Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[C:3]([SiH2:7][O:8][C:9]([CH3:18])([CH3:17])[C:10]1[O:11][CH:12]=[C:13]([CH:15]=[O:16])[N:14]=1)([CH3:6])([CH3:5])[CH3:4].[CH3:19][Al](C)C.[NH4+].[Cl-]>C(Cl)Cl.C1(C)C=CC=CC=1>[C:3]([SiH2:7][O:8][C:9]([CH3:18])([CH3:17])[C:10]1[O:11][CH:12]=[C:13]([CH:15]([OH:16])[CH3:19])[N:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1nc(C=O)co1
Reactant: C[Al](C)C
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(O)c1coc(C(C)(C)O[SiH2]C(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazole-4-carbaldehyde (223 mg, 0.92 mmol) in CH2Cl2 (8.0 mL) was treated at 0° C. with trimethylaluminum (2.50 mL of a 2M solution in toluene, 5.00 mmol). The reaction mixture was then stirred at 0° C. for 45 min. Sat. aq. NH4Cl was then added and the aq. layer was extracted twice with CH2Cl2 and twice with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a colorless oil. TLC:rf (1:1 hept-EA)=0.32. LC-MS-conditions 02: tR=0.97 min, [M+H]+=258.30.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.S1C=CN=C1C(O)(C#C)C.[CH3:35][C:36]1[O:40][N:39]=[C:38]([C:41]([OH:45])([C:43]#[CH:44])[CH3:42])[CH:37]=1>>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:44]#[C:43][C:41]([C:38]4[CH:37]=[C:36]([CH3:35])[O:40][N:39]=4)([OH:45])[CH3:42])[CH:10]=3)[C:6]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: C#CC(C)(O)c1cc(C)on1
Reactant: Nc1nccc(-n2nc(C(=O)N3CCCC3)c3ccc(Br)cc32)n1
Agent: C#CC(C)(O)c1nccs1
Product: Cc1cc(C(C)(O)C#Cc2ccc3c(C(=O)N4CCCC4)nn(-c4ccnc(N)n4)c3c2)no1

Procedure:
The title compound was prepared by procedure described in Example 62-c, by substituting 1-(2-aminopyrimidin-4-yl)-6-bromo-N,N-dimethylindazole-3-carboxamide with 4-{6-bromo-3-[(pyrrolidin-1-yl)carbonyl]indazol-1-yl}pyrimidin-2-amine and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol with 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol in Step 3: 1H NMR (500 MHz, DMSO) delta 1.84-1.93 (5H, m), 1.93-1.98 (2H, m), 2.42 (3H, s), 3.60 (2H, t, J=6.86 Hz), 3.99 (2H, t, J=6.78 Hz), 6.41 (1H, s), 6.57 (1H, s), 7.13 (1H, d, J=5.36 Hz), 7.15 (2H, br. s.), 7.44 (1H, dd, J=8.43, 1.18 Hz), 8.22 (1H, d, J=8.35 Hz), 8.36 (1H, d, J=5.52 Hz), 8.94 (1H, s); LC-MS: m/z=+458.45 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[CH2:10][CH2:9][C:8]([C:18]([O:20]C)=[O:19])=[CH:7][C:6]=2[CH:22]=1.[OH-].[Na+].O.Cl>O1CCCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[CH2:10][CH2:9][C:8]([C:18]([OH:20])=[O:19])=[CH:7][C:6]=2[CH:22]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(Cc2cccs2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1=Cc2cc(Br)ccc2N(Cc2cccs2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a solution of methyl 7-bromo-1-(2-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (810 mg) in a mixture of tetrahydrofuran (60 ml) and methanol (60 ml) was added 1N sodium hydroxide solution (21 ml), and the mixture was stirred at room temperature overnight. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to make acidic (pH=4), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was recrystallized from hexane-ethyl acetate to give 7-bromo-1-(2-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (574 mg) as yellow crystals.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][C:10](O)=O.[CH3:14][NH:15][C:16]1[C:25]([N+:26]([O-])=O)=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]>>[C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][C:10]1[N:15]([CH3:14])[C:16]2[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=[CH:24][C:25]=2[N:26]=1
Reactant: CNc1c(C(=O)OC)cccc1[N+](=O)[O-]
Reactant: Cc1cc(C)c(CC(=O)O)c(C)c1
Product: COC(=O)c1cccc2nc(Cc3c(C)cc(C)cc3C)n(C)c12

