Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.C(=O)([O-])[O-].[Na+].[Na+].ClCCl.[CH3:41][N:42]([CH:44]=O)C>C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:21]3[CH:20]=[C:44]4[C:14]([C:12]([CH3:13])=[N:8][N:42]4[CH3:41])=[CH:23][CH:22]=3)[C:3]=12
Reactant: CN(C)C=O
Reactant: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(I)c2c(N)ncnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: Cc1nn(C)c2cc(-c3nn(C(C)c4oc5ccccc5c(=O)c4-c4cccc(F)c4)c4ncnc(N)c34)ccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 17 %

Procedure:
To a solution of Example 57c (0.400 g, 0.758 mmoles) in DMF (4 ml), ethanol (2 ml) and water (2 ml), intermediate 115 (0.309 g, 1.137 mmoles) and sodium carbonate (0.241 g, 2.27 mmoles) were added and the system is degassed for 30 min Tetrakistriphenylphosphine Palladium (0.043 g, 0.037 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as off-white solid (0.071 g, 17% yield). MP: 270-272° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.08(s,1H), 8.04(d, J=6.8 Hz, 1H), 7.84(m,2H), 7.69(s,1H), 7.69(d, J=10.8 Hz, 1H), 7.53(t, J=7.5 Hz, 1H), 7.33(d, J=8.3 Hz, 2H), 7.03-6.95(m, 3H), 6.06(q, J=7.1 Hz, 1H), 3.99(s,3H), 2.48(s,3H), 1.92(d, J=7.0 Hz, 3H). Mass: 546.24(M++1).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=O>>[NH:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][N:1]1[CH2:9][CH2:8][N:7]([CH2:15][C:11]2[NH:10][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5][N:4]([CH2:15][C:11]2[NH:10][CH:14]=[CH:13][CH:12]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1ccc[nH]1
Reactant: C1CNCCNCCN1
Product: c1c[nH]c(CN2CCN(Cc3ccc[nH]3)CCN(Cc3ccc[nH]3)CC2)c1

Procedure:
1,4,7-tris(pyrrole-2ylmethyl)-1,4,7-triazacyclononane was prepared according to procedure B using TACN and pyrrole-2-carboxaldehyde as starting material.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[Mg]Br.[C:8]1([Mg]Br)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1C[O:19][CH2:18]C1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@H:18]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[OH:19]
Reactant: C1CCOC1
Reactant: Br[Mg]c1ccccc1
Reactant: Br[Mg]c1cccs1
Product: O[C@@H](c1ccccc1)c1cccs1

