Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[F:18][CH:19]([F:30])[O:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1>>[F:18][CH:19]([F:30])[O:20][C:21]1[CH:22]=[CH:23][C:24]([C@@H:27]([NH:29][CH2:16][CH2:15][C:2]2([OH:1])[CH2:14][CH2:13][C:5]3([O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][O:10]3)[CH2:4][CH2:3]2)[CH3:28])=[CH:25][CH:26]=1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Reactant: C[C@H](N)c1ccc(OC(F)F)cc1
Product: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(OC(F)F)cc1
Yield: 65 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-(4-difluoromethoxy-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 65% of theory; LC (method 5): tR=1.02 min; Mass spectrum (ESI+): m/z=414 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:31][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23]4[CH:28]=[CH:27][C:26](=[O:29])[N:25]([CH3:30])[CH:24]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCN(CC)CC.[C:40]([N:44]=[C:45]=[O:46])([CH3:43])([CH3:42])[CH3:41]>CO.CN(C=O)C>[C:40]([NH:44][C:45]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[NH:31][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23]4[CH:28]=[CH:27][C:26](=[O:29])[N:25]([CH3:30])[CH:24]=4)[C:16]=3[CH:15]=2)[CH2:12][CH2:13]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]
Reactant: Cn1cc(Nc2ncnc3[nH]c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc23)ccc1=O
Reactant: CC(C)(C)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1cc(Nc2ncnc3[nH]c(C4=CCN(C(=O)NC(C)(C)C)CC4)cc23)ccc1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-[4-(1-Methyl-6-oxo-1,6-dihydropyridin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (38.0 mg, 0.0845 mmol), 9M of Hydrogen chloride in Methanol (2 mL) and Methanol (2 mL) were combined, and the above miture was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo to obtain a black solid. DMF (3 mL), NEt3 (58.9 μL, 0.423 mmol) and tert-butyl isocyanate (14.5 μL, 0.127 mol) were added, and the mixture was stirred at rt under N2 for 1.5 h. Another portion of tert-butyl isocyanate was added and the reaction was stirred overnight. The mixture was concentrated in vacuo, and the residue was purified by HPLC to obtain the title compound as pink solid. 1H NMR (CD3OD, 400 MHz): δ=1.36 (s, 9H), 2.56 (brs, 2H), 3.61 (m, 2H), 3.62 (s, 3H), 4.07 (brs, 2H), 6.29 (brs, 1H), 6.58 (s, 1H), 6.60 (d, 1H, J=9.6 Hz), 7.71 (dd, 1H, J=2.8 & 9.6 Hz), 8.16 (brs, 2H), 8.19 (s, 1H), 8.25 (d, 1H, J=2.4 Hz). MS (ES+): m/z 422.12 (100) [MH+]. HPLC: tR=20.11 min (ZQ2000, polar—5 min).
Reaction SMILES: I[C:2]1[N:7]2[N:8]=[C:9]([S:19][CH3:20])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25](OB(O)O)=[C:24]([O:33][CH3:34])[CH:23]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(OCC)(=O)C>COCCOC.O.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>[CH3:34][O:33][C:24]1[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[C:23]=1[C:2]1[N:7]2[N:8]=[C:9]([S:19][CH3:20])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C)cc(C)c1OB(O)O
Reactant: CSc1nn2c(I)cccc2c1NC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc(C)cc(C)c1-c1cccc2c(NC(=O)OC(C)(C)C)c(SC)nn12
Temperature: 80 °C
Reaction time: 3 h
Yield: 102.9 %

Procedure:
After dissolving tert-butyl N-[7-iodo-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate (2.0 g) in 1,2-dimethoxyethane (60 mL) and water (30 mL), 4,6-dimethyl-2-methoxyphenylboric acid (1.33 g), tetrakis(triphenylphosphine)palladium (0) complex (865 mg) and barium hydroxide octahydrate (2.34 g) were added and the mixture was heated and stirred at 80° C. for 3 hours. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (2.1 g) was obtained from the n-hexane:ethyl acetate (20:1) fraction as yellow amorphous.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7](C=O)=[CH:6][C:3]=1[C:4]#[N:5].[BH4-].[Na+].Cl.[CH3:15][OH:16]>>[F:1][C:2]1[CH:9]=[C:8]([CH2:15][OH:16])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: CO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: N#Cc1ccc(CO)cc1F

