Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]#[C:2]1.N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:41]I>C1COCC1.CCCCCC>[I:41][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][O:9][CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]#[C:2]1
Reactant: II
Reactant: OCCCCCCOC1C#CCCCCC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: ICCCCCCOC1C#CCCCCC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a magnetically stirred solution of 6-(cyclooct-2-yn-1-yloxy)hexan-1-ol (126 mg, 0.566 mmol, 1 eq) in dry THF (1.5 ml) under Ar atmosphere, Imidazole (1.1 eq, 0.622 mmol, 42 mg) and Ph3P (1.3 eq, 0.736 mmol, 193 mg) were added. The solution was cooled to 0° C. and Iodine (0.680 mmol, 1.2 eq, 173 mg) was added in three portions. Solution was warmed to RT and stirred for 4 h. The reaction was monitored by TLC (hexane 100% as eluent), quenched by addition of a saturated solution of Na2SO3 (3 ml) and the phases were separated. The aqueous phase was extracted with Et2O and combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The obtained raw product was purified using a column of silica gel (40 g) and Hexane as eluent to obtain 3-[(6-iodohexyl)oxy]cyclooct-1-yne.
Reaction SMILES: O1CCN([C:7]2[N:12]=[C:11](C3CCOCC3)[N:10]=[C:9]([C:19]3[CH:20]=[N:21][C:22]([NH2:25])=[N:23][CH:24]=3)[CH:8]=2)CC1.N1CCOCC1>CN1C(=O)CCC1>[N:12]1[CH:7]=[CH:8][C:9]([C:19]2[CH:24]=[N:23][C:22]([NH2:25])=[N:21][CH:20]=2)=[N:10][CH:11]=1
Reactant: Nc1ncc(-c2cc(N3CCOCC3)nc(C3CCOCC3)n2)cn1
Solvent: C1COCCN1
Solvent: CN1CCCC1=O
Product: Nc1ncc(-c2ccncn2)cn1
Temperature: 150 °C

Procedure:
A mixture of 6-morpholino-2-(tetrahydro-2H-pyran-4-yl)-4,5′-bipyrimidin-2′-amine (10 mg, 0.0343 mmol), morpholine (24 mg, 8 equiv, 0.274 mmol) in NMP (0.55 mL) was heated at 150° C. for 10 min in a microwave. The mixture was purified on HPLC to give 6-morpholino-2-tetrahydro-2H-pyran-4-yl)-4,5′-bipyrimidin-2′-amine. LCMS (m/z): 343.1 (MH+). Rt: 1.62 min.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH:5]=[CH:6]1)[CH:3]1[C:9]([O:11][C:12](=[O:13])[CH:2]21)=O.[NH2:14][CH:15]([C:19]([OH:21])=[O:20])[CH:16]([CH3:18])[CH3:17].C([O-])([O-])=O.[K+].[K+]>O>[C:19]([CH:15]([N:14]1[C:12](=[O:13])[CH:2]2[CH:3]([CH:4]3[CH2:7][CH2:8][CH:1]2[CH:6]=[CH:5]3)[C:9]1=[O:11])[CH:16]([CH3:18])[CH3:17])([OH:21])=[O:20]
Reactant: O=C1OC(=O)C2C3C=CC(CC3)C12
Reactant: CC(C)C(N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)C(C(=O)O)N1C(=O)C2C3C=CC(CC3)C2C1=O
Temperature: 25 °C
Yield: 55 %

