Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[C@H:10]([CH2:12][CH:13]([CH3:15])[CH3:14])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].CN1CCOCC1>CC#N>[CH2:1]([O:8][C:9](=[O:16])[C@H:10]([CH2:12][CH:13]([CH3:14])[CH3:15])[NH:11][C@@H:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)Br
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CCOC(=O)[C@@H](C)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Yield: 25.8 %

Procedure:
L-Leucine benzyl ester (186.65 g, 0.843M), ethyl 2-bromopropionate (153.1 g, 0.846M) and N-methylmorpholine (165 ml, 1.5M) were dissolved in dry CH3CN (800 ml) and refluxed for 12 h. The solvent was removed in vacuo and the residue partitioned between H2O (21) and EtOAc (3×11). The organic phase was washed with brine, dried and evaporated in vacuo. The resulting oil was chromatographed on SiO2 in 7.5% EtOAc in hexane to give the title compound (70 g) as the faster running fraction; (Found: C,67.02; H,8.42; N,4.25; C18H27NO4 requires C,67.26; H,8.47; N,4.36); νmax film 1730 cm-1 ; δ (CDCl3) 0.88 and 0.9 (each 3H, each d, each J=6.5 Hz, CH(CH3)2) 1.23 (3H,t,J=7 Hz,CH3CH2O), 1.27 (3H,d,J=7 Hz,CH3CH), 1.5 (2H,m,CHCH2), 1.7 (1H, heptet, J=7 Hz, CH(CH3)2), 2.2 (1H, br s,NH), 3.32 (2H,m, CHNHCH), 4.10 and 4.12 (each 1H, each q, each J=7 Hz, OCH2CH3), 5.12 (2H,s, OCH2C6H5) and 7.34 (5H,s, C6H5); m/e 322 (100%; [m+1])+, 260 (15), 186 (26) and 112 (28).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Br[CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: BrCCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(CCCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
2.8 g of sodium hydride as a 60% dispersion in oil are added in small portions at RT to a solution of 13.35 g of 3,4-dichlorophenylacetonitrile in 100 ml of THF and the reaction mixture is stirred for 3 hours at RT. It is cooled to -20° C., a solution of 16 g of 2-(3-bromopropoxy)tetrahydropyran in 30 ml of THF is added dropwise and the reaction mixture is stirred for 3 hours while the temperature is allowed to rise to RT. It is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water, with a buffer solution of pH 4 and with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a toluene/AcOEt mixture (100/3; v/v) as the eluent to give 11 g of the expected product.
Reaction SMILES: C([N:8]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:36])[CH2:20][N:21]([CH2:23][CH2:24][N:25]2[N:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:35])[CH3:22])=[CH:15][CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])C1C=CC=CC=1>C(O)C.C(OCC)C.[Pd]>[CH3:12][S:9]([NH:8][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:36])[CH2:20][N:21]([CH2:23][CH2:24][N:25]2[N:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:35])[CH3:22])=[CH:15][CH:14]=1)(=[O:10])=[O:11]
Reactant: CN(CCn1ncc2ccccc2c1=O)CC(O)c1ccc(N(Cc2ccccc2)S(C)(=O)=O)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Product: CN(CCn1ncc2ccccc2c1=O)CC(O)c1ccc(NS(C)(=O)=O)cc1
Reaction time: 18 h

