Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[OH:15].C(Cl)Cl.N1C(C)=CC=CC=1C.[F:27][C:28]([F:34])([F:33])[S:29](Cl)(=[O:31])=[O:30]>CN(C)C1C=CN=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][S:29]([C:28]([F:34])([F:33])[F:27])(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: COc1cc2nccc(O)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: O
Product: COc1cc2nccc(OS(=O)(=O)C(F)(F)F)c2cc1OC
Temperature: 25 °C
Yield: 78.5 %

Procedure:
To a dry 1 L RBF containing 6,7-dimethoxy-quinolin-4-ol (20.9 g, 102 mmol), which can be prepared according to the procedure of Riegel, B. (J. Amer. Chem. Soc. 1946, 68, 1264), was added DCM (500 mL), 4-dimethylaminopyridine (1.24 g, 10 mmol) and 2,6-lutidine (24 mL, 204 mmol). The mixture was vigorously stirred at RT. Trifluoromethanesulfonyl chloride (14 mL, 132 mmol) was added dropwise to the solution. After addition was complete, the mixture was stirred ice bath for 2 to 3 hrs. On LC/MS indicating the reaction completion, the reaction mixture was concentrated in vacuo and placed under high vacuum to remove residual 2,6-lutidine. To the resulting brown solids was added methanol (250 mL). The resulting slurry was stirred for 30 min before adding water (1 L). The solids were isolated by filtration, followed by a water wash. The resulting solid was dried under high vacuum overnight yielding trifluoromethanesulfonic acid 6,7-dimethoxy-quinolin-4-yl ester as a light brown solid (27 g, 80%). 1H NMR (400 MHz, DMSO, d6): δ 8.82 (d, 1H), 7.59 (m, 2H), 7.20 (s, 1H), 3.97 (d, 6H). LC/MS: M+H=338.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:5]=[CH:4][C:3]=1[OH:14].Cl[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:5]=[CH:4][C:3]=1[O:14][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Oc1ccc(Cn2cccn2)cc1Cl
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(Cn2cccn2)cc1Cl
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture of 5.0 g of 2-chloro-4-(1-pyrazolyl)methylphenol (produced in Reference Production Example 2), 7.6 g of ethyl chloroacetate, 13.2 g of potassium carbonate and 100 ml of anhydrous dimethylformamide was heated at 50° C. under stirring for 5 hours, and then cooled to room temperature. The reaction mixture was poured into 500 ml of water, which was extracted twice with 50 ml of ethyl acetate. The organic layers were combined, washed with water, saturated aqueous ammonium chloride solution and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude ethyl 2-chloro-4-(1-pyrazolyl)methylphenoxyacetate as an oil.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:14][O:15][C:16]1[C:24]2[O:23][C:22]([CH3:26])([CH3:25])[CH2:21][C:20]=2[C:19]([C:27]2[C@@H:36]3[C@@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[C:30](=[O:37])[N:29]([C:38]3[CH:43]=[CH:42][C:41]([C:44](N4CCN(C/C=C/C5C=CC=CC=5)CC4)=[O:45])=[CH:40][CH:39]=3)[N:28]=2)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[C:24]2[O:23][C:22]([CH3:26])([CH3:25])[CH2:21][C:20]=2[C:19]([C:27]2[C@@H:36]3[C@@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[C:30](=[O:37])[N:29]([C:38]3[CH:43]=[CH:42][C:41]([C:44]([N:10]4[CH2:11][CH2:12][N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH2:8][CH2:9]4)=[O:45])=[CH:40][CH:39]=3)[N:28]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C/C=C/c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Product: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2

Procedure:
Prepared from intermediate product A2 and 1-phenylpiperazine as described for compound 8. Crystallised from diethyl ether as the free base. M.p. 185–186° C.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=4)[N:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.Cl.[N:34]([CH2:37][C@@H:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[N+:35]=[N-:36].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CCOC(C)=O.C(N(CC)CC)C>[N:34]([CH2:37][C@@H:38]([NH:45][C:28]([C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:31])([F:1])[F:32])=[CH:4][CH:5]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=[CH:26]2)=[O:29])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=NC[C@@H](N)c1ccccc1
