Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].[N:19]#[C:20]Br.C(OCC)(=O)C>C1COCC1.O>[C:7]1([S:6][CH2:5][C@H:2]2[CH2:3][O:4][C:20]([NH2:19])=[N:1]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#CBr
Reactant: N[C@H](CO)CSc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: NC1=N[C@@H](CSc2ccccc2)CO1
Reaction time: 8 h

Procedure:
To a stirred mixture of (R)-2-amino-3-phenylsulfanyl-propan-1-ol (0.09 g, 0.49 mmol) and K2CO3 (0.081 g, 0.59 mmol) in THF (3 ml) under an argon atmosphere was added a solution of cyanogen bromide (0.062 g, 0.59 mmol) in THF (1 ml). The mixture was stirred overnight, then ethyl acetate and water were added. The aqueous phase was back-extracted with EtOAc. The combined organics were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: EtOAc/MeOH=95:5) to yield a light yellow solid, (0.026 g, 26%); MS (ISP): 209.1 ((M+H)+.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([OH:13])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].[CH:21]1([CH2:24]Br)[CH2:23][CH2:22]1>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH2:24][CH:21]2[CH2:23][CH2:22]2)[CH:5]=1
Reactant: BrCC1CC1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc([N+](=O)[O-])c(OCC2CC2)c1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
3-Hydroxy-4-nitro-benzoic acid methyl ester (10.5 g) was dissolved in dry DMF (150 ml) under N2 atmosphere. K2CO3 (24.3 g), K1 (2.6 g) and cyclopropylmethylbromide (10.3 ml) were added and the mixture was stirred at 50° C. for 6 hours. The reaction mixture was diluted with water (300 ml) and extracted with Et2O (2×200 ml); the combined organic layers were dried over Na2SO4 and the solvent was removed by evaporation to yield 12.7 g of the desired intermediate.
Reaction SMILES: [C:1]([C:3]1[C:8]([Cl:9])=[C:7]([F:10])[N:6]=[C:5]([F:11])[C:4]=1[Cl:12])#N.[H-].C([Al+]CC(C)C)C(C)C.CO.S(=O)(=O)(O)[OH:26]>C1(C)C=CC=CC=1>[Cl:12][C:4]1[C:5]([F:11])=[N:6][C:7]([F:10])=[C:8]([Cl:9])[C:3]=1[CH:1]=[O:26]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(Cl)c(F)nc(F)c1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=Cc1c(Cl)c(F)nc(F)c1Cl
Temperature: 25 °C

Procedure:
To a mixture, of 10.1 g (0.048 mole) of 4-cyano-3,5-dichloro-2,6-difluoropyridine (from Step A) in 50 ml of toluene that had been cooled to 0° C. was added 6.9 g (0.049 mole) of diisobutylaluminum hydride. After complete addition the reaction mixture was allowed to warm to room temperature and was stirred for approximately seventeen hours. A mixture of methanol and petroleum ether (2:1) was added to the reaction mixture which was then acidified with dilute sulfuric acid. The organic layer was separated from the aqueous layer and was dried over anhydrous sodium sulfate. After being filtered, the solvent was evaporated under reduced pressure, leaving 6.0 g of 3,5-dichloro-2,6-difluoropyridine-4-carboxaldehyde as a residue.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=O)[CH3:9])[CH:5]=[CH:4][CH:3]=1.[CH2:11]([C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[C:14]=1[NH2:15])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1.[Cl-].[Cl-].[Ca+2]>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[N:15][C:14]2[C:16]([CH2:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:13]=2[CH2:11][CH3:12])[CH3:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1cccc(Br)n1
Reactant: CCc1cccc(CC)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCc1cccc(CC)c1N=C(C)c1cccc(Br)n1
Temperature: 25 °C