Procedure:
N-[2-(4-{N-Benzylmethanesulphonamido}phenyl)-2-hydroxyethyl]-N-methyl-2-(phthalazin-1-on-2yl)ethylamine (0.4 g--as solvate from part D) in ethanol (50 ml) containing 5% Pd/C (0.1 g) was stirred under a hydrogen atmosphere (50 p.s.i.) at 50° for 18 hours. The reaction mixture was then filtered and the ethanol removed. The residue was dissolved in methylene chloride and washed three times with sodium bicarbonate solution and three times with brine. The organic layer was dried and evaporated to give an oil which was purified by column chromatography on silica, "Kieselgel 60" (Merck, Trade Mark), eluting with methylene chloride containing methanol (0% up to 2%). The appropriate fractions were combined and evaporated to give an oil which solidified after stirring for 14 hours in diethyl ether, filtration giving the title compound, 0.11 g, m.p. 134°-137°.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[CH2:4][C@@H:3]1[OH:13].[F:14][C:15]([F:22])([F:21])[C:16](OCC)=[O:17].C(N(CC)CC)C>CO>[F:14][C:15]([F:22])([F:21])[C:16]([NH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[CH2:4][C@@H:3]1[OH:13])=[O:17]
Reactant: COc1ccc2c(c1)[C@@H](N)[C@@H](O)C2
Reactant: CCOC(=O)C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)[C@@H](NC(=O)C(F)(F)F)[C@@H](O)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Step AE (1): To a solution of (1R,2S)-1-amino-6-methoxy-2,3-dihydro-1H-inden-2-ol (500 mg) [E. N. Jacobsen, et. al Organic Synthesis 1999, 76, 46-56] in methanol (10 mL) was added ethyl trifluoroacetate (0.83 mL) followed by triethylamine (0.65 mL), and the reaction mixture was stirred at rt for 12 h. The solvents were removed in vacuo to give 2,2,2-trifluoro-N-((1R,2S)-2-hydroxy-6-methoxy-2,3-dihydro-1H-inden-1-yl)acetamide as an oil. HPLC retention time: 1.77 min (method B). MS (ESI) (M+Na)+ 298.13.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1>C(O)C.C(Cl)Cl.[Pt](=O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[CH:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1
Reactant: CN1CC=C(c2cc(C(F)(F)F)ccc2Br)CC1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: ClCCl
Product: CN1CCC(c2cc(C(F)(F)F)ccc2Br)CC1
Reaction time: 1 h
Yield: 2.36 %

Procedure:
4-(2-bromo-5-(trifluoromethyl)phenyl)-1-methyl-1,2,3,6-tetrahydropyridine was dissolved in 20 mL ethanol and the solution was treated with platinum (iv) oxide (0.194 g, 0.854 mmol), and was placed under 45 psi H2 for one hour. LC/MS showed product and debrominated product, so the reaction mixture was diluted with DCM, filtered through a plug of diatomaceous earth and was concentrated. Purification of the crude residue by silica gel column chromatography (0 to 97% EtOAc/heptane, 3% MeOH) gave 4-(2-bromo-5-(trifluoromethyl)phenyl)-1-methylpiperidine (0.065 g, 0.202 mmol, 2.363% yield). m/z (ESI) 322.0 (M+Na)+;
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)c1cc([N+](=O)[O-])ccc1C
Temperature: 0 °C

Procedure:
To 120 ml of concentrated sulfuric acid is added 53.6 g of o-methylacetophenone, while cooling at -10°. To this cold, stirred solution is added a mixture of 32 ml of 70% nitric acid and 48 ml of concentrated sulfuric acid. The reaction solution is stirred for 21/2 hours between -9° and 0° and then poured over 800 g of ice. The mixture is extracted with ether and the organic phase washed with water, saturated Na2CO3 solutions, water and finally brine. The ether solution is dried over MgSO4 and evaporated to dryness to give 56.2 g of a pale yellow oil. The oil is crystallized from 95% ethanol to give 25.4 g of product, mp about 50° C. Recrystallization from hexane afforded product mp 53°-55° C.
Reaction SMILES: C([O:3][C:4](=O)/[CH:5]=[CH:6]/[C:7]1[C:8]([NH:16][CH2:17][CH3:18])=[N:9][C:10]([S:14][CH3:15])=[N:11][C:12]=1[CH3:13])C.N12CCCN=C1CCCCC2>CCN(C(C)C)C(C)C>[CH2:17]([N:16]1[C:8]2[N:9]=[C:10]([S:14][CH3:15])[N:11]=[C:12]([CH3:13])[C:7]=2[CH:6]=[CH:5][C:4]1=[O:3])[CH3:18]
Reactant: CCNc1nc(SC)nc(C)c1/C=C/C(=O)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1c(=O)ccc2c(C)nc(SC)nc21
Yield: 76.5 %