Procedure:
To a solution of 2-fluoro-5-formylbenzonitrile (350 mg, 2.4 mmol) in methanol (11 ml), at 0° C., was added sodium borohydride (107 mg, 2.8 mmol). The reaction mixture was allowed to warm to room temperature over 1 h, before addition of hydrochloric acid (1M, 30 ml). The mixture was extracted with ethyl acetate and the combined extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound (354 mg).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][C:25]2[NH:29][N:28]=[N:27][N:26]=2)=[CH:17][CH:16]=1)C1C=CC=CC=1>[Pd].ClCCl>[NH:29]1[C:25]([CH2:24][CH2:23][CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH2:10])=[CH:16][CH:17]=2)=[N:26][N:27]=[N:28]1
Reactant: O=C(NCCCCc1ccc(OCCCc2nnn[nH]2)cc1)OCc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Product: NCCCCc1ccc(OCCCc2nnn[nH]2)cc1
Yield: 99.5 %

Procedure:
A solution of (4-{4-[3-(1H-tetrazol-5-yl)propoxy]phenyl}butyl)carbamic acid benzyl ester 3 (0.30 g, 0.73 mmol) methanol (20 mL) and dichloromethane (5 mL) was stirred at room temperature overnight under hydrogen atmosphere in the presence of 10% palladium-on-carbon catalyst (0.1 g, 50% wet). The catalyst was removed by suction filtration, and the filtrate was concentrated in vacuo to give the desired product 4 as a white solid (200 mg, 99% yield) which was used for the next step without further purification. m/z (ESI): 276 [C14H21N5O+H]+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][C:8](=[O:10])[N:7]([C:11](=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CCC)[CH2:6][C:5]1=[O:21])(=[O:3])[CH3:2].[CH2:22](C(CCCC)C(Cl)=O)[CH3:23]>>[C:1]([N:4]1[CH2:9][C:8](=[O:10])[N:7]([C:11](=[O:20])[CH:12]([CH2:22][CH3:23])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:6][C:5]1=[O:21])(=[O:3])[CH3:2]
Reactant: CCCCC(CC)C(=O)Cl
Reactant: CCCCCCCCC(=O)N1CC(=O)N(C(C)=O)CC1=O
Product: CCCCC(CC)C(=O)N1CC(=O)N(C(C)=O)CC1=O

Procedure:
##STR25## Synthesized as for 1-Acetyl-4-nonanoyl-2,5-piperazinedione in EXAMPLE I using 2-ethylhexanoyl chloride in place of nonanoyl chloride.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])#[N:24].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[C:25]([C:23]#[N:24])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(c2cccc(Cl)c2)CN(Cc2ccccc2)CCC1=O
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)=C1CCN(Cc2ccccc2)CC1(C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 1-benzyl-3-(3-chlorophenyl)-3-methyl-4-piperidone (50 mmole), ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E- and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate/petroleum ether.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[CH2:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:17][CH2:16]3)=[O:14])[N:38]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:39]2=[O:40])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN3S(=O)(=O)c3ccccc3)CC2)c1
Reactant: O=C=NCc1ccccc1
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3Cc3ccccc3)CC2)c1

Procedure:
In analogy to example 2, (RS)-(1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 2, step 3) was reacted with sodium iodide and benzyl isocyanate to give the title compound as a colorless solid. MS: 532.9 ([M+H]+)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([O:15][CH2:16]C)=[O:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][O-:19].[Na+].[Cl-].[NH4+]>CS(C)=O>[CH3:18][O:19][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)Nc1ccc2c(Cl)nccc2c1
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)Nc1ccc2c(OC)nccc2c1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
In dimethyl sulfoxide (45 ml) was dissolved 2.27 g of 1-chloro-6-ethoxycarbonylaminoisoquinoline (Preparation Example 41). To the mixture was added 28% sodium methoxide solution (8.7 ml), followed by heating under stirring at 110° C. for 1.5 hours. After cooling to room temperature as it was, an aqueous saturated ammonium chloride was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give the title compound (1.75 g, 84%) as a brown oil.
Reaction SMILES: C(OC([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][S:15][C:9]=2[CH2:8][CH2:7]1)=O)C.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[C:16]1([S:22]([C:14]2[S:15][C:9]3[CH2:8][CH2:7][NH:6][CH2:12][CH2:11][C:10]=3[CH:13]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)N1CCc2ccsc2CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=S(=O)(c1ccccc1)c1cc2c(s1)CCNCC2
Temperature: 80 °C