Procedure:
An operation was carried out in the same manner as in Example 14, except that 0.375 mL (0.375 mmol) of commercial 2-thienylmagnesium bromide (1.0 mol/L) was used instead of the anhydrous THF solution of phenylmagnesium bromide. Thus, (S)-2-thienylphenylmethanol was obtained. The conversion rate of the raw material was 89%, while the enantiomeric excess was 69% ee.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:7][CH:8]=1.Cl.C(N=C=N)C.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][NH2:32])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].CCOC(C)=O>C1COCC1>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][NH:32][C:11](=[O:13])[CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(CCN)cc1OC
Reactant: COc1cccc(CCC(=O)O)c1
Agent: CCN=C=N
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(CCC(=O)NCCc2ccc(OC)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a suspension of 3-(3-methoxy-phenyl)-propionic acid (1.19 g, 6.62 mmol) and 3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (1.33 g, 6.95 mmol) in THF (20 mL) is added 2-(3,4-dimethoxy-phenyl)-ethylamine (1.20 g, 6.62 mmol). The mixture is stirred at rt for 14 h. The mixture is poured onto H2O (100 mL) and EtOAc (100 mL). The organic layer is washed successively with saturated sodium hydrogen carbonate solution, 10% citric acid and saturated sodium chloride solution. The resulting organic layer is concentrated under reduced pressure to give the title compound.
Reaction SMILES: CN(C)C=O.S([O:11][CH3:12])(OC)(=O)=O.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[NH:21][C:22]([NH:24][C:25](=[NH:28])[NH:26][CH3:27])=O.C(N(CC)CC)C.[CH3:36][S:37]([OH:40])(=[O:39])=[O:38]>C(#N)C>[CH3:36][S:37]([OH:40])(=[O:39])=[O:38].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[N:21]1[CH:22]=[N:24][C:25]([NH:26][CH3:27])=[N:28][C:12]1=[O:11]
Reactant: COS(=O)(=O)OC
Reactant: CNC(=N)NC(=O)Nc1c(C)cccc1C
Agent: CS(=O)(=O)O
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNc1ncn(-c2c(C)cccc2C)c(=O)n1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To 29.2 grams (0.4 mole) of N,N-dimethylformamide, heated to 50°-60° C., are added dropwise 50.5 grams (0.4 mole) of dimethyl sulfate while maintaining the temperature between 50° and 60° C. After the addition, the reaction mixture is heated at 70°-80° C. for four hours. The reaction mixture is diluted with acetonitrile (150 milliliters) and cooled to approximately 10° C. in an ice water bath. Then 44.0 grams (0.2 mole) of 1-(2',6'-dimethylphenyl)-3-methylamidinourea are added on one portion followed by the dropwise addition of 80.8 grams (0.8 mole) of triethylamine while keeping the temperature below 25° C. The reaction mixture is allowed to come to ambient temperature and stirred for one hour. The solvent is removed in vacuo and the residue diluted with water and the pH adjusted to 10 with ten percent (10%) aqueous sodium hydroxide. The aqueous layer is extracted with chloroform (3 times with 200 milliliters each time) and the combined extracts dried (MgSO4) and concentrated in vacuo. The residual solid is taken up in boiling acetonitrile (350 milliliters) and concentrated to approximately two-thirds of its volume on a steam bath. The hot solution is treated with 21.0 grams (0.22 mole) of methanesulfonic acid and on cooling a white crystalline solid deposits, which is filtered, washed with cold acetonitrile and vacuum dried at 80° C. for one hour at yield 60.6 grams (93%) of 1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one methanesulfonate, m.p. 264°-266° C. dec.
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[H-].[Na+].Cl[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([O:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[N:14][CH:15]=1
Reactant: OC1CN2CCC1CC2
Reactant: Clc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(OC2CN3CCC2CC3)nc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
3-Hydroxy quinuclidine (Aldrich, 3.2 g, 25 mmol) in DMF (anhydrous, 30 mL) was treated with NaH (Aldrich, 99%, 1.2 g, 50 mmol) at ambient temperature for 1 hour. The mixture was then treated with 2-chloro-5-bromopyridine (7.1 g, 30 mmol) and stirred at 100° C. for 6 hours. The mixture reaction was treated with Na2CO3 (2M, 10 mL) at 10° C. and extracted with ethyl acetate (2×50 mL). The extracts were combined and concentrated under reduced pressure. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:2, Rf. 0.20) as oil (5.3 g, yield, 75%). 1H NMR (MeOH-d4, 300 MHz) δ 1.46-1.58 (m, 1H), 1.60-1.88 (m, 2H), 1.96-2.10 (m, 1H), 2.24-2.30 (m, 1H), 2.72-2.98 (m, 5H), 3.42-3.46 (m, 1H), 5.00-5.08 (m, 1H), 6.75 (d, J=8.8 Hz, 1H), 7.77 (dd, J=8.9, 2.4 Hz, 1H), 8.16 (d, J=2.7, 1H) ppm. MS (DCl/NH3) m/z 283 (M+H)+, 285 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1([CH3:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].CCN(C(C)C)C(C)C.[Br:19][C:20]1[C:21](Cl)=[C:22]([C:28](=[O:35])[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[C:23]([CH3:27])=[N:24][C:25]=1[CH3:26]>CC#N.CCOCC>[Br:19][C:20]1[C:21]([N:6]2[CH2:7][CH2:8][C:3]([CH2:1][CH3:2])([CH3:9])[CH2:4][CH2:5]2)=[C:22]([C:28](=[O:35])[C:29]([O:31][CH:32]([CH3:33])[CH3:34])=[O:30])[C:23]([CH3:27])=[N:24][C:25]=1[CH3:26]
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(Cl)c1Br
Reactant: CCC1(C)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOCC
Product: CCC1(C)CCN(c2c(Br)c(C)nc(C)c2C(=O)C(=O)OC(C)C)CC1
Temperature: 80 °C
Reaction time: 24 h
Yield: 98.7 %

