Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][CH2:8][C:9]([N:11]([CH3:32])[CH2:12][CH2:13][N:14]([CH2:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][N:31]=1)[C:24]([O:26]CC)=[O:25])[CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:10])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CO.Cl>O.C1COCC1>[C:1]([O:5][C:6](=[O:33])[CH2:7][CH2:8][C:9]([N:11]([CH3:32])[CH2:12][CH2:13][N:14]([CH2:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][N:31]=1)[C:24]([OH:26])=[O:25])[CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1ccnc(CN(CCN(C)C(=O)CCC(=O)OC(C)(C)C)C(CC)CC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCC(CC)N(CCN(C)C(=O)CCC(=O)OC(C)(C)C)Cc1cc(C(=O)O)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A mixture of 1.9 g of ethyl 2-{[{2-[(4-tert-butoxy-4-oxobutanoyl)(methyl)amino]ethyl}(pentan-3-yl)amino]methyl}isonicotinate, 8.2 mL of a 1.0 M aqueous sodium hydroxide solution, 8.0 mL of methanol, and 16 mL of THF was stirred overnight at room temperature. The mixture was neutralized using 1.0 M hydrochloric acid, water was added thereto, followed by extraction with chloroform-methanol. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, thereby obtaining 1.5 g of 2-{[{2-[(4-tert-butoxy-4-oxobutanoyl)(methyl)amino]ethyl}(pentan-3-yl)amino]methyl}isonicotinic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:19])=[C:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:10]=2)[CH:7]=1.[H-].[Na+].[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[C:14]([O:13][C:12]([N:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]2[C:8]=1[CH3:19])[S:28]([C:22]1[CH:27]=[CH:26][C:25]([C:12]([O:13][CH3:14])=[O:18])=[CH:24][CH:23]=1)(=[O:30])=[O:29])=[O:18])([CH3:15])([CH3:16])[CH3:17]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1c(NC(=O)OC(C)(C)C)nc2ccc(Cl)cn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(S(=O)(=O)N(C(=O)OC(C)(C)C)c2nc3ccc(Cl)cn3c2C)cc1
Reaction time: 0.17 h
Yield: 171.9 %

Procedure:
To a solution of compound 15-B (0.563 g, 2.0 mmol) in DMF (13 mL) at 0° C. was added 60% NaH (0.096 g, 2.4 mmol) and the reaction mixture was stirred for 10 minutes. Benzenesulfonyl chloride (0.563 g, 2.4 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched by the addition of H2O and the solution was extracted with ethyl acetate. After separation of the organic and aqueous layers a sufficient amount of water was added to remove any dissolved DMF from the organic layer. The organic layer was dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure to afford the crude product. The crude material was purified by flash column chromatography, eluting with a hexanes-EtOAc gradient to give compound 15-C as a white solid (0.825 g, 86%); MS m/z (M+H+) 480.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][C:20]=1[OH:21])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])(=[O:4])[CH:2]=[CH2:3].[CH:22]1([N:28]=[C:29]=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C>C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.CC(C)=O>[CH:22]1([NH:28][C:29](=[O:30])[O:21][C:20]2[CH:19]=[CH:18][C:9]([C:10](=[O:11])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:8][C:7]=2[CH2:6][NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C=CC(=O)NCc1cc(C(=O)c2ccccc2)ccc1O
Reactant: O=C=NC1CCCCC1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: C=CC(=O)NCc1cc(C(=O)c2ccccc2)ccc1OC(=O)NC1CCCCC1
Yield: 31 %

Procedure:
A mixture of 30 g (0.107 mole) of 3-acrylamidomethyl-4-hydroxybenzophenone, 13.5 g (0.108 mole) of cyclohexyl isocyanate, 0.2 g of 2,6-di-tert-butyl-p-cresol, 1.5 g of triethylamine and 180 ml of acetone was refluxed for 3 hours and then left to stand. The crystals formed were filtered off, and 26.3 g of the desired product having a melting point of 142°-144° C. were obtained in this manner. A further 13.5 g of the desired carbamate were obtained by evaporating down the mother liquor.
Reaction SMILES: [OH:1][C:2]1[C:21]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])=[C:20]([O:27][CH2:28][O:29][CH3:30])[CH:19]=[C:18]([O:31][CH2:32][O:33][CH3:34])[C:3]=1[C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[CH:9][CH:8]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:35]([O:1][C:2]1[C:21]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])=[C:20]([O:27][CH2:28][O:29][CH3:30])[CH:19]=[C:18]([O:31][CH2:32][O:33][CH3:34])[C:3]=1[C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[CH:9][CH:8]=1)(=[O:37])[CH3:36]
Reactant: COCOc1ccc(C=CC(=O)c2c(OCOC)cc(OCOC)c(CC=C(C)C)c2O)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COCOc1ccc(C=CC(=O)c2c(OCOC)cc(OCOC)c(CC=C(C)C)c2OC(C)=O)cc1
Temperature: 25 °C
Yield: 84 %