Procedure:
The product of Example 1, step (d) (75 mg, 0.33 mmol) was dissolved in 2 mL DCE and treated with phenyl sulfonyl chloride (83 μL, 0.66 mmol) followed by AlCl3 (88 mg, 0.66 mmol). After heating to 80° C. for ½ hour, the reaction was cooled and quenched carefully with 1 M NaOH. The product was extracted into DCM (2×). The organic extracts were concentrated and the residue was dissolved in 3 mL each EtOH and 40% aqueous KOH. The reaction was heated to 100° C. for 14 hours, cooled, and diluted with water. The title compound was extracted into DCM (2×5 mL) and purified by preparative HPLC-MS. 1H NMR (CD3OD) δ 7.96 (d, J=8.1 Hz, 2H), 7.67-7.56 (m, 3H), 5.56 (s, 1H), 3.38-3.32 (m, 4H), 3.27-3.23 (m, 2H), 3.09 (t, J=5.4 Hz, 2H); MS: ESI (positive): 294 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([N+:16]([O-])=O)=[CH:4][C:5]2[O:9][CH:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:6]=2[CH:15]=1.[NH4+].[Cl-]>CO.C1COCC1.O.[Fe]>[NH2:16][C:3]1[C:2]([Br:1])=[CH:15][C:6]2[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][O:9][C:5]=2[CH:4]=1
Reactant: CCOC(=O)c1coc2cc([N+](=O)[O-])c(Br)cc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1coc2cc(N)c(Br)cc12
Yield: 67.6 %

Procedure:
A mixture of crude compound ethyl 5-bromo-6-nitrobenzofuran-3-carboxylate (95 g, 302 mmol), iron filings (50.67 g, 907 mmol) and NH4Cl (97 g, 1.82 mol) in MeOH-THF—H2O (2:2:1, 1000 mL) were stirred at reflux for 3 hours. After being filtered and concentrated in vacuum, the residue was purified by column chromatography (eluted with PE:EA from 20:1 to 10:1) to furnish ethyl 6-amino-5-bromobenzofuran-3-carboxylate (58.00 g, yield: 68%). 1H-NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.85 (s, 1H), 7.03 (s, 1H), 5.55 (br s, 2H), 4.31 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1N.Cl.N([O-])=O.[Na+].[C:17]([S-:19])#[N:18].[K+]>O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[S:19][C:17]#[N:18]
Reactant: N#C[S-]
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: N#CSc1cc([N+](=O)[O-])ccc1Cl
Yield: 39.9 %