Reactant: O=C(O)c1ccc2nc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@@H](NC(=O)c1ccc2nc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-6-carboxylic acid, (F-1a2, 0.78 g, 1.79 mM), (S)-2-azido-1-phenyl-ethylamine hydrochloride (0.36 g, 1.79 mM), EDC (0.41 g, 2.15 mM) and HOBT (10 mg, 0.075 mM), were dissolved in CH2Cl2 (15 mL) and treated with triethylamine (0.75 mL, 5.4 mM). The mixture was stirred at room temperature for 16 h, then was diluted with EtOAc (75 mL) and washed with 0.5 N HCl (20 mL), aqueous NaHCO3 (20 mL), and brine. The EtOAc fraction was dried (MgSO4), filtered and concentrated. ESMS (m+1), 581; calc. Mw, 580.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.[C:10]1([C:16](Cl)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[C:10]1([C:16]([NH:2][C@H:3]2[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O[C@H]1CC[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of trans-4-aminocyclohexanol hydrochloride (2.00 g; 13.19 mmol), triphenylmethyl chloride (4.41 g; 15.83 mmol) and triethylamine (6.44 ml; 46.17 mmol) in 40 ml CH2Cl2 is refluxed overnight. The solids are filtered off and the residue concentrated in vacuo. The resultant product is purified with CH2Cl2 CH2Cl2: ethylacetate (5:1) to obtain trans-4-triphenylmethylaminocyclo-hexanol which is used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1.[N:34]([CH:37]([CH3:39])[CH3:38])=[C:35]=[O:36]>C1COCC1.O>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)([OH:20])[C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)[CH:8]=3)[N:3]=[C:2]([NH:1][C:35]([NH:34][CH:37]([CH3:39])[CH3:38])=[O:36])[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)N=C=O
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(N)nc(-c3cccc(Cl)c3)c2c1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)NC(=O)Nc1nc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3cncn3C)ccc2n1
Temperature: 60 °C
Yield: 20.4 %

Procedure:
A mixture of 2-amino-4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanol (0.00021 mol) obtained in Example B19, and 2-isocyanato-propane (3 equiv, 0.00063 mol) in THF (1 ml) was heated at 60° C. for 5 hours. A few drops of water were added. The mixture was evaporated till dryness and purified by HPLC. The product fractions were collected and the solvent was evaporated, yielding 0.024 g (20.3%) of N-[4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-2-quinazolinyl]-N′-(1-methylethyl)-urea, MS (ESI) m/z: 561 563 565.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:18]3[S:22][C:21]([C@@:23]4([OH:35])[CH2:28][CH2:27][C@H:26]([C:29]([O:31]C)=[O:30])[C:25]([CH3:34])([CH3:33])[CH2:24]4)=[N:20][CH:19]=3)[CH:7]=[C:8]([NH:10][C:11]3[N:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=3)[CH:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl.CO.O>O1CCCC1.CO.O.C(O)(C)C.C(Cl)(Cl)Cl.[Cl-].[Na+].O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:18]3[S:22][C:21]([C@@:23]4([OH:35])[CH2:28][CH2:27][C@H:26]([C:29]([OH:31])=[O:30])[C:25]([CH3:33])([CH3:34])[CH2:24]4)=[N:20][CH:19]=3)[CH:7]=[C:8]([NH:10][C:11]3[N:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(Nc4nccc(C)n4)cc(C4CC4)c3)s2)CC1(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: Cc1ccnc(Nc2cc(-c3cnc([C@@]4(O)CC[C@H](C(=O)O)C(C)(C)C4)s3)cc(C3CC3)c2)n1
Temperature: 120 °C
Yield: 85.7 %

Procedure:
To a solution of the product from Step 1 (41.3 mg, 0.084 mmol) in tetrahydrofuran (0.4 mL) and methanol (0.8 mL) was added sodium hydroxide (1 M in water, 0.153 mL, 0.153 mmol). The reaction mixture was heated to 120° C. for 10 minutes in a microwave oven. An additional charge of sodium hydroxide was added (1 M in water, 0.300 mL, 0.300 mmol) and the vessel was heated again for 10 minutes at 120° C. Upon cooling aqueous hydrogen chloride (2M in water, 0.235 mL, 0.470 mmol) was added and the resulting mixture was diluted with 10% v/v isopropanol/chloroform (20 mL), brine (10 mL), and water (1 mL). The layers were separated and the aqueous layer was re-extracted with 10% v/v isopropanol/chloroform (10 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. Lyophilization of the residue from methanol/water provided (1S,4R)-4-(5-{3-cyclopropyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid (34.3 mg, 0.072 mmol, 84% yield) as an off-white solid. MS ESI: [M+H]+ m/z 461.1.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH3:13][C:14]1[C:21]([O:22][CH3:23])=[C:20]([CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:15]=1[CH:16]=[O:17].O>CCCCCC.CCOCC.O1CCCC1>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH:16]([OH:17])[C:15]2[C:14]([CH3:13])=[C:21]([O:22][CH3:23])[C:20]([CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[CH:8]=1
Reactant: Brc1cccnc1
Reactant: COc1cc(C)c(OC)c(C)c1C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)c(OC)c(C)c1C(O)c1cccnc1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
Then 48 ml of a 1.6M solution of n-butyllithium in hexane was added thereto. After cooling to -60° C., 7.4 ml of 3-bromopyridine was added thereto in portions. Then the mixture was stirred at -60° C. for 30 minutes and a solution of 9.9 g of 2,4-dimethyl-3,6-dimethoxybenzaldehyde in 100 ml of dry ether and 40 ml of dry tetrahydrofuran was added dropwise thereto. After the completion of the addition, the cooling bath was taken off. When the temperature of the reaction mixture reached -10° C., water was added thereto and the mixture was extracted with ethyl acetate. After washing with a saline solution and drying, the solvent was distilled off. Then the residue was purified by silica gel column chromatography (ethyl acetate: hexane=1:5-5:1). Thus 14.0 g of the title compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]2[N:11]=[CH:12][C:13]([C:16]#[N:17])=[C:14](O)[C:9]2=[CH:8][CH:7]=1)=[O:5])[CH3:2].CN(C=O)C.C([O-])([O-])=O.[K+].[K+].[O:29]([C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O=P(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:10]2[N:11]=[CH:12][C:13]([C:16]#[N:17])=[C:14]([NH:42][C:39]3[CH:38]=[CH:37][C:36]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:41][CH:40]=3)[C:9]2=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(O)c(C#N)cnn12
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc2c(Nc3ccc(Oc4ccccc4)cc3)c(C#N)cnn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
Compound 406E (110 mg, 0.476 mmol) was heated in POCl3 (1 ml) at 83-100° C. for 2 h. Excess POCl3 was removed on a rotary evaporator, and the residue was stripped with CH2Cl2 (2 ml). To the solid residue was added DMF (5 ml), K2CO3 (690 mg, 5 mmol) and 4-phenoxy-phenylamine (353 mg, 1.91 mmol) at 0° C. The reaction mixture was degassed and stirred at rt overnight. Solid was filtered off and the filtrate was concentrated, the residue was purified by silica gel flash column chromatography to give the 406 (147 mg, 78%) as a yellow solid (25% EtOAc—Hexanes). LCMS Found: (M+H)+=398.6
Reaction SMILES: [H-].[Na+].[F:3][C:4]([S:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18](=[O:19])[CH2:17][NH:16][C:15]2=[O:20])=[CH:10][CH:9]=1)([F:6])[F:5].C(N(CC)CC)C.Br.Br[CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>CN(C)C=O.O.C(#N)C>[N:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:16]2[CH2:17][C:18](=[O:19])[N:14]([C:11]3[CH:10]=[CH:9][C:8]([S:7][C:4]([F:3])([F:5])[F:6])=[CH:13][CH:12]=3)[C:15]2=[O:20])=[CH:32][CH:33]=1
Reactant: O=C1CNC(=O)N1c1ccc(SC(F)(F)F)cc1
Reactant: BrCc1ccncc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: O=C1CN(Cc2ccncc2)C(=O)N1c1ccc(SC(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
