Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([NH:14][C:15](=[O:26])[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][OH:25])[CH2:19][CH2:18]2)=[C:12](Cl)[CH:11]=[C:10]([CH3:28])[N:9]=1>>[OH:25][CH2:24][CH2:23][N:20]1[CH2:21][CH2:22][N:17]([CH2:16][C:15]([NH:14][C:13]2[C:8]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[N:9][C:10]([CH3:28])=[CH:11][C:12]=2[N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:26])[CH2:18][CH2:19]1
Reactant: Cc1cc(Cl)c(NC(=O)CN2CCN(CCO)CC2)c(Cl)n1
Reactant: C1COCCN1
Product: Cc1cc(N2CCOCC2)c(NC(=O)CN2CCN(CCO)CC2)c(N2CCOCC2)n1
Temperature: 100 °C
Reaction time: 24 h
Yield: 63.9 %

Procedure:
Morpholine (9.0 mL) was added to N-(2,4-dichloro-6-methylpyridin-3-yl)-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide (1.0 g, 2.88 mmol), and the mixture was stirred for 24 hours at 100° C. The reaction mixture was allowed to cool and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (developer: chloroform/ammonia-saturated methanol=50/1), to thereby yield 826 mg of 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(morpholino)-6-methylpyridin-3-yl]acetamide in a yellow amorphous state (yield: 63.9%).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3](=[O:8])[C:4](Cl)=[N:5][OH:6].[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=1[CH:13]=[CH2:14].C(=O)(O)[O-].[K+]>ClC1C=CC=CC=1.O>[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=1[CH:13]1[O:6][N:5]=[C:4]([C:3]([N:2]([CH3:9])[CH3:1])=[O:8])[CH2:14]1
Reactant: CN(C)C(=O)C(Cl)=NO
Reactant: C=Cc1c(F)cccc1F
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: Clc1ccccc1
Product: CN(C)C(=O)C1=NOC(c2c(F)cccc2F)C1
Temperature: 10 °C
Yield: 94.4 %

Procedure:
A 1000-mL round bottom flask equipped with a mechanical stirrer, thermometer and addition funnel was charged with 2-(dimethylamino)-N-hydroxy-2-oxoethanimidoyl chloride (94.0 g, 0.62 mol) and a solution of 2,6-difluorostyrene (84.0 g, 0.60 mol) in chlorobenzene (275 g). The reaction mixture was cooled to 10° C., and a solution of potassium bicarbonate (70 g, 0.70 mol) in water (350 mL) was added dropwise over 1 h while maintaining the reaction temperature between 10 to 15° C. When gas chromatography analysis of the reaction mixture showed about 3% of 2-(dimethylamino)-N-hydroxy-2-oxo-ethanimidoyl chloride remaining, water (200 mL) was added to the reaction mixture. The layers were separated, and the organic layer was washed with water (300 mL) and concentrated under reduced pressure. Toluene was added to the resulting residu, and the mixture was again concentrated under reduced pressure to provide the title compound as an oil (144 g).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8](=[O:21])[C:9]([O:19][CH3:20])=[C:10]([O:17][CH3:18])[C:11]2=[O:16].C(O)(=O)C.[ClH:26]>O>[Cl:26][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8](=[O:21])[C:9]([O:19][CH3:20])=[C:10]([O:17][CH3:18])[C:11]2=[O:16]
Reactant: COC1=C(OC)C(=O)c2c(N)cccc2C1=O
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC1=C(OC)C(=O)c2c(Cl)cccc2C1=O
Temperature: -5 °C

Procedure:
A solution of sodium nitrite (0.69 g, 10 mmol) in water (5 ml) was added at 0°-5° C. to a solution of 5-amino-2,3-dimethoxy-1,4-naphthoquinone (1.17 g, 5 mmol) in 5:1 acetic acid:water (25 ml) containing concentrated hydrochloric acid (1.7 ml). A further quantity of sodium nitrite (0.69 g) was then added to the reaction mixture after cooling to -5° C., followed by a solution of cuprous chloride (0.6 g) in concentrated hydrochloric acid (5 ml). The mixture was allowed to warm to 22° C. and solid cuprous chloride was added portionwise until the mixture assumed a green color. Water was then added to the reaction mixture and the precipitated yellow solid filtered off, washed with water and recrystallized from methanol:water (2:1) giving 1.01 g of 5-chloro-2,3-dimethoxy-1,4-naphthoquinone, mp 120°-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][CH:7]([C:11]([OH:13])=[O:12])[C:6]=2[CH:14]=1.S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][CH:7]([C:11]([O:13][CH2:20][CH3:21])=[O:12])[C:6]=2[CH:14]=1
Reactant: O=C(O)C1CCSc2ccc(Cl)cc21
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCSc2ccc(Cl)cc21

