Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=3)[C:20]([C:28]3[N:29]=[C:30]4[C:36]([C:37](O)=[O:38])=[CH:35][N:34]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:31]4=[N:32][CH:33]=3)=[N:19]2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=[N:63][C:58]2[CH:59]=CC=N[C:57]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)(C)C>CN(C=O)C>[CH:58]([NH:63][C:37]([C:36]1[C:30]2[C:31](=[N:32][CH:33]=[C:28]([C:20]3[C:21]4[C:26](=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[N:18]([CH:16]4[CH2:17][N:14]([CH:1]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)[CH2:15]4)[N:19]=3)[N:29]=2)[N:34]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:46])([CH3:47])[CH3:45])[CH:35]=1)=[O:38])([CH3:59])[CH3:57]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(-c3nn(C4CN(C(c5ccccc5)c5ccccc5)C4)c4cc(F)ccc34)cnc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)N
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C4CN(C(c5ccccc5)c5ccccc5)C4)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
To a solution of 2-[1-(1-benzhydryl-azetidin-3-yl)-6-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (130 mg, 0.20 mmol) in DMF (2 mL) were added HATU (84 mg, 0.22 mmol) and isopropylamine (86 μL, 1.00 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (2×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 50% EtOAc/hexanes to isolate 74 mg (54%) of 2-[1-(1-benzhydryl-azetidin-3-yl)-6-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide as an off-white foamy solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[N:14]=[C:13]([N:15]([CH2:34][CH2:35][CH3:36])[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[NH:33][N:32]=[N:31][N:30]=4)=[CH:19][CH:18]=3)[C:12]([C:37]([O:39]CC3C=CC=CC=3)=[O:38])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[OH-].[Na+]>[CH2:7]([O:8][C:9]1[N:14]=[C:13]([N:15]([CH2:34][CH2:35][CH3:36])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[NH:33][N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:12]([C:37]([OH:39])=[O:38])=[CH:11][CH:10]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1nc(OCc2ccccc2)ccc1C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1nc(OCc2ccccc2)ccc1C(=O)O
Temperature: 80 °C
Yield: 88.7 %

Procedure:
The resultant more polar methyl ester from Example 217A (10.4 mg, 19.5 μmol) was dissolved in 0.1 mL of methanol and 0.09 mL 1.0M aqueous sodium hydroxide. The solution was heated (in a sealed vial) at 80° C. for 28 hours, then cooled and concentrated to an aqueous residue by means of a stream of nitrogen. The residue was partitioned between 5 mL of methylene chloride and 2 mL 1.0M aqueous sodium hydrogen sulfate, then the aqueous phase was extracted with 2×2 mL methylene chloride. The combined organic phases were washed with 2 mL brine, dried through a plug of sodium sulfate, and evaporated under high vacuum to provide a colorless glass. Purification by preparative TLC (1% HOAc in 1:1 CH2Cl2 -EtOAc) produced 9.0 mg (17.3 μmol, 89%) of the title compound as a colorless glass. m.p. 68°-82° C. 1H NMR (CDCl3, 300 MHz) d 0.88 (t, J=7.5 Hz, 3H), 1.37-1.52 (br m, 2H), 3.21-3.31 (br m, 2H), 4.12 (s, 2H), 5.49 (s, 2H), 6.65 (d, J=7.5 Hz, 2H), 6.77 (d, J=9 Hz, 1H), 6.86 (d, J= 7.5 Hz, 2H), 7.20-7.55 (m, 10H), 7.84 (dd, J=1.5, 7 Hz, 1H), 8.25 (d, J=7.5 Hz, 1H). MS (DCl/NH3) m/e 521 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:24][C:25]1[O:26][CH:27]=[CH:28][CH:29]=1>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]([CH2:24][C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: BrCc1ccco1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccc(OC)cc23)CC1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(c2cn(Cc3ccco3)c3ccc(OC)cc23)CC1
Reaction time: 15 h
Yield: 100 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) at room temperature for 15 hours, starting with 0.3 g (1.0 mmol) of 4-(5-methoxy-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 2.11 mL (1.3 mmol) of a freshly prepared 0.61 M solution of 2-bromomethylfuran in ethyl ether. After standard work-up, 0.38 g (100% of yield) of 4-(1-furan-2-ylmethyl-5-methoxy-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=[C:3]1[CH2:12][O:13][C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(O)(=O)C>O>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=[C:3]1[CH2:12][O:13][C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[NH:21][C:20]2=[O:44])=[CH:16][CH:15]=1
Reactant: Cc1ccnc2c1nc(COc1ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc1)n2C
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccnc2c1nc(COc1ccc(CC3SC(=O)NC3=O)cc1)n2C

