Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=2[CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[NH:23][CH2:22][C:21]=12>>[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([C:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=4)=[C:8]([CH3:16])[CH:9]=3)=[O:13])[CH2:22][C:21]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1cc(C(=O)O)ccc1C1=CCCCC1
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1C1=CCCCC1
Yield: 80.3 %

Procedure:
4-Cyclohex-1-en-1-yl-3-methyl-benzoic acid of Step C (0.360 g, 1.66 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.337 g, 1.83 mmol) were reacted in the manner of Example 15, Step D. Purification by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, followed by recrystallization from 1:1 ethyl acetate/petroleum ether afforded the title compound (0.510 g) as white crystals, m.p. 182–183° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([Sn](CCCC)(CCCC)CCCC)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Br[C:42]1[N:47]2[CH:48]=[C:49]([CH3:51])[N:50]=[C:46]2[CH:45]=[CH:44][CH:43]=1>O1CCOCC1.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.S1C=CC=C1C([O-])=O.[Cu+]>[CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([C:18]([OH:21])([CH3:19])[CH3:20])[CH2:16][CH2:17]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([C:42]1[N:47]3[CH:48]=[C:49]([CH3:51])[N:50]=[C:46]3[CH:45]=[CH:44][CH:43]=1)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: Cc1cn2c(Br)cccc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: Cc1cn2c(-c3nc(N4CCOCC4)c4nc(CN5CCC(C(C)(C)O)CC5)n(C)c4n3)cccc2n1
Temperature: 150 °C
Yield: 31.3 %

Procedure:
A mixture of 2-[1-(9-methyl-6-morpholin-4-yl-2-(tributylstannanyl)-9H-purin-8-ylmethyl)-piperidin-4-yl]propan-2-ol (127 mg, 0.19 mmol), 5-bromo-2-methyl-imidazo[1,2-a]pyridine (48 mg, 0.23 mmol), Pd(PPh3)4(22 mg, 0.02 mmol) and copper(I) thiophene-2-carboxylate (7 mg, 0.04 mmol) in dioxane (2 mL) was purged with argon gas then heated at 150° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 0:100) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 692 as a pale yellow solid (30 mg, 31%). LCMS (Method E) RT 4.77 min; [M+H]+ 505. 1H NMR (400 MHz, CHCl3-d): δ 8.98 (s, 1 H); 7.91 (dd, J=7.2, 1.2 Hz, 1 H); 7.66 (d, J=8.8 Hz, 1 H); 7.30-7.25 (m, 1 H); 4.38 (s, 4 H); 3.96 (s, 3 H); 3.89 (t, J=4.7 Hz, 4 H); 3.75 (s, 2 H); 2.96 (d, J=11.0 Hz, 2 H); 2.54 (s, 3 H); 2.12 (t, J=11.0 Hz, 2 H); 1.81-1.71 (m, 1 H); 1.45-1.23 (m, 4 H); 1.19 (s, 6 H)
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.Cl.N([O-])=O.[Na+].[I-:16].[K+]>O.C(OCC)(=O)C>[I:16][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: [I-]
Reactant: Nc1cccc2[nH]ncc12
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Ic1cccc2[nH]ncc12
Temperature: 30 °C
Yield: 25.1 %

Procedure:
A mixture of 4-amino-1H-indazole (50.0 g, 0.375 moles) in water (100 ml) and con. hydrochloric acid (182 ml) was cooled to −10° C. To this a solution of sodium nitrite (51.7 g, 0.75 moles) in water (75 ml) was added drop wise at −10° C. in about 30-60 min. (during addition frothing was observed). In another flask a mixture of potassium iodide (311 g, 1.87 moles) in water (3000 ml) was prepared at room temperature and to this above cooled diazonium salt at 30-40° C. was added in about 30-40 min. The reaction was maintained at 30° C. for 1 h and after completion of reaction, ethyl acetate (500 ml) was added and the reaction mixture was filtered through Celite. The layers were separated and the aq. layer was extracted with ethyl acetate (2×500 ml). The combined organic layers were washed with 5% hypo solution (2×500 ml), brine (500 ml), dried (Na2SO4) and concentrated. Crude product was purified by chromatography (silica gel, hexane, 15-20% ethyl acetate/hexane) to furnish 4-iodo-1H-indazole as an orange solid (23.0 g, 25%). mp: 151-177 C: 1H NMR (200 MHz, CDCl3) δ 12.4 (br, 1H), 8.0 (s, 1H), 7.6 (dd, 2H), 7.1 (d, 1H). ESMS m/z 245 (M+1). Purity: 95-98% (HPLC).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[C:20]([F:21])=[C:19]4[C:14]([CH:15]=[CH:16][CH:17]=[N:18]4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[Na+]>O1CCCC1>[F:21][C:20]1[C:11]([N:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2
Reactant: Fc1c(N2CCC3(CC2)OCCO3)ccc2cccnc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1CCN(c2ccc3cccnc3c2F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.8 %

