Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[N:10]=[C:4]2[CH:3]=1.[C:19](=[O:26])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[NH2:20]>>[C:22]([O:21][C:19](=[O:26])[NH:20][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[N:10]=[C:4]2[CH:3]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: COc1ccccc1-c1nc2cc(Br)ccn2n1
Reactant: CC(C)(C)OC(N)=O
Product: COc1ccccc1-c1nc2cc(NC(=O)OC(C)(C)C)ccn2n1
Yield: 94.9 %

Procedure:
The product was prepared in the same manner as described in example 1c using 7-bromo-2-(2-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (490 mg, 1.61 mmol) and tert-butyl carbamate (350 mg, 2.99 mmol) as starting materials. The reaction affords [2-(2-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-carbamic acid tert-butyl ester (520 mg, 94.8%) as a light yellow solid. mp.: 202.8° C., MS: m/z=341.1 (M+H+)
Reaction SMILES: [C:1]1(=O)[NH:5][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1(=O)NC(=O)C=C1.C1(C2C(=CC=CC=2)CO1)=O>>[NH2:5][CH:1]1[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[CH2:4]1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C1C=CC(=O)N1
Agent: O=C1OCc2ccccc21
Product: NC1Cc2ccccc21

Procedure:
An alternative process is that wherein a 3- or 4-halobenzocyclobutene reactant is treated with a phthalimide or maleimide to produce a 3- or 4-phthalimido-or maleimidobenzocyclobutene. When phthalimide or maleimide is monomeric, for example, phthalide or maleimide themselves, the product can be cleaved by reaction with an amine to produce a corresponding aminobenzocyclobutene. A preferred amine for this purpose is hydrazine, preferably hydrazine hydrate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[CH3:15][CH:16]([CH3:39])[CH:17]([NH:22][C:23]([C:25]1[S:26][CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][CH:31]=2)[N:29]=1)=[O:24])[C:18]([O:20][CH3:21])=[O:19]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:14])[NH:36][C:33]1[CH:34]=[CH:35][C:30]([C:28]2[N:29]=[C:25]([C:23]([NH:22][C@@H:17]([CH:16]([CH3:39])[CH3:15])[C:18]([O:20][CH3:21])=[O:19])=[O:24])[S:26][CH:27]=2)=[CH:31][CH:32]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1Cl
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Product: COC(=O)[C@@H](NC(=O)c1nc(-c2ccc(NC(=O)Nc3ccc(C(F)(F)F)cc3Cl)cc2)cs1)C(C)C

Procedure:
The title compound was synthesized analogous to Example 23, using 2-chloro-4-(trifluoromethyl)-1-isocyanatobenzene and intermediate 3. 1HNMR (DMSO-d6, 300 MHz): δ 9.801 (s, 1H), 8.832-8.804 (d, J=8.4 Hz, 1H), 8.680 (s, 1H), 8.515-8.486 (d, J=8.7 Hz, 1H), 8.348 (s, 1H), 8.095-8.067 (d, J=8.4 Hz, 2H), 7.897-7.893 (d, J=1.2 Hz, 2H), 7.721-7.686 (dd, J=1.8, 9 Hz, 1H), 7.621-7.593 (d, J=8.4 Hz, 2H), 4.401-4.344 (t, J=8.1, 9 Hz, 1H), 3.702 (s, 3H), 2.351-2.280 (m, 1H), 1.003-0.955 (t, J=7.2 Hz, 6H); MS (ESI) m/z 553 (M−H), 555 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]([N:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[O:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.C(O)CCC>CN(C=O)C.CO>[CH3:13][N:12]([CH3:14])[C:11]1[CH:15]=[CH:16][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:27][C:26]3[CH:25]=[CH:24][C:23]([N:20]4[CH2:21][CH2:22][O:17][CH2:18][CH2:19]4)=[CH:29][CH:28]=3)[N:7]=2)=[CH:9][CH:10]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CN(C)c1ccc(-c2ccnc(Cl)n2)cc1
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCCCO
Product: CN(C)c1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Temperature: 25 °C