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 1.07 g of 5-{4-(3,7-dimethyl-3H-imidazo[4,5-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 41) and 16 ml of a 3:1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1:1 to 1:2 by volume as the eluent. The product was crystallized by trituration with ethyl acetate, to give 0.28 g of the title compound, melting at 205-207° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:26][CH:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:29][CH2:28]1.C1CCN2C(=NCCC2)CC1.C(N(CC)CC)C>C(#N)C>[C:36]1([CH2:35][CH2:34][CH2:33][N:30]2[CH2:31][CH2:32][CH:27]([NH:26][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:28][CH2:29]2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: NC1CCN(CCCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCC(=O)NC1CCN(CCCc2ccccc2)CC1
Reaction time: 1 h

Procedure:
To a suspension of 4.21 g (24.03 mmol.) of N-tert-butoxycarbonyl glycine and 5.51 g (35.98 mmol.) of 1-hydroxybenzotriazole monohydrate in acetonitrile (30 ml) was added, at room temperature, 6.90 g (36.0 mmol.) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarboxiimide hydrochloride. The mixture was stirred for one hour. To the reaction system was then added a solution of 7.00 g (24.03 mmol.) of 4-amino-1-(3-phenylpropan-1-yl)piperidine dihydrochloride, 7.32 g (48.08 mmol.) of 1,8-bicyclo[5.4.0]unde-7-cene (DBU) and 3.4 ml (24.4 mmol.) of triethylamine in acetonitrile (20 ml). The mixture was stirred for 2 hours at room temperature. The solvent was distilled off under reduced pressure. To the residue was added chloroform. The mixture was washed with water and a saturated aqueous saline solution, followed by drying over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a column chromatography (methanol/ethyl acetate 30%). The solvent was distilled off under reduced pressure to give the object compound as a yellowish orange liquid product. The yield was 5.35 g (59%).
Reaction SMILES: [CH3:1][C:2]1([CH:15]2[CH2:19][CH2:18][O:17][C:16]2=[O:20])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[NH3:21]>>[OH:17][CH2:18][CH2:19][CH:15]([C:2]1([CH3:1])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:16]([NH2:21])=[O:20]
Reactant: CC1(C2CCOC2=O)OCCc2c1[nH]c1ccccc21
Reactant: N
Product: CC1(C(CCO)C(N)=O)OCCc2c1[nH]c1ccccc21
Temperature: 90 °C