Procedure:
In argon atmosphere, a mixture of 6.00 g (30.0 mmol) of 1-(6-bromopyridin-2-yl)ethanone, 4.69 g (31.5 mmol) of 2,6-diethylaniline, 50 mg of TsOH, and 300 ml of toluene was refluxed for 2-3 h using a Soxhlet apparatus with an extraction thimble filled with anhydrous CaCl2. The reaction mixture was cooled to ambient temperature, passed through a short layer of silica gel 60 (40-63 um), and then evaporated to dryness. The crude product was recrystallized from 50 ml of methanol. Yield 6.20 g (63%) of a yellow crystalline solid. Anal. calc. for C17H19BrN2: C, 61.64; H, 5.78, N, 8.46. Found: C, 61.83; H, 5.88, N, 8.39. 1H NMR (CDCl3): δ 8.32 (dd, J=7.8 Hz, J=0.7 Hz, 1H, 3-H in pyridine), 7.65 (t, J=7.8 Hz, 1H, 4-H in pyridine), 7.57 (dd, J=7.8 Hz, J=0.7 Hz, 1H, 5-H in pyridine), 7.09-7.11 (m, 2H, 3, 5-H in 2, 6-Et2C6H3), 7.02 (m, 1H, 4-H in 2, 6-Et2C6H3), 2.33 (m, 4H, CH2Me), 2.16 (s, 3H, CH3C═N), 1.11 (t, J=7.6 Hz, 6H, CH2Me).
Reaction SMILES: [OH-].[Na+].CC1C=CC(S(O[C:14]2[C:20](=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=O)=O)=CC=1.[CH3:22][CH:23]([C:25]([NH2:27])=[NH:26])[CH3:24].Cl.[NH4+].[Cl-]>O.C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:22][CH:23]([C:25]1[NH:27][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20](=[O:21])[C:14]=2[N:26]=1)[CH3:24]
Reactant: CC(C)C(=N)N
Reactant: Cc1ccc(S(=O)(=O)Oc2cccccc2=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1nc2c(=O)ccccc2[nH]1
Temperature: 30 °C
Yield: 100.7 %

Procedure:
To a mixture of sodium hydroxide 30% in water (24 g) and toluene (30 mL), tropolone tosylate (5 g), isopropylcarbamidine hydrochloride (2.2 g) and tetrabutylammonium bromide (2.3 g) were added successively and the RM was stirred and heated at 30° C. for 1 hour. The reaction mixture was cooled down to room temp, diluted with an excess of sat. aq. NH4Cl solution and then extracted with EtOAc (3×40 ml). The aqueous phase was again extracted with EtOAc (3×50 ml). All the organics were combined, dried (hydrophobic frit) and concentrated under vacuum. The residue was purified by reverse phase chromatography using an acetonitrile-0.1% TFA:Water-0.1% TFA 5%-50% gradient and a 50%-95% gradient. The desired fractions were combined and concentrated under vacuum to yield the title compound (3.4 g). LC/MS MH+ 189, Rt 1.18 min (5 minute run)
Reaction SMILES: [F:1][CH:2]([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Cl[C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:39])[CH:33]([OH:38])[CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>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.O.CC#N.CC#N.O>[F:18][CH:2]([F:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]2[CH2:27][CH2:28][N:29]([C:32](=[O:39])[C@H:33]([OH:38])[CH2:34][CH:35]([CH3:36])[CH3:37])[CH2:30][CH2:31]2)[CH:21]=1
Reactant: CC1(C)OB(c2ccccc2C(F)F)OC1(C)C
Reactant: CC(C)CC(O)C(=O)N1CCN(c2cccc(Cl)c2)CC1
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: O
Solvent: CC#N
Product: CC(C)C[C@@H](O)C(=O)N1CCN(c2cccc(-c3ccccc3C(F)F)c2)CC1
Temperature: 150 °C

Procedure:
2-(2-Difluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (34 mg, 0.11 mmol), 1-[4-(3-Chloro-phenyl)-piperazin-1-yl]-2-hydroxy -4-methyl-pentan-1-one (34 mg, 0.13 mmol), Pd(Ph3P)4 (1.3 mg, 10 μmol), K2CO3 (30.4 mg, 0.22 mmol), CH3CN (900 μL), and H2O (100 μL) were sealed in a microwave vessel and heated by microwave irradiation at 150° C. for 10 minutes. The reaction was filtered and purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) to give 2. LCMS: m/z 403.7 (M+H)+ at 3.72 minutes (10% -99% CH3CN/H2O), (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)[CH2:4][CH:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.[Br:21][C:22]1[CH:36]=[CH:35][C:25]([O:26][C:27]2[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=2)=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[Br:21][C:22]1[CH:36]=[CH:35][C:25]([O:26][C:27]2[CH:34]=[CH:33][C:30]([CH2:31][N:6]3[CH2:7][CH2:8][CH2:9][C@@H:5]3[CH2:4][N:3]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=3)[CH3:2])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(CN(C)CC2CCCN2)cc1
Reactant: O=Cc1ccc(Oc2ccc(Br)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CN(C)C[C@H]2CCCN2Cc2ccc(Oc3ccc(Br)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 93.7 %