Procedure:
A flask was charged with C3 (500 mg, 2.1 mmol), 4-morpholinoaniline (573 mg, 3.2 mmol) and nBuOH (10 mL). The flask was immersed in a 180° C. oil bath for 30 minutes. The reaction mixture was cooled to ambient temperature and the black residue dissolved in DMF and MeOH. The product 67 was purified by HPLC with TFA/ACN as eluent. The TFA salt was removed by extracting with sodium hydroxide and ethylacetate to afford the free base of 67.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18](O)(=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22]>>[C:18]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)(=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCC(=O)O
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CCCCC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 81.7 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 10.0 mg (0.10 mMol) pentanoic acid, 12.8 mg (82%) of the title compound were recovered.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.CC(C)([O-])C.[K+].Br[CH2:19][CH:20]([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]>CC(N(C)C)=O.CCOCC.O>[CH2:22]([O:21][CH:20]([O:24][CH2:25][CH3:26])[CH2:19][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][C:3]1=[O:11])[CH3:23]
Reactant: CCOC(CBr)OCC
Reactant: O=C1COc2ccccc2N1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: CCOC(CN1C(=O)COc2ccccc21)OCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.7 %

Procedure:
Dissolve 2H-1,4-benzoxazin-3(4H)-one (1.0 g, 6.64 mmol) in dimethylacetamide (5 mL); add potassium tert-butoxide (1.54 g, 13.28 mmol); and stir at ambient temperature for 5 minutes. Add 2-bromo-1,1-diethoxyethane (10.1 mL, 66.4 mmol) and tetra-N-butylammonium iodide (2.49 g, 6.64 mmol). Heat the reaction mixture to 80° C. and stir for 2 hours. Thereafter allow the reaction to cool to ambient temperature. Dilute the reaction mixture with Et2O and water; separate the layers; and extract the aqueous layer with additional Et2O. Combine the organic extracts; dry over Na2SO4; filter; and concentrate the filtrate under reduced pressure. Purify via flash column chromatography using a step gradient of 0%, 10%, 20% and 30% of EtOAc in hexanes. Concentrate the desired fractions to afford the title compound (1.65 g, 93.7%) as a waxy solid. 1H (300 MHz, CDCl3): δ 7.36-7.32 (m, 1H), 7.03-6.97 (m, 3H), 4.78 (t, J=5.5 Hz, 1H), 4.59 (s, 2H), 4.02 (d, J=5.5 Hz, 2H), 3.81-3.70 (m, 2H), 3.58-3.48 (m, 2H), 1.16 (t, J=7.0 Hz, 6H).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[C:14]([F:17])([F:16])[F:15])(=O)=O.C[Si](C)(C)[C:20]#[N:21].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C(#N)C.O.C(OCC)(=O)C>[Cl:13][C:9]1[C:8]([C:14]([F:17])([F:16])[F:15])=[C:7]([CH2:6][C:20]#[N:21])[CH:12]=[CH:11][CH:10]=1
Reactant: C[Si](C)(C)C#N
Reactant: CS(=O)(=O)OCc1cccc(Cl)c1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: N#CCc1cccc(Cl)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 583.1 %

Procedure:
To a mixture of 3-chloro-2-(trifluoromethyl)benzyl methanesulfonate (0.150 g, crude) and trimethylsilanecarbonitrile (119 mg, 1.2 mmol) in acetonitrile (5 mL) was added a solution of tetrabutylammonium fluoride in THF (1M, 1.2 mL, 1.2 mmol). The reaction was stirred at room temperature for 2 h. The reaction was treated with ethyl acetate and water, and the separated organic layer was washed with brine, dried and concentrated to give the crude product, which was purified by silica gel column chromatography (10% ethyl acetate in petroleum ether) to afford the title compound (0.10 g, 3.03 mmol, 68% yield over three steps) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.56-7.48 (m, 3H), 3.99 (d, J=2.0 Hz, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1.[CH3:20][O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.CCOC(C)=O>C(O)(C)C>[CH3:20][O:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:2]2[N:3]=[CH:4][C:5]3[CH2:11][N:10]([C:12]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)=[O:13])[CH2:9][CH2:8][C:6]=3[N:7]=2)=[CH:24][CH:23]=1
Reactant: O=C(c1cccnc1)N1CCc2nc(Cl)ncc2C1
Reactant: COc1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COc1ccc(Nc2ncc3c(n2)CCN(C(=O)c2cccnc2)C3)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 24.3 %