Procedure:
A suspension of 4,5-dihydro-3-(1,3,4,9-tetrahydro-1-methyl pyrano[3,4-b]indol-1-yl)-2(3H)-furanone (described in Example 1, 20 g, 0.073 mole) in liquid ammonia is heated at 90° C. in a pressure apparatus for three hours. The apparatus is rinsed with ethanol and the yellow solution is evaporated. The residue is crystallized from methanol to afford α-(2-hydroxyethyl)-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]-indole-1-acetamide (16.15 g), mp 159°-161° C.
Reaction SMILES: Br[C:2]1[N:6]2[C:7](=[O:18])[N:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH2:9][CH2:10][C:5]2=[N:4][C:3]=1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH3:27]B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CN(C=O)C.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>[F:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][C:5]3=[N:4][C:3]([CH2:19][O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:2]([CH3:27])[N:6]3[C:7]2=[O:18])=[CH:12][CH:13]=1
Reactant: CB(O)O
Reactant: O=C1N(c2ccc(F)cc2)CCc2nc(COc3ccccc3)c(Br)n21
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: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cc1c(COc2ccccc2)nc2n1C(=O)N(c1ccc(F)cc1)CC2
Temperature: 150 °C
Reaction time: 0.75 h
Yield: 57.7 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (6.4 mg, 0.0055 mmol) was added to a stirred suspension of 3-bromo-6-(4-fluoro-phenyl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one (116 mg, 0.18 mmol), methylboronic acid (55.05 mg, 0.92 mmol) and K2CO3 (76.3 mg, 0.23 mmol) in a mixture of 1,4-dioxane (7.07 mL) and DMF (1.77 mL) under nitrogen and in a sealed tube. The mixture was stirred at 150° C. for 45 minutes under microwave irradiation. The solvents were evaporated in vacuo and the crude product was purified by flash column chromatography (silica; 7 M solution of ammonia in MeOH in DCM with a gradient of 0/100 to 1.5/98.5 and then AcOEt in DCM with a gradient of 0/100 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo. The product was purified by RP HPLC (C18 XBridge 19×100 5 um, gradient from 80% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 20% CH3CN to 0% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 100% MeOH) to yield 6-(4-fluoro-phenyl)-3-methyl-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one (36.5 mg, 56% yield). 1H NMR (400 MHz, CDCl3) 8 ppm 2.52 (s, 3H), 3.26 (t, J=6.5 Hz, 2H), 3.98 (t, J=6.6 Hz, 2H), 4.96 (s, 2H), 6.97 (br. t, J=7.4, 7.4 Hz, 1H), 7.00-7.06 (m, 2H), 7.09-7.18 (m, 2H), 7.27-7.37 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.[CH3:13][N:14]([CH3:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1C1C=CC=CC=1P(C1C=CC=CC=1C1C=CC=CC=1C)C1C=CC=CC=1C1C=CC=CC=1C>[CH3:12][CH:8]1[CH2:7][C:6]2[C:10](=[C:2]([C:18]3[CH:19]=[CH:20][C:15]([N:14]([CH3:24])[CH3:13])=[CH:16][CH:17]=3)[CH:3]=[CH:4][CH:5]=2)[C:9]1=[O:11]
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: CC1Cc2cccc(Br)c2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1-c1ccccc1P(c1ccccc1-c1ccccc1C)c1ccccc1-c1ccccc1C
Solvent: O
Solvent: COCCOC
Product: CC1Cc2cccc(-c3ccc(N(C)C)cc3)c2C1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 76.5 %

Procedure:
Using a method similar to Example 22, 8.0 g (0.032 mol) of (2), 5.85 g (0.038 mol) of 4-dimethylaminophenylboronic acid and 7.4 g (0.07 mol) of sodium carbonate were placed in 122 ml of dimethoxyethane and 37 ml of water in the reaction vessel, the mixture was degassed a number of times and saturated with argon. 142 mg (0.6 mmol) of palladium acetate and 385 mg (1.3 mmol) of tris(o-tolylphenyl)phosphine were added and the reaction mixture was stirred for 4 hours at 80° C. After addition of 150 ml of water, the mixture was extracted 4 times with 100 ml each time of diethyl ether, the ether phase was washed twice with 50 ml each time of water and dried over magnesium sulfate. Removal of the solvent and column filtration through neutral aluminum oxide (dichloromethane) gave 6.5 g of 2-methyl-7-(4-dimethylamino-phenyl)-1-indanone as an oil.
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:15][OH:16])[CH2:9]1)C1C=CC=CC=1.O.C(N(CC)CC)C.[C:25]([O:32]C([O-])=O)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=O>C(O)=O.CO.[Pd]>[C:28]([O:27][C:25]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:15][OH:16])[CH2:9]1)=[O:32])([CH3:29])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: OCC1CCCCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCCC(CO)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
1-Benzyl perhydroazepin-3-yl methanol (1.30 g, 5.93 mmol) was dissolved in a 4.4% formic acid/methanol solution (30 mL). To this solution, 10% palladium on activated carbon (1.30 g) was added and the mixture was stirred at room temperature for 2 hours. Subsequently, water was added and the mixture was filtered through Celite. The filtrate was concentrated. The resulting residue was dissolved in acetonitrile (15 mL). While the solution was ice-chilled and stirred, triethylamine (1.81 mL, 13.0 mmol) and t-butyl dicarbonate (1.42 g, 6.52 mmol) were added. The reaction mixture was then stirred at room temperature for 4 hours. Subsequently, the mixture was concentrated and ethyl acetate was added. The mixture was sequentially washed with a 5% aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution and brine, followed by drying over magnesium sulfate. Evaporation of the solvent gave 1.13 g (83%) of the desired compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)\[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1>CO.[Pd]>[F:20][C:17]1[CH:18]=[CH:19][C:14](/[C:12](/[CH3:13])=[CH:11]/[N:7]2[C:8]3[CH:9]=[CH:10][CH:2]=[CH:3][C:4]=3[C:5]3[CH2:24][N:23]([CH3:25])[CH2:22][CH2:21][C:6]2=3)=[CH:15][CH:16]=1
Reactant: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: C/C(=C\n1c2c(c3ccccc31)CN(C)CC2)c1ccc(F)cc1