0.087 g sodium hydride is added to a solution of 0.300 g of 3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione in 6 ml of anhydrous dimethylformamide, under an inert atmosphere of argon at a temperature in the region of 20° C., stirring is continued at this temperature for 30 minutes, 0.152 ml of triethylamine and 0.274 g of 4-(bromomethyl)pyridine hydrobromide are successively added, followed by addition of ice-cold water 10 minutes later. The reaction mixture is placed on a cartridge 37 mm in diameter packed with 50 g of Amicon 50 μm octadecyl-grafted silica of ref. conditioned successively with a water/acetonitrile mixture (5/95, v/v) and then a water/acetonitrile mixture (95/5, v/v). The elution was performed with a water/acetonitrile mixture (95/5, v/v) over 20 minutes, followed by a linear gradient from 5% to 95% of acetonitrile over 60 minutes, at a flow rate of 10 ml/minute. The fractions between 580 and 630 ml are concentrated under reduced pressure. 0.220 g of 1-pyrid-4-ylmethyl-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione is thus obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]([CH:15]1[CH2:20][CH:19]([OH:21])[CH2:18][CH2:17][N:16]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:14].OS([O-])(=O)=O.[Na+]>C(Cl)Cl.CCN(CC)CC>[CH3:11][O:12][C:13]([CH:15]1[CH2:20][C:19](=[O:21])[CH2:18][CH2:17][N:16]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:14]
Reactant: COC(=O)C1CC(O)CCN1C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CC(=O)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a mixture of oxalyl chloride ((15 mL, 30 mmol, 2 M dichloromethane) in CH2Cl2 (100 mL) cooled to −78° C. was added DMSO (4.5 mL, 63.4 mmol). The mixture was stirred at this temperature for 1 h, after which 4-hydroxy-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (2.0 g, 7.71 mmol dissolved in CH2Cl2) as added. The mixture stirred for a further 1 h and Et3N (20 mL) was then added and the mixture stirred for another 30 min. The mixture was then allowed to warm to −40° C. and poured into a solution of 10% NaHSO4. The reaction mixture was then extracted with ethyl acetate. The organic extract was then washed with brine and dried over MgSO4 (anhydrous) and the solvent was removed in vacuo and the crude residue was purified by silica gel flash column chromatography giving 1.75 g (88%) of the product as a yellow oil. 1H-NMR (CDCl3), δ(ppm): 4.85 (br, d, 1H), 4.02 (m, 1H), 3.61 (s, 3H), 3.58 (br, 1H), 2.75 (m, 2H), 2.44 (br, 2H), 1.43 (br, s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([OH:23])([C:19]([F:22])([F:21])[F:20])[CH2:6][C:7]([C:10]1[C:18]2[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)([CH3:9])[CH3:8])[CH3:2].[Br:25]Br>C(O)(=O)C.C(=O)(O)[O-].[Na+]>[CH2:1]([O:3][C:4](=[O:24])[C:5]([OH:23])([C:19]([F:21])([F:22])[F:20])[CH2:6][C:7]([C:10]1[C:18]2[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=[C:12]([Br:25])[CH:11]=1)([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(O)(CC(C)(C)c1cccc2c1OCC2)C(F)(F)F
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C(O)(CC(C)(C)c1cc(Br)cc2c1OCC2)C(F)(F)F
Yield: 94.9 %

Procedure:
To a solution of 10 g (29 mmol) of 4-(2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester in 20 mL of acetic acid (HOAc) was added dropwise a solution of 1.55 mL (30 mmol) of bromine in 10 nL of HOAc. The reaction was monitored by proton NMR. An additional 0.5 mL of Br2 was added. The mixture was diluted with saturated aqueous sodium bicarbonate and extracted with diethyl ether. The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford 11.7 g (95%) of 4-(5-bromo-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([CH3:11])=[CH:4][N:3]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:11][C:5]1[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[C:2]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cnc(Cl)c2ccoc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccoc12
Temperature: 100 °C
Yield: 49.7 %

Procedure:
