Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C@H:12]([CH3:15])[CH2:13]O)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:42]I>CCCCCCC.CCOC(C)=O>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C@H:12]([CH3:15])[CH2:13][I:42])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: C[C@H](CO)CN1C(=O)COc2cc(F)ccc21
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: C[C@H](CI)CN1C(=O)COc2cc(F)ccc21
Yield: 86.2 %

Procedure:
The compound (S)-7-Fluoro-4-(3-hydroxy-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (111MF18) (2.57 g, 11.0 mmol), triphenylphosphine (6.61 g, 23.7 mmol), imidazole (1.76 g, 25.8 mmol) and I2 (7.64 g, 30.1 mmol) were mixed according to GP9. CC (SiO2; Heptane/EtOAc 9:1-4) gave the title compound (111MF20) (3.31 g, 89%). 1H NMR (CDCl3) δ 7.00-6.96 (m, 1H), 6.78-6.74 (m, 2H), 4.65-4.56 (m, 2H), 3.92 (d, J=7.6 Hz, 2H), 3.21-3.13 (m, 2H), 2.13-2.03 (m, 1H), 1.04 (d, J=6.4 Hz, 3H); 13C NMR (CDCl3) δ 164.3, 159.0 (d, J=244.4 Hz), 146.6 (d, J=12.0 Hz), 125.0 (d, J=3.0 Hz), 115.9 (d, J=9.7 Hz), 109.4 (d, J=22.5 Hz), 105.5 (d, J=26.0 Hz), 67.8, 46.3, 33.6, 18.9, 11.8.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[O:16][CH2:17][CH3:18].[Li+].[OH-]>C1COCC1.CO>[CH2:17]([O:16][C:7]1[CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=[CH:11][C:6]=1[CH:5]=[CH:4][C:3]([OH:19])=[O:2])[CH3:18]
Reactant: CCOc1cc(C(F)(F)F)ccc1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc(C(F)(F)F)ccc1C=CC(=O)O
Yield: 97.2 %

Procedure:
3-(2-Ethoxy-4-trifluoromethyl-phenyl)-acrylic acid methyl ester (477 mg, 1.74 mmol) was reacted with 1N LiOH (7.5 ml) in THF and CH3OH for 1.5 hrs as described above to yield title compound (440 mg, 97%)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][NH:22]4)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].C1COCC1.C(C(O)=O)(F)(F)F>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][NH:22]4)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1OCC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(-c2nc(-c3cccc4c3CCN4)no2)cc1OCC
Yield: 43 %

Procedure:
To a solution of the product of Step B (0.06 g; 0.172 mmol) in 1M BH3 in THF (0.35 ml; 0.35 mmol) CF3CO2H (0.4 ml) was added drop wise at 0° C. with stirring. After the addition was completed (˜5 min) the reaction was quenched with H2O (0.5 ml) and solvents were removed under reduced pressure. The residue was diluted to 10 ml with EtOAc and was washed with 10% NaOH (2×2 ml), brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.026 g; 43%) as a creamy foam, which was used in the next step without further purification. 1H-NMR (CDCl3) 1.49 (m, 6H); 1.7 (broad s, 1H+H2O); 3.45 (tr, 2H, J=8.9 Hz); 3.65 (tr, 2H, J=8.9 Hz); 4.19 (m, 4H); 6.75 (d, 1H, J=7.7 Hz); 6.97 (d, 1H, J=8.5 Hz); 7.17 (tr, 1H, J=7.7); 7.52 (d, 1H, J=7.2 Hz); 7.68 (d, 1H, J=1.9 Hz); 7.78 (dd, 1H, J=1.9, 7.2 Hz).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].N1CCCC1.[N:13]1([C:19]2[C:20]3[N:28]=[C:27]([CH:29]=O)[CH:26]=[CH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CO>[N:13]1([C:19]2[C:20]3[N:28]=[C:27](/[CH:29]=[C:5]4/[C:4](=[O:6])[NH:3][C:2](=[O:7])[S:1]/4)[CH:26]=[CH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=Cc1ccc2ncnc(N3CCCCC3)c2n1
Reactant: O=C1CSC(=O)N1
Solvent: CO
Solvent: C1CCNC1
Product: O=C1NC(=O)/C(=C/c2ccc3ncnc(N4CCCCC4)c3n2)S1
Temperature: 70 °C
Yield: 48.8 %