Procedure:
To a suspension of bicyclo[2.2.2]oct-5-en-2,3-dicarboxylic anhydride (2.01 g, 11.3 mmol) in H2O (25 mL) was added (dl)-valine (1.58 g, 13.5 mmol) and a solution of K2CO3 (934 mg, 6.8 mmol) in H2O (3 mL). The mixture was heated to reflux temperature and allowed to react for 4 hrs. After cooling to room temperature, the mixture was washed with EtOAc, acidified with conc. HCl until the pH reached 1 and extracted with EtOAc. The organic layer was washed with 5% HCl followed by brine and then dried over Na2SO4. Removal of the solvent gave a beige solid which was recrystallized from EtOAc/hexane to yield the product as off-white crystals: 1.72 g (55% yield), mp=156° C.
Reaction SMILES: [CH:1](=[C:8]([CH2:13][O:14]C(=O)C)[C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH:1](=[C:8]([CH2:13][OH:14])[C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(=Cc1ccccc1)COC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C(=Cc1ccccc1)CO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The crude product (2.1917 g) of methyl 2-benzylidene-3-acetoxypropionate obtained in Example 13 was dissolved in 15 ml of methanol, and 84 mg (97%, 2.04 mmols) of sodium hydroxide were added thereto. The mixture was stirred at room temperature for 4 hours to form methyl 2-benzylidene-3-hydroxypropionate.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3[F:28])=[O:9])=[CH:4][CH:3]=1.[C:31]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([F:28])[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:31])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(CN3CCOCC3)cc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(F)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide, (can be prepared according to the procedure described in PCT patent application, W099/32450) (147 mg) in anhydrous DMF (3 mL) is added K2CO3 (71.2 mg) followed by CH3I (0.026 mL). The reaction mixture is stirred at room temperature for 30 min, then poured into H2O (40 mL) to precipitate the product. The solid is collected, adsorbed onto silica, and chromatographed (1% MeOH in CH2Cl2 (2L)). Fractions homogenous by TLC are combined and concentrated to afford 55.3 mg of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(C(C)C)C(C)C)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)[CH:5]=[CH:4][N:3]=1
Reactant: CN1CCNCC1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN1CCN(c2ccnc(Cl)n2)CC1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A mixture of 2,4-dichloropyrimidine (0.967 g, 6.49 mmol), 1-methylpiperazine (0.65 g, 6.40 mmol), and ethyldiisopropylamine (2.8 mL, 16.22 mmol) in ethanol (13 mL) was stirred at −10° C. for 2 h and then at r.t. overnight. The mixture was partitioned between H2O/brine (3:1; 100 mL) and chloroform (3×70 mL). The combined organic phases were washed once with brine (50 mL) an dried over MgSO4. Removal of solvent yielded a pale-beige solid, which was washed with ethyl acetate/ultrasound to give the desired product as a colourless powder, which was further washed with Et2O. Additional product was obtained upon fractional crystallization of the washing solution. A total of 0.741 g (3.48 mmol, 54%) of 2-chloro-4-(4-methylpiperazin1-yl)pyrimidine was obtained. LC/ESI-MS: m/z=213 [M(35Cl)+H]+; Rt=0.5 min.
Reaction SMILES: [Na].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11].[O:12]1[CH:16]=[CH:15][C:14]([C:17](OCC)=[O:18])=[CH:13]1>C(O)C>[O:12]1[CH:16]=[CH:15][C:14]([C:17]([CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[NH:2][C:3]2=[O:11])=[O:18])=[CH:13]1
Reactant: CCOC(=O)c1ccoc1
Reactant: O=C1Cc2ccccc2N1
Agent: [Na]
Solvent: CCO
Product: O=C1Nc2ccccc2C1C(=O)c1ccoc1
Yield: 3.1 %

