Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:12]=[CH:13][C:14]3[CH:19]=[C:18]([C:20](=[O:24])[N:21]([CH3:23])[CH3:22])[N:17]([CH:25]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:15]=3[N:16]=2)=[N:6][CH:5]=1.[Li+].[OH-].Cl>C1COCC1.O>[CH:25]1([N:17]2[C:15]3[N:16]=[C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:32])=[O:2])=[CH:5][N:6]=4)[N:12]=[CH:13][C:14]=3[CH:19]=[C:18]2[C:20](=[O:24])[N:21]([CH3:22])[CH3:23])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COC(=O)c1ccc(Nc2ncc3cc(C(=O)N(C)C)n(C4CCCCCC4)c3n2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.6 %

Procedure:
To a solution of 6-(7-Cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid methyl ester (146 mg, 0.33 mmol, 1.0 eq) in THF (1.5 mL) was added LiOH (94.7 mg, 4.0 mmol, 12 eq) in 1.5 mL of water. The mixture was stirred at room temperature for 48 h. The reaction mixture was cooled to 0° C. in an ice bath and was acidified with 1N HCl until pH was about 1-2. The solid precipitate was filtered and washed to give the title compound as a light pink solid (52 mg, 0.124 mmol, 37%) and used as is; alternatively it can be extracted out with 20% Isopropanol in dichloromethane) 1H NMR (400 MHz, DMSO-d6) δ ppm 12.99 (br s, 1H) 10.38 (br s, 1H) 8.87 (s, 1H) 8.81 (d, J=2.01 Hz, 1H) 8.53 (d, J=9.03 Hz, 1H) 8.19 (dd, J=9.03, 2.01 Hz, 1H) 6.67 (s, 1H) 4.44 (br s, 1H) 3.07 (d, J=13.05 Hz, 6H) 2.54-2.60 (m, 2H) 1.87-1.98 (m, 2H) 1.75-1.87 (m, 2H) 1.59-1.75 (m, 4H) 1.49 (m, 2H). MS (m/z, MH+): 423.5
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][CH:19]1[CH2:21][O:20]1>CC(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:18][CH:19]1[CH2:21][O:20]1)([O-:3])=[O:2]
Reactant: ClCC1CO1
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccccc1OCC1CO1
Reaction time: 48 h
Yield: 20 %

Procedure:
To a stirred solution of 139 parts of 2-nitrophenol and 138 parts of potassium carbonate in 640 parts of 2-propanone are added dropwise 215 parts of 2-(chloromethyl)oxirane. Upon completion, stirring is continued for 2 days at reflux. The formed precipitate is filtered off and the filter-cake is washed with 2-propanone. The filtrate is evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and petroleumether (1:1 by volume). The product is filtered off and dried, yielding 38 parts (20%) of 2-(2-nitrophenoxymethyl)oxirane; mp. 56° C.
Reaction SMILES: [CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:22]1([NH2:32])[C:31]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=2[CH:25]=[CH:24][CH:23]=1>>[C:22]1([NH:32][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([C:12]3[O:11][N:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:13]=3)=[CH:15][CH:16]=2)[C:31]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: Nc1cccc2c1CCCC2
Product: CCCCCCCCc1noc(-c2ccc(CNc3cccc4c3CCCC4)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-octyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 5,6,7,8-tetrahydronaphthalen-1-ylamine gave the title compound as an oil. M+(LC/MS(ESI)): 418.4. HPLC (Condition A), Rt: 5.83 min (HPLC purity: 82.3%).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:31])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][CH:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH3:30])[N:24]=3)[CH3:22])=[CH:9][CH:10]=2)[CH2:5][NH:4][CH2:3]1>CCCCCC.CC(O)C>[CH3:32][C:2]1([CH3:1])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:31])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][C@H:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH3:30])[N:24]=3)[CH3:22])=[CH:9][CH:10]=2)[CH2:5][NH:4][CH2:3]1
Reactant: CNc1nccc(C(C)Nc2ccccc2C(=O)Nc2ccc3c(c2)CNCC3(C)C)n1
Solvent: CC(C)O
Solvent: CCCCCC
Product: CNc1nccc([C@H](C)Nc2ccccc2C(=O)Nc2ccc3c(c2)CNCC3(C)C)n1