Procedure:
A solution of methyl 4-[[methyl(2-pyrrolidinylmethyl)amino]methyl]benzoate hydrochloride salt (310 mg, 1.04 mmol) and 4-(4-bromophenoxy)benzaldehyde (301 mg, 1.1 mmol) in dichloroethane was stirred as diisopropylethylamine (DIEA, 1 mL) and sodium triacetoxyborohydride (286 mg, 1.35 mmol) were added sequentially at ambient temperature. After stirring at ambient temperature for 17 hours, the reaction mixture was treated with a saturated aqueous solution of sodium bicarbonate and extracted with EtOAc. The combined organic layers were dried and concentrated. Purification by flash chromatography afforded methyl 4-[[[[(R)-1-[[4-(4-bromophenoxy)phenyl]methyl]-2-pyrrolidinyl]methyl]methylamino]methyl]benzoate (510 mg, 94%); 1NMR (400 MHz, DMSO-d6) δ 7.98 (d, 2H), 7.42 (dd, 2H), 7.24 (d, 2H), 6.91 (d, 2H), 6.83 (d, 2H), 3.82 (s, 3H), 4.16 (d, 1H), 3.55 (dd, 2H), 3.23 (d, 1H), 2.90 (m, 1H), 2.42 (m, 1H), 2.55 (dd, 1H), 2.38 (dd, 1H), 2.11 (s, 3H), 2.17 (m, 1H), 1.99 (m, 1H), 1.63 (m, 3H) ppm.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=1)=O)C.CC(C[AlH]CC(C)C)C>C1COCC1>[F:14][C:11]([F:12])([F:13])[C:9]1[N:10]=[C:6]([CH2:4][OH:3])[S:7][CH:8]=1
Reactant: CCOC(=O)c1nc(C(F)(F)F)cs1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCc1nc(C(F)(F)F)cs1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
4-Trifluoromethyl-thiazole-2-carboxylic acid ethyl ester (131 mg) was dissolved in THF (5 ml). The reaction mixture was then cooled to −78° C. DIBAL-H (4.7 ml, 1.0 M in tetrahydrofurane) was added slowly during a period of 10 min. The cooling bath was removed, and the solution was kept under stirring for 30 min at RT. The solution was then cooled to 0° C., and NaF (784 mg) was added, followed by the slow addition of 3 ml water. The product was extracted by ethyl acetate. The solvent was removed, and the crude product was used in alkylation reactions without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:28]2)=[C:23]([CH:26]=1)[C:24]#[N:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([N:27]4[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][OH:35])[CH2:31][CH2:32]4)=[C:23]([C:24]#[N:25])[CH:26]=3)=[O:17])[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#Cc1cc(N)ccc1N1CCN(CCO)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)c(Cl)c1
Product: Cc1c(C(=O)Nc2ccc(N3CCN(CCO)CC3)c(C#N)c2)cnn1-c1ccc(Cl)c(Cl)c1
Yield: 32.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(3,4-dichlorophenyl)-5-methylpyrazole-4-carboxylic acid (2 g) and 5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (2.67 g), the title compound (1.2 g) was obtained, melting point: 195–197° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.Br[CH2:13][CH2:14][CH2:15][Cl:16]>CN(C)C=O>[Cl:16][CH2:15][CH2:14][CH2:13][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a suspension of sodium hydride (50% in oil, 3.9 g, 82 mmol) in dimethylformamide (100 ml) was added p-hydroxybenzaldehyde (5.0 g, 41 mmol). The mixture was stirred at room temperature under an atmosphere of nitrogen for one hour, then treated dropwise with 1-bromo-3-chloropropane (8.1 ml, 82 mmol). The mixture was stirred at room temperature for 12 hours, quenched with methanol and filtered through Celite. The filtrate was dissolved in diethyl ether (500 ml), washed with water (3×200 ml) and dried over Na2 SO4. The ether layer was concentrated to give 6.1 g (80% yield) of 4-chloropropoxybenzaldehyde as a yellow liquid. 1H NMR (CDCl3): δ 9.95 (s, 1H), 7.85 (d, J=8.1 Hz, 2H), 7.01 (d, J=8.1 Hz, 2H), 4.21 (t, J=5 Hz, 2H), 3.81 (t, J=5 Hz, 2H), 1.26 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11](C(O)=O)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C([N:19](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([NH2:19])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(-c2ncccc2Cl)cc1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
The product from Example 24A (104 mg, 0.444 mmol) and triethylamine (0.095 mL, 0.68 mmol) were combined in DMF (3 mL) and treated with diphenylphosphoryl azide (0.14 mL, 0.65 mmol). After stirring for 4 hours, the mixture was treated with water (0.30 mL) and heated at 65° C. for 1 hour. The mixture was allowed to cool to room temperature, diluted with water (7 mL), and extracted with diethyl ether (7 mL). The organic layer was washed with brine (7 mL), dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (50% ethyl acetate in hexanes) to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[N:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([OH:20])[CH2:15]1)([O-:3])=[O:2].N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].CCOCC>CN(C=O)C>[Si:26]([O:20][C@@H:16]1[CH2:17][CH2:18][CH2:19][N:14]([C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:15]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCC[C@@H](O)C1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1
Reaction time: 14 h