Procedure:
A solution of (2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone, Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treated with 4-methoxyaniline (0.018 g, 0.100 mmol). The resulting mixture was heated to 60° C. and allowed to stir overnight. After being allowed to cool to room temperature EtOAc (10 mL) was added to the reaction mixture, and the resulting solution was then washed twice with brine (10 mL). The combined aqueous layers were washed once with EtOAc (10 mL). The organic layers were combined, then dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The resulting crude residue was then purified over silica using a MeOH/CHCl3 gradient. The desired product was obtained in 24.3% yield (0.008 g, 0.024 mmol).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:44]=[CH:45][CH:46]=2)[C:15]([NH:17][C:18]2[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][S:34]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:28]=[CH:27][C:19]=2[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:16])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:49]N(C)C=O.CI>O>[C:1]([C:5]1[N:6]=[C:7]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:44]=[CH:45][CH:46]=2)[C:15]([N:17]([C:18]2[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][S:34]([C:37]3[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=3)(=[O:36])=[O:35])[CH:28]=[CH:27][C:19]=2[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:49])=[O:16])[S:8][CH:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=O
Reactant: CCOC(=O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1cccc(OCc2nc(C(C)(C)C)cs2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCOC(=O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1N(C)C(=O)c1cccc(OCc2nc(C(C)(C)C)cs2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Under ice-cooling, ethyl 2-[3-[(4-tert-butyl-2-thiazolyl)methoxy]benzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxyacetate (266 mg, 0.39 mmol) was added to a mixture of 60% sodium hydride (19 mg, 0.48 mmol) and dimethylformamide (2 ml), and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was again cooled with ice, methyl iodide (29 μl, 0.47 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution and the product formed was extracted with toluene. The extract was washed with water and brine in that order, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (eluent=chloroform:methanol=50:1) to give ethyl 2-[N-[3-[(4-tert-butyl-2-thiazolyl)methoxy]benzoyl]-N-methylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxyacetate (213 mg, 0.31 mmol, 78%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6]([C:8]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[O:9])[CH:5]([CH3:16])[CH2:4][N:3]1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=1.C(=O)(O)[O-:30].[Na+].ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl>ClCCl>[CH3:1][C@H:2]1[CH2:7][N:6]([C:8]([N:10]2[CH2:11][CH2:12][S:13](=[O:30])[CH2:14][CH2:15]2)=[O:9])[C@H:5]([CH3:16])[CH2:4][N:3]1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:27])([F:28])[F:26])[CH:18]=1
Reactant: O=C([O-])O
Reactant: CC1CN(c2ccc(C#N)c(C(F)(F)F)c2)C(C)CN1C(=O)N1CCSCC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C[C@@H]1CN(c2ccc(C#N)c(C(F)(F)F)c2)[C@@H](C)CN1C(=O)N1CCS(=O)CC1
Reaction time: 6 h

Procedure:
A 270 mg portion of 4-[2,5-dimethyl-4-(thiomorpholine-4-carbonyl)piperazin-1-yl]-2-trifluoromethylbenzonitrile synthesized in Example 7-6 was dissolved in 7 ml of dichloromethane, and the solution was mixed with 110 mg of sodium bicarbonate and 155 mg of m-chloroperbenzoic acid (MCPBA) at −78° C. and stirred at the same temperature for 6 hours. The reaction solution was mixed with chloroform, washed with 1 N aqueous sodium hydroxide and saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by a silica gel column chromatography to obtain 232 mg of the title compound from methanol-chloroform (1:50, v/v) eluate.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.[Cl:14][C:15]([Cl:20])([Cl:19])[C:16](Cl)=[O:17].C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[N:3]=[C:4]([C:16](=[O:17])[C:15]([Cl:20])([Cl:19])[Cl:14])[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1
Reactant: Clc1cccnc1-n1cnc(Br)c1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1nc(Br)cn1-c1ncccc1Cl)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1.0 g of 2-(4-bromo-1H-imidazol-1-yl)-3-chloropyridine in 5 ml of dichloromethane was added dropwise a solution of 0.45 ml of trichloroacetyl chloride in 5 ml of dichloromethane at room temperature. The resulting mixture was stirred at room temperature for 1 day. Thereto 0.57 ml of triethylamine was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was subjected to silica gel chromatography to obtain 1.0 g of 1-[4-bromo-1-(3-chloro-2-pyridinyl)-1H-imidazol-2-yl]-2,2,2-trichloroethanone of the formula:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][N:13]2[CH:19]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][S:21]([CH3:20])(=[O:23])=[O:22])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][C:15]([O:18][S:21]([CH3:20])(=[O:23])=[O:22])=[N:14][N:13]2[CH:19]=1
Reactant: COc1cc(O)ccc1-c1cn2[nH]c(=O)ccc2n1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(OS(C)(=O)=O)ccc1-c1cn2nc(OS(C)(=O)=O)ccc2n1

