Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:20][CH2:21][CH2:22]I.[NH:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[C:25]1[S-:33].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:7]([CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:20][CH2:21][CH2:22][S:33][C:25]1[NH:24][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccccc1
Reactant: ClCCCI
Reactant: [S-]c1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCCSc1nc2ccccc2[nH]1)CCc1ccccc1
Reaction time: 0.5 h
Yield: 14 %

Procedure:
Phenethyl-carbamic acid tert-butyl ester (1107 mg, 5.0 mmol) is dissolved in dry DMF (7.75 ml). To this solution, sodium hydride (60% w/w in oil, 302 mg, 7.55 mmol) is added under vigorous stirring and stirring is continued for 30 min. Then 1-chloro-3-iodo-propane (250 mg, 5.0 mmol) is dropped into the solution followed by stirring for 2 h at rt and another hour at 50° C. After switching off the heating and addition of sodium 1H-benzoimidazole-2-thiolate (1722 mg, 10 mmol) the mixture is allowed to stir overnight at rt. All the DMF is evaporated in vacuo and the remaining crude is dissolved in DCE. This organic phase is washed twice with water, dried over Na2SO4 and evaporated to give the crude product which is purified by flash chromatography on silica gel (AcOEt/heptane, 1:9 to 1:1), yielding the title compound (289 mg) in 14% as a colourless oil: tR=2.24 min (LC-2), ESI-MS (pos.): m/z 412.43 [M+H]+, MS (neg.): m/z 410.46 [M−H]+; 1H-NMR (CDCl3): δ (ppm) 1.48 (s, 9H, tBu), 1.89 (br. s, 2H, SCH2CH2), 2.83 (t, 2H, PhCH2CH2N), 3.09 (br. s, 2H), 3.26 (br. s, 1H), 3.42 (t, 2H, PhCH2CH2N), 3.47 (br. s, 2H), 7.13-7.30 (m, 7Harom), 7.52 (m, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH3:9])[CH2:4][CH2:3]1.[Br:11][C:12]1[CH:13]=[C:14](O)[CH:15]=[N:16][CH:17]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]([O:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH3:9])[CH2:4][CH2:3]2)[CH:15]=[N:16][CH:17]=1
Reactant: CC(=O)N1CCC(O)CC1
Reactant: Oc1cncc(Br)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)N1CCC(Oc2cncc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4-Hydroxy-piperidin-1-yl)-ethanone (200 mg 1.40 mmol) and 5-bromo-pyridin-3-ol (248 mg; 1.425 mmol) are added dropwise to a solution of PPh3 (606 mg) in THF (30 ml). DIAD (462 mg) is added to the solution. The mixture is stirred at room temperature overnight. The mixture is washed with water, diluted with DCM and dried over Na2SO4, filtered and concentrated to give 1-[4-(5-bromo-pyridin-3-yloxy)-piperidin-1-yl]-ethanone.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)(=[O:22])[CH3:21].O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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>[C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
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: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1ccccc1-c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Yield: 85.5 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 2-acetylphenylboronic acid (150 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (190 mg, 85.6%) as an oil.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[O:10]1CC[CH2:12][CH2:11]1.[H-].[Na+]>CO.C(OCC)(=O)C>[N:1]1([CH2:12][CH2:11][OH:10])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C1CCOC1
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: OCCn1cnc2ccccc21
Reaction time: 0.33 h

Procedure:
To a flask were added 2.3 g benzimidazole and 40 ml tetrahydrofuran and the mixture was cooled to 10 C under nitrogen. 1.0 g Sodium hydride were added in portions and the reaction mixture was stirred for 20 minutes. 4.0 g 2-Todoethanol were added and the mixture was heated to 50 C for 16 hours. The mixture was quenched slowly with 50 ml water, extracted twice with ethyl acetate and dried over sodium sulfate. Following filtration and solvent removal, the product was purified by silica gel chromatography using 25% methanol in ethyl acetate. A solid was obtained that was dissolved in a hot mixture of 10% methanol in ethyl acetate, cooled, filtered and dried giving 1.4 g white solid.
Reaction SMILES: N1(O[C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)C2C=CC=CC=2N=N1.[NH2:20][C:21]1[CH:26]=[CH:25][O:24][CH2:23][CH:22]=1.C(N(CC)CC)C>CN(C)C=O>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([NH:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:19])=[CH:17][CH:16]=1
Reactant: NC1=CCOC=C1
Reactant: Nc1ccc(C(=O)On2nnc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)NC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.3 %