Procedure:
To a solution of (E)-ethyl-3-(4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl)acrylate (16.8 g, 59.8 mmol) in DIPEA was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 18.21 g, 119.6 mmol) at room temperature. Then the reaction mixture was heated to reflux and reacted for 15 h. After evaporation of solvent, the residue was triturated with acetone. The product 8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (10.77 g, 77% yield) was collected by filtration. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J=9.6 Hz, 1H), 6.63 (d, J=9.6 Hz, 1H), 4.5 (q, J=7.2 Hz, 2H), 2.67 (s, 3H), 2.62 (s, 3H), 1.33 (t, J=7.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[CH2:12]([N:19]1[CH:27]=[C:26]2[C:21]([CH:22]=[C:23](B3OC(C)(C)C(C)(C)O3)[CH:24]=[CH:25]2)=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=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.O>[CH2:12]([N:19]1[CH:27]=[C:26]2[C:21]([CH:22]=[C:23]([C:2]3[C:10]4[N:5]([NH:6][CH:7]=[N:8][C:9]=4[NH2:11])[CH2:4][CH:3]=3)[CH:24]=[CH:25]2)=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnn2ccc(Br)c12
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: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC1=C2C(c3ccc4cn(Cc5ccccc5)nc4c3)=CCN2NC=N1
Yield: 37.9 %

Procedure:
A stirred mixture of 5-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.47 mmol), 2-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (188 mg, 0.56 mmol), sodium carbonate (119 mg, 1.13 mmol), N,N-dimethylformamide (4 mL) and water (0.3 mL) was degassed with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (54 mg, 0.04 mmol) was added, and the reaction was irradiated in a microwave reactor at 150° C. for 15 minutes. The reaction mixture was filtered through Celite®, the pad washed with methanol, and the filtrate concentrated in vacuo. The residue was partitioned between dichloromethane and 1N aqueous hydrochloric acid. The dichloromethane extracts were washed with 5% aqueous sodium bicarbonate solution, then brine, dried (anhydrous sodium sulfate); filtered and concentrated in vacuo to afford 61 mg (38% yield) of yellow solid. 1H-NMR (CD2Cl2): δ 8.04 (d, 1 H), 7.86 (s, 1 H), 7.77 (dd, 1 H), 7.75 (d, 1 H), 7.65 (d; 1 H), 7.40-7.32 (m, 5 H), 7.21 (dd, 1 H), 6.77 (d, 1 H), 6.91 (br s, 2 H), 5,61 (s, 2 H). MS: LC/MS (+esi), m/z=341 [M+H]. RT=2.44 min.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:21](O)=[O:22])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)OCC.C(N(CC)CC)C>O1CCCC1>[CH:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([CH2:21][OH:22])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1CCCCC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(N[C@H](CO)Cc1ccc(O)cc1)OCC1CCCCC1

Procedure:
In 30 ml of tetrahydrofuran, 3.2 g of N-(cyclohexylmethoxycarbonyl)-tyrosine was dissolved. To the solution were added 1.1 g of ethyl chlorocarbonate and 1.0 g of triethylamine while cooling with ice and stirring. After stirring the mixture for 10 minutes, the precipitate was removed by filtration. The filtrate was added to a suspension of 1.0 g of sodium borohydride and 10 ml of tetrahydrofuran cooled with ice. The mixture was stirred for 2 hours, then neutralized with hydrochloric acid and concentrated in vacuo. The residue was extracted with ethyl acetate and the extract was washed with water, dried and concentrated to dryness. The residue was crystallized from ethyl acetate-petroleum ether to give 2.3 of N-(cyclohexylmethoxycarbonyl)-tyrosinol with a melting point of 121-126° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:19][C@H:18]3[N:14]([CH2:15][CH2:16][CH2:17]3)[C:13]3[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:12]=3[C:11]2=[O:26])[CH:5]=1.[CH:28]([C:31](Cl)=O)([CH3:30])[CH3:29]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH:28]([C:31]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[C:6]([N:10]3[CH2:19][C@H:18]4[N:14]([CH2:15][CH2:16][CH2:17]4)[C:13]4[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:12]=4[C:11]3=[O:26])[CH:7]=[CH:8][CH:9]=2)[N:27]=1)([CH3:30])[CH3:29]
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(N)=NO)c1)C2=O
Reactant: CC(C)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3noc(C(C)C)n3)c1)C2=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 110.1 %