Procedure:
A mixture of 2,4-thiazolidinedione (3.4 g; 29.1 mmol; 1.80 eq.), pyrrolidine (269.80 μL; 3.2 mmol; 0.2 eq.) in MeOH (50 mL) was heated at 70° C. A solution of 4-(1-piperidinyl)pyrido[3,2-d]pyrimidine-6-carbaldehyde (Intermediate 1.7) (3.9 g; 16.2 mmol; 1 eq.) in MeOH (50 mL) was slowly added over 1.5 hour at 70° C. After 2 h under reflux after the addition, the reaction was complete. A precipitate was formed. The hot reaction mixture was filtered and the solid was washed with cold MeOH to give (5Z)-5-{[4-(1-piperidinyl)pyrido[3,2-d]pyrimidin-6-yl]methylene}-1,3-thiazolidine-2,4-dione (1) (2.70 g; 48%) as an orange powder in 98% HPLC purity.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([N:13]([CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH2:14][CH2:15][CH3:16])[CH2:8]2.B(Br)(Br)Br>>[N:19]1([CH2:18][CH2:17][N:13]([CH2:14][CH2:15][CH3:16])[CH:7]2[CH2:6][CH2:5][C:4]3[C:3]([OH:2])=[CH:12][CH:11]=[CH:10][C:9]=3[CH2:8]2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: CCCN(CCN1CCNCC1)C1CCc2c(cccc2OC)C1
Agent: BrB(Br)Br
Product: CCCN(CCN1CCNCC1)C1CCc2c(O)cccc2C1
Yield: 77.5 %

Procedure:
This compound was prepared from 38b (4.2 g, 12.6 mmol), and boron tribromide (39 ml) following Procedure F to give 39b (3.1 g, 78%). 1H NMR (400 MHz, CDCl3) 0.99-1.02 (t, 3H, 7.6 Hz), 1.28-1.30 (m, 2H), 1.71-1.83 (m, 3H), 2.26-2.29 (m, 1H), 2.57-2.06 (m, 1H), 2.72-2.77 (m, 4H), 2.97-3.07 (m, 5H), 3.16-3.21 (m, 9H), 6.58-6.59 (d, 1H, J=8 Hz), 6.61-6.28 (m, 1H, J=8 Hz), 6.92-6.95 (t, 1H, J=Hz).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[F:13].[Cl-].[Cl-].[Cl-].[Al+3]>Cl>[Cl:5][C:6]1[C:7]([F:13])=[CH:2][C:1]([OH:3])=[C:10]([C:9](=[O:12])[CH3:8])[CH:11]=1
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1cc(Cl)c(F)cc1O
Temperature: 60 °C
Yield: 100 %

Procedure:
Acetyl chloride (3.6 mL, 51 mmol) was added to 4-chloro-3-fluorophenol (5.1 g, 35 mmol) and the resulting mixture was heated at 60° C. for 2 hours. Aluminum trichloride (7.0 g, 52 mmol) was added and the mixture was heated at 180° C. for 30 minutes. The mixture was cooled to room temperature. The mixture was cooled to 0° C. and 1 N HCl solution (100 mL) was added dropwise over 30 minutes. The precipitate was washed well with water and dried under vacuum to give the desired compound (6.6 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]\[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([N+:23]([O-])=O)[CH:16]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C([O-])=O.[NH4+].N>C(#N)C.[Pt]>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15](/[CH:14]=[CH:13]\[C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:16][C:17]=1[NH2:23]
Reactant: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Agent: [Pt]
Agent: N
Agent: O=C[O-]
Solvent: CC#N
Product: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1N