Procedure:
To a solution of 4-ethyl-4-methylpiperidine (0.760 g, 5.98 mmol) and DIEA (2.1 mL, 11.9 mmol) in anhydrous CH3CN (15 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (2.0 g, 5.98 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 24 h; cooled, diluted with ether, washed with water, brine, and dried (MgSO4). The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient eluted (5-15% EtOAc/hexanes) using an Isolera chromatography station to give isopropyl 2-(5-bromo-4-(4-ethyl-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate 2.51 g (99%). 1H NMR (500 MHz, CDCl3) δ 5.07-5.02 (m, 1H), 3.32 (br. s, 2H), 3.18 (br.s, 2H), 2.61 (s, 3H), 2.29 (s, 3H), 1.29-1.28 (m 12H), 0.89 (s, 3H), 0.80 (t, J=7.3 Hz, 3H). UPLC (M+H)=427.3.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([Cl:22])=[CH:12][C:3]=1[O:4][C@H:5]1[CH2:8][C@H:7]([CH2:9][NH:10][CH3:11])[CH2:6]1.C(N(CC)CC)C.[CH3:30][C:31]1[C:35]([C:36](Cl)=[O:37])=[C:34]([CH3:39])[O:33][N:32]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:15]=[C:14]([CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([Cl:22])=[CH:12][C:3]=1[O:4][C@H:5]1[CH2:6][C@H:7]([CH2:9][N:10]([CH3:11])[C:36]([C:35]2[C:31]([CH3:30])=[N:32][O:33][C:34]=2[CH3:39])=[O:37])[CH2:8]1
Reactant: Cc1noc(C)c1C(=O)Cl
Reactant: CNC[C@H]1C[C@H](Oc2cc(Cl)c(CN3CCCC3)cc2Cl)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1C(=O)N(C)C[C@H]1C[C@H](Oc2cc(Cl)c(CN3CCCC3)cc2Cl)C1
Product: Cl

