8.0 Hz, 1H). MS (ESI) m/z 420.0 (M+Na)+ and 396.0 (M−H)−.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[Cl:17].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[O:9][C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[C:22]1[CH:21]=[CH:20][C:19]([F:18])=[CH:24][C:23]=1[F:25]
Reactant: Cc1nn(C)c(Br)c1Oc1ccc(F)cc1Cl
Reactant: OB(O)c1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1nn(C)c(-c2ccc(F)cc2F)c1Oc1ccc(F)cc1Cl
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-4-(2-chloro-4-fluorophenoxy)-1,3-dimethyl-1H-pyrazole (i.e. the product of Step C) (250 mg, 0.78 mmol) in 1,2-dimethoxyethane/water (5 mL, 2:1) was sparged with a subsurface stream of argon for 30 minutes, and then 2,4-difluorophenylboronic acid (371 mg, 2.34 mmol), potassium carbonate (1.08g, 7.82 mmol) and tetrakis(triphenylphosphine)palladium (90 mg, 0.078 mmol) were added. The reaction mixture was heated to 80° C. for 15 h, and then cooled and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography (5 to 30% gradient of ethyl acetate in hexanes as eluant) to provide the title compound, a compound of the present invention, as a pale yellow solid (150 mg) melting at 70-72° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][SH:12])=[CH:2]1.[C:13]([O:19][CH3:20])(=[O:18])[CH2:14][C:15]([CH3:17])=O.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:20][O:19][C:13](=[O:18])[CH2:14][C:15]1([CH3:17])[C:2]2[NH:1][C:9]3[C:4]([C:3]=2[CH2:10][CH2:11][S:12]1)=[CH:5][CH:6]=[CH:7][CH:8]=3
Reactant: COC(=O)CC(C)=O
Reactant: SCCc1c[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)CC1(C)SCCc2c1[nH]c1ccccc21
Reaction time: 12 h

Procedure:
Indole-3-ethanethiol (1.5 g.) and methyl acetoacetate are mixed with 50 ml. of benzene and the solution heated for 30 min. (bath temperature 70°-80°C.). p-Toluenesulfonic acid (0.15 g.) is added and the reaction mixture is subjected to reflux and stirring for 12 hours. Water formed in the reaction mixture during this period is collected by a water separator. After cooling the benzene solution is washed with a 10% solution of sodium bicarbonate, water, saturated brine and dried over sodium sulfate. Evaporation of the benzene solution yields the ester, 1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid methyl ester as the semi-solid, γmaxCHCl3 1715 cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:15]2[CH:11]([N:12]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:13][CH:14]2[C:16]([OH:18])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:31])=[N-].N(N(C)C(N)=O)=O.[OH-].[K+]>CCOC(C)=O.CCOCC>[CH3:31][O:17][C:16]([CH:14]1[CH2:13][N:12]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:15]12)=[O:18]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC2C1C(C(=O)O)CN2C(=O)OCc1ccccc1
Agent: CN(N=O)C(N)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)C2CCN(C(=O)OC(C)(C)C)C12

Procedure:
To a solution of crude 72 (0.47 g) in EtOAc (10 mL) and Et2O (10 mL) was added an ethereal solution of diazomethane that was prepared by treatment of N-nitroso-N-methyl urea (0.5 g) in Et2O (10 mL) with 1M KOH (10 mL). After consumption of starting material (monitored by TLC), the reaction mixture was diluted with HOAc. The solution was extracted with EtOAc, washed with saturated NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated to give a dark oil that was purified by HPLC (2″ Dynamax® SiO2, 10% EtOAc/hexane to 100% EtOAc over 30 min) to give 76 (0.19 g) as a yellow-colored oil. 1H NMR (CDCl3, 300 MHz): δ7.40-7.29 (m, 5H), 5.23-5.09 (m, 2H), 4.56-4.52 (m, 2H), 4.11-4.04 (m, 1H), 3.69 (s, 3H), 3.45-3.42 (m, 1H), 3.22-3.12 (m, 1H), 2.27-2.10 (m, 1H), 1.96 (m, 1H), 1.47 (s, 9H) ppm. Mass spectrum, m/z [405.2] (M+H)+.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].C(=O)([O-])[O-].[K+].[K+].[C:39](Cl)(=[O:41])[CH3:40]>CN(C)C=O>[C:39]([N:11]1[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=2)[C@H:9]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:10]1)(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reaction time: 3 h

