Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:6]([NH2:8])=[O:7])[C:3]([NH2:5])=[O:4].S(=O)(=O)(O)[OH:10].[CH:14](OCC)(OCC)OCC.[ClH:24]>O.CC(O)C>[OH2:4].[OH2:10].[ClH:24].[OH:4][C:3]1[NH:5][CH:14]=[N:1][C:2]=1[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)C(N)C(N)=O
Reactant: CCOC(OCC)OCC
Reactant: O=S(=O)(O)O
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: NC(=O)c1nc[nH]c1O
Temperature: 80 °C
Reaction time: 7 h

Procedure:
Under the nitrogen atmosphere, 10.0 g of 2-aminomalonamide and 44 mg of sulfuric acid were added to 200 mL of 2-propanol. After heating to 80° C., 35.4 mL of triethyl orthoformate was added dropwise to the mixture over 10 minutes. Subsequently, the reaction mixture was stirred for 7 hours at 80° C. Color of the reaction liquid was deep blue when the reaction was completed. Subsequently, after cooling to 58° C., the reaction mixture was added with 10 mL of water followed by 8 mL of conc. hydrochloric acid. After cooling the reaction mixture to 5° C., the crystal was collected by filtration and then washed with 40 mL of acetone to give 15.6 g of 5-hydroxy-1H-imidazole-4-carboxamide hydrochloric acid salt dihydrate as a green crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[C:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:20]=[CH:19][C:3]=1[C:4]([C:6]1[C:14]([Cl:15])=[C:13]([Cl:16])[C:12]([Cl:17])=[C:11]([Cl:18])[C:7]=1[C:8](O)=[O:9])=[O:5].[CH3:28][N:29]([CH3:39])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]([CH3:38])[CH3:37])[CH:31]=1.C(OC(=O)C)(=O)C.Cl>O>[CH3:37][N:36]([CH3:38])[C:32]1[CH:31]=[C:30]([N:29]([CH3:39])[CH3:28])[CH:35]=[CH:34][C:33]=1[C:4]1([C:3]2[CH:19]=[CH:20][C:21]([N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])=[CH:22][C:2]=2[CH3:1])[C:6]2[C:7](=[C:11]([Cl:18])[C:12]([Cl:17])=[C:13]([Cl:16])[C:14]=2[Cl:15])[C:8](=[O:9])[O:5]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: CCN(CC)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c(C)c1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCN(CC)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c(C)c1
Temperature: 95 °C

Procedure:
A mixture of 2-(2-methyl-4-(diethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (22.4 g.), N,N,N',N'-tetramethyl-m-phenylenediamine (8.20 g.) and acetic anhydride (75 g.) was heated (to 95° C.) during one to two hours, then refluxed with dilute hydrochloric acid (32 g. concentrated hydrochloric acid plus 160 ml. water) during one and one-half hours. The resulting mixture was poured into water and the pH was adjusted. Recrystallization of the resulting product from toluene afforded 3-(2,4-bis(dimethylamino)phenyl)-3-(2-methyl-4-(diethylamino)phenyl)-4,5,6,7-tetrachlorophthalide (I: X=(CH3)2N, Y2 =CH3, Y4 =(CH3CH2)2N, Z4 =Z5 =Z6 =Z7 =Cl) (m.p. 236°-238° C.; after slurrying in acetone, 237°-239° C.).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][NH:6][C@H:5]([C:8]([OH:10])=O)[C@@H:4]([C:11]([O:13][CH3:14])=[O:12])[CH2:3]1.[C:15]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O.C(N(CC)C(C)C)(C)C.C(Cl)Cl.Cl[C:72]([O:74][CH3:75])=[O:73]>>[OH:1][C@H:2]1[CH2:7][N:6]([C:72]([O:74][CH3:75])=[O:73])[C@H:5]([C:8]([N:24]2[CH2:25][CH2:26][N:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:22][CH2:23]2)=[O:10])[C@@H:4]([C:11]([O:13][CH3:14])=[O:12])[CH2:3]1
Reactant: COC(=O)[C@H]1C[C@@H](O)CN[C@@H]1C(=O)O
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COC(=O)Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H]1C[C@@H](O)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a mixture of (2S,3S,5R)-5-hydroxy-3-(methoxycarbonyl)piperidine-2-carboxylic acid (3.140 g, 0.01545 mol), 1-phenyl-piperazine (2.597 mL, 0.01700 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (7.518 g, 0.01700 mol) in N,N-dimethylformamide (10.00 mL, 0.1291 mol) was added N,N-diisopropylethylamine (3.230 mL, 0.01854 mol) at 0 Celsius. After stirred at rt overnight. the reaction mixture was diluted with methylene chloride (90.0 mL, 1.40 mol) and then cooled to 0 Celsius. To the mixture was added N,N-diisopropylethylamine (5.38 mL, 0.0309 mol) followed by methyl chloroformate (2.39 mL, 0.0309 mol). The mixture was stirred at rt for 2 h and then concentrated to dry. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated to dry. The residue was purified on silica gel, eluting with 0 to 100% EtOAc in hexane, to give The titled compound (5.20 g, 83.0%). MS (ESI): (M+H)+=406.1.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:9]#[N:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Br-:23].[C:9]([C:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:7][N+:1]([CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([CH2:6][CH2:5]1)[CH2:2][CH2:3]2)#[N:10]
Reactant: BrCCCc1ccccc1
Reactant: N#CC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Product: N#CC(c1ccccc1)(c1ccccc1)C12CC[N+](CCCc3ccccc3)(CC1)C2
Product: [Br-]
Yield: 44.3 %