Procedure:
A solution was prepared by dissolving (Z)-3,4,4′,5-tetramethoxy-3′-nitrostilbene (raw material 5) (8.63 g, 25.0 mmol) in acetonitrile (100 ml) succeeded by addition of ammonium formate (5.21 g, 82.6 mmol, 330 mole % to the above nitrostilbene derivative (raw material 5)), 5% platinum on carbon (water-content: 60.91%, 4.99 g, 0.50 mmol as platinum) and aqueous ammonia (28%, 1.69 ml, 25 mmol) to be reacted at 30° C. for 23 hours in an argon atmosphere. At the conclusion of the reaction, the catalyst and the insoluble matter were separated by filtration and the filtrate was subjected to quantitative analysis by HPLC. Formation of the objective substance, (Z)-2-methoxy-5-[2-(3,4,5-trimethoxyphenyl)vinyl]aniline (objective substance 6; represented by the above formula (6)) (6.52 g, 20.7 mmol, 83%), was confirmed, as was formation of a by-product (E)-2-methoxy-5-[2-(3,4,5-trimethoxyphenyl)vinyl]aniline (by-product 7; represented by the above formula (7)) (0.55 g, 1.73 mmol, 6.9%) and a by-product 2-methoxy-5-[2-(3,4,5-trimethoxyphenyl)ethyl]aniline (by-product 8; represented by the above formula (8)) (0.52 g, 1.63 mmol, 6.5%). Formation was not observed for the by-product 2-(4-methoxy-3-nitrophenyl)-1-(3,4,5-trimethoxyphenyl)ethane (by-product 9; represented by the above formula (9)).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[C:10](=[N:16]/[O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.[Pt](=O)=O>[NH2:1][C:4]1[CH:5]=[C:6](/[C:10](=[N:16]/[O:17][CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)/C(=N\OCC(=O)OC(C)(C)C)c1cccc([N+](=O)[O-])c1
Agent: O=[Pt]=O
Solvent: CCO
Product: CCOC(=O)/C(=N\OCC(=O)OC(C)(C)C)c1cccc(N)c1
Temperature: 20 °C
Reaction time: 0.67 h
Yield: 96.3 %