Procedure:
A liquid mixture of 13.75 g of the 2'-hydroxy-4,4',6'-tris(methoxymethoxy)-3'-(3-methyl-2-butenyl)chalcone, 40 ml of acetic anhydride and 40 ml of anhydrous pyridine was stirred at room temperature to effect a reaction. Then, the reaction mixture was added into 200 ml of a cooled saturated solution of sodium hydrogencarbonate and the mixture was stirred at 0° C. for 30 minutes. The mixture was extracted with 1500 ml of ether, and the ether layer was washed with water, shaken with a saturated aqueous solution of copper sulfate, washed with water, shaken with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by distillation, and the residue was subjected to the silica gel column chromatography (300 g of 230-400 mesh silica gel, n-hexane/ethyl acetate=4/1, 0.3 kg/cm2). Fractions of 100 ml were collected and the 35th to 37th fractions were combined to obtain 12.58 g (yield=84.0%) of 2'-acetoxy-4,4',6'-tris(methoxymethoxy)-3'-(3-methyl-2-butenyl)chalcone in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:4][C:3]=1/[CH:14]=[CH:15]/[C:16]([O:18]CC)=O.C>C(O)C.C1(C)C(C)=CC=CC=1>[CH3:8][C:7]1[CH:6]=[C:5]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)[CH:4]=[C:3]2[C:2]=1[NH:1][C:16](=[O:18])[CH2:15][CH2:14]2
Reactant: CCOC(=O)/C=C/c1cc(-n2cnnn2)cc(C)c1N
Solvent: CCO
Solvent: Cc1ccccc1C
Product: Cc1cc(-n2cnnn2)cc2c1NC(=O)CC2

Procedure:
A suspension of trans-ethyl 3-(2-amino-3-methyl-5-[tetrazol-1-yl]phenyl)prop-2-enoate (2.5 g) in ethanol (250 cm3) was hydrogenated at 60° and 15 p.s.i. (1.04×105Pa) pressure over 10% palladised charcoal (1 g) for 11/2 hours. The cooled mixture was filtered through "Solkafloc" (Trade Mark) and evaporated in vacuo to afford a solid. A suspension of this solid in xylene (100 cm3) was heated under reflux for 7 hours. The mixture was then cooled and the product filtered off and washed with dichloromethane:methanol, 5:1, to afford 3,4-dihydro-8-methyl-6-(tetrazol-1-yl)-2-(1H)-quinolone, m.p. 271°-272°, (1.37 g).
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]2[CH2:6][CH2:7][CH2:8][C:2]=12.[CH2:9]=[O:10]>>[OH:10][CH2:9][C:4]1[N:3]2[CH2:6][CH2:7][CH2:8][C:2]2=[CH:1][N:5]=1
Reactant: C=O
Reactant: c1ncn2c1CCC2
Product: OCc1ncc2n1CCC2
Temperature: 160 °C
Yield: 38 %

