Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:22][NH:23][CH3:24])=[CH:12]2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(Cl)c2)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(Cl)c2)c1
Product: Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 103.6 %

Procedure:
tert-Butyl {{1-[(3-chlorophenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl}methylcarbamate (726 mg) was dissolved in dichloromethane (3 ml), trifluoroacetic acid (2 ml) was added at 0° C., and the mixture was stirred at room temperature for 15 min. The reaction solution was basified by the dropwise addition to 6% aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and eluted with ethyl acetate-methanol (19:1). The obtained pale-yellow oil was dissolved in ethyl acetate, 4 mol/L hydrogen chloride-ethyl acetate solution was added, activated carbon was added and the mixture was filtered through celite. The celite was washed sufficiently with methanol and the filtrate was concentrated under reduced pressure. The residue was crystallized from ethyl acetate and hexane, and recrystallized from ethyl acetate-ethanol to give the title compound as colorless crystals (yield 324 mg, 52%).
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CI.[C:21](=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O.O>[NH2:1][C:2]1[S:10][C:5]2[CH2:6][N:7]([CH3:21])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1sc2c(c1C(=O)c1ccccc1)CCNC2
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCc2c(sc(N)c2C(=O)c2ccccc2)C1
Temperature: 65 °C
Yield: 77 %

Procedure:
2-Amino-3-benzoyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (2 mmol), as prepared in Example 8, and methyl iodide (3 mmol) were dissolved in dry dimethyformamide (20 mL). Finely ground anhydrous potassium carbonate (1.9 g) and sodium iodide (0.2 g) were added to the solution and the resulting mixture was warmed to 65° C. overnight under nitrogen. After this period (TLC control), the reaction mixture was cooled, diluted with water, extracted with diethyl ether (3×50 mL), and dried on sodium sulfate. The crude product was isolated and then purified by column chromatography eluting with ethyl acetate and petroleum ether solutions to give the desired compound. (m.p. 164-165° C.; 77% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]([NH:16][CH2:17][CH2:18][NH2:19])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(N(CC)CC)C>C(O)C>[C:12]([O:11][C:9](=[O:10])[NH:16][CH2:17][CH2:18][NH:19][C:5]1[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Clc1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNc1ncc(Br)cn1
Temperature: 80 °C
Yield: 85.4 %

Procedure:
A mixture of 5-bromo-2-chloropyrimidine (500 mg), N-Boc-ethylenediamine (496 mg), and triethylamine (1 mL) in ethanol (10 mL) was heated at 80° C. for 4 hours. The reaction was then concentrated in vacuo and the residue purified by preparative HPLC (hexanes:EtOAc; 60:40) to afford compound 10 (700 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1([C:5]2[N:10]=[C:9]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:8]3=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=[CH:21][N:7]3[N:6]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[C:22]1([C:19]2[CH:20]=[CH:21][N:7]3[C:8]=2[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][C:5]([C:2]2([NH:1][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:3][CH2:4]2)=[N:6]3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC1(c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NC1(c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.6 %

Procedure:
To a stirred solution of 2-(1-aminocyclopropyl)-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (60.0 mg, 0.168 mmol)) in DCM (15 mL) was added pyridine (0.0200 mL, 0.253 mmol) followed by methanesulfonylchloride (0.0200 mL, 0.253 mmol) and the reaction stirred at RT for 2 h then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed with water (2×30 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Condition B-94 as described in general methods) to give N-(1-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropyl)methanesulfonamide (26.0 mg, 35.5%) as white solid. LCMS Condition B-34: retention time 2.32 min, [M+1]=435.0. HPLC Condition B-31: retention time 7.72 min, Purity 99.61%. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25-1.31 (m, 2H), 1.36-1.42 (m, 2H), 2.99 (s, 3H), 4.71 (d, J=4.8 Hz, 2H), 6.71 (d, J=2.7 Hz, 1H), 7.07 (t, J=4.8 Hz, 1H), 7.27 (ddd, J=6.8 Hz, J=5.5 Hz, J=1.0 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.41-7.45 (m, 1H), 7.47-7.57 (m, 4H), 7.72-7.77 (m, 2H), 8.06 (s, 1H), 8.35-8.40 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[O:4][N:3]=1.[CH2:8]([O:10][C:11](=[O:20])[CH2:12][C:13]([CH:15]=[CH:16]OCC)=[O:14])[CH3:9]>>[CH2:8]([O:10][C:11](=[O:20])[CH2:12][C:13]([CH:15]=[CH:16][NH:7][C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1)=[O:14])[CH3:9]
Reactant: CCOC=CC(=O)CC(=O)OCC
Reactant: Cc1cc(N)on1
Product: CCOC(=O)CC(=O)C=CNc1cc(C)no1
Reaction time: 0.75 h