Procedure:
0.3 g (1.17 mmol) of 2-(2-Methoxy-4-hydroxyphenyl)-5H-imidazo[1,2-b]pyridazin-6-one are dissolved in 10 ml of 1N sodium hydroxide solution. At 20° C., 1.3 g (1.17 mmol) of methanesulphonic acid chloride is added dropwise. By simultaneously adding 2N sodium hydroxide solution the pH is kept at 10-11.
Reaction SMILES: [NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C@H:2]([C:6]([N:8]1[CH2:16][CH2:15][CH2:14][C@H:9]1[C:10]([O:12]C)=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4]>O.[OH-].[Na+]>[NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[C@H:2]([C:6]([N:8]1[CH2:16][CH2:15][CH2:14][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
3 (3.76 g, 10.4 mmol) was dissolved in 30 ml of water/acteone (1/5 v/v) and 11.4 ml NaOH (1N) was added. After completion of the reaction the organic solvent was removed by evaporation and the resulting solution was diluted by 15 ml NaHCO3 solution (saturated). Then the mixture was extracted three times by 10 ml of acetic acid ethyl ester. After that the solution was brought to pH2 by adding HCl (15% in water). The resulting mixture was extracted three times by 30 ml of acetic acid ethyl ester. The organic layer was separated and washed three times with brine, dried (Na2SO4) and evaporated.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.OC(C(F)(F)F)=O.[NH2:31][CH2:32][C:33]1[O:37][N:36]=[C:35]([CH:38]([CH3:40])[CH3:39])[CH:34]=1>>[CH:38]([C:35]1[CH:34]=[C:33]([CH2:32][NH:31][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[O:37][N:36]=1)([CH3:40])[CH3:39]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(C)c1cc(CN)on1
Solvent: O=C(O)C(F)(F)F
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCc2cc(C(C)C)no2)cn1
Yield: 81 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 5-aminomethyl-3-isopropylisoxazole TFA instead of methylamine, to the title compound (112 mg, 81%) which was obtained as a colourless gum. MS: m/e=433.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([O:54][CH3:55])[C:40]=1[OH:56]>>[NH2:30][C@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:42]=[C:41]([O:54][CH3:55])[C:40]([OH:56])=[C:39]([Cl:38])[CH:44]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(Nc4ccc(N5CCC[C@H](N)C5)nc4)c3c2)cc(Cl)c1O
Yield: 45.4 %