A stirred mixture of commercially available 4-chloro-7-methyl-furo[3,2-c]pyridine (2.5 g, 14.9 mmol), tert-butyl piperazine-1-carboxylate (3.33 g, 17.9 mmol), sodium tert.-butoxide (2.01 g, 20.9 mmol), palladium(II) acetate (335 mg, 1.49 mmol) and 2-(di-tert.-butylphosphino) biphenyl (445 mg, 1.49 mmol) in toluene (33.0 ml) was heated for 16 h at 100° C. The mixture was cooled and water (10 ml) was added. The mixture was extracted with ethylacetate (2×20 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. The crude product (5.9 g) was further purified by flash chromatography on silica gel (10% to 100% ethyl acetate in heptane) to yield tert-butyl 4-(7-methyl-furo[3,2-c]pyridin-4-yl)-piperazine-1-carboxylate as a yellow solid (2.35 g, 50%), MS (ISP) m/z=318.3 [(M+H)+], mp 108.5° C.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:42][CH2:43][CH3:44])[C:34]=1[C:35]1[CH:40]=[CH:39][N:38]=[C:37]([F:41])[CH:36]=1)[C:29]([OH:31])=O)[CH3:24].Cl.[NH:46]1[C:50]([C:51]2[CH:52]=[C:53]3[C:63](=[CH:64][CH:65]=2)[O:62][C:56]2([CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[CH2:55][C:54]3=[O:66])=[N:49][N:48]=[N:47]1>O.CN(C=O)C.CCN(CC)CC>[CH2:43]([O:42][C:33]1[CH:32]=[C:28]([C:29]([N:59]2[CH2:60][CH2:61][C:56]3([CH2:55][C:54](=[O:66])[C:53]4[C:63](=[CH:64][CH:65]=[C:51]([C:50]5[NH:49][N:48]=[N:47][N:46]=5)[CH:52]=4)[O:62]3)[CH2:57][CH2:58]2)=[O:31])[CH:27]=[C:26]([O:25][CH2:23][CH3:24])[C:34]=1[C:35]1[CH:40]=[CH:39][N:38]=[C:37]([F:41])[CH:36]=1)[CH3:44]
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1-c1ccnc(F)c1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)cc(OCC)c1-c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Et3N (290 μL), HOBT (160 mg) and WSC hydrochloride (200 mg) were added to a DMF (8 mL) solution of 3,5-diethoxy-4-(2-fluoropyridin-4-yl)benzoic acid (266 mg) and 6-(tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (325 mg), and stirred overnight at room temperature. Water was added to the reaction liquid, the formed solid was taken out through filtration, and the solid was washed with water and ether. The solid was dried under reduced pressure to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 8.42 (1H, d, J=4.0 Hz), 8.25-8.20 (2H, m), 7.32 (1H, d, J=8.0 Hz), 7.29-7.26 (1H, m), 7.10 (1H, s), 6.76 (2H, s), 4.32-4.18 (1H, m), 4.08 (4H, q, J=8.0 Hz), 3.64-3.20 (3H, m), 2.98 (2H, s), 2.10-1.75 (4H, m), 1.17 (6H, t, J=8.0 Hz). MS [M+H]+=573.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[NH:9][C:10](=[O:14])[CH:11]([CH3:13])[O:12][C:7]=2[CH:6]=1)=[O:4].[H-].[Na+].I[CH:20]([CH3:22])[CH3:21].O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[N:9]([CH:20]([CH3:22])[CH3:21])[C:10](=[O:14])[CH:11]([CH3:13])[O:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)OC(C)C(=O)N2
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)OC(C)C(=O)N2C(C)C
Temperature: 60 °C
Reaction time: 5 h
Yield: 46.5 %

Procedure:
To a solution of 7-methoxycarbonyl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (prepared in Preparation 1) (6.1 g) in dimethylformamide (120 ml) were added 60% sodium hydride (in oil) (1.1 g) and 2-iodopropane (4.3 g) and the mixture was stirred at 60° C. for 5 hours. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was subjected to purification by column chromatography using ethyl acetate/hexane [1:4 (v/v)] to give 7-methoxycarbonyl-2-methyl-4-(2-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (3.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=4[O:24][CH3:25])[C:13](=[O:14])[C:4]=2[CH:3]=1)=[C:9]([C:26]#[N:27])[N:8]=[CH:7]3.Cl.[NH2:31][OH:32].C[O-].[Na+].CO>CN(C=O)C.O>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=4[O:24][CH3:25])[C:13](=[O:14])[C:4]=2[CH:3]=1)=[C:9]([C:26]([NH:31][OH:32])=[NH:27])[N:8]=[CH:7]3
Reactant: COc1ccc(CN2Cc3c(C#N)ncn3-c3ccc(Cl)cc3C2=O)c(OC)c1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: COc1ccc(CN2Cc3c(C(=N)NO)ncn3-c3ccc(Cl)cc3C2=O)c(OC)c1
Reaction time: 8 h

Procedure:
8-Chloro-5-(2,4-dimethoxy-benzyl)-6-oxo-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carbonitrile (2 g, 4.9 mmol) and hydroxylamine HCl (1 g, 14.6 mmol) were suspended in DMF (10 mL) and treated slowly with a 5.4 M solution of sodium methylate in methanol (2.7 mL, 14.6 mmol). The yellow suspension was stirred overnight. The suspension was cooled in ice and diluted with water (20 mL) and stirred for 1 h in ice. The crystals were filtered off and washed with cold water (5 mL). One obtained white crystals (1.9 g, 89%). m/z 442 (MH+).