Procedure:
To a stirred solution of 2.8 g (0.12 mole) of sodium in 200 ml of ethanol was added 13.3 g (0.10 mole) of 2-oxindole, followed by 16.8 g of ethyl 3-furoate. The mixture was heated under reflux for 47 hours, cooled and then the solvent was removed by evaporation in vacuo. The residue was triturated under 200 ml of ether, and the solid was collected by filtration and discarded. The filtrate was evaporated in vacuo, and the residue triturated under diisopropyl ether and recovered by filtration. The solid was suspended in 250 ml of water, which was then acidified with concentrated hydrochloric acid. This mixture was stirred to give a solid, which was recovered by filtration. This latter solid was recrystallized from acetic acid followed by acetonitrile to give 705 mg of the title compound, mp 185°-186° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[S:6]1[C:10]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1>N1C=CC=CC=1>[S:6]1[C:10]2[CH:11]=[C:12]([NH:15][S:2]([CH3:1])(=[O:4])=[O:3])[CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2ncsc2c1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
Methanesulfonyl chloride (4.93 mL, 63.7 mmol) was added over 5 min to a solution of benzothiazol-6-ylamine (9.58 g, 63.8 mmol) in pyridine (100 mL) at 25° C. The resulting mixture was stirred at 25° C. for 30 min, and then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Trituration of the residue with diethyl ether afforded a solid that was collected by vacuum filtration and dried in vacuo to afford the desired product, N-benzothiazol-6-yl-methanesulfonamide (13.3 g, 58.3 mmol, 91% yield) as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ: 3.03 (3H, s), 7.36 (1H, dd, J1=2.3 Hz, J2=8.6 Hz), 7.94 (1H, d, J=1.6 Hz), 8.02 (1H, d, J=9.2 Hz), 9.27 (1H, s), 9.95 (1H, s).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[C:7]3[S:8][CH:9]=[CH:10][C:11]=3[C:12](=O)[C:2]1=2.[CH2:15]([CH:17]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:18][Mg]Br)[CH3:16].Cl[Sn]Cl>C1COCC1.Cl>[CH2:15]([CH:17]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:18][C:6]1[C:7]2[S:8][CH:9]=[CH:10][C:11]=2[C:12]([CH2:6][CH:3]([CH2:4][CH3:5])[CH2:2][CH2:12][CH2:11][CH3:7])=[C:2]2[S:1][CH:5]=[CH:4][C:3]=12)[CH3:16]
Reactant: CCCCC(CC)C[Mg]Br
Reactant: O=C1c2ccsc2C(=O)c2ccsc21
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Product: CCCCC(CC)Cc1c2ccsc2c(CC(CC)CCCC)c2ccsc12
Temperature: 60 °C
Yield: 13 %

Procedure:
To a suspension of benzo[1,2-b:4,5-b′]dithiophene-4,8-dione (25) (Beimling, P.; Koβmehl, G. Chem. Ber. 1986, 119, 3198) (4.9 g, 22.2 mmol) in 100 mL of THF was added 2-ethylhexyl magnesium bromide (111 mL, 1M in diethyl ether). The mixture was then heated at 60° C. for 24 h., and cooled to r.t. following by adding SnCl2 (13.47 g, 71.04 mmol) in 190 mL of 10% HCl. The mixture was heated at 60° C. for 24 h. THF was removed under reduced pressure. The residure was dissolved in ether, washed with water, sat. NaHCO3, brine and water. The organic layer was dried over MgSO4 and then concentrated. Column chromatography with hexane gave 1.2 g (13%) of desired product 26. 1H-NMR (400 MHz, CDCl3): ppm 7.46 (d, 2H, J=5.6 Hz), 7.42 (d, 2H, J=5.6 Hz), 3.18-3.06 (m, 4H), 1.97 (hep, 2H, J=6.4 Hz), 1.43-1.18 (m, 16H), 0.91-0.81 (m, 12H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][OH:10])=[C:4]([F:11])[CH:3]=1.[CH3:12][N:13](C=O)C>C(Cl)Cl.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.[C-]#N.[Zn+2].[C-]#N>[F:11][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[C:5]=1[CH2:9][OH:10])[C:12]#[N:13]
Reactant: CN(C)C=O
Reactant: OCc1c(F)cc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClCCl
Solvent: O
Product: N#Cc1cc(F)c(CO)c(F)c1
Temperature: 90 °C