Procedure:
To a mixture of 1.1441 g (4.5 mmole) of 4-amino-benzoic acid benzotriazol-1-yl ester and 8 mL of dry dimethylformamide was added 0.6575 g (6.5 mmole) of 4-amino-pyran followed by 0.4554 g (0.45 mmole) of triethylamine. The mixture stirred at room temperature for 90 minutes. Volatiles were removed under reduced pressure and the residue taken up in ethyl acetate, and the organic layer washed once with 100 mL of 0.5 M sodium carbonate, twice with 75 mL water, and then 75 mL brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.5378 g 4-amino-N-(tetrahydro-pyran-4-yl)-benzamide, which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:20]([NH:23][C:24](=[O:37])[C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[CH:27][CH:26]=2)(=[O:22])=[O:21])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:3])=[O:2].Cl[C:39]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[O:40]>N1C=CC=CC=1.C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[C:6]([S:20]([NH:23][C:24]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][N:34]([C:39]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[O:40])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)=[O:37])(=[O:21])=[O:22])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][S:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([O-:3])=[O:2]
Reactant: COCCOC(=O)Cl
Reactant: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COCCOC(=O)N1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(NCCSc4ccccc4)c([N+](=O)[O-])c3)cc2)CC1
Reaction time: 18 h

Procedure:
A solution of Example 173A (54.1 mg, 0.1 mmol) in pyridine (2 mL) and triethylamine (1 mL) at room temperature was treated with 2-methoxyethyl chloroformate (0.2 mmol), stirred for 18 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 0-5% methanol/dichloromethane) to provide the desired product. MS (ESI(−)) m/e 642 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ8.66 (t, 1H), 8.55 (d, 1H), 7.89 (dd, 1H), 7.75 (d, 2H), 7.30-7.40 (m, 2H), 7.31-7.25 (m, 2H), 7.21-7.07 (m, 2H), 6.90 (d, 2H), 4.16-4.12 (m, 2H), 3.63 (q, 2H), 3.54-3.43 (m, 4H), 3.31-3.20 (m, 8H), 3.23 (s, 3H).
Reaction SMILES: CC1(C)OC(=O)[C:5](=[CH:9][NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)[C:4](=O)[O:3]1.CCCCCC.C(OCC)(=O)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[N:10]1[CH:9]=[CH:5][C:4](=[O:3])[N:12]2[C:11]=1[C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:14]=[CH:13]2
Reactant: CC1(C)OC(=O)C(=CNc2ncnc3ccccc23)C(=O)O1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=c1ccnc2c3ccccc3ncn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.4 %

Procedure:
A mixture of 2,2-dimethyl-5-[(4-quinazolinyl)amino]methylene-1,3-dioxane-4,6-dione (3.5 g) in diphenylether (15 ml) was stirred for 10 minutes at 250°-260° C. and then cooled to ambient temperature. To the reaction mixture was added hexane and allowed to to stand at ambient temperature to give crystals, which were separated by filtration and washed with hexane to give crude crystals (3 g). The crude crystals were subjected to a column chromatography using silica gel (developing solvent: a mixture of ethyl acetate and hexane (3:7)). The eluate was concentrated under reduced pressure to give crystals, which were recrystallized from chloroform and hexane to give 4H-pyrimido[1,2-c]quinazoline-4-one (1.6 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]1([F:31])[CH2:18][CH2:17][C:16]([CH2:29][NH2:30])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[F:31][C:13]1([F:12])[CH2:14][CH2:15][C:16]([CH2:29][NH:30][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[CH3:11])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=2)[CH2:17][CH2:18]1
Reactant: NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1
Reactant: Cc1ccc(F)cc1C(=O)O
Product: Cc1ccc(F)cc1C(=O)NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1

Procedure:
From 5-fluoro-2-methylbenzoic acid and C-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=431.2, tR (minutes, Method D)=0.79
Reaction SMILES: CS(O[CH:6]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][CH2:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12](=[O:25])[CH2:11][CH2:10]1)(=O)=O.[CH3:31][C:32](C)=[O:33].[S:35]1C=CC=C1CC([O-])=O.[K+]>O>[C:32]([S:35][CH:6]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][CH2:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12](=[O:25])[CH2:11][CH2:10]1)(=[O:33])[CH3:31]
Reactant: O=C([O-])Cc1cccs1
Reactant: CC(C)=O
Reactant: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)OS(C)(=O)=O
Agent: [K+]
Solvent: O
Product: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)SC(C)=O
Reaction time: 18 h

