Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:22][CH2:23][CH3:24])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15](=O)[CH:16]=[CH:17]N(C)C)[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[NH2:25][C:26]([NH2:28])=[NH:27]>C(O)C>[CH2:22]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15]3[CH:16]=[CH:17][N:25]=[C:26]([NH2:28])[N:27]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:23][CH3:24]
Reactant: N=C(N)N
Reactant: CCCN(CCC)C1CCc2cccc(C(=O)C=CN(C)C)c2C1
Solvent: CCO
Product: CCCN(CCC)C1CCc2cccc(-c3ccnc(N)n3)c2C1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
2-Di-n-propylamino-8-(1-oxo-3-(dimethylamino)-prop-2-enyl)-1,2,3,4-tetrahydronaphthalene, prepared as in Example 8 (0.18 g; 0.55 mmol) was dissolved in 3 ml of ethanol. To the mixture was added 0.07 g (1.1 mmol) of guanidine, and the mixture was stirred at 60° C. under nitrogen for 18 hours. The mixture then was cooled to room temperature during which a crystalline solid formed. The crystals were filtered, washed with isopropyl alcohol, ether, and dried in vacuo to give 70 mg of the title compound as glistening plates. The product was recrystallized from isopropyl alcohol to obtain colorless crystals, m.p. 188°-189° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:5]=2[CH:4]=1.Cl[CH2:19][C:20](=[O:22])[CH3:21]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][N:12]([CH2:19][C:20](=[O:22])[CH3:21])[CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:5]=2[CH:4]=1
Reactant: CC(=O)CCl
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Product: COc1ccc2c3c(c(=O)oc2c1)CN(CC(C)=O)CC3
Yield: 55 %

Procedure:
Prepared by the method described for Example 26 from 1,2,3,4-tetrahydro-8-methoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one (3.46 g, 0.015 moles) and 1-chloro-2-propanone (2.0 g, 0.022 moles). Recrystallization from methanol gave the product (2.37 g), mp 123°-125° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([O:16]CC)=[O:15])[CH2:9][CH2:8]2)[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[NH:3]1.[OH-].[Na+].CO>C(O)(=O)C>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][CH2:8]2)[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[NH:3]1
Reactant: CCOC(=O)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
Compounds of formula A in which Z=2,3-dihydro-2-oxo-1H-benzimidazol-1-yl and L=(N-methylene)piperidin-4-yl are prepared from β-aminotetralins (VII) or phenethylamines (XI) and [4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]acetic acid (Schemes 6–7). For example, 4-(2-keto-1-benzimidazolinyl)piperidine is reacted with a bromoacetic acid ester, such as ethyl bromoacetate, in the presence of an amine base, such as diusopropylethylamine, in an inert solvent such as acetonitrile, at a temperature ranging from ambient temperature to reflux, to afford ethyl [4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]acetate. This ester is subjected to hydrolysis under basic conditions, for example, by treatment with sodium hydroxide in an alcoholic solution such as aqueous methanol, to yield, upon acidification with an inorganic or organic acid such as hydrochloric or acetic acid for example, [4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]acetic acid. This carboxylic acid is reacted directly with βaminotetralins (VII) or phenethylamines (XI), in the presence of an amine base, under peptide coupling conditions described above, to afford benzimidazolinones (XVII) and (XVIII) of formula A in which Y=carbonyl and L=(N-methylene)piperidin-4-yl (Schemes 6–7).
Reaction SMILES: [C:1]1([CH2:7][S:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:18][C:19]3[O:20][C:21]([C:24]4[N:25](C(OC(C)(C)C)=O)[C:26]5[C:31]([CH:32]=4)=[CH:30][CH:29]=[CH:28][CH:27]=5)=[CH:22][N:23]=3)[CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[C:24]1[C:21]1[O:20][C:19]([NH:18][C:14]2[CH:13]=[C:12]([NH:11][S:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:10])[CH:17]=[CH:16][CH:15]=2)=[N:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cnc(Nc3cccc(NS(=O)(=O)Cc4ccccc4)c3)o2)cc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Cc1ccccc1)Nc1cccc(Nc2ncc(-c3cc4ccccc4[nH]3)o2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.4 %

