Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH2:32]>>[C:33]1([C:31]2[N:32]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:28][N:30]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NC(=NO)c1ccccc1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ccccc3)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 30 mg (0.22 mmol, 1.1 eq.) of N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 10 mg (10% of theory)
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].FC(F)(F)C(O)=O.[Cl:12][C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]3[N:42]=[C:28]4[CH:29]([C:35]5[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=5)[CH2:30][C:31](=[O:34])[CH2:32][CH2:33][N:27]4[N:26]=3)=[CH:20][C:19]=2[O:43][CH3:44])[CH:17]=1.C(O)(C(F)(F)F)=O>C1COCC1.[Cu]I>[Cl:12][C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]3[N:42]=[C:28]4[CH:29]([C:35]5[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=5)[CH2:30][C:31]([CH2:1][CH3:2])([OH:34])[CH2:32][CH2:33][N:27]4[N:26]=3)=[CH:20][C:19]=2[O:43][CH3:44])[CH:17]=1
Reactant: CC[Mg]Br
Reactant: COc1cc(Nc2nc3n(n2)CCC(=O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Agent: [Cu]I
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCC1(O)CCn2nc(Nc3ccc(-n4cnc(Cl)c4)c(OC)c3)nc2C(c2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 13.4 %

Procedure:
A 25 mL round bottom flask was charged with copper (I) iodide (8.16 mg, 0.043 mmol) in THF (1 mL), and cooled to 0° C. A solution of ethylmagnesium bromide (0.714 mL, 2.142 mmol, 3 M in Et2O) was added dropwise to the stirred solution and stirred for 20 min. To this was added 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (100 mg, 0.214 mmol, from example 137) in THF (1 mL) and the reaction was stirred at 0° C. for an additional 2 h and then slowly warmed to rt and stirred for 16 h. The reaction mixture was quenched slowly with saturated ammonium chloride, and the aqueous layer was extracted with EtOAc (×3). The combined organic layers were then washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (MeOH/water/trifluoroacetic acid) to afford the titled compound (14.2 mg, 10% yield) as a TFA salt. LC-MS (M+H)+ 497.2. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.14 (1 H, br. s.), 7.45-7.97 (2 H, m), 7.05-7.20 (6 H, m), 4.63-4.77 (2 H, m), 4.36-4.49 (1 H, m), 3.88 (3 H, s), 1.88-2.35 (4 H, m), 1.71 (2 H, q, J=7.4 Hz), 1.24-1.51 (1 H, m), 1.03 (3 H, t, J=7.5 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.CI.[C:13](=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:13][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1
Reactant: COC(=O)c1cc(O)no1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(OC)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
2.86 g of methyl 3-hydroxyisoxazole-5-carboxylate was dissolved in 10 ml of N,N-dimethylformamide, and 4.25 g of methyl iodide and 4.15 g of potassium carbonate were then added under ice-cooling. The mixture was stirred at room temperature overnight. The reaction mixture was added to 0.1 M hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.23 g of methyl 3-methoxyisoxazole-5-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([C:30]([OH:33])([CH3:31])[CH3:32])=[C:27]([CH3:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: Cc1nc(Cl)ccc1C(C)(C)O
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1C(C)(C)O

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and 2-(6-chloro-2-methylpyridin-3-yl)propan-2-ol (89 mg, 0.48 mmol) as starting materials.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=4)[CH:15]=3)[CH:10]=[CH:9]2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:33][NH2:34].O>CS(C)=O>[CH3:33][NH:34][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=4)[CH:15]=3)[CH:10]=[CH:9]2)[N:5]=[CH:6][N:7]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cccc(-c2ccc3ccn(-c4cc(Cl)ncn4)c3c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CNc1cc(-n2ccc3ccc(-c4cccc([N+](=O)[O-])c4)cc32)ncn1
Temperature: 100 °C
Reaction time: 15 h
Yield: 98 %

Procedure:
1-(6-Chloropyrimidin-4-yl)-6-(3-nitrophenyl)-1H-indole (200 mg, 0.57 mmol) and potassium carbonate (788 mg, 7.5 mmol) were dissolved in DMSO (5 mL). Methylamine hydrochloride (192 mg, 2.85 mmol) was added at room temperature. The reaction mixture was stirred at 100° C. for 15 hours. After cooling to room temperature, water was added and the reaction mixture was stirred for 1 hour. Thus prepared solid was filtered, washed with water, and dried in the air. N-Methyl-6-(6-(3-nitrophenyl)-1H-indol-1-yl)pyrimidin-4-amine (193 mg) was yielded as white solid.
Reaction SMILES: [CH3:1][C:2]([O-])(C)[CH3:3].[K+].[C:7](=[N:20][CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:22]1=[O:35])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Br)C#C.C1(C)C=CC=CC=1>C1COCC1>[C:7](=[N:20][C:21]1([CH2:3][C:2]#[CH:1])[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[C:22]1=[O:35])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[Si](C)(C)CCOCN1CCCC(N=C(c2ccccc2)c2ccccc2)C1=O
Reactant: CC(C)(C)[O-]
Agent: C#CCBr
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C#CCC1(N=C(c2ccccc2)c2ccccc2)CCCN(COCC[Si](C)(C)C)C1=O
Reaction time: 0.67 h
Yield: 32.8 %

