Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[C:15]1[N:23]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[CH:16]=1)[CH:2]=[CH2:3].[O:34]1CCCC1>C(O)C.[OH-].[K+].OO>[CH3:14][N:10]1[C:11]2[C:7](=[CH:6][C:5]([O:4][CH2:1][CH2:2][CH2:3][OH:34])=[CH:13][CH:12]=2)[C:8]([C:15]2[N:23]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[CH:16]=2)=[CH:9]1.[CH3:14][N:10]1[C:11]2[C:7](=[CH:6][C:5]([O:4][CH2:1][CH:2]([OH:34])[CH3:3])=[CH:13][CH:12]=2)[C:8]([C:15]2[N:23]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[CH:16]=2)=[CH:9]1
Reactant: C1CCOC1
Reactant: C=CCOc1ccc2c(c1)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(OCC(C)O)cc34)cc3cccnc32)cc1
Product: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(OCCCO)cc34)cc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A solution of 2-(5-allyloxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine [91 mg, Reference Example 15(a)] in dry tetrahydrofuran (5 mL) was treated with a solution of borane-tetrahydrofuran complex in tetrahydrofuran(1200 μl, 1.0M). After stirring at ambient temperature for 7 hours the reaction mixture was treated with ethanol (9 drops), 5N potassium hydroxide (4 drops) and hydrogen peroxide (6 drops) and stirring was continued for 12 hours during which time a white solid was precipitated. The reaction mixture was diluted with water (50 mL) and the pH of this mixture was adjusted to 10 by addition of potassium hydroxide solution (1M) before exhaustively extracting with ethyl acetate. The combined organic extracts were dried over sodium sulfate then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and pentane (2:1, v/v) to give 3-{1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-5-yloxy}-propan-1-ol (50 mg) as a colourless solid [TLC: RF=0.15 (ethyl acetate). MS: 476(MH+)] and 3-{1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-5-yloxy}-propan-2-ol (8 mg) as a colourless solid. [TLC: RF=0.3 (ethyl acetate); MS: 476(MH+)].
Reaction SMILES: Cl.[C:2]([C:6]1[N:7]=[C:8]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][C:14]=3[CH:15]=2)[S:9][CH:10]=1)([CH3:5])([CH3:4])[CH3:3].[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=[CH:24]1.C(N(CC)CC)C.CN(C)CC(N)C>ClCCl>[C:2]([C:6]1[N:7]=[C:8]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]([N:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25]([C:32]([O:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[O:33])=[CH:24]4)=[O:21])=[CH:16][C:14]=3[CH:15]=2)[S:9][CH:10]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1csc(-c2cc3cc(C(=O)Cl)ccc3o2)n1
Reactant: O=C(OCc1ccccc1)c1c[nH]c2ccccc12
Agent: CC(N)CN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1csc(-c2cc3cc(C(=O)n4cc(C(=O)OCc5ccccc5)c5ccccc54)ccc3o2)n1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
A mixture of 2-(4-tert-butylthiazol-2-yl)benzofuran-5-carbonyl chloride hydrochloride (140 mg), benzyl indole-3-carboxylate (73.3 mg), triethylamine (0.089 ml) and N,N-dimethylaminopyridine (4 mg) in dichloromethane (4 ml) was stirred under reflux for 7 hours. After being cooled to room temperature, the mixture was treated with N,N-dimethylpropylenediamine (0.018 ml) and diluted with dichloromethane. The dichloromethane solution was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was subjected to column chromatography on silica gel and eluted with a mixture of n-hexane and ethyl acetate. The fractions containing the objective compound were combined and concentrated under reduced pressure to give benzyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]carbonyl}indole-3-carboxylate (121 mg).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)[C:11]2=[O:21])=[CH:6][CH:5]=1.[CH2:24](I)[CH3:25]>>[CH2:24]([N:17]1[CH2:18][CH2:19][C:12]2([C:11](=[O:21])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:15][C:16]1=[O:20])[CH3:25]
Reactant: CCI
Reactant: O=C1CC2(CCN1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Product: CCN1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1=O