Procedure:
98 g. of 3-methyl-5-aminoisoxazole (1 mol.) and 186 g. of ethoxymethyleneacetoacetic acid ethyl ester (1 mol.) are heated with stirring for 45 minutes at 130°. After this period, ethanol is removed under reduced pressure. The residue solidifies on cooling and is recrystallized from ethanol, m.p. 93°-95°, yield 208 g. (87%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[C:12]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=3)C(=O)[O:18][N:17]=2)=[N:13][O:14][N:15]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[Cl:28][C:23]1[CH:22]=[C:21]([NH:20][C:16]([C:12]2[C:11]([CH2:10][CH2:9][NH:8][S:31]([CH3:30])(=[O:33])=[O:32])=[N:15][O:14][N:13]=2)=[N:17][OH:18])[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: NCCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)NCCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
To a solution of 3-[4-(2-amino ethyl)-1,2,5-oxadiazol-3-yl]-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one trifluoroacetate (16.0 mg, 0.037 mmol) in DCM (1.0 mL) was added TEA (15 μL, 0.11 mmol) and methanesulfonyl chloride (4.2 μL, 0.055 mmol). The resulting mixture was stirred at rt for 1 h and then the solvent was removed under reduced pressure. The residue was dissolve in MeOH (1 mL) and 2.0 M sodium hydroxide in water (0.10 mL) was added. After stirring for 4 h, the reaction solution was diluted with MeOH and a few drop of acetic acid and then purified by preparative LCMS to give the desired product as a white solid (14.1 mg, 78.3%). MF=C12H13ClFN5O4S; LCMS calculated C12H14ClFN5O4S (M+H)+: m/z=377.0.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[Cl:23])[CH:19]([C:24](Cl)=[O:25])[CH2:18][CH2:17]2>>[ClH:13].[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[Cl:23])[CH:19]([C:24]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:25])[CH2:18][CH2:17]2
Reactant: O=C(Cl)C1CCc2cc(Cl)c(Cl)cc21
Reactant: C1CCC(CN2CCCC2)NC1
Product: Cl
Product: O=C(C1CCc2cc(Cl)c(Cl)cc21)N1CCCCC1CN1CCCC1
Yield: 32.6 %

Procedure:
From 1.18 g of 2-(pyrrolidin-1-ylmethyl)piperidine, and 1.87 g of 5,6-dichloroindan-1-carbonyl chloride. 0.51 g of the title compound was obtained melting at 245°-250° C. using a procedure similar to that in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH:14]([CH3:15])[C:5]=3[C:4]=2[CH:3]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([C:18]([F:28])([F:17])[F:27])=[CH:24][CH:23]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH:14]([CH3:15])[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC1c2c([nH]c3ccc(Cl)cc23)CCN1C
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC1c2c(n(CCc3ccc(C(F)(F)F)nc3)c3ccc(Cl)cc23)CCN1C

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-1,2-dimethyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH2:1]([O:8][CH:9]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[F:33][C:34]([F:43])([F:42])[C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38]>ClCCl.CN(C)C1C=CN=CC=1.O>[CH2:14]([O:13][CH:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:10]([NH:38][C:37]1[CH:39]=[CH:40][CH:41]=[C:35]([C:34]([F:33])([F:42])[F:43])[CH:36]=1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)C(OCc1ccccc1)OCc1ccccc1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cccc(C(F)(F)F)c1)C(OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
A stirred solution of dibenzyloxyacetic acid (4.0 g, prepared as described in Step 2) in dichloromethane (40 ml) was cooled to 0° C. and treated dropwise with, successively, 4-N,N-dimethylformamide (100 mg) and oxalyl chloride (2.0 g). After thirty minutes, pyridine (3.52 g), 3-trifluoromethyl aniline (2.64 g) and 4-dimethylaminopyridine (100 mg) were added. The mixture was stirred at 0° C. for a further thirty minutes then allowed to warm to room temperature. After three hours, it was poured into water, extracted with ethyl acetate and the extracts washed successively with dilute hydrochloric acid, water, aqueous sodium bicarbonate solution, and brine. After drying over magnesium sulphate, the extracts were evaporated under reduced pressure to give the title compound (5.62 g) as an orange gum, sufficiently pure to be used in Step 4.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][CH:6]=1.CI.[C:18](=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[F:15][C:2]([F:1])([F:14])[CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:18])=[O:12])[CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)c1cccc(OCC(F)(F)F)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CI
Product: COC(=O)c1cccc(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.5 %