Procedure:
Following the general procedure outlined in Example 24, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)acetonitrile (0.044 g, 0.152 mmol) and (3-bromopropyl)benzene (0.035 mL, 0.230 mmol) in 2CH3CN/3CHCl3 (3.5 mL) were reacted to give the desired product (0.0328 g, 44.3%). EI-MS m/z 407 (M+) Rt (1.82 min).
Reaction SMILES: C1(CC(Cl)=O)C=CC=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][CH2:33][CH3:34])=[CH:28][CH:27]=1.[C:35]1([CH2:41][C:42]([N:44]=[C:45]=[S:46])=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.C(O)C>[C:35]1([CH2:41][C:42]([N:44]=[C:45]=[S:46])=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]([CH2:33][CH3:34])[C:45]([NH:44][C:42](=[O:43])[CH2:41][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[S:46])=[CH:28][CH:27]=1
Reactant: CCNc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Agent: O=C(Cc1ccccc1)N=C=S
Agent: O=C(Cl)Cc1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCN(C(=S)NC(=O)Cc1ccccc1)c1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
2-Phenylethanoyl isothiocyanate was prepared using commercially available 2-phenylethanoyl chloride (80 mg) as a starting compound according to the description of the literature. N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-N-ethylamine (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-phenylethanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (38 mg, yield 48%).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH2:6]([O:8][C:9]([C:11](=[CH:16][C:17]1[CH:21]=[CH:20][O:19][CH:18]=1)[CH2:12][C:13](O)=O)=[O:10])[CH3:7]>C(OC(=O)C)(=O)C.ClCCl>[C:1]([O:4][C:13]1[C:18]2[O:19][CH:20]=[CH:21][C:17]=2[CH:16]=[C:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccoc1)CC(=O)O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc(OC(C)=O)c2occc2c1
Yield: 60.4 %

Procedure:
Sodium acetate (10 g, 120 mmol) was added under vigorous stirring to a solution of 3-(ethoxycarbonyl)-4-(furan-3-yl)but-3-enoic acid (12.3 g, 48 mmol) in 100 mL of acetic anhydride. The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 70° C. until the solvent distillation ceased. The obtained crude product was suspended in 250 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 100 mL of dichloromethane. The combined solutions were washed by 200 mL of a saturated aqueous solution of NaHCO3 and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (150×100 mm) with hexane/ethyl acetate mixture (3:1) to give the desired product 5.2 g (29 mmol, 61%) as a yellow solid.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]([F:26])([F:25])[C:8]1[CH:24]=[CH:23][CH:22]=[CH:21][C:9]=1[CH2:10][CH:11]1[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][NH:12]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:26][C:7]([F:25])([F:6])[C:8]1[CH:24]=[CH:23][CH:22]=[CH:21][C:9]=1[CH2:10][CH:11]1[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][N:12]1[C:2]([O:4][CH3:5])=[O:3]
Reactant: COC(=O)C1CCNC(Cc2ccccc2C(F)(F)F)C1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 108.5 %