Procedure:
Following general procedure D, (S)-tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinoline-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (100 mg, 0.17 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (74 mg, 0.26 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (42 mg, 45% over 2 steps) as an orange-yellow solid: 1H NMR (500 MHz, MeOD+TFA-d) δ 9.40 (br s, 1H), 8.28-8.20 (m, 2H), 8.10 (br s, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.65 (dd, J=9.1, 2.8 Hz, 1H), 7.05 (d, J=9.1 Hz, 1H), 6.99 (s, 1H), 6.83 (br s, 1H), 4.52 (d, J=11.7 Hz, 1H), 4.04-3.96 (m, 1H), 3.91 (s, 3H), 3.37-3.18 (m, 3H), 2.87 (br s, 1H), 2.21-2.14 (m, 1H), 1.96-1.87 (m, 1H), 1.76-1.62 (m, 2H), 1.27-1.16 (m, 4H). ESI MS m/z 544 [C30H30ClN5O3+H]+; HPLC>99.0% (AUC), tR=10.76 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[F:23][C:24]([F:29])([F:28])[CH2:25][CH2:26]O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:26][CH2:25][C:24]([F:29])([F:28])[F:23])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: OCCC(F)(F)F
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Product: FC(F)(F)CCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound IId was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and 3,3,3-trifluoropropan-1-ol following the general procedure for the Mitsunobu reaction as described above.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C:19](=[O:26])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([O:18][C:19](=[O:26])[NH:20][CH2:21][CH2:22][CH2:23][CH:24]=[O:25])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(NCCCCO)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CCCCNC(=O)OCc1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of dimethyl sulfoxide (4.50 g, 57.6 mmol) in CH2Cl2 (24 mL) was added dropwise at −70° C. to a solution of oxalyl chloride (3.94 g, 31.0 mmol) in CH2Cl2 (72 mL), then after 15 min a solution of (4-hydroxy-butyl)-carbamic acid benzyl ester (4.95 g, 22.2 mmol) in CH2Cl2 (36 mL) was added dropwise. After 60 min triethylamine (11.2 g, 111 mmol) was added, then after 20 min the reaction mixture was allowed to reach RT over 2 h. The reaction mixture was washed with water, dried (MgSO4) and filtered to afford (4-oxo-butyl)-carbamic acid benzyl ester as CH2Cl2 solution. This was added at RT to a mixture of (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (3.63 g, 22.2 mmol), sodium triacetoxyborohydride (5.17 g, 24.4 mmol), AcOH (2.66 g, 44.3 mmol), and triethylamine (2.24 g, 22.2 mmol), then after 16 h the reaction mixture was washed with 2 M aq. sodium carbonate solution. The organic layer was washed with water, dried (MgSO4) and filtered, and evaporated. Chromatography (SiO2; CH2Cl2→CH2Cl2/MeOH/25% aq. ammonia solution 90:10:0.25) afforded the title compound (4.54 g, 62%). Colorless gum, MS: 435.3 (M+H)+.
Reaction SMILES: C(O)(=O)C.C1([SiH3])C=CC=CC=1.C([N:15]1[N:19]=[N:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]4[C:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[C:38]([OH:47])[C:37]([C:48]([F:51])([F:50])[F:49])=[CH:36][CH:35]=4)=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)=[N:16]1)C=C>C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:47][C:38]1[C:37]([C:48]([F:51])([F:50])[F:49])=[CH:36][CH:35]=[C:34]([CH2:33][O:32][C:29]2[CH:30]=[CH:31][C:26]([C:23]3[CH:22]=[CH:21][C:20]([C:17]4[NH:18][N:19]=[N:15][N:16]=4)=[CH:25][CH:24]=3)=[CH:27][CH:28]=2)[C:39]=1[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]
Reactant: C=CCn1nnc(-c2ccc(-c3ccc(OCc4ccc(C(F)(F)F)c(O)c4C(=O)OC(C)(C)C)cc3)cc2)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [SiH3]c1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(-c4nnn[nH]4)cc3)cc2)ccc(C(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (74 mg, 64.4 μmol), acetic acid (0.4 ml, 6.44 mmol) and phenylsilane (0.397 ml, 3.22 mmol) were added to a solution of the mixture (712 mg, 1.29 mmol) obtained in Example (95-3) in methylene chloride (6 ml) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 3 hours. The formed solid was filtered and washed with methylene chloride to give the title compound (469 mg, yield: 71%).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:26]=[O:27]>O>[NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[C:3]=1[CH:26]=[O:27]
Reactant: Cn1c(=O)cc(N)n(-c2ccccc2)c1=O
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(=O)c(C=O)c(N)n(-c2ccccc2)c1=O
Yield: 75 %

Procedure:
6-Amino-3-methyl-1-phenyl-2,4 (1H, 3H)-pyrimidinedione (5.00 g, 23 mmol) was suspended in dimethylformamide (77 mL). To the resultant suspension was added phosphorus oxychloride (2.57 mL, 27.6 mmol), and the resultant mixture was reacted at 60° C. for 3 h. The reaction mixture was diluted with water, and adjusted to ca. pH 12 with sodium hydroxide. The precipitates formed in the reaction mixture was filtered to give a crude product. The crude product was recrystallized from a mixture of ethanol, ethyl acetate and water to give an aldehyde, 6-amino-5-formyl-3-methyl-1-phenyl-2,4 (1H, 3H)-pyrimidinedione (yield 75%).