Procedure:
Example 381, ({trans-3-[2,5-dichloro-4-(pyrrolidin-1-ylmethyl)phenoxy]cyclobutyl}methyl)methylamine (100 mg, 0.29 mmol) and triethylamine (0.04 mL, 0.29 mmol) were dissolved in CH2Cl2 (2 mL). 3,5-Dimethylisoxazole-4-carbonyl chloride (47 mg, 0.29 mmol) was added dropwise under stirring. The mixture was stirred at RT for 3 h and sat. K2CO3 was added. The mixture was stirred at RT for 20 h, dried with Na2SO4, and evaporated. The residue was purified chromatographically (silica gel 40-63 μm, 5 ml, CCl4/CHCl3 100:0→0:100, then CHCl3/MeOH 100:0→95:5). The residue was dissolved in ether (1 mL). 4N HCl/dioxane (0.10 mL) was added, and the reaction mixture was evaporated to dryness, recrystallized from i-PrOH/Et2O. The crystals were separated by filtration and dryed in vacuo to give the title compound (86 mg, 59%) as yellow crystals. LC/MS data: 466.2 (M+H) (calculated for C23H29Cl2N3O3 466.41). 1H NMR-data (DMSO-d6): 10.646 (br.s, 1H, NH+); 7.99 (s, 1H, NH); 6.83-7.24 (m, 1H, Ar—H); 4.66-5.17 (m, 1H), 4.32-4.44 (m, 2H); 3.37-3.72 (m, 4H); 3.03-3.16 (m, 2H); 2.91 (s, 3H); 2.64-2.79 (m, 1H); 2.31-2.43 (m, 4H); 2.11-2.66 (m, 6H); 1.97-2.07 (m, 2H); 1.83-1.94 (m, 2H).
Reaction SMILES: C([O:5][C:6]([C:8]1[N:12]([CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][N:15]=2)[N:11]=[C:10]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)[CH:9]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:31][C:26]1[CH:25]=[C:24]([C:10]2[CH:9]=[C:8]([C:6]([OH:7])=[O:5])[N:12]([CH2:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][N:15]=3)[N:11]=2)[CH:29]=[CH:28][C:27]=1[Cl:30]
Reactant: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)c(Cl)c3)cc2C(=O)OC(C)(C)C)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)c(Cl)c3)cc2C(=O)O)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the intermediate from step E (551 mg, 1.19 mmol) in DCM (10 mL) was added TFA (10 mL). After stirring at room temperature for 4 hours the reaction mixture was concentrated in vacuo and azeotroped with toluene (3×). A white solid obtained. This material was used in the next step without any further purification. LC-MS: 2.38 min; (M+H)=406.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12]1([C:18](=O)[C:19]([O:21]C)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:19]([OH:21])=[O:20]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: COC(=O)C(=O)c1ccccc1
Product: O=C(O)C(=C1C(=O)Nc2ccc(Br)cc21)c1ccccc1
Yield: 45.2 %

Procedure:
5-Bromooxindole (640 mg) was reacted with methyl phenylglyoxylate (540 mg) using method A to give 470 mg (45%) of the title compound.
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35][CH2:36][CH2:37]Br>CN(C=O)C>[C:17]([C:16]1[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:2]([CH3:4])([N:1]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH3:3])=[CH:6][CH:7]=2)=[N:12][C:13]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[N:14][CH:15]=1)#[N:18]
Reactant: CC(C)(N)c1ccc(-c2nc(Nc3ccc(F)cc3)ncc2C#N)cc1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(c1ccc(-c2nc(Nc3ccc(F)cc3)ncc2C#N)cc1)N1CCCC1
Reaction time: 12 h
Yield: 51.1 %

Procedure:
To a solution of the compound (1.0 g,2.88 mmol) of Example 20 in DMF (20 mL) was added potassium carbonate (786 mg, 5.7 mmol) and 1,4-dibromobutane (622 mg, 2.88 mmol) and the resulting mixture stirred at 60° for 12 h. The reaction was partitioned between brine and ethyl acetate then the organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to column chromatography to give the title compound (591 mg) as a yellow solid, m.p. 124°. δH (d6 DMSO) 8.58 (1H, s), 7.94 (2H, dapp, J 8.4 Hz), 7.63 (4H, m), 6.96 (2H, tapp, J 8.7 Hz), 3.23 (4H, s), 2.61 (4H, s) and 1.47 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][C:3]=1[CH3:21].[CH3:22][N:23]1[CH2:28][CH2:27][O:26][C:25]2[CH:29]=[C:30]([C:33](O)=[O:34])[CH:31]=[N:32][C:24]1=2>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:33]([C:30]3[CH:31]=[N:32][C:24]4[N:23]([CH3:22])[CH2:28][CH2:27][O:26][C:25]=4[CH:29]=3)=[O:34])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:4][C:3]=1[CH3:21]
Reactant: Cc1cc(-c2cc(N)cnc2OCC(F)(F)F)ccc1Cl
Reactant: CN1CCOc2cc(C(=O)O)cnc21
Product: Cc1cc(-c2cc(NC(=O)c3cnc4c(c3)OCCN4C)cnc2OCC(F)(F)F)ccc1Cl