Procedure:
Ethyl (Z)-3-amino-alpha-tert-butoxycarbonylmethoxyiminophenylacetate can be obtained in the following manner: 0.15 g of platinum dioxide is added to a solution of 2.61 g of ethyl (Z)-3-nitro-alpha-tert-butoxycarbonylmethoxyiminophenylacetate in 70 cm3 of ethanol. The suspension is stirred for 40 minutes at a temperature near to 20° C. under a hydrogen atmosphere (128 kPa). The catalyst is separated by filtration and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give 2.3 g of ethyl (Z)-3-amino-alpha-tert-butoxycarbonylmethoxyiminophenylacetate in the form of an oil which is used as such in the subsequent syntheses.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:37][C:38]1[CH:42]=[CH:41][O:40][N:39]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:14]4=[N:15][CH:16]=3)=[N:7][N:8]2[CH2:37][C:38]2[CH:42]=[CH:41][O:40][N:39]=2)=[CH:4][CH:3]=1
Reactant: BrCc1ccon1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(Cc4ccon4)c4cc(Cl)ccc34)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
2-(6-Chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (80 mg, 165 μmol) was dissolved in DMF (1 mL) and cooled to 0° C. Sodium hydride (10.6 mg, 264 μmol) was added and the mixture was stirred for 30 min at 0° C. 3-(Bromomethyl)isoxazole (29.4 mg, 181 μmol) was added and the mixture warmed to room temperature. After 15 h, the mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 20-50% ethyl acetate in hexanes, 15 min gradient) gave 2-(6-chloro-1-(isoxazol-3-ylmethyl)-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (91 mg, 161 μmol, 97.5%) as a yellow powder. MS (M+Na)+=588 (88% purity); 1H NMR (CDCl3) δ: 9.27 (s, 1H), 8.47 (d, J=8.7 Hz, 1H), 8.34-8.43 (m, 2H), 8.16 (d, J=8.3 Hz, 1H), 8.03 (s, 1H), 7.57 (s, 1H), 6.33 (d, J=1.5 Hz, 1H), 5.77 (s, 2H), 5.73 (s, 2H), 4.38-4.56 (m, 1H), 3.53-3.65 (m, 2H), 1.35-1.46 (m, 6H), 0.89-1.01 (m, 2H), −0.07-0.02 (m, 9H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1([C:14](=[O:25])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1([C:14](=[O:25])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:23])[CH3:24])=[CH:18][CH:17]=2)[CH2:9][CH2:10][N:11]([C:35](=[O:36])[NH:34][C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=2)[CH2:12][CH2:13]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)c1ccc(NC(=O)C2(NC(=O)OC(C)(C)C)CCNCC2)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(NC(=O)C2(NC(=O)OC(C)(C)C)CCN(C(=O)Nc3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
A mixture of 36 mg (0.1 mmol) [4-(4-Isopropyl-phenylcarbamoyl)-piperidin-4-yl]-carbamic acid tert-butyl ester, 16.5 mg (0.12 mmol) 4-fluorophenyl isocyanate and 32 mg (0.31 mmol) NEt3 in 1 mL DCM was shaken at room temperature over night. After evaporation to dryness the residue was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and HCOOH. The product containing fractions were evaporated to yield 38.5 mg (77%) of the title compound. MS (m/e): 499.3 [(M+H)+].
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:9][C:10]#[N:11]>>[O:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:9][C:10]#[N:11]
Reactant: O=C1CCCCC1
Reactant: N#CCBr
Product: N#CCC1CCCCC1=O

Procedure:
Cyclohexanone is reacted with bromoacetonitrile by the method of Example 65 to generate the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=[O:12])[CH2:4][CH2:3]1.[Br:16]N1C(=O)CCC1=O>C(Cl)Cl>[Br:16][C:13]1[CH:14]=[CH:15][C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:9][C:10]=1[CH:11]=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1CCN(c2cccc(C=O)c2)CC1
Solvent: ClCCl
Product: CN1CCN(c2ccc(Br)c(C=O)c2)CC1
Reaction time: 0.17 h
Yield: 95 %

Procedure:
A solution of 3-(4-Methyl-piperazin-1-yl)-benzaldehyde (49 mmol) in methylene chloride (150 ml) was slowly (30 min) added a solution of N-bromosuccinimide (98 mmol) in methylene chloride (450 ml). The mixture was stirred for 10 min, washed with 2M sodium hydroxide and the organic phase was removed under reduced pressure. The resulting oil was purified by column chromatography giving the title compound as 90% pure black oil in 95% yield (the impurity being 4-bromo-3-(4-methyl-piperazin-1-yl)-benzaldehyde).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:12](=O)([O:18]C(C)(C)C)[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]>O1CCOCC1.O.C(OCC)C>[C:14]([O:13][C:12]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: Nc1ccc(CO)cc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-aminobenzyl alcohol (2.00 g, 16.2 mmol) in 10 mL of dioxane was added a solution of sodium hydroxide (0.65 g, 16 mmol) in 40 mL of water at room temperature. After addition of di-tert-butyl carbonate (4.95 g, 22.7 mmol), the reaction mixture was stirred at room temperature overnight. The mixture was diluted with diethyl ether, and the solution was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo to obtain crude 4-(tert-butoxycarbonylamino)benzyl alcohol.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3C(=O)C4=CC=CC=C4C3=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[NH2:17][CH2:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Yield: 47.2 %