Procedure:
This material was prepared as a off-white solid in analogy to example 1 step E) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-1,7-dione and ethyl iodide. MS (ESI): 357.1 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34]C)=[O:33])[CH2:29]2)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[CH:15][CH:14]=2)[O:10][N:9]=1)[CH3:2].O.[OH-].[Li+].C(O)(=O)C>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]2)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[CH:17][CH:18]=2)[O:10][N:9]=1)[CH3:2]
Reactant: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3cccc(F)c3)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc(CN2CC(C(=O)O)C2)sc1-c1noc(-c2ccc(Oc3cccc(F)c3)cc2)n1
Yield: 54.1 %

Procedure:
The title compound (83 mg) was synthesized in a yield of 54% as a white crystalline solid by conducting the reaction similar to that mentioned in Example 2 (2e) using methyl 1-[(4-ethyl-5-{5-[4-(3-fluorophenoxy)phenyl]-1,2,4-oxadiazol-3-yl}-2-thienyl)methyl]azetidine-3-carboxylate (0.16 mg, 0.32 mmol) that was obtained in Example 17 (17c), lithium hydroxide monohydrate (30 mg, 0.71 mmol), and acetic acid (39 μL, 0.71 mmol).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[N:11]1([CH2:17][CH2:18][CH2:19][C:20]2[C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[NH:22][CH:21]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[OH-].[Na+]>ClCCl>[N:11]1([CH2:17][CH2:18][CH2:19][C:20]2[C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[NH:22][C:21]=2[CH:3]=[O:4])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: c1[nH]c2c(c1CCCN1CCOCC1)CCCC2
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1[nH]c2c(c1CCCN1CCOCC1)CCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.4 %

Procedure:
To an ice-cooled solution of 0.32 mL (4.1 mmol) of dimethylformamide in 3 mL of dichloromethane was added dropwise 0.4 mL (4.1 mmol) of phosphorus oxychloride. The reaction mixture was stirred at room temperature for 15 minutes and a solution of 680 mg (2.7 mmol) of 3-(3-morpholin-4-yl-propyl)-4,5,6,7-tetrahydro-1H-indole in 20 mL of dichloromethane was added dropwise at 0° C. The mixture was refluxed at 60° C. for 4 hours and cooled in an ice bath. Ice cubes were slowly added to the mixture followed by addition of 2 N sodium hydroxide to pH 12. The mixture was stirred at room temperature for 30 minutes and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give crude product which was purified on a silica gel column eluting with dichloromethane-methanol-ammonium hydroxide (98:2:1) to give 600 mg (83% yield) of 3-(3-morpholin-4-yl-propyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde as a dark red oil. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 11.33 (s, br, 1H, NH). MS m/z 277 [M+1].
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[CH3:10].Br[CH2:24][CH:25]([CH3:27])[CH3:26]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.CN(C)P(N(C)C)(N(C)C)=O>[CH2:9]([O:11][C:12](=[O:22])[CH:13]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[CH2:24][CH:25]([CH3:27])[CH3:26])[CH3:10]
Reactant: CC(C)CBr
Reactant: CCOC(=O)Cc1ccc(Cl)c(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(CC(C)C)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 96.3 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (4.88 mL of 0.29 M stock solution, 1.41 mmol) cooled to −78° C. was treated with (3,4-dichloro-phenyl)-acetic acid ethyl ester (300 mg, 1.28 mmol) in tetrahydrofuran/hexamethylphosphoramide (3.2 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of 1-bromo-2-methyl-propane (1.53 mL, 1.41 mmol) in hexamethylphosphoramide (1 mL). The reaction mixture was stirred at −78° C. for 6 h. The reaction was then warmed to 25° C. and stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of saturated aqueous ammonium chloride solution (1 mL). This mixture was poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-4-methyl-pentanoic acid ethyl ester (356.4 mg, 95.8%) as a clear oil: EI-HRMS m/e calcd for C14H18Cl2O2 (M+) 288.0683, found 288.0677.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-])=O.C(=O)([O-])O.[Na+].[CH3:25][O:26][C:27]1[C:28]([NH2:33])=[CH:29][CH:30]=[CH:31][CH:32]=1.[H][H]>C(O)C.[C].[Pd].O1CCCC1.O>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[NH2:17]
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: COc1ccccc1N
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccccc1Nc1ccc(-c2nc3ccccc3o2)cc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.5 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.16 mmol) in ethanol (5 mL) was added sodium hydrogen carbonate (195 mg, 2.32 mmol) and o-anisidine (357 mg, 2.90 mmol), and this was heated to reflux with stirring for 4 hours. After the reaction was complete, this was cooled to room temperature, water was added, and this was extracted with chloroform. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The crystals obtained were added to a tetrahydrofuran (5 mL) solution containing 10% palladium-carbon (50 mg), a hydrogen atmosphere was substituted in the flask, and this was stirred at room temperature for 8 hours. After the reaction was complete, this was filtered through Celite and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (51.9 mg, 14% yield) as red crystals.
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[C:5](CC)(CC)[C:6]#[N:7].[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1>[C:14]1(=[CH:5][C:6]#[N:7])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Reactant: O=C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC=C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.3 %