Procedure:
2-Chloro-5-nitroaniline (90.0 g, 522 mmole) and 6 N HCl (600 mL) were stirred at room temperature until a homogeneous paste was obtained. Sodium nitrite (40.5 g, 585 mmole) in water (60 mL) was added drop by drop to this solution at 0° C. under inert atmosphere. After the addition was complete, the mixture was stirred for an additional hour. This was added in portions to a solution of KSCN (72.0 g, 738 mmole) and CuSCN (63.0 g, 522 mmole) in water (200 mL) at room temperature over a period of 2 hrs. On adding the diazonium salt to the thiocyanates, the solution turned from yellow to black with foaming. The mixture was stirred overnight and then filtered. The precipitate was washed with CH2Cl2 three times. The filtrate was also washed with CH2Cl2. The combined organic extracts were washed with water and dried with MgSO4. The solvent was then removed and the crude mixture was further recrystallized in hexane to yield light yellow powder (44.7 g, 42%). mp 103° C. (lit. 102° C.). 1H NMR (250 MHz, CDCl3) δ: 8.32 (d, 1H, J=2.5 Hz), 8.10 (dd, 1H, J=8.8, 2.5 Hz), 7.66 (d, 1H, J=8.8 Hz). 13C NMR (62.5 MHz, CDCl3) δ:147.0, 138.7, 131.1, 124.6, 124.0, 107.4. HR-MS (EI): calcd. for C7H3ClN2O2S 213.9600 [M+]. found 213.9598.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:12][CH2:13]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(CN2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
To a solution of 1-BOC-4-formyl-piperidine (210 mg) in dry 1,2-dichloroethane (10 mL), was added morpholine (86 mg) and glacial acetic acid (60 μL) and stirred for 1 h at room temperature. To the mixture was added sodium triacetoxyborohydride (272 mg) and the mixture stirred for 12 h. The reaction mixture was extracted into DCM (25 mL), washed with 50% sodium bicarbonate solution (10 mL), brine (10 mL), and dried (MgSO4). The solvents were removed in vacuo to give a residue which was purified by flash chromatography to give 4-morpholine-4-ylmethyl-piperidine-1-carboxylic acid tert-butyl ester (120 mg). Treatment with TFA yielded the desired amine which was isolated as the TFA salt.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[CH:10]=[N:9][N:8]([CH3:11])[C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:20]([CH:22](Br)[CH3:23])[CH3:21]>CN(C)C=O>[CH3:11][N:8]1[C:6]2[N:7]=[C:2]3[S:1][CH:22]([CH3:23])[CH:20]([CH3:21])[N:3]3[C:4](=[O:12])[C:5]=2[CH:10]=[N:9]1
Reactant: Cn1ncc2c(=O)[nH]c(S)nc21
Reactant: CC(Br)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1Sc2nc3c(cnn3C)c(=O)n2C1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 12.1 %

Procedure:
In 200 ml of dimethylformamide was dissolved 10.0 g (54.9 mmol) of 4,5-dihydro-6-mercapto-1-methylpyrazolo[3,4-d]pyrimidin-4(1H)-one [Helv. Chim. Acta, 42, 349 (1959)], and 15.2 g (110 mmol) of potassium carbonate and 10.1 ml (82.3 mmol) of 2,3-dibromobutane were added to the solution, followed by stirring at 80° C. for 3 hours. After evaporation of the solvent, the residue was subjected to partition between chloroform and water, and the chloroform layer was concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform to give 1.57 g (12%) of Compound 41. The compound was recrystallized from ethyl acetate/hexane for purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][N:3]=1.[CH:18]1([C@H:24]([NH2:26])[CH3:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[OH-].[Na+]>CN1CCCC1=O>[CH:18]1([C@H:24]([NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:4][N:3]=2)[CH3:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Reactant: C[C@@H](N)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: C[C@@H](Nc1nnc(-c2ccccc2)c2ccccc12)C1CCCCC1
Yield: 75.5 %

Procedure:
To 400 ml of N-methylpyrrolidone, 144.4 g (0.6 mol) of 1-chloro-4-phenylphthalazine and 230 g (1.8 mol) of (R)-(-)-1-cyclohexylethylamine were added, and the mixture was heated to 120° to 130° C. for 6 hours with stirring. After completion of the reaction, the mixture was cooled and added with 4.0 l of 5% aqueous NaOH solution, and then extracted with chloroform. The organic layer was dried over MgSO4, concentrated and purified by silica gel column chromatography (eluent; ethyl acetate/hexane/chloroform=1:3:1). After recrystallization from ether/chloroform, 150.2 g of (R)-1-(1-cyclohexylethylamino)-4-phenylphthalazine was obtained. m.p. 164.0°-167.0° C.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:16][CH:17]1[NH:21][C:20](=O)[CH2:19][CH2:18]1.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:20]3[CH2:19][CH2:18][CH:17]([CH3:16])[N:21]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC1CCC(=O)N1
Reactant: Clc1cccc2c1Oc1ccccc1N2
Solvent: O=P(Cl)(Cl)Cl
Product: CC1CCC(N2c3ccccc3Oc3c(Cl)cccc32)=N1