Procedure:
The title compound was prepared from mesityleneacetic acid and methyl 2-(methylamino)-3-nitrobenzoate in the similar method described in Reference Example 5.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([C:23]([N:25]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29][N:28]3[CH:36]=[CH:37][N:38]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[N:38]1[CH:37]=[CH:36][N:28]2[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[CH3:1])=[CH:40][CH:39]=3)=[O:24])[CH2:26][C:27]=12
Reactant: Nc1ccc(C(=O)N2Cc3nccn3Cc3ccccc32)cc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3nccn3Cc3ccccc32)cc1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 1.5 mmol of triethylamine. After stirring for 15 minutes, 1 mmol of 10,11-dihydro-10-(4-aminobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine is added and the mixture stirred for 5 hours. The reaction mixture is washed with water, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography to give the desired product as a solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.CO[C:20]1C=CC=[C:22]([NH2:26])[CH:21]=1.[H-].[Na+].[CH2:29]1[CH2:33][O:32][CH2:31][CH2:30]1>CCCCCC.CCOC(C)=O>[CH3:31][O:32][C:33]1[CH:29]=[CH:30][C:22]([NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:3]=2)=[CH:21][CH:20]=1
Reactant: COc1cccc(N)c1
Reactant: C1CCOC1
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2nc(-c3ccccc3)nc3ccccc23)cc1
Temperature: 25 °C
Yield: 22 %

Procedure:
To a solution of 4-chloro-2-phenylquinazoline (590 mg, 2.45 mmol) in THF (10 mL) was added m-anisidine (301 mg, 2.45 mmol) and NaH (60%, 120 mg, 3.0 mmol). The mixture was refluxed for 24 h. After cooled to room temperature, the mixture was diluted with 1:1 hexane/EtOAc (100 mL), washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (3:1 hexane/EtOAc) to yield the title compound as a white solid (173 mg, 0.53 mmol, 22%). 1H NMR (CDCl3): 8.54-8.51 (m, 2H), 8.00-7.74 (m, 5H), 7.52-7.47 (m, 4H), 7.38 (s, 1H), 7.02-7.00 (m, 2H), 3.88 (s, 3H).
Reaction SMILES: C[C:2]([CH3:5])([O-])C.[K+].[C:7]([O:11][CH3:12])(=[O:10])[CH:8]=[CH2:9].C1(C)C(S(C[N+:23]#[C-])(=O)=O)=CC=CC=1>C1COCC1>[NH:23]1[CH:2]=[CH:5][C:8]([C:7]([O:11][CH3:12])=[O:10])=[CH:9]1
Reactant: CC(C)(C)[O-]
Reactant: C=CC(=O)OC
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc[nH]c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of potassium-tert-butoxide (105 g) in THF (1.2 L) was added dropwise a solution of methyl acrylate (66 g) and toluenesulfonylmethyl isocyanide (150 g) in THF (300 ml). The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography on silica gel (Petrol:ethyl acetate=5:1) to give the desired compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:22])=[N:19][C:20]=1[CH3:21]>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:22][C:18]2[CH:17]=[CH:16][C:15]([CH3:14])=[C:20]([CH3:21])[N:19]=2)[CH:7]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: Cc1ccc(N)nc1C
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1ccc(C)c(C)n1
Temperature: 140 °C
Yield: 36 %

Procedure:
A pressure tube was charged with ethyl 4,6-dichloropyridazine-3-carboxylate (300 mg, 1.36 mmol), 5,6-dimethylpyridin-2-amine (249 mg, 2.04 mmol) in acetonitrile (8 mL) and the mixture was heated in an oil bath at 140° C. for 18 h. After cooling to room temperature, the mixture was concentrated in vacuo, adsorbed on silica gel and then purified by chromatography (silica, 50 μm, 80 g column from Analogix, 0% to 10% acetone in dichloromethane, 20 min) to afford ethyl 6-chloro-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxylate (150 mg, 36%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.20 (s, 1H) 8.86 (s, 1H) 7.57 (d, J=8.08 Hz, 1H) 6.97 (d, J=8.08 Hz, 1H) 4.40 (q, J=7.24 Hz, 2H) 2.42 (s, 3H) 2.23 (s, 3H) 1.35 (t, J=7.20 Hz, 3H); LCMS (EI/CI) m/z: 307 [M+H].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH3:30])=[O:24])[C:5]1=[O:31].C(N(C(C)C)CC)(C)C.[C:41](OC(=O)C)(=[O:43])[CH3:42].O>CN(C=O)C>[C:41]([NH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH3:30])=[O:24])[C:5]1=[O:31])(=[O:43])[CH3:42]
Reactant: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN)c1=O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCNC(C)=O)c1=O
Temperature: 0 °C