Procedure:
To a solution of 7-(1.4-dioxa-8-azaspiro[4.5]dec-8-yl)-8-fluoroquinoline (Example J, Step 2; 1.30 g) in tetrahydrofuran (60 mL) was added aq. 2N aqueous HCl (10 mL). The resulting mixture was stirred at room temperature for 18 hours and then heated at 60° C. for 5 hours. The reaction mixture was cooled to room temperature, poured into 1N aqueous NaOH and extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated on a rotary evaporator. The crude product was purified by flash chromatography using hexane/acetone to give 0.89 g of the desired product as a yellow solid; MS (ES) m/z (relative intensity): 245 (M+H)+ (100).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[O:13][CH2:14][C:15]([N:17]1[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:19][C@H:18]1[CH3:32])=[O:16])C.O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]([O:13][CH2:14][C:15]([N:17]2[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH2:19][C@H:18]2[CH3:32])=[O:16])=[C:6]([CH2:5][C:4]([OH:33])=[O:3])[CH:11]=1
Reactant: CCOC(=O)Cc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CC(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.8 %

Procedure:
To a solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acetic acid ethyl ester (5.1 g, 10.7 mmol) in tetrahydrofuran (30 mL), methanol (30 mL) and water (6 mL) was added lithium hydroxide monohydrate (2.2 g, 53.5 mmol). The reaction was stirred for 18 hour at ambient temperature. The reaction was then concentrated in vacuo and the remaining solution was acidified with a 1M aqueous hydrochloric acid and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was diluted with minimal dichloromethane and diethyl ether was added. A white precipitate was collected by filtration to give the title compound (3.93 g).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH2:30]([CH2:32][NH2:33])[OH:31]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][NH:33][CH2:32][CH2:30][OH:31])[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: NCCO
Product: OCCNCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 28 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and ethanolamine to give the title compound in 28% yield; NMR Spectrum: 2.68 (t, 2H), 2.98-3.00 (m, 2H), 3.46-3.49 (m, 2H), 4.36 (t, 2H), 5.29 (s, 2H), 7.23 (d, 1H), 7.37 (t, 1H), 7.54-7.58 (m, 2H), 7.86-7.93 (m, 2H), 8.27 (s, 1H), 8.59 (d, 1H), 8.65 (br s, 1H); Mass Spectrum: 456 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[CH:18]12[C:25](=O)[CH:22]([CH2:23][CH2:24]1)[CH2:21][CH2:20][CH2:19]2.[BH4-].[Na+].[OH-].[Na+]>ClCCl.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH:18]12[CH2:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][CH:20]([N:15]1[CH2:16][CH2:17][CH:12]([N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9](=[O:11])[CH3:10])[CH2:13][CH2:14]1)[CH2:19]2
Reactant: O=C1C2CCCC1CC2
Reactant: CC(=O)N(c1ccc(F)cc1)C1CCNCC1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N(c1ccc(F)cc1)C1CCN(C2CC3CCC(C3)C2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-(4-fluoro-phenyl)-N-piperidin-4-yl-acetamide (60 mg; 0.25 mmol; 1 eq.), see Example 6 for deprotecting procedure, and bicyclo[3.2.1]octan-8-one (37 mg, 0.3 mmol, 1.2 eq.) were dissolved in dichloromethane (1.5 mL) and DCM (1.5 mL) and treated with Ti(OiPr)4 (213 mg, 0.75 mol, 3 eq.). The reaction was stirred under nitrogen at room temperature for 48 hours, then cooled in a dry ice/isopropanol bath to ˜−40° C. and quenched with