Procedure:
To a stirred solution of tert-butyl 2-(2-((3-(phenylmethylsulfonamido)phenyl)amino)oxazol-5-yl)-1H-indole-1-carboxylate 28 (0.24 g, 0.441 mmol) in anhydrous CH2Cl2 (20 mL) was added 1:1 mixture of CH2Cl2:Trifluoroacetic acid (10 mL) at room temperature. Reaction was stirred for 1.5 hour at ambient temperature. It was quenched with aq. saturated NaHCO3 and CH2Cl2 layer was separated. After evaporation of solvent, crude product was purified using MPLC silica column (Biotage) (Acetone/hexane as an eluent) to obtain N-(3-((5-(1H-indol-2-yl)oxazol-2-yl)amino)phenyl)-1-phenyl methane sulfonamide 29 (0.14 g, 71% yield).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](I)[CH:9]=1)(=[O:3])[CH3:2].[CH3:27][C:28]1[C:32](B(O)O)=[C:31]([CH3:36])[O:30][N:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:32]2[C:28]([CH3:27])=[N:29][O:30][C:31]=2[CH3:36])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(I)c1
Reactant: Cc1noc(C)c1B(O)O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(-c2c(C)noc2C)c1
Yield: 53 %

Procedure:
By carrying out the operation analogously to example 13, starting from 3-iodophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation I, and 3,5-dimethyl-4-isoxazoleboronic acid, the expected product is obtained in the form of a pink powder with a yield of 53%.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[NH:4][CH:3]1[C:14]([NH:16][C:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[O:19][CH:18]=1)=[O:15].[H-].[Na+].[CH2:30](I)[CH3:31]>CN(C)C=O>[CH2:30]([N:4]1[CH:3]([C:14]([NH:16][C:17]2[C:22](=[O:23])[C:21]3[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=3[O:19][CH:18]=2)=[O:15])[C:2](=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5]1(=[O:13])=[O:12])[CH3:31]
Reactant: O=C(Nc1coc2ccccc2c1=O)C1NS(=O)(=O)c2ccccc2C1=O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(C(=O)Nc2coc3ccccc3c2=O)C(=O)c2ccccc2S1(=O)=O

Procedure:
5,0 g of 3,4-dihydro-4-oxo-N-(4-oxo-4H-1-benzopyran-3-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide and 0,68 g of a sodium hydride suspension (50% in petroleum) are dissolved, with rigorous stirring, in 100 ml of dimethylformamide of 4°. 2,5 g of ethyl iodide are added and allowed to react for 2 hours. The reaction mixture is concentrated to one-third of its original volume, and ethanol is slowly added until crystals begin to precipitate. After some standing at room temperature, the crystals are filtered off, washed with ice-cold ethanol and recrystallised from ethanol/chloroform. After filtration and drying, 2-ethyl-3,4-dihydro-4-oxo-N-(4-oxo-4H-1-benzopyran-3-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide, of m.p. 235°-237°, is obtained.
Reaction SMILES: Cl.C([O:4][C:5]([C:7]1([NH2:12])[CH2:10][CH:9]([CH3:11])[CH2:8]1)=[O:6])C.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][C:16]=1[O:24][CH2:25][CH2:26][C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1>>[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:12][C:7]2([C:5]([OH:4])=[O:6])[CH2:8][CH:9]([CH3:11])[CH2:10]2)=[O:20])=[CH:17][C:16]=1[O:24][CH2:25][CH2:26][C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)C1(N)CC(C)C1
Reactant: COc1ccc(C(=O)O)cc1OCCc1cccc(C)c1
Agent: Cl
Product: COc1ccc(C(=O)NC2(C(=O)O)CC(C)C2)cc1OCCc1cccc(C)c1