Procedure:
A mixture of (4-bromo-2,6-difluorophenyl)methanol (1.12 g, 5.0 mmol), Pd(PPh3)4 (323 mg, 0.28 mmol) and zinc cyanide (587 mg, 5.0 mmol) was prepared in DMF (7 mL) under nitrogen atmosphere and heated at 90° C. for 18 hours. The mixture was diluted with DCM and water. The organic phase was passed through a hydrophobic frit and the solvent evaporated in vacuo. The residue was purified by flash chromatography (silica, iso-hexane/EtOAc) to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.28-7.21 (2H, m), 4.83 (2H, d, J=6.7 Hz), 1.95 (1H, t, J=6.7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]([NH2:15])=[C:6]2[C:10]=1[N:9]([CH2:11][CH3:12])[S:8](=[O:14])(=[O:13])[CH2:7]2.C(N(CC)CC)C.[C:24](Cl)(Cl)=[S:25]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]([CH2:11][CH3:12])[S:8](=[O:14])(=[O:13])[CH2:7][C:6]=2[C:5]([N:15]=[C:24]=[S:25])=[C:4]([F:16])[CH:3]=1
Reactant: CCN1c2c(Cl)cc(F)c(N)c2CS1(=O)=O
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN1c2c(Cl)cc(F)c(N=C=S)c2CS1(=O)=O

Procedure:
To a solution of 7-chloro-1-ethyl-5-fluoro-1,3-dihydro-2,1-benzisothiazol-4-amine 2,2-dioxide (0.5 g, 1.88 mmol) and triethylamine (0.6 mL) in anhydrous tetrahydrofuran (THF, 10 mL), thiophosgene (0.238 g, 1.1 eq) in THF (2 mL) was added dropwise at room temperature under a nitrogen atmosphere. The resulting reaction mixture was heated at reflux for 2 days. The solvents were removed in vacuo to give the title compound of Step A which was used in Step B.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([NH2:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([NH:12][S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc2c(Cl)ccnc12
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc2c(Cl)ccnc12)c1ccccc1
Yield: 61.3 %

Procedure:
In a similar fashion using route 14 general procedure 26, 4-chloro-quinolin-8-ylamine 464 (228 mg, 1.28 mmol), benzenesulfonyl chloride (0.2 ml, 1.53 mmol) pyridine (0.21 ml, 2.56 mmol) in DCM (10 ml) gave the title compound (250 mg, 61%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [C:1]([C:6]1[O:7][C:8]2[C:16]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=4)=[CH:21][CH:20]=3)=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[CH:11]=1)([O:3]CC)=[O:2].C(=O)(O)[O-].[Na+]>C(O)C.O>[C:1]([C:6]1[O:7][C:8]2[C:16]([CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=4)=[CH:23][CH:24]=3)=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[CH:11]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)c1cc(=O)c2cccc(COc3ccc(OCc4ccc5ccccc5n4)cc3)c2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(=O)c2cccc(COc3ccc(OCc4ccc5ccccc5n4)cc3)c2o1
Yield: 61.7 %