methanol (4 mL). The reaction was stirred for 15 minutes at that temperature, then treated with 4.0 eq sodium borohydride (37 mg, 1 mmol). The reaction was slowly warmed to room temperature and stirred for 2 hours. The reaction was then treated with 1 N NaOH (2 mL), stirred vigorously for 30 minutes, filtered through Celite and the solids rinsed with CH2Cl2 (4×5 mL). The filtrates were combined and washed with H2O, saturated brine, dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by preparative HPLC (2-99 H2O—CH3CN gradient, 15 minute method) to afford the desired product. LC/MS M/Z 345.3, retention time 2.34 minutes 10-99% CH3CN/H2O gradient with 0.05% TFA.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])[N:9]=2)[CH2:4]1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[O:35]>CN(C=O)C>[OH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:10]1[N:9]=[C:8]([N:5]2[CH2:6][CH2:7][C@@H:3]([CH2:2][NH:1][C:34](=[O:35])[O:36][CH2:37][CH2:38][O:39][CH3:40])[CH2:4]2)[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[N:11]=1
Reactant: COCCOC(=O)Cl
Reactant: Cc1ccc2c(N3CC[C@@H](CN)C3)nc(-c3ccccc3O)nc2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCOC(=O)NC[C@@H]1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
A solution of 2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (0.12 g, 0.35 mmol) and triethylamine (98 μL, 0.7 mmol) in anhydrous DMF (4.0 mL) was cooled in an ice bath. 2-Methoxyethyl chloroformate (40 mL, 0.35 mmol) was added, and the ice bath was removed. The solution was stirred at room temperature overnight. Purification via silica gel chromatography using 0-10% MeOH in CH2Cl2 gave 2-methoxyethyl ((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate (0.12 g, 80%). LC/MS: m/z 437.5 (M+H)+ at 2.20 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:10][CH3:11])=[C:6]([CH:9]=1)[C:7]#[N:8].CO.Cl>C1COCC1.C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:10][CH3:11])=[C:6]([CH:9]=1)[CH2:7][NH2:8]
Reactant: CSc1ccc(Cl)cc1C#N
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CSc1ccc(Cl)cc1CN
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
5-Chloro-2-methylsulfanyl-benzonitrile (3.9 g, 21.2 mmol) was dissolved in THF (42 mL) and cooled to 0 degrees C. Borane-THF complex (50 mL of a 1M THF solution) was added dropwise. After 10 minutes at 0 degrees C. the reaction was warmed to 65 degrees C. for 4 h. Methanol (approximately 30 mL) was added to the reaction at 0 degrees C. The reaction was warmed to room temperature and stirred for 10 minutes. The reaction solution was concentrated in-vacuo to yield a thick oil which was dissolved in 50% THF/MeOH (30 mL). 4M HCl (30 mL) was added slowly. After 10 minutes, the solution was partitioned between water (10 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (30 mL) and the organic layers were discarded. The aqueous layer was neutralized to pH9 with 5M NaOH. The solution was extracted with DCM (3×70 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to yield 2.9 g of 5-chloro-2-methylsulfanyl-benzylamine as a pale yellow oil, 1H NMR 400 MHz (CDCl3) δ 7.33 (d, 1H, J=2.4 Hz), 7.22 (dd, 1H, J=2.4, 8.4 Hz), 7.13 (d, 1H, J=5 8.4 Hz), 3.89 (s, 2H), 2.48 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].[S:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1>>[S:9]1[CH2:10][CH:11]=[C:12]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:14]1
Reactant: C#Cc1ccccn1
Reactant: O=C1CCSCC1
Product: C(#Cc1ccccn1)C1=CCSCC1