Procedure:
A mixture of 6-chloro-3,4-dihydro-2H-1-benzothiopyran-4-carboxylic acid (12.56 g, 0.055 mol) and concentrated sulfuric acid (20 mL) in ethanol is heated at reflux for 29 hours, cooled, concentrated in vacuo and diluted with a water/methylene chloride mixture. The aqueous phase is separated and extracted with methylene chloride. The organic phase and organic extracts are combined, dried, decolorized with activated carbon and concentrated in vacuo to give the title product as a pale yellow oil (12.34 g) which is identified by 1H and 13CNMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([OH:15])=O)[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:44][O:45][CH2:46][CH2:47][NH2:48].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([NH:48][CH2:47][CH2:46][O:45][CH3:44])=[O:15])[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1
Reactant: O=C(O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Reactant: COCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCNC(=O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21

Procedure:
The title compound was prepared in a manner similar to PREPARATION x26 using (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetic acid (PREPARATION x25, 50 mg, 0.176 mmol), HATU (87 mg, 0.228 mmol), 2-methoxyethylamine (20 mg, 0.263 mmol) and triethylamine (0.073 mL, 0.527 mmol) in DMF (2 mL). ESI-MS m/z [M+H]+ calc'd for C14H20ClN6O3, 342.13; found 342.2.
Reaction SMILES: [NH2:1][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][B:12]1[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:1][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:19])([CH3:20])[O:13]2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(N)CCCCB1OC(C)(C)C(C)(C)O1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)NCc1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 34.3 %

Procedure:
A solution of ethyl 2-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (119 mg, 0.42 mmol) in 1,2-dichloroethane (1 mL) was treated with 4-chlorobenzaldehyde (89 mg, 0.63 mmol). After stirring for 10 minutes, sodium triacetoxyborohydride (230 mg, 1.05 mmol) was added and stirring was continued for 18 hours. The reaction was diluted with ethyl acetate, washed with saturated aq sodium bicarbonate and sat'd aq sodium chloride, dried over MgSO4, and concentrated. Purification by column chromatography (4-32% ethyl acetate in heptane afford ethyl 2-(4-chlorobenzylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (59 mg, 34%). Rf 0.28 (20% ethyl acetate in heptane). 1H NMR (CDCl3, 300 MHz) δ 7.29-7.25 (m, 4H), 4.21 (q, J=7.7 Hz, 2H), 3.78, 3.58 (ABq, JAB=13.2 Hz, 2H), 3.20 (t, J=7.0 Hz, 1H), 1.80-1.57 (m, 2H), 1.42-1.34 (m, 4H), 1.30-1.21 (m, 15H), 0.77 (t, J=7.0 Hz, 2H). ESI MS found for C21H33B1Cl1N1O4 m/z [410.1 (M+1)].
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1)[NH2:24]>CN1CCCC1=O.C(OCC)(=O)C>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:3]3[N:10]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=4)[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1
Reactant: OCc1ccc(Cn2ccc3ncnc(Cl)c32)cc1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: OCc1ccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)cc1
Temperature: 140 °C
Yield: 93 %

Procedure:
{4-[(4-Chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]phenyl}methanol (354 mg) and 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (488 mg) were dissolved in 1-methyl-2-pyrrolidone (2.58 mL), and the mixture was stirred with heating at 140° C. for 2 hrs. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (80 mL) and partitioned with saturated aqueous sodium hydrogen carbonate (30 mL). The organic layer was washed with saturated brine (30 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→0:100) to give the title compound (588 mg) as a powder.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1F.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:11]=1[O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: FC(F)(F)c1ccc(Oc2ccc(I)cc2)c(Cl)c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a solution of 4-iodophenol (200 mg) in dimethylsulfoxide (1 ml), 218 mg of 2-chloro-1-fluoro-4-(trifluoromethyl)benzene and 251 mg of potassium carbonate were added, and the reaction solution was stirred at 120° C. for 3 hours. The reaction solution was cooled, ethyl acetate was added, the insoluble matter was filtered off, and the filtrate was washed with water and a saturated saline solution and dried over an anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (98:2-80/20)) to afford the title compound as a colorless oil.
Reaction SMILES: [CH:1]1[C:6](O)=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH2:11][CH2:10]1.[Cl-].[Al+3].[Cl-].[Cl-].O>ClC(Cl)C(Cl)Cl.CCOCC>[CH3:8][C:3]1[CH:2]=[CH:1][CH:6]=[C:5]([CH:4]=1)[C:9]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:15]
Reactant: Cc1ccc(O)cc1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Solvent: ClC(Cl)C(Cl)Cl
Product: Cc1cccc(C(=O)CCC(=O)O)c1
Temperature: 60 °C