Procedure:
Sodium hydride (60% in oil, 0.80 g, 20 mmol) was suspended in 50 mL tetrahydrofuran and chilled in ice under nitrogen. Diethylcyanomethyl phosphonate (3.85 g, 22 mmol) was added dropwise in 10 mL tetrahydrofuran and stirring continued for 15 minutes to give a clear solution. Cyclohexanone (1.90 g, 19 mol) was added in 5 mL tetrahydrofuran and the reaction mixture allowed to warm up to room temperature. The liquor was decanted and the residue washed three times with ether. The liquor and washings were combined, washed with dilute hydrochloric acid and water, dried over magnesium sulphate, filtered, and evaporated to dryness. The residue was purified by chromatography on silica eluting with heptane/ethyl acetate 4:1 to give the required product as a colorless oil (1.5 g. 67%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([C:14]([NH:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21]([C:26]([OH:28])=[O:27])=[CH:20]4)=[O:15])=[CH:11][C:10]=2[CH:29]=1)=[O:4].Cl.[N:31]1([C:36](N)=[NH:37])C=CC=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH:1]([CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([C:14]([NH:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21]([C:26]([OH:28])=[O:27])=[CH:20]4)=[O:15])=[CH:11][C:10]=2[CH:29]=1)=[O:4])[C:36]([NH2:37])=[NH:31]
Reactant: N=C(N)n1cccn1
Reactant: NCC(=O)Nc1ccc2oc(C(=O)Nc3ccc4[nH]c(C(=O)O)cc4c3)cc2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N=C(N)NCC(=O)Nc1ccc2oc(C(=O)Nc3ccc4[nH]c(C(=O)O)cc4c3)cc2c1

Procedure:
170 mg (0.05 mmol) 131 was treated overnight with 73.5 mg (0.5 mmol) pyrazole-1-carboxamidine hydrochloride and 172 μL diisopropylethylamine dissolved in 2 mL DMF. Next day the resin was drained, washed five times with DMF to give 132 which was treated immediately to cleave the compound off, as described below in Example 121.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]([C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32])#[N:27]>C(#N)C>[C:26]([C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)=[O:32])#[N:27]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN1CCN(c2cccc3ccc(NC(=O)c4cccc(C#N)c4)cc23)CC1
Yield: 60 %

Procedure:
The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.213 g, 0.883 mmol) and triethylamine (0.258 mL, 1.94 mmol) and 3-cyanobenzoyl chloride (0.322 g, 1.94 mmol) in acetonitrile (10 mL) with stirring at reflux for 2 hours and then at room temperature overnight. The mixture was concentrated and the residue was taken up in methylene chloride. This organic solution was washed with 0.5N sodium hydroxide, dried over calcium sulfate and concentrated. The product was isolated by silica gel flash chromatography and recrystallization from isopropyl alcohol to yield 0.184 g of (60%) of the title compound: mp 220°-222° C. Analysis calculated for C23H22N4O: C, 74.57; H, 5.99; N, 15.12. Found: C, 74.42; H, 5.78; N, 14.96.
Reaction SMILES: [H][H].N1[CH2:14][CH2:13]NCCNCCNCC1.[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:17][CH2:16][CH2:15][CH2:20][CH2:19][CH2:15][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:13][CH3:14]
Reactant: c1ccccc1
Reactant: C1CNCCNCCNCCN1
Reactant: [H][H]
Product: CCCCCCCCCCCCC