Procedure:
(S)—N′-Hydroxy-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzamidine (120 mg, 0.31 mmol) obtained in Step 1 was dissolved in pyridine (1.5 mL), and the mixture was stirred overnight at 90° C. after adding isopropylcarbonyl chloride (0.039 mL, 0.38 mmol) under ice-cooled conditions. The mixture was diluted with chloroform, washed with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by concentrating the mixture under reduced pressure was then purified by silica gel column chromatography to give (S)-5-[3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (149 mg, quantitative).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:21]=[C:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19](=[O:20])[N:11]3[N:10]=2)=[CH:5][CH:4]=1.[Na].[CH3:23][OH:24]>>[C:19]([C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:12]1[CH:21]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:10][N:11]=1)([O:24][CH3:23])=[O:20]
Reactant: COc1ccc(-c2cc3n(n2)C(=O)c2ccccc2-3)cc1
Reactant: CO
Agent: [Na]
Product: COC(=O)c1ccccc1-c1cc(-c2ccc(OC)cc2)[nH]n1
Reaction time: 8 h

Procedure:
A mixture of 2-(4-methoxyphenyl)pyrazolo[5,1-a]isoindol-8-one (100 mg), methanol(10 ml), and sodium (0.1 g), was stirred overnight at 25°. Evaporation of the methanol left 120 mg (96%) of colorless gum which was the ester 3-(2-carbomethoxyphenyl)-5-(4-methoxyphenyl)pyrazole. The crude ester was dissolved in benzene and stirred overnight with 2 g of Florisil. Filtration and evaporation of the benzene solution, followed by recrystallization from hexane-ethyl acetate (1:1), gave 3-(2-carbomethoxyphenyl)-5-(4-methoxyphenyl)pyrazole, mp 92°-93°.
Reaction SMILES: N[C:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[CH:3][C:4]#[N:5].Cl.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][NH2:22].[OH-].[Na+]>Cl>[F:12][C:9]1[CH:8]=[CH:7][C:6]([C:2]2[CH:3]=[C:4]([NH2:5])[N:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH3:14])[N:22]=2)=[CH:11][CH:10]=1
Reactant: N#CC=C(N)c1ccc(F)cc1
Reactant: Cc1ccccc1NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccccc1-n1nc(-c2ccc(F)cc2)cc1N
Temperature: 25 °C
Yield: 85.3 %

Procedure:
To a solution of 3-amino-3-(4-fluorophenyl)acrylonitrile (600 mg, 3.70 mmol) in 1 N HCl (6 mL) was added (2-methylphenyl)hydrazine hydrochloride (558 mg, 3.51 mmol). The reaction was allowed to reflux for 16 h, and then cooled to rt. The resulting mixture was basified to pH 12 by slow addition of 1 N aqueous sodium hydroxide. The precipitate was collected by filtration, and then recrystallized from EtOH/Et2O to afford the intermediate (800 mg, 81%) as a light orange solid. 1H NMR (400 MHz, CD2Cl2) δ 2.20 (s, 3H), 2.14 (br s, 2H), 5.91 (s, 1H), 7.06 (t, 2H), 7.36 (d, 4H), 7.75 (m, 2H). This material was used without further purification.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:36]([CH2:44][CH2:45][OH:46])[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:40]([C:38]1[CH:39]=[C:35]([NH:34][C:33]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([N:3]5[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]5[CH3:1])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:32])[N:36]([CH2:44][CH2:45][OH:46])[N:37]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(CCO)n1
Reactant: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCO)c4ccccc43)cn12
Temperature: 80 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
A mixture of Intermediate 139c (125 mg, 0.33 mmol), Intermediate 110b (115 mg, 0.33 mmol) and DIPEA (115 μL, 0.66 mmol) in dioxane (3 mL) was stirred at 80° C. overnight. After cooling, the reaction mixture was partitioned between water and DCM. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC, using a gradient of 0-10% MeOH in DCM, to afford the title compound (94 mg, 48%). A sample of this (40.0 mg) was further purified by MDAP (Method 7) purification to afford the title compound (20 mg) as a white solid. LCMS (Method 5): Rt 3.64 min, m/z 589 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.83 (3H, d, J=5.6 Hz), 1.16 (9H, s), 1.83-1.96 (2H, m), 1.97-2.07 (1H, m), 2.08-2.17 (1H, m), 2.95 (114, ddd, J=12.0, 7.2, 4.9 Hz), 3.17 (1H, dt, J=12.2, 3.3 Hz), 3.36-3.44 (2H, m), 3.62 (2H, q, J=5.5 Hz), 3.72-3.80 (2H, m), 3.81-3.88 (1H, m), 3.88-3.92 (2H, t, J=6.0 Hz), 4.81 (114, td, J=8.5, 6.1 Hz), 4.96 (1H, t, J=5.0 Hz), 5.52 (1H, t, J=4.2 Hz), 6.02 (1H, s), 7.05 (1H, d, J=8.6 Hz), 7.18 (1H, dd, J=9.9, 2.1 Hz), 7.22-7.27 (1H, m), 7.30-7.37 (3H, m), 7.62 (1H, d, J=9.9 Hz), 7.79 (1H, d, J=1.9 Hz), 8.16 (1H, s).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:27]3[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=3)[CH2:35][CH2:34]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccc(OC)cc3)CC2)c(OC)nc1C
Yield: 78 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(4-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].C(OC([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[CH2:23][C:24](O)=O)=O)(C)(C)C>>[Br:1][C:2]1[C:3]2[N:9]=[C:24]([CH2:23][CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][NH:17]3)[NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: Nc1cccc(Br)c1N
Product: Brc1cccc2[nH]c(CC3CCCCN3)nc12