Procedure:
A solution of 1 g. of ethyl 15-methanesulfonyloxy-9-oxo-prostanoate (Example 90) in 50 ml. of acetone containing 735 mg. of purified potassium thiolacetate is kept at the reflux temperature for 2 hours, then at room temperature for 18 hours. The mixture is diluted with water and the resulting solution is washed with saturated sodium chloride solution, dried with magnesium sulfate and taken to dryness. The residue is chromatographed on silica gel to give an oil;
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]([NH2:13])[C:8]2([CH3:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([NH:23][C:24]3[C:25](=O)[C:26](=[O:30])[C:27]=3[O:28]C)[C:17]=2[NH:16][N:15]=1>CO>[N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([NH:23][C:24]3[C:27](=[O:28])[C:26](=[O:30])[C:25]=3[NH:13][CH:7]([C:5]3[O:6][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:8]3([CH3:12])[CH2:9][O:10][CH2:11]3)[C:17]=2[NH:16][N:15]=1
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Reactant: COc1c(Nc2cccc3nn[nH]c23)c(=O)c1=O
Solvent: CO
Product: Cc1ccc(C(Nc2c(Nc3cccc4nn[nH]c34)c(=O)c2=O)C2(C)COC2)o1
Temperature: 50 °C
Yield: 43.1 %

Procedure:
A mixture of 263 mg (1.45 mmol, 1.2 eq) of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine and 1.02 g (1.21 mmol, 1 eq) of 3-(3H-benzotriazol-4-ylamino)-4-methoxycyclobut-3-ene-1,2-dione at 29% in 25 ml of methanol was heated at 50° C. for 24 hours. The insoluble material (dimer) was filtered off and the filtrate was evaporated. The residue was chromatographed on silica gel (column puriFlash PF-30SIHP/40G, Spot II) eluted with dichloromethane/methanol (gradient). The solid was taken up with ethyl acetate and this organic phase was washed several times with a 1 N sodium dihydrogen phosphate solution, dried over magnesium sulfate, filtered and evaporated. 205 mg of 3-(3H-benzotriazol-4-ylamino)-4-{[(5-methyl furan-2-yl)-(3-methyloxetan-3-yl)methyl]amino}cyclobut-3-ene-1,2-dione were obtained in the form of a yellow solid. (Mp=178-180° C.). Yield=43%, LC/MS: 95.97% [393].
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:6]([CH3:21])=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1.C(OCC)(=O)C>[CH3:21][C:6]1[C:5]([CH2:4][CH2:3][OH:2])=[CH:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:13][CH:12]=2)[N:7]=1
Reactant: COC(=O)Cc1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.6 g (8.40 mmol) of the above prepared [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester dissolved in 15 ml of dry tetrahydrofuran was added under an argon atmosphere within 15 minutes to a stirred suspension of 0.38 g (10 mmol) of lithium aluminum hydride in 5 ml of tetrahydrofuran. The reaction was exothermic. Subsequently, the mixture was stirred at room temperature for 1 hour. Then, 1 ml of ethyl acetate was dropped into the reaction mixture, followed by water, drop after drop, under argon, with stirring and cooling until the gas evolution ceased. The reaction mixture was then diluted with 50 ml of ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated i. V. and the residue was chromatographed on SiO2 with a mixture of dichloromethane and tert.-butyl methyl ether (4/1 vol./vol.) as eluent. Thereby, 1.88 g of the title compound was obtained as white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]([OH:25])=O)=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([CH:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)=[O:34])[N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>N1C=CC=CC=1.CC#N.C(Cl)(Cl)Cl>[CH2:7]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([CH:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[O:34])[N:28]=2)=[O:25])=[CH:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN1CCC(C(=O)c2cccc(N)n2)CC1
Reactant: O=C(O)c1cn(Cc2ccccc2)c2ccccc12
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cn(Cc4ccccc4)c4ccccc34)n2)CC1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 51.2 %