Procedure:
A mixture of 6-(2,2,2-trifluoroethoxy)picolinic acid (2.40 g, 10.9 mmol, Step-1), methyl iodide (3.39 mL, 54.3 mmol) and potassium carbonate (4.50 g, 32.6 mmol) in DMA (54 mL) is stirred at rt for 4 hours. The reaction mixture is poured into water (100 mL) and extracted with n-hexane/EtOAc (1:10, 100 mL). The organic layer is washed with water (100 mL), and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (5:1) to give 1.14 g (45% yield) of the title compound as colorless oil.
Reaction SMILES: S(O[CH2:12][CH2:13][N:14]1[C:18]2=[CH:19][C:20]3[N:21]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([F:35])[CH:28]=4)[CH:23]=[N:24][C:25]=3[CH:26]=[C:17]2[CH:16]=[N:15]1)(C1C=CC(C)=CC=1)(=O)=O.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.CN(C=O)C>O>[N:36]1([CH2:12][CH2:13][N:14]2[C:18]3=[CH:19][C:20]4[N:21]=[C:22]([C:27]5[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([F:35])[CH:28]=5)[CH:23]=[N:24][C:25]=4[CH:26]=[C:17]3[CH:16]=[N:15]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: COc1ccc(-c2cnc3cc4cnn(CCOS(=O)(=O)c5ccc(C)cc5)c4cc3n2)cc1F
Reactant: C1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cnc3cc4cnn(CCN5CCCCC5)c4cc3n2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
A mixture of 1-(2-tosyloxyethyl)-7-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-g]quinoxaline (0.3 g), piperdine (0.11 g) and 20 ml of anhydrous DMF is stirred at room temperature overnight. The mixture is heated to gentle reflux for 21/2 hours. After cooling, it is poured into water and the precipitate is filtered, washed with water and air dried. This is then purified by chromatography using (3:7-1:9) methylene chloride in ethylacetate as eluent. 0.220 g of desired product to obtain 1-(2-piperdin-1-ylethyl)-7-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-g]quinoxaline (m.p. 117°-120° C. (dec)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[N+:11]([O-])([OH:13])=[O:12]>OS(O)(=O)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:4]([CH:3]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cccc(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
3-Fluorobenzoic acid (1 g, 7.13 mmol) was dissolved in concentrated H2SO4 (2 ml) by warming slightly above room temperature. The solution was cooled to 0° C. Fuming nitric acid (539 mg, 8.56 mmol) was added slowly to the solution while keeping the temperature below 0° C. The solution was stirred at 0° C. for 3 h. The solution was poured into ice water, the solid formed were filtered, washed by cold water, and dried to yield 1.2 g (92%) of white solids. M.P. 122° C. 1H NMR (DMSO-d6): 7.60 (dt, J=2.9, 8.5 Hz, 1H), 7.71 (dd, J=2.9, 8.6 Hz, 1H), 8.13 (dd, J=4.8, 8.8 Hz, 1H). EIMS m/z 186 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[N:13]1([C:8]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)=[O:10])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCOCC1

Procedure:
Using 4-nitro-benzoic acid (334 mg) instead of 3-nitro-benzoic acid, and morpholine (209 μl) instead of 1-ethyl-piperazine, in the same manner as Step A in Example 1-D-101, the desired compound was obtained (363.5 mg, 77%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:14]=2)=[N:5][C:4]([CH2:26][OH:27])=[N:3]1.[C:28](O)(=[O:30])[CH3:29]>>[C:28]([O:27][CH2:26][C:4]1[N:5]=[C:6]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:14]=2)[N:2]([CH3:1])[N:3]=1)(=[O:30])[CH3:29]
Reactant: Cn1nc(CO)nc1NCCCCOc1cccc(CN2CCCCC2)c1
Reactant: CC(=O)O
Product: CC(=O)OCc1nc(NCCCCOc2cccc(CN3CCCCC3)c2)n(C)n1

Procedure:
A solution of 1-methyl-5-[[4-[3-(1-piperidinylmethyl)phenoxy]butyl]amino]-1H-1,2,4-triazole-3-methanol (100 mg) in glacial acetic acid (5 ml) was heated under reflux for 8 h. The mixture was evaporated and the residue was triturated with ether to give the title compound as a white solid (97 mg) m.p. 119°-20°. tlc. System B,Rf 0.8.
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][NH:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C>C(#N)C>[O:1]([CH2:8][CH2:9][O:10][S:13](=[O:15])(=[O:14])[NH:12][CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNS(=O)(=O)Cl
Reactant: OCCOc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNS(=O)(=O)OCCOc1ccccc1

Procedure:
This compound was prepared according to the procedure used in Example 112. Thus, a mixture of 14.8 g (0.1 mole) of 2-phenoxyethanol (Matheson, Coleman, and Bell), 15.6 g (0.12 mole) of methylsulfamoyl chloride and 12.3 g (0.12 mole) of triethylamine in 150 ml of acetonitrile gave a viscous oil that solidified upon standing. The solid was recrystallized from benzene-petroleum ether (30°-60° C.) to yield 15.4 g (67%) of shiny, white flakes, mp 66°-68° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[N:12]=[CH:13][N:14]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]=2)[OH:10])=[CH:5][C:4]=1[F:35])#[N:2]>C(Cl)Cl.O=[Mn]=O>[C:29]1([C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:14]2[CH:15]=[C:11]([C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:35])[CH:5]=3)=[O:10])[N:12]=[CH:13]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N#Cc1ccc(C(O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1F
Agent: O=[Mn]=O
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1F