Procedure:
The title compound was prepared using the method of Description 18 from 3-bromobenzene-1,2-diamine (0.50 g, 2.7 mmol) and 2-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.65 g, 2.7 mmol), as a pale brown amorphous solid (0.70 g, 88%)
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[CH3:2].Br[CH2:12][C:13]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[O:14].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:1]([N:3]([CH2:12][C:13]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[CH3:2]
Reactant: CCNc1cccc(C)c1
Reactant: O=C(CBr)OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCN(CC(=O)OCC(F)(F)F)c1cccc(C)c1
Yield: 94.5 %

Procedure:
A mixture of 13.5 g (0.1 mole) N-ethyl-m-toluidine, 22.1 g (0.1 mole) trifluoroethyl bromoacetate and 7.0 g (0.051 mole) potassium carbonate in 100 ml of acetone was heated at reflux for two hours. Water (10 ml) was added and the mixture heated at reflux overnight. Solvent was removed on a rotary evaporator, ether added and the layers separated. The aqueous layer was extracted with ether. The combined ether solution was washed once with 50 ml of water and dried over sodium sulfate. Removal of ether gave 26.0 g brown oil which gave one spot by thin layer chromatography and was used as isolated (94%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[NH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])=[CH:10][C:2]=1[Cl:1])=[O:6]
Reactant: NCC1CCCCN1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCCCC2CN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-aminomethylpiperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.93 minutes; C23H25Cl2N5O2 (474.39); mass spectrum: (M−H)−=473/475/477 (chlorine isotope).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:11])[CH:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1.Cl.[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([NH:27]N)[CH:24]=[CH:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)C>O>[CH3:2][N:3]([CH3:11])[CH:4]1[CH2:9][C:8]2[C:24]3[C:23](=[CH:22][C:21]([O:20][CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)=[CH:26][CH:25]=3)[NH:27][C:7]=2[CH2:6][CH2:5]1
Reactant: CN(C)C1CCC(=O)CC1
Reactant: NNc1cccc(OCc2ccccc2)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN(C)C1CCc2[nH]c3cc(OCc4ccccc4)ccc3c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 15.8 g. of 4-dimethylaminocyclohexanone hydrochloride and 20.3 g. of 3-benzyloxyphenylhydrazine hydrochloride (m.p. 165°-168° C.) in 225 ml. of absolute ethyl alcohol was heated under reflux for three hours, cooled to room temperature, and diluted with 50 ml. of water. After standing for three hours the resulting crystals were collected by filtration and washed with ethyl alcohol to give, after recrystallization from ethyl alcohol, 6.1 g. of 3-(dimethylamino)-7-(benzyloxy)-1,2,3,4-tetrahydrocarbazole hydrochloride, m.p. 237°-239° C.