Procedure:
KOtBu 1.7M in THF (4.32 mL, 7.34 mmol) was added dropwise to a solution of 3-(benzhydrylideneamino)-1-(2-trimethylsilylethoxymethyl)piperidin-2-one (which may be prepared as described in Description 22) (2.5 g, 6.12 mmol) and propargyl bromide 80 wt % in toluene (0.95 mL, 8.57 mmol) in THF (100 mL) at 0° C. under N2. The reaction was stirred for 40 mins. The reaction was quenched by the addition of satd. aq. NaHCO3 and then diluted with EtOAc. The phases were separated, the organic layer was dried (Na2SO4) and the solvent was evaporated to afford an oil. The material was purified by SP4, 100 g SNAP, 0 to 50% EtOAc/i-hexane to afford product: 3-(benzhydrylideneamino)-3-prop-2-ynyl-1-(2-trimethylsilylethoxymethyl)-piperidin-2-one (D23) (897 mg, 2.0082 mmol, 32.8% yield) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[OH:28][CH2:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1>>[OH:28][CH2:29][C:30]1[CH:35]=[C:34]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:19])([F:18])[F:20])=[CH:14][CH:15]=2)=[O:8])[CH:33]=[CH:32][CH:31]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cccc(CO)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 57 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and (3-(hydroxymethyl)phenyl)boronic acid to afford a yellow foam. HPLC (Condition 4) tR=4.57 min, UPLC-MS (Condition 3) tR=0.99 min, m/z=474.4 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.62-1.73 (m, 1H) 1.80 (m, J=8.60 Hz, 1H) 2.85 (d, J=11.73 Hz, 1H) 3.12-3.26 (m, 2H) 3.34-3.47 (m, 1H) 4.09-4.19 (m, 1H) 4.55 (d, J=5.47 Hz, 2H) 4.80 (d, J=3.52 Hz, 1H) 5.24 (t, J=5.67 Hz, 1H) 7.22 (d, J=7.43 Hz, 1H) 7.27-7.43 (m, 5H) 7.79-7.90 (m, 2H) 7.94 (d, J=2.35 Hz, 1H) 8.71 (d, J=2.35 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:12]=[CH:11][O:10][CH:9]=1.[OH:13][C:14]([CH3:47])([CH3:46])[CH2:15][C@@:16]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:21][C:20](=[O:22])[N:19]([C@H:23]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH3:24])[CH2:18][CH2:17]1>CN(C)C=O>[O:10]1[CH:11]=[CH:12][C:8]([C:28]2[CH:27]=[CH:26][C:25]([C@@H:23]([N:19]3[CH2:18][CH2:17][C@:16]([CH2:15][C:14]([OH:13])([CH3:46])[CH3:47])([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[O:21][C:20]3=[O:22])[CH3:24])=[CH:30][CH:29]=2)=[CH:9]1
Reactant: Brc1ccoc1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(-c2ccoc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
2 M aqueous Na2CO3 solution (0.70 mL) was added to a solution of 3-bromo-furan (75 μL) and (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.33 g) in dimethylformamide (3 mL). The resulting mixture was sparged with argon for 10 min, before [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) dichloromethane complex (16 mg) was added. The mixture was heated to 90° C. and stirred at this temperature for 2 h. After cooling to ambient temperature, water was added, and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 80:20->0:100) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[OH:14].[OH-].[CH2:17]([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.CI>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:10]([CH3:11])([CH3:12])[CH3:13])[CH:7]=[CH:6][C:5]=1[O:14][CH3:17]
Reactant: COC(=O)c1cc(C(C)(C)C)ccc1O
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(C)(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 6.0 g of 5-(tert-butyl)-2-hydroxybenzoic acid methyl ester in a round bottom flask was added tetrabutyl-ammoniumhydroxide 40% solution (7.45 g, 1 eq). The resulting solution was stirred at room temperature for 2 hr. All water was evaporated under reduced pressure and then in vacuo. To remove trace water, the salt was dried in a vacuum oven overnight and yielded 12.9 g (99%). To a solution of 12.9 g of tetra-butylammonium salt in 50 ml dry THF was slowly added methyliodide (3.61 mL, 2 eq). The resulting solution was stirred at room temperature for 2 hr. After the reaction was completed, the product was filtered out using ammonium iodide salt and washed with ethylacetate twice. The pH was adjusted to pH=2–3 using 1M HCl solution. This organic layer was collected by extraction with ethylacetate and water three times. The organic layer was dried over anhydrous magnesium sulfate (MgSO4). The organic layer was evaporated and the residue was purified by column chromatography (ethylacetate:hexane=1:5) (yield: 3.8 g, 60.0%) 1H NMR (CDCl3, 300 MHz): δ 1.30 (s, 9H), 3.86 (s, 3H), 3.90 (s, 3H), 6.90 (d, J=10.5 Hz, 1H), 7.47 (d, J=9.0 Hz, 1H), 7.82 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].O.[OH-].[Li+].O>CO>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([S:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: COC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(SCCC(=O)O)cc(C(C)(C)C)c1O
Reaction time: 8 h