Procedure:
Methyl chloroformate (1.399 mL, 18.07 mmol) in DCM (40 mL) was added to a solution of methyl 2-(2-(trifluoromethyl)benzyl)piperidine-4-carboxylate (4.19 g, 13.9 mmol) and DIPEA (7.28 mL, 41.69 mmol) in DCM (60 mL). The reaction mixture was stirred for 1.5 h at room temperature, then washed with satd NaHCO3. The phases were separated and the organic phase dried using a phase separator to give crude dimethyl 2-(2-(trifluoromethyl)-benzyl)piperidine-1,4-dicarboxylate (5.42 g, 109%). MS m/z 360 (M+H)+
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([NH:12][C:13]([CH3:45])([CH3:44])[C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH2:41][NH2:42])=[CH:31][CH:30]=2)[C:18]1=[O:43])=[O:15])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:53][N:54]=[C:55]=[O:56]>C(Cl)Cl>[CH2:2]([O:9][C:10]([NH:12][C:13]([CH3:45])([CH3:44])[C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH2:41][NH:42][C:55]([NH:54][CH3:53])=[O:56])=[CH:33][CH:34]=2)[C:18]1=[O:43])=[O:15])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Reactant: CN=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)C(C)(C)NC(=O)OCc3ccccc3)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 87.1 %

Procedure:
To a solution of 8.57 g (13.7 mmol) of 2-benzyloxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(aminomethyl)[1,1'-biphenyl]-4-yl]methyl]-1H-benzazepin-3(R)-yl]-propanamide, hydrochloride (Step I) in 75 mL of dry methylene chloride under nitrogen atmosphere was added 2.28 mL (16.4 mmol) of triethylamine followed by 0.89 mL (15 mmol) of methyl isocyanate. After stirring at room temperature for 45 minutes the solvent was removed under vacuum. The resulting material was dissolved in methylene chloride and purified by flash column chromatography on silica gel eluting with ethyl acetate/methanol (96:4) to afford 7.73 g (87%) of product as a white foam. 1H NMR (200 MHz, CD3OD): δ 1.39 (s, 6H), 1.82 (m, 1H), 2.15-2.60 (m, 3H), 2.63 (s, 3H), 4.13 (s, 2H), 4.36 (m, 1H), 4.86 (d, 15 Hz, 1H), 4.85 (s, 2H), 5.32 (d, 15 Hz, 1H), 7.08-7.43 (m, 17H). FAB-MS: calculated for C38H41N5O5 647; found 648(M+H, 80%).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O>>[CH:1]1([NH:4][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[C:7]([O:6][CH3:5])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1cccc(C=O)c1
Reactant: NC1CC1
Product: COc1cccc(CNC2CC2)c1

Procedure:
prepared by reaction of cyclopropylamine with 3-methoxy-benzaldehyde
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:24][O:25][C:26]([C:28]1[CH:33]=[N:32][C:31](Cl)=[CH:30][N:29]=1)=[O:27]>>[CH3:24][O:25][C:26]([C:28]1[CH:33]=[N:32][C:31]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:23])[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=3)([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:4]=2)=[CH:30][N:29]=1)=[O:27]
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1cnc(Cl)cn1
Product: COC(=O)c1cnc(Oc2ccc(Cl)c(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c2)cn1