Procedure:
A solution of 1-(2-aminoethyl)-N-[2-(ethyloxy)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.020 g, 0.047 mmol) and diisopropyl ethylamine (0.041 mL, 0.24 mmol) in DMF (5 mL) under nitrogen was treated with acetic anhydride (0.0044 mL, 0.047 mmol) at ambient temperature. The reaction was warmed slightly to solubilize the reacted at ambient temperature for 10 min. Water was added (2 mL) and the reaction was cooled to 0° C. and concentrated in vacuo. The resulting residue was treated with 1 N NaHSO4 and filtered then triturated with Et2O and dried in vacuo to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-D6) δ ppm 1.1 (t, J=6.9 Hz, 3 H), 1.7 (s, 3 H), 3.3 (dd, J=12.5, 5.3 Hz, 2 H), 3.5 (q, J=7.0 Hz, 2 H), 3.5 (s, 4 H), 4.1 (s, 2 H), 4.3 (t, J=6.7 Hz, 2 H), 7.1 (t, J=9.0 Hz, 2 H), 7.4 (dd, J=8.4, 5.5 Hz, 2 H), 8.0 (t, J=5.6 Hz, 1 H), 8.2 (s, 1 H), 8.6 (s, 1 H), 10.4 (s, 1 H), 17.1 (s, 1 H); ES+ MS: 471 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[O:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[C:25]([CH3:27])[CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O.O>[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]4[C:14]5[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=5[O:12][CH:11]=4)=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:30])[CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: Nc1nccc2occ(-c3ccc4c(c3)CCN4)c12
Reactant: Cc1cc(F)cc(CC(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(F)cc(CC(=O)N2CCc3cc(-c4coc5ccnc(N)c45)ccc32)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 88.2 %

Procedure:
A mixture of 3-(2,3-dihydro-1H-indol-5-yl)furo[3,2-c]pyridin-4-amine (150 mg, 0.440 mmol), 3-fluoro-5-methylphenylacetic acid (78 mg, 0.464 mmol), HATU (184 mg, 0.484 mmol), and Hunig's base (0.31 mL, 1.775 mmol) in N,N-Dimethylformamide (DMF) (3 mL) was stirred at room temperature for 4 days. Water (10 mL) was added, the mixture was stirred for about 4 hours, and the precipitate was collected by vacuum filtration. The solid was dried in the vacuum oven overnight to give 3-{1-[(3-fluoro-5-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-4-amine (164 mg, 0.388 mmol, 88% yield) as a tan solid. LC/MS (ES) m/z=402 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.32 (s, 3H), 3.24 (t, J=8.46 Hz, 2H), 3.87 (s, 2H), 4.24 (t, J=8.59 Hz, 2H), 5.53 (s, 2H), 6.90-7.00 (m, 4H), 7.30 (d, J=8.34 Hz, 1H), 7.39 (s, 1H), 7.86 (d, J=5.81 Hz, 1H), 7.92 (s, 1H), 8.17 (d, J=8.34 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1.OO.C(C(C)=[O:22])C>O>[NH2:1][C:2]1[C:15]2[C:14](=[O:22])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc2c1Cc1ccccc1C2=O
Reactant: CCC(C)=O
Agent: OO
Solvent: O
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The moist paste of 4-aminoanthrone is introduced into 300 ml of water and warmed to 60° C under nitrogen. The pH is checked every 1/4 of an hour and should lie in the range between 7.5 and 8.5. 75 ml of potassium waterglass (d = 1.25) are then added, whereupon a pH of 11 results. 375 ml of H2O2 solution are then added dropwise in the course of 2.5 hours, the solution being prepared by diluting 200 ml of 35% strength hydrogen peroxide (d = 1.135) to 1.0 liter. The mixture is warmed to 70° C and kept at this temperature for one hour. 500 ml of the azeotrope of methyl ethyl ketone (88%) and water (12%) which boils at 73.4° C, are then added and the mixture is heated to the boil for 10 hours (temperature 74° C). It is then cooled to 20° C, stirred for 1 hour at room temperature and then filtered. The residue is covered twice with 150 ml of water at a time, to remove the adhering methyl ethyl ketone. The azeotrope (boiling point 73° C) is recovered almost quantitatively from the combined filtrates by distillation. 4 g of a solid substance which contains about 50% of 1-aminoanthraquinone are isolated from the distillation residue. To remove adhering silica the moist paste of the 1-aminoanthraquinone, in 500 ml of water and 60 ml of concentrated sodium hydroxide solution (d = 1.48) must be subjected to incipient distillation for ~15 minutes. To avoid objectionable foaming during this operation, 5 drops of anti-foam agent are added. The product is filtered off hot, and the adhering sodium hydroxide solution is eluted with a little hot water. The paste weighs 140 g. It is dried at 70° C. 91 g are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].[CH:18]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])=[CH2:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:23]([S:20]([CH:18]=[CH:19][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17])(=[O:22])=[O:21])[CH3:24]
Reactant: C=CS(=O)(=O)CC
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)C=Cc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1
Yield: 65.3 %