Procedure:
To a solution of (4-cyano-3-fluorophenyl)[1-(triphenylmethyl)imidazol-4-yl]methanol, as described above in Step A, (10.0 g, 21.8 mmol) in CH2Cl2 (300 mL) was added MnO2 (18.9 g, 218 mmol) and the resulting mixture was heated to reflux for 18 hours. The mixture was allowed to cool, then filtered through a pad of celite, washing with CH2Cl2. The filtrate was concentrated under reduced pressure to provide the titled product as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[N:12]=2)[CH:4]=1)[CH3:2].[N:19]1([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:27]3[CH2:28][CH2:29][CH:24]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:25][CH2:26]3)[N:12]=2)[CH:4]=1)[CH3:2]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: CCc1cc(-c2cccc(C=O)n2)c(C)[nH]c1=O
Product: CCc1cc(-c2cccc(CN3CCC(N4CCCC4)CC3)n2)c(C)[nH]c1=O

Procedure:
5′-Ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-6-carbaldehyde prepared in accordance with PREPARATION 11 is reacted with 4-pyrrolidinyl-piperidine as described in Method A, Example 123 to give the title compound. MS: m/e=381 (M+H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][CH2:29][C:30](O)=[O:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:48][C@H:49]([C:57]([CH:59]1[CH:66]2[CH2:67][CH:62]3[CH2:63][CH:64]([CH2:68][C:60]1([NH2:69])[CH2:61]3)[CH2:65]2)=[O:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>O1CCCC1>[C:1]([NH:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][CH2:29][C:30]([NH:48][C@H:49]([C:57]([CH:59]1[CH:66]2[CH2:67][CH:62]3[CH2:63][CH:64]([CH2:68][C:60]1([NH2:69])[CH2:61]3)[CH2:65]2)=[O:58])[CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: N[C@@H](Cc1ccccc1)C(=O)C1C2CC3CC(C2)CC1(N)C3
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)C1C2CC3CC(C2)CC1(N)C3
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of 1.88 g of Boc-L-tyrosyl-D-methionyl-glycine and 0.45 ml of N-methylmorpholine in 25 ml of dry tetrahydrofuran under nitrogen is cooled to -45° C. with stirring. To the cooled solution is added 0.52 ml of isobutylchloroformate. The reaction mixture is allowed to warm to -20° C. over a 10 minute period and is then cooled to -35° C. Following the addition of 1.9 g of L-phenylalanyl-1-aminoadamantane the reaction mixture is warmed to room temperature and allowed to stand overnight. The reaction mixture is filtered and the tetrahydrofuran is removed under reduced pressure. The residue is dissolved in methylene chloride and washed with cold 1 M potassium bisulfate solution and saturated sodium chloride solution. Removal of the solvent and purification by chromatography on silica gel gives Boc-tyrosyl-D-methionyl-glycyl-phenylalanyl-1-aminoadamantane which is represented by the following formula ##STR39##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[N:14]([CH3:39])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH2:37][CH3:38])[N:16]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.CC(O)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[N:14]([CH3:39])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH2:37][CH3:38])[N:16]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=C3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Reaction time: 65 h
Yield: 83.4 %

Procedure:
To a solution of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene]azetidine-1-carboxylic acid tert-butyl ester (1.1 g, 2.07 mmol) in EtOH (40 mL) and AcOH (15 mL) was added 10% Pd/C (200 mg) and the resulting mixture stirred under an atmosphere of H2 for 65 h. The reaction mixture was filtered through Celite®, washing with EtOAc, and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 70-100%) affording the title compound as an orange oil (0.92 g, 83%). LCMS (method H): RT 3.01 min [M+H]+ 533.4
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].[N:23]1([C:28]2[CH:29]=[C:30]([C:34]3[O:39]C(C)(C)[O:37][C:36](=O)[CH:35]=3)[CH:31]=[CH:32][CH:33]=2)[CH:27]=[CH:26][N:25]=[CH:24]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:10][C:9]=1[NH:21][C:36](=[O:37])[CH2:35][C:34]([C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[CH:29]=1)=[O:39])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Yield: 58.3 %

Procedure:
Prepared from (3-amino-3′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G38) (151 mg, 0.5 mmol) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10) (135 mg, 0.5 mmol) according to the general procedure K. Obtained as an orange solid (150 mg).