Procedure:
To a stirred mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (0.15 g) and potassium carbonate (0.14 g) in dimethylformamide (10 ml) was added acetyl chloride (0.04 ml) at room temperature. After being stirred for 3 hours, the reaction mixture was quenched with water (50 ml) and extracted with dichloromethane (50 ml). The organic layer was washed with aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified on a silica gel column (10 g) eluting with a mixture of dichloromethane and methanol (20:1). The fractions containing object compound were collected and evaporated under reduced pressure. To the resulting oily product was added a mixed solvent of ethyl ether and diisopropyl ether, and the mixture was concentrated under reduced pressure. The obtained powder was collected by filtration and dried in vacuo to give (2R)-4-acetyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (0.09 g) as a powder.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[C:16]=1[S:23](Cl)(=[O:25])=[O:24].[OH-].[Na+]>O1CCOCC1.[Na].O>[C:7]1([CH:2]([NH:1][S:23]([C:16]2[C:17]([Cl:22])=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=2[Cl:14])(=[O:25])=[O:24])[CH2:3][C:4]([OH:6])=[O:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(CC(=O)O)c1ccccc1
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CC(NS(=O)(=O)c1c(Cl)cc(Cl)cc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
1.15 g of 3-amino-3-phenylpropionic acid are dissolved in 25 ml of dioxane and 7 ml of 1N sodium. hydroxide and 1.95 g of 2,4,6-trichlorobenzenesulphonyl chloride in 5 ml of dioxane are gradually added, while maintaining the pH at 10.5-11 by addition of 1N sodium hydroxide. After stirring for 2 hours at RT, the mixture is diluted with 100 ml of water, extracted twice with EtOAc and acidified to pH=2 by addition of 6N HCl. The solid formed is drained, washed with water and dried at 40° C. 2.09 g of the expected product are obtained, m.p.=218-219° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)[CH:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22]>>[C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=3)[CH:3]=2)=[CH:25][CH:24]=1)#[N:22]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Product: N#Cc1ccc(-c2cc(-c3ccc(O)c(F)c3)nc3ccc(O)cc23)cc1
Yield: 52 %

Procedure:
This compound was prepared from 6b using 4-cyanophenylboronic acid according to method P. Yellow powder; Yield: 52%; mp 266-267° C.; 1H-NMR (400 MHz, DMSO-d6) δ 6.97 (d, J=2.7 Hz, 1H), 7.07 (t, J=8.8 Hz, 1H), 7.34 (dd, J=9.0, 2.6 Hz, 1H), 7.82 (d, J=8.5 Hz, 2H), 7.92 (s, 1H), 7.95-8.00 (m, 2H), 8.07-8.10 (m, 3H), 10.00 (s, 1H), 10.21 (s, 1H); MS (ESI) m/z 355 ([M−H]−), 357 ([M+H]+); Anal. Calcd for C22H13FN2O2: C, 74.15; H, 3.68; N, 7.86. Found: C, 73.69; H, 3.53; N, 7.86.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29][CH2:30][NH2:31]>>[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29][CH2:30][NH:31][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: NCCc1ccc2ccccc2c1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cn1
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3ccc4ccccc4c3)cc2)cn1
Yield: 50.3 %