Procedure:
The compound of step 1 (65 mg, 0.413 mmol) was coupled to 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid in analogy to step 1 of example 3. The ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield the title compound as mixture of the cis isomer and the trans isomer.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:29][NH:30][CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>CS(C)=O.CO>[NH:24]1[C:25]2[C:21](=[C:20]([C:18]3[CH:17]=[C:16]4[C:12]([CH:13]=[N:14][NH:15]4)=[C:11]([NH:10][C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([N:30]([CH3:29])[CH:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[N:7]=4)=[O:9])[CH:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: CNC1CCOCC1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(F)n1
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1cccc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1)C1CCOCC1
Temperature: 160 °C
Yield: 26 %

Procedure:
6-Fluoro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (50 mg, 0.14 mmol) and methyl(tetrahydro-2H-pyran-4-yl)amine (31 mg, 0.27 mmol) were dissolved in DMSO (0.5 ml) in a microwave vial. DIPEA (0.141 ml) was added and the mixture was heated at 160° C. for 4 h under microwave irradiation. The reaction mixture was diluted with MeOH (0.5 ml) and was purified by Mass Directed Automated Preparative HPLC (Method C). Fractions containing product were blown to dryness and the residue dissolved in methanol. This solution was loaded onto a 1 g aminopropyl column which was eluted with MeOH (1 column volume). The solvent was removed under a stream of nitrogen to give the title compound (17 mg) as a cream solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([NH:14][CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[N:6][CH:5]=1.[ClH:29]>C1COCC1.O1CCOCC1>[ClH:29].[ClH:29].[CH3:1][O:2][C:3](=[O:28])[C:4]1[C:9]([C:10]([F:12])([F:13])[F:11])=[CH:8][C:7]([NH:14][CH:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COC(=O)c1cnc(NC2CCNCC2)cc1C(F)(F)F

Procedure:
A solution of 6-(1-tert-butoxycarbonyl-piperidin-4-ylamino)-4-trifluoromethyl-nicotinic acid methyl ester (1.65 g, 4.09 mmol) in THF (10 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 1 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 304.0 [M+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:21][CH2:22][C:23]([CH3:26])([OH:25])[CH3:24].C(=O)(O)[O-].[Na+]>CS(C)=O.CCOC(C)=O>[OH:25][C:23]([CH3:26])([CH3:24])[CH2:22][NH:21][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)(O)CN
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccc([N+](=O)[O-])c(NCC(C)(C)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 3-fluoro-4-nitrobenzoate (2.0 g, 10.04 mmol) in DMSO (10.04 mL) was added cesium carbonate (9.82 g, 30.1 mmol) and 1-amino-2-methylpropan-2-ol (0.985 g, 11.05 mmol). The reaction mixture was stirred at ambient temperature for 30 min. Saturated sodium bicarbonate and EtOAc were added to the mixture. The aqueous layer was extracted EtOAc (3×). The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound without further purification (3.18 g): LC-MS [M+1]=269.2.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([CH3:35])([O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])C.[OH-].[Na+].Cl>CCO>[C:26]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23]([C:19]2[O:20][C:21]([CH3:22])=[C:17]([CH2:16][CH2:15][S:14][C:11]3[CH:12]=[CH:13][C:8]([O:7][C:5]([CH3:35])([CH3:6])[C:4]([OH:36])=[O:3])=[CH:9][CH:10]=3)[N:18]=2)=[CH:28][CH:27]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(SCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCSc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
2-Methyl-2-{4-[2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethylsulfanyl]phenoxy}propionic acid ethyl ester (0.23 mmol) was dissolved in EtOH (10 mL) and 5N NaOH (0.5 mL) was added. The reaction was stirred overnight at room temperature. The reaction was acidified with 5N HCl and the product was extracted into ethyl acetate, dried (MgSO4) and concentrated to give 96 mg crude product.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([Cl:20])[C:14]=1[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>>[C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([Cl:20])[C:14]=1[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Oc1cc(C(=O)O)cc(Cl)c1OC(C)(C)C
Reactant: COC(=O)c1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(OC(C)(C)C)c(OC(C)(C)C)c2)cc1
Yield: 50 %