Procedure:
A mixture of 6,7-dihydro-5H-pyrrolo[1,2-c]imidazole (7 g) and paraformaldehyde (4 g) was heated at 160° C., to which was added, 20 minutes later, paraformaldehyde (2 g), and, further 20 minutes later, paraformaldehyde (1 g), followed by heating for 45 minutes. The reaction mixture was subjected to a silica gel chromatography (4.0 cm×15 cm), eluting with methanol-methylene chloride (1:9). The object fraction was concentrated. To the concentrate were added ethanol and diethyl ether to give 6,7-dihydro-3-hydroxymethyl-5H-pyrrolo[1,2-c]imidazole (3.4 g) as colorless needles, m.p. 110°-120° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[OH:12].C(N(CC)C(C)C)(C)C.[CH3:22][O:23][CH2:24]Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([O:12][CH2:22][O:23][CH3:24])=[CH:4][C:5]=1[CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)c1cc(O)c(Br)cc1Br
Reactant: COCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COCOc1cc(C(C)C)c(Br)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a solution of 2,4-dibromo-5-isopropylphenol (512 g, 1.74 mol) in chloroform (1.74 L), N,N-diisopropylethylamine (364 mL, 2.09 mol) was added, and cooled on ice. Chloromethyl methyl ether (159 mL, 2.09 mol) was added dropwise over 60 minutes, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled on ice, and a 1M aqueous solution of sodium hydroxide (1.5 L) was added dropwise to separate the organic layer. The organic layer was washed with a 1M aqueous solution of sodium hydroxide (1.5 L) and water (1.5 L), and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure. The resulting residue was purified by distillation under reduced pressure (0.93 to 1.5 hpa, 122° C. to 137° C.) to give 1,5-dibromo-2-isopropyl-4-(methoxymethoxy)benzene (548 g, 96%) as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15](O)=[O:16])=[CH:10]3)[C:6]=2[CH:18]=1.C(Cl)(C([Cl:23])=O)=O.CN(C)C=O>C(#N)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]([Cl:23])=[O:16])=[CH:10]3)[C:6]=2[CH:18]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Solvent: ClCCl
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(Cl)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 94 %

Procedure:
Into a 10000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 9-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid (450 g, 1.46 mol, 1.00 equiv) in ACN (4500 mL), followed by the addition of (COCl)2 (450 mL) dropwise with stirring at 0° C. over 45 min. To this was added N,N-dimethylformamide (5 mL). The resulting solution was stirred at room temperature for 7 h, diluted with 2000 mL of DCM and concentrated under vacuum to afford 450 g (94%) of 9-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carbonyl chloride as a gray solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:25]2[NH:29][N:28]=[N:27][N:26]=2)[CH:22]=[CH:23][CH:24]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH:20]=3)(=[O:16])=[O:15])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1cccc(-c2ccc(F)cc2)c1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1cccc(-c2ccc(F)cc2)c1
Yield: 65.8 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from [3-(4-fluorophenyl)phenyl]sulfonyl chloride (15 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8 mg, 0.05 mmol) giving 13 mg (66%) of the title compound. MS (ESI+) calcd for C19H14FN5O2S 395.085224, found 395.085454.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][CH:13]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:10])[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=O.S(Cl)(Cl)=O.[Br:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[C:33]([F:38])[CH:32]=1.N1C=CC=CC=1>ClCCl>[CH:24]1[C:25]2[CH:13]([CH2:12][O:11][C:9]([N:1]3[CH2:8][CH2:7][CH2:6][C@@H:2]3[C:3](=[O:5])[NH:35][C:34]3[CH:36]=[CH:37][C:31]([Br:30])=[CH:32][C:33]=3[F:38])=[O:10])[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]=2[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1ccc(Br)cc1F
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cc1F)[C@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Fmoc-D-Pro (1.2 g, 3.56 mmol) was suspended in 10 mL dry dichloromethane (DCM), cooled in an ice water bath, and then thionyl chloride (0.78 mL, 10.7 mmol) was added slowly. After addition was complete, the ice water bath was removed and the reaction was stirred at ambient temperature overnight. The solution was concentrated to dryness. The oil was redissolved in 20 mL dry DCM under an Ar atmosphere, and 4-bromo-2-fluoroaniline (0.81 g, 4.3 mmol) was added, followed by dry pyridine (0.87 mL, 10.7 mmol). The mixture was stirred at ambient temperature for 4 hours, then concentrated. The residue was redissolved in 100 mL EtOAc, washed with 1M HCl (3×50 mL), brine (2×50 mL), dried with MgSO4, filtered and concentrated to yield the title product as a sticky oil. (1.8 g, 99%) APCI (AP+): 509.2, 511.2 (M+H)+.
Reaction SMILES: [N:1]1([N:6]=[CH:7][C:8]2[C:16]3[C:11](=[CH:12][C:13]([NH:17][C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4[C:20]([OH:22])=O)=[CH:14][CH:15]=3)[N:10]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:9]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH3:35][N:36]1[C:40]([CH2:41][NH2:42])=[CH:39][C:38]([CH3:43])=[N:37]1>>[CH3:35][N:36]1[C:40]([CH2:41][NH:42][C:20](=[O:22])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[NH:17][C:13]2[CH:12]=[C:11]3[C:16]([C:8]([CH:7]=[N:6][N:1]4[CH:2]=[CH:3][CH:4]=[CH:5]4)=[N:9][N:10]3[CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])=[CH:15][CH:14]=2)=[CH:39][C:38]([CH3:43])=[N:37]1
Reactant: C[Si](C)(C)CCOCn1nc(C=Nn2cccc2)c2ccc(Nc3ccccc3C(=O)O)cc21
Reactant: Cc1cc(CN)n(C)n1
Product: Cc1cc(CNC(=O)c2ccccc2Nc2ccc3c(C=Nn4cccc4)nn(COCC[Si](C)(C)C)c3c2)n(C)n1