Procedure:
Methyl 3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propanoate (1.0 g, 3 mmole) was added to a clear solution of lithium hydroxide hydrate (0.64 g, 15 mmole) in methanol (15 ml). Water was added until the solution became cloudy and the mixture was then stirred overnight. The mixture was concentrated to about 10 ml and acidified with cold (5° ) 10% hydrochloric acid. The resultant precipitate was collected by filtration, washed with water, and air dried Recrystallization from cyclohexane gave the title compound, m.p. 108°-110°.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([F:28])[CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[C:21]([F:28])[CH:20]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1ccc(Cl)cc1F
Product: N#Cc1cc(-c2ccc(Cl)cc2F)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, light brown solid (65 mg, 77%), MS (ISP) m/z=340.3 [(M+H)+], mp 278° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-chloro-2-fluoro-phenylboronic acid (56.7 mg, 0.325 mmol).
Reaction SMILES: [C:1]1([C:7](=O)[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3]C=1.C1(C(=O)C(OC2C=CC([Cl:34])=CC=2)=O)C=CC=CC=1>[Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:34][C:5]1[CH:4]=[CH:3][C:7]([C:8]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:9])=[CH:1][CH:6]=1
Reactant: O=C(Oc1ccc(Cl)cc1)C(=O)c1ccccc1
Reactant: O=C(Oc1ccccc1)C(=O)c1ccccc1
Agent: [Cl-]
Agent: c1ccc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: O=C(Oc1ccccc1)c1ccc(Cl)cc1

Procedure:
The decarbonylation reaction of Example 79 was repeated except that phenyl phenylglyoxylate (PPG) was replaced with 4-chlorophenyl phenylglyoxylate (4-CPPG), and that the amounts of tetraphenylphosphonium chloride and chloroform were changed as set forth in Table 13. The results are set forth in Table 13.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([F:32])[CH:38]=3)[C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: OB(O)c1cccc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1cccc(F)c1)N1CCN(C2CCC2)CC1
Yield: 35 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), 3-fluorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless solid (35%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].C([Si](C)(C)[O:20][CH2:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=1[Cl:32])(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S([O-])(O)=O.[Na+]>O.CC(N(C)C)=O>[Cl:32][C:25]1[CH:26]=[C:27]([C:28]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:30]=[CH:31][C:24]=1[O:23][CH2:22][CH2:21][OH:20]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(C=O)cc1Cl
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCCO)c(Cl)c3)nc2c1
Temperature: 150 °C
Reaction time: 17 h
Yield: 14.1 %

Procedure:
A mixture of 3-chloro-4-hydroxy-benzaldehyde (227 mg, 1.45 mmol), (2-bromoethoxy)-tert-butyldimethylsilane (347 mg, 1.45 mmol), cesium carbonate (709 mg, 2.18 mmol) and DMSO (2 mL) was stirred at 80° C. for 17 h. The reaction mixture was cooled to room temperature and water (50 mL) was added. The resulting precipitate was filtered off, washed with water, air-dried, dissolved in a small amount of ethyl acetate and purified by column chromatography. 4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-3-chloro-benzaldehyde was obtained as a white solid (yield: 267 mg, 58%). To a 100 mL round-bottomed flask was added 2-amino-4,6-dimethoxy-benzamide (166 mg, 0.85 mmol), 4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-3-chloro-benzaldehyde (267 mg, 0.85 mmol), p-toluenesulfonic acid monohydrate (21 mg, 0.11 mmol), sodium hydrogensulfite (216 mg, 1.2 mmol) and dimethylacetamide (5 mL). The mixture was stirred in a 150° C. oil bath under nitrogen for 17 h. After cooling to room temperature, water (50 mL) was added. The precipitate was filtered off, washed with water and air-dried. The crude product was purified by column chromatography to give 2-(3-chloro-4-(2-hydroxyethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (45 mg, 23%). Selected data: MS (ES) m/z: 377.03; MP 287-288° C. (decomposed).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[Cl:10][C:11]1[C:16]([C:17]#[N:18])=[C:15](Cl)[N:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:10][C:11]1[C:16]([C:17]#[N:18])=[C:15]([NH:9][C:6]2[CH:7]=[N:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[N:14]=[CH:13][N:12]=1
Reactant: CSc1ccc(N)cn1
Reactant: N#Cc1c(Cl)ncnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ccc(Nc2ncnc(Cl)c2C#N)cn1
Reaction time: 1.5 h