Procedure:
N-(4,4-Dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-[1-(2-methylamino-pyrimidin-4-yl)-ethylamino]-benzamide (190 mg, 0.44 mmol) was separated on a chiral column (Chiralcel AD, 250×4.6 (mm) 10u, n-Hexane/i-PrOH/0.2% DEA (70:30), 1 mL/min). The (S) enantiomer was isolated. MS m/z: 431.3 (M+H). Calc'd. for C25H31N6O-431.55.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][C:12]([NH2:15])=[N:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[C:20](N)=[CH:21][CH:22]=[CH:23][CH:24]=1>C(O)(=O)C>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=1[NH:15][C:12]1[CH2:13][CH2:14][N:10]([S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:16])=[CH:6][CH:5]=2)(=[O:9])=[O:8])[N:11]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(N)=N2)cc1
Reactant: COc1ccccc1N
Solvent: CC(=O)O
Product: COc1ccccc1NC1=NN(S(=O)(=O)c2ccc(C)cc2)CC1

Procedure:
A mixture of 4,5-dihydro-1-(4-toluenesulphonyl)-1H-pyrazol-3-amine (8.08 g) (Organic Synthesis 48,8, (1968)), o-anisidine (8.0 g) and glacial acetic acid (80 ml) was heated on a steam bath for 4 hours. The reaction mixture was cooled, filtered and washed with ether to give the sub-title product, 7.6 g, mp 176°-9°.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7](=[O:9])[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[BrH:17]>C(O)(=O)C>[BrH:17].[CH3:1][CH:2]1[CH2:3][NH:4][CH2:5][CH2:6][C:7](=[O:9])[CH2:8]1
Reactant: CC1CC(=O)CCN(C(=O)OC(C)(C)C)C1
Agent: Br
Solvent: CC(=O)O
Product: CC1CNCCC(=O)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
13.7 g tert-butyl 3-methyl-5-oxoazepane-1-carboxylat was dissolved in 350 mL acetic acid and 99 mL hydro bromide solution (33%) in acetic acid was added. The mixture was stirred for 1.5 h at RT. The volatiles were removed in vacuo and the residue was used in the next step without further purification. (M+H)+: 128
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:17][C:16]2[CH:18]=[C:19](Br)[CH:20]=[CH:21][C:15]=2[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])#[CH:24].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.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.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:24]#[C:23][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=[CH:21][C:15]=2[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(Br)cc2[nH]1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(C#C[Si](C)(C)C)cc2[nH]1
Temperature: 80 °C
Yield: 62.1 %

Procedure:
A mixture of 2-(6-bromo-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (309 mg, 0.84 mmol), ethynyl-trimethyl-silane (1.2 mL, 8.4 mmol), tetrakis(triphenylphosphine)palladium (97 mg, 0.08 mmol), copper(I) iodide (32 mg, 0.16 mmol) and triethylamine (0.7 mL, 5.04 mmol) in 5 ml DMF was heated to 80° C. for 8 hours. The reaction mixture was cooled and dissolved in ethyl acetate and washed with 5% lithium chloride aqueous solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 2-(6-trimethylsilanylethynyl-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, yield 62%). LCMS-ESI−: calc'd for C21H29N3O2Si: 383.56. Found: 384.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:17]=[C:16]([S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:25][CH3:26])(=[O:11])=[O:10].[N+:27]([C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1)([O-:29])=[O:28]>C(Cl)Cl.N1C=CC=CC=1>[CH3:26][O:25][C:13]1[CH:14]=[CH:15][C:16]([S:18]([C:21]([F:24])([F:22])[F:23])(=[O:20])=[O:19])=[CH:17][C:12]=1[S:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:36]([C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([N+:27]([O-:29])=[O:28])[CH:31]=1)(=[O:37])=[O:38])(=[O:10])=[O:11]
Reactant: COc1ccc(S(=O)(=O)C(F)(F)F)cc1S(=O)(=O)Nc1ccccc1N
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)C(F)(F)F)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
To a solution of N-(2-aminophenyl)-2-methoxy-5-trifluoromethanesulfonylbenzenesulfonamide (2 mmol, prepared as in Example A) in DCM (4 mL) and pyridine (4 mL), 3-nitrobenzenesulfonyl chloride (2.2 mmol) was added at RT and the reaction mixture was then allowed to stir at RT. The reaction mixture was then diluted with DCM (20 mL). The organic phase was washed with 10% aqueous HCl (20 mL), water (20 mL) and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to afford 1.04 g of 2-methoxy-N-[2-(3-nitrobenzenesulfonylamino)phenyl]-5-trifluoromethanesulfonylbenzenesulfonamide. LC: Tr 1.17 min, MS: 596.6 (M+1)+. 1H NMR (CDCl3, 400 MHz): δ 4.27 (s, 3H), 6.76 (d, 1H), 6.78(bs, 1H), 7.05 (m, 1H), 7.16 (m, 2H), 7.34 (d, 1H), 7.68 (bs, 1H), 7.72 (t, 1H), 8.01 (dd, 1H), 8.20 (dd, 1H), 8.25 (d, 1H), 8.46 (dd, 1H), 8.55 (d, 1H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]([C:12]1[N:17]=[C:16]([C:18](=O)[CH3:19])[CH:15]=[CH:14][CH:13]=1)[CH3:11].[C:21]1([CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([C:18](=[N:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH3:28])[CH3:19])[N:17]=1)[CH3:11]
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cccc2C)n1
Reactant: Cc1ccccc1N
Solvent: Cc1ccccc1
Product: CC(=Nc1ccccc1C)c1cccc(C(C)=Nc2c(C)cccc2C)n1