Procedure:
A preferred preparation of the compounds of formula IIa wherein R12 is hydrogen is to react 1,4,7,10-tetraazacyclododecane, known in the art, with dimethylformamidedimethylacetal in the presence of benzene to yield 1,4,7,10-tetraazatricyclo-[5.5,1.0]tridecane. This “tricyclic” compound is reacted with an ethanol/water mixture to yield 1-formyl-1,4,7,10-tetraazacyclododecane. This formyl compound is then reacted with t-butyl bromoacetate to yield 1-formyl-4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane, tris-t-butylester. Finally, the ester groups are removed in the presence of strong acid, such as sulfuric acid, to yield a compound of formula IIa wherein R12 is hydrogen. The most preferred methods are included in Dischino, et al., Inorg. Chem., 30, 1265, 1991.
Reaction SMILES: C([C@@H](NC(C1C=C(C)C2N=C(CCC)N(CC3C=CC(C4C=CC=CC=4C4NN=NN=4)=CC=3)C=2C=1)=O)CC(=O)NOCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:55]([C@@H:62]([NH:75][C:76]([C:78]1[CH:107]=[C:106]([CH3:108])[C:81]2[N:82]([CH2:88][C:89]3[CH:94]=[CH:93][C:92]([C:95]4[CH:100]=[CH:99][CH:98]=[CH:97][C:96]=4[C:101]4[NH:105][N:104]=[N:103][N:102]=4)=[CH:91][CH:90]=3)[C:83]([CH2:85][CH2:86][CH3:87])=[N:84][C:80]=2[CH:79]=1)=[O:77])[CH2:63][C:64](=[O:74])[NH:65][O:66]CC1C=CC=CC=1)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>CCO.C(O)(=O)C.[Pd]>[CH2:55]([C@@H:62]([NH:75][C:76]([C:78]1[CH:107]=[C:106]([CH3:108])[C:81]2[N:82]([CH2:88][C:89]3[CH:94]=[CH:93][C:92]([C:95]4[CH:100]=[CH:99][CH:98]=[CH:97][C:96]=4[C:101]4[NH:102][N:103]=[N:104][N:105]=4)=[CH:91][CH:90]=3)[C:83]([CH2:85][CH2:86][CH3:87])=[N:84][C:80]=2[CH:79]=1)=[O:77])[CH2:63][C:64](=[O:74])[NH:65][OH:66])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: CCCc1nc2cc(C(=O)N[C@@H](CC(=O)NOCc3ccccc3)Cc3ccccc3)cc(C)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Pd]
Agent: CCCc1nc2c(C)cc(C(=O)N[C@@H](CC(=O)NOCc3ccccc3)Cc3ccccc3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: CCCc1nc2cc(C(=O)N[C@@H](CC(=O)NO)Cc3ccccc3)cc(C)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 12 h

Procedure:
A mixture of 7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-benzoimidazole-5-carboxylic acid ((R)-1-benzyl-2-benzyloxycarbamoylethyl)amide and 7-methyl-2-propyl-1-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-benzoimidazole-5-carboxylic acid ((R)-1-benzyl-2-benzyloxycarbamoylethyl)amide were dissolved in EtOH (50 mL), followed by the addition of 10% Pd/C (200 mg). The final mixture was bubbled with nitrogen gas for 5 minutes, and degassed. The reaction mixture was stirred under hydrogen (1 atm) for 12 hours, and filtered through Celite®. The filtrate was concentrated to afford a pale brown oil. The oil was dissolved in 50% aqueous acetic acid, and purified by reversed phase preparative HPLC. The desired product, compound 2-b (minor component), was isolated as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:18]1[N:27]=[C:26]([N:28]([CH3:30])[CH3:29])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.C(N(CC)CC)C>CC(O)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:9][CH2:10][C@@H:11]([CH2:14][NH:15][C:18]2[N:27]=[C:26]([N:28]([CH3:30])[CH3:29])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CN)CC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CN(C)c1nc(NC[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)nc2ccccc12
Temperature: 170 °C
Yield: 64.1 %