Procedure:
To a solution of (R)-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ol (3.35 g, 11.5 mmol) and imidazole (1.02 g, 15.0 mmol) in DMF at ambient temperature under nitrogen was added tert-butyldimethylsilylchloride (1.91 g, 12.7 mmol). The reaction was allowed to stir for 24 h, at which point additional 0.3 g tert-butyldimethylsilylchloride was added. The reaction was allowed to stir for an additional 14 h, and was then poured into Et2O/saturated aqueous NaHCO3. The organic layer was washed 2× H2O, 1× brine, dried over anhydrous MgSO4, filtered and concentrated to a yellow oil. The crude material was treated with hexanes and adsorbed onto silica gel and passed through a Redi-Sep® pre-packed silica gel column (80 g) eluting with 0-20% EtOAc/hexane. The product-containing fractions were concentrated to afford (R)-3-(tert-butyldimethylsilyloxy)-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine as a yellow oil. MS m/z=405 [M+H]+. Calc'd for C18H27F3N2O3Si: 404.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[Na]N1C2C(=CC=CC=2)C=C1.[CH3:22][Si:23](Cl)([CH3:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[CH3:22][Si:23]([CH3:28])([C:24]([CH3:27])([CH3:26])[CH3:25])[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Agent: [Na]n1ccc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)n1ccc2ccccc21
Yield: 79 %

Procedure:
1-(dimethyl-t-butylsilyl)indole is prepared by treatment of indole with sodium hydride in THF at temperature followed by the reaction of 1-sodioindole with dimethyl-t-butylsilyl chloride in THF according to the procedure described in D. Dhanak, C. B. Reese J. Chem. Soc., Perkin Trans. 1 1986, 2181-2186. The yield is 79%. The physical and spectral characteristics are described in this article.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]#[N:22])[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:12][C:11]([F:14])([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]#[N:22])[CH2:17][CH2:16]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: N#CC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Yield: 92.6 %

Procedure:
A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (5.56 g, 25 mmol), piperidine-4-carbonitrile (3.03 g, 27.50 mmol) and DIPEA (5.66 mL, 32.50 mmol) in DMF (50 mL) was heated at 70° C. for 1 hour. The solution was evaporated and partitioned between DCM and 1M aqueous K2CO3. The organic phase was washed with brine, dried over MgSO4, evaporated and the residue was triturated with ether. The solid was collected by filtration, washed with ether and dried under vacuum to afford 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidine-4-carbonitrile (6.86 g, 93%) as a cream crystalline solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][C:10]2[CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[CH3:16][NH2:17]>C(Cl)Cl>[CH3:16][NH:17][S:12]([C:8]1[CH:7]=[CH:6][C:5]2[CH2:4][CH2:3][C:2](=[O:1])[CH2:11][C:10]=2[CH:9]=1)(=[O:14])=[O:13]
Reactant: O=C1CCc2ccc(S(=O)(=O)Cl)cc2C1
Reactant: CN
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc2c(c1)CC(=O)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a solution of 7-oxo-5,6,7,8-tetrahydro-naphthalene-2-sulfonyl chloride (see Preparative Example 3, 1.14 g, 4.7 mmol) in CH2Cl2 (10 mL) at 15° C. (using a water bath) was added MeNH2 (2M in THF, 7 mL, 14 mmol, 3 eq) dropwise. After stirring at room temperature for 30 minutes, the mixture was diluted with CH2Cl2 (30 mL), washed with H2O (20 mL), dried (Na2SO4), and concentrated. The residue was chromatographed on silica by eluting with 20% EtOAc/hexanes to give 0.45 g (40%) of 7-oxo-5,6,7,8-tetrahydro-naphthalene-2-sulfonic acid methylamide as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.70 (d, 1H, J=8.1 Hz), 7.63 (s, 1H), 7.40 (d, 1H, J=8.1 Hz), 4.66 (q, 1H, J=5.4 Hz), 3.64 (s, 2H), 3.14 (t, 2H, J=6.6 Hz), 3.65 (d, 3H, J=5.4 Hz), 2.57 (t, 2H, J=6.6 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C@H:20]4[CH2:24][CH2:23][CH2:22][O:21]4)[CH:14]=3)[C:9]2=[O:25])=[CH:4][C:3]=1[F:26].[CH3:27][O:28][C@@H:29]1[CH2:33][NH:32][CH2:31][C@H:30]1[N:34]([CH3:36])[CH3:35]>>[CH3:35][N:34]([CH3:36])[C@H:30]1[C@H:29]([O:28][CH3:27])[CH2:33][N:32]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C@H:20]5[CH2:24][CH2:23][CH2:22][O:21]5)[CH:14]=4)[C:9]3=[O:25])=[CH:4][C:3]=2[F:26])[CH2:31]1
Reactant: CO[C@@H]1CNC[C@H]1N(C)C
Reactant: O=c1c2ccc(OC[C@H]3CCCO3)cc2ccn1-c1ccc(Br)c(F)c1
Product: CO[C@@H]1CN(c2ccc(-n3ccc4cc(OC[C@H]5CCCO5)ccc4c3=O)cc2F)C[C@H]1N(C)C