Procedure:
5.0 g (0.0188 mol) of 1-{6-[1-(2,6-Dimethyl-phenylimino)-ethyl]-pyridin-2-yl}-ethanone 1 (5.0 g, 0.0188 mol), 2.62 g (0.02445 mol) of ortho-tolylamine 5, 100 g of fresh molecular sieves, and 100 ml of toluene were kept at 100° C. for 3 days under the flow of nitrogen. The solvent was removed in a rotary evaporator and the residue was recrystallized from 20 ml of ethanol. The yield of (2,6-dimethyl-phenyl)-{1-[6-(1-o-tolylimino-ethyl)-pyridin-2-yl]-ethylidene}-amine 4 was 4.74 g (71%) as a yellow solid.
Reaction SMILES: [Li+].[Cl-].[Cl:3][C:4]([Cl:15])([Cl:14])[C@@H:5]1[N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[C:7](=[O:13])[O:6]1.[Li+].CC([N-]C(C)C)C.[CH:24](OC)=[O:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[O:13]=[C:7]1[O:6][C@H:5]([C:4]([Cl:3])([Cl:14])[Cl:15])[N:9]2[CH2:10][CH2:11][CH2:12][C@@:8]12[CH:24]=[O:25]
Reactant: COC=O
Reactant: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@H]12
Agent: CC(C)[N-]C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: O=C[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
After adding approximately 3.5 g LiCl bei −78° C. to a solution of 14.092 g (57.64 mmol, 1.0 eq) of the protected proline 103, 138 ml (86.46 mmol, 1.5 eq, 0.625 M) LDA in THF were dropped in over the course of 60 min. The solution was stirred for 30 min at this temperature, and then 15 ml (241.85 mmol, 4.0 eq) HCOOMe was very slowly dropped in over 120 min. The solution was stirred for another 30 min at −78° C., and then brought to a temperature of −40° C. over the course of 1 h. 120 ml of a 10% citric acid solution in water was then added, the substance was extracted 3× with 120 ml MTBE respectively, and the combined organic phases were washed with 500 ml saturated NaCl solution, dried over magnesium sulfate, and the solvent was removed under reduced pressure. Chromatography on silica gel with EtOAc/CyHex 1:4 as eluent yielded 10.388 g (38.12 mmol, 66%) of the product 104 as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>ClCCl.CN(C1C=CN=CC=1)C.O>[S:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:6]1[CH:5]=[CH:4][C:3]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[C:2]([NH:1][C:22](=[O:23])[O:24][CH2:25][CH3:26])[CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Nc1cc(-c2cccs2)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
To a solution of tert-butyl (2-amino-4-(thiophen-2-yl)phenyl)carbamate (0.20 g, 0.69 mmol, 1.0 equiv.) in dichloromethane (4 mL) was added ethyl chloroformate (0.08 mL, 0.83 mmol, 1.2 equiv.), TEA (0.19 mL, 1.37 mmol, 2.0 equiv.) and DMAP (8 mg, 0.07 mmol, 0.1 equiv.) at 0° C. The reaction was warmed to room temperature and stirred for 16 h. The reaction was then diluted with dichloromethane and water. The organic layer was separated, washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified on column chromatography (silica gel, 20% EtOAc/hexanes) to give tert-butyl ethyl (4-(thiophen-2-yl)-1,2-phenylene)dicarbamate (0.11 g, 44% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:19]([C:22]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:23])=[CH:18][C:15]=1[CH2:16][OH:17].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.CCOCC>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:19]([C:22]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:23])[CH3:24])=[CH:18][C:15]=1[CH:16]=[O:17]
Reactant: CC(C)(C)CC(C)(C)c1ccc(OCCOCCOC2CCCCO2)c(CO)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)CC(C)(C)c1ccc(OCCOCCOC2CCCCO2)c(C=O)c1
Reaction time: 8 h
Yield: 95.9 %