Procedure:
A mixture of cis-(4-aminomethyl-cyclohexyl)-carbamic acid tert-butyl ester (1.14 g, 5 mmol), (2-chloro-quinazoline-4-yl)-dimethyl-amine obtained in step B of example 1 (1.035 g, 5 mmol), and triethylamine (1.5 mL, 11 mmol) in 2-propanol (2.5 mL) was heated at 170° C. for 35 min using a Smith Microwave Synthesizer. The mixture was concentrated and the residue was purified by column chromatography (silica gel, CH2Cl2 to 10% 2 M NH3/MeOH in CH2Cl2) to give cis-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (1.28 g, 80%) as a white solid.
Reaction SMILES: OC[CH:3]1[CH:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][CH:6]2[CH:5]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[O:4]1.[C:32]([O:35][CH2:36]C)(=[O:34])[CH3:33].[CH3:38]S(C)=O>>[CH3:36][O:35][C:32](=[O:34])[CH:33]=[CH:38][CH:3]1[CH:7]2[CH:6]([O:10][C:9]([CH3:11])([CH3:12])[O:8]2)[CH:5]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH:22][C:23]([NH:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:24])[O:4]1
Reactant: CC1(C)OC2C(CO)OC(n3cnc4c(NC(=O)Nc5ccccc5)ncnc43)C2O1
Reactant: CCOC(C)=O
Reactant: CS(C)=O
Product: COC(=O)C=CC1OC(n2cnc3c(NC(=O)Nc4ccccc4)ncnc32)C2OC(C)(C)OC12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a vial containing the starting compound, 1-[9-(6-Hydroxymethyl-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl]-3-phenyl-urea (1.07 g, 2.5 mmol), in 10 ml of dimethylsulfoxide was added IBX (1.06 g, 3.75 mmol) in one portion at RT. The white solid gradually dissolved as the reaction proceeded. After stirring at RT for 2 hours, methyl(triphenylphosphorylidene) acetate (0.84 g, 2.5 mmol) was added in one portion. The reaction was run at RT overnight. To the reaction mixture was added ethyl acetate (100 ml), which was washed with saturated NaHCO3, brine, and dried over MgSO4. After removal of solvent, the residue was recrystallized with isopropyl alcohol to provide the title compound. MW calculated for C23H24N6O6 (MH+) 481.5. found 481.3 by LCMS.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:49]=[CH:48][C:31]([O:32][C:33]2[CH:34]=[CH:35][C:36]3[N:37]([CH:39]=[C:40]([NH:42][C:43]([CH:45]4[CH2:47][CH2:46]4)=[O:44])[N:41]=3)[N:38]=2)=[CH:30][CH:29]=1>CN(C)C(=O)C.O1CCCC1>[CH:45]1([C:43]([NH:42][C:40]2[N:41]=[C:36]3[CH:35]=[CH:34][C:33]([O:32][C:31]4[CH:30]=[CH:29][C:28]([NH:27][C:7]([C:5]5[N:4]([C:10]6[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=6)[N:3]=[C:2]([CH3:1])[CH:6]=5)=[O:9])=[CH:49][CH:48]=4)=[N:38][N:37]3[CH:39]=2)=[O:44])[CH2:46][CH2:47]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1
Reactant: Cc1cc(C(=O)O)n(-c2ccccc2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)cc2)n(-c2ccccc2)n1
Yield: 65.2 %

Procedure:
Using 3-methyl-1-phenyl-1H-pyrazole-5-carboxylic acid (196 mg, 0.97 mmol), tetrahydrofuran (2.0 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (85 μL, 0.97 mmol), N-[6-(4-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.65 mmol) and N,N-dimethylacetamide (4.0 mL), and in the same manner as in Example 255, the title compound (209 mg, 65%) was obtained as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]([CH3:13])[CH2:9][NH:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[Br:20][CH2:21][C:22](Br)=[O:23]>C(OCC)(=O)C>[Br:20][CH2:21][C:22]([CH2:12][CH2:11][NH:10][CH2:9][C@@H:8]([NH:7][C:6](=[O:14])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:13])=[O:23]
Reactant: O=C(Br)CBr
Reactant: CCNC[C@H](C)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C[C@@H](CNCCC(=O)CBr)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a cold (0° C.) stirred solution of tert-butyl[(1S)-2-(ethylamino)-1-methylethyl]carbamate (11.0 g, 54.6 mmol) in a mixture of ethyl acetate (107 mL) and saturated aqueous sodium bicarbonate (65 mL), bromoacetyl bromide (12.1 g, 60.0 mmol) was added portionwise under an atmosphere of nitrogen. The mixture was allowed to warm up to room temperature over a period of 3.5 hours. The organic phase was separated, washed successively with saturated aqueous sodium bicarbonate, and brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was concentrated as a solution in toluene under vacuum to afford the title compound. ES MS M+1=323, 325.