Procedure:
(E)-8-Chloro-5-(2-(4-fluorophenyl)prop-1-enyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.200 g) was dissolved in MeOH which was hydrogenated over 10% Pd—C at 40° C. and 30 bars H2. The progress of reaction was monitored by TLC. The solvent was evaporated and the residue was purified by HPLC. 1H NMR (CDCl3, TFA salt) δ (ppm): 7.58 (m, 2H), 7.42 (m, 1H), 7.25 (m, 3H), 7.15 (m, 2H), 6.80 (s, 1H), 4.80 (m, 1H), 4.20 (m, 1H), 3.90 (m, 1H), 3.35 (m, 2H), 3.05 (s, 3H), 2.90 (m, 1H), 1.95 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[F:14])=[N:4][C:3]=1[C:15]#[N:16].C(=O)(O)[O-:18].[Na+]>OS(O)(=O)=O>[Br:1][C:2]1[O:6][C:5]([C:7]2[C:8]([F:14])=[CH:9][CH:10]=[CH:11][C:12]=2[F:13])=[N:4][C:3]=1[C:15]([NH2:16])=[O:18]
Reactant: N#Cc1nc(-c2c(F)cccc2F)oc1Br
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1Br
Yield: 94 %

Procedure:
A solution of 5-bromo-2-(2,6-difluorophenyl)oxazole-4-carbonitrile (0.010 g, 0.04 mmol) in concentrated H2SO4 (0.4 mL) was stirred at room temperature for 4 hours. The reaction was neutralised with saturated sodium bicarbonate solution and extracted with EtOAc. The organic phase was dried over MgSO4 and the solvent removed in vacuo to afford 5-bromo-2-(2,6-difluorophenyl)oxazole-4-carboxamide (0.010 g, 0.03 mmol, 94%) as a white solid. 1H NMR (CDCl3) δ 5.79 (1H, br. s), 6.95 (1H, br. s), 7.07 (2H, t), 7.49 (1H, m). LCMS (1) Rt: 1.59 min; m/z (ES+) 303/305.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:37])(=O)=O)=CC=1>C1COCC1>[F:37][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)([CH3:16])[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COC(=O)C(C)c1ccc2ncccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(F)c1ccc2ncccc2c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 75.4 %