Procedure:
The title compound was prepared in analogy to Example 132 from 4-chloro-3-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (obtained in Example 130, step 7) with methyl-5-chloropyrazine-2-carboxylate [CAS Reg. No. 33332-25-1]. MS (m/e)=502.1 [MH+].
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:34]([NH:36][CH2:37][CH3:38])[CH3:35]>CN(C)C=O.O>[CH2:34]([N:36]([CH2:37][CH3:38])[C:7]([C:6]1[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:11][CH:10]=1)=[O:9])[CH3:35]
Reactant: CCNCC
Reactant: O=C(O)c1ccc(CO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
4-Hydroxymethylbenzoic acid (10.0 g) was dissolved in N,N-dimethylformamide (200 ml), added with 1-hydroxybenzotriazole (9.766 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl, 13.855 g) and stirred at room temperature for 1 hour. The reaction mixture was added with diethylamine (13.6 ml) and further stirred at room temperature for 1 hour. The reaction mixture was added with water (200 ml) and extracted twice with dichloromethane (200 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=1:2) to obtain 12.80 g of the title compound. Yield: 94%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:16]=[N:15][C:9]2[O:10][CH2:11][C:12](=[O:14])[NH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[CH3:17]C([O-])(C)C.[K+].CI.O>CN(C)C(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:16]=[N:15][C:9]2[O:10][CH2:11][C:12](=[O:14])[N:13]([CH3:17])[C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CI
Product: CCOC(=O)c1cnc2c(c1)N(C)C(=O)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a solution of 2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylic acid ethyl ester (1.518 g) in N,N-dimethylacetamide (15 ml) were added KOtBu (0.843 g) and methyl iodide (1.067 g). The mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, CH2Cl2/MeOH 1:0=>9:1) to give the title compound (0.936 g) as a brown solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:37])([F:36])[O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[N:21]=[C:20]([N:22]3[C:26]([C:27]([F:30])([F:29])[F:28])=[C:25]([C:31]([O:33]CC)=[O:32])[CH:24]=[N:23]3)[CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[F:38][C:39]([F:50])([F:49])[C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.[C:51]([O-:54])([O-])=[O:52].[Na+].[Na+]>CC#N>[C:51]([OH:54])([C:27]([F:30])([F:29])[F:28])=[O:52].[F:37][C:8]([F:36])([C:5]1[CH:6]=[CH:7][C:2]([C:43]2[CH:44]=[CH:45][C:40]([C:39]([F:50])([F:49])[F:38])=[CH:41][CH:42]=2)=[CH:3][CH:4]=1)[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:21]=[C:20]([N:22]2[C:26]([C:27]([F:29])([F:30])[F:28])=[C:25]([C:31]([OH:33])=[O:32])[CH:24]=[N:23]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OC(F)(F)c3ccc(Br)cc3)n2)c1C(F)(F)F
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(O)C(F)(F)F
Product: O=C(O)c1cnn(-c2cccc(-c3ccccc3OC(F)(F)c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)n2)c1C(F)(F)F
Temperature: 90 °C
Reaction time: 0.58 h

Procedure:
A mixture of the title compound from Example 300 Step A (50.0 mg, 0.086 mmol), 4-trifluoromethylphenylboronic acid (35 mg, 0.18 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (9.0 mg, 0.013 mmol), Na2CO3 (0.1 mL, 2.0 M aqueous, 0.2 mmol), and MeCN (1 mL) was stirred at 90° C. for 35 min. The crude mixture was dried concentrated in vacuo. Treatment with a mixture of 0.1 mL each of 3 N NaOH, dioxane and MeOH at 50° C. for 10 min, followed by reverse phase HPLC using a YMC C-18 column (65 to 100% acetonitrile in water, each with 0.1% v/v TFA) provided the title compound: LCMS m/z 599.9 [M−F]+; 1H NMR (500 MHz, acetone-d6) δ 8.34 (m, 2H), 8.03 (d, J=7.6 Hz, 1H), 7.99 (d, J=8.2 Hz, 1H), 7.95-7.78 (m, 7H), 7.69 (d, J=8.5 Hz, 2H), 7.62 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([C:24](=[O:28])[C:25]([OH:27])=O)[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[N:11]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:10]=1.[CH3:37][NH:38][CH3:39].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([C:24](=[O:28])[C:25]([N:38]([CH3:39])[CH3:37])=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[N:11]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:35])[CH3:36])[N:10]=1
Reactant: CNC
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(=O)C(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(=O)C(=O)N(C)C)c3)cc12
Temperature: 60 °C

Procedure:
To a solution of {3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-oxo-acetic acid. (100 mg, 0.20 mmol), dimethylamine (2 N in THF, 0.143 mL, 0.29 mmol), and diisopropylethylamine (37 mg, 0.29 mmol) in THF (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (110 mg, 0.29 mmol.). The resulting suspension was heated to 60° C. with stirring until all was dissolved. The solvent was evaporated and the residue was used in next step without purification. MS: m/z 531 (M+H+).
Reaction SMILES: [C:1]1([CH:7]2[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH:11]([CH3:24])[CH2:12][O:13][C:14]1[CH:15]=[C:16]([OH:23])[C:17](=[CH:21][CH:22]=1)[C:18]([NH2:20])=[O:19]>CC(O)C>[C:18]([C:17]1[CH:21]=[CH:22][C:14]([O:13][CH2:12][CH:11]([NH:10][CH2:8][CH:7]([OH:9])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH3:24])=[CH:15][C:16]=1[OH:23])(=[O:19])[NH2:20]
Reactant: c1ccc(C2CO2)cc1
Reactant: CC(N)COc1ccc(C(N)=O)c(O)c1
Solvent: CC(C)O
Product: CC(COc1ccc(C(N)=O)c(O)c1)NCC(O)c1ccccc1