Procedure:
A mixture of (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (0.25 g), ethyl vinyl sulphone (0.14 g), tri-o-tolylphosphine (0.075 g), palladium (II) acetate (0.013 g), triethylamine (0.25 mL) and acetonitrile (3 mL) was heated under reflux for 17 hours in an atmosphere of nitrogen. The mixture was evaporated and the residue was chromatographed on silica gel. Elution with dichloromethane/ethanol/concentrated aqueous ammonia (90:8:1) gave the title compound as a foam (0.185 g): TLC (dichloromethane/-ethanol/concentrated aqueous ammonia, 90:10:1): Rf =0.5. Anal. Calcd for C18H24N2O2S. 0.2 CH2Cl2 : C,62.55; H,7.04; N,8.02. Found: C,62.65; H,6.94; N,7.92.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH2:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[C:22](OC)[CH:23]=2)[N:18]=[CH:17][N:16]=1.C1C[O:40][CH2:39]C1>>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7]2[C:15]1([O:40][CH3:39])[C:24]2[C:19](=[CH:20][C:21]([O:27][CH2:28][CH2:29][CH2:30][N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:22][CH:23]=2)[N:18]=[CH:17][NH:16]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COC1(C2C(=O)Nc3ccc(F)cc32)NC=Nc2cc(OCCCN3CCOCC3)ccc21
Reaction time: 0.5 h

Procedure:
Sodium hydride (80 mg, 3.4 mmol, pre-washed with petroleum ether) was added to a solution of 5-fluorooxindole (423 mg, 2.8 mmol), (prepared according to Synthesis 1993, 51), in THF (10 ml) at ambient temperature under argon. The resulting suspension was stirred for 30 minutes and a partial solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (236 mg, 0.7 mmol), (prepared as described for the starting material in Example 5), in a 1/1 mixture of THFIDMF (14 ml), was added and the reaction mixture was stirred at ambient temperature for 15 hours. The volatiles were then removed by evaporation and the residue purified by column flash chromatography using an increasingly polar mixture of methylene chloride and methanol (2 to 10%) as eluent. The purified product was dissolved in a minimum volume of methanol and a 2.9M solution of hydrogen chloride in ether was added to the solution. During the evaporation of the solvents a solid precipitated which was collected by filtration, washed with ether and dried under vacuum to give 4-(5-fluorooxindol-3-yl)-4-methoxy-7-(3-morpholinopropoxy)quinazoline as a hydrochloride salt (298 mg, 81%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)=[O:3].Cl[Si:12]([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C.CN(C)C=O>CCCCC>[F:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([O:3][Si:12]([CH3:15])([CH3:14])[CH3:13])=[CH2:1])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: C[Si](C)(C)Cl
Solvent: CCCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(O[Si](C)(C)C)c1ccc(F)cc1
Yield: 37 %