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-3-methyl-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example 57 a) and 3,4-dihydro-4-methyl-2H-pyrido[3,2-b]-1,4-oxazine-7-carboxylic acid (CAN 915707-58-3) as starting materials; MS (EI) 493.1(M+H)+.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[C:11]([NH:27][C:28]([NH:30][C:31]2[C:36]([CH:37]([CH3:39])[CH3:38])=[CH:35][CH:34]=[CH:33][C:32]=2[CH:40]([CH3:42])[CH3:41])=[O:29])[C:10]1=[O:43])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:6]([CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[C:11]([NH:27][C:28]([NH:30][C:31]2[C:32]([CH:40]([CH3:41])[CH3:42])=[CH:33][CH:34]=[CH:35][C:36]=2[CH:37]([CH3:39])[CH3:38])=[O:29])[C:10]1=[O:43])([OH:7])=[O:5]
Reactant: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CC(=O)OC(C)(C)C)c3ncccc23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CC(=O)O)c3ncccc23)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 405.3 %

Procedure:
To a solution of N-[(1-tert-butoxycarbonylmethyl)-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (110 mg, 0.19 mmol) in methylene chloride (20 ml) was added trifluoroacetic acid (1 ml, 13 mmol), and the mixture was stirred at room temperature for 1.5 hour. The mixture was concentrated under reduced pressure, diluted with water, and basified with 4N aqueous NaOH solution, and washed with ethyl acetate. The aqueous layer was acidified with 2N aqueous HCl solution, extracted with ethyl acetate, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure, and purified by preparative thin layer chromatography to give the title compound (41 mg, 0.77 mmol).
Reaction SMILES: I[C:2]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[C:28]([O:32][CH3:33])(=[O:31])[CH:29]=[CH2:30]>C1CCCCC1.C(OCC)(=O)C>[CH3:33][O:32][C:28](=[O:31])/[CH:29]=[CH:30]/[C:2]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: C=CC(=O)OC
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C#N)cc3)CC2)c1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: COC(=O)/C=C/c1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc(C#N)cc2)CC1

Procedure:
Prepared in analogy to example 139 from 4-[4-(2-Iodo-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile (Example AG) and methyl acrylate. Chromatography (SiO2; cyclohexane/ethyl acetate 3:7) yields the title compound as a slightly yellow solid (M+H+: 454.3)
Reaction SMILES: [Br:1]([O-])(=O)=O.[Na+].[F:6][C:7]([F:21])([F:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].S(=O)(O)[O-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O.C(OCC)(=O)C>[Br:1][CH:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]([F:20])([F:21])[F:6])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)Cc1ccccc1C(F)(F)F
Reactant: [O-][Br+2]([O-])[O-]
Agent: O=S([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(Br)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
585 mg (3.89 mmol) of sodium bromate were initially charged in 2 ml of water, and 300 mg (1.29 mmol) of ethyl 2-(trifluoromethyl)phenylacetate, dissolved in 2.5 ml of ethyl acetate, were added at RT. A solution of 403 mg (3.89 mmol) of sodium bisulfite in 3.8 ml of water was then added slowly. The mixture was stirred at RT for 18 h. 5 ml of 10% strength aqueous sodium dithionite solution were then added. The mixture was extracted with 15 ml of ethyl acetate, and the organic phase was washed in each case once with 5 ml of 10% strength sodium dithionite solution and 5 ml of saturated sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1, then 10:1). This gave 186 mg of a mixture consisting of the title compound and the starting material ethyl 2-(trifluoromethyl)phenylacetate (ratio 16:84 according to GC/MS [Method 20]). This mixture was once more reacted with 362 mg (2.40 mmol) of sodium bromate and 250 mg (2.40 mmol) of sodium bisulfite according to the procedure described above. Work-up gave a mixture of 31% title compound and 69% ethyl 2-(trifluoromethyl)phenylacetate, which was reacted further without any further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:17]([O:19][C:20](=O)[C:12]=12)=[O:18]>C(O)(=O)C>[O:18]=[C:17]1[C:13]2[C:12](=[N:11][CH:16]=[CH:15][CH:14]=2)[C:20](=[O:19])[N:1]1[CH:2]([CH2:3][CH2:4][C:5]([NH2:6])=[O:7])[C:8]([OH:10])=[O:9]
Reactant: O=C1OC(=O)c2ncccc21
Reactant: NC(=O)CC[C@H](N)C(=O)O
Solvent: CC(=O)O
Product: NC(=O)CCC(C(=O)O)N1C(=O)c2cccnc2C1=O
Yield: 25.6 %