Procedure:
Add oxalyl chloride (0.18 mL, 2.1 mmol) dropwise to a solution of 1-benzylindol-3-carboxylic acid (0.48 g, 1.9 mmol) in pyridine and CH3CN (5 mL each) cooled in an ice bath. Stir the reaction mixture for 2.25 hr. and then add a suspension of 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (0.56 g, 1.9 mmol) in CH3CN (5 mL) and pyridine (12 mL). Warm the reaction mixture to room temperature overnight. Quench the reaction with cold H2O (20 mL) and dilute with CHCl3. Adjust the pH to 11 with Na2CO3 and separate the layers. Extract the aqueous layer with CHCl3 (2×30 mL). Combine the organic fractions and dry with anhydrous MgSO4, filter and concentrate the mixture in vacuo. Purify the product by chromatography on a silica gel column, eluting with methanol/CH2Cl2 (5:95) followed by methanol/CH2Cl2 (10:90) to afford the sub-title compound (0.44 g, 51%). 1H NMR (CD3OD) 8.45 (d, J=8 Hz, 1H), 8.32 (s, 1H), 8.26 (m, 1H), 7.95 (t, J=8 Hz, 1H), 7.72 (d, J=8 Hz, 1H), 7.45 (m, 1H), 7.22-7.37 (m, 7H), 5.51 (s, 2H), 3.90 (m, 1H), 2.93-3.01 (m, 2H), 2.33 (s, 3H), 2.21-2.31 (m, 2H), 1.92-1.99 (m, 2H), 1.71-1.84 (m, 2H); CIMS (Methane) m/z 453 [C28H28N4O2+H]+.
Reaction SMILES: NC1SC(CC)=CN=1.C(OC=C(C(OCC)=O)C(OCC)=O)C.[C:24]([CH:29]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:30][NH:31][C:32]1[S:33][C:34]([CH2:37][CH3:38])=[CH:35][N:36]=1)([O:26][CH2:27][CH3:28])=[O:25].C(Cl)(Cl)Cl>C(OCC)(=O)C.CCCCCC>[C:24]([C:29]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:30][NH:31][C:32]1[S:33][C:34]([CH2:37][CH3:38])=[CH:35][N:36]=1)([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C(CNc1ncc(CC)s1)C(=O)OCC
Agent: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CCc1cnc(N)s1
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CNc1ncc(CC)s1)C(=O)OCC

Procedure:
2-Amino-5-ethylthiazole (11.7 g., 91.3 mmoles) and diethyl ethoxymethylenemalonate (21.7 g., 100.43 mmoles) were combined and heated on a steam bath for 45 minutes. 2-(2,2-Dicarbethoxyethylamino)-5-ethylthiazole (27.2 g., Rf 0.6 and 0.7 respectively, on silica gel thin layer chromatography, with chloroform/1% ethanol and with 2:1 hexane:ethyl acetate as eluant) was obtained as an oil by cooling and used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=2)[C:11]2[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=3)[C:11]3[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CCc1cc2c(NCc3ccc(OC)c(Cl)c3)nc(Cl)nc2s1
Reactant: Cc1ncc[nH]1
Product: CCc1cc2c(NCc3ccc(OC)c(Cl)c3)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-ethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-ethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C[O-].[Na+].[C:4]([C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[N:11][CH:12]=1)(=[NH:6])[NH2:5].C[C:21](C)([C:25]([O-])=[O:26])[C:22]([O-])=[O:23].Cl>CO.O>[OH:26][C:25]1[N:6]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:18])[CH3:17])=[N:11][CH:12]=2)[NH:5][C:22](=[O:23])[CH:21]=1
Reactant: CC(C)(C(=O)[O-])C(=O)[O-]
Reactant: CC(C)(C)C(=O)Nc1ccc(C(=N)N)cn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(-c2nc(O)cc(=O)[nH]2)cn1
Temperature: 82 °C