Procedure:
0.74 g of 2-carboethoxy-8-(4-(quinoline-2-ylmethoxy)phenoxymethyl)-4-oxo-4H-1-benzopyran and 0.7 g sodium bicarbonate are combined in 50 ml of ethanol and 5 ml of water. After refluxing for 1.5 hours the mixture is concentrated and the residue diluted with ether. The resulting solid is collected, suspended in water and the pH adjusted to 6 with 1 molar hydrochloric acid. The resulting solid is crystallized from aqueous acetic acid, then tetrahydrofuran/hexane to give 0.43 g 2-carboxy-8-(4- (quinolin-2-ylmethoxy)phenoxymethyl)-4-oxo-4H-1-benzopyran; m.p. 221°-24° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:15])[NH:12]C(=O)N[C:9]2=[O:14])=[CH:4][CH:3]=1.[OH-:16].[Na+].Cl>O>[NH2:12][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:15])[C:9]([OH:16])=[O:14]
Reactant: [OH-]
Reactant: CC1(c2ccc(Br)cc2)NC(=O)NC1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(N)(C(=O)O)c1ccc(Br)cc1
Temperature: 145 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A mixture of 5-(4-bromo-phenyl)-5-methyl-imidazolidine-2,4-dione (4.0 g, 14.9 mmol) and 3 N NaOH (50 mL) was heated in a sealed tube at 145° C. for two days, then diluted with water (100 mL). The solution was adjusted to pH=4 with 6 N HCl carefully and subsequently stirred at room temperature for 2 hours. The precipitate was filtered off, washed with water. The collected white solid was dried under vacuum to give the product (2.5 g, 65%). m/z 243.7, 245.7 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23][CH3:24])[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:3]1=[O:30].OO.C(O)(=[O:35])C>C(Cl)Cl.CC#N>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23]([CH3:24])=[O:35])[N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=3)[N:11]=[C:5]2[N:4]([CH2:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:3]1=[O:30]
Reactant: CC(=O)O
Reactant: CSc1c2c(=O)n(C)c(=O)n(CC(C)(C)C)c2nn1Cc1ccc(S(C)(=O)=O)cc1
Agent: OO
Solvent: ClCCl
Solvent: CC#N
Product: Cn1c(=O)c2c(S(C)=O)n(Cc3ccc(S(C)(=O)=O)cc3)nc2n(CC(C)(C)C)c1=O
Temperature: 25 °C
Yield: 58.5 %

Procedure:
5-methyl-2-(4-(methylsulfonyl)benzyl)-3-(methylthio)-7-neopentyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (11.4 mg, 0.022 mmol) is dissolved in CH2Cl2 (200 μL) and CH3CN (100 μL), and then 30% H2O2 aqueous solution (75 μL, 0.66 mmol) is added, followed by acetic acid (6.6 mg, 0.11 mmol). The reaction mixture is stirred at room temperature over a weekend, and then purified by a semi-preparative HPLC to give 6 mg of product as white solids. MS (ESI) m/z 467.1 [M+H]+.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C1COCC1.C(C1C=CC=CC=1)C.CCCCCCC.[CH3:29][CH:30]([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32].[C:37]1(=[O:43])[O:42][C:40](=[O:41])[CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C.O>[CH2:34]([O:33][C:31](=[O:32])[C:30]([CH3:36])([CH3:29])[C:40](=[O:41])[CH2:39][CH2:38][C:37]([OH:42])=[O:43])[CH3:35]
Reactant: CCOC(=O)C(C)C
Reactant: O=C1CCC(=O)O1
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: CCOC(=O)C(C)(C)C(=O)CCC(=O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
To dehydrated THF (20 mL) was added a 2.0M LDA/THF-ethylbenzene-heptane solution (7.88 mL), this was cooled to around −78° C. in a dry ice-methanol bath, and a solution of ethyl 2-methylpropanoate (1.74 g) in dehydrated THF (5 mL) was slowly added dropwise. After the mixture was stirred at around −78° C. for 1 hour, this solution was added dropwise to a suspension of succinic acid anhydride (1.50 g) in dehydrated THF (5 mL) over 5 minutes under an ice bath. After stirred at the same temperature for 40 minutes, the mixture was stirred at room temperature for 3 hours. Into the reaction solution was slowly placed water under an ice bath, ethyl acetate and an aqueous saturated sodium bicarbonate solution were added, followed by extraction. To the resulting aqueous phase was added 1N hydrochloric acid to adjust a pH at around 3, followed by extraction with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was washed with dichloromethane, a compound derived from succinic acid anhydride was removed by filtration, and the resulting filtrate was concentrated under reduced pressure to obtain the title compound (2.22 g) having the following physical property values.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1)=[O:4].[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@H:7]([O:9][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CC(O)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@H](OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of cis-trans mixture of 3-hydroxy-cyclobutanecarboxylic acid methyl ester (1.30 g, 10 mmol) in DMF 13 mL, NaH (50% in oil, 720 mg, 15 mmol) is added at 0° C. After stirring at 0° C. for 15 minutes, benzyl bromide (1.43 ml, 12 mmol) is added at 0° C. The mixture is stirred at room temperature for 2 hours and quenched with H2O. The solution is extracted with AcOEt. The organic layer is washed with H2O and brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give trans-3-benzyloxy-cyclobutanecarboxylic acid methyl ester (340 mg, 15.4%); TLC (hexane/AcOEt, 5:1) Rf 0.40, 1H NMR (400 MHz, chloroform-d) ppm 2.26-2.34 (m, 2H), 2.48-2.52 (m, 2H), 3.02-3.06 (m, 1H), 3.69 (s, 3H), 4.26-4.33 (m, 1H), 4.42 (s, 2H), 7.27-7.35 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][N:12]=1.ClC1C=CC(C(NC2C=CC(I)=C(C)C=2)=O)=CN=1>>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=2[F:1])=[O:16])=[CH:13][N:12]=1
Reactant: Nc1ccc(I)cc1F
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Product: O=C(Nc1ccc(I)cc1F)c1ccc(Cl)nc1