Procedure:
A stirred suspension of (S)-glutamine (14.6 g, 100 mmol) and 2,3-pyridinedicarboxylic anhydride (14.9 g, 100 mmol) in 100 mL of acetic acid is heated and refluxed for 1 hour. The reaction solution is cooled to form a solid. The solid is removed by filtration and washed with acetic acid to yield 7.11 g (26%) of 2-(1,3-dioxo-4-azaisoindolin-2yl)glutaramic acid. The product can be further purified by slurring in 700 mL of refluxing ethanol, cooling, filtering, and drying to produce a white powder with a melting point of 222°-226° C.; 1H NMR (DMSO-d6) δ 13.25 (br s, 1 H, COOH), 9.04 (dd, 1 H, J=1.2, 4.9 Hz, pyr), 8.37 (dd, 1 H, J =1.2, 7.8 Hz, pyr), 7.85 (dd, 1 H, J=4.9, 7.8 Hz, pyr), 7.20 (s, 1 H, CONH2), 6.73 (s, 1 H, CONH2), 4.83 (dd, 1 H, J=10.2, 4.8 Hz, CHN), 2.55-1.90 (m, 4 H, CH2CH2); 13C NMR (DMSO-d6) δ1173.22, 170.21, 165.8, 165.7, 155.4, 150.9, 131.7, 128.3, 126.9, 51.5, 31.4, 24.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:20][CH3:21])=[N:15][C:16]([C:17](O)=[O:18])=[C:10]2[CH:9]1[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][N:35](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.CN.C1COCC1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:20][CH3:21])=[N:15][C:16]([C:17](=[O:18])[NH:35][CH3:34])=[C:10]2[CH:9]1[CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCc1nc(C(=O)O)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCc1nc(C(=O)NC)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
To a solution of 3-ethyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-1,7-dicarboxylic acid 7-tert-butyl ester (47 mg; 0.100 mmol) in anhydrous DMF (1 ml) was added successively TBTU (35 mg; 0.110 mmol), DIPEA (51 μl; 0.300 mmol), and finally 2M methylamine in THF (0.15 ml; 0.300 mmol). The resulting reaction mixture was further stirred at rt, under nitrogen, for 16 h, and was then purified by preparative HPLC to give the pure product 3-ethyl-1-methylcarbamoyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (27.8 mg; 0.057 mmol; 58%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]([C:19]1[CH:20]=[C:21]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[C:22]([O:36][CH3:37])=[C:23]([NH:25][C:26](=[O:35])[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([OH:34])[CH:28]=2)[CH:24]=1)([CH3:18])([CH3:17])[CH3:16]>C(#N)C.CN(C)C=O.O>[C:15]([C:19]1[CH:20]=[C:21]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[C:22]([O:36][CH3:37])=[C:23]([NH:25][C:26](=[O:35])[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([O:34][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:28]=2)[CH:24]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: Clc1ccnc(Cl)n1
Reactant: COc1c(NC(=O)c2ccc(C)c(O)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: COc1c(NC(=O)c2ccc(C)c(Oc3ccnc(Cl)n3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
567 mg 2,4-dichloropyrimidine and 663 mg potassium carbonate are added to 1.50 g N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-3-hydroxy-4-methyl-benzamide in 15 ml acetonitrile and 3 ml N,N-dimethylformamide, and the reaction mixture is stirred overnight at ambient temperature. Then another 57 mg 2,4-dichloropyrimidine are added, and the mixture is stirred for a further hour at ambient temperature. For working up the reaction mixture is diluted with water and the white precipitate formed is filtered off, washed with water and dried in the desiccator.