Procedure:
A mixture of 2.8 g of 4-diphenylmethyl-1-(3-phthalimidopropyl)piperidine (prepared as described in Preparation 44') and 0.90 g of hydrazine hydrate in 100 ml of ethanol was heated under reflux for 2 hours. At the end of this time, the mixture was cooled to room temperature and filtered. The mixture was concentrated by evaporation under reduced pressure, to give 0.93 g (yield 47%) of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2=[O:12].[F:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:29])[C:26](O)=[O:27])[CH2:21][CH2:20]2)=[CH:16][CH:15]=1>C(OCC)C>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:26](=[O:27])[C:25]([N:22]3[CH2:21][CH2:20][CH:19]([CH2:18][C:17]4[CH:16]=[CH:15][C:14]([F:13])=[CH:31][CH:30]=4)[CH2:24][CH2:23]3)=[O:29])=[CH:10][CH:9]=2)[C:5](=[O:12])[NH:6]1
Reactant: Nc1ccc2c(c1)C(=O)NC2=O
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CCOCC
Product: O=C(Nc1ccc2c(c1)C(=O)NC2=O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from 5-amino-isoindole-1,3-dione [Tetrahedron 54, 7485. (1998)] and [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic-acid (Example 1b) according to the method described in Example 1c. Melting Point: 226-228° C. (diethylether)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([CH3:12])=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Br[C:23]1[S:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:9]([C:8]1[C:3]([O:2][CH3:1])=[C:4]([C:23]2[S:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][CH:24]=2)[CH:5]=[C:6]([CH3:12])[CH:7]=1)([O-:11])=[O:10]
Reactant: O=C(O)c1ccc(Br)s1
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cc(C)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(-c2ccc(C(=O)O)s2)cc(C)cc1[N+](=O)[O-]
Yield: 73.2 %

Procedure:
2-(2-Methoxy-5-methyl-3-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 24a (4.0 g, 14.5 mmol), 5-bromothiophene-2-carboxylic acid (1.0 g, 4.8 mmol), tetrakis(triphenylphosphine)palladium (0.276 g, 0.24 mmol) and sodium carbonate (1.01 g, 9.6 mmol) were dissolved in 30 mL of 1,4-dioxane and 10 mL of water. The reaction mixture was heated to reflux for 1 hour. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure and the residue was dissolved in water. The mixture was filtered to remove tetrakis(triphenylphosphine)palladium and the filtrate was extracted with ethyl acetate. The aqueous layer was acidified to form precipitates. The precipitates were dissolved in ethyl acetate, dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain the title compound 5-(3-nitro-2-methoxy-5-methyl-phenyl)thiophene-2-carboxylic acid 24b (1.03 g, 73.6%) as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](Cl)[N:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[CH3:25][NH:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>C(#N)C>[CH:27]1([N:26]([CH3:25])[C:19]2[N:18]=[C:17]([N:14]3[CH2:15][CH2:16][CH:11]([C:8]4[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:2])=[O:24])=[CH:10][CH:9]=4)[CH2:12][CH2:13]3)[CH:22]=[CH:21][N:20]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CNC1CCCC1
Reactant: COC(=O)Cc1ccc(C2CCN(c3ccnc(Cl)n3)CC2)cc1
Solvent: CC#N
Product: CN(c1nccc(N2CCC(c3ccc(CC(=O)O)cc3)CC2)n1)C1CCCC1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
To 2.70 g (7.81 mmol) {4-[1-(2-chloro-pyrimidin-4-yl)-piperidin-4-yl]-phenyl}-acetic acid methyl ester (XII.2) in 20 mL ACN are added 2.64 mL (23.4 mmol) N-methyl-cyclopentylamine. The mixture is stirred for 2 h at 150° C. under microwave irradiation. After that time, the solvent is evaporated, the residue taken up in 60 mL ethanol and 30 mL 1N NaOH are added. The mixture is stirred for 1 h at rt and for 1 h at 40° C. Subsequently, 30 mL 1N HCl are added, the mixture is concentrated in vacuo and extracted with DCM. The organic layer is dried over sodium sulphate and the solvent is evaporated. The residue is purified by column chromatography (silica gel; DCM:EtOH 80:20) to yield the desired product.
Reaction SMILES: Cl.Cl[CH:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[F:25])[CH3:4].[NH2:26][C@H:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32].N[C@@H](CCN)C(O)=O>>[Cl:24][C:20]1[C:19]([F:25])=[C:18]([NH:17][C:8]2[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([CH:3]([NH:26][C@H:27]4[CH2:31][CH2:30][NH:29][C:28]4=[O:32])[CH3:4])[CH:6]=3)[N:11]=[CH:10][N:9]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C(C)Cl
Reactant: N[C@H]1CCNC1=O
Agent: Cl
Agent: NCC[C@H](N)C(=O)O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C(C)N[C@H]1CCNC1=O