Procedure:
A mixture of 0,96 g of phenyl-ethylene oxide and 2.1 g of 4-(2-amino-propoxy)-salicylamide in 25 ml of 2-propanol is refluxed for 15 hours. The reaction mixture is then evaporated, the residue is partitioned between 10 ml of water and 100 ml of ethyl acetate and the organic phase is washed three times with water. On drying over magnesium sulfate and evaporating the organic phase, crude α-[N-[2-(4-carbamoyl-3-hydroxy-phenoxy)-1-methyl-ethyl]-aminomethyl]-benzyl alcohol is obtained and this is recrystallised analogously to Example 2 and in this way gives the two enantiomer pairs with a melting point of 171°-173° and 149°-151° respectively.
Reaction SMILES: CCN(CC)CC.[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([C:18](=[O:22])[C:19](Cl)=[O:20])=[CH:12][NH:13]2.OC(C(F)(F)F)=O.[C:30]1([C:36]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[NH:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([C:18](=[O:22])[C:19]([N:41]1[CH2:42][CH2:43][N:38]([C:36](=[NH:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:39][CH2:40]1)=[O:20])=[CH:12][NH:13]2
Reactant: O=C(Cl)C(=O)c1c[nH]c2cccc(F)c12
Reactant: N=C(c1ccccc1)N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N=C(c1ccccc1)N1CCN(C(=O)C(=O)c2c[nH]c3cccc(F)c23)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Et3N (2 ml) was added into a solution of 2-(4-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride (1.56 g) and phenyl(piperazin-1-yl)methanimine TFA salt (1.98 g) in THF (20 ml) and reaction was stirred at room temperature for 17 hours before quenched with saturated aqueous NaHCO3 solution (50 ml). The aqueous layer was extracted with ethyl acetate (3×50 ml). The organic phase combined and dried over anhydrous MgSO4. Concentration in vacuo provided a crude product, which was purified by silica gel column chromatography to afford 1-(4-fluoro-1H-indol-3-yl)-2-(4-(imino(phenyl)methyl)piperazin-1-yl)ethane-1,2-dione.
Reaction SMILES: N1([NH:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])CCNCC1.[OH:18][C:19]([CH3:24])([CH3:23])[C:20](O)=[O:21].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH2:48]([N:50](CC)[CH2:51][CH3:52])[CH3:49]>O1CCCC1>[OH:18][C:19]([CH3:24])([CH3:23])[C:20]([N:50]1[CH2:51][CH2:52][N:7]([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[CH2:49][CH2:48]1)=[O:21]
Reactant: CCN(CC)CC
Reactant: O=C(NN1CCNCC1)OCc1ccccc1
Reactant: CC(C)(O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 92.1 %

Procedure:
Benzyl piperazine-1-carbamate (2.203 g, 10.0 mmol) was dissolved in tetrahydrofuran (50 ml); 2-hydroxy-2-methylpropionic acid (1.25 g, 12.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.30 g, 12.0 mmol), 1-hydroxy-1H-benzotriazole monohydrate (1.84 g, 12.0 mmol) and triethylamine (3.35 ml, 24.0 mmol) were added; and the reaction mixture was stirred at room temperature for 7 hours. The reaction mixture was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and dried under reduced pressure to yield the title compound (2.823 g, 9.21 mmol, 92.1%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=1>>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][C:26]4[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: Cn1ccnc1CCl
Agent: Cl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1nccn1C
Yield: 95.2 %

Procedure:
Using an analogous procedure to that described in Example 25, 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (224 mg, 0.7 mmol), (prepared as described for the starting material in Example 24), and 2-chloromethyl-1-methylimidazole hydrochloride (140 mg, 0.8 mmol) were combined to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((1-methylimidazol-2-yl)methoxy)quinazoline hydrochloride (150 mg, 44%). 1H NMR Spectrum: (DMSOd6) 3.94(s, 3H); 4.02(s, 3H); 5.69(s, 2H); 7.44(dd, 1H); 7.6(t, 1H); 7.64(s, 1H); 7.67(dd, 1H); 7.72(d, 1H); 7.81(d, 1H); 8.46(s, 1H); 8.81(s, 1H) MS-ESI: 414 [MH]+