Procedure:
To a solution of methyl 2-(quinolin-6-yl)propanoate (0.868 g, 4.03 mmol) in THF (1.1M, 3.7 mL) at −78° C. was added LiHMDS (1M in THF) (5.24 ml, 5.24 mmol). The reaction was stirred at −78° C. for ˜15 minutes, then to it was added a solution of N-fluorobenzenesulfonimide (1.40 g, 4.44 mmol) in THF(1.0M, 4.5 mL). The reaction was allowed to warm to −10° C. over 2 h. The reaction was filtered through a plug of Celite, washed with EtOAc and the filtrate was then concentrated in vacuo. The concentrated material was rediluted with EtOAc and washed with saturated NH4Cl solution. The aqueous layer was then extracted with EtOAc, and the organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude material was dissolved in minimal DCM and purified via MPLC (eluting with isocratic 40% EtOAc:Hexanes to yield methyl 2-fluoro-2-(quinolin-6-yl)propanoate (0.709 g, 75.4% yield) as a yellow oil. To synthesize the corresponding acid, methyl 2-fluoro-2-(quinolin-6-yl)propanoate was saponified in a method similar to that of 2-(quinolin-6-yl)propanoic acid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:6]=2[N:7]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:21]1[O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][S:12][C:8]3[C:6]4[N:7]=[C:2]([N:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)[N:3]=[C:4]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[C:5]=4[N:11]=[CH:10][N:9]=3)=[CH:15][C:16]=2[O:22]1
Reactant: Clc1nc(N2CCOCC2)c2ncnc(SCc3ccc4c(c3)OCO4)c2n1
Reactant: C1CNCCN1
Product: c1nc(SCc2ccc3c(c2)OCO3)c2nc(N3CCNCC3)nc(N3CCOCC3)c2n1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(3,4-methylenedioxybenzyl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 200°-202° C.) and piperazine.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C@@H:9]2[NH:12][C:11](=[O:13])[C@H:10]2[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=[N:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Si:49](Cl)([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]>CN(C=O)C>[C:1]1([CH:7]=[CH:8][C@@H:9]2[N:12]([Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])[C:11](=[O:13])[C@H:10]2[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=[N:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(N=C(NCCCC[C@@H]1C(=O)N[C@H]1C=Cc1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](CCCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 0° C. DMF (25 mL) solution of compound 33 (6.8 g, 12.3 mmol) was added triethylamine (2.05 g, 20 mmol) and tert-butyldimethylsilyl chloride (3.05 g, 20 mmol). The reaction mixture was warmed to room temperature and stirred for 1.5 h. The suspension was partitioned between Et2O and pH 7.0 aqueous buffer. The organic layer was dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography to afford 8.4 g (quantitative) of the title product.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]([C:17]1[CH:18]=[C:19]([CH2:33][N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][C:23]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:22]2[OH:32])=O.[CH2:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(O)(=O)C>C(O)C.C1COCC1>[CH2:40]([NH:47][CH2:15][C:17]1[CH:18]=[C:19]([CH2:33][N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][C:23]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:22]2[OH:32])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CCOC(=O)c1cnc2c(C=O)cc(CN3CCOCC3)cc2c1O
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2c(CNCc3ccccc3)cc(CN3CCOCC3)cc2c1O
Reaction time: 1.5 h
Yield: 107 %

Procedure:
Sodium triacetoxyborohydride (1.0 g) is added to a stirred solution of ethyl 8-formyl-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxylate (Preparation 27, 515 mg), benzylamine (340 mg) and acetic acid (360 mg) in a mixture of ethanol/THF (10 mL, 1/1). The solution is stirred for 90 min. The solvents are evaporated. The residue is taken up in chloroform and is applied to a silica gel column which is eluted with 1-3% methanol/chloroform followed by 4% methanol/chloroform to afford 697 mg of the title compound which is crystallized from methanol/ether. Physical characteristics: 1H NMR (CDCl3) δ1.43, 2.47, 3.59, 3.72, 3.90, 4.26, 4.42, 7.34, 7.51, 8.23, 8.59. Anal. Found: C, 68.59; H, 6.65; N, 9.64.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])(OCC)=O.Cl.[N+:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[OH:36])[CH2:30]CN)([O-:26])=[O:25].Cl>>[C:13]1(=[O:22])[N:12]([CH2:7][CH2:30][C:29]2[CH:33]=[CH:34][C:35]([OH:36])=[C:27]([N+:24]([O-:26])=[O:25])[CH:28]=2)[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NCCc1ccc(O)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1c2ccccc2C(=O)N1CCc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.8 %

Procedure:
7.58 g of potassium carbonate and 6.02 g of N-carboethoxyphthalimide were added to 180 ml of an aqueous solution of 6.01 g of 3-nitrotyramine hydrochloride and stirred for 15 hours at room temperature. 6N hydrochloric acid was gradually added to the reaction mixture at 0° C. so that the pH value of the mixture was adjusted to be 1 (one). The crystals thus precipitated out were removed by means of filtration and recrystallized from methanol to obtain 7.79 g (yield: 91%) of 4-[2-(phthalimido)ethyl]-2-nitrophenol as yellow crystals.