Procedure:
Prepared in a similar manner to that described for Example 6 above except using 2-[3-(Pyrrol-1-yliminomethyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-ylamino]-benzoic acid and C-(2,5-Dimethyl-2H-pyrazol-3-yl)-methylamine. 1H NMR (CDCl3) δ 9.56 (1H, s), 8.68 (1H, s), 8.30 (1H, d, J=8.7 Hz), 7.49 (1H, d, J=8.3 Hz), 7.43 (1H, dd, J=7.9, 1.5 Hz), 7.36–7.31 (2H, m), 7.23 (2H, t, J=2.6 Hz), 7.17 (1H, dd, J=8.7, 1.9 Hz), 6.83 (1H, t, J=7.2 Hz), 6.32 (1H, bt), 6.29 (2H, t, J=2.3 Hz), 6.01 (1H, s), 5.67 (2H, s), 4.61 (2H, d, J=5.6 Hz), 3.60 (3H, s), 3.58 (2H, t, J=8.3 Hz), 2.22 (3H, s), 0.90 (2H, t, J=8.7 Hz), 0.06 (9H, s).
Reaction SMILES: [CH3:1][NH2:2].C[Al](C)C.[CH3:7][S:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[CH:23]=[C:22]([C:24]([O-:26])=O)[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1>C1COCC1.C1(C)C=CC=CC=1.ClCCCl>[CH3:1][NH:2][C:24]([C:22]1[N:21]=[CH:20][N:19]([CH2:18][C:16]2[CH:15]=[CH:14][C:12]3[N:13]=[C:9]([S:8][CH3:7])[S:10][C:11]=3[CH:17]=2)[CH:23]=1)=[O:26]
Reactant: CN
Reactant: CSc1nc2ccc(Cn3cnc(C(=O)[O-])c3)cc2s1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CNC(=O)c1cn(Cc2ccc3nc(SC)sc3c2)cn1
Temperature: 70 °C
Reaction time: 0.03 h
Yield: 58 %

Procedure:
To a stirred solution of methylamine (623 μL of a 2 M solution in THF, 1.3 mmol) at 0° C. was added trimethylaluminum (623 μL of a 2 M solution in toluene, 1.2 mmol). The mixture was stirred for 2 min and then a solution of 1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-1H-imidazole-4-carboxylate (80 mg, 0.25 mmol) from Step 1 of this Example in DCE (1 mL) was added dropwise. The reaction vessel was sealed and the mixture was heated at 70° C. for 20 h. The mixture was then concentrated under reduced pressure and the residue was purified by silica gel flash chromatography eluting with 5% MeOH in EtOAc to afford N-methyl-1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-1H-imidazole-4-carboxamide (46 mg, 58%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.98 (d, J=1.3 Hz, 1H), 7.81-7.94 (m, 3H), 7.71 (d, J=1.1 Hz, 1H), 7.42 (dd, J=1.6, 8.4 Hz, 1H), 5.33 (s, 2H), 2.78 (s, 3H), 2.70 (d, J=4.9 Hz, 3H). LCMS (ESI) m/z 319 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([NH2:18])=[CH:5][C:6]2[N:7]([N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1.C(N(CC)CC)C.C[Al](C)C.[N:30]1([C:34]([C:36]2[CH:37]=[N:38][N:39]([CH3:46])[C:40]=2[C:41](OCC)=[O:42])=[O:35])[CH2:33][CH2:32][CH2:31]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[N:30]1([C:34]([C:36]2[CH:37]=[N:38][N:39]([CH3:46])[C:40]=2[C:41]([NH:18][C:4]2[C:3]([CH3:2])=[CH:8][N:7]3[N:9]=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:11]=[C:6]3[CH:5]=2)=[O:42])=[O:35])[CH2:31][CH2:32][CH2:33]1
Reactant: CCOC(=O)c1c(C(=O)N2CCC2)cnn1C
Reactant: Cc1cn2nc(-c3ccccc3)nc2cc1N
Agent: C[Al](C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Product: Cc1cn2nc(-c3ccccc3)nc2cc1NC(=O)c1c(C(=O)N2CCC2)cnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.3 %