Procedure:
Methyl 4-(3,4-di-tert-butoxy-5-chlorobenzamido)benzoate (5) (185 mg, 50%) was prepared from 3,4-di-tert-butoxy-5-chlorobenzoic acid (3) (250 mg, 0.831 mmol) using a procedure essentially the same as in Step (i) for AAA-019 except that methyl 4-aminobenzoate was used instead of methyl 4-amino-2-methylenzoate and TEA (579 μL, 4.16 mmol) was used as base instead of DIPEA: m/z 432 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 10.54 (1H, s), 7.96 (2H, d), 7.91 (2H, d), 7.86 (1H, d), 7.60 (1H, d), 3.84 (3H, s), 1.41 (9H, s), 1.32 (9H, s).
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[C:5]1([C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[OH:8])[OH:6].[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O.O1CCOCC1>[F:3][CH:2]([F:4])[O:6][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[OH:8]
Reactant: Oc1ccccc1O
Reactant: FC(F)Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Oc1ccccc1OC(F)F

Procedure:
275 g of chlorodifluoromethane are passed into a solution of 100 g of pyrocatechol, 220 g of sodium hydroxide and 60 g of sodium dithionite in 500 ml of water and 400 ml of dioxane at 50°-55° C. analogously to L. N. Sedova et al., Zh. Org. Khim. 6, 568 (1970). After distillation at 61°-62° C./1.0-1.1 kPa, a mixture of 1,2-bis(difluoromethoxy)benzene and 2-difluoromethoxyphenol is obtained, the products being separated by chromatography on silica gel by means of cyclohexane/ethyl acetate (4:1).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=3)[C:20]([NH:22][NH2:23])=[O:21])[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:27]=1.[CH:28]([N:31]=[C:32]=O)([CH3:30])[CH3:29].C(=O)(O)[O-].[Na+].C(Cl)(Cl)Cl>ClCCl>[CH:28]([NH:31][C:32]1[O:21][C:20]([C:19]2[CH:18]=[C:17]([N:14]3[CH2:13][C@H:12]4[N:8]([CH2:9][CH2:10][CH2:11]4)[C:7]4[N:27]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[C:15]3=[O:16])[CH:26]=[CH:25][CH:24]=2)=[N:22][N:23]=1)([CH3:30])[CH3:29]
Reactant: CC(C)N=C=O
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)NN)c1)C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nnc(NC(C)C)o3)c1)C2=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 21 %

Procedure:
(S)-3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic hydrazide (300 mg, 0.780 mmol) obtained in Step 2 of Example 56 was dissolved in dichloromethane (16 mL), and the mixture was stirred at room temperature for 14 hours after adding isopropyl isocyanate (0.092 mL, 0.936 mmol). Thereafter, a saturated aqueous sodium bicarbonate solution and chloroform were added to the mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Using the resulting residue, (S)-5-[3-(5-isopropylamino-1,3,4-oxadiazol-2-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (74.0 mg, 21%) was obtained in the same manner as in Step 3 of Example 52.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[C:15]([F:25])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.ClC1C=C2C(C3N=C(N[C@H]4CCCNC4)C(F)=CN=3)=CNC2=NC=1.C(N(C(C)C)CC)(C)C.[CH:59]1([C:63](Cl)=[O:64])[CH2:62][CH2:61][CH2:60]1>C(Cl)Cl.CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][N:21]([C:63]([CH:59]5[CH2:62][CH2:61][CH2:60]5)=[O:64])[CH2:20]4)[C:15]([F:25])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1N[C@H]1CCCNC1
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C1CCC1)N1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of (S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-amine hydrochloride, 5b, (0.04 g, 0.11 mmol) in CH2Cl2 (1.40 mL) and DMF (300μ was added N,N-diisopropyl-N-ethylamine (0.30 mL, 1.70 mmol) followed by cyclobutanecarbonyl chloride (0.01 g. 0.12 mmol). The reaction mixture was allowed to stir at room temperature for 17 hours. The mixture was concentrated in vacuo, dissolved in 1 mL of DMSO and purified by preparatory HPLC (0.1% ammonium formate-H2O/acetonitrile) to afford the desired product, 395.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]([CH2:37][CH2:38][O:39][CH3:40])[CH2:33][CH2:34][O:35][CH3:36])[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[CH3:40][O:39][CH2:38][CH2:37][N:32]([CH2:33][CH2:34][O:35][CH3:36])[CH:29]1[CH2:28][CH2:27][N:26]([C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:14]([C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:12]=3[CH3:13])=[O:15])=[CH:25][C:22]=2[C:23]#[N:24])[CH2:31][CH2:30]1
Reactant: COCCN(CCOC)C1CCN(c2ccc(N)cc2C#N)CC1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Product: COCCN(CCOC)C1CCN(c2ccc(NC(=O)c3cnn(-c4ccc(Cl)cc4)c3C)cc2C#N)CC1
Yield: 34.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.83 g) and 5-amino-2-[4-bis(2-methoxyethyl)aminopiperidin-1-yl]benzonitrile (0.9 g), the title compound (0.52 g) was obtained, melting point: 152° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH2:25]([N:32]1[CH2:37][CH2:36][CH:35](O)[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH:35]2[CH2:34][CH2:33][N:32]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:37][CH2:36]2)=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(Br)ccc1C(=O)OC1CCN(Cc2ccccc2)CC1
Yield: 58.7 %