Procedure:
Using a method similar to Example 405, using 5-(4-formylphenoxy)pyridine-2-carboxamide (Example 388, Part D) (0.0366 g, 0.151 mmol) and 2-naphthalen-2-ylethylamine (0.0286 g, 0.166 mmol) gives the title compound (0.0302 g, 50.3%): TOF MS ES+ 398.2 (M+H)+, HRMS calcd for C2-5H24N3O2 398.1869 (M+H)+, found 398.1833, time 0.39 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, 30-99% over 19 min], tR=9.2 min, 98.0% purity.
Reaction SMILES: [CH2:1]([CH:3]([CH2:21][CH3:22])[C:4]([N:6]1[CH2:20][CH2:19][C:9]2([NH:13][C:12](=[O:14])[C@H:11]([CH2:15][CH2:16][S:17][CH3:18])[NH:10]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].O.C[Si]([Cl:28])(C)C>CC(CC)=O>[ClH:28].[CH2:21]([CH:3]([CH2:1][CH3:2])[C:4]([N:6]1[CH2:7][CH2:8][C:9]2([NH:13][C:12](=[O:14])[C@H:11]([CH2:15][CH2:16][S:17][CH3:18])[NH:10]2)[CH2:19][CH2:20]1)=[O:5])[CH3:22]
Reactant: C[Si](C)(C)Cl
Agent: CCC(CC)C(=O)N1CCC2(CC1)NC(=O)[C@H](CCSC)N2
Solvent: CCC(C)=O
Solvent: O
Product: Cl
Reaction time: 8 h

Procedure:
8-(2-ethylbutyryl)-3-(S)-(2-methylsulfanylethyl)-1,4,8-triazaspiro[4,5-]-decan-2-one (140 mg, 0.4 mmol) was dissolved in ethyl methyl ketone (1 mL), and water (4 μL) and TMSCl (59 μL) were added and the mixture was stirred overnight. The solid matter was isolated by filtration and dried in vacuo. The product 8-(2-ethylbutyryl)-3-(S)-(2-methylsulfanylethyl)-1,4,8-triazaspiro[4,5-]-decan-2-one hydrochloride was obtained in a yield of 117 mg (75%).
Reaction SMILES: CN(C=O)C.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:31][C:32]1[C:37]([CH2:38]Br)=[C:36]([O:40][CH3:41])[C:35]([O:42][CH3:43])=[C:34]([O:44][CH3:45])[C:33]=1[O:46][CH3:47].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])([CH2:38][C:37]2[C:32]([Br:31])=[C:33]([O:46][CH3:47])[C:34]([O:44][CH3:45])=[C:35]([O:42][CH3:43])[C:36]=2[O:40][CH3:41])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(OCc2ccccc2)cc1
Reactant: COc1c(Br)c(CBr)c(OC)c(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1c(Br)c(OC)c(OC)c(OC)c1OC)(C(=O)OCC)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.6 %

Procedure:
A DMF (120 ml) suspension of ethyl 2-(4-benzyloxyphenyl)-2-ethoxycarbonylacetate (12.0 g, 35.1 mmols), 1-bromo-6-bromomethyl-2,3,4,5-tetramethoxybenzene (16.9 g, 45.6 mmols) and potassium carbonate (14.5 g, 105 mmols) was stirred at room temperature for 6 hours, and then 1-bromo-6-bromomethyl-2,3,4,5-tetramethoxybenzene (2.60 g, 7.02 mmols) was added thereto stirring was continued at room temperature for further 6 hours. Water was added to the reaction mixture, which was then extracted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by recrystallization (from hexane-ethyl acetate) to obtain the entitled compound (11.0 g) as crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.C(N(CCCC)CCCC)CCC.[I-].ClC1C=CC=C[N+]=1C.[NH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:43]2[N:47]([CH2:48][C:49]3[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=3)[C:46]3[CH:56]=[CH:57][CH:58]=[CH:59][C:45]=3[N:44]=2)[CH2:38][CH2:37]1>ClCCl>[NH2:1][C:2]1[C:3]([C:8]([NH:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH:39]([NH:42][C:43]3[N:47]([CH2:48][C:49]4[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=4)[C:46]4[CH:56]=[CH:57][CH:58]=[CH:59][C:45]=4[N:44]=3)[CH2:38][CH2:37]2)=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccnc1C(=O)O
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: Nc1nccnc1C(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38 %