Procedure:
To an argon purged solution of 6-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine hydrochloride (147 mg, 564 μmol) and triethylamine (78.6 μl, 564 μmol) in dioxane (8 ml) is added trimethylaluminum (2M solution in toluene, 705 μl, 1.41 mmol). The resulting mixture is stirred for 1 hour at 25° C., then ethyl 4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxylate (134 mg, 564 μmol) is added; the mixture is heated to 100° C. and stirred for 18 hours. As no conversion is detected N-ethyl diisopropylamine (246 μl, 1.41 mmol) and another portion of trimethylaluminum (2M solution in toluene, 705 μl, 1.41 mmol) are added, the mixture is stirred for 1 hours at 25° C. and then for further 20 hours at 100° C. The crude material is loaded on silica and purified by flash chromatography on a 20 g silica column using heptane/ethyl acetate 10-100% as eluent affording 4-(azetidine-1-carbonyl)-1-methyl-N-(6-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide (57 mg, 24.3%) as a light yellow solid. mp.: 226-8° C. MS: m/z=416.2 (M+H+).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[NH2:23][C:24]1[C:29]2=[C:30]([C:43]3[CH:48]=[CH:47][C:46]([NH:49][C:50]([NH:52][C:53]4[CH:58]=[C:57]([C:59]([F:62])([F:61])[F:60])[CH:56]=[CH:55][N:54]=4)=[O:51])=[CH:45][CH:44]=3)[C:31]([CH:40]([OH:42])[CH3:41])=[C:32]([CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[N:28]2[N:27]=[CH:26][N:25]=1.C([O-])(O)=O.[Na+].CCOC(C)=O>CS(C)=O.O>[C:40]([C:31]1[C:30]([C:43]2[CH:48]=[CH:47][C:46]([NH:49][C:50]([NH:52][C:53]3[CH:58]=[C:57]([C:59]([F:60])([F:61])[F:62])[CH:56]=[CH:55][N:54]=3)=[O:51])=[CH:45][CH:44]=2)=[C:29]2[N:28]([C:32]=1[CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[N:27]=[CH:26][N:25]=[C:24]2[NH2:23])(=[O:42])[CH3:41]
Reactant: CC(O)c1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccn3)cc2)c2c(N)ncnn2c1CN1CCOCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)c1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccn3)cc2)c2c(N)ncnn2c1CN1CCOCC1
Yield: 33.3 %