Procedure:
A suspension of sodium methoxide (432 mg, 8.0 mmol), N-(5-carbamimidoylpyridin-2-yl)pivalamide (880 mg, 4.0 mmol) and dimethylmalonate (457 μL, 4.0 mmol) in 15 mL methanol is refluxed at 82° C. for 14 hours. The resulting suspension is dissolved in 15 mL water and acidified using 6M HCl. The precipitate is filtered, rinsed with water, air/vacuum dried and used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[NH2:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:30][C:25]=2[N:24]=[CH:23]1>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][N:22]2[C:26]3[CH:27]=[CH:28][C:29]([C:31]4[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=4)=[CH:30][C:25]=3[N:24]=[CH:23]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COCCc1ccc(OCC2CO2)cc1
Reactant: NCCn1cnc2cc(C3=NNC(=O)CC3)ccc21
Product: CC(C)COCCc1ccc(OCC(O)CNCCn2cnc3cc(C4=NNC(=O)CC4)ccc32)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isobutoxy-ethyl)-phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)pyridazinone.
Reaction SMILES: [N:1]1([C:9]2[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][C:10]=2[F:17])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:18]([C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH:23]=[C:24]([CH3:31])[N:25]=[CH:26]2)=[C:19]=[O:20].N(C1C=CC=C2C=1C=CN=C2)=C=O>>[N:1]1([C:9]2[CH:16]=[CH:15][C:12]([CH2:13][NH:14][C:19]([NH:18][C:21]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:22]=3[CH:23]=[C:24]([CH3:31])[N:25]=[CH:26]4)=[O:20])=[CH:11][C:10]=2[F:17])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Reactant: NCc1ccc(N2CCCCCCC2)c(F)c1
Agent: O=C=Nc1cccc2cnccc12
Product: Cc1cc2c(NC(=O)NCc3ccc(N4CCCCCCC4)c(F)c3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 61B using 4-(1-azocanyl)-3-fluorobenzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 1H NMR (300 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.37 (s, 1H), 8.56 (m, 2H), 8.01 (d, 1H, J=8.4 Hz), 7.81 (t, 1H, J=8.4 Hz), 7.45 (t, 1H), 7.02 (m, 2H), 6.90 (m, 1H), 4.25 (d, 2H, J=6 Hz), 3.35 (m, 4H), 2.77 (s, 3H), 1.67 (m, 4H), 1.54 (m, 6H); MS (ESI) 421 (M+H)+; Anal. Calcd for C25H29FN4O.HCl: C, 65.71; H, 6.62; N, 12.26. Found: C, 65.44; H, 6.49; N, 12.15.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:12](=[O:13])[NH:11][C:10]3[CH:14]=[CH:15][NH:16][C:9]=3[CH:8]=2)[CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:19]=[C:20]2[CH2:31][C@@H:30]([CH2:32][C:33](O)=[O:34])[C:29](=[O:36])[N:28]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:27][C:21]2=[C:22]2[C:26]=1[NH:25][CH:24]=[CH:23]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]2[CH2:31][C@@H:30]([CH2:32][C:33](=[O:34])[N:1]3[CH2:2][CH2:3][CH:4]([C:7]4[C:12](=[O:13])[NH:11][C:10]5[CH:14]=[CH:15][NH:16][C:9]=5[CH:8]=4)[CH2:5][CH2:6]3)[C:29](=[O:36])[N:28]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:27][C:21]2=[C:22]2[C:26]=1[NH:25][CH:24]=[CH:23]2
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ccc23)C[C@@H](CC(=O)O)C1=O
Reactant: O=c1[nH]c2cc[nH]c2cc1C1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ccc23)C[C@@H](CC(=O)N2CCC(c3cc4[nH]ccc4[nH]c3=O)CC2)C1=O
Temperature: 25 °C
Yield: 16.2 %

Procedure:
To 6-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridin-5(4H)-one (60.0 mg, 0.276 mmol) was added (S)-2-(7-chloro-2-neopentyl-3-oxo-1,2,3,4,5,8-hexahydroazepino[3,4-e]indol-4-yl) acetic acid (100 mg, 0.276 mmol), EDC (58.3 mg, 0.304 mmol), HOBT (41.0 mg, 0.304 mmol), DMF (2.0 ml) at rt, followed by diisopropylethylamine (0.192 ml, 1.10 mmol). The resulting mixture was stirred at rt over night, partial of the solvent was removed under N2, and the residue was purified on reverse phase PrepHPLC to afford the expected products(25.2 mg, 16%), (S)-7-chloro-2-neopentyl-4-(2-oxo-2-(4-(5-oxo-4,5-dihydro-1H-pyrrolo [3,2-b]pyridin-6-yl)piperidin-1-yl)ethyl)-1,2,4,5-tetrahydroazepino [3,4-e]indol-3 (8H)-one, as a tan solid. 1H-NMR (400 MHz, MeOD) d 0.79 (d, J=5.29 Hz, 11H) 1.52-1.62 (m, 1H) 1.81 (s, 1H) 2.38-2.49 (m, 1H) 2.75 (s, 1H) 3.01 (d, J=13.35 Hz, 1H) 3.09-3.21 (m, 4H) 3.66 (d, J=13.85 Hz, 1H) 3.96 (s, 3H) 3.99-4.06 (m, 1H) 4.24 (s, 1H) 4.65 (d, J=17.37 Hz, 2H) 5.46-5.55 (m, 1H) 6.27 (dd, J=5.29, 3.02 Hz, 1H) 7.22 (s, 1H) 7.36 (dd, J=7.81, 3.02 Hz, 1H) 8.24 (s, 1H); Mass spec 562.48 (MH+) calc for C31H36ClN5O3 561.25.