Procedure:
Reaction of 4-chlorophenoxazine, 5-methyl 2-pyrrolidinone and phosphorus oxychloride according to the procedure of Example 1 provides the free base 4-CHLORO-10-(5-METHYL-1-PYRROLIN-2-YL)PHENOXAZINE, m.p. 120°-122° C., from ethanol. Conversion of the free base to the hydrochloride salt affords 4-CHLORO-10-(5-METHYL-1-PYRROLIN-2-YL)PHENOXAZINE HYDROCHLORIDE, m.p. 228°-230° C., (dec.) (corr.), by trituration with hot benzene.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3](B(O)O)[CH:2]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl.[CH3:25][Si:26]([CH3:63])([CH3:62])[CH2:27][CH2:28][O:29][CH2:30][N:31]([CH2:54][O:55][CH2:56][CH2:57][Si:58]([CH3:61])([CH3:60])[CH3:59])[C:32]1[N:37]2[N:38]=[CH:39][C:40](I)=[C:36]2[N:35]=[C:34]([CH:42]2[CH2:47][CH2:46][CH:45]([CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:44][CH2:43]2)[CH:33]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:61][Si:58]([CH3:59])([CH3:60])[CH2:57][CH2:56][O:55][CH2:54][N:31]([CH2:30][O:29][CH2:28][CH2:27][Si:26]([CH3:63])([CH3:62])[CH3:25])[C:32]1[N:37]2[N:38]=[CH:39][C:40]([C:3]3[CH:2]=[N:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[C:36]2[N:35]=[C:34]([CH:42]2[CH2:47][CH2:46][CH:45]([CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:44][CH2:43]2)[CH:33]=1
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 58.6 %

Procedure:
To a 40 mL scintillation vial was charged 3-quinoline boronic acid (0.73 mmol, 127 mg), K3PO4 (1.46 mmol, 310 mg) and PdCl2(dppf).CH2Cl2 (0.049 mmol, 40 mg). To this mixture was added a solution of ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate (335 mg, 0.49 mmol) in dioxane (9 mL). To this suspension was added distilled H2O (1 mL). The resulting solution was stirred at 100° C. for 18 hours. The reaction was concentrated in vacuo and then purified via silica gel chromatography (0% to 60% ethyl acetate in hexanes gradient) to yield ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate (198 mg, 287 μmol, 59% yield) as yellow oil.
Reaction SMILES: ClCCCCC(Cl)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][N:15]=[C:14]2[O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.[Cl:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([N:38]=[C:39]=[S:40])=[O:37]>C1(C)C=CC=CC=1.C(O)C>[Cl:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([N:38]=[C:39]=[S:40])=[O:37].[Cl:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([NH:38][C:39]([NH:28][C:27]1[CH:29]=[CH:30][C:24]([O:23][C:14]2[C:13]3[C:18](=[CH:19][C:20]([O:21][CH3:22])=[C:11]([O:10][CH3:9])[CH:12]=3)[N:17]=[CH:16][N:15]=2)=[CH:25][CH:26]=1)=[S:40])=[O:37]
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(CCCCCl)N=C=S
Agent: O=C(Cl)CCCCCl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)CCCCCl)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
5-Chloropentanoyl isothiocyanate was prepared using commercially available 5-chloropentanoyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 5-chloropentanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (46 mg, yield 58%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[I-].[CH3:16][S+](C)(C)=O.CC(C)([O-])C.[Na+]>C1COCC1.CN(C=O)C>[O:1]1[C:2]2([CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH2:16]1
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (0.50 g, 2.51 mmol) in THF/DMF (2:1, 6 mL) at 60° C. was added trimethylsulfoxonium iodide (0.58 g, 2.63 mmol) and sodium t-butoxide (0.25 g, 2.63 mmol). The reaction mixture was stirred at 60° C. for 30 min, cooled to RT and concentrated. Water was added and the mixture was extract with EtOAc twice. The combined organics were dried over Na2SO4, filtered and concentrated. Purification on silica gel (3:1, hexanes:EtOAc) gave tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate as a clear oil that solidified upon standing.