Procedure:
This compound was prepared by the method of Raval et al., J. Univ. Bombay, 7Pt. 3, 184 (1983); CA 33, 3779 (1989). p-Cresol (4.0 g, 37 mmol) and succinic anhydride (3.4 g, 34 mmol) were combined in 1,1,2,2-tetrachloroethane (40 mL) and the mixture was heated to 60° C. Aluminum chloride (9.5 g, 71 mmol) was then added to the solution at a rate of 2 g/20 min. Once this was complete the reaction was heated to 135° C. for 30 min. After cooling, water and ether (30 mL of each) were added and the aqueous layer was extracted with 3×°mL of ether. The combined organic fractions were dried and the remaining residue was purified by flash silica chromatography to yield 2.2 g (28.5%). 1H NMR δ7.62 (s, 1H), 7.30 (d, 1H), 6.85 (d, 1H), 3.32 (t, 2H), 2.35 (t, 2H), 2.22 (s, 1H).
Reaction SMILES: [O:1]1[CH:3]2[C:4]3[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:5]=3[O:6][C:7]([CH3:9])([CH3:8])[CH:2]12.Cl.[Cl:18][CH2:19][CH2:20][CH2:21][NH2:22].[OH-].[Na+].O>O1CCOCC1.C(OCC)(=O)C>[ClH:18].[Cl:18][CH2:19][CH2:20][CH2:21][NH:22][C@H:3]1[C@H:2]([OH:1])[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:4]1=2
Reactant: NCCCCl
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C2OC21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H](NCCCCl)[C@@H]1O
Yield: 18.9 %

Procedure:
3,4-Epoxy-3,4-dihydro-2,2-dimethyl-6-nitro-2H-benzo[b]pyran (0.50g.), prepared as described in British Pat. No. 1,495,526, chloropropylamine hydrochloride (0.65g.), and sodium hydroxide pellets (0.20g.) in dioxan (25 ml) and water (3 ml) were stirred at room temperature for 6 days. Dilution with water and isolation via ethyl acetate gave a gum (0.62g.) which was separated, by application to silica gel plates and development with ethyl acetate- 60-80° petroleum ether mixture, into starting epoxide (0.34g.) and an amine fraction (0.25g.). The latter was dissolved in diethyl ether and treated with ethereal hydrogen chloride to give trans-4-(3-chloropropylamino)-3,4-dihydro-2,2-dimethyl-6-nitro-2H-benzo[b]-pyran-3-ol hydrochloride (0.15g.); m.p. 242°-243°.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:51][C@H:52]([CH:57]([CH3:59])[CH3:58])[C:53]([O:55][CH3:56])=[O:54]>CN(C=O)C>[CH3:56][O:55][C:53](=[O:54])[CH:52]([NH:51][C:9](=[O:11])[CH:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][O:6][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:21][CH:20]=1)[CH:57]([CH3:59])[CH3:58]
Reactant: CC(C)(C)OC(=O)NC(COc1ccc(Br)cc1)C(=O)O
Reactant: COC(=O)[C@H](N)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)C(NC(=O)C(COc1ccc(Br)cc1)NC(=O)OC(C)(C)C)C(C)C
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A solution of the compound obtained in step e above (22e) (816 mg, 2.27 mmol), NMM (0.55 mL, 4.922 mmol) and HOBt (521 mg, 3.864 mmol) in DMF (10 mL) was stirred at 0° C. for 10 minutes, then the reaction was cooled to −15° C., and EDCI (478 mg, 2.497 mmol) was added. The reaction was stirred for 30 minutes at −15° C. and then allowed to warm to room temperature, (R)-methyl 2-amino-3-methylbutanoate hydrochloride (417 mg, 2.497 mmol) was added. After being stirred overnight, the reaction mixture was concentrated under vacuum; the residue was diluted with EtOAc and washed with brine. The combined organic layers were dried and concentrated; the residue was purified by silica gel column chromatography to give the title compound as colourless oil (900 mg, 84%).
Reaction SMILES: [CH2:1]([Si:3]1([CH2:19][CH3:20])[Si:6]([CH2:9][CH3:10])([CH2:7][CH3:8])[Si:5]([CH2:13][CH3:14])([CH2:11][CH3:12])[Si:4]1([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:2].[C:21]1([Si:27]([Li])([CH3:29])[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH3:31][Si:32]([CH3:35])([CH3:34])Cl.C(=O)(O)[O-].[Na+]>CCCCCC.O1CCCC1>[CH2:17]([Si:4]([CH2:15][CH3:16])([Si:3]([CH2:19][CH3:20])([CH2:1][CH3:2])[Si:6]([CH2:7][CH3:8])([CH2:9][CH3:10])[Si:5]([CH2:11][CH3:12])([CH2:13][CH3:14])[Si:32]([CH3:35])([CH3:34])[CH3:31])[Si:27]([CH3:29])([CH3:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:18]
Reactant: [Li][Si](C)(C)c1ccccc1
Reactant: CC[Si]1(CC)[Si](CC)(CC)[Si](CC)(CC)[Si]1(CC)CC
Reactant: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC[Si](CC)([Si](C)(C)C)[Si](CC)(CC)[Si](CC)(CC)[Si](CC)(CC)[Si](C)(C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47 %