Procedure:
2.0 g (0.0093 mol) of 4-bromo-2-methylbenzoic acid were boiled under reflux in 15 ml (0.175 mol) of oxalyl chloride for 3 hrs. After removal of the excess oxalyl chloride the mixture was concentrated twice with 10 ml of toluene each time. The residue was dissolved in 15 ml of toluene, treated with 2.33 ml (0.01675 mol) of triethylamine and 2.67 g (0.01395 mol) of 1-benzyl-4-hydroxypiperidine and boiled at reflux for 18 hrs. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane (1:3). 2.12 g (59%) of 1-benzyl-piperidin-4-yl 4-bromo-2-methyl-benzoate were obtained as a yellow oil.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=[O:9].[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=[O:9]
Reactant: Cc1ccccc1CC(=O)O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)Cc1ccccc1CBr
Temperature: 2.5 °C

Procedure:
To a solution of 97.0 g (0.646 mol) o-tolylacetic acid in 1.75 L carbon tetrachloride was added 115.0 g (0.646 mol) N-bromosuccinimide and 3.4 g (0.021 mol) 2,2′-azobisisobutyronitrile. The mixture was heated at reflux under a nitrogen atmosphere for 4 h. After the mixture was cooled to 0-5° C. for 30 min, the solids were removed by filtration and washed with a small portion of carbon tetrachloride. This solid was triturated with water (0.8 L), collected on a filter, and washed with 500 mL of water to give 2-bromomethylphenylacetic acid. The filtrate was concentrated to a volume of 150 ml, and the resulting slurry cooled to 0-5° C. for 30 min. A second batch of product was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][NH:53][CH2:54][CH:55]([C:57]2[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=2)[OH:56])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][N:53]([CH2:54][CH:55]([C:57]2[CH:58]=[CH:59][C:60]([F:63])=[CH:61][CH:62]=2)[OH:56])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNCC(O)c2ccc(F)cc2)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CC(O)c2ccc(F)cc2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67.5 %

Procedure:
To a solution of 80 mg (0.5 mmol) of 1H-indole-7-carboxylic acid and 159 mg of TBTU (0.5 mmol) in 6 ml DMF, were added 0.43 ml (2.48 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 150 mg (0.5 mmol) of [rac]-(4-tert-butyl-benzyl)-[2-(4-fluoro-phenyl)-2-hydroxy-ethyl]-amine were added. After stirring for 17 h at rt, the reaction mixture was diluted with 60 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; heptane/EtOAc 2:1) to give 150 mg (66%) of an white solid. MS (ISP) 445.4 (M+H)+.