Procedure:
Reactants: 2-ethynylpyridine (6.0 mmol, 618 mg), tetrahydrothiopyran-4-one (6.0 mmol, 696 mg); yields 2-(3,6-dihydro-2H-thiopyran-4-ylethynyl)pyridine as a transparent oil (150 mg, 12% overall yield). 1H NMR (CDCl3, 300 MHz) δ 8.57 (m, 1H), 7.61 (m, 1H), 7.40 (m, 1H), 7.21 (m, 1H), 6.46 (m, 1H), 3.27 (m, 2H), 2.78 (m, 2H), 2.57 (m, 2H). MS (EI ionization) 201 (M+).
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([F:11])[C:5]([F:12])=[C:4](F)[C:3]=1[F:14].[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C1(=O)OCCC1>[CH2:15]([O:22][C:4]1[C:5]([F:12])=[C:6]([F:11])[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[C:3]=1[F:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1c(F)c(F)c(F)c(F)c1F
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C1CCCO1
Product: O=[N+]([O-])c1c(F)c(F)c(OCc2ccccc2)c(F)c1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
21.3 g of pentafluoronitrobenzene (0.1 mol) and 12 g of benzyl alcohol (0.11 mol, i.e. a 10% excess) are dissolved in 200 ml of dry γ-butyrolactone in a three-neck flask fitted with stirrer. 30 g of potassium carbonate (0.22 mol) are then added in portions, and the mixture is stirred at room temperature for 24 hours. The reaction solution is then filtered via a fluted filter, and the crude product is extracted by shaking with 200 ml of ethyl acetate and 300 ml of water. The organic phase is washed three times with water, dried over sodium sulfate and evaporated to half in a rotary evaporator. The reaction product crystallizes from the initially viscous solution. The precipitated reaction product is then recrystallized from a mixture of methylene chloride and petrol ether (volume ratio 1:1) and then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([N:16]2[CH2:21][CH:20]([CH3:22])[O:19][CH:18]([CH3:23])[CH2:17]2)[N:3]=1.O.[NH2:25][NH2:26].Cl>>[NH2:9][C:8]1[C:7]2[C:2](=[N:3][C:4]([N:16]3[CH2:21][CH:20]([CH3:22])[O:19][CH:18]([CH3:23])[CH2:17]3)=[CH:5][C:6]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:26][N:25]=1
Reactant: NN
Reactant: CC1CN(c2cc(-c3ccccc3)c(C#N)c(Cl)n2)CC(C)O1
Agent: Cl
Solvent: O
Product: CC1CN(c2cc(-c3ccccc3)c3c(N)n[nH]c3n2)CC(C)O1

Procedure:
3-Amino-6-(2,6-dimethyl-morpholino)-4-phenyl-1H-pyrazolo[3,4-b]-pyridine was prepared analogous to Example 1 from 2-chloro-6-(2,6-dimethyl-morpholino)-4-phenyl-3-cyano-pyridine (m.p. 165°-178° C.; mixture of isomers) and hydrazine hydrate. M.p. of the hydrochloride: 235°-238° C. (decomp.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[OH:14].C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[CH2:21]([O:14][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH:6]=[CH:7][C:2]=1[CH3:1])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(Nc2nccs2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(Nc2nccs2)cc1OCc1ccccc1
Yield: 58 %