Procedure:
The above benzyl alcohol (37 g, 0.08 mol) in dichloromethane (150 ml) was added dropwise to a suspension of pyridinium dichromate (36.25 g, 0.14 mole, Tetrahedron Letters, 399 [1979]) in dichloromethane (250 ml), with stirring. Stirring was continued overnight, and then the reaction mixture was diluted with ether and filtered through a magnesium sulfatesilica gel pad. The filtrate was washed with 1N hydrochloric acid and then it was evaporated in vacuo to give 31.2 g (87% yield) of 2-(2-[2-(2-tetrahydropyranyloxy)ethoxy]ethoxy)-5-t-octylbenzaldehyde, as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3Br)[CH2:5][C:4]=2[N:3]=1.NC1N=C[C:28]2[C:27](=O)[CH2:26][CH:25](C3C=CC(F)=CC=3C3C=NC=CC=3)[CH2:24][C:23]=2N=1.C1(B(O)O)C=CC=CC=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:5][C:4]=2[N:3]=1
Reactant: Nc1ncc2c(n1)CC(c1ccc(F)cc1-c1cccnc1)CC2=O
Reactant: Nc1ncc2c(n1)CC(c1ccccc1Br)CC2=O
Agent: OB(O)c1ccccc1
Product: Nc1ncc2c(n1)CC(c1ccccc1-c1ccccc1)CC2=O

Procedure:
The title compound was prepared from 2-amino-7-(2-bromo-phenyl)-7,8-dihydro-6H-quinazolin-5-one (example 2/h stage 2), following the procedure describing the synthesis of 2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-7,8-dihydro-6H-quinazolin-5-one (example 4/a stage 1) except for phenylboronic acid replacing 3-pyridylboronic acid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]2[N:23]=[N:24][N:25]=[C:17]2[C:16]=1[NH:26][C:27](=O)[CH2:28][O:29][CH2:30][CH3:31])(=O)C>C(O)C.O>[CH2:30]([O:29][CH2:28][C:27]1[N:14]([CH2:13][CH2:12][CH2:11][OH:10])[C:15]2[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]3[N:23]=[N:24][N:25]=[C:17]3[C:16]=2[N:26]=1)[CH3:31]
Reactant: CCOCC(=O)Nc1c(NCCCOC(C)=O)c(C)c(C)n2nnnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOCc1nc2c(c(C)c(C)n3nnnc23)n1CCCO
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A solution of 6 M potassium carbonate (0.9 mL, 5.2 mmmol) was added to a solution of crude 3-({8-[(ethoxyacetyl)amino]-5,6-dimethyltetraazolo[1,5-a]pyridin-7-yl}amino)propyl acetate from Part C in 3:1 ethanol/water (12 mL) at room temperature. The solution was stirred for 3 days, then was heated to 80° C. More 6 M potassium carbonate (3 mL) was added after 1 day. After another day, 6 M potassium carbonate (5 mL) was added again. The temperature was increased to 85° C. and stirring was continued one more day. The solvent was removed under reduced pressure and the residue was partitioned between chloroform (100 mL) and saturated aqueous sodium bicarbonate (30 mL). The layers were separated and the aqueous layer was extracted with chloroform (3×20 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (2>20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 0.35 g of 3-[8-(ethoxyrnethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]propan-1-ol as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.[N-:14]=[N+:15]=[N-:16].[Na+].O>CS(C)=O>[N:14]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)=[N+:15]=[N-:16]
Reactant: O=Cc1ccc(OCCCBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCCOc1ccc(C=O)cc1
Reaction time: 16 h
Yield: 92.4 %