Procedure:
6-Methylsulfanyl-pyridin-3-ylamine (500.0 mg, 3.57 mmol, 1.0 equivalent) in DMF (1 mL) was added drop wise to a suspension of 4,6-dichloro-pyrimidine-5-carbonitrile (616.9 mg, 3.57 mmol, 1.0 equivalent), potassium carbonate (542.1 mg, 3.92 mmol, 1.1 equivalent) at 0° C. under stirring. The reaction was left reacting at room temperature for 1.5 hours. Product was crystallized using ethyl acetate, hexane getting a yellow solid as product (650.00 mg, 65.62%). LCMS (ESI) for C11H8ClN5S: m/z 278.0 (M+H+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH2:10]([Mg]Br)[CH3:11].C1COCC1>Cl>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2([NH2:7])[CH2:11][CH2:10]2)=[CH:8][CH:9]=1
Reactant: N#Cc1ccc(Br)nc1
Reactant: CC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: NC1(c2ccc(Br)nc2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
An oven dried 2 L round-bottom flask equipped with a mechanical stirrer is charged with anhydrous THF (750 mL) followed by Ti(Oi-Pr)4 (72.8 mL, 246 mmol) under Ar atmosphere. The solution is purged under Ar and heated to 50° C. 6-Bromo-nicotinonitrile (30.0 g, 164 mmol) is added to the mixture followed by dropwise addition (over 40 minutes) of 1M solution of ethylmagnesium bromide in THF (410 mL, 410 mmol). The reaction is allowed to stir at 50° C. After 3 hours, the reaction mixture is cooled to room temperature and a 3M aqueous solution of HCl (approx 350 mL) is added. The mixture is transfered to a separatory funnel and is washed with ethyl ether (3×500 mL). The aqueous layer is allowed to stand overnight. The aqueous layer is then basified to pH 10 with 2M aqueous solution of NaOH. The solution is diluted with EtOAc (500 mL) and the resulting solution is vigorously stirred for 5 minutes. The solution is allowed to stand while the layers slowly separated. The organic layer is decanted and the same extraction process is repeated twice. The organic layers are combined, washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo to yield an oil. The crude oil is purified by silica gel chromatography using a gradient of 0-10% MeOH in CH2Cl2 to afford 1-(6-bromo-pyridin-3-yl)-cyclopropylamine as an oil, which slowly crystallizes (ES+ m/z 213.3, 215.3).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([O:11][CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([NH:13][C:2]2[C:3]3[CH2:10][CH2:9][CH:8]([O:11][CH3:12])[C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:15][CH:16]=1)#[N:19]
Reactant: COC1CCc2c(Cl)ncnc21
Reactant: N#Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC1CCc2c(Nc3ccc(C#N)cc3)ncnc21
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 40.7 %

Procedure:
0.92 g of 4-chloro-6,7-dihydro-7-methoxy-5H-cyclopenta[d]pyrimidine [prepared as described in step (e) above] and 0.59 g of p-aminobenzonitrile were dissolved in 5 ml of ethanol, and the solution was stirred at 130° C. for 10 minutes. At the end of this time, the mixture was cooled to room temperature, and the resulting solid reaction product was pulverized. 50 ml of a 1N aqueous solution of sodium hydroxide and 200 ml of ethyl acetate were added to the resulting powder, and the ethyl acetate layer was separated, washed with water and dried over anhydrous sodium sulfate. The ethyl acetate was evaporated off under reduced pressure, and the resulting residue was purified by silica gel column chromatography, eluted with ethyl acetate, to give 0.54 g of the title compound as colorless crystals melting at 167°-169° C.
Reaction SMILES: Cl.[C:2]1([O:12][CH2:13][CH2:14][CH2:15]Br)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:17]([NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:2]1([O:12][CH2:13][CH2:14][CH2:15][N:29]2[CH2:30][CH2:31][CH:26]([NH:25][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:27][CH2:28]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCOc1cccc2ccccc12
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(NC1CCN(CCCOc2cccc3ccccc23)CC1)c1ccccc1

Procedure:
The title compound as its hydrochloride, m.p. 228° C (decomp.), was prepared by the method of Example 52 using 3-naphthyloxypropyl bromide (2.07 g.), 4-benzamidopiperidine (1.8 g.) and anhydrous potassium carbonate (1.24 g.). (Found: C, 70.4; H, 7.0; N, 6.6. C25H28N2O2HCl requires C, 70.65; H, 6.9; N, 6.6%).