Procedure:
Following the general procedure for O-alkylation, Method A, a mixture of 2-methyl-5-(thiazol-2-ylamino)phenol (70 mg, 0.34 mmol) and K2CO3 (52 mg, 0.32 mmol) in acetone (4.4 mL) was treated with benzyl bromide (58 mg, 0.34 mmol) at RT. Reaction control by TLC showed full conversion after 2 h 30 min. Subsequent benzyl bromide (20 microliter) and K2CO3 (20 mg) were added and stirred over night The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 3/1) in 58% yield (58 mg).
Reaction SMILES: C(O[C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:5]=1)=O.[N:22]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:16]1([S:13]([N:6]2[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:12]3[C:4]([N:25]3[CH2:24][CH2:23][N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26]3)=[CH:5]2)(=[O:15])=[O:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=COc1cn(S(=O)(=O)c2ccccc2)c2ncccc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)CC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Into a 150 mL sealed tube was placed 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl formate (1.5 g, 4.97 mmol). To this was added tert-butyl piperazine-1-carboxylate (9.24 g, 49.68 mmol). Addition of p-toluenesulfonic acid (171 mg, 0.99 mmol) was next. To the mixture was added toluene (70 mL). After nitrogen bubbled, the resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at 120° C. in a bath of oil. The mixture was concentrated by evaporation under vacuum using a rotary evaporator. The residue was dissolved in 300 mL of ethyl acetate. The resulting mixture was washed 2 times with 150 mL of brine. The mixture was dried over Na2SO4. The residue was purified by eluting through a column with a 1:2 ethyl acetate/petroleum ether solvent system. This resulted in 420 mg (18%) of tert-butyl 4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperazine-1-carboxylate as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].Cl.[NH2:13][CH:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([S:29][CH:30]([F:32])[F:31])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)[CH2:15][OH:16].C(=O)(O)[O-].[Na+]>ClCCl.O>[F:32][CH:30]([F:31])[S:29][C:26]1[CH:25]=[CH:24][C:23]([C:20]2[CH:21]=[CH:22][C:17]([CH:14]([NH:13][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=3[F:11])[CH2:15][OH:16])=[CH:18][CH:19]=2)=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: NC(CO)c1ccc(-c2ccc(SC(F)F)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(NC(CO)c1ccc(-c2ccc(SC(F)F)cc2)cc1)c1c(F)cccc1F
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A solution of 0.137 g (0.776 mmol) of 2,6-difluorobenzoyl chloride in 1 mL of dichloromethane was added dropwise to a mixture of 0.23 g (0.693 mmol) of β-amino-4'-[(difluoromethyl)thio][1,1'-biphenyl]-4-ethanol hydrochloride salt, 1.5 mL of dichloromethane, and 1.5 mL of sodium bicarbonate (saturated aqueous solution). The mixture was stirred for 2 h, and was diluted with 10 mL of water. The mixture was extracted with 3×20 mL of dichloromethane, 35 mL of dichloromethane and the organic phase separated. The combined extracts were dried and evaporated. Chromatography on silica gel (eluted with ethyl acetate/hexane (1:1)) gave the product 0.28 g (93% yield) as a white solid m.p. 156.5-157° C. IR(Nujol): 3294, 1649, 1624, 1589, 1535, 1309, 1233, 1071, 1004, 819 cm-1. 1H-NMR(CDCl3): δ2.15 (t, J=5.75 Hz, 1H), 4.03-4.06 (m, 2H), 5.33-5.37 (m, 1H), 6.81 (d, J=7.2 Hz, 1H), 6.86 (t, J=57 Hz, 1H), 6.94-6.99 (m, 2H), 7.35-7.43 (m, 1H), 7.48 (d, J=8 Hz, 2H), 7.50-7.65 (m, 6H).
Reaction SMILES: [O:1]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[O:4][CH2:3][CH2:2]1)[N:11]=[CH:10][CH:9]=[C:8]3O.P(Br)(Br)[Br:17].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:17][C:8]1[C:7]2[C:12](=[CH:13][CH:14]=[C:5]3[O:4][CH2:3][CH2:2][O:1][C:6]3=2)[N:11]=[CH:10][CH:9]=1
Reactant: Oc1ccnc2ccc3c(c12)OCCO3
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccnc2ccc3c(c12)OCCO3
Temperature: 25 °C
Yield: 90 %

Procedure:
2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-10-ol (2.8 g) in dry DMF (8 mL) was cooled in ice and phosphorus tribromide (0.7 mL) added drop-wise, and the mixture was stirred, with ice-cooling for 30 minutes then allowed to warm to room temperature and stirred for a further 2 hours. It was cooled in ice and sodium carbonate solution was added and the solid was collected, washed well with water, and dried in vacuo, to afford a pale yellow solid (1.65 g, 90%). LC/MS (ES) m/z 267.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@@H:3]([C:14](OC)=[O:15])[NH:2]1.[BH4-].[Na+]>C(O)C>[OH:15][CH2:14][C@@H:3]1[CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1][NH:2]1
Reactant: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC[C@@H]1Cc2c([nH]c3ccccc23)CN1
Reaction time: 12 h
Yield: 68.5 %

Procedure:
A mixture of 15 g of methyl (3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxylate, 6.99 g of NaBH4, and 225 ml of 80% ethanol is stirred at room temperaure for 12 hours, and then refluxed for 1.5 hours. The insoluble materials are filtered off and washed with hot ethanol. The filtrate and the washing are combined and distilled to remove the solvent. Water (40 ml) is added to the residue, and the solution is stirred for 40 minutes. The precipitates are collected by filtration, dried and then recrystallized from ethanol. 9.03 g of (3S)-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline are obtained as colorless needles. Yield: 79.4%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=O)[N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH:11]1[CH2:16][OH:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH:11]2[CH2:16][OH:17])[N:3]=1
Reactant: OCC1COCCN1
Reactant: O=Cc1nccc(Cl)n1
Product: OCC1COCCN1Cc1nccc(Cl)n1

Procedure:
The title compound was prepared according to the general procedure in Example 45, Step 1 using 4-chloropyrimidine-2-carbaldehyde (0.573 g, 4.02 mmol) and morpholin-3-ylmethanol (0.565 g, 4.82 mmol) as the starting materials.