Procedure:
To a stirred mixture of 2.1 parts of 3-amino-2-pyrazinecarboxylic acid, 2.8 parts of N,N-dibutylbutanamine and 195 parts of dichloromethane were added 3.83 parts of 2-chloro-1-methlypridinium iodide. After stirring for 15 minutes at room temperature, 5.5 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine were added and stirring was continued for one hour. The reaction mixture was washed with water, dried, filtered and evaporated. The residue was stirred in 2,2'-oxybispropane. The latter was decanted and the residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1,1'-oxybisethane, yielding 2.8 parts (38%) of 3-amino-N-[2-[4-[[1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-2-pyrazinecarboxamide; mp. 156.9° C. (compound 113).
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][C:12]1[CH:19]=[CH:18][C:16]([OH:17])=[C:14]([OH:15])[CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23]>C(Cl)(Cl)Cl>[C:22]([O:15][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][NH:9][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:8])[CH:19]=[CH:18][C:16]=1[O:17][C:22](=[O:23])[C:21]([CH3:26])([CH3:25])[CH3:20])(=[O:23])[C:21]([CH3:26])([CH3:25])[CH3:20]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(NCCc1ccc(O)c(O)c1)c1cccnc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)Oc1ccc(CCNC(=O)c2cccnc2)cc1OC(=O)C(C)(C)C

Procedure:
To a suspension of 5.16 g (0.02 mol) finely powdered nicotinoyldopamine in 100 ml chloroform, 7.23 g (0.06 mol) trimethylacetyl chloride were added under stirring. The mixture was refluxed for 6 hours and then filtered. The filtrate was washed with water free of chloride ions, then washed once with a 5% solution of NaHCO3, then with water. The chloroform was evaporated and the residue was chromatographed by using a silica gel G column and 2% methanol in chloroform as the eluent. The first fraction was collected and evaporated and the residue was crystallized from ether/petroleum ether. Yield, 6.2 g (73%) of a white crystalline solid, m.p. 112°-114° C., NMR (CDCl3) δ9.06 (bs, 1H, C2 pyridine proton), 8.73 (bd, 1H, C6 pyridine proton) 8.30-8.13 (m, 1H, C4 pyridine proton), 7.46-7.10 (m, 5H, C6H3 +C5 pyridine proton+CONH), 3.66 (q, 2H, J=6.25 Hz, --N--CH2), 3.0 (t, 2H, J=6 Hz, --CH2), 1.41 [s, 18H, 2--C(CH3)3 ]. Anal. Calcd for C24H30N2O5 : C, 67,58; H, 7.09; N, 6.56. Found: C, 67.61; H, 7.10; N, 6.54.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:26])[C:11]([CH3:25])=[C:12]([CH2:14][NH:15][C:16]3[C:17]([CH3:24])=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=3[CH3:22])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:26])[C:11]([CH3:25])=[C:12]([CH2:14][NH:15][C:16]3[C:17]([CH3:24])=[C:18]([CH:19]=[CH:20][C:21]=3[CH3:22])[O:23][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(-c2cccc(F)c2)cc(CNc2c(C)ccc(O)c2C)c1C
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(C)ccc(OCC(=O)OC(C)C)c2C)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a solution 3-[[5-(3-fluorophenyl)-2,3-dimethyl-phenyl]methylamino]-2,4-dimethyl-phenol (87.5 mg, 0.25 mmol, 1.0 eq) in DMF (10 mL) was added Cs2CO3 (0.16 g, 0.51 mmol, 2.0 eq). The reaction mixture was stirred at room temperature for 30 min then isopropyl bromoacetate (56 mg, 0.3 mmol, 1.2 eq) was added and the reaction stirred for a further 1 h. The resulting mixture was poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether: EtOAc, 100:1 to 30:1) to give the title compound as a colorless oil (80 mg, 69%).