Procedure:
In an argon atmosphere, to a tetrahydrofuran solution (1 ml) of 52 mg (0.15 mmol) of octaethylcyclotetrasilane was added 0.56 ml (0.15 mmol) of a tetrahydrofuran solution (0.27M) of phenyldimethylsilyllithium, and stirred at 0° C. for 15 minutes. Trimethylchlorosilane in an amount of 108 mg (1.0 mmol) was added, and reacted at room temperature for 3 hours. Hexane (2 ml) and saturated aqueous sodium bicarbonate solution (2 ml) were added, stirred, the hexane layer was separated, and dried with magnesium sulfate. The resulting crude product was purified by a silica gel column chromatography (hexane) to give 39 mg (47% yield) of 2,2,3,3,4,4,5,5-octaethyl-1,1,6,6,6-pentamethyl-1-phenylhexasilane (2).
Reaction SMILES: [NH2:1][C:2]1[C:11]2=[N:12][N:13]([CH2:30][CH2:31][CH3:32])[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.O.NN>C(O)C>[NH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]1[N:13]([CH2:30][CH2:31][CH3:32])[N:12]=[C:11]2[C:10]=1[C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:3]=[C:2]2[NH2:1]
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CCCn1nc2c(N)nc3ccccc3c2c1CCCCN
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of 2-[4-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]-1H-isoindole-1,3(2H)-dione (7.21 g, 16.9 mmol) and hydrazine hydrate (4.22 g, 84.3 mmol) in ethanol (400 mL) was heated at reflux for 2 hours. The resulting solution was allowed to cool to room temperature, filtered, and concentrated under reduced pressure to yield 3.52 g of 1-(4-aminobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine as a yellow solid, mp 137-139° C.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=2[OH:24])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[OH-].[Na+].[BrH:27].[Br:28]Br>CC(C)=O.O>[C:20]([C:12]1[CH:13]=[C:14]([C:16]([CH3:17])([CH3:18])[CH3:19])[CH:15]=[C:10]([N:2]2[N:3]=[C:4]3[C:9]([Br:28])=[CH:8][CH:7]=[C:6]([Br:27])[C:5]3=[N:1]2)[C:11]=1[OH:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)C)c1
Reactant: BrBr
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)c1cc(-n2nc3c(Br)ccc(Br)c3n2)c(O)c(C(C)(C)C)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 5.1 %

Procedure:
Benzotriazol-2-yl-4,6-di-tert-butyl-phenol (48.6 g, 0.15 mol) was placed in a 3-neck 1-L flask equipped with a stir bar, an addition funnel, a reflux condenser, and a flow control adapter. Through a three-way connecting tube the nitrogen flow was diverted to the flask via the condenser and to an oil bubbler. The bubbler was connected to a filtration flask containing aqueous sodium hydroxide. Hydrobromic acid (45% in acetic acid, 300 mL) was added. The system was purged with nitrogen for 15 min. The slurry was heated to 110° C. for 0.5 h and bromine (23.2 mL, 0.45 mol, 3 equivalent) was added dropwise. The addition was completed in 1 h and the mixture was stirred for an additional 1 h. Three more portions of bromine (3×23.2 mL, 3×0.45 mol) were added and stirring continued for one more hour. The flask was cooled to room temperature. Water (200 mL) was added and the mixture was filtered. The solid was collected and dissolved in dichloroethane (0.5 L). The solution was neutralized first with NaOH (aq) and then with NaHCO3 (aq). The organic layer was dried over magnesium sulfate. The drying agent was filtered off. The solvent of the filtrate was removed by rotary evaporation resulting in a viscous oil. Upon addition of acetone (200 mL) yellow crystalline solid was produced. The product was purified by recrystallization from acetone. Purity: 99+%. Yield: 5.1%. Melting point 244-246° C.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[F:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:9]=1
Reactant: N#Cc1ccc(F)cc1Br
Reactant: O=C1CCCN1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1ccc(F)cc1N1CCCC1=O
Temperature: 105 °C
Yield: 86.9 %