Procedure:
6-Chloro-N-(2-fluoro-4-iodo-phenyl)-nicotinamide was prepared from 2-fluoro-4-iodo aniline and 6-chloronicotinoyl chloride following a procedure similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after precipitation out of a small volume of CH2Cl2 with hexanes. HRMS m/z calcd for C12H7N2OFClI [M+H]+: 376.9349. Found: 376.9349.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[C:7]([CH3:15])[C:6]=1[N+:16]([O-:18])=[O:17])(=O)C.C[O-].[Na+]>CO>[CH3:15][C:7]1[C:6]([N+:16]([O-:18])=[O:17])=[C:5]([CH:10]=[C:9]([CH3:11])[C:8]=1[N+:12]([O-:14])=[O:13])[NH2:4]
Reactant: CC(=O)Nc1cc(C)c([N+](=O)[O-])c(C)c1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(N)c([N+](=O)[O-])c(C)c1[N+](=O)[O-]
Yield: 66.5 %

Procedure:
A mixture of N-acetyl-3,5-dimethyl-2,4-dinitroaniline (14.6 g, 57 mmol) and sodium methoxide (25 wt % solution in methanol) (26 mL) and methanol (200 mL) is heated to reflux for 90 minutes. The mixture is rotary evaporated and the residue is partitioned between water and chloroform. The organic layer is dried (magnesium sulfate) and rotary evaporated. The residue is purified by flash chromatography on silica gel (25% ethyl acetateihexane) to afford 3,5-dimethyl-2,4-dinitroaniline (8.0 g) as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:22]([O:24][CH2:25][C:26](Cl)=O)[CH3:23].C(N(CC)CC)C>C(O)C>[CH2:22]([O:24][CH2:25][C:26]1[N:12]([CH2:13][C:14]([CH3:20])([CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:23]
Reactant: CCOC(=O)C(C)(C)CNc1c(N)cnc2ccccc12
Reactant: CCOCC(=O)Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3ccccc3c2n1CC(C)(C)C(=O)OCC
Reaction time: 8 h
Yield: 36.9 %

Procedure:
A modification of the method described in Part C of Example 5 was used to treat ethyl 3-[(3-aminoquinolin-4-yl)amino]-2,2-dimethylpropanoate (15.5 g, 60.2 mmol, prepared in Parts A through D of Example 26) with ethoxyacetyl chloride (8.7 g, 71 mmol) followed by triethylamine (24.4 mL, 175 mmol). The reaction with ethoxyacetyl chloride was stirred overnight, and the reaction with triethylamine was heated at reflux in ethanol (125 mL) for four days. Following the work-up procedure, the crude product was purified by column chromatography on silica gel (eluting with dichloromethane:methanol in a gradient from 100:0 to 95:5) to provide 7.9 g of ethyl 3-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2,2-dimethylpropanoate as an oil.