Procedure:
Dess-Martin periodinane (342.9 mg, 0.809 mmol) was added to a stirring solution of N-{4-[4-amino-6-(1-hydroxyethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]-triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)-pyridin-2-yl]urea (300 mg, 0.54 mmol) in DMSO (3 mL). The reaction was allowed to stir until complete by HPLC. Saturated aq. NaHCO3 solution (0.25 volumes) was added until a lot of solid had crashed out. Then 2 volumes of EtOAc and 0.5 volumes of H2O was added. This was allowed to stir overnight and the next day the excess liquid was removed via pipette. Careful addition of 5-10 mL of Et2O and 2 mL of CH2Cl2 provided an off white suspension. This was filtered to give a the title compound (100 mg, 0.18 mmol, 31% yield, 2 steps) as pure white powder. 1H-NMR (DMSO-d6). δ 10.20 (s, 1H), 10.04 (s, 1H), 8.67 (d, J=5.1 Hz, 1H), 8.20 (s, 1H), 8.10 (s, 1H), 7.78 (d, J=8.7 Hz, 2H), 7.52-7.48 (m, 3H), 4.19 (s, 2H), 3.63-3.60 (m, 4H), 2.56-2.53 (m, 4H), 2.19 (s, 3H). MS [M+H]+=555; LCMS RT=2.51 min.
Reaction SMILES: Cl.[CH3:2][C:3]12[CH2:8][C:7]1([CH3:9])[CH2:6][NH:5][CH2:4]2.Cl[CH2:11][C:12]#[C:13][CH2:14][OH:15].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:2][C:3]12[CH2:8][C:7]1([CH3:9])[CH2:6][N:5]([CH2:11][C:12]#[C:13][CH2:14][OH:15])[CH2:4]2
Reactant: OCC#CCCl
Reactant: CC12CNCC1(C)C2
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC12CN(CC#CCO)CC1(C)C2
Temperature: 25 °C

Procedure:
To a stirring solution of 1,5-dimethyl-3-azabicyclo[3.1.0]hexane hydrochloride (0.3 gm, 2 mmol) in chloroform (50 ml), 1-chloro-4-hydroxy-2-butyne (0.11 gm, 1 mmol), followed by triethylamine (0.3 gm, 3 mmol) were added. The reaction mixture was refluxed for 3 hours and then allowed to cool to room temperature. The solvents were evaporated in vacuo. The residual oil was purified by column chromatography using silicagel (100-200 mesh), eluting the compound with 50-50 ethyl acetate-hexane mixture.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([O:23]C)=[O:22])=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.O>[F:26][C:2]([F:1])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([OH:23])=[O:22])=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc2c(Nc3ccc(OC(F)(F)F)cc3)ncnc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(Nc3ccc(OC(F)(F)F)cc3)ncnc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
A mixture of methyl 4-(4-(trifluoromethoxy)phenylamino)quinazoline-7-carboxylate (156 mg, 0.43 mmol), LiOH (25.5 mg, 1.07 mmol) was dissolved in THF (4 ml) and H2O (1 mL). The mixture was stirred at 60° C. for 3 h. Acidified with acetic acid resulted brown solid which was collected by filtration. It was then dried in vacuo and used for the next step without any further purification (120 mg, 80% Yield). 1H NMR 400 MHz (DMSO-d6) δ 12.25 (s, 1H), 10.12 (s, 1H), 8.68 (s, 1H), 8.65 (d, 1H, J=1.6 Hz), 8.20-8.11 (m, 2H), 8.02 (d, 2H, J=8.8 Hz), 7.42 (d, 2H, J=8.8 Hz. MS m/z 350.1 (M+1).
Reaction SMILES: [C:1]1(=O)[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([NH2:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:9]([N:17]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCN
Reactant: O=C1CCCCCO1
Product: CCCCCCCCN1CCCCCC1=O

Procedure:
Alternatively, equimolar amounts of 6-hexanolactone and n-octylamine were heated at 190° for 20 hours. In this time, water was distilled off slowly. The residue was distilled to obtain 1-octyl-azacycloheptan-2-one.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH2:5][CH2:4][N:3]1[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Li]CCCC.CCOCC.[C:36](=[O:38])=[O:37].OS([O-])(=O)=O.[K+]>C1COCC1.O>[C:36]([C:9]1[S:10][C:6]2[CH2:5][CH2:4][N:3]([CH2:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:2](=[O:1])[C:7]=2[CH:8]=1)([OH:38])=[O:37]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2CCc3sccc3C2=O)CC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCN2CCc3sc(C(=O)O)cc3C2=O)CC1
Reaction time: 0.5 h

Procedure:
A solution of 2-4 (3.65 g, 0.01 moles) in THF (100 ml) was treated at -78° with n-BuLi (in hexane) and stirring was continued for 30 minutes. This was then poured into a slurry of Et2O/CO2 and this was stirred for 0.5 hours. A solution of 10% KHSO4 was added, and after stirring for 10 minutes, the reaction mixture was diluted with H2O. The organic phase was separated, washed with H2O, brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica gel eluting with CHCl3 (95)/MeOH(5) to give pure 2-5, Rf 0.5.