Procedure:
A 48 mL pressure vessel containing 2-bromo-4-fluorobenzonitrile (1.00 g, 5.00 mmol), 2-pyrrolidinone (0.46 mL, 6.00 mmol), Cs2CO3 (2.28 g, 7.0 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos) (0.231 g, 0.40 mmol) in dioxane (6 mL) was degassed with argon for 15 min. Pd2 dba3 was introduced and the reaction mixture heated at 105° C. for 48 h. The mixture was cooled, diluted with ethyl acetate or dioxane, and then filtered through Celite. The resulting mixture was concentrated in vacuo and subjected to column chromatography on silica gel with hexanes:ethyl acetate (3:7) gradient as the eluent to afford the title compound as a white solid (0.887 g, 87% yield): 1H NMR (400 MHz, CDCl3) δ ppm: 7.69 (1H, dd, J=5.8, 8.6 Hz), 7.22 (1H, dd, J=2.5, 9.6 Hz), 7.07 (1H, ddd, J 2.5, 7.6, 8.6 Hz), 3.96 (2H, t, J=7.0 Hz), 2.62 (2H, t, J=8.1 Hz), 2.30–2.22 (2H, m); LCMS (+ESI, M+H+) m/z 205.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([N:11]([CH2:19][CH3:20])[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[CH3:10].[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[C:21]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([N:11]([CH2:9][CH3:10])[CH2:19][CH3:20])=[CH:13][CH:14]=1)(=[O:23])[CH3:22]
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)c1ccc(NC(C)=O)cc1
Temperature: 0 °C
Yield: 80 %

Procedure:
Triethylamine (22.3 g, 30.6 mL, 0.22 mol) was added to a suspension of N,N-diethyl-p-phenylenediamine hydrochloride (20 g, 0.1 mol) in dichloromethane (150 mL) at room temperature. The mixture was cooled to 0° C. and acetyl chloride (7.85 g, 0.1 mol) was added dropwise, with stirring. The mixture was allowed to warm to room temperature, and the precipitate which had formed was removed by filtration. The solid residue was washed with dichloromethane, and the combined dichloromethane solutions were concentrated. The dark oil produced was triturated with hexanes (100 mL) to afford a light brown crystalline solid, which was purified by recrystallization from 50% aqueous ethanol to afford the N-acetyl-4-diethylaminoaniline (16.5 g, 80% yield) as a gray solid. The structure of this compound was confirmed by mass spectroscopy and by 1H NMR spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=S)[NH:8][C:6]=2[N:7]=1.[OH2:12].Cl[O-].[Na+].Cl>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:12])[NH:8][C:6]=2[N:7]=1
Reactant: O
Reactant: Nc1ncc2sc(=S)[nH]c2n1
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Product: Nc1ncc2sc(=O)[nH]c2n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 27.4 %

Procedure:
5-Amino-3H-thiazolo[4,5-d]pyrimidin-2-thione (0.24 g, 1.3 mmol, 1.0 eq) was dissolved in 8 ml water containing 0.1 g NaOH (2.5 mmol, 2.5 eq). The resulting solution was heated to 80° C. A solution of sodium hypochlorite (NaClO) (4.4 ml, 10-13% solution, 5 eq) was added slowly to the above solution at about 80° C. and stirring was continued at 80-90° C. for 30 minutes. The solution was cooled down to about 70° C. and a concentrated HCl solution (0.3 ml, 37%, 2.3 eq.) was added, after which the resulting solution was heated to 80-90° C. for one hour. The reaction mixture was cooled down to room temperature and filtered through a pad of celite. The pH of the filtrate was adjusted to 5-5.5 using 10% NaOH solution. The resulting mixture was heated up to 60° C. for 1 hour, cooled to room temperature and stirred for at least two hours, filtered and washed with water and acetonitrile to afford 0.06 g (27%) of 5-amino-3H-thiazolo[4,5-d]pyrimidin-2-one as a pale yellow solid. 1H NMR, HPLC and LCMS analyses of this product are identical to the product described in Step 3 of Example 1.