Procedure:
2-(4-Bromo-3-fluorophenyl)-6-[(R)-1-(tetrahydrofuran-2-yl)methoxy]-2H-isoquinolin-1-one and ((3R*,4R*)-4-methoxy-pyrrolidin-3yl)-dimethylamine were reacted according to Method R1. In this way the product was obtained with molecular weight 481.57 (C27H32FN3O4); MS (ESI): 482 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([O:12][CH3:13])[CH:3]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]#[N:21].C[O-].[Na+].C(O)(C)C>O>[NH2:9][C:8]1[C:7]2[C:2](=[CH:3][C:4]([O:12][CH3:13])=[C:5]([O:10][CH3:11])[CH:6]=2)[N:1]=[C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)[N:21]=1
Reactant: COc1cc(N)c(C#N)cc1OC
Reactant: N#Cc1ccccn1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COc1cc2nc(-c3ccccn3)nc(N)c2cc1OC

Procedure:
8.9 g. (0.05 mol) of 6-aminoveratronitrile, 5.2 g. (0.05 mol) of 2-pyridine carbonitrile and 5.4 g. (0.1 mol) of sodium methoxide in 250 ml. of isopropanol are refluxed for 48 hours under a nitrogen atmosphere. The reaction mixture is then decomposed with water and the isopropanol is distilled off. 80 ml. of diethyl ether and 80 ml. of water are added and the layers are separated. The water is distilled off from the aqueous layer and the residue is dissolved in 100 ml. of chloroform. The solution is filtered and the chloroform is distilled off. The residue is crystallized from toluene to give 4-amino-6,7-dimethoxy-2-(2-pyridyl)quinazoline, m.p. 248° - 251°C. The base is converted into the monohydrochloride, and the salt after crystallization from a mixture of water and isopropanol, melts above 310°C.
Reaction SMILES: [OH-].[Na+].Cl[CH2:4][C:5]([NH:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])=[O:6]>O.C(O)(C)C>[NH:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[O:11][CH2:4][C:5]1=[O:6]
Reactant: O=C(CCl)Nc1ccccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C1COC(=O)c2ccccc2N1
Temperature: 80 °C
Yield: 87 %

Procedure:
A solution of sodium hydroxide (2 g, 50 mole) in water (12 ml) was added to a stirred slurry of 2-chloroacetamidobenzoic acid (10.3 g, 48 mmole) in isopropanol (22.5 ml) and water (87.5 ml). The mixture was stirred until a solution formed and then heated at 80° C. for 4 hours. The solution was cooled to 0° C. and the crystalline solid collected, washed with water and dried in vacuo at 50° C. to give the product (7.4 g, 87%), m.p. 200°-201° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[CH:14]=3)[N:9](S(C3C=CC(C)=CC=3)(=O)=O)[CH:8]=2)=[C:5]([CH3:45])[N:4]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[CH:48]=2)[N:3]=1.[OH-].[Li+]>C1COCC1.CO.O>[CH3:1][C:2]1[C:6]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:16]4[CH:17]=[CH:18][C:19]([N:22]5[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]5)=[CH:20][CH:21]=4)[CH:14]=3)[NH:9][CH:8]=2)=[C:5]([CH3:45])[N:4]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[CH:48]=2)[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(C)c4)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cccc(Cn2nc(C)c(-c3c[nH]c4ncc(-c5ccc(N6CCN(C(=O)OC(C)(C)C)CC6)cc5)cc34)c2C)c1
Yield: 34.7 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(4-(3-(3,5-dimethyl-1-(3-methylbenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (90 mg, 0.1 mmol) was hydrolyzed by lithium hydroxide (9 mg, 0.3 mmol), THF/Methanol/water (1/1/0.5 ml) to afford 20 mg (29% yield) of the titled compound. MS: m/z=577.2 (M+1).