Procedure:
A mixture of 4-(3-bromopropyloxy)benzaldehyde (3.5 g, 14.5 mmol) and sodium azide (29 mmol, 1.9 g) in DMSO (70 ml) was stirred for 16 h, poured into water (100 ml) and extracted twice with diethyl ether. The extracts were washed with water (50 ml) and saturated aqueous sodium chloride, dried over sodium sulphate and evaporated to give a colourless oil (2.75 g). M+ 205; 360 MHz 1H n.m.r (CDCl3) 7.84 (2H, d, J 11 Hz), 7.02 (2H, d, J 11 Hz), 4.14 (2H, t, J 5.9 Hz), 3.55 (2 H, t, J 6.5 Hz), 2.09 (2 H, app. pentet, J 6.2 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:6]([NH2:8])[CH:7]=1.Cl[C:17]1[CH:26]=[CH:25][N:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][C:21]([CH3:27])=[N:22]2>>[CH3:27][C:21]1[N:22]=[C:23]2[C:18]([C:17]([NH:8][C:6]3[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[S:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)=[CH:26][CH:25]=[N:24]2)=[CH:19][CH:20]=1
Reactant: Cc1ccc(Sc2ccccn2)c(N)c1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc(Sc2ccccn2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product of Example 227b (60 mg, 0.278 mmol) was reacted with the product from Example 1d (50 mg, 0.278 mmol) for 16 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (24 mg, 28%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.44 (s, 3 H), 2.73 (s, 3 H), 6.45 (d, J=6.99 Hz, 1 H), 7.02-7.12 (m, J=7.72, 1.10 Hz, 2 H), 7.40-7.49 (m, 2 H), 7.50-7.58 (m, J=1.84 Hz, 1 H), 7.72 (dd, J=8.46, 3.31 Hz, 2 H), 8.21-8.27 (m, J=2.94, 0.74 Hz, 1 H), 8.38 (d, J=6.99 Hz, 1 H), 8.85 (d, J=8.82 Hz, 1 H), 10.99 (s, 1 H); MS (ESI+) m/z 359 (M+H−TFA)+; (ESI−) m/z 357 (M−H−TFA)−.
Reaction SMILES: [C:1]1([CH:7]([CH2:10][CH3:11])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=[C:15]([C:19]([O:21]O)=O)[CH:14]=1>>[CH2:10]([C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:14][CH:15]1[CH2:19][O:21]1)[C:8]#[N:9])[CH3:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC(C#N)c1ccccc1
Product: CCC(C#N)(CC1CO1)c1ccccc1

Procedure:
The title compound was prepared by the methods described in Examples 2 and 3 except that 2-phenylbutyronitrile was used instead of methyl 2-phenylbutyrate and complete epoxidation required adding a second quantity of m-chloroperbenzoic acid. The resultant light-yellow oil was used in subsequent reactions without furher purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][CH:18]2[CH2:32][CH:21]3[CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH:20]3[CH2:19]2)=[N:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)=[N:6][CH:7]=1.Cl.CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:17][CH:18]2[CH2:32][CH:21]3[CH2:22][NH:23][CH2:24][CH:20]3[CH2:19]2)=[N:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:15][CH2:16]3)[NH:11][N:10]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Nc4cc(C5CC5)[nH]n4)ncc3Cl)CC2C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Clc1cnc(Nc2cc(C3CC3)[nH]n2)nc1NC1CC2CNCC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution of tert-butyl 5-((5-chloro-2-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (560.3 mg, 1.22 mmol) in DCM (15 mL) was added a solution of HCl in EtOAc (15 mL, 60 mmol). The reaction mixture was stirred at rt for 1 h and concentrated in vacuo. The residue was dissolved in water (30 mL) and adjusted to pH=10 with a saturated Na2CO3 aqueous solution, then extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/5) to give the title compound as a pale yellow solid (0.31 g, 71%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([NH2:20])[CH2:19][CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:17]1([NH:20][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[CH2:19][CH2:18]1
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NC2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (670 mg, 2.92 mmol) and cyclopropylamine (167 mg, 2.92 mmol) in 15 mL anhydrous DMF was added HATU (1.11 g, 2.92 mmol) and the resulting mixture stirred at RT under nitrogen atmosphere for 3 h. The mixture was washed with water and extracted with ethyl acetate (2×50 mL). The organics were washed with brine, separated, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by Biotage MPLC (silica gel 40+ column) eluting with 50% ethyl acetate in hexane to afford the product (704 mg, 89%). ESI-MS calculated for C14H24N2O3: Exact Mass: 268.18. Found 169.17 (M-Boc)+ and 291.15 (MNa)+.