Procedure:
A mixture of 34.56 g (0.25 mol) of 4-fluoroacetophenone, 32.6 g (0.3 mol) of chlorotrimethylsilane, 60.6 g (0.6 mol) of triethylamine and 100 ml of dimethylformamide was refluxed overnight, cooled, and diluted with 200 ml of pentane. This mixture was washed successively three times with 300 ml of cold 5% aqueous sodium bicarbonate, with cold 1.5 N hydrochloric acid, and with 5% aqueous sodium bicarbonate, dried and distilled to give 19.44 g of 1-(4-fluorophenyl)vinyloxytrimethylsilane as a colorless liquid: bp 55°-57° C. (0.12 mm); 19F NMR (CFCl3) δ-114.1 ppm (m); 1H NMR (CFCl3) δ 0.25 ppm (s, 9H), 4.35 ppm (d,J=1.5 Hz, 1H), 4.77 ppm (d,J=1.5 Hz, 1H), 6.9 ppm (m, 2H) and 7.5 ppm (m, 2H). Anal. Calcd. for C11H15FOSi: C, 62.82; H, 7.19; Found: C, 62.97; H, 7.31.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C)C=O.[CH3:48][O:49][C:50]1[CH:51]=[C:52]([C@H:56]([NH2:58])[CH3:57])[CH:53]=[CH:54][CH:55]=1>O>[Br:1][C:2]1[S:3][C:4]([C:7]([NH:58][C@@H:56]([C:52]2[CH:53]=[CH:54][CH:55]=[C:50]([O:49][CH3:48])[CH:51]=2)[CH3:57])=[O:9])=[CH:5][N:6]=1
Reactant: O=C(O)c1cnc(Br)s1
Reactant: COc1cccc([C@@H](C)N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc([C@@H](C)NC(=O)c2cnc(Br)s2)c1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To a stirring solution of 2-bromothiazole-5-carboxylic acid (0.3 g, 1.442 mmol), diisopropyl ethylamine (0.205 g, 1.586 mmol) and HATU (0.603 g, 1.586 mmol) in dimethylformamide (7.21 mL, 1.442 mmol) was added (R)-1-(3-methoxyphenyl)ethanamine (0.218 g, 1.442 mmol) dropwise. After stirring for 12 hours at 50° C., the reaction was poured into water (50 mL). The precipitated solid was then collected by filtration washing successively with water (2×50 mL) and hexanes (2×50 mL). The recovered product was used without further purification in the next step.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]([S:11]([O-:13])=[O:12])[S:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[Li+].[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>C(#N)C>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:2]2[C:7]3[CH:8]=[C:9]([S:11]([CH2:19][C:18]4[CH:21]=[CH:22][CH:23]=[C:16]([Br:15])[CH:17]=4)(=[O:13])=[O:12])[S:10][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: O=S([O-])c1cc2c(Cl)nccc2s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: BrCc1cccc(Br)c1
Agent: [Li+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2nccc3sc(S(=O)(=O)Cc4cccc(Br)c4)cc23)CC1

Procedure:
Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 3-bromobenzylbromide (0.59 mmol) as described in Method P above and then reacted further with tert-butyl-piperazine-1-carboxylate as described in Method Q. Yield 0.023 g (10% over two steps). Beige solid. 1H NMR (300 MHz, CDCl3) δ 8.16 (d, J=6 Hz, 1H), 7.50-7.55 (m, 2H), 7.32-7.40 (m, 2H), 7.10-7.24 (m, 3H), 4.44 (s, 2H), 3.61-3.73 (m, 8H), 1.50 (s, 9H); MS (ESI+) for C23H26BrN3O4S2 m/z 554 (M+H)+. HPLC 77%, RT 4.07 min (ACE3 C8 50×4.6 mm, 5-50% acetonitrile in 3 min).
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:16]([C:18]1[S:19][C:20](=[NH:35])[N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][C:25]([O:33][CH3:34])=[C:26]([O:31][CH3:32])[CH:27]=3)[C:22]=12)#[N:17]>O>[C:16]([C:18]1[S:19][C:20](=[N:35][C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][C:25]([O:33][CH3:34])=[C:26]([O:31][CH3:32])[CH:27]=3)[C:22]=12)#[N:17]
Reactant: COc1cc2c(cc1OC)-c1c(C#N)sc(=N)n1CC2
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2c(cc1OC)-c1c(C#N)sc(=NC(=O)c3ccccc3)n1CC2

Procedure:
5 ml. of pyridine and 0.3 ml. of benzoyl chloride are added to 0.5 g. of 1-cyano-3-imino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinoline, and the mixture is refluxed for 0.5 hours. After cooling, the mixture is diluted with water. 0.6 g. of 1-cyano-3-benzoylimino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a] isoquinoline is obtained in crystalline state; m.p.: 274°-276°C (after recrystallization from a mixture of dimethylformamide and butanol).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:10][C:4]=2[CH:3]=1.[CH2:17]([O:20][C:21](Cl)=[O:22])[CH2:18][CH3:19]>>[CH2:17]([O:20][C:21]([N:10]1[C:4]2[CH:3]=[C:2]([Br:1])[N:7]=[CH:6][C:5]=2[CH:8]=[C:9]1[C:11]1[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=1)=[O:22])[CH2:18][CH3:19]
Reactant: CCCOC(=O)Cl
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Product: CCCOC(=O)n1c(-c2cnn(C)c2)cc2cnc(Br)cc21

Procedure:
Prepared according to Preparation 128 using 6-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22) and propylchloroformate. 1H-NMR (500 MHz, CDCl3): δ 0.96 (t, J=7.4 Hz, 3H), 1.38 (m, 2H), 3.97 (s, 3H), 4.36 (t, J=6.7 Hz, 2H), 6.59 (s, 1H), 7.62 (s, 1H), 7.65 (s, 1H), 8.17 (s. 1H), 8.56 (s, 1H)