Procedure:
6-(1-Chloroethyl)-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine hydrochloride (Described in Example 91) was coupled with (3S)-3-aminopyrrolidin-2-one (prepared from (2S)-2,4-diaminobutanoic acid according to the method in Synthesis 1978, 614) using an analogous method to that described for the equivalent step in Example 62 to give (3S)-3-[(1-{4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}ethyl)amino]pyrrolidin-2-one as a 1:1 mixture of diastereoisomers; 1H NMR Spectrum: (DMSO d6) 1.42 and 1.46 (both d, 1.5H); 1.71 and 1.81 (both m, 0.5H); 2.09 and 2.31 (both m, 0.5H); 3.00 (t, 0.5H); 3.11 (m, 1.5H); 3.23 (t, 1H); 4.03 (s, 3H); 4.27 and 4.52 (both m, 0.5H); 7.25 and 7.27 (both s, 0.5H); 7.34 (m, 1H); 7.53 (m, 1H); 7.61 (m, 1H); 7.74 and 7.77 (both s, 0.5H); 8.49 (m, 2H); 9.79 and 9.88 (both s, 0.5H); Mass Spectrum: (M+H)+ 430.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:7]=1[O:19]C.O.Cl>ClCCl>[F:5][C:6]1[CH:11]=[C:10]([C:12]([F:14])([F:15])[F:13])[C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:7]=1[OH:19]
Reactant: COc1cc([N+](=O)[O-])c(C(F)(F)F)cc1F
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cc(O)c(F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
A 1N solution of boron tribromide in dichloromethane (15 ml) was added dropwise to a solution of 1-fluoro-2-methoxy-4-nitro-5-(trifluoromethyl)benzene obtained in Reference Example 16 (1.4 g) in dichloromethane (5 ml) with ice-cooling. After stirring at room temperature overnight, water and 1N hydrochloric acid was added to the reaction mixture. After stirring for 30 minutes, an organic layer was separated, washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography (developing solvent:ethyl acetate-hexane=1:3) to obtain the title compound as crystals (0.5 g, 38%).
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][N:13]3[C:21]4[C:20](=[O:22])[N:19]([CH3:23])[C:18](=[O:24])[N:17]([CH3:25])[C:16]=4[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>CN(C=O)C.O>[CH3:23][N:19]1[C:20](=[O:22])[C:21]2[N:13]([CH2:12][C:11]3[CH:26]=[CH:27][C:8]([C:6](=[O:7])[C:5]4[CH:28]=[CH:29][C:2]([O:1][CH2:38][CH2:39][N:40]5[CH2:45][CH2:44][O:43][CH2:42][CH2:41]5)=[CH:3][CH:4]=4)=[CH:9][CH:10]=3)[CH:14]=[N:15][C:16]=2[N:17]([CH3:25])[C:18]1=[O:24]
Reactant: ClCCN1CCOCC1
Reactant: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(O)cc3)cc2)n(C)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(OCCN4CCOCC4)cc3)cc2)n(C)c1=O
Yield: 42.4 %

Procedure:
A solution of 7-[4-(4-hydroxybenzoyl)benzyl)-1,3-dimethylxanthine (170 mg), potassium carbonate (200 mg) and 1-chloro-2-morpholinoethane hydrochloride (87 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate: acetone =1:1:1) to provide the title compound (93 mg).